JP2000229958A - Substituted bezylamines - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound characterized by existing a substituent having a ring containing heterocyclic groups substituted by oxo or thioxo group, and having an excellent ileum type bile acid transporter inhibitory activity. SOLUTION: This compound is expressed by formula I [R1, R2 are each a 3-10C cycloalkyl, a 6-10C aryl, a heterocyclic group or the like; R3, R4 are each H, a halogen, a 1-6C alkyl or the like; A is a group of formula II or III (B is a single bond or a 1-6C alkylene; rings Ar1, Ar2 are each a heterocyclic group substituted by 1-2 oxo or thioxo group); D is a group having CH or nitrogen; E is a group having O, S or NH, or a group having NHCO; and F is a single bond or a 1-6C alkylene], for example, 5-[3-(phenyl((1R)-1phenyl- ethylamino)methyl)benzilidene]thiazolidine-2,4-dione. The compound of the formula I is produced e.g. by using a compound of formula IV as a starting material.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to substituted benzylamines having an excellent ileal bile acid transporter inhibitory action.

[0002]

BACKGROUND OF THE INVENTION Hyperlipidemia is one of the three major risk factors for ischemic heart disease. In particular, it is widely known that lowering a high blood cholesterol level is useful for treating or preventing ischemic heart disease. It recognized. As currently available therapeutic agents for hyperlipidemia, for example, HMG-CoA reductase inhibitors and anion exchange resins are known, and these agents treat or prevent hyperlipidemia or arteriosclerosis. [Am. J. Cardiol., 76, 899-905 (199
Five)].

[0003] HMG-CoA reductase inhibitors have an inhibitory effect on cholesterol synthesis and LDL (low depletion) in the liver.
It has the effect of taking up blood cholesterol and promoting its excretion into bile by increasing nsity lipoprotein (Science, 232, 34 (1986)).
The usefulness and safety of these drugs are widely recognized and used by many patients.

[0004] Further, the anion exchange resin adsorbs bile acids and prevents reabsorption of bile acids in the intestine, thereby promoting the conversion of cholesterol to bile acids in the liver. N. Engl. J. Med., 302, 1210
-1222 (1980)]. As such an anion exchange resin, for example, a method using cholestyramine has already been put to practical use, and since the drug is hardly absorbed into the body, hyperlipidemia in children who are required to be more safe is required. It is regarded as a first-line drug in the treatment of diseases. However, cholestyramine has the drawbacks that it is extremely difficult for patients to take because cholestyramine has an extremely large dose per dose and further has a rough feel of the resin when taken in the mouth. In addition, the anion exchange resin also adsorbs and discharges certain kinds of vitamins, minerals, drugs, and the like. Therefore, it is necessary to consider replenishment of vitamins and changes in the administration method of concomitant drugs, and thus there are many problems.

In recent years, a protein has been cloned that acts in the first step of bile acid reabsorption in the ileum, an ileal bile acid transporter [Wong MH et al, J. Bio.
l. Chem., 269, 1340-1347 (1994)]. It is thought that if ileal bile acid transporter activity can be inhibited, a pharmacological effect similar to that of cholestyramine can be obtained. Attempted [Wess
G. et al, J. Med. Chem., 37, 873-875 (1994)].

Prior art relating to compounds similar to the compounds of the present invention includes the following.

(1) Japanese Patent Application Laid-Open No. 57-145850 (EP058779A)

[0008]

Embedded image [In the above compound (A), R ₁ and R ₂ form an unbranched alkyleneimino group having 3 to 6 carbon atoms with the bonding nitrogen atom, and have a carbonyl group instead of methylene. You may. ] Are disclosed.

In the compound (I) of the present invention, a compound having a structure similar to that of the prior art includes a ring Ar ₁ or Ar _1
2 is a heterocyclic group substituted by one or two oxo or thioxo, and B is a compound in which a single bond is present. While the compound is bonded to the benzene ring via an atom, the heterocyclic group in the ring Ar ₁ or Ar ₂ of the compound (I) of the present invention is bonded to another group via a carbon atom in the ring. They differ in that they do.

Furthermore, the unbranched alkyleneimino group in the compound (A) has no thioxo as a substituent, whereas the heterocyclic ring Ar ₁ or Ar ₂ in the compound (I) of the present invention. The groups also differ in that they have one or two oxo or thioxo as essential substituents.

In addition, this publication discloses the structure of the compound (I) of the present invention wherein R ₁ and R ₂ in the above compound (A) are unbranched alkyleneimino groups having a carbonyl group instead of methylene. A compound having a structure similar to
The compound (I) of the present invention is not specifically disclosed at all.
Even if the compound closest to the structure of is selected, at most, only the following compounds are disclosed.

[0012]

Embedded image Furthermore, the compound (A) is disclosed as a compound having a blood glucose lowering action, and its use as an ileal bile acid transporter inhibitory action is not described or suggested.

(2) Japanese Patent Publication No. GB3723232 This publication discloses the following general formula (B)

[0014]

Embedded image [In the above compound (B), R ₂ has a phenyl group, R ₄ has a hydrogen atom or a methyl group, and n is 4 to 6
It is. And a 4- to 6-membered alkyleneamino group substituted with an oxide as an essential substituent of the phenyl group having R ₁ as a substituent.

In the compound (I) of the present invention, a compound having a structure similar to that of the prior art includes a ring Ar ₁ or Ar _1
2 is a heterocyclic group substituted by one or two oxo or thioxo, and a compound in which B is a single bond, wherein the 4- to 6-membered alkyleneamino group in the compound (B) is
While the heterocyclic group in the ring Ar ₁ or Ar ₂ of the compound (I) of the present invention is bonded to the benzene ring via the nitrogen atom in the ring, They differ in that they are bonded to other groups.

Further, 4 to 6 in the above compound (B)
The membered alkyleneamino group has an oxide group as a substituent of the nitrogen atom in the group but does not have oxo or thioxo, whereas ring A of compound (I) of the present invention has
The heterocyclic group for r ₁ or Ar ₂ is also different in that it has one or two oxo or thioxo as an essential substituent.

In addition, this publication discloses the compound (I) of the present invention.
The compound having a structure similar to the structure of the above is not specifically disclosed at all, and even if a compound closest to the structure of the compound (I) of the present invention is selected, at most the following compound Only disclosed.

[0018]

Embedded image Furthermore, the compound (B) is disclosed as a therapeutic agent for diabetes or hypertension, and its use as an ileal bile acid transporter inhibitory action is neither described nor suggested.

(3) JP-A-5-155828 (E
P478328A) In this publication, the following general formula (C)

[0020]

Embedded image [In the above compound (C), R ¹ is a 4- to 8-membered heterocyclic ring which may be substituted with oxo, and m is 0 to 1
X is an integer of 0, X and Y are C ₁ -C ₁₅ alkyl groups, Z is an optional substituent, and R ¹ is bonded to the benzene ring via an alkylene group having at least 2 carbon atoms. I have. ] Are disclosed.

In the compound (I) of the present invention, a compound whose structure is close to that of the prior art is a heterocyclic group in which one or two rings Ar ₂ are substituted with oxo or thioxo,
E but is a compound which is a group having a -NH-, a heterocyclic group of 4 to 8-membered ring in the definition of R ¹ in the compound (C), the benzene ring via an alkylene group of at least 2 or more carbon atoms When E is a group having —NH—, the heterocyclic group in the ring Ar ₂ of the compound (I) of the present invention is bonded to the benzene ring via a single bond or a methylene group. They differ in that they are joined.

Further, R of the above compound (C)¹In the definition of
The 4- to 8-membered heterocyclic group in the formula
Does not have the ring of the compound (I) of the present invention
Ar ₁Or Ar_TwoIs a required substituent.
Also having 1 or 2 oxo or thioxo
I do.

In addition, this publication discloses the compound (I) of the present invention.
The compound having a structure similar to the structure of is not specifically disclosed at all.

Further, the above compound (C) is disclosed in the above publication as a compound having a fibrinogen receptor antagonistic activity, and its use as an ileal bile acid transporter inhibitor is neither described nor suggested.

(4) WO98 / 23155 This publication discloses the following general formula (D)

[0026]

Embedded image [In the above compound (D), E is a 1,2-phenylene group, A is O, S, N, etc., G is C or N, W is O, S, etc., and X is H, R ² is H, Y is —CH (OR ¹⁵ ) —, —CHR ¹⁵ O—, etc., R ¹⁵ is cycloalkyl, phenyl, benzyl group, etc., and Z is cycloalkyl group, etc. It is. ] Are disclosed.

In the compound (I) of the present invention, a compound having a structure similar to that of the prior art includes a ring Ar ₁ or Ar
₂ is a heterocyclic group substituted with one or two oxo or thioxo groups, and a compound in which E is an oxygen atom.

[0028]

Embedded image [In the above formula, A, G, X, W, and R ² indicate consent as described above. Is a 1,2-phenylene group E
Wherein the compound (I) of the present invention is directly substituted
Is a group having the formula (A-1) and E is an oxygen atom, the ring Ar ₁ is always substituted with a phenyl group via —CH ＝.

Further, the compound (I) of the present invention has the formula (A-
When the group having 2) and E is an oxygen atom, the ring Ar
₂ differs from the above compound (D) also in that it is substituted with a phenyl group via a methylene group.

In addition, this publication discloses the compound (I) of the present invention.
The compound having a structure similar to the structure of is not specifically disclosed at all.

Further, the compound (D) is disclosed in the above publication as a bactericide, and its use as an ileal bile acid transporter inhibitor is not described or suggested.

(5) WO 99/21837 In this publication, the following general formula (E)

[0033]

Embedded image [In the above compound (E), X represents a hydrogen atom, N
(R) ₂ , Y is a hydrogen atom or the like, W is a hydrogen atom, N (R) ₂ , CH (R) ₂ , R is an aryl,
An aryloxy group or the like, and Q is a group represented by the following general formula (E-
1), groups having (E-2) and the like

[0034]

Embedded image (In the above formula, R ₁ is a hydrogen atom, an alkyl group, or the like;
R ₂ is an alkyl or haloalkyl group, and R ₃ is hydrogen, a halogen atom, or the like. ) And Z is amino,
Hydroxy and the like. ] Are disclosed.

In the compound (I) of the present invention, those having a structure similar to that of the prior art include a ring Ar ₁ or Ar _1
2 is a heterocyclic group substituted by one or two oxo or thioxo, and a compound in which E is an oxygen atom. On the other hand, when compound (I) of the present invention is a group having the formula (A-1) and E is an oxygen atom,
The difference is that the ring Ar ₁ is always substituted with a phenyl group via —CH ＝.

Further, the compound (I) of the present invention has the formula (A-
When E is an oxygen atom, the ring A
r ₂ is different from the above compound (E) in that r ₂ is substituted with a phenyl group via a methylene group.

The gazette also discloses the compound (I) of the present invention.
The compound having a structure similar to the structure of is not specifically disclosed at all.

Further, the above compound (E) is disclosed in the above publication as a herbicide, and its use as an ileal bile acid transporter inhibitor is neither described nor suggested.

(6) Japanese Patent Application Laid-Open No. 11-199570 This publication discloses the following general formula (F)

[0040]

Embedded image [In the above formula, Ar 1 and Ar 2 are each an aromatic group which may have a substituent, X is a hydrogen atom, and Q is an oxygen atom, a sulfur atom which may be oxidized, and a substituent. A divalent linear aliphatic hydrocarbon group which may be via a divalent group selected from imino which may be substituted, and which may have a substituent, wherein ring A has a substituent. A 5- to 7-membered nitrogen-containing ring which may be substituted. ] Are disclosed.

The compounds of the present invention (I) has a heterocyclic group having oxo or thioxo as essential substituents as essential to the substituent of the benzene ring, the present publication, Ar ¹
Alternatively, a heterocyclic group having oxo or thioxo as an essential substituent as an substituent of Ar ² , or an alkyl or alkenyl group substituted with the heterocyclic group is not disclosed at all.

In addition, this publication discloses the compound (I) of the present invention
The compound having a structure similar to the structure of is not specifically disclosed at all.

Further, the above compound (F) is disclosed in the above publication as a compound having an inhibitory action on neuronal degeneration in the cerebrum, an inhibitory action on brain tissue destruction, and an inhibitory action on cytokine production in human macrophage cells and the cerebrum. No use as an ileal bile acid transporter inhibitor is described or suggested.

[0044]

DISCLOSURE OF THE INVENTION The inventors of the present invention have conducted long-term studies on the synthesis of ileal-type bile acid transporter-inhibiting derivatives and their pharmacological activities. The present inventors have found that the compound has an excellent inhibitory effect on the type bile acid transporter, and completed the present invention.

Still another object of the present invention is to provide a medicament containing a substituted benzylamine as an active ingredient.

[0046]

(1) The substituted benzylamines, pharmaceutically acceptable salts, esters or other derivatives thereof of the present invention have the following general formula (I).

[0047]

Embedded image Wherein R ¹ is a C ₃ -C ₁₀ cycloalkyl group, C ₆ -C
₁₀ aryl group, heterocyclic group, C ₃ -C ₁₀ cycloalkyl group substituted with 1 to 5 groups selected from substituent groups a and b, 1 to 5 group selected from substituent groups a and b A 5-substituted C ₆ -C ₁₀ aryl group or a heterocyclic group substituted by 1 to 5 groups selected from substituent groups a and b, wherein R ² is a C ₃ -C ₁₀ cycloalkyl group; Alkyl group, C ₆ -C
₁₀ aryl groups, heterocyclic groups, C ₃ -C ₁₀ cycloalkyl groups substituted by 1 to 3 groups selected from substituent group a,
C substituted with 1 to 3 groups selected from a substituent group a
₆ -C ₁₀ aryl group, or represents a 1 to 3-substituted heterocyclic group with a group selected from Substituent Group a, R ³ and R
⁴ is the same or different and represents a hydrogen atom or a group selected from substituent group a, and A represents the following formula (A-1) or (A
-2)

[0048]

Embedded image

[0049]

Embedded image (Wherein B represents a single bond or a C ₁ -C ₆ alkylene group, and rings Ar ₁ and Ar ₂ represent a heterocyclic group substituted with one or two oxo or thioxo groups). Show,
D represents a group having CH or a nitrogen atom; E is an oxygen atom, a sulfur atom, a group having -NH- or -NHCO-
And F represents a single bond or a C ₁ -C ₆ alkylene group.

Wherein A represents a group having the formula (A-2), and E represents a group having a sulfur atom, -NH- or -NHC
When a group having O- is shown, B represents a single bond or a methylene group, A represents a group having the formula (A-2), and when E represents an oxygen atom, B represents a methylene group. <Substituent group a> halogen atom, C ₁ -C ₆ alkyl group, C
₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, amino group, mono--C ₁ -C ₆ alkylamino group and a di -C ₁ -C ₆
Alkylamino group <substituent group b> hydroxy group, carboxy group, C ₁ -C ₆
Alkoxycarbonyl group, carbamoyl group, mono-C ₁
-C ₆ alkylcarbamoyl group, a di -C ₁ -C ₆ alkylcarbamoyl group, a nitro group, C ₃ -C ₁₀ cycloalkyl group, C ₆ -C ₁₀ aryl group, C ₆ -C _{1 0} aryloxy group, C ₇ -C ₁₆ aralkyloxy group, C ₆ -C ₁₀ arylthio group, and, 1 to have been three substituted with a group selected from substituent group a, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀
Aryl, C ₆ -C ₁₀ aryloxy, C ₇ -C ₁₆ aralkyloxy and C ₆ -C ₁₀ arylthio group.

Among these, preferred compounds include
(2) Formula (Ia) or (Ib)

[0052]

Embedded imageA compound having the general formula (Ia):
(4) A compound wherein A is a group having the formula (A-1)
(5) When A is a group having the formula (A-1),
B is a single bond or C₁-C_TwoCompounds that are alkyl groups
(6) When A is a group having the formula (A-1),
Wherein B is a single bond or a methylene group, (7)
 When A is a group having the formula (A-1), B is
(8) A compound which is a bond, wherein thiazolidine-2,
4-dione-5-yridenyl or 2-thioxothiazoly
A compound which is a gin-4-one-5-yridenyl group,
(9) A is thiazolidine-2,4-dione-5-i
A compound which is a ridenyl group, (10) wherein A is a compound represented by the formula (A-
(11) A compound which is a group having 2) wherein A is a group represented by the formula (A)
-2) when B is a methylene group
Compound (12) wherein A is a group having the formula (A-2)
Wherein B is a single bond, (13) ring Ar
_TwoIs substituted with one or two oxo or thioxo,
5-membered heterocyclic group containing at least one nitrogen atom
Compound, (14) Ring Ar_TwoBut thiazolidine-2,4
-Dione-5-yl, 2-thioxothiazolidine-4-
On-5-yl, oxazolidine-2,4-dione-5
-Yl, 2-thioxooxazolidin-4-one-5
Yl, [1,2,4] oxadiazol-5-one-3
-Yl, [1,2,4] oxadiazole-5-thione
-3-yl, [1,2,4] thiadiazol-5-one
-3-yl, [1,2,4] thiadiazole-5-thio
N-3-yl, [1,3,4] oxadiazole-2-
On-5-yl, [1,3,4] oxadiazole-2
-Thion-5-yl, [1,2,4] triazole-3
-On-5-yl or [1,2,4] triazole-3
A compound which is -thione-5-yl group, (15) ring Ar
_TwoIs thiazolidine-2,4-dione-5-yl or 2
-Thioxothiazolidine-4-one-5-yl group
Compound, (16) Ring Ar_TwoBut thiazolidine-2,4
-A compound which is a -dione-5-yl group, (17) D is
A compound which is a group having CH, (18) D is a nitrogen atom
(19) E is -NH- or -NH
A compound which is a group having CO—, (20) E is —N
A compound which is a group having H-, (21) F is₁−
C_FourA compound which is an alkylene group;
Compounds that are len, methylmethylene or ethylmethylene groups
(23) a compound wherein F is a methylmethylene group,
(24) R¹But C_Five-C₆Cycloalkyl group, C₆−
C_TenSelected from aryl groups, heterocyclic groups and substituent groups a and b
Substituted with 1 to 3 groups_Five-C₆Cycloalkyl
1 to 5 groups selected from the group consisting of
Replaced C₆-C_TenAryl group or substituent group a and
1 to 3 heterocyclic groups substituted with a group selected from b and b
(25) R¹But C_Five-C₆Cycloal
Kill group, C₆-C_TenAryl group, heterocyclic group, substituent group a
1 to 3 substituted with a group selected from and b₆−
C_TenAn aryl group or a group selected from substituent groups a and b
A heterocyclic group substituted by 1 to 3 groups with
(26) R¹But C₆-C_TenAryl group, cyclohex
A group selected from a sil group, a heterocyclic group, and substituent groups a and b
Substituted with one to three C₆-C_TenAn aryl group, or
1 to 3 substituents selected from substituent groups a and b
(27) R is a compound represented by the following heterocyclic group:¹But C₆−
C_TenAn aryl group, a group selected from substituent groups a and b
1 to 3 substituted C₆-C_TenAryl group, 5-6
5- to 5-membered aromatic heterocyclic group or a benzene ring
A compound which is a 6-membered aromatic heterocyclic group, (28) R¹But,
C₆-C_TenAryl group, 1 to 3 substituted C₆-C_Ten
An aryl group (the substituent is a substituent group a,
Xy group, nitro group, C_Three-C_{1 0}Cycloalkyl group, C₆−
C_TenAryl group, C₆-C_TenAryloxy group, C₇-C
₁₆Aralkyloxy group, C₆-C_TenArylthio group, average
And one to three substituents selected from a group selected from substituent group a.
C_Three-C_TenCycloalkyl, C₆-C_TenAryl,
C₆-C_TenAryloxy, C₇-C₁₆Aralkyloxy
And C₆-C_TenSelected from the group consisting of arylthio groups
Group. ) A 5- or 6-membered aromatic heterocyclic group or
A 5- or 6-membered aromatic heterocyclic group fused to a benzene ring
Compound, (29) R¹But C₆-C_TenAryl group, 1
C substituted with up to three₆-C_TenAn aryl group (the substituent is
Halogen atom, C₁-C₆Alkyl group, C₁-C₆Haloal
Kill group, C₁-C₆Alkoxy group, nitro group, C_Three-C_Ten
Cycloalkyl group, C₆-C _TenAryl group, C₆-C_TenA
Reeloxy group and C₆-C_TenConsists of an arylthio group
A group selected from the group. ) 5- or 6-membered aromatic complex
5- or 6-membered aromatic compound fused to a cyclic group or a benzene ring
A compound which is a ring group, (30) R¹But C₆-C_TenA
Reel group, 1 to 3 substituted C₆-C_TenAryl group
(The substituent is a halogen atom, C₁-C₆An alkoxy group,
Nitro group and C ₆-C_TenSelected from the group consisting of aryl groups
Is the chosen group. ), Thienyl group, furyl group, pylori
, Thiazolyl, oxazolyl, imidazolyl
Group, pyridyl group, or thienyl
, Furyl, pyrrolyl, thiazolyl, oxazolyl, i
A compound which is a midazolyl or pyridyl group, (31)
 R¹Is phenyl, 1-naphthyl, 2-naphthyl, 3
-Fluorophenyl, 4-fluorophenyl, 3-chloro
Rophenyl, 4-chlorophenyl, 3,4-difluoro
Phenyl, 3,4-dichlorophenyl, 3-methoxyphenyl
Phenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl
Phenyl, 3,4,5-trimethoxyphenyl, 4-nitro
Rophenyl, 2-biphenyl, thienyl or pyridyl groups
(32) R¹Is phenyl, 3-fur
Orophenyl, 3-chlorophenyl, 3,4-difluoro
Lophenyl, 3,4-dichlorophenyl, 1-naphthy
A compound that is a 2-thienyl or 4-pyridyl group,
(33) R^TwoBut C_Five-C₆Cycloalkyl group, C₆−
C_TenSelected from an aryl group, a heterocyclic group and a substituent group a
Substituted with 1 to 3 groups₆-C_TenAryl group, also
Is substituted with 1 to 3 groups selected from the substituent group a.
A compound which is a heterocyclic group, (34) R^TwoBut cyclohe
Xyl group, 5- or 6-membered aromatic heterocyclic group, condensed with benzene ring
Combined 5- or 6-membered aromatic heterocyclic group, C₆-C_TenAryl
Group or C substituted with 1 to 3 groups₆-C_TenAryl group
(The substituent is a halogen atom, C₁-C₆Alkyl group and
C₁-C₆A group selected from the group consisting of alkoxy groups
You. (35) R^TwoBut C₆-C_TenAnts
Group, thienyl group, furyl group, pyrrolyl group, thiazolyl group
Group, oxazolyl group, imidazolyl group, pyridyl group,
Thienyl, furyl, pyrrolyl, fused with a benzene ring,
Thiazolyl, oxazolyl, imidazolyl or pyri
A zyl group or one substituted C₆-C_TenAryl group
(The substituent is a halogen atom, C₁-C₆An alkyl group or
C₁-C₆It is an alkoxy group. ), (3)
6) R^TwoBut C₆-C_TenAryl group, 2-thienyl
Group, 4-pyridyl group or one-substituted C₆-C_Ten
An aryl group (the substituent is a halogen atom or C₁-C₆A
It is a lucoxy group. (37) R
^TwoIs a phenyl group or a phenyl group substituted by 1
(The substituent is a halogen atom or C₁-C₆Alkoxy group
It is. (38) R^TwoBut pheny
4-fluorophenyl, 4-chlorophenyl or 4
A compound which is a -methoxyphenyl group, (39) R^ThreePassing
And R^FourAre the same or different and are a hydrogen atom, a halogen atom
Child, C₁-C₆Alkoxy group, amino group or di-C₁-C₆
A compound which is an alkylamino group, (40) R^ThreeAnd R
^FourIs the same or different and is a hydrogen atom, a halogen atom or
C ₁-C₆A compound which is an alkoxy group, (41) R^ThreePassing
And R^FourIs a hydrogen atom, (42) selected from the following:
Any one of the selected compounds, 5- [3-((1-
(3-Fluorophenyl) ethylamino)-(4-metho
Xyphenyl) methyl) benzyl] thiazolidine-2,
4-dione, 5- [3-((1- (4-fluorophenyl
Ru) ethylamino)-(4-methoxyphenyl) methyl
Ru) benzyl] thiazolidine-2,4-dione, 5-
[3-((1- (3-chlorophenyl) ethylamino)
-(4-methoxyphenyl) methyl) benzyl] thiazo
Lysine-2,4-dione, 5- [3-((1- (4-
(Rolophenyl) ethylamino)-(4-methoxyphenyl)
Ru) methyl) benzyl] thiazolidine-2,4-dioxide
5- [3-((1- (3,4-difluorophenyl)
Ru) ethylamino)-(4-methoxyphenyl) methyl
Ru) benzyl] thiazolidine-2,4-dione, 5-
[3-((2- (3,4-difluorophenyl) propyl
Onylamino)-(4-methoxyphenyl) methyl)
Nzil] thiazolidine-2,4-dione, 5- [3-
((-1- (1-naphthyl) ethylamino) -phenyl
Methyl) benzyl] thiazolidine-2,4-dione, 5
-[3-((1- (2-thienyl) ethylamino)-
(4-methoxyphenyl) methyl) benzyl] thiazoly
Gin-2,4-dione, 5- [3-((1- (4-pyri
(Zyl) ethylamino)-(4-fluorophenyl) methyl
Ru) benzyl] thiazolidine-2,4-dione, 5-
[3-((1- (4-pyridyl) ethylamino)-(4
-Methoxyphenyl) methyl) benzyl] thiazolidine
-2,4-dione, 5- [3- (phenyl- (1-fe
Nylethylamino) methyl) benzyl] thiazolidine-
2,4-dione, 5- [3-((2-phenylpropio
Nylamino) -phenylmethyl) benzyl] thiazolidi
-2,4-dione, 5- [3-((1- (3-fluoro
(Rophenyl) ethylamino)-(4-methoxyphenyl)
Ru) methyl) benzyl] -2-thioxothiazolidine-
4-one, 5- [3-((1- (4-fluorophenyl
Ru) ethylamino)-(4-methoxyphenyl) methyl
Ru) benzyl] -2-thioxothiazolidine-4-o
, 5- [3-((1- (3-chlorophenyl) ethyl
Amino)-(4-methoxyphenyl) methyl) benzyl
L] -2-thioxothiazolidine-4-one, 5- [3
-((1- (4-chlorophenyl) ethylamino)-
(4-methoxyphenyl) methyl) benzyl] -2-thio
Oxothiazolidine-4-one, 5- [3-((1-
(3,4-difluorophenyl) ethylamino)-(4
-Methoxyphenyl) methyl) benzyl] -2-thioki
Sothiazolidin-4-one, 5- [3-((2- (3,
4-difluorophenyl) propionylamino)-(4
-Methoxyphenyl) methyl) benzyl] -2-thioki
Sothiazolidin-4-one, 5- [3-((-1- (1
-Naphthyl) ethylamino) -phenylmethyl) benzyl
2-thiothiothiazolidine-4-dione, 5-
[3-((1- (2-thienyl) ethylamino)-(4
-Methoxyphenyl) methyl) benzyl] -2-thioki
Sothiazolidin-4-one, 5- [3-((1- (4-
Pyridyl) ethylamino)-(4-methoxyphenyl)
Methyl) benzyl] -2-thioxothiazolidine-4-
On, 5- [3-((1-phenylethylamino) -f
Enylmethyl) benzyl] -2-thioxothiazolidine
-4-one, and 5- [3-((2-phenylpropio
Nilamino) -phenylmethyl) benzyl] -2-thio
Xothiazolidin-4-one can be mentioned.
(43) The ileal bile acid transporter of the present invention
Inhibitors are compounds having the general formula (II),
Uses acceptable salts, their esters or other derivatives
Contains as an ingredient.

[0053]

Embedded image Wherein R ¹ is a C ₃ -C ₁₀ cycloalkyl group, C ₆ -C
₁₀ aryl group, heterocyclic group, C ₃ -C ₁₀ cycloalkyl group substituted with 1 to 5 groups selected from substituent groups a and b, 1 to 5 group selected from substituent groups a and b A 5-substituted C ₆ -C ₁₀ aryl group or a heterocyclic group substituted by 1 to 5 groups selected from substituent groups a and b, wherein R ² is a C ₃ -C ₁₀ cycloalkyl group; Alkyl group, C ₆ -C
₁₀ aryl groups, heterocyclic groups, C ₃ -C ₁₀ cycloalkyl groups substituted by 1 to 3 groups selected from substituent group a,
C substituted with 1 to 3 groups selected from a substituent group a
₆ -C ₁₀ aryl group, or represents a 1 to 3-substituted heterocyclic group with a group selected from Substituent Group a, R ³ and R
⁴ is the same or different and represents a hydrogen atom or a group selected from substituent group a, and A represents the following formula (A-1) or (A
-3)

[0054]

Embedded image

[0055]

Embedded image (Wherein B represents a single bond or a C ₁ -C ₆ alkylene group, and rings Ar ₁ and Ar ₃ represent a heterocyclic group substituted with one or two oxo or thioxo groups). Show,
D represents a group having CH or a nitrogen atom; E is an oxygen atom, a sulfur atom, a group having -NH- or -NHCO-
And F represents a single bond or a C ₁ -C ₆ alkylene group. <Substituent group a> halogen atom, C ₁ -C ₆ alkyl group, C
₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, amino group, mono--C ₁ -C ₆ alkylamino group and a di -C ₁ -C ₆
Alkylamino group <substituent group b> hydroxy group, carboxy group, C ₁ -C ₆
Alkoxycarbonyl group, carbamoyl group, mono-C ₁
-C ₆ alkylcarbamoyl group, a di -C ₁ -C ₆ alkylcarbamoyl group, a nitro group, C ₃ -C ₁₀ cycloalkyl group, C ₆ -C ₁₀ aryl group, C ₆ -C ₁₀ aryloxy group, C ₇ - C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ substituted with 1 to 3 C ₁₆ aralkyloxy groups, C ₆ -C ₁₀ arylthio groups and groups selected from substituent group a.
Aryl, C ₆ -C ₁₀ aryloxy, C ₇ -C ₁₆ aralkyloxy and C ₆ -C ₁₀ arylthio group.

Among these, preferred compounds include
(44) The following general formula (IIa) or (IIb)

[0057]

Embedded image(45) having the general formula (IIa)
Compound (46) wherein A is a group having the formula (A-1)
(47) A is a group having the formula (A-1)
In some cases, B is a single bond or C₁-C_TwoIs an alkyl group
Compound (48) wherein A is a group having the formula (A-1)
Wherein B is a single bond or a methylene group,
(49) When A is a group having the formula (A-1),
 A compound in which B is a single bond, (50) A is thiazo
Lysine-2,4-dione-5-yridenyl or 2-thio
Oxothiazolidine-4-one-5-yridenyl group
Compound, (51) wherein A is thiazolidine-2,4-di
(52) A wherein A is a compound of the formula
A compound which is a group having the formula (A-3), (53) A
Is a group having the formula (A-3),₁−
C₆(54) A compound represented by the formula (A)
-3) when B is C₁-C_TwoAlkyl
(55) A is a group having the formula (A-3),
When B is a methylene group, (5
6) when A is a group having the formula (A-3),
Is a single bond, (57) Ring Ar_ThreeBut oki
At least 1 substituted with 1 or 2
A compound which is a 5-membered heterocyclic group containing nitrogen atoms,
(58) Ring Ar_ThreeIs 2,4-dioxothiazolidini
2,4-dithioxothiazolidinyl, 4-oxo-
2-thioxo-thiazolidinyl, 2,4-dioxooxo
Sazolidinyl, 2,4-dithiooxooxazolidinyl,
4-oxo-2-thiooxooxazolidinyl, 5-oxo
So [1,2,4] oxadiazolidinyl, 5-thioxo
[1,2,4] oxadiazolidinyl, 5-oxo
[1,2,4] thiadiazolidinyl, 5-thioxo
[1,2,4] thiadiazolidinyl, 2-oxo [1,2
3,4] oxadiazolidinyl, 2-thioxo [1,
3,4] oxadiazolidinyl, 3-oxo [1,2,
4] triazolidinyl or 3-thioxo [1,2,4]
Compound which is a triazolidinyl group, (59) ring Ar_Three
Is thiazolidine-2,4-dione-5-yl, 2-thio
Oxothiazolidine-4-one-5-yl, oxazoly
Zin-2,4-dione-5-yl, 2-thioxooxa
Zolidin-4-one-5-yl, [1,2,4] oxa
Diazol-5-one-3-yl, [1,2,4] oxo
Sadiazol-5-thion-3-yl, [1,2,4]
Thiadiazol-5-one-3-yl, [1,2,4]
Thiadiazol-5-thion-3-yl, [1,3,
4] oxadiazol-2-one-5-yl, [1,
3,4] oxadiazol-2-thion-5-yl,
[1,2,4] triazol-3-one-5-yl or
[1,2,4] triazol-3-thion-5-yl group
(60) a ring Ar_ThreeIs a thiazolidine-
2,4-dione-5-yl or 2-thioxothiazolidi
A compound which is a non-4-one-5-yl group, (61) a ring,
Ar_ThreeIs a thiazolidine-2,4-dione-5-yl group
(62) D is a group having CH
Compound, (63) a compound wherein D is a nitrogen atom, (6)
4) E is a group having -NH- or -NHCO-
(65) E is a group having -NH-
Compound, (66) F is C₁-C_FourIs an alkylene group
Compound (67) wherein F is methylene, methylmethylene or
Is a compound having an ethylmethylene group, and (68) F is
A compound which is a tylmethylene group, (69) R¹But C_Five
-C₆Cycloalkyl group, C₆-C_TenAryl group, heterocycle
1 to 3 groups selected from groups and substituent groups a and b
Transformed C_Five-C₆Cycloalkyl group, substituent groups a and b
C substituted with 1 to 5 substituents selected from₆-C_TenA
A reel group or a group selected from substituent groups a and b
(70) a compound which is a substituted heterocyclic group having 1 to 3 substituent (s);
 R¹But C_Five-C₆Cycloalkyl group, C₆-C_TenAnts
Group, heterocyclic group, group selected from substituent groups a and b
Substituted with one to three C₆-C_TenAn aryl group, or
1 to 3 substituents selected from substituent groups a and b
(71) R which is a heterocyclic group¹But C₆−
C_TenAryl group, cyclohexyl group, heterocyclic group, substituent
C substituted by 1 to 3 groups selected from groups a and b
₆-C_TenSelected from aryl groups or substituent groups a and b
Is a heterocyclic group substituted by 1 to 3 substituents
Object, (72) R¹But C₆-C_TenAryl group, substituent
C substituted by 1 to 3 groups selected from groups a and b
₆-C_TenAn aryl group, a 5- or 6-membered aromatic heterocyclic group, or
Is a 5- or 6-membered aromatic heterocyclic group fused to a benzene ring
Certain compounds, (73) R¹But C₆-C_TenAryl
Group, 1 to 3 substituted C₆-C_TenAryl group (the
The substituent includes a substituent group a, and a hydroxy group, a nitro group,
Group, C_Three-C_{1 0}Cycloalkyl group, C₆-C_TenAryl
Group, C₆-C_TenAryloxy group, C₇-C₁₆Aralkyl
Oxy group, C₆-C_TenArylthio group and substituent
C substituted with 1 to 3 groups selected from group a,_Three−
C_TenCycloalkyl, C₆-C_TenAryl, C₆-C_TenA
Reeloxy, C₇-C₁₆Aralkyloxy and C₆-C
_TenA group selected from the group consisting of arylthio groups
You. ) 5- or 6-membered aromatic heterocyclic group or benzene ring
A compound which is a 5- or 6-membered aromatic heterocyclic group condensed with
(74) R¹But C₆-C_TenAryl group, 1 to 3
Replaced C₆-C_TenAryl group (the substituent is halogen
Atom, C₁-C₆Alkyl group, C₁-C₆Haloalkyl
Group, C₁-C₆Alkoxy group, nitro group, C_Three-C_TenShiku
Loalkyl group, C₆-C _TenAryl group, C₆-C_TenAlly
Roxy group and C₆-C_TenGroup consisting of arylthio groups
Group selected from ) 5- or 6-membered aromatic heterocycle
Group or 5- or 6-membered aromatic heterocyclic fused with a benzene ring
A compound which is a cyclic group, (75) R¹But C₆-C_TenAnts
Group, 1 to 3 substituted C₆-C_TenAryl group
(The substituent is a halogen atom, C₁-C₆An alkoxy group,
Nitro group and C ₆-C_TenSelected from the group consisting of aryl groups
Is the chosen group. ), Thienyl group, furyl group, pylori
, Thiazolyl, oxazolyl, imidazolyl
Group, pyridyl group, or thienyl
, Furyl, pyrrolyl, thiazolyl, oxazolyl, i
A compound which is a midazolyl or pyridyl group, (76)
 R¹Is phenyl, 1-naphthyl, 2-naphthyl, 3
-Fluorophenyl, 4-fluorophenyl, 3-chloro
Rophenyl, 4-chlorophenyl, 3,4-difluoro
Phenyl, 3,4-dichlorophenyl, 3-methoxyphenyl
Phenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl
Phenyl, 3,4,5-trimethoxyphenyl, 4-nitro
Rophenyl, 2-biphenyl, thienyl or pyridyl groups
(77) R¹Is phenyl, 3-fur
Orophenyl, 3-chlorophenyl, 3,4-difluoro
Lophenyl, 3,4-dichlorophenyl, 1-naphthy
A compound that is a 2-thienyl or 4-pyridyl group,
(78) R^TwoBut C_Five-C₆Cycloalkyl group, C₆−
C_TenSelected from an aryl group, a heterocyclic group and a substituent group a
Substituted with 1 to 3 groups₆-C_TenAryl group, also
Is substituted with 1 to 3 groups selected from the substituent group a.
A compound which is a heterocyclic group, (79) R^TwoBut cyclohe
Xyl group, 5- or 6-membered aromatic heterocyclic group, condensed with benzene ring
Combined 5- or 6-membered aromatic heterocyclic group, C₆-C_TenAryl
Group or C substituted with 1 to 3 groups₆-C_TenAryl group
(The substituent is a halogen atom, C₁-C₆Alkyl group and
C₁-C₆A group selected from the group consisting of alkoxy groups
You. (80) R^TwoBut C₆-C_TenAnts
Group, thienyl group, furyl group, pyrrolyl group, thiazolyl group
Group, oxazolyl group, imidazolyl group, pyridyl group,
Thienyl, furyl, pyrrolyl, fused with a benzene ring,
Thiazolyl, oxazolyl, imidazolyl or pyri
A zyl group or one substituted C₆-C_TenAryl group
(The substituent is a halogen atom, C₁-C₆An alkyl group or
C₁-C₆It is an alkoxy group. ), (8)
1) R^TwoBut C₆-C_TenAryl group, 2-thienyl
Group, 4-pyridyl group or one-substituted C₆-C_Ten
An aryl group (the substituent is a halogen atom or C₁-C₆A
It is a lucoxy group. (82) R
^TwoIs a phenyl group or a phenyl group substituted by 1
(The substituent is a halogen atom or C₁-C₆Alkoxy group
It is. (83) R^TwoBut pheny
4-fluorophenyl, 4-chlorophenyl or 4
A compound which is a -methoxyphenyl group, (84) R^ThreePassing
And R^FourAre the same or different and are a hydrogen atom, a halogen atom
Child, C₁-C₆Alkoxy group, amino group or di-C₁-C₆
A compound which is an alkylamino group, (85) R^ThreeAnd R
^FourIs the same or different and is a hydrogen atom, a halogen atom or
C ₁-C₆A compound which is an alkoxy group, (86) R^ThreePassing
And R^FourIs a hydrogen atom, (87) a compound selected from the following:
Any one of the selected compounds, 5- [3-((1-
(3-Fluorophenyl) ethylamino)-(4-metho
Xyphenyl) methyl) benzyl] thiazolidine-2,
4-dione, 5- [3-((1- (4-fluorophenyl
Ru) ethylamino)-(4-methoxyphenyl) methyl
Ru) benzyl] thiazolidine-2,4-dione, 5-
[3-((1- (3-chlorophenyl) ethylamino)
-(4-methoxyphenyl) methyl) benzyl] thiazo
Lysine-2,4-dione, 5- [3-((1- (4-
(Rolophenyl) ethylamino)-(4-methoxyphenyl)
Ru) methyl) benzyl] thiazolidine-2,4-dioxide
5- [3-((1- (3,4-difluorophenyl)
Ru) ethylamino)-(4-methoxyphenyl) methyl
Ru) benzyl] thiazolidine-2,4-dione, 5-
[3-((2- (3,4-difluorophenyl) propyl
Onylamino)-(4-methoxyphenyl) methyl)
Nzil] thiazolidine-2,4-dione, 5- [3-
((-1- (1-naphthyl) ethylamino) -phenyl
Methyl) benzyl] thiazolidine-2,4-dione, 5
-[3-((1- (2-thienyl) ethylamino)-
(4-methoxyphenyl) methyl) benzyl] thiazoly
Gin-2,4-dione, 5- [3-((1- (4-pyri
(Zyl) ethylamino)-(4-fluorophenyl) methyl
Ru) benzyl] thiazolidine-2,4-dione, 5-
[3-((1- (4-pyridyl) ethylamino)-(4
-Methoxyphenyl) methyl) benzyl] thiazolidine
-2,4-dione, 5- [3- (phenyl- (1-fe
Nylethylamino) methyl) benzyl] thiazolidine-
2,4-dione, 5- [3-((2-phenylpropio
Nylamino) -phenylmethyl) benzyl] thiazolidi
-2,4-dione, 5- [3-((1- (3-fluoro
(Rophenyl) ethylamino)-(4-methoxyphenyl)
Ru) methyl) benzyl] -2-thioxothiazolidine-
4-one, 5- [3-((1- (4-fluorophenyl
Ru) ethylamino)-(4-methoxyphenyl) methyl
Ru) benzyl] -2-thioxothiazolidine-4-o
, 5- [3-((1- (3-chlorophenyl) ethyl
Amino)-(4-methoxyphenyl) methyl) benzyl
L] -2-thioxothiazolidine-4-one, 5- [3
-((1- (4-chlorophenyl) ethylamino)-
(4-methoxyphenyl) methyl) benzyl] -2-thio
Oxothiazolidine-4-one, 5- [3-((1-
(3,4-difluorophenyl) ethylamino)-(4
-Methoxyphenyl) methyl) benzyl] -2-thioki
Sothiazolidin-4-one, 5- [3-((2- (3,
4-difluorophenyl) propionylamino)-(4
-Methoxyphenyl) methyl) benzyl] -2-thioki
Sothiazolidin-4-one, 5- [3-((-1- (1
-Naphthyl) ethylamino) -phenylmethyl) benzyl
2-thiothiothiazolidine-4-dione, 5-
[3-((1- (2-thienyl) ethylamino)-(4
-Methoxyphenyl) methyl) benzyl] -2-thioki
Sothiazolidin-4-one, 5- [3-((1- (4-
Pyridyl) ethylamino)-(4-methoxyphenyl)
Methyl) benzyl] -2-thioxothiazolidine-4-
On, 5- [3-((1-phenylethylamino) -f
Enylmethyl) benzyl] -2-thioxothiazolidine
-4-one, and 5- [3-((2-phenylpropio
Nilamino) -phenylmethyl) benzyl] -2-thio
Xothiazolidin-4-one can be mentioned.

In the above formula, “C ₃ -C ₁₀ cycloalkyl” and “Substituent group a” in the definition of R ¹ and R ² and Substituent group b
C ₃ -C ₁₀ cycloalkyl group "and" one to five substituted C ₃ -C ₁₀ cycloalkyl groups selected from substituent group a and b 1 to which is three substituted with a group selected from The C ₃ -C ₁₀ cycloalkyl moiety of the group is, for example, an optionally fused 3 to 10-membered saturated cyclic hydrocarbon group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and adamantyl. It can be mentioned, preferably a C ₅ -C ₆ cycloalkyl group, particularly preferably a cyclohexyl group.

[0059] In the above formulas, R ^1, "C ₆ -C ₁₀ aryl group" in the definition of R ² and substituent group b, C ₆ to "substituted 1 to 3 groups selected from Substituent Group a -C ₁₀ C ₆ -C ₁₀ aryl moiety of the aryl group "and" a 1 to 5 substituted by a group selected from substituent group a and b the C ₆ -C ₁₀ aryl group "is, for example, phenyl, indenyl And an aromatic hydrocarbon group having 6 to 10 carbon atoms such as naphthyl, preferably a phenyl or 1-naphthyl group, and particularly preferably a phenyl group.

[0060] In the above formula, "heterocyclic group" in the definition of R ¹ and R ^2, "is 1 to 3 substituted with a group selected from Substituent group a heterocycle group" and "substituent group a and The heterocyclic group part of the “heterocyclic group substituted by 1 to 5 groups selected from b” represents a 5- to 7-membered heterocyclic group containing 1 to 3 sulfur atoms, oxygen atoms and / or nitrogen atoms. , For example frills,
Thienyl, pyrrolyl, azepinyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl,
Isothiazolyl, 1,2,3-oxadiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyranyl,
Aromatic heterocyclic groups such as pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and morpholinyl, thiomorpholinyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl,
Corresponding to these groups such as imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl,
Partially or completely reduced groups can be mentioned. Further, the heterocyclic group may be condensed with another cyclic group such as a benzene ring. Inil,
Groups such as indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, carbazolyl, carbolinyl, acridinyl, isoindolinyl. In such a heterocyclic group, preferably a 5- or 6-membered aromatic heterocyclic group or a 5- or 6-membered aromatic heterocyclic group fused to a benzene ring, more preferably thienyl,
Furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl, pyridyl, or condensed with a benzene ring, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl,
An imidazolyl or pyridyl group, more preferably a thienyl or pyridyl group, and particularly preferably 2
-Thienyl or 4-pyridyl group.

In the above formula, “C ₁ ” in the definition of B and F
-C ₆ alkylene group ", for example, methylene, methylmethylene, ethylene, ethylmethylene, propylene, trimethylene, tetramethylene, 1-methyltrimethylene,
1 to 6 carbon atoms such as 2-methyltrimethylene, 3-methyltrimethylene, pentamethylene, hexamethylene
Linear or branched alkylene groups, and in B,
It is preferably a C ₁ -C ₂ alkylene group, particularly preferably a methylene group, and in F, a C ₁ -C ₄ alkylene group, more preferably methylene, methylmethylene or ethylmethylene. And particularly preferably a methylmethylene group.

In the above formula, the “heterocyclic group substituted by one or two oxo or thioxo” in the definition of ring Ar ₁ is:
The above "heterocyclic group" represents a group substituted by one or two oxo or thioxo, and represents a group in which one carbon atom contained in ring Ar ₁ is bonded to one carbon atom by a double bond; That is, it represents a group having the following formula (A-1).

[0063]

Embedded image Such “heterocyclic groups substituted by one or two oxo or thioxo” include, for example, thiazolidine-2,4
-Dione-5-ylidene, thiazolidine-2,4-dithione-5-ylidene, 2-thioxo-thiazolidine-4
-On-5-ylidene, oxazolidine-2,4-dione-5-ylidene, oxazolidine-2,4-dithione-5-ylidene, 2-thioxo-oxazolidine-4-
On-5-ylidene, isoxazolidine-3,5-dione-4-ylidene, isoxazolidine-3,5-dithione-4-ylidene, 3-thioxoisoxazolidine-5
-On-4-ylidene, [1,2,4] oxadiazolidine-5-one-3-ylidene, [1,2,4] oxadiazolidine-5-thione-3-ylidene, [1,3
4] oxadiazolidine-2-one-5-ylidene,
[1,3,4] oxadiazolidine-2-thione-5
Ilidene, [1,2,4] thiadiazolidine-5-one-3-ylidene, [1,2,4] thiadiazolidine-5
-Thione-3-ylidene, [1,2,4] triazolidine-3-one-5-ylidene, [1,2,4] triazolidine-3-thione-5-ylidene, and preferably,
Thiazolidine-2,4-dione-5-ylidene or 2-
Thioxo-thiazolidine-4-one-5-ylidene group, particularly preferably thiazolidine-2,4-dione-5.
-An ylidene group.

In the above formula, “heterocyclic group substituted by one or two oxo or thioxo” in the definition of ring Ar ₂ is:
The above “heterocyclic group” represents a group substituted by 1 or 2 oxo or thioxo, and represents a group bonded to B by one carbon atom contained in ring Ar ₂ , that is, the following formula (A- The group having 2) is shown.

[0065]

Embedded image Such “heterocyclic groups substituted by one or two oxo or thioxo” include, for example, thiazolidine-2,4
-Dion-5-yl, thiazolidine-2,4-dithion-5-yl, 2-thioxo-thiazolidine-4-one-
5-yl, oxazolidine-2,4-dione-5-yl, oxazolidine-2,4-dithion-5-yl,
-Thioxo-oxazolidin-4-one-5-yl, isoxazolidin-3,5-dione-4-yl, isoxazolidine-3,5-dithion-4-yl, 3-thioxoisoxazolidin-5-one- 4-yl, [1, 2,
4] oxadiazolidine-5-one-3-yl, [1,
2,4] oxadiazolidine-5-thion-3-yl,
[1,3,4] oxadiazolidine-2-one-5-yl, [1,3,4] oxadiazolidine-2-thione-
5-yl, [1,2,4] thiadiazolidine-5-one-3-yl, [1,2,4] thiadiazolidine-5-thion-3-yl, [1,2,4] triazolidine -3-
On-5-yl, [1,2,4] triazolidine-3-
Thion-5-yl, 4H- [1,2,4] oxadiazol-5-one-3-yl, [1,2,4] oxadiazol-5-thion-3-yl, [1,3 , 4] oxadiazol-2-one-5-yl, [1,3,4] oxadiazol-2-thion-5-yl, [1,2,4]
Thiadiazol-5-one-3-yl, [1,2,4]
Thiadiazol-5-thion-3-yl, [1,2,
4] triazol-3-one-5-yl, [1,2,2
4] a triazol-3-thion-5-yl group, preferably substituted by 1 or 2 oxo or thioxo,
5-membered heterocyclic group containing at least one nitrogen atom, more preferably thiazolidine-2,4-dione-5
-Yl, 2-thioxothiazolidin-4-one-5-yl, oxazolidine-2,4-dione-5-yl, 2-
Thioxoxazolidin-4-one-5-yl, [1,
2,4] oxadiazol-5-one-3-yl,
[1,2,4] oxadiazol-5-thion-3-yl, [1,2,4] thiadiazol-5-one-3-yl, [1,2,4] thiadiazol-5-thione-3 −
Yl, [1,3,4] oxadiazol-2-one-5
-Yl, [1,3,4] oxadiazol-2-thion-5-yl, [1,2,4] triazol-3-one-
5-yl or [1,2,4] triazol-3-thion-5-yl group, more preferably thiazolidine-
It is a 2,4-dione-5-yl or 2-thioxothiazolidin-4-one-5-yl group, and particularly preferably a thiazolidine-2,4-dione-5-yl group.

In the above formula, the “heterocyclic group substituted by one or two oxo or thioxo” in the definition of ring Ar ₃ is:
The above "heterocyclic group" represents a group substituted by one or two oxo or thioxo groups. The “heterocyclic group substituted by one or two oxo or thioxo” in the definition of the above-mentioned rings Ar ₁ and Ar ₂ is a —CH ＝ group or B only by one carbon atom contained in the rings Ar ₁ and Ar _2. The group bonded to the ring Ar ₃ represents a group bonded to B by one carbon atom or a hetero atom contained in the ring Ar ₃ . Such ring Ar ₃ represents a group having the following formula (A-3).

[0067]

Embedded image Examples of such “heterocyclic groups substituted by one or two oxo or thioxo” include, for example, 2,4-dioxothiazolidinyl, 2,4-dithiothiazolidinyl,
Oxo-2-thioxo-thiazolidinyl, 2,4-dioxooxazolidinyl, 2,4-dithiooxooxazolidinyl, 4-oxo-2-thiooxooxazolidinyl,
3,5-dioxoisoxazolidinyl, 3,5-dithioisoxazolidinyl, 5-oxo-3-thioxoisoxazolidinyl, 2-oxo [1,3,4] oxadiazo Lysinyl, 2-thioxo [1,3,4] oxadiazolidinyl, 5-oxo [1,2,4] oxadiazolidinyl, 5-thioxo [1,2,4] oxadiazolidinyl, 3, 5-dioxo [1,2,4] oxadiazolidinyl, 3,5-dithioxo [1,2,4] oxadiazolidinyl, 3-oxo-5-thioxo [1,2,4]
Oxadiazolidinyl, 2-oxo [1,3,4] thiadiazolidinyl, 2-thioxo [1,3,4] thiadiazolidinyl, 5-oxo [1,2,4] thiadiazolidinyl, 5-thioxo [1,2,4] thiadiazolidinyl, 3-oxo [1,2,4] triazolidinyl, 3-
Thioxo [1,2,4] triazolidinyl, 2-oxo [1,3,4] oxadiazolyl, 2-thioxo [1,
3,4] oxadiazolyl, 5-oxo [1,2,4]
Oxadiazolyl, 5-thioxo [1,2,4] oxadiazolyl, 2-oxo [1,3,4] thiadiazolyl, 2-thioxo [1,3,4] thiadiazolyl, 5-
Oxo [1,2,4] thiadiazolyl, 5-thioxo [1,2,4] thiadiazolyl, 3-oxo [1,2,4]
4] triazolyl or 3-thioxo [1,2,4] triazolyl group, preferably a 5-membered heterocyclic group containing at least one nitrogen atom and substituted with one or two oxo or thioxo groups; Yes, more preferably 2,4-dioxothiazolidinyl, 2,4-dithioxothiazolidinyl, 4-oxo-2-thioxo-thiazolidinyl,
2,4-dioxooxazolidinyl, 2,4-dithiooxooxazolidinyl, 4-oxo-2-thiooxooxazolidinyl, 5-oxo [1,2,4] oxadiazolidinyl, 5-thioxo [1,2,4] oxadiazolidinyl, 5-oxo [1,2,4] thiadiazolidinyl,
5-thioxo [1,2,4] thiadiazolidinyl, 2-
Oxo [1,3,4] oxadiazolidinyl, 2-thioxo [1,3,4] oxadiazolidinyl, 3-oxo [1,2,4] triazolidinyl or 3-thioxo [1,2,4] A triazolidinyl group, more preferably thiazolidine-2,4-dione-5-yl, 2-thioxothiazolidine-4-one-5-yl, oxazolidine-2,4-dione-5-yl, Thioxooxazolidin-4-one-5-yl, [1,2,4] oxadiazol-5-one-3-yl, [1,2,4] oxadiazol-5-thion-3-yl, [1,2,4]
Thiadiazol-5-one-3-yl, [1,2,4]
Thiadiazol-5-thion-3-yl, [1,3,
4] oxadiazol-2-one-5-yl, [1,
3,4] oxadiazol-2-thion-5-yl,
A [1,2,4] triazol-3-one-5-yl or [1,2,4] triazol-3-thion-5-yl group, and even more preferably a thiazolidine-2,4-dione. -5-yl or 2-thioxothiazolidine-4-one-5-yl group, particularly preferably thiazolidine-
2,4-dione-5-yl group.

In the above formula, the “halogen atom” in the definition of the substituent group “a” is a fluorine, chlorine, bromine or iodine atom.
Preferably it is a fluorine, chlorine or bromine atom, particularly preferably a fluorine atom.

In the above formula, “C” in the definition of the substituent group “a”
₁ -C ₆ alkyl group ", for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s- butyl, t- butyl, pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl,
3,3-dimethylbutyl, 2,2-dimethylbutyl,
1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbutyl, 2
A linear or branched alkyl group having 1 to 6 carbon atoms such as -ethylbutyl group, preferably a C ₁ -C ₄ alkyl group, more preferably a C ₁ -C ₂ alkyl group. And particularly preferably a methyl group.

In the above formula, “C” in the definition of the substituent group “a”
₁ -C ₆ haloalkyl group ", the" C ₁ -C ₆ alkyl group "in a group which has a halogen atom is substituted, for example, trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl , 2,2-dibromoethyl, preferably C ₁ -C ₄
It is a haloalkyl group, more preferably a C ₁ -C ₂ haloalkyl group, and particularly preferably a trifluoromethyl group.

In the above formula, “C” in the definition of the substituent group “a”
₁-C₆The “alkoxy group” is the same as the “C ₁-C₆Alkyl group "
Represents a group bonded to an oxygen atom, for example, methoxy,
Toxic, propoxy, isopropoxy, butoxy, iso
Butoxy, s-butoxy, t-butoxy, pentoxy,
Isopentoxy, 2-methylbutoxy, neopentoxy
Si, hexyloxy, 4-methylpentoxy, 3-methyl
Lupentoxy, 2-methylpentoxy, 3,3-dimethyl
Rubutoxy, 2,2-dimethylbutoxy, 1,1-dimethyl
Tilbutoxy, 1,2-dimethylbutoxy, 1,3-di
Such as methylbutoxy and 2,3-dimethylbutoxy groups
A linear or branched alkoxy group having 1 to 6 carbon atoms
And preferably C₁-C_FourAn alkoxy group, more preferably
Is C₁-C_TwoAn alkoxy group, particularly preferably methoxy
Group.

In the above formula, “mono-C ₁ -C ₆ alkylamino group” in the definition of the substituent group “a” refers to a group in which _one of the above “C ₁ -C ₆ alkyl groups” is bonded to an amino group, For example, methylamino, ethylamino, propylamino, isopropylamino, butylamino, isobutylamino,
s-butylamino, t-butylamino, pentylamino, isopentylamino, 2-methylbutylamino, neopentylamino, 1-ethylpropylamino, hexylamino, isohexylamino, 4-methylpentylamino, 3-methylpentyl Amino, 2-methylpentylamino, 1-methylpentylamino, 3,3-dimethylbutylamino, 2,2-dimethylbutylamino, 1,1
-Dimethylbutylamino, 1,2-dimethylbutylamino, 1,3-dimethylbutylamino, 2,3-dimethylbutylamino, 2-ethylbutylamino, preferably a C ₁ -C ₄ alkylamino group. Yes, more preferably C
An ₁ -C ₂ alkylamino group, particularly preferably a methylamino group.

In the above formula, “di-C ₁ -C ₆ alkylamino group” in the definition of the substituent group “a” refers to a group in which the above “C ₁ -C ₆ alkyl group” is bonded to two amino groups, For example,
Dimethylamino, diethylamino, N- ethyl -N- methylamino, dipropylamino, dibutylamino, dipentyl amino, dihexyl amino group, preferably a di -C ₁ -C ₄ alkylamino group, more preferably the Jee
It is a C ₁ -C ₂ alkylamino group, particularly preferably a dimethylamino group.

In the above formula, “C” in the definition of substituent group b
₁ -C ₆ alkoxycarbonyl group "represents a group wherein" C ₁ -C ₆ alkoxy group "is bonded to a carbonyl group, e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxy Carbonyl, s-butoxycarbonyl, t-butoxycarbonyl, pentoxycarbonyl, isopentoxycarbonyl, 2-methylbutoxycarbonyl, neopentoxycarbonyl, hexyloxycarbonyl, 4-methylpentoxycarbonyl, 3-
Methylpentoxycarbonyl, 2-methylpentoxycarbonyl, 3,3-dimethylbutoxycarbonyl, 2,
2-dimethylbutoxycarbonyl, 1,1-dimethylbutoxycarbonyl, 1,2-dimethylbutoxycarbonyl, 1,3-dimethylbutoxycarbonyl, 2,3-dimethylbutoxycarbonyl, preferably C ₁ -C ₄
An alkoxycarbonyl group, more preferably C ₁ -C ₂
It is an alkoxycarbonyl group, particularly preferably a methoxycarbonyl group.

In the above formula, the “mono-C ₁ -C ₆ alkylcarbamoyl group” in the definition of the substituent group b is the above-mentioned “C ₁ -C ₆ -alkylcarbamoyl group”.
—C ₆ alkyl group ”represents a group bonded to one carbamoyl group, for example, methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl, isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl, s
-Butylcarbamoyl, t-butylcarbamoyl, pentylcarbamoyl, isopentylcarbamoyl, 2-methylbutylcarbamoyl, neopentylcarbamoyl,
1-ethyl-propylcarbamoyl, a hexylcarbamoyl group, preferably a mono--C ₁ -C ₄ alkylcarbamoyl group, more preferably a mono--C ₁ -C ₂ alkylcarbamoyl group, particularly preferably a methyl It is a carbamoyl group.

In the above formula, the “di-C ₁ -C ₆ alkylcarbamoyl group” in the definition of the substituent group b is the same as the aforementioned “C _1-
A `` C ₆ alkyl group '' indicates a group bonded to two carbamoyl groups, and is, for example, dimethylcarbamoyl, diethylcarbamoyl, N-ethylN-methylcarbamoyl, dipropylcarbamoyl, dibutylcarbamoyl, dipentylcarbamoyl, or dihexylcarbamoyl. Is a di-C ₁ -C ₄ alkylcarbamoyl group, more preferably a di-C ₁ -C ₂ alkylcarbamoyl group, and particularly preferably a dimethylcarbamoyl group.

In the above formula, “C” in the definition of substituent group b
₆ -C ₁₀ C ₆ -C ₁₀ aryloxy moiety of aryloxy group "and" a 1 to 3 substituted with a group selected from Substituent group a a C ₆ -C ₁₀ aryloxy group ", the" C ₆
-C ₁₀ aryl group "represents groups bound to an oxygen atom, for example, phenoxy, 1-indenyl-oxy, 2-indenyl oxy, 3-indenyloxy, 1-naphthyloxy, it is a 2-naphthyloxy group And preferably a phenoxy group.

In the above formula, “C” in the definition of substituent group b
C ₇ -C ₁₆ aralkyloxy part of the ₇ -C ₁₆ aralkyloxy group "and" a 1 to 3 substituted with a group selected from Substituent group a a C ₇ -C ₁₆ aralkyloxy group ", benzyloxy, α-naphthylmethoxy, β-naphthylmethoxy, indenylmethoxy, diphenylmethoxy, triphenylmethoxy, 1-phenethyloxy, 2-phenethyloxy, 1-naphthylethoxy, 2-naphthylethoxy, 1-phenylpropoxy, 2-phenylpropoxy , 3-phenylpropoxy, 1-naphthylpropoxy, 2-naphthylpropoxy, 3-naphthylpropoxy, 1-phenylbutoxy, 2-phenylbutoxy,
-Phenylbutoxy, 4-phenylbutoxy, 1-naphthylbutoxy, 2-naphthylbutoxy, 3-naphthylbutoxy, 4-naphthylbutoxy, 1-phenylpentyloxy, 2-phenylpentyloxy, 3-phenylpentyloxy, 4-phenyl Pentyloxy, 5-phenylpentyloxy, 1-naphthylpentyloxy, 2
-Naphthylpentyloxy, 3-naphthylpentyloxy, 4-naphthylpentyloxy, 5-naphthylpentyloxy, 1-phenylhexyloxy, 2-phenylhexyloxy, 3-phenylhexyloxy, 4-phenylhexyloxy, 5-phenyl Hexyloxy,
6-phenylhexyloxy, 1-naphthylhexyloxy, 2-naphthylhexyloxy, 3-naphthylhexyloxy, 4-naphthylhexyloxy, 5-naphthylhexyloxy or 6-naphthylhexyloxy, preferably benzyl An oxy group.

In the above formula, “C” in the definition of substituent group b
₆ -C ₁₀ C ₆ -C ₁₀ arylthio moiety of the arylthio group "and" a 1 to 3 substituted with a group selected from Substituent group a a C ₆ -C ₁₀ arylthio group ", the" C ₆ -C _Ten
An `` aryl group '' indicates a group bonded to a sulfur atom, for example,
It is a phenylthio, 1-indenylthio, 2-indenylthio, 3-indenylthio, 1-naphthylthio, or 2-naphthylthio group, preferably a phenylthio group.

In the above, R^TwoIn the definition of
C substituted by 1 to 3 groups selected from group a_Three−
C_TenSpecific examples of "cycloalkyl group" include, for example, 2
-Fluorocyclopropyl, 2-chlorocyclopropyl
, 2- or 3-fluorocyclopentyl, 2-
Or 3-chlorocyclopentyl, 2-, 3- or
4-fluorocyclohexyl, 2-, 3- or 4-
Chlorocyclohexyl, 2-, 3- or 4-bromo
Cyclohexyl, 2-, 3- or 4-iodocyclo
Hexyl, 2-methylcyclopropyl, 2-methylcycl
Lopropyl, 2- or 3-methylcyclopentyl,
2- or 3-methylcyclopentyl, 2-, 3-young
Or 4-methylcyclohexyl, 2-, 3- or
4-ethylcyclohexyl, 2-trifluoromethyl
Chloropropyl, 2- or 3-trifluoromethyl
Clopentyl, 2- or 3-trifluoromethyl
Clopentyl, 2-, 3- or 4-trifluoromethyl
Tylcyclohexyl, 2-methoxycyclopropyl, 2
-Or 3-methoxycyclopentyl, 2- or
3-methoxycyclopentyl, 2-, 3- or 4-
Methoxycyclohexyl, 2-, 3- or 4-ethoxy
Xycyclohexyl, 2-aminocyclopropyl, 2-
Or 3-aminocyclopentyl, 2- or 3-
Aminocyclopentyl, 2-, 3- or 4-amino
Cyclohexyl, 2-methylaminocyclopropyl, 2
-Or 3-methylaminocyclopentyl, 2-young
Is 3-methylaminocyclopentyl, 2-, 3-young
4-methylaminocyclohexyl, 2-dimethyla
Minocyclopropyl, 2- or 3-dimethylamino
Cyclopentyl, 2- or 3-dimethylaminocyclyl
Lopentyl, 2-, 3- or 4-dimethylaminosi
Clohexyl, 3,4-difluorocyclohexyl,
3,4-dichlorocyclohexyl, 2,3-dimethoxy
Cyclohexyl, 3,4-dimethoxycyclohexyl,
3,5-dimethoxycyclohexyl, 3,4,5-tri
A methoxycyclohexyl group, preferably 1 to 3
Replaced C _Five-C₆A cycloalkyl group (the substituent is
Halogen atom, C₁-C₆Alkyl and C ₁-C₆Alkoki
And a group selected from the group consisting of: )
More preferably, a single-substituted cyclohexyl group (the substituent
Is a halogen atom, C₁-C₆Alkyl and C₁-C₆Al
It is a group selected from the group consisting of a coxy group. )
And particularly preferably, 4-fluorocyclohexyl,
Chlorocyclohexyl, 4-methylcyclohexyl or
4-methoxycyclohexyl group.

In the definition of R ² , “C _6- substituted with 1 to 3 groups selected from a substituent group a”
Specific examples of the “C ₁₀ aryl group” include, for example, 2-, 3
-Or 4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 2-, 3- or 4-bromophenyl, 2-, 3- or 4-iodophenyl, 2
-, 3- or 4-methylphenyl, 2-, 3- or 4-ethylphenyl, 2-, 3- or 4-trifluoromethylphenyl, 2-, 3- or 4-methoxyphenyl, 2-, 3- Or 4-ethoxyphenyl, 2-, 3- or 4-aminophenyl, 2-, 3
-Or 4-methylaminophenyl, 2-, 3- or 4-dimethylaminophenyl, 2,4-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2,4-dichlorophenyl, 3,4 −
Dichlorophenyl, 3,5-dichlorophenyl, 3,4
-Dibromophenyl, 2,3-dimethylphenyl, 3,
4-dimethylphenyl, 3,5-dimethylphenyl,
2,3-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-fluoro-4-methoxyphenyl, 4-methyl-2-methoxyphenyl, 6 -Fluoro-4-methyl-2-methoxyphenyl, 5-fluoroinden-3-yl, 5-fluoroinden-3-yl,
5-methylinden-3-yl, 5-methoxyinden-3-yl, 5-fluoroinden-2-yl, 5-chloroinden-2-yl, 5-methylinden-2-yl, 5-methoxyinden- 2-yl, 5-fluoronaphthalen-2-yl, 5-fluoronaphthalen-2-yl, 5-methylnaphthalen-2-yl, 5-methoxynaphthalen-2-yl, 5-fluoronaphthalen-1-yl, -Fluoronaphthalen-1-yl, 5-methylnaphthalen-1-yl, 5-methoxynaphthalen-1-yl group, preferably 1 to 3 substituted C ₆ -C
_{A 10} aryl group (the substituent is a group selected from the group consisting of a halogen atom, a C ₁ -C ₆ alkyl and a C ₁ -C ₆ alkoxy group), and more preferably one is substituted. C ₆ -C ₁₀ aryl group (the substituent is a halogen atom,
It is a C ₁ -C ₆ alkyl or C ₁ -C ₆ alkoxy group. )
And still more preferably a single-substituted phenyl group (the substituent is a halogen atom or a C ₁ -C ₆ alkoxy group), particularly preferably 4-fluorophenyl, -Chlorophenyl or 4-methoxyphenyl group.

In the above, specific examples of the “heterocyclic group substituted by 1 to 3 groups selected from the substituent group a” in the definition of R ² include, for example, 3-, 4- or 5-
-Methylfuran-2-yl, 2-, 4- or 5-methylfuran-3-yl, 3-, 4- or 5-fluorothiophen-2-yl, 3-, 4- or 5-bromothiophen-2 -Yl, 3-, 4- or 5-methylthiophen-2-yl, 2-, 4- or 5-methylthiophen-3-yl, 3-, 4- or 5-ethylthiophen-2-yl, 2- , 4- or 5-ethylthiophen-3-yl, 3-, 4- or 5-methoxythiophen-2-yl, 2-, 4- or 5-methoxythiophen-3-yl, 3- or 4-methylthiazole -5-yl, 3-, 4- or 5-fluorobenzothiophen-2-yl, 3-, 4- or 5
-Bromobenzothiophen-2-yl, 3-, 4- or 5-methylbenzothiophen-2-yl, 3-, 4
-Or 5-methoxybenzothiophen-2-yl,
2-, 4- or 5-fluorobenzothiophene-3
-Yl, 2-, 4- or 5-bromobenzothiophen-3-yl, 2-, 4- or 5-methylbenzothiophen-3-yl, 2-, 4- or 5-methoxybenzothiophen-3-yl , 4-, 5-, 6- or 7-methylbenzothiophen-2-yl group, preferably 1 to 3 substituted heterocyclic groups (the substituents being
Halogen atom, a group selected from the group consisting of C ₁ -C ₆ alkyl and C ₁ -C ₆ alkoxy group. And more preferably a single-substituted heterocyclic group (the substituent is a halogen atom, a C ₁ -C ₆ alkyl or a C ₁ -C ₆ alkoxy group), and still more preferably. Is a single or substituted 5- or 6-membered aromatic heterocyclic group (the substituent is a halogen atom, a C ₁ -C ₆ alkyl or a C ₁ -C ₆ alkoxy group), and particularly preferably. Is a single-substituted thienyl or pyridyl group (the substituent is a halogen atom or C ₁
—C ₆ alkoxy group. ).

In the above, R¹In the definition of
1 to 5 substituted with groups selected from groups a and b
C_Three-C_TenSpecific examples of "cycloalkyl group" include
If R^TwoSelected from the substituent group a in the definition of
Substituted with 1 to 3 groups_Three-C_TenCycloalkyl
Group ", 2-hydroxycyclopropyl, 2- or 3
-Hydroxycyclopentyl, 2-, 3- or 4-
Hydroxycyclohexyl, 2-carboxycyclopro
Pill, 2- or 3-carboxycyclopentyl, 2
-, 3- or 4-carboxycyclohexyl, 2-
Methoxycarbonylcyclopropyl, 2- or 3-
Methoxycarbonylcyclopentyl, 2-, 3-young
Is 4-methoxycarbonylcyclohexyl, 2-, 3-
Or 4-carbamoylcyclohexyl, 2-, 3-
Or 4-methylcarbamoylcyclohexyl, 2
-, 3- or 4-dimethylcarbamoylcyclohexyl
Sil, 2-nitrocyclopropyl, 2- or 3-di
Trocyclopentyl, 2-, 3- or 4-nitrosi
Clohexyl, 2- or 3-cyclohexylcyclo
Pentyl, 2-, 3- or 4-cyclohexylcyclic
Rohexyl, 2-phenylcyclopropyl, 2-young
Is 3-phenylcyclopentyl, 2-, 3- or 4
-Phenylcyclohexyl, 2-phenoxycyclopro
Pill, 2- or 3-phenoxycyclopentyl, 2
-, 3- or 4-phenoxycyclohexyl, 2-
Benzyloxycyclopropyl, 2- or 3-ben
Ziroxycyclopentyl, 2-, 3- or 4-be
Ndyloxycyclohexyl, 2-phenylthiocyclo
Propyl, 2- or 3-phenylthiocyclopentic
, 2-, 3- or 4-phenylthiocyclohexyl
And preferably 1 to 3 substituted C_Five-C₆
Cycloalkyl group (the substituent is a halogen atom, C ₁−
C₆Alkyl, C₁-C₆Alkoxy and C₆-C_TenAlly
A group selected from the group consisting of )
Preferably, one substituted cyclohexyl group (the substituent
Is a halogen atom, C₁-C₆Alkyl, C₁-C₆Arco
Kishi and C₆-C_TenSelected from the group consisting of aryl groups
Group. ).

In the above, specific examples of the “C ₆ -C ₁₀ aryl group substituted with 1 to 5 groups selected from substituent groups a and b” in the definition of R ¹ include, for example, R ²
In the definition of the above, “1 is a group selected from the substituent group a.
To 3-substituted C ₆ -C _{1 0} aryl group ", 2-, 3
-Or 4-hydroxyphenyl, 2-, 3- or 4-carboxyphenyl, 2-, 3- or 4-methoxycarbonylphenyl, 2-, 3- or 4-ethoxycarbonylphenyl, 2-, 3- or 4- Carbamoylphenyl, 2-, 3- or 4-methylcarbamoylphenyl, 2-, 3- or 4-dimethylcarbamoylphenyl, 2-, 3- or 4-nitrophenyl, 2-, 3- or 4-cyclopentylphenyl, 2 -, 3- or 4-cyclohexylphenyl, 2-, 3- or 4-phenoxyphenyl, 2
-, 3- or 4-diphenyl, 2-, 3- or 4-benzyloxyphenyl, 3,4-dibenzyloxyphenyl, 3,5-dibenzyloxyphenyl,
-, 3- or 4-phenylthiophenyl, 5-hydroxyinden-3-yl, 5-nitroindene-3-
Yl, 5-cyclohexylinden-3-yl, 5-phenylinden-3-yl, 5-phenoxyindene-
3-yl, 5-benzyloxyinden-3-yl, 5
-Phenylthioinden-3-yl, 5-hydroxyinden-2-yl, 5-nitroinden-2-yl,
-Cyclohexylinden-2-yl, 5-phenylinden-2-yl, 5-phenoxyinden-2-yl, 5-benzyloxyinden-2-yl, 5-phenylthioinden-2-yl, 5-hydroxynaphthalene -2-yl, 5-nitronaphthalen-2-yl, 5-
Cyclohexylnaphthalen-2-yl, 5-phenylnaphthalen-2-yl, 5-phenoxynaphthalen-2-
Yl, 5-benzyloxynaphthalen-2-yl, 5-
Phenylthionaphthalen-2-yl, 5-hydroxynaphthalen-1-yl, 5-nitronaphthalen-1-yl, 5-cyclohexylnaphthalen-1-yl, 5-phenylnaphthalen-1-yl, 5-phenoxynaphthalene-1 -Yl, 5-benzyloxynaphthalen-1-yl, 5-phenylthionaphthalen-1-yl group,
And is preferably a C ₆ -C ₁₀ aryl group substituted by 1 to 3 groups selected from substituent groups a and b,
More preferably, 1 to 3 substituted C ₆ -C ₁₀ aryl groups (the substituents are the substituent group a and a hydroxy group, a nitro group, a C ₃ -C ₁₀ cycloalkyl group, a C _6- C ₁₀
An aryl group, a C ₆ -C ₁₀ aryloxy group, a C ₇ -C ₁₆ aralkyloxy group, a C ₆ -C ₁₀ arylthio group, and a C ₁ -C 3 substituted with a group selected from a substituent group a ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ aryl, C
₆ -C ₁₀ aryloxy, a radical selected from the group consisting of C ₇ -C ₁₆ aralkyloxy and C ₆ -C ₁₀ arylthio group. ), More preferably, 1 to 3-substituted C ₆ -C ₁₀ aryl group, (said substituent is a halogen atom, C ₁ -C ₆ alkyl, C ₁ -C ₆ haloalkyl groups, C
₁ -C ₆ alkoxy group, a nitro group, C ₃ -C ₁₀ cycloalkyl group, C ₆ -C ₁₀ aryl group, C ₆ -C ₁₀ aryloxy group, and a C ₆ -C ₁₀ group consisting of an arylthio group Group. ), And even more preferably more, 1 to 3-substituted C ₆ -C ₁₀ aryl group (the substituent is a halogen atom, C ₁ -C ₆ alkoxy group, a nitro group, and a C
It consists ₆ -C ₁₀ aryl group is a group selected from the group. And even more preferably 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl,
4-chlorophenyl, 3,4-difluorophenyl,
3,4-dichlorophenyl, 3-methoxyphenyl, 4
-Methoxyphenyl, 3,4-dimethoxyphenyl,
3,4,5-trimethoxyphenyl, 4-nitrophenyl or 2-biphenyl group, particularly preferably 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl or 3,4-dichlorophenyl group. is there.

In the above, specific examples of the “heterocyclic group substituted by 1 to 5 groups selected from substituent groups a and b” in the definition of R ¹ include, for example, the aforementioned “heterocyclic group in the definition of R ² ”. Heterocyclic group substituted by 1 to 3 groups selected from substituent group a ", 3-, 4- or 5-hydroxyfuran-2-yl, 2-, 4- or 5-hydroxyfuran-3- Yl, 3-, 4- or 5-hydroxythiophen-2-yl, 3-, 4- or 5-nitrothiophen-2-yl, 3-, 4- or 5-phenylthiophen-2-yl, 2-, 4- or 5-hydroxythiophen-3-yl, 2-, 4- or 5
-Nitrothiophen-3-yl, 2-, 4- or 5
-Phenylthiophen-3-yl, 1-, 2- or 3-hydroxypyridin-4-yl, 1-, 2- or 3-nitropyridin-4-yl, 1-, 2- or 3-phenylpyridin-4 -Yl group, preferably
1 to 3 substituted heterocyclic groups (the substituents are halogen atoms, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₆
—C ₁₀ is a group selected from the group consisting of aryl groups. ), And more preferably, a single substituted heterocyclic group (the substituent is a halogen atom, C ₁ -C ₆ alkyl, C ₁
-C ₆ alkoxy and C ₆ -C ₁₀ aryl group. And particularly preferably a monosubstituted thienyl or pyridyl group, wherein said substituents are halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy and C ₆ -C ₁₀ aryl. ).

"Pharmacologically acceptable salts thereof" means that the compound (I) or (II) of the present invention is reacted with an acid when it has a basic group such as an amino group.
Also, when it has an acidic group such as a carboxy group, it can be made into a salt by reacting with a base,
Show the salt.

The salt based on a basic group is preferably
Inorganic acid salts such as hydrohalides such as hydrofluoride, hydrochloride, hydrobromide and hydroiodide, nitrates, perchlorates, sulfates and phosphates; methanesulfonic acid Salts, lower alkane sulfonates such as trifluoromethane sulfonate, ethane sulfonate, benzene sulfonate,
aryl sulfonates such as p-toluenesulfonate, acetate, malate, fumarate, succinate,
Organic acid salts such as citrate, ascorbate, tartrate, oxalate, and maleate; and amino acid salts such as glycine, lysine, arginine, ornithine, glutamate, and aspartate. be able to.

On the other hand, the salt based on an acidic group is preferably an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt; an alkaline earth metal salt such as a calcium salt or a magnesium salt; an aluminum salt; Metal salts such as salts; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N-methylglucamine salts, guanidine salts,
Diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt, piperazine salt, tetramethylammonium salt, tris (hydroxymethyl) amino Amine salts such as organic salts such as methane salts; and amino acid salts such as glycine salts, lysine salts, arginine salts, ornithine salts, glutamates, and aspartates.

The compound having the general formula (I) or (II) according to the present invention absorbs water by leaving it in the air or recrystallizing, thereby adsorbing water, adhering water or hydrate. And such hydrates are also included in the salts of the present invention.

The compound having the general formula (I) or (II) of the present invention may have various isomers due to the presence of an asymmetric carbon atom in the molecule. In the compounds of the present invention, these isomers and mixtures of these isomers may all be of a single formula, ie of the general formula (I) or (II)
Indicated by Accordingly, the present invention includes all these isomers and mixtures of these isomers in any proportion.

The term "ester" in the above description refers to the ester of the compound (I) or (II) of the present invention, since the compound can be converted to an ester. "Ester of a carboxy group" can be mentioned, and an ester in which each ester residue is "a general protecting group" or "a protecting group that can be cleaved in vivo by a biological method such as hydrolysis". .

"General protecting group" means a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis.

As the “general protecting group” for the “ester of hydroxyl group”, preferably, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, Methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl,
Tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl,
Alkanoyl groups such as 14-methylpentadecanoyl, 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl, henicosanoyl, chloroacetyl,
Halogenated alkylcarbonyl groups such as dichloroacetyl, trichloroacetyl, trifluoroacetyl, lower alkoxyalkylcarbonyl groups such as methoxyacetyl, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, (E) -2-methyl-2-butenoyl An "aliphatic acyl group" such as an unsaturated alkylcarbonyl group (preferably a lower aliphatic acyl group having 1 to 6 carbon atoms); benzoyl, α
Arylcarbonyl groups such as naphthoyl and β-naphthoyl, halogenated arylcarbonyl groups such as 2-bromobenzoyl and 4-chlorobenzoyl, 2,4,6
A lower alkylated arylcarbonyl group such as trimethylbenzoyl and 4-toluoyl, a lower alkoxylated arylcarbonyl group such as 4-anisoyl, and a nitrated aryl such as 4-nitrobenzoyl and 2-nitrobenzoyl. Arylcarbonyl group such as carbonyl group, 2- (methoxycarbonyl) benzoyl, and aryl group such as 4-phenylbenzoyl.
"Aromatic acyl groups" such as aryloxycarbonyl groups; lower alkoxycarbonyl groups such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl and isobutoxycarbonyl; An "alkoxycarbonyl group" such as a lower alkoxycarbonyl group substituted with a halogen or a tri-lower alkylsilyl group such as 2,2,2-trichloroethoxycarbonyl and 2-trimethylsilylethoxycarbonyl; tetrahydropyran-
2-yl, 3-bromotetrahydropyran-2-yl,
"Tetrahydropyranyl or tetrahydrothiopyranyl group" such as 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran-2-yl, tetrahydro A "tetrahydrofuranyl or tetrahydrothiofuranyl group" such as thiofuran-2-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl,
One or two aryl groups such as tri-lower alkylsilyl groups such as methyldiisopropylsilyl, methyldi-t-butylsilyl and triisopropylsilyl, and diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl. "Silyl group" such as substituted tri-lower alkylsilyl group; lower such as methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, t-butoxymethyl "A" such as alkoxymethyl group, lower alkoxylated lower alkoxymethyl group such as 2-methoxyethoxymethyl, halogeno lower alkoxymethyl group such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl; Kokishimechiru group "; 1-ethoxyethyl, 1- (isopropoxy) lower alkoxylated ethyl group such as ethyl," substituted ethyl group such as a halogenated ethyl group such as 2,2,2-trichloroethyl; "
Benzyl, α-naphthylmethyl, β-naphthylmethyl,
A lower alkyl group substituted with one to three aryl groups such as diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl,
Methylbenzyl, 2,4,6-trimethylbenzyl,
Lower alkyl such as 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl An "aralkyl group" such as a lower alkyl group substituted with one to three aryl groups having an aryl ring substituted with a lower alkoxy, nitro, halogen, or cyano group;
“Alkenyloxycarbonyl groups” such as vinyloxycarbonyl and allyloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,
And an "aralkyloxycarbonyl group" in which the aryl ring may be substituted with one or two lower alkoxy or nitro groups such as -nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl.

The “general protecting group” for the “ester of a carboxy group” is preferably the aforementioned “C ₁ -C ₆ alkyl group”; ethenyl, 1-propenyl, 2-propenyl, 1-methyl- 2-propenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-
2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1
-Methyl-1-butenyl, 3-methyl-2-butenyl,
1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl, 1-pentenyl, 2-pentenyl,
1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-3-pentenyl,
2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-4-pentenyl 1
-Hexenyl, 2-hexenyl, 3-hexenyl, 4-
Lower alkenyl groups such as hexenyl and 5-hexenyl; ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-ethyl-2
-Propynyl, 2-butynyl, 1-methyl-2-butynyl, 2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-
Methyl-3-butynyl, 1-ethyl-3-butynyl, 2
-Pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl, 1-methyl-3
-Pentynyl, 2-methyl-3-pentynyl, 4-pentynyl, 1-methyl-4-pentynyl, 2-methyl-4
-Pentynyl, 2-hexynyl, 3-hexynyl, 4-
Hexynyl, lower alkynyl groups such as 5-hexynyl; said "C ₁ -C ₆ haloalkyl group"; 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxy-butyl, 4-hydroxy Hydroxy "lower alkyl group" such as butyl; "lower aliphatic acyl" such as acetylmethyl- "lower alkyl group";"aralkylgroup";"silylgroup"
Can be mentioned.

The term “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” means that it is cleaved in a human body by a biological method such as hydrolysis to produce a free acid or a salt thereof. It refers to a protecting group, and whether such a derivative is administered by intravenous injection to experimental animals such as rats and mice,
Subsequent examination of the body fluids of the animals allows the determination of the ability to detect the original compound or a pharmacologically acceptable salt thereof, which can be determined by the "esters of hydroxyl groups" and such "biological methods such as hydrolysis in vivo." As the protecting group which can be cleaved by, preferably, formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxy Methyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovale Ryloxyethyl, 1-hexanoyloxyethyl,
1-formyloxypropyl, 1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexa Noyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1
1- such as butyryloxypentyl, 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl
("Lower aliphatic acyl" oxy) "lower alkyl",
Cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1
1-("cycloalkyl" carbonyloxy) "lower alkyl" such as -cyclopentylcarbonyloxybutyl, 1-cyclohexylcarbonyloxybutyl,
1- (acyloxy) "lower alkyl group" such as 1-("aromatic acyl" oxy) "lower alkyl group" such as benzoyloxymethyl; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, Propoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl, 1- (methoxycarbonyloxy) Ethyl, 1- (ethoxycarbonyloxy) ethyl, 1-
(Propoxycarbonyloxy) ethyl, 1- (isopropoxycarbonyloxy) ethyl, 1- (butoxycarbonyloxy) ethyl, 1- (isobutoxycarbonyloxy) ethyl, 1- (t-butoxycarbonyloxy) ethyl, 1- ( Pentyloxycarbonyloxy)
Ethyl, 1- (hexyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy)
Propyl, 1- (cyclohexyloxycarbonyloxy) propyl, 1- (cyclopentyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl , 1- (methoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) propyl, 1
-(Propoxycarbonyloxy) propyl, 1- (isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyloxy) propyl, 1- (isobutoxycarbonyloxy) propyl, 1- (pentyloxycarbonyloxy) propyl, 1- ( Hexyloxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) butyl, 1- (propoxycarbonyloxy) butyl, 1-
(Isopropoxycarbonyloxy) butyl, 1- (butoxycarbonyloxy) butyl, 1- (isobutoxycarbonyloxy) butyl, 1- (methoxycarbonyloxy) pentyl, 1- (ethoxycarbonyloxy)
(Lower alkoxycarbonyloxy) alkyl groups such as pentyl, 1- (methoxycarbonyloxy) hexyl, 1- (ethoxycarbonyloxy) hexyl;
(5-phenyl-2-oxo-1,3-dioxolene-
4-yl) methyl, [5- (4-methylphenyl) -2
-Oxo-1,3-dioxolen-4-yl] methyl,
[5- (4-methoxyphenyl) -2-oxo-1,3
-Dioxolen-4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3-dioxolene-
4-yl] methyl, [5- (4-chlorophenyl) -2
-Oxo-1,3-dioxolen-4-yl] methyl,
(2-oxo-1,3-dioxolen-4-yl) methyl, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-ethyl-2-oxo-1,
3-dioxolen-4-yl) methyl, (5-propyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-isopropyl-2-oxo-1,3-dioxolen-4-yl) "Carbonyloxyalkyl groups" such as methyl, oxodioxorenylmethyl groups such as (5-butyl-2-oxo-1,3-dioxolen-4-yl) methyl; phthalidyl, dimethylphthalidyl, dimethoxyphthalic; “Phthalidyl group” such as jill: the above “lower aliphatic acyl group”: the above “aromatic acyl group”: “half ester salt residue of succinic acid”: “phosphate ester residue”: “ester of amino acid or the like” "Residue forming": carbamoyl group: carbamoyl group substituted with one or two lower alkyl groups: and "1- It can be exemplified acyloxy) alkyloxycarbonyl group ", preferably a" carbonyloxy alkyl group ".

On the other hand, the “protecting group that can be cleaved in vivo by a biological method such as hydrolysis” as the “ester of a carboxy group” is preferably methoxyethyl,
1-ethoxyethyl, 1-methyl-1-methoxyethyl, 1- (isopropoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1-dimethyl-1-methoxyethyl, ethoxymethyl, n-propoxymethyl ,
Lower alkoxy lower alkyl groups such as isopropoxymethyl, n-butoxymethyl, t-butoxymethyl, 2
Lower alkoxylated lower alkoxy lower alkyl groups such as methoxyethoxymethyl, "aryl" oxy "lower alkyl groups" such as phenoxymethyl, 2,2,2
“Alkoxy lower alkyl groups” such as halogenated lower alkoxy lower alkyl groups such as trichloroethoxymethyl and bis (2-chloroethoxy) methyl; “lower alkoxy” carbonyl “lower alkyl groups” such as methoxycarbonylmethyl "Cyano" lower alkyl "such as cyanomethyl, 2-cyanoethyl;" lower alkyl "such as methylthiomethyl, ethylthiomethyl
"Thiomethyl group";"aryl" thiomethyl group such as phenylthiomethyl and naphthylthiomethyl; "lower alkyl optionally substituted with halogen" such as 2-methanesulfonylethyl and 2-trifluoromethanesulfonylethyl Sulfonyl "lower alkyl group"; 2
-"Aryl" sulfonyl "lower alkyl group" such as benzenesulfonylethyl and 2-toluenesulfonylethyl; the "1- (acyloxy)" lower alkyl group ";the" phthalidyl group ";the" aryl group ";
The "lower alkyl group"; the "carboxyalkyl group" such as carboxymethyl; and the "amide-forming residue of amino acid" such as phenylalanine.

The "other derivatives" include, when the compound (I) or (II) of the present invention has an amino group and / or a carboxy group, the above "pharmacologically acceptable salts" and the above "esters thereof". The derivative is shown because other derivatives can be used. Such derivatives include, for example, amide derivatives.

Specific examples of the compound having the general formula (I) or (II) of the present invention include, for example, the following Tables 1 to 3
However, the present invention is not limited to these compounds. Table 1
The compounds in Table 3 have the formulas (IIc), (IId),
It has the structural formula of (IIe).

In Tables 1 to 3, the substituents of R ¹ , R ² and A are as follows.

[0100]

Embedded image

[0101]

Embedded image

[0102]

Embedded image

[0103]

Embedded image

[0104]

Embedded image Abbreviations in the table are as follows. Bz: benzyl group Et: ethyl group cHx: cyclohexyl group Me: methyl group Ph: phenyl group. [Table 1]

[0105]

Embedded image Compd. R ¹ R ² R ³ R ⁴ ADEF No. Substituent No. Substituent No. Substituent No. 1-1 (38) (38) HH (1) -CH- -NH- -CH (Me)-1-2 (45) (109) HH (1) -CH- -NH- -CH (Me)- 1-3 (46) (109) HH (1) -CH- -NH- -CH (Me)-1-4 (52) (109) HH (1) -CH- -NH- -CH (Me)- 1-5 (64) (64) HH (1) -CH- -NH- -CH (Me)-1-6 (64) (109) HH (1) -CH- -NH- -CH (Me)- 1-7 (108) (109) HH (1) -CH- -NH- -CH (Me)-1-8 (109) (64) HH (1) -CH- -NH- -CH (Me)- 1-9 (109) (109) HH (1) -CH- -NH- -CH (Me)-1-10 (109) (109) HH (1) -CH- -O- -CH (Me)- 1-11 (109) (109) HH (1) -CH- -S- -CH (Me)-1-12 (109) (109) HH (1) -CH- -NHCO- -CH (Me)- 1-13 (109) (109) HH (2) -CH- -NH- -CH (Me)-1-14 (64) (64) HH (3) -CH- -NH- -CH (Me)- 1-15 (64) (109) HH (3) -CH- -NH- -CH (Me)-1-16 (109) (64) HH (3) -CH- -NH- -CH (Me)- 1-17 (109) (109) HH (3) -CH- -NH- -CH (Me)-1-18 (45) (109) HH (9) -CH- -NH- -CH (Me)- 1-19 (46) (109) HH (9) -CH- -NH- -CH (Me)-1-20 (52) (109) HH (9) -CH- -NH- -CH (Me)- 1-21 (64) (64) HH (9) -CH- -NH- -CH (Me)-1-22 (64) (109) HH (9) -CH- -NH- -CH (Me)- 1-23 (108) (109) HH (9) -CH- -NH- -CH (Me)-1-24 (109) (64) HH (9) -CH- -NH- -CH (Me )-1-25 (109) (109) HH (9) -CH- -NH- -CH (Me)-1-26 (38) (109) HH (10) -CH- -NH- -CH (Me )-1-27 (44) (109) HH (10) -CH- -NH- -CH (Me)-1-28 (45) (46) HH (10) -CH- -NH- -CH (Me )-1-29 (45) (64) HH (10) -CH- -NH- -CH (Me)-1-30 (45) (109) HH (10) -CH- -NH- -CH (Me )-1-31 (45) (64) HH (10) N -NH- -CH (Me)-1-32 (45) (109) HH (10) N -NH- -CH (Me)-1- 33 (46) (46) HH (10) -CH- -NH- -CH (Me)-1-34 (46) (64) HH (10) -CH- -NH- -CH (Me)-1- 35 (46) (109) HH (10) -CH- -NH- -CH (Me)-1-36 (46) (64) HH (10) N -NH- -CH (Me)-1-37 ( 46) (109) HH (10) N -NH- -CH (Me)-1-38 (48) (109) HH (10) -CH- -NH- -CH (Me)-1-39 (49) (64) HH (10) -CH- -NH- -CH (Me)-1-40 (49) (109) HH (10) -CH- -NH- -CH (Me)-1-41 (50) (109) HH (10) -CH- -NH- -CH (Me)-1-42 (51) (64) HH (10) -CH- -NH- -CH (Me)-1-43 (51) (109) HH (10) -CH- -NH- -CH (Me)-1-44 (52) (46) HH (10) -CH- -NH- -CH (Me)-1-45 (52) (64) HH (10) -CH- -NH- -CH (Me)-1-46 (52) (109) HH (10) -CH- -NH- -CH (Me)-1-47 (52) (64) HH (10) N -NH- -CH (Me)-1-48 (52) (109) HH (10) N -NH- -CH (Me)-1-49 (53) (109) HH (10) -CH- -NH- -CH (Me) -1-50 (55) (64) HH (10) -CH- -NH- -CH (Me)-1-51 (55) (109) HH (10) -CH- -NH- -CH (Me)-1-52 (59) (109) HH (10) -CH- -NH- -CH (Me)-1-53 (62) (109) HH (10) -CH- -NH- -CH (Me)-1-54 (63) (64) HH (10) -CH- -NH- -CH (Me)-1-55 (63) (109) HH (10) -CH- -NH- -CH (Me)-1-56 (64) (46) HH (10) -CH- -NH- -CH (Me)-1-57 (64) (64) HH (10) -CH- -NH- -CH (Me)-1-58 (64) (109) HH (10) -CH- -NH- -CH (Me)-1-59 (64) (64) HH (10) N -NH- -CH (Me)-1-60 (64) (109) HH (10) N -NH- -CH (Me)- 1-61 (66) (109) HH (10) -CH- -NH- -CH (Me)-1-62 (68) (64) HH (10) -CH- -NH- -CH (Me)- 1-63 (68) (109) HH (10) -CH- -NH- -CH (Me)-1-64 (70) (64) HH (10) -CH- -NH- -CH (Me)- 1-65 (70) (109) HH (10) -CH- -NH- -CH (Me)-1-66 (86) (64) HH (10) -CH- -NH- -CH (Me)- 1-67 (86) (109) HH (10) -CH- -NH- -CH (Me)-1-68 (101) (109) HH (10) -CH- -NH- -CH (Me)- 1-69 (102) (109) HH (10) -CH- -NH- -CH (Me)-1-70 (103) (64) HH (10) -CH- -NH- -CH (Me)- 1-71 (103) (109) HH (10) -CH- -NH- -CH (Me)-1-72 (106) (109) HH (10) -CH- -NH- -CH (Me)-1-73 (108) (46) HH (10) -CH- -NH- -CH (Me)-1-74 (108) (64) HH (10) -CH- -NH- -CH (Me)-1-75 (108) (109) HH (10) -CH- -NH- -CH (Me)-1-76 (108) (64) HH (10) N -NH- -CH (Me) -1 -77 (108) (109) HH (10) N -NH- -CH (Me) -1 -78 (109) (46) HH (10) -CH- -NH- -CH (Me)-1-79 (109) (64) HH (10) -CH- -NH- -CH (Me)-1-80 (109) (109) HH (10) -CH- -NH- -CH (Me)-1-81 (109) (64) HH (10) N -NH- -CH (Me)-1-82 (109) (109) HH (10) N- NH- -CH (Me)-1-83 (109) (109) HH (12) -CH- -NH- -CH (Me)-1-84 (64) (64) HH (13) -CH-- NH- -CH (Me)-1-85 (64) (109) HH (13) -CH- -NH- -CH (Me)-1-86 (109) (64) HH (13) -CH-- NH- -CH (Me)-1-87 (109) (109) HH (13) -CH- -NH- -CH (Me)-1-88 (45) (109) HH (15) -CH-- NH- -CH (Me)-1-89 (46) (109) HH (15) -CH- -NH- -CH (Me)-1-90 (52) (109) HH (15) -CH-- NH- -CH (Me)-1-91 (64) (64) HH (15) -CH- -NH- -CH (Me)-1-92 (64) (109) HH (15) -CH-- NH- -CH (Me)-1-93 (108) (109) HH (15) -CH- -NH- -CH (Me)-1-94 (109) (64) HH (15) -CH-- NH- -CH (Me)-1-95 (109) (109) HH (15) -CH- -NH --CH (Me)-1-96 (38) (109) HH (16) -CH- -NH- -CH (Me)-1-97 (44) (109) HH (16) -CH- -NH --CH (Me)-1-98 (45) (46) HH (16) -CH- -NH- -CH (Me)-1-99 (45) (64) HH (16) -CH- -NH --CH (Me)-1-100 (45) (109) HH (16) -CH- -NH- -CH (Me)-1-101 (45) (64) HH (16) N -NH-- CH (Me)-1-102 (45) (109) HH (16) N -NH- -CH (Me)-1-103 (46) (46) HH (16) -CH- -NH- -CH ( (Me)-1-104 (46) (64) HH (16) -CH- -NH- -CH (Me)-1-105 (46) (109) HH (16) -CH- -NH- -CH ( Me)-1-106 (46) (64) HH (16) N -NH- -CH (Me)-1-107 (46) (109) HH (16) N -NH- -CH (Me) -1 -108 (48) (109) HH (16) -CH- -NH- -CH (Me)-1-109 (49) (64) HH (16) -CH- -NH- -CH (Me) -1 -110 (49) (109) HH (16) -CH- -NH- -CH (Me)-1-111 (50) (109) HH (16) -CH- -NH- -CH (Me) -1 -112 (51) (64) HH (16) -CH- -NH- -CH (Me)-1-113 (51) (109) HH (16) -CH- -NH- -CH (Me) -1 -114 (52) (46) HH (16) -CH- -NH- -CH (Me)-1-115 (52) (64) HH (16) -CH- -NH- -CH (Me) -1 -116 (52) (109) HH (16) -CH- -NH- -CH (Me)-1-117 (52) (64) HH (16) N -NH- -CH (Me)-1-118 (52) (109) HH (16) N -NH- -CH (Me)-1-119 (53) (109) HH (16) -CH- -NH- -CH (Me)-1-120 (55) (64) HH (16) -CH- -NH- -CH (Me)-1-121 (55) (109) HH (16) -CH- -NH- -CH (Me)-1-122 (59) (109) HH (16) -CH- -NH- -CH (Me)-1-123 (62) (109) HH (16) -CH- -NH- -CH (Me)-1-124 (63) (64) HH (16) -CH- -NH- -CH (Me)-1-125 (63) (109) HH (16) -CH- -NH- -CH (Me)-1-126 (64) (46) HH (16) -CH- -NH- -CH (Me)-1-127 (64) (64) HH (16) -CH- -NH- -CH (Me)-1-128 (64) (109) HH (16) -CH- -NH- -CH (Me)-1-129 (64) (64) HH (16) N -NH- -CH (Me)-1-130 (64) (109) HH (16) N -NH- -CH (Me)-1-131 (66) (109) HH (16) -CH- -NH- -CH (Me)-1-132 (68) (64) HH (16) -CH- -NH- -CH (Me)-1-133 (68) (109) HH (16) -CH- -NH- -CH (Me)-1-134 (70) (64) HH (16) -CH- -NH- -CH (Me)-1-135 (70) (109) HH (16) -CH- -NH- -CH (Me)-1-136 (86) (64) HH (16) -CH- -NH- -CH (Me)-1-137 (86) (109) HH (16) -CH- -NH- -CH (Me)-1-138 (101) (109) HH (16) -CH- -NH- -CH (Me)-1-139 (102) (109) HH (16) -CH- -NH- -CH (Me)-1-140 (103) (64) HH (16) -CH- -NH- -CH (Me)-1-141 (103) (109) HH (16) -CH- -NH- -CH (Me)-1-142 (10 6) (109) HH (16) -CH- -NH- -CH (Me)-1-143 (108) (46) HH (16) -CH- -NH- -CH (Me)-1-144 ( 108) (64) HH (16) -CH- -NH- -CH (Me)-1-145 (108) (109) HH (16) -CH- -NH- -CH (Me)-1-146 ( 108) (64) HH (16) N -NH- -CH (Me)-1-147 (108) (109) HH (16) N -NH- -CH (Me)-1-148 (109) (46 ) HH (16) -CH- -NH- -CH (Me)-1-149 (109) (64) HH (16) -CH- -NH- -CH (Me)-1-150 (109) (109) ) HH (16) -CH- -NH- -CH (Me)-1-151 (109) (64) HH (16) N -NH- -CH (Me)-1-152 (109) (109) HH (16) N -NH- -CH (Me)-1-153 (45) (109) HH (19) -CH- -NH- -CH (Me)-1-154 (46) (109) HH (19 ) -CH- -NH- -CH (Me)-1-155 (52) (109) HH (19) -CH- -NH- -CH (Me)-1-156 (64) (64) HH (19 ) -CH- -NH- -CH (Me)-1-157 (64) (109) HH (19) -CH- -NH- -CH (Me)-1-158 (108) (109) HH (19 ) -CH- -NH- -CH (Me)-1-159 (109) (64) HH (19) -CH- -NH- -CH (Me)-1-160 (109) (109) HH (19 ) -CH- -NH- -CH (Me)-1-161 (45) (109) HH (24) -CH- -NH- -CH (Me)-1-162 (46) (109) HH (24 ) -CH- -NH- -CH (Me)-1-163 (52) (109) HH (24) -CH- -NH- -CH (Me)-1-164 (64) (64) HH (24 ) -CH- -NH- -CH (Me)-1-16 5 (64) (109) HH (24) -CH- -NH- -CH (Me)-1-166 (108) (109) HH (24) -CH- -NH- -CH (Me) -1- 167 (109) (64) HH (24) -CH- -NH- -CH (Me)-1-168 (109) (109) HH (24) -CH- -NH- -CH (Me)-1- 169 (45) (109) HH (26) -CH- -NH- -CH (Me)-1-170 (46) (109) HH (26) -CH- -NH- -CH (Me)-1- 171 (52) (109) HH (26) -CH- -NH- -CH (Me)-1-172 (64) (64) HH (26) -CH- -NH- -CH (Me) -1- 173 (64) (109) HH (26) -CH- -NH- -CH (Me)-1-174 (108) (109) HH (26) -CH- -NH- -CH (Me)-1- 175 (109) (64) HH (26) -CH- -NH- -CH (Me)-1-176 (109) (109) HH (26) -CH- -NH- -CH (Me)-1- 177 (109) (109) HH (28) -CH- -NH- -CH (Me)-1-178 (109) (109) HH (31) -CH- -NH- -CH (Me) -1- 179 (109) (109) HH (32) -CH- -NH- -CH (Me)- . [Table 2]

[0106]

Embedded image  Compd. R¹ R^Two R^Three R^Four A D E F No. Substituent No. Substituent No. Substituent No.  2-1 (38) (38) HH (1) -CH- -NH- -CH (Me)-2-2 (38) (109) HH (1) -CH- -NH- -CH (Me)- 2-3 (44) (109) HH (1) -CH- -NH- -CH (Me)-2-4 (45) (46) HH (1) -CH- -NH- -CH (Me)- 2-5 (45) (64) HH (1) -CH- -NH- -CH (Me)-2-6 (45) (109) HH (1) -CH- -NH- -CH (Me)- 2-7 (45) (64) HH (1) N -NH- -CH (Me)-2-8 (45) (109) HH (1) N -NH- -CH (Me)-2-9 ( 46) (46) HH (1) -CH- -NH- -CH (Me)-2-10 (46) (64) HH (1) -CH- -NH- -CH (Me)-2-11 ( 46) (109) HH (1) -CH- -NH- -CH (Me)-2-12 (46) (64) HH (1) N -NH- -CH (Me)-2-13 (46) (109) HH (1) N -NH- -CH (Me)-2-14 (48) (109) HH (1) -CH- -NH- -CH (Me)-2-15 (49) (64 ) HH (1) -CH- -NH- -CH (Me)-2-16 (49) (109) HH (1) -CH- -NH- -CH (Me)-2-17 (50) (109) ) HH (1) -CH- -NH- -CH (Me)-2-18 (51) (64) HH (1) -CH- -NH- -CH (Me)-2-19 (51) (109) ) HH (1) -CH- -NH- -CH (Me)-2-20 (52) (46) HH (1) -CH- -NH- -CH (Me)-2-21 (52) (64 ) HH (1) -CH- -NH- -CH (Me)-2-22 (52) (109) HH (1) -CH- -NH- -CH (Me)-2-23 (52) (64 ) HH (1) N -NH- -CH (Me)-2-24 (52) (109) HH (1) N -NH- -CH (Me)-2-25 (5 3) (109) HH (1) -CH- -NH- -CH (Me)-2-26 (55) (64) HH (1) -CH- -NH- -CH (Me)-2-27 ( 55) (109) HH (1) -CH- -NH- -CH (Me)-2-28 (59) (109) HH (1) -CH- -NH- -CH (Me)-2-29 ( 62) (109) HH (1) -CH- -NH- -CH (Me)-2-30 (63) (64) HH (1) -CH- -NH- -CH (Me)-2-31 ( 63) (109) HH (1) -CH- -NH- -CH (Me)-2-32 (64) (46) HH (1) -CH- -NH- -CH (Me)-2-33 ( 64) (64) HH (1) -CH- -NH- -CH (Me)-2-34 (64) (109) HH (1) -CH- -NH- -CH (Me)-2-35 ( 64) (64) HH (1) N -NH- -CH (Me)-2-36 (64) (109) HH (1) N -NH- -CH (Me)-2-37 (66) (109 ) HH (1) -CH- -NH- -CH (Me)-2-38 (68) (64) HH (1) -CH- -NH- -CH (Me)-2-39 (68) (109 ) HH (1) -CH- -NH- -CH (Me)-2-40 (70) (64) HH (1) -CH- -NH- -CH (Me)-2-41 (70) (109 ) HH (1) -CH- -NH- -CH (Me)-2-42 (86) (64) HH (1) -CH- -NH- -CH (Me)-2-43 (86) (109 ) HH (1) -CH- -NH- -CH (Me)-2-44 (101) (109) HH (1) -CH- -NH- -CH (Me)-2-45 (102) (109) ) HH (1) -CH- -NH- -CH (Me)-2-46 (103) (64) HH (1) -CH- -NH- -CH (Me)-2-47 (103) (109) ) HH (1) -CH- -NH- -CH (Me)-2-48 (106) (109) HH (1) -CH- -NH- -CH (Me)-2-49 (108) (46) HH (1) -CH- -NH- -CH (Me)-2-50 (108) (64) HH (1) -CH- -NH- -CH (Me)-2-51 (108) (109) HH (1) -CH- -NH- -CH (Me)-2-52 (108) (64) HH (1) N -NH --CH (Me)-2-53 (108) (109) HH (1) N -NH- -CH (Me)-2-54 (109) (38) HH (1) -CH- -NH-- CH (Me)-2-55 (109) (46) HH (1) -CH- -NH- -CH (Me)-2-56 (109) (64) HH (1) -CH- -NH-- CH (Me)-2-57 (109) (109) HH (1) -CH- -NH- -CH (Me)-2-58 (109) (109) HH (1) -CH- -O-- CH (Me)-2-59 (109) (109) HH (1) -CH- -S- -CH (Me)-2-60 (109) (109) HH (1) -CH- -NHCO-- CH (Me)-2-61 (109) (64) HH (1) N -NH- -CH (Me)-2-62 (109) (109) HH (1) N -NH- -CH (Me) -2-63 (45) (109) HH (2) -CH- -NH- -CH (Me)-2-64 (46) (109) HH (2) -CH- -NH- -CH (Me) -2-65 (52) (109) HH (2) -CH- -NH- -CH (Me)-2-66 (64) (64) HH (2) -CH- -NH- -CH (Me) -2-67 (64) (109) HH (2) -CH- -NH- -CH (Me)-2-68 (108) (109) HH (2) -CH- -NH- -CH (Me) -2-69 (109) (64) HH (2) -CH- -NH- -CH (Me)-2-70 (109) (109) HH (2) -CH- -NH- -CH (Me) -2-71 (45) (64) HH (3) -CH- -NH- -CH (Me)-2 -72 (45) (109) HH (3) -CH- -NH- -CH (Me)-2-73 (46) (64) HH (3) -CH- -NH- -CH (Me)-2 -74 (46) (109) HH (3) -CH- -NH- -CH (Me)-2-75 (49) (109) HH (3) -CH- -NH- -CH (Me)-2 -76 (51) (109) HH (3) -CH- -NH- -CH (Me)-2-77 (52) (64) HH (3) -CH- -NH- -CH (Me)-2 -78 (52) (109) HH (3) -CH- -NH- -CH (Me)-2-79 (55) (109) HH (3) -CH- -NH- -CH (Me)-2 -80 (63) (109) HH (3) -CH- -NH- -CH (Me)-2-81 (64) (64) HH (3) -CH- -NH- -CH (Me)-2 -82 (64) (109) HH (3) -CH- -NH- -CH (Me)-2-83 (68) (109) HH (3) -CH- -NH- -CH (Me)-2 -84 (70) (109) HH (3) -CH- -NH- -CH (Me)-2-85 (86) (109) HH (3) -CH- -NH- -CH (Me)-2 -86 (103) (109) HH (3) -CH- -NH- -CH (Me)-2-87 (108) (64) HH (3) -CH- -NH- -CH (Me)-2 -88 (108) (109) HH (3) -CH- -NH- -CH (Me)-2-89 (109) (64) HH (3) -CH- -NH- -CH (Me)-2 -90 (109) (109) HH (3) -CH- -NH- -CH (Me)-2-91 (109) (109) HH (3) -CH- -O- -CH (Me)-2 -92 (109) (109) HH (3) -CH- -S- -CH (Me)-2-93 (109) (109) HH (3) -CH- -NHCO- -CH (Me)-2 -94 (64) (64) HH (4) -CH- -NH- -CH (Me)-2-95 (64) (109) HH (4) -CH- -NH- -CH (Me)-2-96 (109) (64) HH (4) -CH- -NH- -CH (Me)-2-97 (109) (109) HH (4) -CH- -NH- -CH (Me)-2-98 (64) (64) HH (5) -CH- -NH- -CH (Me)-2-99 (64) (109) HH (5) -CH- -NH- -CH (Me)-2-100 (109) (64) HH (5) -CH- -NH- -CH (Me)-2-101 (109) (109) HH (5) -CH- -NH- -CH (Me)-2-102 (64) (64) HH (6) -CH- -NH- -CH (Me)-2-103 (64) (109) HH (6) -CH- -NH- -CH (Me)-2-104 (109) (64) HH (6) -CH- -NH- -CH (Me)-2-105 (109) (109) HH (6) -CH- -NH- -CH (Me)-2-106 (64) (64) HH (7) -CH- -NH- -CH (Me)-2-107 (64) (109) HH (7) -CH- -NH- -CH (Me)-2-108 (109) (64) HH (7) -CH- -NH- -CH (Me)-2-109 (109) (109) HH (7) -CH- -NH- -CH (Me)-2-110 (64) (64) HH (8) -CH- -NH- -CH (Me)-2-111 (64) (109) HH (8) -CH- -NH- -CH (Me)-2-112 (109) (64) HH (8) -CH- -NH- -CH (Me)-2-113 (109) (109) HH (8) -CH- -NH- -CH (Me)-2-114 (38) (109) HH (9) -CH- -NH- -CH (Me)-2-115 (44) (109) HH (9) -CH- -NH- -CH (Me)-2-116 (45) (46) HH (9) -CH- -NH- -CH (Me)-2-117 (45) (64) HH (9) -CH- -NH- -CH (Me)-2-11 8 (45) (109) HH (9) -CH- -NH- -CH (Me)-2-119 (45) (64) HH (9) N -NH- -CH (Me)-2-120 ( 45) (109) HH (9) N -NH- -CH (Me)-2-121 (46) (46) HH (9) -CH- -NH- -CH (Me)-2-122 (46) (64) HH (9) -CH- -NH- -CH (Me)-2-123 (46) (109) HH (9) -CH- -NH- -CH (Me)-2-124 (46) (64) HH (9) N -NH- -CH (Me)-2-125 (46) (109) HH (9) N -NH- -CH (Me)-2-126 (48) (109) HH (9) -CH- -NH- -CH (Me)-2-127 (49) (64) HH (9) -CH- -NH- -CH (Me)-2-128 (49) (109) HH (9) -CH- -NH- -CH (Me)-2-129 (50) (109) HH (9) -CH- -NH- -CH (Me)-2-130 (51) (64) HH (9) -CH- -NH- -CH (Me)-2-131 (51) (109) HH (9) -CH- -NH- -CH (Me)-2-132 (52) (46) HH (9) -CH- -NH- -CH (Me)-2-133 (52) (64) HH (9) -CH- -NH- -CH (Me)-2-134 (52) (109) HH (9) -CH- -NH- -CH (Me)-2-135 (52) (64) HH (9) N -NH- -CH (Me)-2-136 (52) (109) HH (9 ) N -NH- -CH (Me)-2-137 (53) (109) HH (9) -CH- -NH- -CH (Me)-2-138 (55) (64) HH (9)- CH- -NH- -CH (Me)-2-139 (55) (109) HH (9) -CH- -NH- -CH (Me)-2-140 (59) (109) HH (9)- CH- -NH- -CH (Me)-2-141 (62) (109) HH (9) -CH- -NH- -CH (Me)-2-142 (63) (64) HH (9) -CH- -NH- -CH (Me)-2-143 (63) (109) HH (9) -CH- -NH- -CH (Me)-2-144 (64) (46) HH (9) -CH- -NH- -CH (Me)-2-145 (64) (64) HH (9) -CH- -NH- -CH (Me)-2-146 (64) (109) HH (9) -CH- -NH- -CH (Me)-2-147 (64) (64) HH (9) N -NH- -CH (Me)-2-148 (64) (109) HH (9) N -NH- -CH (Me)-2-149 (66) (109) HH (9)- CH- -NH- -CH (Me)-2-150 (68) (64) HH (9) -CH- -NH- -CH (Me)-2-151 (68) (109) HH (9)- CH- -NH- -CH (Me)-2-152 (70) (64) HH (9) -CH- -NH- -CH (Me)-2-153 (70) (109) HH (9)- CH- -NH- -CH (Me)-2-154 (86) (64) HH (9) -CH- -NH- -CH (Me)-2-155 (86) (109) HH (9)- CH- -NH- -CH (Me)-2-156 (101) (109) HH (9) -CH- -NH- -CH (Me)-2-157 (102) (109) HH (9)- CH- -NH- -CH (Me)-2-158 (103) (64) HH (9) -CH- -NH- -CH (Me)-2-159 (103) (109) HH (9)- CH- -NH- -CH (Me)-2-160 (106) (109) HH (9) -CH- -NH- -CH (Me)-2-161 (107) (46) HH (9)- CH- -NH- -CH (Me)-2-162 (108) (64) HH (9) -CH- -NH- -CH (Me)-2-163 (108) (109) HH (9)- CH- -NH- -CH (Me)-2-164 (108) (64) HH (9) N -NH- -CH (Me)-2-165 (108) (109) HH (9) N -NH- -CH (Me)-2-166 (109) (46) HH (9) -CH- -NH- -CH (Me)-2-167 (109) (64) HH (9) -CH- -NH- -CH (Me)-2-168 (109) (109) HH (9) -CH- -NH- -CH (Me)-2-169 (109) (64) HH (9) N -NH- -CH (Me)-2-170 (109) (109) HH (9) N- NH- -CH (Me)-2-171 (35) (108) HH (10) -CH- -NH- single bond 2-172 (35) (109) HH (10) -CH- -NH- single bond 2-173 (36) (108) HH (10) -CH- -NH- single bond 2-174 (36) (109) HH (10) -CH- -NH- single bond 2-175 (36) (108 ) HH (10) N -NH- single bond 2-176 (36) (109) HH (10) N -NH- single bond 2-177 (37) (108) HH (10) -CH- -NH-- CH (Me)-2-178 (37) (109) HH (10) -CH- -NH- -CH (Me)-2-179 (38) (38) HH (10) -CH- -NH-- CH (Me)-2-180 (38) (46) HH (10) -CH- -NH- -CH (Me)-2-181 (38) (64) HH (10) -CH- -NH-- CH (Me)-2-182 (38) (108) HH (10) -CH- -NH- -CH (Me)-2-183 (38) (109) HH (10) -CH- -NH-- CH (Me)-2-184 (38) (64) HH (10) N -NH- -CH (Me)-2-185 (38) (108) HH (10) N -NH- -CH (Me) -2-186 (38) (109) HH (10) N -NH- -CH (Me) -2-187 (39) (108) HH (10) -CH- -NH- -CH (Me)-2-188 (39) (109) HH (10) -CH- -NH- -CH (Me) -2-189 (40) (108) HH (10) -CH- -NH- -CH (Me)-2-190 (40) (109) HH (10) -CH- -NH- -CH (Me) -2-191 (41) (108) HH (10) -CH- -NH- -CH (Me)-2-192 (41) (109) HH (10) -CH- -NH- -CH (Me) -2-193 (42) (108) HH (10) -CH- -NH- -CH (Me)-2-194 (42) (109) HH (10) -CH- -NH- -CH (Me) -2-195 (43) (108) HH (10) -CH- -NH- -CH (Me)-2-196 (43) (109) HH (10) -CH- -NH- -CH (Me) -2-197 (44) (46) HH (10) -CH- -NH- -CH (Me)-2-198 (44) (64) HH (10) -CH- -NH- -CH (Me) -2-199 (44) (108) HH (10) -CH- -NH- -CH (Me)-2-200 (44) (109) HH (10) -CH- -NH- -CH (Me) -2-201 (44) (64) HH (10) N -NH- -CH (Me)-2-202 (44) (108) HH (10) N -NH- -CH (Me)-2-203 (44) (109) HH (10) N -NH- -CH (Me)-2-204 (45) (37) HH (10) -CH- -NH- -CH (Me)-2-205 (45 ) (38) HH (10) -CH- -NH- -CH (Me)-2-206 (45) (44) HH (10) -CH- -NH- -CH (Me)-2-207 (45 ) (45) HH (10) -CH- -NH- -CH_Two-2-208 (45) (45) HH (10) -CH- -NH- -CH (Me)-2-209 (45) (45) HH (10) -CH- -O- -CH (Me) -2-210 (45) (45) HH (10) -CH- -S- -CH (Me)-2-211 (45) (45) HH (10) -CH- -NHCO- -CH (Me) -2-212 (45) (45) 4-FH (10) -CH- -NH- -CH (Me)-2-213 (45) (45) 4-MeO H (10) -CH- -NH- -CH (Me)-2-214 (45) (45) HH (10) N -NH- -CH (Me)-2-215 (45) (46) HH (10) -CH- -NH- single bond 2-216 (45) (46) HH (10) -CH- -NH- -CH_Two-2-217 (45) (46) HH (10) -CH- -NH- -CH (Me)-2-218 (45) (46) HH (10) -CH- -NH- -CH (Et) -2-219 (45) (46) HH (10) -CH- -O- -CH (Me)-2-220 (45) (46) HH (10) -CH- -S- -CH (Me) -2-221 (45) (46) HH (10) -CH- -NHCO- -CH (Me)-2-222 (45) (46) 4-FH (10) -CH- -NH- -CH ( Me)-2-223 (45) (46) 5-FH (10) -CH- -NH- -CH (Me)-2-224 (45) (46) 4-Cl H (10) -CH-- NH- -CH (Me)-2-225 (45) (46) 4-MeO H (10) -CH- -NH- -CH (Me)-2-226 (45) (46) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-227 (45) (46) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-228 (45) (46) HH (10) N -NH- -CH (Me)-2-229 (45) (46) HH (10) N -O- -CH (Me)-2-230 (45) (46) HH (10) N -S- -CH (Me)-2-231 (45) (46) HH (10) N -NHCO- -CH (Me)-2-232 (45) (47) HH (10)- CH- -NH- -CH (Me)-2-233 (45) (48) HH (10) -CH- -NH- -CH (Me)-2-234 (45) (49) HH (10)- CH- -NH- -CH_Two-2-235 (45) (49) HH (10) -CH- -NH- -CH (Me)-2-236 (45) (49) HH (10) -CH- -O- -CH (Me) -2-237 (45) (49) HH (10) -CH- -S- -CH (Me)-2-238 (45) (49) HH (10) -CH- -NHCO- -CH (Me) -2-239 (45) (49) 4-FH (10) -CH- -NH- -CH (Me)-2-240 (45) (49) 4-MeO H (10) -CH- -NH- -CH (Me)-2-241 (45) (49) HH (10) N -NH- -CH (Me)-2-242 (45) (50) HH (10) -CH- -NH- -CH (Me)-2-243 (45) (51) HH (10) -CH- -NH- -CH_Two-2-244 (45) (51) HH (10) -CH- -NH- -CH (Me)-2-245 (45) (51) HH (10) -CH- -O- -CH (Me) -2-246 (45) (51) HH (10) -CH- -S- -CH (Me)-2-247 (45) (51) HH (10) -CH- -NHCO- -CH (Me) -2-248 (45) (51) 4-FH (10) -CH- -NH- -CH (Me)-2-249 (45) (51) 4-MeO H (10) -CH- -NH- -CH (Me)-2-250 (45) (51) HH (10) N -NH- -CH (Me)-2-251 (45) (58) HH (10) -CH- -NH- -CH (Me)-2-252 (45) (59) HH (10) -CH- -NH- -CH (Me)-2-253 (45) (60) HH (10) -CH- -NH- -CH (Me)-2-254 (45) (62) HH (10) -CH- -NH- -CH (Me)-2-255 (45) (63) HH (10) -CH- -NH- -CH_Two-2-256 (45) (63) HH (10) -CH- -NH- -CH (Me)-2-257 (45) (63) HH (10) -CH- -O- -CH (Me) -2-258 (45) (63) HH (10) -CH- -S- -CH (Me)-2-259 (45) (63) HH (10) -CH- -NHCO- -CH (Me) -2-260 (45) (63) 4-FH (10) -CH- -NH- -CH (Me)-2-261 (45) (63) 4-MeO H (10) -CH- -NH- -CH (Me)-2-262 (45) (63) HH (10) N -NH- -CH (Me)-2-263 (45) (64) HH (10) -CH- -NH- single bond 2-264 (45) (64) HH (10) -CH- -NH- -CH_Two-2-265 (45) (64) HH (10) -CH- -NH- -CH (Me)-2-266 (45) (64) HH (10) -CH- -NH- -CH (Et) -2-267 (45) (64) HH (10) -CH- -O- -CH (Me)-2-268 (45) (64) HH (10) -CH- -S- -CH (Me) -2-269 (45) (64) HH (10) -CH- -NHCO- -CH (Me)-2-270 (45) (64) 4-FH (10) -CH- -NH- -CH ( Me)-2-271 (45) (64) 5-FH (10) -CH- -NH- -CH (Me)-2-272 (45) (64) 4-Cl H (10) -CH-- NH- -CH (Me)-2-273 (45) (64) 4-MeO H (10) -CH- -NH- -CH (Me)-2-274 (45) (64) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-275 (45) (64) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-276 (45) (64) HH (10) N -NH- -CH (Me)-2-277 (45) (64) HH (10) N -O- -CH (Me)-2-278 (45) (64) HH (10) N -S- -CH (Me)-2-279 (45) (64) HH (10) N -NHCO- -CH (Me)-2-280 (45) (65) HH (10)- CH- -NH- -CH (Me)-2-281 (45) (66) HH (10) -CH- -NH- -CH_Two-2-282 (45) (66) HH (10) -CH- -NH- -CH (Me)-2-283 (45) (66) HH (10) -CH- -O- -CH (Me) -2-284 (45) (66) HH (10) -CH- -S- -CH (Me)-2-285 (45) (66) HH (10) -CH- -NHCO- -CH (Me) -2-286 (45) (66) 4-FH (10) -CH- -NH- -CH (Me)-2-287 (45) (66) 4-MeO H (10) -CH- -NH- -CH (Me)-2-288 (45) (66) HH (10) N -NH- -CH (Me)-2-289 (45) (67) HH (10) -CH- -NH- -CH (Me)-2-290 (45) (68) HH (10) -CH- -NH- -CH_Two-2-291 (45) (68) HH (10) -CH- -NH- -CH (Me)-2-292 (45) (68) HH (10) -CH- -O- -CH (Me) -2-293 (45) (68) HH (10) -CH- -S- -CH (Me)-2-294 (45) (68) HH (10) -CH- -NHCO- -CH (Me) -2-295 (45) (68) 4-FH (10) -CH- -NH- -CH (Me)-2-296 (45) (68) 4-MeO H (10) -CH- -NH- -CH (Me)-2-297 (45) (68) HH (10) N -NH- -CH (Me)-2-298 (45) (69) HH (10) -CH- -NH- -CH (Me)-2-299 (45) (72) HH (10) -CH- -NH- -CH (Me)-2-300 (45) (73) HH (10) -CH- -NH- -CH (Me)-2-301 (45) (74) HH (10) -CH- -NH- -CH (Me)-2-302 (45) (75) HH (10) -CH- -NH- -CH (Me)-2-303 (45) (76) HH (10) -CH- -NH- -CH (Me)-2-304 (45) (77) HH (10) -CH- -NH- -CH (Me)-2-305 (45) (101) HH (10) -CH- -NH- -CH (Me)-2-306 (45) (102) HH (10) -CH- -NH- -CH (Me)-2-307 (45) (103) HH (10) -CH- -NH- -CH_Two-2-308 (45) (103) HH (10) -CH- -NH- -CH (Me)-2-309 (45) (103) HH (10) -CH- -O- -CH (Me) -2-310 (45) (103) HH (10) -CH- -S- -CH (Me)-2-311 (45) (103) HH (10) -CH- -NHCO- -CH (Me) -2-312 (45) (103) 4-FH (10) -CH- -NH- -CH (Me)-2-313 (45) (103) 4-MeO H (10) -CH- -NH- -CH (Me)-2-314 (45) (103) HH (10) N -NH- -CH (Me)-2-315 (45) (104) HH (10) -CH- -NH- -CH (Me)-2-316 (45) (105) HH (10) -CH- -NH- -CH (Me)-2-317 (45) (106) HH (10) -CH- -NH- -CH (Me)-2-318 (45) (108) HH (10) -CH- -NH- single bond 2-319 (45) (108) HH (10) -CH- -NH- -CH_Two-2-320 (45) (108) HH (10) -CH- -NH- -CH (Me)-2-321 (45) (108) HH (10) -CH- -NH- -CH (Et) -2-322 (45) (108) HH (10) -CH- -O- -CH (Me)-2-323 (45) (108) HH (10) -CH- -S- -CH (Me) -2-324 (45) (108) HH (10) -CH- -NHCO- -CH (Me)-2-325 (45) (108) 4-FH (10) -CH- -NH- -CH ( Me)-2-326 (45) (108) 5-FH (10) -CH- -NH- -CH (Me)-2-327 (45) (108) 4-Cl H (10) -CH-- NH- -CH (Me)-2-328 (45) (108) 4-MeO H (10) -CH- -NH- -CH (Me)-2-329 (45) (108) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-330 (45) (108) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-331 (45) (108) HH (10) N -NH- -CH (Me)-2-332 (45) (108) HH (10) N -O- -CH (Me)-2-333 (45) (108) HH (10) N -S- -CH (Me)-2-334 (45) (108) HH (10) N -NHCO- -CH (Me)-2-335 (45) (109) HH (10)- CH- -NH- single bond 2-336 (45) (109) HH (10) -CH- -NH- -CH_Two-2-337 (45) (109) HH (10) -CH- -NH- -CH (Me)-2-338 (45) (109) HH (10) -CH- -NH- -CH (Et) -2-339 (45) (109) HH (10) -CH- -O- -CH (Me)-2-340 (45) (109) HH (10) -CH- -S- -CH (Me) -2-341 (45) (109) HH (10) -CH- -NHCO- -CH (Me)-2-342 (45) (109) 4-FH (10) -CH- -NH- -CH ( Me)-2-343 (45) (109) 5-FH (10) -CH- -NH- -CH (Me)-2-344 (45) (109) 4-Cl H (10) -CH-- NH- -CH (Me)-2-345 (45) (109) 4-MeO H (10) -CH- -NH- -CH (Me)-2-346 (45) (109) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-347 (45) (109) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-348 (45) (109) HH (10) N -NH- -CH (Me)-2-349 (45) (109) HH (10) N -O- -CH (Me)-2-350 (45) (109) HH (10) N -S- -CH (Me)-2-351 (45) (109) HH (10) N -NHCO- -CH (Me)-2-352 (46) (37) HH (10)- CH- -NH- -CH (Me)-2-353 (46) (38) HH (10) -CH- -NH- -CH (Me)-2-354 (46) (44) HH (10)- CH- -NH- -CH (Me)-2-355 (46) (45) HH (10) -CH- -NH- -CH_Two-2-356 (46) (45) HH (10) -CH- -NH- -CH (Me)-2-357 (46) (45) HH (10) -CH- -O- -CH (Me) -2-358 (46) (45) HH (10) -CH- -S- -CH (Me)-2-359 (46) (45) HH (10) -CH- -NHCO- -CH (Me) -2-360 (46) (45) 4-FH (10) -CH- -NH- -CH (Me)-2-361 (46) (45) 4-MeO H (10) -CH- -NH- -CH (Me)-2-362 (46) (45) HH (10) N -NH- -CH (Me)-2-363 (46) (46) HH (10) -CH- -NH- single bond 2-364 (46) (46) HH (10) -CH- -NH- -CH_Two-2-365 (46) (46) HH (10) -CH- -NH- -CH (Me)-2-366 (46) (46) HH (10) -CH- -NH- -CH (Et) -2-367 (46) (46) HH (10) -CH- -O- -CH (Me)-2-368 (46) (46) HH (10) -CH- -S- -CH (Me) -2-369 (46) (46) HH (10) -CH- -NHCO- -CH (Me)-2-370 (46) (46) 4-FH (10) -CH- -NH- -CH ( Me)-2-371 (46) (46) 5-FH (10) -CH- -NH- -CH (Me)-2-372 (46) (46) 4-Cl H (10) -CH-- NH- -CH (Me)-2-373 (46) (46) 4-MeO H (10) -CH- -NH- -CH (Me)-2-374 (46) (46) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-375 (46) (46) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-376 (46) (46) HH (10) N -NH- -CH (Me)-2-377 (46) (46) HH (10) N -O- -CH (Me)-2-378 (46) (46) HH (10) N -S- -CH (Me)-2-379 (46) (46) HH (10) N -NHCO- -CH (Me)-2-380 (46) (47) HH (10)- CH- -NH- -CH (Me)-2-381 (46) (48) HH (10) -CH- -NH- -CH (Me)-2-382 (46) (49) HH (10)- CH- -NH- -CH_Two-2-383 (46) (49) HH (10) -CH- -NH- -CH (Me)-2-384 (46) (49) HH (10) -CH- -O- -CH (Me) -2-385 (46) (49) HH (10) -CH- -S- -CH (Me)-2-386 (46) (49) HH (10) -CH- -NHCO- -CH (Me) -2-387 (46) (49) 4-FH (10) -CH- -NH- -CH (Me)-2-388 (46) (49) 4-MeO H (10) -CH- -NH- -CH (Me)-2-389 (46) (49) HH (10) N -NH- -CH (Me)-2-390 (46) (50) HH (10) -CH- -NH- -CH (Me)-2-391 (46) (51) HH (10) -CH- -NH- -CH_Two-2-392 (46) (51) HH (10) -CH- -NH- -CH (Me)-2-393 (46) (51) HH (10) -CH- -O- -CH (Me) -2-394 (46) (51) HH (10) -CH- -S- -CH (Me)-2-395 (46) (51) HH (10) -CH- -NHCO- -CH (Me) -2-396 (46) (51) 4-FH (10) -CH- -NH- -CH (Me)-2-397 (46) (51) 4-MeO H (10) -CH- -NH- -CH (Me)-2-398 (46) (51) HH (10) N -NH- -CH (Me)-2-399 (46) (58) HH (10) -CH- -NH- -CH (Me)-2-400 (46) (59) HH (10) -CH- -NH- -CH (Me)-2-401 (46) (60) HH (10) -CH- -NH- -CH (Me)-2-402 (46) (62) HH (10) -CH- -NH- -CH (Me)-2-403 (46) (63) HH (10) -CH- -NH- -CH_Two-2-404 (46) (63) HH (10) -CH- -NH- -CH (Me)-2-405 (46) (63) HH (10) -CH- -O- -CH (Me) -2-406 (46) (63) HH (10) -CH- -S- -CH (Me)-2-407 (46) (63) HH (10) -CH- -NHCO- -CH (Me) -2-408 (46) (63) 4-FH (10) -CH- -NH- -CH (Me)-2-409 (46) (63) 4-MeO H (10) -CH- -NH- -CH (Me)-2-410 (46) (63) HH (10) N -NH- -CH (Me)-2-411 (46) (64) HH (10) -CH- -NH- single bond 2-412 (46) (64) HH (10) -CH- -NH- -CH_Two-2-413 (46) (64) HH (10) -CH- -NH- -CH (Me)-2-414 (46) (64) HH (10) -CH- -NH- -CH (Et) -2-415 (46) (64) HH (10) -CH- -O- -CH (Me)-2-416 (46) (64) HH (10) -CH- -S- -CH (Me) -2-417 (46) (64) HH (10) -CH- -NHCO- -CH (Me)-2-418 (46) (64) 4-FH (10) -CH- -NH- -CH ( Me)-2-419 (46) (64) 5-FH (10) -CH- -NH- -CH (Me)-2-420 (46) (64) 4-Cl H (10) -CH-- NH- -CH (Me)-2-421 (46) (64) 4-MeO H (10) -CH- -NH- -CH (Me)-2-422 (46) (64) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-423 (46) (64) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-424 (46) (64) HH (10) N -NH- -CH (Me)-2-425 (46) (64) HH (10) N -O- -CH (Me)-2-426 (46) (64) HH (10) N -S- -CH (Me)-2-427 (46) (64) HH (10) N -NHCO- -CH (Me)-2-428 (46) (65) HH (10)- CH- -NH- -CH (Me)-2-429 (46) (66) HH (10) -CH- -NH- -CH_Two-2-430 (46) (66) HH (10) -CH- -NH- -CH (Me)-2-431 (46) (66) HH (10) -CH- -O- -CH (Me) -2-432 (46) (66) HH (10) -CH- -S- -CH (Me)-2-433 (46) (66) HH (10) -CH- -NHCO- -CH (Me) -2-434 (46) (66) 4-FH (10) -CH- -NH- -CH (Me)-2-435 (46) (66) 4-MeO H (10) -CH- -NH- -CH (Me)-2-436 (46) (66) HH (10) N -NH- -CH (Me)-2-437 (46) (67) HH (10) -CH- -NH- -CH (Me)-2-438 (46) (68) HH (10) -CH- -NH- -CH_Two-2-439 (46) (68) HH (10) -CH- -NH- -CH (Me)-2-440 (46) (68) HH (10) -CH- -O- -CH (Me) -2-441 (46) (68) HH (10) -CH- -S- -CH (Me)-2-442 (46) (68) HH (10) -CH- -NHCO- -CH (Me) -2-443 (46) (68) 4-FH (10) -CH- -NH- -CH (Me)-2-444 (46) (68) 4-MeO H (10) -CH- -NH- -CH (Me)-2-445 (46) (68) HH (10) N -NH- -CH (Me)-2-446 (46) (69) HH (10) -CH- -NH- -CH (Me)-2-447 (46) (72) HH (10) -CH- -NH- -CH (Me)-2-448 (46) (73) HH (10) -CH- -NH- -CH (Me)-2-449 (46) (74) HH (10) -CH- -NH- -CH (Me)-2-450 (46) (75) HH (10) -CH- -NH- -CH (Me)-2-451 (46) (76) HH (10) -CH- -NH- -CH (Me)-2-452 (46) (77) HH (10) -CH- -NH- -CH (Me)-2-453 (46) (101) HH (10) -CH- -NH- -CH (Me)-2-454 (46) (102) HH (10) -CH- -NH- -CH (Me)-2-455 (46) (103) HH (10) -CH- -NH- -CH_Two-2-456 (46) (103) HH (10) -CH- -NH- -CH (Me)-2-457 (46) (103) HH (10) -CH- -O- -CH (Me) -2-458 (46) (103) HH (10) -CH- -S- -CH (Me)-2-459 (46) (103) HH (10) -CH- -NHCO- -CH (Me) -2-460 (46) (103) 4-FH (10) -CH- -NH- -CH (Me)-2-461 (46) (103) 4-MeO H (10) -CH- -NH- -CH (Me)-2-462 (46) (103) HH (10) N -NH- -CH (Me)-2-463 (46) (104) HH (10) -CH- -NH- -CH (Me)-2-464 (46) (105) HH (10) -CH- -NH- -CH (Me)-2-465 (46) (106) HH (10) -CH- -NH- -CH (Me)-2-466 (46) (108) HH (10) -CH- -NH- single bond 2-467 (46) (108) HH (10) -CH- -NH- -CH_Two-2-468 (46) (108) HH (10) -CH- -NH- -CH (Me)-2-469 (46) (108) HH (10) -CH- -NH- -CH (Et) -2-470 (46) (108) HH (10) -CH- -O- -CH (Me)-2-471 (46) (108) HH (10) -CH- -S- -CH (Me) -2-472 (46) (108) HH (10) -CH- -NHCO- -CH (Me)-2-473 (46) (108) 4-FH (10) -CH- -NH- -CH ( Me)-2-474 (46) (108) 5-FH (10) -CH- -NH- -CH (Me)-2-475 (46) (108) 4-Cl H (10) -CH-- NH- -CH (Me)-2-476 (46) (108) 4-MeO H (10) -CH- -NH- -CH (Me)-2-477 (46) (108) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-478 (46) (108) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-479 (46) (108) HH (10) N -NH- -CH (Me)-2-480 (46) (108) HH (10) N -O- -CH (Me)-2-481 (46) (108) HH (10) N -S- -CH (Me)-2-482 (46) (108) HH (10) N -NHCO- -CH (Me)-2-483 (46) (109) HH (10)- CH- -NH- single bond 2-484 (46) (109) HH (10) -CH- -NH- -CH_Two-2-485 (46) (109) HH (10) -CH- -NH- -CH (Me)-2-486 (46) (109) HH (10) -CH- -NH- -CH (Et) -2-487 (46) (109) HH (10) -CH- -O- -CH (Me)-2-488 (46) (109) HH (10) -CH- -S- -CH (Me) -2-489 (46) (109) HH (10) -CH- -NHCO- -CH (Me)-2-490 (46) (109) 4-FH (10) -CH- -NH- -CH ( Me)-2-491 (46) (109) 5-FH (10) -CH- -NH- -CH (Me)-2-492 (46) (109) 4-Cl H (10) -CH-- NH- -CH (Me)-2-493 (46) (109) 4-MeO H (10) -CH- -NH- -CH (Me)-2-494 (46) (109) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-495 (46) (109) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-496 (46) (109) HH (10) N -NH- -CH (Me)-2-497 (46) (109) HH (10) N -O- -CH (Me)-2-498 (46) (109) HH (10) N -S- -CH (Me)-2-499 (46) (109) HH (10) N -NHCO- -CH (Me)-2-500 (47) (64) HH (10)- CH- -NH- -CH (Me)-2-501 (47) (108) HH (10) -CH- -NH- -CH (Me)-2-502 (47) (109) HH (10)- CH- -NH- -CH (Me)-2-503 (48) (46) HH (10) -CH- -NH- -CH (Me)-2-504 (48) (64) HH (10)- CH- -NH- -CH (Me)-2-505 (48) (108) HH (10) -CH- -NH- -CH (Me)-2-506 (48) (109) HH (10)- CH- -NH- -CH (Me)- 2-507 (48) (64) HH (10) N -NH- -CH (Me)-2-508 (48) (108) HH (10) N -NH- -CH (Me)-2-509 ( 48) (109) HH (10) N -NH- -CH (Me)-2-510 (49) (45) HH (10) -CH- -NH- -CH (Me)-2-511 (49) (46) HH (10) -CH- -NH- -CH (Me)-2-512 (49) (49) HH (10) -CH- -NH- -CH (Me)-2-513 (49) (51) HH (10) -CH- -NH- -CH (Me)-2-514 (49) (63) HH (10) -CH- -NH- -CH (Me)-2-515 (49) (64) HH (10) -CH- -NH- -CH (Me)-2-516 (49) (66) HH (10) -CH- -NH- -CH (Me)-2-517 (49) (68) HH (10) -CH- -NH- -CH (Me)-2-518 (49) (108) HH (10) -CH- -NH- -CH (Me)-2-519 (49) (108) HH (10) N -NH- -CH (Me)-2-520 (49) (109) HH (10) -CH- -NH- -CH (Me)-2-521 (49) (109 ) HH (10) N -NH- -CH (Me)-2-522 (50) (46) HH (10) -CH- -NH- -CH (Me)-2-523 (50) (64) HH (10) -CH- -NH- -CH (Me)-2-524 (50) (108) HH (10) -CH- -NH- -CH (Me)-2-525 (50) (109) HH (10) -CH- -NH- -CH (Me)-2-526 (50) (64) HH (10) N -NH- -CH (Me)-2-527 (50) (108) HH (10 ) N -NH- -CH (Me)-2-528 (50) (109) HH (10) N -NH- -CH (Me)-2-529 (51) (45) HH (10) -CH- -NH- -CH (Me)-2- 530 (51) (46) HH (10) -CH- -NH- -CH (Me)-2-531 (51) (49) HH (10) -CH- -NH- -CH (Me)-2- 532 (51) (51) HH (10) -CH- -NH- -CH (Me)-2-533 (51) (63) HH (10) -CH- -NH- -CH (Me)-2- 534 (51) (64) HH (10) -CH- -NH- -CH (Me)-2-535 (51) (66) HH (10) -CH- -NH- -CH (Me)-2- 536 (51) (68) HH (10) -CH- -NH- -CH (Me)-2-537 (51) (108) HH (10) -CH- -NH- -CH (Me)-2- 538 (51) (108) HH (10) N -NH- -CH (Me)-2-539 (51) (109) HH (10) -CH- -NH- -CH (Me)-2-540 ( 51) (109) HH (10) N -NH- -CH (Me)-2-541 (52) (37) HH (10) -CH- -NH- -CH (Me)-2-542 (52) (38) HH (10) -CH- -NH- -CH (Me)-2-543 (52) (44) HH (10) -CH- -NH- -CH (Me)-2-544 (52) (45) HH (10) -CH- -NH- -CH_Two-2-545 (52) (45) HH (10) -CH- -NH- -CH (Me)-2-546 (52) (45) HH (10) -CH- -O- -CH (Me) -2-547 (52) (45) HH (10) -CH- -S- -CH (Me)-2-548 (52) (45) HH (10) -CH- -NHCO- -CH (Me) -2-549 (52) (45) 4-FH (10) -CH- -NH- -CH (Me)-2-550 (52) (45) 4-MeO H (10) -CH- -NH- -CH (Me)-2-551 (52) (46) HH (10) -CH- -NH- single bond 2-552 (52) (46) HH (10) -CH- -NH- -CH_Two-2-553 (52) (46) HH (10) -CH- -NH- -CH (Me)-2-554 (52) (46) HH (10) -CH- -NH- -CH (Et) -2-555 (52) (46) HH (10) -CH- -O- -CH (Me)-2-556 (52) (46) HH (10) -CH- -S- -CH (Me) -2-557 (52) (46) HH (10) -CH- -NHCO- -CH (Me)-2-558 (52) (46) 4-FH (10) -CH- -NH- -CH ( Me)-2-559 (52) (46) 5-FH (10) -CH- -NH- -CH (Me)-2-560 (52) (46) 4-Cl H (10) -CH-- NH- -CH (Me)-2-561 (52) (46) 4-MeO H (10) -CH- -NH- -CH (Me)-2-562 (52) (46) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-563 (52) (46) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-564 (52) (46) HH (10) N -NH- -CH (Me)-2-565 (52) (46) HH (10) N -O- -CH (Me)-2-566 (52) (46) HH (10) N -S- -CH (Me)-2-567 (52) (46) HH (10) N -NHCO- -CH (Me)-2-568 (52) (47) HH (10)- CH- -NH- -CH (Me)-2-569 (52) (48) HH (10) -CH- -NH- -CH (Me)-2-570 (52) (49) HH (10)- CH- -NH- -CH_Two-2-571 (52) (49) HH (10) -CH- -NH- -CH (Me)-2-572 (52) (49) HH (10) -CH- -O- -CH (Me) -2-573 (52) (49) HH (10) -CH- -S- -CH (Me)-2-574 (52) (49) HH (10) -CH- -NHCO- -CH (Me) -2-575 (52) (49) 4-FH (10) -CH- -NH- -CH (Me)-2-576 (52) (49) 4-MeO H (10) -CH- -NH- -CH (Me)-2-577 (52) (49) HH (10) N -NH- -CH (Me)-2-578 (52) (50) HH (10) -CH- -NH- -CH (Me)-2-579 (52) (51) HH (10) -CH- -NH- -CH_Two-2-580 (52) (51) HH (10) -CH- -NH- -CH (Me)-2-581 (52) (51) HH (10) -CH- -O- -CH (Me) -2-582 (52) (51) HH (10) -CH- -S- -CH (Me)-2-583 (52) (51) HH (10) -CH- -NHCO- -CH (Me) -2-584 (52) (51) 4-FH (10) -CH- -NH- -CH (Me)-2-585 (52) (51) 4-MeO H (10) -CH- -NH- -CH (Me)-2-586 (52) (51) HH (10) N -NH- -CH (Me)-2-587 (52) (58) HH (10) -CH- -NH- -CH (Me)-2-588 (52) (59) HH (10) -CH- -NH- -CH (Me)-2-589 (52) (62) HH (10) -CH- -NH- -CH (Me)-2-590 (52) (63) HH (10) -CH- -NH- -CH_Two-2-591 (52) (63) HH (10) -CH- -NH- -CH (Me)-2-592 (52) (63) HH (10) -CH- -O- -CH (Me) -2-593 (52) (63) HH (10) -CH- -S- -CH (Me)-2-594 (52) (63) HH (10) -CH- -NHCO- -CH (Me) -2-595 (52) (63) 4-FH (10) -CH- -NH- -CH (Me)-2-596 (52) (63) 4-MeO H (10) -CH- -NH- -CH (Me)-2-597 (52) (63) HH (10) N -NH- -CH (Me)-2-598 (52) (64) HH (10) -CH- -NH- single bond 2-599 (52) (64) HH (10) -CH- -NH- -CH_Two-2-600 (52) (64) HH (10) -CH- -NH- -CH (Me)-2-601 (52) (64) HH (10) -CH- -NH- -CH (Et) -2-602 (52) (64) HH (10) -CH- -O- -CH (Me)-2-603 (52) (64) HH (10) -CH- -S- -CH (Me) -2-604 (52) (64) HH (10) -CH- -NHCO- -CH (Me)-2-605 (52) (64) 4-FH (10) -CH- -NH- -CH ( Me)-2-606 (52) (64) 5-FH (10) -CH- -NH- -CH (Me)-2-607 (52) (64) 4-Cl H (10) -CH-- NH- -CH (Me)-2-608 (52) (64) 4-MeO H (10) -CH- -NH- -CH (Me)-2-609 (52) (64) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-610 (52) (64) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-611 (52) (64) HH (10) N -NH- -CH (Me)-2-612 (52) (64) HH (10) N -O- -CH (Me)-2-613 (52) (64) HH (10) N -S- -CH (Me)-2-614 (52) (64) HH (10) N -NHCO- -CH (Me)-2-615 (52) (65) HH (10)- CH- -NH- -CH (Me)-2-616 (52) (66) HH (10) -CH- -NH- -CH_Two-2-617 (52) (66) HH (10) -CH- -NH- -CH (Me)-2-618 (52) (66) HH (10) -CH- -O- -CH (Me) -2-619 (52) (66) HH (10) -CH- -S- -CH (Me)-2-620 (52) (66) HH (10) -CH- -NHCO- -CH (Me) -2-621 (52) (66) 4-FH (10) -CH- -NH- -CH (Me)-2-622 (52) (66) 4-MeO H (10) -CH- -NH- -CH (Me)-2-623 (52) (66) HH (10) N -NH- -CH (Me)-2-624 (52) (67) HH (10) -CH- -NH- -CH (Me)-2-625 (52) (68) HH (10) -CH- -NH- -CH_Two-2-626 (52) (68) HH (10) -CH- -NH- -CH (Me)-2-627 (52) (68) HH (10) -CH- -O- -CH (Me) -2-628 (52) (68) HH (10) -CH- -S- -CH (Me)-2-629 (52) (68) HH (10) -CH- -NHCO- -CH (Me) -2-630 (52) (68) 4-FH (10) -CH- -NH- -CH (Me)-2-631 (52) (68) 4-MeO H (10) -CH- -NH- -CH (Me)-2-632 (52) (68) HH (10) N -NH- -CH (Me)-2-633 (52) (72) HH (10) -CH- -NH- -CH (Me)-2-634 (52) (73) HH (10) -CH- -NH- -CH (Me)-2-635 (52) (74) HH (10) -CH- -NH- -CH (Me)-2-636 (52) (75) HH (10) -CH- -NH- -CH (Me)-2-637 (52) (76) HH (10) -CH- -NH- -CH (Me)-2-638 (52) (77) HH (10) -CH- -NH- -CH (Me)-2-639 (52) (101) HH (10) -CH- -NH- -CH (Me)-2-640 (52) (102) HH (10) -CH- -NH- -CH (Me)-2-641 (52) (103) HH (10) -CH- -NH- -CH_Two-2-642 (52) (103) HH (10) -CH- -NH- -CH (Me)-2-643 (52) (103) HH (10) -CH- -O- -CH (Me) -2-644 (52) (103) HH (10) -CH- -S- -CH (Me)-2-645 (52) (103) HH (10) -CH- -NHCO- -CH (Me) -2-646 (52) (103) 4-FH (10) -CH- -NH- -CH (Me)-2-647 (52) (103) 4-MeO H (10) -CH- -NH- -CH (Me)-2-648 (52) (103) HH (10) N -NH- -CH (Me)-2-649 (52) (104) HH (10) -CH- -NH- -CH (Me)-2-650 (52) (105) HH (10) -CH- -NH- -CH (Me)-2-651 (52) (106) HH (10) -CH- -NH- -CH (Me)-2-652 (52) (108) HH (10) -CH- -NH- single bond 2-653 (52) (108) HH (10) -CH- -NH- -CH_Two-2-654 (52) (108) HH (10) -CH- -NH- -CH (Me)-2-655 (52) (108) HH (10) -CH- -NH- -CH (Et) -2-656 (52) (108) HH (10) -CH- -O- -CH (Me)-2-657 (52) (108) HH (10) -CH- -S- -CH (Me) -2-658 (52) (108) HH (10) -CH- -NHCO- -CH (Me)-2-659 (52) (108) 4-FH (10) -CH- -NH- -CH ( Me)-2-660 (52) (108) 5-FH (10) -CH- -NH- -CH (Me)-2-661 (52) (108) 4-Cl H (10) -CH-- NH- -CH (Me)-2-662 (52) (108) 4-MeO H (10) -CH- -NH- -CH (Me)-2-663 (52) (108) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-664 (52) (108) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-665 (52) (108) HH (10) N -NH- -CH (Me)-2-666 (52) (108) HH (10) N -O- -CH (Me)-2-667 (52) (108) HH (10) N -S- -CH (Me)-2-668 (52) (108) HH (10) N -NHCO- -CH (Me)-2-669 (52) (109) HH (10)- CH- -NH- single bond 2-670 (52) (109) HH (10) -CH- -NH- -CH_Two-2-671 (52) (109) HH (10) -CH- -NH- -CH (Me)-2-672 (52) (109) HH (10) -CH- -NH- -CH (Et) -2-673 (52) (109) HH (10) -CH- -O- -CH (Me)-2-674 (52) (109) HH (10) -CH- -S- -CH (Me) -2-675 (52) (109) HH (10) -CH- -NHCO- -CH (Me)-2-676 (52) (109) 4-FH (10) -CH- -NH- -CH ( Me)-2-677 (52) (109) 5-FH (10) -CH- -NH- -CH (Me)-2-678 (52) (109) 4-Cl H (10) -CH-- NH- -CH (Me)-2-679 (52) (109) 4-MeO H (10) -CH- -NH- -CH (Me)-2-680 (52) (109) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-681 (52) (109) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-682 (52) (109) HH (10) N -NH- -CH (Me)-2-683 (52) (109) HH (10) N -O- -CH (Me)-2-684 (52) (109) HH (10) N -S- -CH (Me)-2-685 (52) (109) HH (10) N -NHCO- -CH (Me)-2-686 (53) (46) HH (10)- CH- -NH- -CH (Me)-2-687 (53) (64) HH (10) -CH- -NH- -CH (Me)-2-688 (53) (109) HH (10)- CH- -NH- -CH (Me)-2-689 (53) (64) HH (10) N -NH- -CH (Me)-2-690 (53) (109) HH (10) N -NH --CH (Me)-2-691 (54) (64) HH (10) -CH- -NH- -CH (Me)-2-692 (54) (109) HH (10) N -NH-- CH (Me)-2-693 (54) (109) H H (10) -CH- -NH- -CH (Me)-2-694 (55) (45) H H
 (10) -CH- -NH- -CH (Me) -2-695 (55) (46) HH
 (10) -CH- -NH- -CH (Me)-2-696 (55) (49) HH
 (10) -CH- -NH- -CH (Me) -2-697 (55) (51) HH
 (10) -CH- -NH- -CH (Me) -2-698 (55) (63) HH
 (10) -CH- -NH- -CH (Me) -2-699 (55) (64) HH
 (10) -CH- -NH- -CH (Me)-2-700 (55) (66) HH
 (10) -CH- -NH- -CH (Me)-2-701 (55) (68) HH
 (10) -CH- -NH- -CH (Me)-2-702 (55) (108) HH
 (10) -CH- -NH- -CH (Me)-2-703 (55) (108) HH
 (10) N-NH--CH (Me) -2-704 (56) (108) HH
 (10) -CH- -NH- -CH (Me)-2-705 (55) (109) HH
 (10) -CH- -NH- -CH (Me)-2-706 (55) (109) HH
 (10) N-NH--CH (Me) -2-707 (56) (109) HH
 (10) -CH- -NH- -CH (Me)-2-708 (57) (64) HH
 (10) -CH- -NH- -CH (Me) -2-709 (57) (108) HH
 (10) -CH- -NH- -CH (Me)-2-710 (57) (109) HH
 (10) -CH- -NH- -CH (Me)-2-711 (58) (64) HH
 (10) -CH- -NH- -CH (Me)-2-712 (58) (108) HH
 (10) -CH- -NH- -CH (Me)-2-713 (58) (109) HH
 (10) -CH- -NH- -CH (Me)-2-714 (59) (46) HH
 (10) -CH- -NH- -CH (Me)-2-715 (59) (64) HH
 (10) -CH- -NH- -CH (Me)-2-716 (59) (108) HH
 (10) -CH- -NH- -CH (Me)-2-717 (59) (109) HH
 (10) -CH- -NH- -CH (Me)-2-718 (59) (64) HH
 (10) N-NH- -CH (Me) -2-719 (59) (108) HH
 (10) N-NH--CH (Me) -2-720 (60) (108) HH
 (10) -CH- -NH- -CH (Me)-2-721 (59) (109) HH
 (10) N-NH--CH (Me) -2-723 (61) (64) HH
 (10) -CH- -NH- -CH (Me)-2-724 (61) (108) HH
 (10) -CH- -NH- -CH (Me)-2-725 (61) (109) HH
 (10) -CH- -NH- -CH (Me)-2-726 (62) (46) HH
 (10) -CH- -NH- -CH (Me)-2-727 (62) (64) HH
 (10) -CH- -NH- -CH (Me)-2-728 (62) (108) HH
 (10) -CH- -NH- -CH (Me)-2-729 (62) (109) HH
 (10) -CH- -NH- -CH (Me)-2-730 (62) (64) HH
 (10) N-NH--CH (Me) -2-731 (62) (108) HH
 (10) N-NH--CH (Me) -2-732 (62) (109) HH
 (10) N-NH- -CH (Me) -2-733 (63) (45) HH
 (10) -CH- -NH- -CH (Me) -2-734 (63) (46) HH
 (10) -CH- -NH- -CH (Me)-2-735 (63) (49) HH
 (10) -CH- -NH- -CH (Me)-2-736 (63) (51) HH
 (10) -CH- -NH- -CH (Me)-2-737 (63) (63) HH
 (10) -CH- -NH- -CH (Me) -2-738 (63) (64) HH
 (10) -CH- -NH- -CH (Me) -2-739 (63) (66) HH
 (10) -CH- -NH- -CH (Me)-2-740 (63) (68) HH
 (10) -CH- -NH- -CH (Me) -2-741 (63) (108) HH
 (10) -CH- -NH- -CH (Me)-2-742 (63) (108) HH
 (10) N-NH--CH (Me) -2-743 (63) (109) HH
 (10) -CH- -NH- -CH (Me)-2-744 (63) (109) HH
 (10) N-NH--CH (Me) -2-745 (64) (37) HH
 (10) -CH- -NH- -CH (Me)-2-746 (64) (38) HH
 (10) -CH- -NH- -CH (Me)-2-747 (64) (44) HH
 (10) -CH- -NH- -CH (Me)-2-748 (64) (45) HH
 (10) -CH- -NH- -CH₂-2-749 (64) (45) H H
 (10) -CH- -NH- -CH (Me)-2-750 (64) (45) H H
 (10) -CH- -O- -CH (Me) -2-752 (64) (45) HH
 (10) -CH- -NHCO- -CH (Me) -2-753 (64) (45) 4-F H
 (10) -CH- -NH- -CH (Me)-2-754 (64) (45) 4-MeOH
 (10) -CH- -NH- -CH (Me)-2-755 (64) (46) HH
 (10) -CH- -NH- single bond 2-756 (64) (46) HH
 (10) -CH- -NH- -CH₂-2-757 (64) (46) H H
 (10) -CH- -NH- -CH (Me)-2-758 (64) (46) HH
 (10) -CH- -NH- -CH (Et)-2-759 (64) (46) HH
 (10) -CH- -O- -CH (Me)-2-760 (64) (46) HH
 (10) -CH- -S- -CH (Me) -2-761 (64) (46) HH
 (10) -CH- -NHCO- -CH (Me)-2-762 (64) (46) 4-F H
 (10) -CH- -NH- -CH (Me) -2-763 (64) (46) 5-F H
 (10) -CH- -NH- -CH (Me) -2-764 (64) (46) 4-ClH
 (10) -CH- -NH- -CH (Me)-2-765 (64) (46) 4-MeOH
 (10) -CH- -NH- -CH (Me) -2-766 (64) (46) 5-MeOH
 (10) -CH- -NH- -CH (Me) -2-767 (64) (46) 4-MeO 5-Me
O (10) -CH- -NH- -CH (Me)-2-768 (64) (46) H H
 (10) N-NH- -CH (Me) -2-769 (64) (46) HH
 (10) N—O——CH (Me) — 2-770 (64) (46) H H
 (10) NS-CH (Me) -2-771 (64) (46) HH
 (10) N-NHCO--CH (Me) -2-772 (64) (47) HH
 (10) -CH- -NH- -CH (Me)-2-773 (64) (48) HH
 (10) -CH- -NH- -CH (Me)-2-774 (64) (49) HH
 (10) -CH- -NH- -CH₂-2-775 (64) (49) H H
 (10) -CH- -NH- -CH (Me)-2-776 (64) (49) HH
 (10) -CH- -O- -CH (Me)-2-777 (64) (49) HH
 (10) -CH- -S- -CH (Me)-2-778 (64) (49) HH
 (10) -CH- -NHCO- -CH (Me)-2-779 (64) (49) 4-F H
 (10) -CH- -NH- -CH (Me) -2-781 (64) (49) HH
 (10) N-NH--CH (Me) -2-782 (64) (50) HH
 (10) -CH- -NH- -CH (Me) -2-783 (64) (51) HH
 (10) -CH- -NH- -CH₂− 2-784 (64) (51) H H
 (10) -CH- -NH- -CH (Me)-2-785 (64) (51) HH
 (10) -CH- -O- -CH (Me)-2-786 (64) (51) HH
 (10) -CH- -S- -CH (Me)-2-787 (64) (51) HH
 (10) -CH- -NHCO- -CH (Me)-2-788 (64) (51) 4-F H
 (10) -CH- -NH- -CH (Me)-2-789 (64) (51) 4-MeOH
 (10) -CH- -NH- -CH (Me)-2-790 (64) (51) HH
 (10) N-NH--CH (Me) -2-791 (64) (58) HH
 (10) -CH- -NH- -CH (Me)-2-792 (64) (59) HH
 (10) -CH- -NH- -CH (Me)-2-793 (64) (62) HH
 (10) -CH- -NH- -CH (Me)-2-794 (64) (63) HH
 (10) -CH- -NH- -CH₂-2-795 (64) (63) H H
 (10) -CH- -NH- -CH (Me)-2-796 (64) (63) HH
 (10) -CH- -O- -CH (Me)-2-797 (64) (63) HH
 (10) -CH- -S- -CH (Me)-2-798 (64) (63) HH
 (10) -CH- -NHCO- -CH (Me)-2-799 (64) (63) 4-F H
 (10) -CH- -NH- -CH (Me) -2-800 (64) (63) 4-MeOH
 (10) -CH- -NH- -CH (Me)-2-801 (64) (63) H H
 (10) N-NH- -CH (Me) -2-802 (64) (64) HH
 (10) -CH- -NH- single bond 2-803 (64) (64) HH
 (10) -CH- -NH- -CH₂-2-804 (64) (64) H H
 (10) -CH- -NH- -CH (Me)-2-805 (64) (64) H H
 (10) -CH- -NH- -CH (Et)-2-806 (64) (64) HH
 (10) -CH- -O- -CH (Me)-2-807 (64) (64) HH
 (10) -CH- -S- -CH (Me)-2-808 (64) (64) H H
 (10) -CH- -NHCO- -CH (Me) -2-810 (64) (64) 5-F H
 (10) -CH- -NH- -CH (Me) -2-81 1 (64) (64) 4-ClH
 (10) -CH- -NH- -CH (Me)-2-812 (64) (64) 4-MeOH
 (10) -CH- -NH- -CH (Me) -2-813 (64) (64) 5-MeOH
 (10) -CH- -NH- -CH (Me)-2-814 (64) (64) 4-MeO 5-Me
O (10) -CH--NH--CH (Me) -2-815 (64) (64) HH
 (10) N-NH--CH (Me) -2-816 (64) (64) HH
 (10) N—O——CH (Me) -2-817 (64) (64) H H
 (10) NS-CH (Me) -2-818 (64) (64) HH
 (10) N-NHCO- -CH (Me) -2-819 (64) (65) HH
 (10) -CH- -NH- -CH (Me)-2-820 (64) (66) HH
 (10) -CH- -NH- -CH₂-2-821 (64) (66) H H
 (10) -CH- -NH- -CH (Me)-2-822 (64) (66) HH
 (10) -CH- -O- -CH (Me)-2-823 (64) (66) HH
 (10) -CH- -S- -CH (Me)-2-824 (64) (66) 4-F H
 (10) -CH- -NH- -CH (Me) -2-825 (64) (66) 4-MeOH
 (10) -CH- -NH- -CH (Me)-2-826 (64) (66) HH
 (10) N-NH--CH (Me) -2-827 (64) (67) HH
 (10) -CH- -NH- -CH (Me)-2-828 (64) (68) HH
 (10) -CH- -NH- -CH₂-2-829 (64) (68) H H
 (10) -CH- -NH- -CH (Me)-2-830 (64) (68) HH
 (10) —CH——O——CH (Me) -2-831 (64) (68) H H
 (10) -CH- -S- -CH (Me) -2-832 (64) (68) HH
 (10) -CH- -NHCO- -CH (Me) -2-833 (64) (68) 4-F H
 (10) -CH- -NH- -CH (Me)-2-834 (64) (68) 4-MeOH
 (10) -CH- -NH- -CH (Me)-2-835 (64) (68) HH
 (10) N-NH--CH (Me) -2-836 (64) (72) HH
 (10) -CH- -NH- -CH (Me) -2-837 (64) (73) HH
 (10) -CH- -NH- -CH (Me) -2-839 (64) (75) HH
 (10) -CH- -NH- -CH (Me)-2-840 (64) (76) HH
 (10) -CH- -NH- -CH (Me) -2-841 (64) (77) HH
 (10) -CH- -NH- -CH (Me)-2-842 (64) (101) HH
 (10) -CH- -NH- -CH (Me) -2-843 (64) (102) HH
 (10) -CH- -NH- -CH (Me)-2-844 (64) (103) HH
 (10) -CH- -NH- -CH₂− 2-845 (64) (103) H H
 (10) -CH- -NH- -CH (Me)-2-846 (64) (103) HH
 (10) -CH- -O- -CH (Me)-2-847 (64) (103) HH
 (10) -CH- -S- -CH (Me)-2-848 (64) (103) HH
 (10) -CH- -NHCO- -CH (Me) -2-849 (64) (103) 4-F H
 (10) -CH- -NH- -CH (Me)-2-850 (64) (103) 4-MeOH
 (10) -CH- -NH- -CH (Me) -2-851 (64) (103) HH
 (10) N-NH- -CH (Me) -2-852 (64) (104) HH
 (10) -CH- -NH- -CH (Me) -2-853 (64) (105) HH
 (10) -CH- -NH- -CH (Me)-2-854 (64) (106) HH
 (10) -CH- -NH- -CH (Me)-2-855 (64) (108) HH
 (10) -CH- -NH- single bond 2-856 (64) (108) HH
 (10) -CH- -NH- -CH₂− 2-857 (64) (108) H H
 (10) -CH- -NH- -CH (Me)-2-858 (64) (108) HH
 (10) -CH- -NH- -CH (Et)-2-859 (64) (108) HH
 (10) -CH- -O- -CH (Me)-2-860 (64) (108) HH
 (10) -CH- -S- -CH (Me) -2-861 (64) (108) HH
 (10) -CH- -NHCO- -CH (Me) -2-862 (64) (108) 4-F H
 (10) -CH- -NH- -CH (Me) -2-863 (64) (108) 5-FH
 (10) -CH- -NH- -CH (Me)-2-864 (64) (108) 4-ClH
 (10) -CH- -NH- -CH (Me)-2-865 (64) (108) 4-MeOH
 (10) -CH- -NH- -CH (Me)-2-866 (64) (108) 5-MeOH
 (10) -CH- -NH- -CH (Me)-2-868 (64) (108) HH (10) N -NH- -CH (Me)-2-869 (64) (108) HH (10 ) N -O- -CH (Me)-2-870 (64) (108) HH (10) N -S- -CH (Me)-2-871 (64) (108) HH (10) N -NHCO --CH (Me)-2-872 (64) (109) HH (10) -CH- -NH- single bond 2-873 (64) (109) HH (10) -CH- -NH- -CH_Two-2-874 (64) (109) HH (10) -CH- -NH- -CH (Me)-2-875 (64) (109) HH (10) -CH- -NH- -CH (Et) -2-876 (64) (109) HH (10) -CH- -O- -CH (Me)-2-877 (64) (109) HH (10) -CH- -S- -CH (Me) -2-878 (64) (109) HH (10) -CH- -NHCO- -CH (Me)-2-879 (64) (109) 4-FH (10) -CH- -NH- -CH ( Me)-2-880 (64) (109) 5-FH (10) -CH- -NH- -CH (Me)-2-881 (64) (109) 4-Cl H (10) -CH-- NH- -CH (Me)-2-882 (64) (109) 4-MeO H (10) -CH- -NH- -CH (Me)-2-883 (64) (109) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-884 (64) (109) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-885 (64) (109) HH (10) N -NH- -CH (Me)-2-886 (64) (109) HH (10) N -O- -CH (Me)-2-887 (64) (109) HH (10) N -S- -CH (Me)-2-888 (64) (109) HH (10) N -NHCO- -CH (Me)-2-889 (65) (108) HH (10)- CH- -NH- -CH (Me)-2-890 (65) (109) HH (10) -CH- -NH- -CH (Me)-2-891 (66) (46) HH (10)- CH- -NH- -CH (Me)-2-892 (66) (64) HH (10) -CH- -NH- -CH (Me)-2-893 (66) (66) HH (10)- CH- -NH- -CH (Me)-2-894 (66) (108) HH (10) -CH- -NH- -CH (Me)-2-895 (66) (109) HH (10)- CH- -NH- -CH (Me)- 2-896 (66) (64) H H (10) N-NH- -CH (Me)-2-897 (66) (66) H H
 (10) N-NH--CH (Me) -2-898 (66) (108) HH
 (10) N-NH--CH (Me) -2-899 (67) (108) HH
 (10) -CH- -NH- -CH (Me)-2-900 (66) (109) HH
 (10) N-NH--CH (Me) -2-901 (67) (109) HH
 (10) -CH- -NH- -CH (Me)-2-902 (68) (45) HH
 (10) -CH- -NH- -CH (Me)-2-903 (68) (46) HH
 (10) -CH- -NH- -CH (Me)-2-904 (68) (49) HH
 (10) -CH- -NH- -CH (Me)-2-905 (68) (51) HH
 (10) -CH- -NH- -CH (Me)-2-906 (68) (63) HH
 (10) -CH- -NH- -CH (Me)-2-907 (68) (64) HH
 (10) -CH- -NH- -CH (Me)-2-908 (68) (66) HH
 (10) -CH- -NH- -CH (Me)-2-909 (68) (68) HH
 (10) -CH- -NH- -CH (Me)-2-910 (68) (109) HH
 (10) -CH- -NH- -CH (Me)-2-911 (68) (109) HH
 (10) N-NH--CH (Me) -2-912 (69) (109) HH
 (10) -CH- -NH- -CH (Me)-2-913 (70) (45) HH
 (10) -CH- -NH- -CH (Me)-2-914 (70) (46) HH
 (10) -CH- -NH- -CH (Me)-2-915 (70) (49) HH
 (10) -CH- -NH- -CH (Me)-2-916 (70) (51) HH
 (10) -CH- -NH- -CH (Me)-2-917 (70) (63) HH
 (10) -CH- -NH- -CH (Me)-2-918 (70) (64) HH
 (10) -CH- -NH- -CH (Me)-2-919 (70) (66) HH
 (10) -CH- -NH- -CH (Me)-2-920 (70) (68) HH
 (10) -CH- -NH- -CH (Me)-2-921 (70) (108) HH
 (10) -CH- -NH- -CH (Me)-2-922 (70) (108) HH
 (10) N-NH--CH (Me) -2-923 (70) (109) HH
 (10) -CH- -NH- -CH (Me)-2-924 (70) (109) HH
 (10) N-NH--CH (Me) -2-926 (71) (109) HH
 (10) -CH- -NH- -CH (Me)-2-927 (72) (64) HH
 (10) -CH- -NH- -CH (Me) -2-928 (72) (108) HH
 (10) -CH- -NH- -CH (Me)-2-929 (72) (109) HH
 (10) -CH- -NH- -CH (Me)-2-930 (73) (64) HH
 (10) -CH- -NH- -CH (Me)-2-931 (73) (108) HH
 (10) -CH- -NH- -CH (Me) -2-932 (73) (109) HH
 (10) -CH- -NH- -CH (Me)-2-933 (74) (108) HH
 (10) -CH- -NH- -CH (Me)-2-934 (74) (109) HH
 (10) -CH- -NH- -CH (Me)-2-935 (75) (64) HH
 (10) -CH- -NH- -CH (Me)-2-936 (75) (108) HH
 (10) -CH- -NH- -CH (Me)-2-937 (75) (109) HH
 (10) -CH- -NH- -CH (Me)-2-938 (76) (108) HH
 (10) -CH- -NH- -CH (Me)-2-939 (76) (109) HH
 (10) -CH- -NH- -CH (Me)-2-940 (77) (108) HH
 (10) -CH- -NH- -CH (Me) -2-941 (77) (109) HH
 (10) -CH- -NH- -CH (Me)-2-942 (78) (108) HH
 (10) -CH- -NH- -CH (Me)-2-943 (78) (109) HH
 (10) -CH- -NH- -CH (Me)-2-944 (79) (108) HH
 (10) -CH- -NH- -CH (Me)-2-945 (79) (109) HH
 (10) -CH- -NH- -CH (Me)-2-946 (80) (108) HH
 (10) -CH- -NH- -CH (Me)-2-947 (80) (109) HH
 (10) -CH- -NH- -CH (Me)-2-948 (81) (108) HH
 (10) -CH- -NH- -CH (Me)-2-949 (81) (109) HH
 (10) -CH- -NH- -CH (Me)-2-950 (82) (108) HH
 (10) -CH- -NH- -CH (Me) -2-951 (82) (109) HH
 (10) -CH- -NH- -CH (Me) -2-952 (83) (108) HH
 (10) -CH- -NH- -CH (Me) -2-953 (83) (109) HH
 (10) -CH- -NH- -CH (Me)-2-955 (84) (109) HH (10) -CH- -NH- -CH (Me)-2-956 (85) (64) HH (10) -CH- -NH- -CH (Me)-2-957 (85) (108) HH (10) -CH- -NH- -CH (Me)-2-958 (85) (109) HH (10) -CH- -NH- -CH (Me)-2-959 (86) (45) HH (10) -CH- -NH- -CH (Me)-2-960 (86) (46) HH (10) -CH- -NH- -CH (Me)-2-961 (86) (49) HH (10) -CH- -NH- -CH (Me)-2-962 (86) (51) HH (10) -CH- -NH- -CH (Me)-2-963 (86) (63) HH (10) -CH- -NH- -CH (Me)-2-964 (86) (64) HH (10) -CH- -NH- -CH (Me)-2-965 (86) (66) HH (10) -CH- -NH- -CH (Me)-2-966 (86) (68) HH (10) -CH- -NH- -CH (Me)-2-967 (86) (108) HH (10) -CH- -NH- -CH (Me)-2-968 (86) (108) HH (10) -CH- -NH--(CH_Two)_Two-2-969 (86) (108) HH (10) N -NH- -CH (Me)-2-970 (87) (108) HH (10) -CH- -NH- -CH (Me)-2 -971 (86) (109) HH (10) -CH- -NH- -CH (Me)-2-972 (86) (109) HH (10) -CH- -NH--(CH_Two)_Two-2-973 (86) (109) HH (10) N -NH- -CH (Me)-2-974 (87) (109) HH (10) -CH- -NH- -CH (Me)-2 -975 (88) (64) HH (10) -CH- -NH- -CH (Me)-2-976 (88) (108) HH (10) -CH- -NH- -CH (Me)-2 -977 (88) (109) HH (10) -CH- -NH- -CH (Me)-2-978 (89) (108) HH (10) -CH- -NH- -CH (Me)-2 -979 (89) (109) HH (10) -CH- -NH- -CH (Me)-2-980 (90) (64) HH (10) -CH- -NH- -CH (Me)-2 -981 (90) (66) HH (10) -CH- -NH- -CH (Me)-2-982 (90) (108) HH (10) -CH- -NH- -CH (Me) -2 -983 (90) (109) HH (10) -CH- -NH- -CH (Me)-2-984 (91) (108) HH (10) -CH- -NH- -CH (Me) -2 -985 (91) (109) HH (10) -CH- -NH- -CH (Me)-2-986 (92) (108) HH (10) -CH- -NH- -CH (Me)-2 -987 (92) (109) HH (10) -CH- -NH- -CH (Me)-2-988 (92) (64) HH (10) -CH- -NH- -CH (Me)-2 -989 (93) (108) HH (10) -CH- -NH- -CH (Me)-2-990 (93) (109) HH (10) -CH- -NH- -CH (Me)-2 -991 (94) (108) HH (10) -CH- -NH- -CH (Me)-2-992 (94) (109) HH (10) -CH- -NH- -CH (Me)-2 -993 (95) (46) HH (10) -CH- -NH- -CH (Me)-2-994 (95) (64) HH (10) -CH- -NH- -CH (Me)-2 -995 (95) (108) HH (10) -CH- -NH- -CH (Me)-2-996 (95) (109) HH (10) -CH- -NH- -CH (Me)-2-997 (96) (46) HH (10) -CH- -NH- -CH (Me)-2-998 (96) (108) HH (10) -CH- -NH- -CH (Me)-2-999 (96) (108) HH (10) -CH- -NH--(CH_Two)_Two-2-1000 (96) (109) H H (10) -CH- -NH- -CH (Me)-2-1001 (96) (109) H H (10) -CH- -NH--(CH_Two)_Two-2-1002 (97) (108) HH (10) -CH- -NH- -CH (Me)-2-1003 (97) (109) HH (10) -CH- -NH- -CH (Me) -2-1004 (98) (108) HH (10) -CH- -NH- -CH (Me)-2-1005 (98) (109) HH (10) -CH- -NH- -CH (Me) -2-1006 (99) (108) HH (10) -CH- -NH- -CH (Me)-2-1007 (99) (109) HH (10) -CH- -NH- -CH (Me) -2-1008 (100) (108) HH (10) -CH- -NH- -CH (Me)-2-1009 (100) (109) HH (10) -CH- -NH- -CH (Me) -2-1010 (101) (46) HH (10) -CH- -NH- -CH (Me)-2-1011 (101) (64) HH (10) -CH- -NH- -CH (Me) -2-1012 (101) (108) HH (10) -CH- -NH- -CH (Me)-2-1013 (101) (109) HH (10) -CH- -NH- -CH (Me) -2-1014 (101) (64) HH (10) N -NH- -CH (Me)-2-1015 (101) (109) HH (10) N -NH- -CH (Me)-2-1016 (102) (46) HH (10) -CH- -NH- -CH (Me)-2-1017 (102) (64) HH (10) -CH- -NH- -CH (Me)-2-1018 (102) (108) HH (10) -CH- -NH- -CH (Me)-2-1019 (102) (109) HH (10) -CH- -NH- -CH (Me)-2-1020 (102) (64) HH (10) N -NH- -CH (Me)-2-1021 (102) (108) HH (10) N -NH- -CH (Me)-2-1022 (102) ( 109) HH (10) N -NH- -CH (Me)-2-1023 (103) (46) HH (10) -CH- -NH-- CH (Me)-2-1024 (103) (49) HH (10) -CH- -NH- -CH (Me)-2-1025 (103) (51) HH (10) -CH- -NH-- CH (Me)-2-1026 (103) (63) HH (10) -CH- -NH- -CH (Me)-2-1027 (103) (64) HH (10) -CH- -NH-- CH (Me)-2-1028 (103) (66) HH (10) -CH- -NH- -CH (Me)-2-1029 (103) (68) HH (10) -CH- -NH-- CH (Me)-2-1030 (103) (108) HH (10) -CH- -NH- -CH (Me)-2-1031 (103) (108) HH (10) N -NH- -CH ( Me)-2-1032 (103) (109) HH (10) -CH- -NH- -CH (Me)-2-1033 (103) (109) HH (10) N -NH- -CH (Me) -2-1034 (104) (108) HH (10) -CH- -NH- -CH (Me)-2-1035 (104) (109) HH (10) -CH- -NH- -CH (Me) -2-1036 (105) (108) HH (10) -CH- -NH- -CH (Me)-2-1037 (105) (109) HH (10) -CH- -NH- -CH (Me) -2-1038 (106) (46) HH (10) -CH- -NH- -CH (Me)-2-1039 (106) (64) HH (10) -CH- -NH- -CH (Me) -2-1040 (106) (108) HH (10) -CH- -NH- -CH (Me)-2-1041 (106) (109) HH (10) -CH- -NH- -CH (Me) -2-1042 (106) (64) HH (10) N -NH- -CH (Me)-2-1043 (106) (108) HH (10) N -NH- -CH (Me)-2-1044 (106) (109) HH (10) N -NH- -CH (Me)-2-1045 (107) (108) HH (10)- CH- -NH- -CH (Me)-2-1046 (107) (109) HH (10) -CH- -NH- -CH (Me)-2-1047 (108) (37) HH (10)- CH- -NH- -CH (Me)-2-1048 (108) (38) HH (10) -CH- -NH- -CH (Me)-2-1049 (108) (44) HH (10)- CH- -NH- -CH (Me)-2-1050 (108) (45) HH (10) -CH- -NH- -CH_Two-2-1051 (108) (45) HH (10) -CH- -NH- -CH (Me)-2-1052 (108) (45) HH (10) -CH- -O- -CH (Me) -2-1053 (108) (45) HH (10) -CH- -S- -CH (Me)-2-1054 (108) (45) HH (10) -CH- -NHCO- -CH (Me) -2-1055 (108) (45) 4-FH (10) -CH- -NH- -CH (Me)-2-1056 (108) (45) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1057 (108) (46) HH (10) -CH- -NH- single bond 2-1058 (108) (46) HH (10) -CH- -NH- -CH_Two-2-1059 (108) (46) HH (10) -CH- -NH- -CH (Me)-2-1060 (108) (46) HH (10) -CH- -NH- -CH (Et) -2-1061 (108) (46) HH (10) -CH- -O- -CH (Me)-2-1062 (108) (46) HH (10) -CH- -S- -CH (Me) -2-1063 (108) (46) HH (10) -CH- -NHCO- -CH (Me)-2-1064 (108) (46) 4-FH (10) -CH- -NH- -CH ( (Me)-2-1065 (108) (46) 5-FH (10) -CH- -NH- -CH (Me)-2-1066 (108) (46) 4-Cl H (10) -CH-- NH- -CH (Me)-2-1067 (108) (46) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1068 (108) (46) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-1069 (108) (46) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-1070 (108) (46) HH (10) N -NH- -CH (Me)-2-1071 (108) (46) HH (10) N -O- -CH (Me)-2-1072 (108) (46) HH (10) N -S- -CH (Me)-2-1073 (108) (46) HH (10) N -NHCO- -CH (Me)-2-1074 (108) (47) HH (10)- CH- -NH- -CH (Me)-2-1075 (108) (48) HH (10) -CH- -NH- -CH (Me)-2-1076 (108) (49) HH (10)- CH- -NH- -CH_Two-2-1077 (108) (49) HH (10) -CH- -NH- -CH (Me)-2-1078 (108) (49) HH (10) -CH- -O- -CH (Me) -2-1079 (108) (49) HH (10) -CH- -S- -CH (Me)-2-1080 (108) (49) HH (10) -CH- -NHCO- -CH (Me) -2-1081 (108) (49) 4-FH (10) -CH- -NH- -CH (Me)-2-1082 (108) (49) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1083 (108) (49) HH (10) N -NH- -CH (Me)-2-1084 (108) (50) HH (10) -CH- -NH- -CH (Me)-2-1085 (108) (51) HH (10) -CH- -NH- -CH_Two-2-1086 (108) (51) HH (10) -CH- -NH- -CH (Me)-2-1087 (108) (51) HH (10) -CH- -O- -CH (Me) -2-1088 (108) (51) HH (10) -CH- -S- -CH (Me)-2-1089 (108) (51) HH (10) -CH- -NHCO- -CH (Me) -2-1090 (108) (51) 4-FH (10) -CH- -NH- -CH (Me)-2-1091 (108) (51) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1092 (108) (51) HH (10) N -NH- -CH (Me)-2-1093 (108) (58) HH (10) -CH- -NH- -CH (Me)-2-1094 (108) (59) HH (10) -CH- -NH- -CH (Me)-2-1095 (108) (62) HH (10) -CH- -NH- -CH (Me)-2-1096 (108) (63) HH (10) -CH- -NH- -CH_Two-2-1097 (108) (63) HH (10) -CH- -NH- -CH (Me)-2-1098 (108) (63) HH (10) -CH- -O- -CH (Me) -2-1099 (108) (63) HH (10) -CH- -S- -CH (Me)-2-1100 (108) (63) HH (10) -CH- -NHCO- -CH (Me) -2-1101 (108) (63) 4-FH (10) -CH- -NH- -CH (Me)-2-1102 (108) (63) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1103 (108) (63) HH (10) N -NH- -CH (Me)-2-1104 (108) (64) HH (10) -CH- -NH- single bond 2-1 105 (108) (64) HH (10) -CH- -NH- -CH_Two-2-1106 (108) (64) HH (10) -CH- -NH- -CH (Me)-2-1107 (108) (64) HH (10) -CH- -NH- -CH (Et) -2-1108 (108) (64) HH (10) -CH- -O- -CH (Me)-2-1109 (108) (64) HH (10) -CH- -S- -CH (Me) -2-1110 (108) (64) HH (10) -CH- -NHCO- -CH (Me)-2-1111 (108) (64) 4-FH (10) -CH- -NH- -CH ( (Me)-2-1112 (108) (64) 5-FH (10) -CH- -NH- -CH (Me)-2-1113 (108) (64) 4-Cl H (10) -CH-- NH- -CH (Me)-2-1114 (108) (64) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1115 (108) (64) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-1116 (108) (64) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-1117 (108) (64) HH (10) N -NH- -CH (Me)-2-1118 (108) (64) HH (10) N -O- -CH (Me)-2-1119 (108) (64) HH (10) N -S- -CH (Me)-2-1120 (108) (64) HH (10) N -NHCO- -CH (Me)-2-1121 (108) (65) HH (10)- CH- -NH- -CH (Me)-2-1122 (108) (66) HH (10) -CH- -NH- -CH_Two-2-1123 (108) (66) HH (10) -CH- -NH- -CH (Me)-2-1124 (108) (66) HH (10) -CH- -O- -CH (Me) -2-1125 (108) (66) HH (10) -CH- -S- -CH (Me)-2-1126 (108) (66) 4-FH (10) -CH- -NH- -CH ( Me)-2-1127 (108) (66) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1128 (108) (66) HH (10) N -NH- -CH (Me)-2-1129 (108) (67) HH (10) -CH- -NH- -CH (Me)-2-1130 (108) (68) HH (10) -CH- -NH- -CH_Two-2-1131 (108) (68) HH (10) -CH- -NH- -CH (Me)-2-1132 (108) (68) HH (10) -CH- -O- -CH (Me) -2-1133 (108) (68) HH (10) -CH- -S- -CH (Me)-2-1134 (108) (68) HH (10) -CH- -NHCO- -CH (Me) -2-1135 (108) (68) 4-FH (10) -CH- -NH- -CH (Me)-2-1136 (108) (68) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1137 (108) (68) HH (10) N -NH- -CH (Me)-2-1138 (108) (72) HH (10) -CH- -NH- -CH (Me)-2-1139 (108) (73) HH (10) -CH- -NH- -CH (Me)-2-1140 (108) (74) HH (10) -CH- -NH- -CH (Me)-2-1141 (108) (75) HH (10) -CH- -NH- -CH (Me)-2-1142 (108) (76) HH (10) -CH- -NH- -CH (Me)-2-1143 (108) (77) HH (10) -CH- -NH- -CH (Me)-2-1144 (108) (101) HH (10) -CH- -NH- -CH (Me)-2-1145 (108) (102) HH (10) -CH- -NH- -CH (Me)-2-1146 (108) (103) HH (10) -CH- -NH- -CH_Two-2-1147 (108) (103) HH (10) -CH- -NH- -CH (Me)-2-1148 (108) (103) HH (10) -CH- -O- -CH (Me) -2-1149 (108) (103) HH (10) -CH- -S- -CH (Me)-2-1150 (108) (103) HH (10) -CH- -NHCO- -CH (Me) -2-1151 (108) (103) 4-FH (10) -CH- -NH- -CH (Me)-2-1152 (108) (103) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1153 (108) (103) HH (10) N -NH- -CH (Me)-2-1154 (108) (104) HH (10) -CH- -NH- -CH (Me)-2-1155 (108) (105) HH (10) -CH- -NH- -CH (Me)-2-1156 (108) (106) HH (10) -CH- -NH- -CH (Me)-2-1157 (108) (108) HH (10) -CH- -NH- single bond 2-1158 (108) (108) HH (10) -CH- -NH- -CH_Two-2-1159 (108) (108) HH (10) -CH- -NH- -CH (Me)-2-1160 (108) (108) HH (10) -CH- -NH- -CH (Et) -2-1161 (108) (108) HH (10) -CH- -O- -CH (Me)-2-1162 (108) (108) HH (10) -CH- -S- -CH (Me) -2-1163 (108) (108) HH (10) -CH- -NHCO- -CH (Me)-2-1164 (108) (108) 4-FH (10) -CH- -NH- -CH ( (Me)-2-1165 (108) (108) 5-FH (10) -CH- -NH- -CH (Me)-2-1166 (108) (108) 4-Cl H (10) -CH-- NH- -CH (Me)-2-1167 (108) (108) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1168 (108) (108) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-1169 (108) (108) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-1170 (108) (108) HH (10) N -NH- -CH (Me)-2-1171 (108) (108) HH (10) N -O- -CH (Me)-2-1172 (108) (108) HH (10) N -S- -CH (Me)-2-1173 (108) (108) HH (10) N -NHCO- -CH (Me)-2-1174 (108) (109) HH (10)- CH- -NH- single bond 2-1175 (108) (109) HH (10) -CH- -NH- -CH_Two-2-1176 (108) (109) HH (10) -CH- -NH- -CH (Me)-2-1177 (108) (109) HH (10) -CH- -NH- -CH (Et) -2-1178 (108) (109) HH (10) -CH- -O- -CH (Me)-2-1179 (108) (109) HH (10) -CH- -S- -CH (Me) -2-1180 (108) (109) HH (10) -CH- -NHCO- -CH (Me)-2-1181 (108) (109) 4-FH (10) -CH- -NH- -CH ( (Me)-2-1182 (108) (109) 5-FH (10) -CH- -NH- -CH (Me)-2-1183 (108) (109) 4-Cl H (10) -CH-- NH- -CH (Me)-2-1184 (108) (109) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1185 (108) (109) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-1186 (108) (109) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-1187 (108) (109) HH (10) N -NH- -CH (Me)-2-1188 (108) (109) HH (10) N -O- -CH (Me)-2-1189 (108) (109) HH (10) N -S- -CH (Me)-2-1190 (108) (109) HH (10) N -NHCO- -CH (Me)-2-1191 (109) (37) HH (10)- CH- -NH- -CH (Me)-2-1192 (109) (38) HH (10) -CH- -NH- -CH (Me)-2-1193 (109) (44) HH (10)- CH- -NH- -CH (Me)-2-1194 (109) (45) HH (10) -CH- -NH- -CH_Two-2-1195 (109) (45) HH (10) -CH- -NH- -CH (Me)-2-1196 (109) (45) HH (10) -CH- -O- -CH (Me) -2-1197 (109) (45) HH (10) -CH- -S- -CH (Me)-2-1198 (109) (45) HH (10) -CH- -NHCO- -CH (Me) -2-1199 (109) (45) 4-FH (10) -CH- -NH- -CH (Me)-2-1200 (109) (45) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1201 (109) (46) HH (10) -CH- -NH- single bond 2-1202 (109) (46) HH (10) -CH- -NH- -CH_Two-2-1203 (109) (46) HH (10) -CH- -NH- -CH (Me)-2-1204 (109) (46) HH (10) -CH- -NH- -CH (Et) -2-1205 (109) (46) HH (10) -CH- -O- -CH (Me)-2-1206 (109) (46) HH (10) -CH- -S- -CH (Me) -2-1207 (109) (46) HH (10) -CH- -NHCO- -CH (Me)-2-1208 (109) (46) 4-FH (10) -CH- -NH- -CH ( Me)-2-1209 (109) (46) 5-FH (10) -CH- -NH- -CH (Me)-2-1210 (109) (46) 4-Cl H (10) -CH-- NH- -CH (Me)-2-1211 (109) (46) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1212 (109) (46) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-1213 (109) (46) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-1214 (109) (46) HH (10) N -NH- -CH (Me)-2-1215 (109) (46) HH (10) N -O- -CH (Me)-2-1216 (109) (46) HH (10) N -S- -CH (Me)-2-1217 (109) (46) HH (10) N -NHCO- -CH (Me)-2-1218 (109) (47) HH (10)- CH- -NH- -CH (Me)-2-1219 (109) (48) HH (10) -CH- -NH- -CH (Me)-2-1220 (109) (49) HH (10)- CH- -NH- -CH_Two-2-1221 (109) (49) HH (10) -CH- -NH- -CH (Me)-2-1222 (109) (49) HH (10) -CH- -O- -CH (Me) -2-1223 (109) (49) HH (10) -CH- -S- -CH (Me)-2-1224 (109) (49) HH (10) -CH- -NHCO- -CH (Me) -2-1225 (109) (49) 4-FH (10) -CH- -NH- -CH (Me)-2-1226 (109) (49) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1227 (109) (49) HH (10) N -NH- -CH (Me)-2-1228 (109) (50) HH (10) -CH- -NH- -CH (Me)-2-1229 (109) (50) HH (10) N -NH- -CH (Me)-2-1230 (109) (51) HH (10) -CH- -NH- -CH_Two-2-1231 (109) (51) HH (10) -CH- -NH- -CH (Me)-2-1232 (109) (51) HH (10) -CH- -O- -CH (Me) -2-1233 (109) (51) HH (10) -CH- -S- -CH (Me)-2-1234 (109) (51) HH (10) -CH- -NHCO- -CH (Me) -2-1235 (109) (51) 4-FH (10) -CH- -NH- -CH (Me)-2-1236 (109) (51) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1237 (109) (51) HH (10) N -NH- -CH (Me)-2-1238 (109) (58) HH (10) -CH- -NH- -CH (Me)-2-1239 (109) (59) HH (10) -CH- -NH- -CH (Me)-2-1240 (109) (62) HH (10) -CH- -NH- -CH (Me)-2-1241 (109) (63) HH (10) -CH- -NH- -CH_Two-2-1242 (109) (63) HH (10) -CH- -NH- -CH (Me)-2-1243 (109) (63) HH (10) -CH- -O- -CH (Me) -2-1244 (109) (63) HH (10) -CH- -S- -CH (Me)-2-1245 (109) (63) HH (10) -CH- -NHCO- -CH (Me) -2-1246 (109) (63) 4-FH (10) -CH- -NH- -CH (Me)-2-1247 (109) (63) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1248 (109) (63) HH (10) N -NH- -CH (Me)-2-1249 (109) (64) HH (10) -CH- -NH- single bond 2-1250 (109) (64) HH (10) -CH- -NH- -CH_Two-2-1251 (109) (64) HH (10) -CH- -NH- -CH (Me)-2-1252 (109) (64) HH (10) -CH- -NH- -CH (Et) -2-1253 (109) (64) HH (10) -CH- -O- -CH (Me)-2-1254 (109) (64) HH (10) -CH- -S- -CH (Me) -2-1255 (109) (64) HH (10) -CH- -NHCO- -CH (Me)-2-1256 (109) (64) 4-FH (10) -CH- -NH- -CH ( Me)-2-1257 (109) (64) 5-FH (10) -CH- -NH- -CH (Me)-2-1258 (109) (64) 4-Cl H (10) -CH-- NH- -CH (Me)-2-1259 (109) (64) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1260 (109) (64) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-1261 (109) (64) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-1262 (109) (64) HH (10) N -NH- -CH (Me)-2-1263 (109) (64) HH (10) N -O- -CH (Me)-2-1264 (109) (64) HH (10) N -S- -CH (Me)-2-1265 (109) (64) HH (10) N -NHCO- -CH (Me)-2-1266 (109) (65) HH (10)- CH- -NH- -CH (Me)-2-1267 (109) (66) HH (10) -CH- -NH- -CH_Two-2-1268 (109) (66) HH (10) -CH- -NH- -CH (Me)-2-1269 (109) (66) HH (10) -CH- -O- -CH (Me) -2-1270 (109) (66) HH (10) -CH- -S- -CH (Me)-2-1271 (109) (66) 4-FH (10) -CH- -NH- -CH ( Me)-2-1272 (109) (66) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1273 (109) (66) HH (10) N -NH- -CH (Me)-2-1274 (109) (67) HH (10) -CH- -NH- -CH (Me)-2-1275 (109) (68) HH (10) -CH- -NH- -CH_Two-2-1276 (109) (68) HH (10) -CH- -NH- -CH (Me)-2-1277 (109) (68) HH (10) -CH- -O- -CH (Me) -2-1278 (109) (68) HH (10) -CH- -S- -CH (Me)-2-1279 (109) (68) HH (10) -CH- -NHCO- -CH (Me) -2-1280 (109) (68) 4-FH (10) -CH- -NH- -CH (Me)-2-1281 (109) (68) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1282 (109) (68) HH (10) N -NH- -CH (Me)-2-1283 (109) (72) HH (10) -CH- -NH- -CH (Me)-2-1284 (109) (73) HH (10) -CH- -NH- -CH (Me)-2-1285 (109) (74) HH (10) -CH- -NH- -CH (Me)-2-1286 (109) (75) HH (10) -CH- -NH- -CH (Me)-2-1287 (109) (76) HH (10) -CH- -NH- -CH (Me)-2-1288 (109) (77) HH (10) -CH- -NH- -CH (Me)-2-1289 (109) (101) HH (10) -CH- -NH- -CH (Me)-2-1290 (109) (102) HH (10) -CH- -NH- -CH (Me)-2-1291 (109) (103) HH (10) -CH- -NH- -CH_Two-2-1292 (109) (103) HH (10) -CH- -NH- -CH (Me)-2-1293 (109) (103) HH (10) -CH- -O- -CH (Me) -2-1294 (109) (103) HH (10) -CH- -S- -CH (Me)-2-1295 (109) (103) HH (10) -CH- -NHCO- -CH (Me) -2-1296 (109) (103) 4-FH (10) -CH- -NH- -CH (Me)-2-1297 (109) (103) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1298 (109) (103) HH (10) N -NH- -CH (Me)-2-1299 (109) (104) HH (10) -CH- -NH- -CH (Me)-2-1300 (109) (105) HH (10) -CH- -NH- -CH (Me)-2-1301 (109) (106) HH (10) -CH- -NH- -CH (Me)-2-1302 (109) (108) HH (10) -CH- -NH- single bond 2-1303 (109) (108) HH (10) -CH- -NH- -CH_Two-2-1304 (109) (108) HH (10) -CH- -NH- -CH (Me)-2-1305 (109) (108) HH (10) -CH- -NH- -CH (Et) -2-1306 (109) (108) HH (10) -CH- -O- -CH (Me)-2-1307 (109) (108) HH (10) -CH- -S- -CH (Me) -2-1308 (109) (108) HH (10) -CH- -NHCO- -CH (Me)-2-1309 (109) (108) 4-FH (10) -CH- -NH- -CH ( Me)-2-1310 (109) (108) 5-FH (10) -CH- -NH- -CH (Me)-2-1311 (109) (108) 4-Cl H (10) -CH-- NH- -CH (Me)-2-1312 (109) (108) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1313 (109) (108) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-1314 (109) (108) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-1315 (109) (108) HH (10) N -NH- -CH (Me)-2-1316 (109) (108) HH (10) N -O- -CH (Me)-2-1317 (109) (108) HH (10) N -S- -CH (Me)-2-1318 (109) (108) HH (10) N -NHCO- -CH (Me)-2-1319 (109) (109) HH (10)- CH- -NH- single bond 2-1320 (109) (109) HH (10) -CH- -NH- -CH_Two-2-1321 (109) (109) HH (10) -CH- -NH- -CH (Me)-2-1322 (109) (109) HH (10) -CH- -NH- -CH (Et) -2-1323 (109) (109) HH (10) -CH- -O- -CH (Me)-2-1324 (109) (109) HH (10) -CH- -S- -CH (Me) -2-1325 (109) (109) HH (10) -CH- -NHCO- -CH (Me)-2-1326 (109) (109) 4-FH (10) -CH- -NH- -CH ( Me)-2-1327 (109) (109) 5-FH (10) -CH- -NH- -CH (Me)-2-1328 (109) (109) 4-Cl H (10) -CH-- NH- -CH (Me)-2-1329 (109) (109) 4-MeO H (10) -CH- -NH- -CH (Me)-2-1330 (109) (109) 5-MeO H ( 10) -CH- -NH- -CH (Me)-2-1331 (109) (109) 4-MeO 5-MeO (10) -CH- -NH- -CH (Me)-2-1332 (109) (109) HH (10) N -NH- -CH (Me)-2-1333 (109) (109) HH (10) N -O- -CH (Me)-2-1334 (109) (109) HH (10) N -S- -CH (Me)-2-1335 (109) (109) HH (10) N -NHCO- -CH (Me)-2-1336 (64) (64) HH (11)- CH- -NH- -CH (Me)-2-1337 (64) (109) HH (11) -CH- -NH- -CH (Me)-2-1338 (109) (64) HH (11)- CH- -NH- -CH (Me)-2-1339 (109) (109) HH (11) -CH- -NH- -CH (Me)-2-1340 (45) (64) HH (12)- CH- -NH- -CH (Me)-2-1341 (45) (109) HH (12) -CH- -NH- -CH (Me)-2-1342 (46) (64) HH (12) -CH- -NH- -CH (Me)-2-1343 (46) (109) HH (12) -CH- -NH- -CH (Me)-2-1344 (49) (109) HH (12) -CH- -NH- -CH (Me)-2-1345 (51) (109) HH (12) -CH- -NH- -CH (Me)-2-1346 (52) (64) HH (12) -CH- -NH- -CH (Me)-2-1347 (52) (109) HH (12) -CH- -NH- -CH (Me)-2-1348 (55) (109) HH (12) -CH- -NH- -CH (Me)-2-1349 (63) (109) HH (12) -CH- -NH- -CH (Me)-2-1350 (64) (64) HH (12) -CH- -NH- -CH (Me)-2-1351 (64) (109) HH (12) -CH- -NH- -CH (Me)-2-1352 (68) (109) HH (12) -CH- -NH- -CH (Me)-2-1353 (70) (109) HH (12) -CH- -NH- -CH (Me)-2-1354 (86) (109) HH (12) -CH- -NH- -CH (Me)-2-1355 (103) (109) HH (12) -CH- -NH- -CH (Me)-2-1356 (108) (64) HH (12) -CH- -NH- -CH (Me)-2-1357 (108) (109) HH (12) -CH- -NH- -CH (Me)-2-1358 (109) (64) HH (12) -CH- -NH- -CH (Me)-2-1359 (109) (109) HH (12) -CH- -NH- -CH (Me)-2-1360 (37) (109) HH (13) -CH- -NH- -CH (Me)-2-1361 (38) (64) HH (13) -CH- -NH- -CH (Me)-2-1362 (38) (109) HH (13) -CH- -NH- -CH (Me)-2-1363 (44) (64) HH (13) -CH- -NH- -CH (Me )-2-1364 (44) (109) HH (13) -CH- -NH- -CH (Me)-2-1365 (45) (45) HH (13) -CH- -NH- -CH (Me )-2-1366 (45) (46) HH (13) -CH- -NH- -CH (Me)-2-1367 (45) (49) HH (13) -CH- -NH- -CH (Me )-2-1368 (45) (51) HH (13) -CH- -NH- -CH (Me)-2-1369 (45) (63) HH (13) -CH- -NH- -CH (Me )-2-1370 (45) (64) HH (13) -CH- -NH- -CH (Me)-2-1371 (45) (66) HH (13) -CH- -NH- -CH (Me )-2-1372 (45) (68) HH (13) -CH- -NH- -CH (Me)-2-1373 (45) (109) HH (13) -CH- -NH- -CH (Me )-2-1374 (45) (109) HH (13) N -NH- -CH (Me)-2-1375 (46) (45) HH (13) -CH- -NH- -CH (Me)- 2-1376 (46) (46) HH (13) -CH- -NH- -CH (Me)-2-1377 (46) (49) HH (13) -CH- -NH- -CH (Me)- 2-1378 (46) (51) HH (13) -CH- -NH- -CH (Me)-2-1379 (46) (63) HH (13) -CH- -NH- -CH (Me)- 2-1380 (46) (64) HH (13) -CH- -NH- -CH (Me)-2-1381 (46) (66) HH (13) -CH- -NH- -CH (Me)- 2-1382 (46) (68) HH (13) -CH- -NH- -CH (Me)-2-1383 (46) (109) HH (13) -CH- -NH- -CH (Me)- 2-1384 (46) (109) HH (13) N -NH- -CH (Me)-2-1385 (47) (109) HH (13) -CH- -NH- -CH (Me)-2- 1386 (48) (64) HH (13) -CH- -NH- -CH (Me)-2-1387 (48) (109) HH (13) -CH- -NH- -CH (Me)-2-1388 (49) (46) HH (13) -CH- -NH- -CH (Me)-2-1389 (49) (64) HH (13) -CH- -NH- -CH (Me)-2-1390 (49) (109) HH (13) -CH- -NH- -CH (Me)-2-1391 (49) (64) HH (13) N -NH- -CH (Me)-2-1392 (49 ) (109) HH (13) N -NH- -CH (Me)-2-1393 (50) (64) HH (13) -CH- -NH- -CH (Me)-2-1394 (50) ( 109) HH (13) -CH- -NH- -CH (Me)-2-1395 (51) (46) HH (13) -CH- -NH- -CH (Me)-2-1396 (51) ( 64) HH (13) -CH- -NH- -CH (Me)-2-1397 (51) (109) HH (13) -CH- -NH- -CH (Me)-2-1398 (51) ( 64) HH (13) N -NH- -CH (Me)-2-1399 (51) (109) HH (13) N -NH- -CH (Me)-2-1400 (52) (45) HH ( 13) -CH- -NH- -CH (Me)-2-1401 (52) (46) HH (13) -CH- -NH- -CH (Me)-2-1402 (52) (49) HH ( 13) -CH- -NH- -CH (Me)-2-1403 (52) (51) HH (13) -CH- -NH- -CH (Me)-2-1404 (52) (63) HH ( 13) -CH- -NH- -CH (Me)-2-1405 (52) (64) HH (13) -CH- -NH- -CH (Me)-2-1406 (52) (66) HH ( 13) -CH- -NH- -CH (Me)-2-1407 (52) (68) HH (13) -CH- -NH- -CH (Me)-2-1408 (52) (109) HH ( 13) -CH- -NH- -CH (Me)-2-1409 (52) (109) HH (13) N -NH- -CH (Me)-2-1410 (53) (64) HH (13) -CH- -NH- -CH (Me)-2-1411 (53) (109) HH (13) -CH- -NH- -CH (Me)-2-1412 (55) (46) HH (13) -CH- -NH- -CH (Me)-2-1413 (55) (64) HH (13) -CH- -NH- -CH (Me)-2-1414 (55) (109) HH (13) -CH- -NH- -CH (Me)-2-1415 (55) (64) HH (13) N -NH- -CH (Me)-2-1416 (55) (109) HH (13) N- NH- -CH (Me)-2-1417 (57) (109) HH (13) -CH- -NH- -CH (Me)-2-1418 (58) (109) HH (13) -CH-- NH- -CH (Me)-2-1419 (59) (64) HH (13) -CH- -NH- -CH (Me)-2-1420 (59) (109) HH (13) -CH-- NH- -CH (Me)-2-1421 (62) (64) HH (13) -CH- -NH- -CH (Me)-2-1422 (62) (109) HH (13) -CH-- NH- -CH (Me)-2-1423 (63) (46) HH (13) -CH- -NH- -CH (Me)-2-1424 (63) (64) HH (13) -CH-- NH- -CH (Me)-2-1425 (63) (109) HH (13) -CH- -NH- -CH (Me)-2-1426 (63) (64) HH (13) N -NH- -CH (Me)-2-1427 (63) (109) HH (13) N -NH- -CH (Me)-2-1428 (64) (45) HH (13) -CH- -NH- -CH (Me)-2-1429 (64) (46) HH (13) -CH- -NH- -CH (Me)-2-1430 (64) (49) HH (13) -CH- -NH-- CH (Me)-2-1431 (64) (51) HH (13) -CH- -NH- -CH (Me)-2-1432 (64) (63) HH (13) -CH- -NH-- CH (Me)-2-1433 (64) (64) HH (13) -CH- -NH- -CH (Me)-2-1434 (64) (66) HH (13) -CH- -NH-- CH (Me)-2-1435 (64) (68) HH (13) -CH- -NH- -CH (Me)-2-1436 (64) (109) HH (13) -CH- -NH-- CH (Me)-2-1437 (64) (109) HH (13) N -NH- -CH (Me)-2-1438 (66) (64) HH (13) -CH- -NH- -CH ( (Me)-2-1439 (66) (109) HH (13) -CH- -NH- -CH (Me)-2-1440 (68) (64) HH (13) -CH- -NH- -CH ( (Me)-2-1441 (68) (109) HH (13) -CH- -NH- -CH (Me)-2-1442 (68) (64) HH (13) N -NH- -CH (Me) -2-1443 (68) (109) HH (13) N -NH- -CH (Me)-2-1444 (69) (109) HH (13) -CH- -NH- -CH (Me)-2 -1445 (70) (64) HH (13) -CH- -NH- -CH (Me)-2-1446 (70) (109) HH (13) -CH- -NH- -CH (Me)-2 -1447 (70) (64) HH (13) N -NH- -CH (Me)-2-1448 (70) (109) HH (13) N -NH- -CH (Me)-2-1449 (73 ) (109) HH (13) -CH- -NH- -CH (Me)-2-1450 (75) (109) HH (13) -CH- -NH- -CH (Me)-2-1451 (76 ) (109) HH (13) -CH- -NH- -CH (Me)-2-1452 (85) (109) HH (13) -CH- -NH- -CH (Me)-2-145 3 (86) (64) HH (13) -CH- -NH- -CH (Me)-2-1454 (86) (109) HH (13) -CH- -NH- -CH (Me)-2- 1455 (86) (64) HH (13) N -NH- -CH (Me)-2-1456 (86) (109) HH (13) N -NH- -CH (Me)-2-1457 (88) (109) HH (13) -CH- -NH- -CH (Me)-2-1458 (90) (109) HH (13) -CH- -NH- -CH (Me)-2-1459 (92) (109) HH (13) -CH- -NH- -CH (Me)-2-1460 (95) (109) HH (13) -CH- -NH- -CH (Me)-2-1461 (101) (64) HH (13) -CH- -NH- -CH (Me)-2-1462 (101) (109) HH (13) -CH- -NH- -CH (Me)-2-1463 (102) (64) HH (13) -CH- -NH- -CH (Me)-2-1464 (102) (109) HH (13) -CH- -NH- -CH (Me)-2-1465 (103) (64) HH (13) -CH- -NH- -CH (Me)-2-1466 (103) (109) HH (13) -CH- -NH- -CH (Me)-2-1467 (103) (64) HH (13) N -NH- -CH (Me)-2-1468 (103) (109) HH (13) N -NH- -CH (Me)-2-1469 (106) (64) HH (13) -CH- -NH- -CH (Me)-2-1470 (106) (109) HH (13) -CH- -NH- -CH (Me)-2-1471 (108) (45) HH (13) -CH- -NH- -CH (Me)-2-1472 (108) (46) HH (13) -CH- -NH- -CH (Me)-2-1473 (108) (49) HH (13) -CH- -NH- -CH (Me)-2-1474 (108) (51) HH (13) -CH- -NH- -CH (Me)-2- 1475 (108) (63) HH (13) -CH- -NH- -CH (Me)-2-1476 (108) (64) HH (13) -CH- -NH- -CH (Me)-2- 1477 (108) (66) HH (13) -CH- -NH- -CH (Me)-2-1478 (108) (68) HH (13) -CH- -NH- -CH (Me)-2- 1479 (108) (109) HH (13) -CH- -NH- -CH (Me)-2-1480 (108) (109) HH (13) N -NH- -CH (Me)-2-1481 ( 109) (45) HH (13) -CH- -NH- -CH (Me)-2-1482 (109) (46) HH (13) -CH- -NH- -CH (Me)-2-1483 ( 109) (49) HH (13) -CH- -NH- -CH (Me)-2-1484 (109) (51) HH (13) -CH- -NH- -CH (Me)-2-1485 ( 109) (63) HH (13) -CH- -NH- -CH (Me)-2-1486 (109) (64) HH (13) -CH- -NH- -CH (Me)-2-1487 ( 109) (66) HH (13) -CH- -NH- -CH (Me)-2-1488 (109) (68) HH (13) -CH- -NH- -CH (Me)-2-1489 ( 109) (109) HH (13) -CH- -NH- -CH (Me)-2-1490 (109) (109) HH (13) N -NH- -CH (Me)-2-1491 (64) (64) HH (14) -CH- -NH- -CH (Me)-2-1492 (64) (109) HH (14) -CH- -NH- -CH (Me)-2-1493 (109) (64) HH (14) -CH- -NH- -CH (Me)-2-1494 (109) (109) HH (14) -CH- -NH- -CH (Me)-2-1495 (38) (109) HH (15) -CH- -NH- -CH (Me)-2-1496 (44) (109) HH (15) -CH- -NH-- CH (Me)-2-1497 (45) (46) HH (15) -CH- -NH- -CH (Me)-2-1498 (45) (64) HH (15) -CH- -NH-- CH (Me)-2-1499 (45) (109) HH (15) -CH- -NH- -CH (Me)-2-1500 (45) (64) HH (15) N -NH- -CH ( Me)-2-1501 (45) (109) HH (15) N -NH- -CH (Me)-2-1502 (46) (46) HH (15) -CH- -NH- -CH (Me) -2-1503 (46) (64) HH (15) -CH- -NH- -CH (Me)-2-1504 (46) (109) HH (15) -CH- -NH- -CH (Me) -2-1505 (46) (64) HH (15) N -NH- -CH (Me)-2-1506 (46) (109) HH (15) N -NH- -CH (Me)-2-1507 (48) (109) HH (15) -CH- -NH- -CH (Me)-2-1508 (49) (64) HH (15) -CH- -NH- -CH (Me)-2-1509 (49) (109) HH (15) -CH- -NH- -CH (Me)-2-1510 (50) (109) HH (15) -CH- -NH- -CH (Me)-2-1511 (51) (64) HH (15) -CH- -NH- -CH (Me)-2-1512 (51) (109) HH (15) -CH- -NH- -CH (Me)-2-1513 (52) (46) HH (15) -CH- -NH- -CH (Me)-2-1514 (52) (64) HH (15) -CH- -NH- -CH (Me)-2-1515 (52) (109) HH (15) -CH- -NH- -CH (Me)-2-1516 (52) (64) HH (15) N -NH- -CH (Me)-2-1517 (52 ) (109) HH (15) N -NH- -CH (Me)-2-1518 (53) (109) HH (15) -CH- -NH- -CH (Me)-2-1519 (5 5) (64) HH (15) -CH- -NH- -CH (Me)-2-1520 (55) (109) HH (15) -CH- -NH- -CH (Me)-2-1521 ( 59) (109) HH (15) -CH- -NH- -CH (Me)-2-1522 (62) (109) HH (15) -CH- -NH- -CH (Me)-2-1523 ( 63) (64) HH (15) -CH- -NH- -CH (Me)-2-1524 (63) (109) HH (15) -CH- -NH- -CH (Me)-2-1525 ( 64) (46) HH (15) -CH- -NH- -CH (Me)-2-1526 (64) (64) HH (15) -CH- -NH- -CH (Me)-2-1527 ( 64) (109) HH (15) -CH- -NH- -CH (Me)-2-1528 (64) (64) HH (15) N -NH- -CH (Me)-2-1529 (64) (109) HH (15) N -NH- -CH (Me)-2-1530 (66) (109) HH (15) -CH- -NH- -CH (Me)-2-1531 (68) (64 ) HH (15) -CH- -NH- -CH (Me)-2-1532 (68) (109) HH (15) -CH- -NH- -CH (Me)-2-1533 (70) (64 ) HH (15) -CH- -NH- -CH (Me)-2-1534 (70) (109) HH (15) -CH- -NH- -CH (Me)-2-1535 (86) (64 ) HH (15) -CH- -NH- -CH (Me)-2-1536 (86) (109) HH (15) -CH- -NH- -CH (Me)-2-1537 (101) (109 ) HH (15) -CH- -NH- -CH (Me)-2-1538 (102) (109) HH (15) -CH- -NH- -CH (Me)-2-1539 (103) (64 ) HH (15) -CH- -NH- -CH (Me)-2-1540 (103) (109) HH (15) -CH- -NH- -CH (Me)-2-1541 ( 106) (109) HH (15) -CH- -NH- -CH (Me)-2-1542 (108) (46) HH (15) -CH- -NH- -CH (Me)-2-1543 ( 108) (64) HH (15) -CH- -NH- -CH (Me)-2-1544 (108) (109) HH (15) -CH- -NH- -CH (Me)-2-1545 ( 108) (64) HH (15) N -NH- -CH (Me)-2-1546 (108) (109) HH (15) N -NH- -CH (Me)-2-1547 (109) (46 ) HH (15) -CH- -NH- -CH (Me)-2-1548 (109) (64) HH (15) -CH- -NH- -CH (Me)-2-1549 (109) (109) ) HH (15) -CH- -NH- -CH (Me)-2-1550 (109) (64) HH (15) N -NH- -CH (Me)-2-1551 (109) (109) HH (15) N -NH- -CH (Me)-2-1552 (36) (109) HH (16) -CH- -NH- single bond 2-1553 (36) (109) HH (16) N -NH -single bond 2-1554 (37) (109) HH (16) -CH- -NH- -CH (Me)-2-1555 (38) (46) HH (16) -CH- -NH- -CH ( (Me)-2-1556 (38) (64) HH (16) -CH- -NH- -CH (Me)-2-1557 (38) (109) HH (16) -CH- -NH- -CH ( Me)-2-1558 (38) (64) HH (16) N -NH- -CH (Me)-2-1559 (38) (109) HH (16) N -NH- -CH (Me)-2 -1560 (44) (46) HH (16) -CH- -NH- -CH (Me)-2-1561 (44) (64) HH (16) -CH- -NH- -CH (Me)-2 -1562 (44) (109) HH (16) -CH- -NH- -CH (Me)-2-1563 (44) (64) HH (16) N -NH- -CH (Me)-2-1564 (44) (109) HH (16) N -NH- -CH (Me)-2-1565 (45) (37) HH (16) -CH- -NH- -CH (Me)-2-1566 (45) (38) HH (16) -CH- -NH- -CH (Me)-2-1567 (45) (44) HH (16) -CH- -NH- -CH (Me)-2-1568 (45) (45) HH (16) -CH- -NH- -CH_Two-2-1569 (45) (45) HH (16) -CH- -NH- -CH (Me)-2-1570 (45) (45) HH (16) -CH- -O- -CH (Me) -2-1571 (45) (45) HH (16) -CH- -S- -CH (Me)-2-1572 (45) (45) HH (16) -CH- -NHCO- -CH (Me) -2-1573 (45) (45) 4-FH (16) -CH- -NH- -CH (Me)-2-1574 (45) (45) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1575 (45) (45) HH (16) N -NH- -CH (Me)-2-1576 (45) (46) HH (16) -CH- -NH- single bond 2-1577 (45) (46) HH (16) -CH- -NH- -CH_Two-2-1578 (45) (46) HH (16) -CH- -NH- -CH (Me)-2-1579 (45) (46) HH (16) -CH- -NH- -CH (Et) -2-1580 (45) (46) HH (16) -CH- -O- -CH (Me)-2-1581 (45) (46) HH (16) -CH- -S- -CH (Me) -2-1582 (45) (46) HH (16) -CH- -NHCO- -CH (Me)-2-1583 (45) (46) 4-FH (16) -CH- -NH- -CH ( (Me)-2-1584 (45) (46) 5-FH (16) -CH- -NH- -CH (Me)-2-1585 (45) (46) 4-Cl H (16) -CH-- NH- -CH (Me)-2-1586 (45) (46) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1587 (45) (46) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-1588 (45) (46) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-1589 (45) (46) HH (16) N -NH- -CH (Me)-2-1590 (45) (46) HH (16) N -O- -CH (Me)-2-1591 (45) (46) HH (16) N -S- -CH (Me)-2-1592 (45) (46) HH (16) N -NHCO- -CH (Me)-2-1593 (45) (47) HH (16)- CH- -NH- -CH (Me)-2-1594 (45) (48) HH (16) -CH- -NH- -CH (Me)-2-1595 (45) (49) HH (16)- CH- -NH- -CH_Two-2-1596 (45) (49) HH (16) -CH- -NH- -CH (Me)-2-1597 (45) (49) HH (16) -CH- -O- -CH (Me) -2-1598 (45) (49) HH (16) -CH- -S- -CH (Me)-2-1599 (45) (49) HH (16) -CH- -NHCO- -CH (Me) -2-1600 (45) (49) 4-FH (16) -CH- -NH- -CH (Me)-2-1601 (45) (49) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1602 (45) (49) HH (16) N -NH- -CH (Me)-2-1603 (45) (50) HH (16) -CH- -NH- -CH (Me)-2-1604 (45) (51) HH (16) -CH- -NH- -CH_Two-2-1605 (45) (51) HH (16) -CH- -NH- -CH (Me)-2-1606 (45) (51) HH (16) -CH- -O- -CH (Me) -2-1607 (45) (51) HH (16) -CH- -S- -CH (Me)-2-1608 (45) (51) HH (16) -CH- -NHCO- -CH (Me) -2-1609 (45) (51) 4-FH (16) -CH- -NH- -CH (Me)-2-1610 (45) (51) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1611 (45) (51) HH (16) N -NH- -CH (Me)-2-1612 (45) (58) HH (16) -CH- -NH- -CH (Me)-2-1613 (45) (59) HH (16) -CH- -NH- -CH (Me)-2-1614 (45) (60) HH (16) -CH- -NH- -CH (Me)-2-1615 (45) (62) HH (16) -CH- -NH- -CH (Me)-2-1616 (45) (63) HH (16) -CH- -NH- -CH_Two-2-1617 (45) (63) HH (16) -CH- -NH- -CH (Me)-2-1618 (45) (63) HH (16) -CH- -O- -CH (Me) -2-1619 (45) (63) HH (16) -CH- -S- -CH (Me)-2-1620 (45) (63) HH (16) -CH- -NHCO- -CH (Me) -2-1621 (45) (63) 4-FH (16) -CH- -NH- -CH (Me)-2-1622 (45) (63) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1623 (45) (63) HH (16) N -NH- -CH (Me)-2-1624 (45) (64) HH (16) -CH- -NH- single bond 2-1625 (45) (64) HH (16) -CH- -NH- -CH_Two-2-1626 (45) (64) HH (16) -CH- -NH- -CH (Me)-2-1627 (45) (64) HH (16) -CH- -NH- -CH (Et) -2-1628 (45) (64) HH (16) -CH- -O- -CH (Me)-2-1629 (45) (64) HH (16) -CH- -S- -CH (Me) -2-1630 (45) (64) HH (16) -CH- -NHCO- -CH (Me)-2-1631 (45) (64) 4-FH (16) -CH- -NH- -CH ( Me)-2-1632 (45) (64) 5-FH (16) -CH- -NH- -CH (Me)-2-1633 (45) (64) 4-Cl H (16) -CH-- NH- -CH (Me)-2-1634 (45) (64) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1635 (45) (64) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-1636 (45) (64) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-1637 (45) (64) HH (16) N -NH- -CH (Me)-2-1638 (45) (64) HH (16) N -O- -CH (Me)-2-1639 (45) (64) HH (16) N -S- -CH (Me)-2-1640 (45) (64) HH (16) N -NHCO- -CH (Me)-2-1641 (45) (65) HH (16)- CH- -NH- -CH (Me)-2-1642 (45) (66) HH (16) -CH- -NH- -CH_Two-2-1643 (45) (66) HH (16) -CH- -NH- -CH (Me)-2-1644 (45) (66) HH (16) -CH- -O- -CH (Me) -2-1645 (45) (66) HH (16) -CH- -S- -CH (Me)-2-1646 (45) (66) HH (16) -CH- -NHCO- -CH (Me) -2-1647 (45) (66) 4-FH (16) -CH- -NH- -CH (Me)-2-1648 (45) (66) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1649 (45) (66) HH (16) N -NH- -CH (Me)-2-1650 (45) (67) HH (16) -CH- -NH- -CH (Me)-2-1651 (45) (68) HH (16) -CH- -NH- -CH_Two-2-1652 (45) (68) HH (16) -CH- -NH- -CH (Me)-2-1653 (45) (68) HH (16) -CH- -O- -CH (Me) -2-1654 (45) (68) HH (16) -CH- -S- -CH (Me)-2-1655 (45) (68) HH (16) -CH- -NHCO- -CH (Me) -2-1656 (45) (68) 4-FH (16) -CH- -NH- -CH (Me)-2-1657 (45) (68) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1658 (45) (68) HH (16) N -NH- -CH (Me)-2-1659 (45) (69) HH (16) -CH- -NH- -CH (Me)-2-1660 (45) (72) HH (16) -CH- -NH- -CH (Me)-2-1661 (45) (73) HH (16) -CH- -NH- -CH (Me)-2-1662 (45) (74) HH (16) -CH- -NH- -CH (Me)-2-1663 (45) (75) HH (16) -CH- -NH- -CH (Me)-2-1664 (45) (103) HH (16) -CH- -NH- -CH (Me)-2-1665 (45) (108) HH (16) -CH- -NH- -CH (Me)-2-1666 (45) (109) HH (16) -CH- -NH- single bond 2-1667 (45) (109) HH (16) -CH- -NH- -CH_Two-2-1668 (45) (109) HH (16) -CH- -NH- -CH (Me)-2-1669 (45) (109) HH (16) -CH- -NH- -CH (Et) -2-1670 (45) (109) HH (16) -CH- -O- -CH (Me)-2-1671 (45) (109) HH (16) -CH- -S- -CH (Me) -2-1672 (45) (109) HH (16) -CH- -NHCO- -CH (Me)-2-1673 (45) (109) 4-FH (16) -CH- -NH- -CH ( (Me)-2-1674 (45) (109) 5-FH (16) -CH- -NH- -CH (Me)-2-1675 (45) (109) 4-Cl H (16) -CH-- NH- -CH (Me)-2-1676 (45) (109) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1677 (45) (109) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-1678 (45) (109) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-1679 (45) (109) HH (16) N -NH- -CH (Me)-2-1680 (45) (109) HH (16) N -O- -CH (Me)-2-1681 (45) (109) HH (16) N -S- -CH (Me)-2-1682 (45) (109) HH (16) N -NHCO- -CH (Me)-2-1683 (46) (37) HH (16)- CH- -NH- -CH (Me)-2-1684 (46) (38) HH (16) -CH- -NH- -CH (Me)-2-1685 (46) (44) HH (16)- CH- -NH- -CH (Me)-2-1686 (46) (45) HH (16) -CH- -NH- -CH_Two-2-1687 (46) (45) HH (16) -CH- -NH- -CH (Me)-2-1688 (46) (45) HH (16) -CH- -O- -CH (Me) -2-1689 (46) (45) HH (16) -CH- -S- -CH (Me)-2-1690 (46) (45) HH (16) -CH- -NHCO- -CH (Me) -2-1691 (46) (45) 4-FH (16) -CH- -NH- -CH (Me)-2-1692 (46) (45) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1693 (46) (45) HH (16) N -NH- -CH (Me)-2-1694 (46) (46) HH (16) -CH- -NH- single bond 2-1695 (46) (46) HH (16) -CH- -NH- -CH_Two-2-1696 (46) (46) HH (16) -CH- -NH- -CH (Me)-2-1697 (46) (46) HH (16) -CH- -NH- -CH (Et) -2-1698 (46) (46) HH (16) -CH- -O- -CH (Me)-2-1699 (46) (46) HH (16) -CH- -S- -CH (Me) -2-1700 (46) (46) HH (16) -CH- -NHCO- -CH (Me)-2-1701 (46) (46) 4-FH (16) -CH- -NH- -CH ( (Me)-2-1702 (46) (46) 5-FH (16) -CH- -NH- -CH (Me)-2-1703 (46) (46) 4-Cl H (16) -CH-- NH- -CH (Me)-2-1704 (46) (46) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1705 (46) (46) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-1706 (46) (46) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-1707 (46) (46) HH (16) N -NH- -CH (Me)-2-1708 (46) (46) HH (16) N -O- -CH (Me)-2-1709 (46) (46) HH (16) N -S- -CH (Me)-2-1710 (46) (46) HH (16) N -NHCO- -CH (Me)-2-1711 (46) (47) HH (16)- CH- -NH- -CH (Me)-2-1712 (46) (48) HH (16) -CH- -NH- -CH (Me)-2-1713 (46) (49) HH (16)- CH- -NH- -CH_Two-2-1714 (46) (49) HH (16) -CH- -NH- -CH (Me)-2-1715 (46) (49) HH (16) -CH- -O- -CH (Me) -2-1716 (46) (49) HH (16) -CH- -S- -CH (Me)-2-1717 (46) (49) HH (16) -CH- -NHCO- -CH (Me) -2-1718 (46) (49) 4-FH (16) -CH- -NH- -CH (Me)-2-1719 (46) (49) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1720 (46) (49) HH (16) N -NH- -CH (Me)-2-1721 (46) (50) HH (16) -CH- -NH- -CH (Me)-2-1722 (46) (51) HH (16) -CH- -NH- -CH_Two-2-1723 (46) (51) HH (16) -CH- -NH- -CH (Me)-2-1724 (46) (51) HH (16) -CH- -O- -CH (Me) -2-1725 (46) (51) HH (16) -CH- -S- -CH (Me)-2-1726 (46) (51) HH (16) -CH- -NHCO- -CH (Me) -2-1727 (46) (51) 4-FH (16) -CH- -NH- -CH (Me)-2-1728 (46) (51) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1729 (46) (51) HH (16) N -NH- -CH (Me)-2-1730 (46) (58) HH (16) -CH- -NH- -CH (Me)-2-1731 (46) (59) HH (16) -CH- -NH- -CH (Me)-2-1732 (46) (60) HH (16) -CH- -NH- -CH (Me)-2-1733 (46) (62) HH (16) -CH- -NH- -CH (Me)-2-1734 (46) (63) HH (16) -CH- -NH- -CH_Two-2-1735 (46) (63) HH (16) -CH- -NH- -CH (Me)-2-1736 (46) (63) HH (16) -CH- -O- -CH (Me) -2-1737 (46) (63) HH (16) -CH- -S- -CH (Me)-2-1738 (46) (63) HH (16) -CH- -NHCO- -CH (Me) -2-1739 (46) (63) 4-FH (16) -CH- -NH- -CH (Me)-2-1740 (46) (63) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1741 (46) (63) HH (16) N -NH- -CH (Me)-2-1742 (46) (64) HH (16) -CH- -NH- single bond 2-1743 (46) (64) HH (16) -CH- -NH- -CH_Two-2-1744 (46) (64) HH (16) -CH- -NH- -CH (Me)-2-1745 (46) (64) HH (16) -CH- -NH- -CH (Et) -2-1746 (46) (64) HH (16) -CH- -O- -CH (Me)-2-1747 (46) (64) HH (16) -CH- -S- -CH (Me) -2-1748 (46) (64) HH (16) -CH- -NHCO- -CH (Me)-2-1749 (46) (64) 4-FH (16) -CH- -NH- -CH ( (Me)-2-1750 (46) (64) 5-FH (16) -CH- -NH- -CH (Me)-2-1751 (46) (64) 4-Cl H (16) -CH-- NH- -CH (Me)-2-1752 (46) (64) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1753 (46) (64) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-1754 (46) (64) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-1755 (46) (64) HH (16) N -NH- -CH (Me)-2-1756 (46) (64) HH (16) N -O- -CH (Me)-2-1757 (46) (64) HH (16) N -S- -CH (Me)-2-1758 (46) (64) HH (16) N -NHCO- -CH (Me)-2-1759 (46) (65) HH (16)- CH- -NH- -CH (Me)-2-1760 (46) (66) HH (16) -CH- -NH- -CH_Two-2-1761 (46) (66) HH (16) -CH- -NH- -CH (Me)-2-1762 (46) (66) HH (16) -CH- -O- -CH (Me) -2-1763 (46) (66) HH (16) -CH- -S- -CH (Me)-2-1764 (46) (66) HH (16) -CH- -NHCO- -CH (Me) -2-1765 (46) (66) 4-FH (16) -CH- -NH- -CH (Me)-2-1766 (46) (66) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1767 (46) (66) HH (16) N -NH- -CH (Me)-2-1768 (46) (67) HH (16) -CH- -NH- -CH (Me)-2-1769 (46) (68) HH (16) -CH- -NH- -CH_Two-2-1770 (46) (68) HH (16) -CH- -NH- -CH (Me)-2-1771 (46) (68) HH (16) -CH- -O- -CH (Me) -2-1772 (46) (68) HH (16) -CH- -S- -CH (Me)-2-1773 (46) (68) HH (16) -CH- -NHCO- -CH (Me) -2-1774 (46) (68) 4-FH (16) -CH- -NH- -CH (Me)-2-1775 (46) (68) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1776 (46) (68) HH (16) N -NH- -CH (Me)-2-1777 (46) (69) HH (16) -CH- -NH- -CH (Me)-2-1778 (46) (72) HH (16) -CH- -NH- -CH (Me)-2-1779 (46) (73) HH (16) -CH- -NH- -CH (Me)-2-1780 (46) (74) HH (16) -CH- -NH- -CH (Me)-2-1781 (46) (75) HH (16) -CH- -NH- -CH (Me)-2-1782 (46) (76) HH (16) -CH- -NH- -CH (Me)-2-1783 (46) (77) HH (16) -CH- -NH- -CH (Me)-2-1784 (46) (109) HH (16) -CH- -NH- single bond 2-1785 (46) (109) HH (16) -CH- -NH- -CH_Two-2-1786 (46) (109) HH (16) -CH- -NH- -CH (Me)-2-1787 (46) (109) HH (16) -CH- -NH- -CH (Et) -2-1788 (46) (109) HH (16) -CH- -O- -CH (Me)-2-1789 (46) (109) HH (16) -CH- -S- -CH (Me) -2-1790 (46) (109) HH (16) -CH- -NHCO- -CH (Me)-2-1791 (46) (109) 4-FH (16) -CH- -NH- -CH ( (Me)-2-1792 (46) (109) 5-FH (16) -CH- -NH- -CH (Me)-2-1793 (46) (109) 4-Cl H (16) -CH-- NH- -CH (Me)-2-1794 (46) (109) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1795 (46) (109) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-1796 (46) (109) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-1797 (46) (109) HH (16) N -NH- -CH (Me)-2-1798 (46) (109) HH (16) N -O- -CH (Me)-2-1799 (46) (109) HH (16) N -S- -CH (Me)-2-1800 (46) (109) HH (16) N -NHCO- -CH (Me)-2-1801 (47) (64) HH (16)- CH- -NH- -CH (Me)-2-1802 (47) (109) HH (16) -CH- -NH- -CH (Me)-2-1803 (48) (46) HH (16)- CH- -NH- -CH (Me)-2-1804 (48) (64) HH (16) -CH- -NH- -CH (Me)-2-1805 (48) (109) HH (16)- CH- -NH- -CH (Me)-2-1806 (48) (64) HH (16) N -NH- -CH (Me)-2-1807 (48) (109) HH (16) N -NH- -CH (Me)-2-1808 (49) (45) HH (16) -CH- -NH- -CH (Me)-2-1809 (49) (46) HH (16) -CH- -NH- -CH (Me)-2-1810 (49) (49) HH (16) -CH- -NH- -CH (Me)-2-1811 (49) (51) HH (16) -CH- -NH- -CH (Me)-2-1812 (49) (63) HH (16) -CH- -NH- -CH (Me)-2-1813 (49) (64) HH (16) -CH- -NH- -CH (Me)-2-1814 (49) (66) HH (16) -CH- -NH- -CH (Me)-2-1815 (49) (68) HH (16) -CH- -NH- -CH (Me)-2-1816 (49) (109) HH (16) -CH- -NH- -CH (Me)-2-1817 (49) (109) HH (16) N -NH --CH (Me)-2-1818 (50) (46) HH (16) -CH- -NH- -CH (Me)-2-1819 (50) (64) HH (16) -CH- -NH --CH (Me)-2-1820 (50) (109) HH (16) -CH- -NH- -CH (Me)-2-1821 (50) (64) HH (16) N -NH-- CH (Me)-2-1822 (50) (109) HH (16) N -NH- -CH (Me)-2-1823 (51) (45) HH (16) -CH- -NH- -CH ( (Me)-2-1824 (51) (46) HH (16) -CH- -NH- -CH (Me)-2-1825 (51) (49) HH (16) -CH- -NH- -CH ( Me)-2-1826 (51) (51) HH (16) -CH- -NH- -CH (Me)-2-1827 (51) (63) HH (16) -CH- -NH- -CH ( (Me)-2-1828 (51) (64) HH (16) -CH- -NH- -CH (Me)-2-1829 (51) (66) HH (16) -CH- -NH- -CH ( Me)- 2-1830 (51) (68) HH (16) -CH- -NH- -CH (Me)-2-1831 (51) (109) HH (16) -CH- -NH- -CH (Me)- 2-1832 (51) (109) HH (16) N -NH- -CH (Me)-2-1833 (52) (37) HH (16) -CH- -NH- -CH (Me)-2- 1834 (52) (38) HH (16) -CH- -NH- -CH (Me)-2-1835 (52) (44) HH (16) -CH- -NH- -CH (Me)-2- 1836 (52) (45) HH (16) -CH- -NH- -CH_Two-2-1837 (52) (45) HH (16) -CH- -NH- -CH (Me)-2-1838 (52) (45) HH (16) -CH- -O- -CH (Me) -2-1839 (52) (45) HH (16) -CH- -S- -CH (Me)-2-1840 (52) (45) HH (16) -CH- -NHCO- -CH (Me) -2-1841 (52) (45) 4-FH (16) -CH- -NH- -CH (Me)-2-1842 (52) (45) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1843 (52) (46) HH (16) -CH- -NH- single bond 2-1844 (52) (46) HH (16) -CH- -NH- -CH_Two-2-1845 (52) (46) HH (16) -CH- -NH- -CH (Me)-2-1846 (52) (46) HH (16) -CH- -NH- -CH (Et) -2-1847 (52) (46) HH (16) -CH- -O- -CH (Me)-2-1848 (52) (46) HH (16) -CH- -S- -CH (Me) -2-1849 (52) (46) HH (16) -CH- -NHCO- -CH (Me)-2-1850 (52) (46) 4-FH (16) -CH- -NH- -CH ( Me)-2-1851 (52) (46) 5-FH (16) -CH- -NH- -CH (Me)-2-1852 (52) (46) 4-Cl H (16) -CH-- NH- -CH (Me)-2-1853 (52) (46) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1854 (52) (46) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-1855 (52) (46) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-1856 (52) (46) HH (16) N -NH- -CH (Me)-2-1857 (52) (46) HH (16) N -O- -CH (Me)-2-1858 (52) (46) HH (16) N -S- -CH (Me)-2-1859 (52) (46) HH (16) N -NHCO- -CH (Me)-2-1860 (52) (47) HH (16)- CH- -NH- -CH (Me)-2-1861 (52) (48) HH (16) -CH- -NH- -CH (Me)-2-1862 (52) (49) HH (16)- CH- -NH- -CH_Two-2-1863 (52) (49) HH (16) -CH- -NH- -CH (Me)-2-1864 (52) (49) HH (16) -CH- -O- -CH (Me) -2-1865 (52) (49) HH (16) -CH- -S- -CH (Me)-2-1866 (52) (49) HH (16) -CH- -NHCO- -CH (Me) -2-1867 (52) (49) 4-FH (16) -CH- -NH- -CH (Me)-2-1868 (52) (49) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1869 (52) (49) HH (16) N -NH- -CH (Me)-2-1870 (52) (50) HH (16) -CH- -NH- -CH (Me)-2-1871 (52) (51) HH (16) -CH- -NH- -CH_Two-2-1872 (52) (51) HH (16) -CH- -NH- -CH (Me)-2-1873 (52) (51) HH (16) -CH- -O- -CH (Me) -2-1874 (52) (51) HH (16) -CH- -S- -CH (Me)-2-1875 (52) (51) HH (16) -CH- -NHCO- -CH (Me) -2-1876 (52) (51) 4-FH (16) -CH- -NH- -CH (Me)-2-1877 (52) (51) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1878 (52) (51) HH (16) N -NH- -CH (Me)-2-1879 (52) (58) HH (16) -CH- -NH- -CH (Me)-2-1880 (52) (59) HH (16) -CH- -NH- -CH (Me)-2-1881 (52) (62) HH (16) -CH- -NH- -CH (Me)-2-1882 (52) (63) HH (16) -CH- -NH- -CH_Two-2-1883 (52) (63) HH (16) -CH- -NH- -CH (Me)-2-1884 (52) (63) HH (16) -CH- -O- -CH (Me) -2-1885 (52) (63) HH (16) -CH- -S- -CH (Me)-2-1886 (52) (63) HH (16) -CH- -NHCO- -CH (Me) -2-1887 (52) (63) 4-FH (16) -CH- -NH- -CH (Me)-2-1888 (52) (63) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1889 (52) (63) HH (16) N -NH- -CH (Me)-2-1890 (52) (64) HH (16) -CH- -NH- single bond 2-1891 (52) (64) HH (16) -CH- -NH- -CH_Two-2-1892 (52) (64) HH (16) -CH- -NH- -CH (Me)-2-1893 (52) (64) HH (16) -CH- -NH- -CH (Et) -2-1894 (52) (64) HH (16) -CH- -O- -CH (Me)-2-1895 (52) (64) HH (16) -CH- -S- -CH (Me) -2-1896 (52) (64) HH (16) -CH- -NHCO- -CH (Me)-2-1897 (52) (64) 4-FH (16) -CH- -NH- -CH ( (Me)-2-1898 (52) (64) 5-FH (16) -CH- -NH- -CH (Me)-2-1899 (52) (64) 4-Cl H (16) -CH-- NH- -CH (Me)-2-1900 (52) (64) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1901 (52) (64) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-1902 (52) (64) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-1903 (52) (64) HH (16) N -NH- -CH (Me)-2-1904 (52) (64) HH (16) N -O- -CH (Me)-2-1905 (52) (64) HH (16) N -S- -CH (Me)-2-1906 (52) (64) HH (16) N -NHCO- -CH (Me)-2-1907 (52) (65) HH (16)- CH- -NH- -CH (Me)-2-1908 (52) (66) HH (16) -CH- -NH- -CH_Two-2-1909 (52) (66) HH (16) -CH- -NH- -CH (Me)-2-1910 (52) (66) HH (16) -CH- -O- -CH (Me) -2-1911 (52) (66) HH (16) -CH- -S- -CH (Me)-2-1912 (52) (66) HH (16) -CH- -NHCO- -CH (Me) -2-1913 (52) (66) 4-FH (16) -CH- -NH- -CH (Me)-2-1914 (52) (66) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1915 (52) (66) HH (16) N -NH- -CH (Me)-2-1916 (52) (67) HH (16) -CH- -NH- -CH (Me)-2-1917 (52) (68) HH (16) -CH- -NH- -CH_Two-2-1918 (52) (68) HH (16) -CH- -NH- -CH (Me)-2-1919 (52) (68) HH (16) -CH- -O- -CH (Me) -2-1920 (52) (68) HH (16) -CH- -S- -CH (Me)-2-1921 (52) (68) HH (16) -CH- -NHCO- -CH (Me) -2-1922 (52) (68) 4-FH (16) -CH- -NH- -CH (Me)-2-1923 (52) (68) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1924 (52) (68) HH (16) N -NH- -CH (Me)-2-1925 (52) (72) HH (16) -CH- -NH- -CH (Me)-2-1926 (52) (73) HH (16) -CH- -NH- -CH (Me)-2-1927 (52) (74) HH (16) -CH- -NH- -CH (Me)-2-1928 (52) (75) HH (16) -CH- -NH- -CH (Me)-2-1929 (52) (76) HH (16) -CH- -NH- -CH (Me)-2-1930 (52) (77) HH (16) -CH- -NH- -CH (Me)-2-1931 (52) (109) HH (16) -CH- -NH- single bond 2-1932 (52) (109) HH (16) -CH- -NH- -CH_Two-2-1933 (52) (109) HH (16) -CH- -NH- -CH (Me)-2-1934 (52) (109) HH (16) -CH- -NH- -CH (Et) -2-1935 (52) (109) HH (16) -CH- -O- -CH (Me)-2-1936 (52) (109) HH (16) -CH- -S- -CH (Me) -2-1937 (52) (109) HH (16) -CH- -NHCO- -CH (Me)-2-1938 (52) (109) 4-FH (16) -CH- -NH- -CH ( (Me)-2-1939 (52) (109) 5-FH (16) -CH- -NH- -CH (Me)-2-1940 (52) (109) 4-Cl H (16) -CH-- NH- -CH (Me)-2-1941 (52) (109) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1942 (52) (109) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-1943 (52) (109) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-1944 (52) (109) HH (16) N -NH- -CH (Me)-2-1945 (52) (109) HH (16) N -O- -CH (Me)-2-1946 (52) (109) HH (16) N -S- -CH (Me)-2-1947 (52) (109) HH (16) N -NHCO- -CH (Me)-2-1948 (53) (46) HH (16)- CH- -NH- -CH (Me)-2-1949 (53) (64) HH (16) -CH- -NH- -CH (Me)-2-1950 (53) (109) HH (16)- CH- -NH- -CH (Me)-2-1951 (53) (64) HH (16) N -NH- -CH (Me)-2-1952 (53) (109) HH (16) N -NH --CH (Me)-2-1953 (55) (45) HH (16) -CH- -NH- -CH (Me)-2-1954 (55) (46) HH (16) -CH- -NH- -CH (Me)-2-1955 (55) (49) HH (16) -CH- -NH- -CH (Me)-2-1956 (55) (51) HH (16) -CH- -NH- -CH (Me)-2-1957 (55) (63) HH (16) -CH- -NH- -CH (Me)-2-1958 (55) (64) HH (16) -CH- -NH- -CH (Me)-2-1959 (55) (66) HH (16) -CH- -NH- -CH (Me)-2-1960 (55) (68) HH (16) -CH- -NH- -CH (Me)-2-1961 (55) (109) HH (16) -CH- -NH- -CH (Me)-2-1962 (55) (109) HH (16) N -NH --CH (Me)-2-1963 (57) (64) HH (16) -CH- -NH- -CH (Me)-2-1964 (57) (109) HH (16) -CH- -NH --CH (Me)-2-1965 (58) (64) HH (16) -CH- -NH- -CH (Me)-2-1966 (58) (109) HH (16) -CH- -NH --CH (Me)-2-1967 (59) (46) HH (16) -CH- -NH- -CH (Me)-2-1968 (59) (64) HH (16) -CH- -NH --CH (Me)-2-1969 (59) (109) HH (16) -CH- -NH- -CH (Me)-2-1970 (59) (64) HH (16) N -NH-- CH (Me)-2-1971 (59) (109) HH (16) N -NH- -CH (Me)-2-1972 (62) (46) HH (16) -CH- -NH- -CH ( (Me)-2-1973 (62) (64) HH (16) -CH- -NH- -CH (Me)-2-1974 (62) (109) HH (16) -CH- -NH- -CH ( Me)-2-1975 (62) (64) HH (16) N -NH- -CH (Me)-2-1976 (62) (109) HH (16) N -NH- -CH (Me)-2 -1 977 (63) (45) HH (16) -CH- -NH- -CH (Me)-2-1978 (63) (46) HH (16) -CH- -NH- -CH (Me)-2- 1979 (63) (49) HH (16) -CH- -NH- -CH (Me)-2-1980 (63) (51) HH (16) -CH- -NH- -CH (Me)-2- 1981 (63) (63) HH (16) -CH- -NH- -CH (Me)-2-1982 (63) (64) HH (16) -CH- -NH- -CH (Me)-2- 1983 (63) (66) HH (16) -CH- -NH- -CH (Me)-2-1984 (63) (68) HH (16) -CH- -NH- -CH (Me)-2- 1985 (63) (109) HH (16) -CH- -NH- -CH (Me)-2-1986 (63) (109) HH (16) N -NH- -CH (Me)-2-1987 ( 64) (37) HH (16) -CH- -NH- -CH (Me)-2-1988 (64) (38) HH (16) -CH- -NH- -CH (Me)-2-1989 ( 64) (44) HH (16) -CH- -NH- -CH (Me)-2-1990 (64) (45) HH (16) -CH- -NH- -CH_Two-2-1991 (64) (45) HH (16) -CH- -NH- -CH (Me)-2-1992 (64) (45) HH (16) -CH- -O- -CH (Me) -2-1993 (64) (45) HH (16) -CH- -S- -CH (Me)-2-1994 (64) (45) HH (16) -CH- -NHCO- -CH (Me) -2-1995 (64) (45) 4-FH (16) -CH- -NH- -CH (Me)-2-1996 (64) (45) 4-MeO H (16) -CH- -NH- -CH (Me)-2-1997 (64) (46) HH (16) -CH- -NH- single bond 2-1998 (64) (46) HH (16) -CH- -NH- -CH_Two-2-1999 (64) (46) HH (16) -CH- -NH- -CH (Me)-2-2000 (64) (46) HH (16) -CH- -NH- -CH (Et) -2-2001 (64) (46) HH (16) -CH- -O- -CH (Me)-2-2002 (64) (46) HH (16) -CH- -S- -CH (Me) -2-2003 (64) (46) HH (16) -CH- -NHCO- -CH (Me)-2-2004 (64) (46) 4-FH (16) -CH- -NH- -CH ( Me)-2-2005 (64) (46) 5-FH (16) -CH- -NH- -CH (Me)-2-2006 (64) (46) 4-Cl H (16) -CH-- NH- -CH (Me)-2-2007 (64) (46) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2008 (64) (46) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-2009 (64) (46) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-2010 (64) (46) HH (16) N -NH- -CH (Me)-2-2011 (64) (46) HH (16) N -O- -CH (Me)-2-2012 (64) (46) HH (16) N -S- -CH (Me)-2-2013 (64) (46) HH (16) N -NHCO- -CH (Me)-2-2014 (64) (47) HH (16)- CH- -NH- -CH (Me)-2-2015 (64) (48) HH (16) -CH- -NH- -CH (Me)-2-2016 (64) (49) HH (16)- CH- -NH- -CH_Two-2-2017 (64) (49) HH (16) -CH- -NH- -CH (Me)-2-2018 (64) (49) HH (16) -CH- -O- -CH (Me) -2-2019 (64) (49) HH (16) -CH- -S- -CH (Me)-2-2020 (64) (49) HH (16) -CH- -NHCO- -CH (Me) -2-2021 (64) (49) 4-FH (16) -CH- -NH- -CH (Me)-2-2022 (64) (49) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2023 (64) (49) HH (16) N -NH- -CH (Me)-2-2024 (64) (50) HH (16) -CH- -NH- -CH (Me)-2-2025 (64) (51) HH (16) -CH- -NH- -CH_Two-2-2026 (64) (51) HH (16) -CH- -NH- -CH (Me)-2-2027 (64) (51) HH (16) -CH- -O- -CH (Me) -2-2028 (64) (51) HH (16) -CH- -S- -CH (Me)-2-2029 (64) (51) HH (16) -CH- -NHCO- -CH (Me) -2-2030 (64) (51) 4-FH (16) -CH- -NH- -CH (Me)-2-2031 (64) (51) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2032 (64) (51) HH (16) N -NH- -CH (Me)-2-2033 (64) (58) HH (16) -CH- -NH- -CH (Me)-2-2034 (64) (59) HH (16) -CH- -NH- -CH (Me)-2-2035 (64) (62) HH (16) -CH- -NH- -CH (Me)-2-2036 (64) (63) HH (16) -CH- -NH- -CH_Two-2-2037 (64) (63) HH (16) -CH- -NH- -CH (Me)-2-2038 (64) (63) HH (16) -CH- -O- -CH (Me) -2-2039 (64) (63) HH (16) -CH- -S- -CH (Me)-2-2040 (64) (63) HH (16) -CH- -NHCO- -CH (Me) -2-2041 (64) (63) 4-FH (16) -CH- -NH- -CH (Me)-2-2042 (64) (63) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2043 (64) (63) HH (16) N -NH- -CH (Me)-2-2044 (64) (64) HH (16) -CH- -NH- single bond 2-2045 (64) (64) HH (16) -CH- -NH- -CH_Two-2-2046 (64) (64) HH (16) -CH- -NH- -CH (Me)-2-2047 (64) (64) HH (16) -CH- -NH- -CH (Et) -2-2048 (64) (64) HH (16) -CH- -O- -CH (Me)-2-2049 (64) (64) HH (16) -CH- -S- -CH (Me) -2-2050 (64) (64) HH (16) -CH- -NHCO- -CH (Me)-2-2051 (64) (64) 4-FH (16) -CH- -NH- -CH ( Me)-2-2052 (64) (64) 5-FH (16) -CH- -NH- -CH (Me)-2-2053 (64) (64) 4-Cl H (16) -CH-- NH- -CH (Me)-2-2054 (64) (64) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2055 (64) (64) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-2056 (64) (64) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-2057 (64) (64) HH (16) N -NH- -CH (Me)-2-2058 (64) (64) HH (16) N -O- -CH (Me)-2-2059 (64) (64) HH (16) N -S- -CH (Me)-2-2060 (64) (64) HH (16) N -NHCO- -CH (Me)-2-2061 (64) (65) HH (16)- CH- -NH- -CH (Me)-2-2062 (64) (66) HH (16) -CH- -NH- -CH_Two-2-2063 (64) (66) HH (16) -CH- -NH- -CH (Me)-2-2064 (64) (66) HH (16) -CH- -O- -CH (Me) -2-2065 (64) (66) HH (16) -CH- -S- -CH (Me)-2-2066 (64) (66) 4-FH (16) -CH- -NH- -CH ( Me)-2-2067 (64) (66) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2068 (64) (66) HH (16) N -NH- -CH (Me)-2-2069 (64) (67) HH (16) -CH- -NH- -CH (Me)-2-2070 (64) (68) HH (16) -CH- -NH- -CH_Two-2-2071 (64) (68) HH (16) -CH- -NH- -CH (Me)-2-2072 (64) (68) HH (16) -CH- -O- -CH (Me) -2-2073 (64) (68) HH (16) -CH- -S- -CH (Me)-2-2074 (64) (68) HH (16) -CH- -NHCO- -CH (Me) -2-2075 (64) (68) 4-FH (16) -CH- -NH- -CH (Me)-2-2076 (64) (68) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2077 (64) (68) HH (16) N -NH- -CH (Me)-2-2078 (64) (72) HH (16) -CH- -NH- -CH (Me)-2-2079 (64) (73) HH (16) -CH- -NH- -CH (Me)-2-2080 (64) (74) HH (16) -CH- -NH- -CH (Me)-2-2081 (64) (75) HH (16) -CH- -NH- -CH (Me)-2-2082 (64) (76) HH (16) -CH- -NH- -CH (Me)-2-2083 (64) (77) HH (16) -CH- -NH- -CH (Me)-2-2084 (64) (109) HH (16) -CH- -NH- single bond 2-2085 (64) (109) HH (16) -CH- -NH- -CH_Two-2-2086 (64) (109) HH (16) -CH- -NH- -CH (Me)-2-2087 (64) (109) HH (16) -CH- -NH- -CH (Et) -2-2088 (64) (109) HH (16) -CH- -O- -CH (Me)-2-2089 (64) (109) HH (16) -CH- -S- -CH (Me) -2-2090 (64) (109) HH (16) -CH- -NHCO- -CH (Me)-2-2091 (64) (109) 4-FH (16) -CH- -NH- -CH ( Me)-2-2092 (64) (109) 5-FH (16) -CH- -NH- -CH (Me)-2-2093 (64) (109) 4-Cl H (16) -CH-- NH- -CH (Me)-2-2094 (64) (109) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2095 (64) (109) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-2096 (64) (109) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-2097 (64) (109) HH (16) N -NH- -CH (Me)-2-2098 (64) (109) HH (16) N -O- -CH (Me)-2-2099 (64) (109) HH (16) N -S- -CH (Me)-2-2100 (64) (109) HH (16) N -NHCO- -CH (Me)-2-2101 (66) (46) HH (16)- CH- -NH- -CH (Me)-2-2102 (66) (64) HH (16) -CH- -NH- -CH (Me)-2-2103 (66) (109) HH (16)- CH- -NH- -CH (Me)-2-2104 (66) (64) HH (16) N -NH- -CH (Me)-2-2105 (66) (109) HH (16) N -NH --CH (Me)-2-2106 (68) (45) HH (16) -CH- -NH- -CH (Me)-2-2107 (68) (46) HH (16) -CH- -NH- -CH (Me)-2-2108 (68) (49) HH (16) -CH- -NH- -CH (Me)-2-2109 (68) (51) HH (16) -CH- -NH- -CH (Me)-2-2110 (68) (63) HH (16) -CH- -NH- -CH (Me)-2-2111 (68) (64) HH (16) -CH- -NH- -CH (Me)-2-2112 (68) (66) HH (16) -CH- -NH- -CH (Me)-2-2113 (68) (68) HH (16) -CH- -NH- -CH (Me)-2-2114 (68) (109) HH (16) -CH- -NH- -CH (Me)-2-2115 (68) (109) HH (16) N -NH --CH (Me)-2-2116 (69) (109) HH (16) -CH- -NH- -CH (Me)-2-2117 (70) (45) HH (16) -CH- -NH --CH (Me)-2-2118 (70) (46) HH (16) -CH- -NH- -CH (Me)-2-2119 (70) (49) HH (16) -CH- -NH --CH (Me)-2-2120 (70) (51) HH (16) -CH- -NH- -CH (Me)-2-2121 (70) (63) HH (16) -CH- -NH --CH (Me)-2-2122 (70) (64) HH (16) -CH- -NH- -CH (Me)-2-2123 (70) (66) HH (16) -CH- -NH --CH (Me)-2-2124 (70) (68) HH (16) -CH- -NH- -CH (Me)-2-2125 (70) (109) HH (16) -CH- -NH --CH (Me)-2-2126 (70) (109) HH (16) N -NH- -CH (Me)-2-2127 (73) (64) HH (16) -CH- -NH-- CH (Me)-2-2128 (73) (109) HH (16) -CH- -NH- -CH (Me)-2-2129 (75) (64) HH (16) -CH- -NH-- CH (M e)-2-2130 (75) (109) HH (16) -CH- -NH- -CH (Me)-2-2131 (76) (109) HH (16) -CH- -NH- -CH ( (Me)-2-2132 (85) (64) HH (16) -CH- -NH- -CH (Me)-2-2133 (85) (109) HH (16) -CH- -NH- -CH ( (Me)-2-2134 (86) (45) HH (16) -CH- -NH- -CH (Me)-2-2135 (86) (46) HH (16) -CH- -NH- -CH ( Me)-2-2136 (86) (49) HH (16) -CH- -NH- -CH (Me)-2-2137 (86) (51) HH (16) -CH- -NH- -CH ( Me)-2-2138 (86) (63) HH (16) -CH- -NH- -CH (Me)-2-2139 (86) (64) HH (16) -CH- -NH- -CH ( (Me)-2-2140 (86) (66) HH (16) -CH- -NH- -CH (Me)-2-2141 (86) (68) HH (16) -CH- -NH- -CH ( Me)-2-2142 (86) (109) HH (16) -CH- -NH- -CH (Me)-2-2143 (86) (109) HH (16) N -NH- -CH (Me) -2-2144 (88) (64) HH (16) -CH- -NH- -CH (Me)-2-2145 (88) (109) HH (16) -CH- -NH- -CH (Me) -2-2146 (90) (109) HH (16) -CH- -NH- -CH (Me)-2-2147 (92) (109) HH (16) -CH- -NH- -CH (Me) -2-2148 (95) (109) HH (16) -CH- -NH- -CH (Me)-2-2149 (101) (46) HH (16) -CH- -NH- -CH (Me) -2-2150 (101) (64) HH (16) -CH- -NH- -CH (Me)-2-2151 (101) (109) HH (16) -CH- -NH- -CH (M e)-2-2152 (101) (64) HH (16) N -NH- -CH (Me)-2-2153 (101) (109) HH (16) N -NH- -CH (Me)-2 -2154 (102) (46) HH (16) -CH- -NH- -CH (Me)-2-2155 (102) (64) HH (16) -CH- -NH- -CH (Me) -2 -2156 (102) (109) HH (16) -CH- -NH- -CH (Me)-2-2157 (102) (64) HH (16) N -NH- -CH (Me)-2-2158 (102) (109) HH (16) N -NH- -CH (Me)-2-2159 (103) (46) HH (16) -CH- -NH- -CH (Me)-2-2160 (103 ) (49) HH (16) -CH- -NH- -CH (Me)-2-2161 (103) (51) HH (16) -CH- -NH- -CH (Me)-2-2162 (103 ) (63) HH (16) -CH- -NH- -CH (Me)-2-2163 (103) (64) HH (16) -CH- -NH- -CH (Me)-2-2164 (103 ) (66) HH (16) -CH- -NH- -CH (Me)-2-2165 (103) (68) HH (16) -CH- -NH- -CH (Me)-2-2166 (103 ) (109) HH (16) -CH- -NH- -CH (Me)-2-2167 (103) (109) HH (16) N -NH- -CH (Me)-2-2168 (106) ( 46) HH (16) -CH- -NH- -CH (Me)-2-2169 (106) (64) HH (16) -CH- -NH- -CH (Me)-2-2170 (106) ( 109) HH (16) -CH- -NH- -CH (Me)-2-2171 (106) (64) HH (16) N -NH- -CH (Me)-2-2172 (106) (109) HH (16) N -NH- -CH (Me)-2-2173 (107) (109) HH (16) -CH- -NH- -CH (Me )-2-2174 (108) (37) HH (16) -CH- -NH- -CH (Me)-2-2175 (108) (38) HH (16) -CH- -NH- -CH (Me )-2-2176 (108) (44) HH (16) -CH- -NH- -CH (Me)-2-2177 (108) (45) HH (16) -CH- -NH- -CH_Two-2-2178 (108) (45) HH (16) -CH- -NH- -CH (Me)-2-2179 (108) (45) HH (16) -CH- -O- -CH (Me) -2-2180 (108) (45) HH (16) -CH- -S- -CH (Me)-2-2181 (108) (45) HH (16) -CH- -NHCO- -CH (Me) -2-2182 (108) (45) 4-FH (16) -CH- -NH- -CH (Me)-2-2183 (108) (45) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2184 (108) (46) HH (16) -CH- -NH- single bond 2-2185 (108) (46) HH (16) -CH- -NH- -CH_Two-2-2186 (108) (46) HH (16) -CH- -NH- -CH (Me)-2-2187 (108) (46) HH (16) -CH- -NH- -CH (Et) -2-2188 (108) (46) HH (16) -CH- -O- -CH (Me)-2-2189 (108) (46) HH (16) -CH- -S- -CH (Me) -2-2190 (108) (46) HH (16) -CH- -NHCO- -CH (Me)-2-2191 (108) (46) 4-FH (16) -CH- -NH- -CH ( (Me)-2-2192 (108) (46) 5-FH (16) -CH- -NH- -CH (Me)-2-2193 (108) (46) 4-Cl H (16) -CH-- NH- -CH (Me)-2-2194 (108) (46) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2195 (108) (46) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-2196 (108) (46) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-2197 (108) (46) HH (16) N -NH- -CH (Me)-2-2198 (108) (46) HH (16) N -O- -CH (Me)-2-2199 (108) (46) HH (16) N -S- -CH (Me)-2-2200 (108) (46) HH (16) N -NHCO- -CH (Me)-2-2201 (108) (47) HH (16)- CH- -NH- -CH (Me)-2-2202 (108) (48) HH (16) -CH- -NH- -CH (Me)-2-2203 (108) (49) HH (16)- CH- -NH- -CH_Two-2-2204 (108) (49) HH (16) -CH- -NH- -CH (Me)-2-2205 (108) (49) HH (16) -CH- -O- -CH (Me) -2-2206 (108) (49) HH (16) -CH- -S- -CH (Me)-2-2207 (108) (49) HH (16) -CH- -NHCO- -CH (Me) -2-2208 (108) (49) 4-FH (16) -CH- -NH- -CH (Me)-2-2209 (108) (49) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2210 (108) (49) HH (16) N -NH- -CH (Me)-2-2211 (108) (50) HH (16) -CH- -NH- -CH (Me)-2-2212 (108) (51) HH (16) -CH- -NH- -CH_Two-2-2213 (108) (51) HH (16) -CH- -NH- -CH (Me)-2-2214 (108) (51) HH (16) -CH- -O- -CH (Me) -2-2215 (108) (51) HH (16) -CH- -S- -CH (Me)-2-2216 (108) (51) HH (16) -CH- -NHCO- -CH (Me) -2-2217 (108) (51) 4-FH (16) -CH- -NH- -CH (Me)-2-2218 (108) (51) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2219 (108) (51) HH (16) N -NH- -CH (Me)-2-2220 (108) (58) HH (16) -CH- -NH- -CH (Me)-2-2221 (108) (59) HH (16) -CH- -NH- -CH (Me)-2-2222 (108) (62) HH (16) -CH- -NH- -CH (Me)-2-2223 (108) (63) HH (16) -CH- -NH- -CH_Two-2-2224 (108) (63) HH (16) -CH- -NH- -CH (Me)-2-2225 (108) (63) HH (16) -CH- -O- -CH (Me) -2-2226 (108) (63) HH (16) -CH- -S- -CH (Me)-2-2227 (108) (63) HH (16) -CH- -NHCO- -CH (Me) -2-2228 (108) (63) 4-FH (16) -CH- -NH- -CH (Me)-2-2229 (108) (63) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2230 (108) (63) HH (16) N -NH- -CH (Me)-2-2231 (108) (64) HH (16) -CH- -NH- single bond 2-2232 (108) (64) HH (16) -CH- -NH- -CH_Two-2-2233 (108) (64) HH (16) -CH- -NH- -CH (Me)-2-2234 (108) (64) HH (16) -CH- -NH- -CH (Et) -2-2235 (108) (64) HH (16) -CH- -O- -CH (Me)-2-2236 (108) (64) HH (16) -CH- -S- -CH (Me) -2-2237 (108) (64) HH (16) -CH- -NHCO- -CH (Me)-2-2238 (108) (64) 4-FH (16) -CH- -NH- -CH ( (Me)-2-2239 (108) (64) 5-FH (16) -CH- -NH- -CH (Me)-2-2240 (108) (64) 4-Cl H (16) -CH-- NH- -CH (Me)-2-2241 (108) (64) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2242 (108) (64) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-2243 (108) (64) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-2244 (108) (64) HH (16) N -NH- -CH (Me)-2-2245 (108) (64) HH (16) N -O- -CH (Me)-2-2246 (108) (64) HH (16) N -S- -CH (Me)-2-2247 (108) (64) HH (16) N -NHCO- -CH (Me)-2-2248 (108) (65) HH (16)- CH- -NH- -CH (Me)-2-2249 (108) (66) HH (16) -CH- -NH- -CH_Two-2-2250 (108) (66) HH (16) -CH- -NH- -CH (Me)-2-2251 (108) (66) HH (16) -CH- -O- -CH (Me) -2-2252 (108) (66) HH (16) -CH- -S- -CH (Me)-2-2253 (108) (66) 4-FH (16) -CH- -NH- -CH ( Me)-2-2254 (108) (66) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2255 (108) (66) HH (16) N -NH- -CH (Me)-2-2256 (108) (67) HH (16) -CH- -NH- -CH (Me)-2-2257 (108) (68) HH (16) -CH- -NH- -CH_Two-2-2258 (108) (68) HH (16) -CH- -NH- -CH (Me)-2-2259 (108) (68) HH (16) -CH- -O- -CH (Me) -2-2260 (108) (68) HH (16) -CH- -S- -CH (Me)-2-2261 (108) (68) HH (16) -CH- -NHCO- -CH (Me) -2-2262 (108) (68) 4-FH (16) -CH- -NH- -CH (Me)-2-2263 (108) (68) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2264 (108) (68) HH (16) N -NH- -CH (Me)-2-2265 (108) (72) HH (16) -CH- -NH- -CH (Me)-2-2266 (108) (73) HH (16) -CH- -NH- -CH (Me)-2-2267 (108) (74) HH (16) -CH- -NH- -CH (Me)-2-2268 (108) (75) HH (16) -CH- -NH- -CH (Me)-2-2269 (108) (76) HH (16) -CH- -NH- -CH (Me)-2-2270 (108) (77) HH (16) -CH- -NH- -CH (Me)-2-2271 (108) (109) HH (16) -CH- -NH- single bond 2-2272 (108) (109) HH (16) -CH- -NH- -CH_Two-2-2273 (108) (109) HH (16) -CH- -NH- -CH (Me)-2-2274 (108) (109) HH (16) -CH- -NH- -CH (Et) -2-2275 (108) (109) HH (16) -CH- -O- -CH (Me)-2-2276 (108) (109) HH (16) -CH- -S- -CH (Me) -2-2277 (108) (109) HH (16) -CH- -NHCO- -CH (Me)-2-2278 (108) (109) 4-FH (16) -CH- -NH- -CH ( (Me)-2-2279 (108) (109) 5-FH (16) -CH- -NH- -CH (Me)-2-2280 (108) (109) 4-Cl H (16) -CH-- NH- -CH (Me)-2-2281 (108) (109) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2282 (108) (109) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-2283 (108) (109) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-2284 (108) (109) HH (16) N -NH- -CH (Me)-2-2285 (108) (109) HH (16) N -O- -CH (Me)-2-2286 (108) (109) HH (16) N -S- -CH (Me)-2-2287 (108) (109) HH (16) N -NHCO- -CH (Me)-2-2288 (109) (37) HH (16)- CH- -NH- -CH (Me)-2-2289 (109) (38) HH (16) -CH- -NH- -CH (Me)-2-2290 (109) (44) HH (16)- CH- -NH- -CH (Me)-2-2291 (109) (45) HH (16) -CH- -NH- -CH_Two-2-2292 (109) (45) HH (16) -CH- -NH- -CH (Me)-2-2293 (109) (45) HH (16) -CH- -O- -CH (Me) -2-2294 (109) (45) HH (16) -CH- -S- -CH (Me)-2-2295 (109) (45) HH (16) -CH- -NHCO- -CH (Me) -2-2296 (109) (45) 4-FH (16) -CH- -NH- -CH (Me)-2-2297 (109) (45) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2298 (109) (46) HH (16) -CH- -NH- single bond 2-2299 (109) (46) HH (16) -CH- -NH- -CH_Two-2-2300 (109) (46) HH (16) -CH- -NH- -CH (Me)-2-2301 (109) (46) HH (16) -CH- -NH- -CH (Et) -2-2302 (109) (46) HH (16) -CH- -O- -CH (Me)-2-2303 (109) (46) HH (16) -CH- -S- -CH (Me) -2-2304 (109) (46) HH (16) -CH- -NHCO- -CH (Me)-2-2305 (109) (46) 4-FH (16) -CH- -NH- -CH ( (Me)-2-2306 (109) (46) 5-FH (16) -CH- -NH- -CH (Me)-2-2307 (109) (46) 4-Cl H (16) -CH-- NH- -CH (Me)-2-2308 (109) (46) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2309 (109) (46) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-2310 (109) (46) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-2311 (109) (46) HH (16) N -NH- -CH (Me)-2-2312 (109) (46) HH (16) N -O- -CH (Me)-2-2313 (109) (46) HH (16) N -S- -CH (Me)-2-2314 (109) (46) HH (16) N -NHCO- -CH (Me)-2-2315 (109) (47) HH (16)- CH- -NH- -CH (Me)-2-2316 (109) (48) HH (16) -CH- -NH- -CH (Me)-2-2317 (109) (49) HH (16)- CH- -NH- -CH_Two-2-2318 (109) (49) HH (16) -CH- -NH- -CH (Me)-2-2319 (109) (49) HH (16) -CH- -O- -CH (Me) -2-2320 (109) (49) HH (16) -CH- -S- -CH (Me)-2-2321 (109) (49) HH (16) -CH- -NHCO- -CH (Me) -2-2322 (109) (49) 4-FH (16) -CH- -NH- -CH (Me)-2-2323 (109) (49) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2324 (109) (49) HH (16) N -NH- -CH (Me)-2-2325 (109) (50) HH (16) -CH- -NH- -CH (Me)-2-2326 (109) (51) HH (16) -CH- -NH- -CH_Two-2-2327 (109) (51) HH (16) -CH- -NH- -CH (Me)-2-2328 (109) (51) HH (16) -CH- -O- -CH (Me) -2-2329 (109) (51) HH (16) -CH- -S- -CH (Me)-2-2330 (109) (51) HH (16) -CH- -NHCO- -CH (Me) -2-2331 (109) (51) 4-FH (16) -CH- -NH- -CH (Me)-2-2332 (109) (51) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2333 (109) (51) HH (16) N -NH- -CH (Me)-2-2334 (109) (58) HH (16) -CH- -NH- -CH (Me)-2-2335 (109) (59) HH (16) -CH- -NH- -CH (Me)-2-2336 (109) (62) HH (16) -CH- -NH- -CH (Me)-2-2337 (109) (63) HH (16) -CH- -NH- -CH_Two-2-2338 (109) (63) HH (16) -CH- -NH- -CH (Me)-2-2339 (109) (63) HH (16) -CH- -O- -CH (Me) -2-2340 (109) (63) HH (16) -CH- -S- -CH (Me)-2-2341 (109) (63) HH (16) -CH- -NHCO- -CH (Me) -2-2342 (109) (63) 4-FH (16) -CH- -NH- -CH (Me)-2-2343 (109) (63) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2344 (109) (63) HH (16) N -NH- -CH (Me)-2-2345 (109) (64) HH (16) -CH- -NH- single bond 2-2346 (109) (64) HH (16) -CH- -NH- -CH_Two-2-2347 (109) (64) HH (16) -CH- -NH- -CH (Me)-2-2348 (109) (64) HH (16) -CH- -NH- -CH (Et) -2-2349 (109) (64) HH (16) -CH- -O- -CH (Me)-2-2350 (109) (64) HH (16) -CH- -S- -CH (Me) -2-2351 (109) (64) HH (16) -CH- -NHCO- -CH (Me)-2-2352 (109) (64) 4-FH (16) -CH- -NH- -CH ( (Me)-2-2353 (109) (64) 5-FH (16) -CH- -NH- -CH (Me)-2-2354 (109) (64) 4-Cl H (16) -CH-- NH- -CH (Me)-2-2355 (109) (64) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2356 (109) (64) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-2357 (109) (64) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-2358 (109) (64) HH (16) N -NH- -CH (Me)-2-2359 (109) (64) HH (16) N -O- -CH (Me)-2-2360 (109) (64) HH (16) N -S- -CH (Me)-2-2361 (109) (64) HH (16) N -NHCO- -CH (Me)-2-2362 (109) (65) HH (16)- CH- -NH- -CH (Me)-2-2363 (109) (66) HH (16) -CH- -NH- -CH_Two-2-2364 (109) (66) HH (16) -CH- -NH- -CH (Me)-2-2365 (109) (66) HH (16) -CH- -O- -CH (Me) -2-2366 (109) (66) HH (16) -CH- -S- -CH (Me)-2-2367 (109) (66) 4-FH (16) -CH- -NH- -CH ( Me)-2-2368 (109) (66) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2369 (109) (66) HH (16) N -NH- -CH (Me)-2-2370 (109) (67) HH (16) -CH- -NH- -CH (Me)-2-2371 (109) (68) HH (16) -CH- -NH- -CH_Two-2-2372 (109) (68) HH (16) -CH- -NH- -CH (Me)-2-2373 (109) (68) HH (16) -CH- -O- -CH (Me) -2-2374 (109) (68) HH (16) -CH- -S- -CH (Me)-2-2375 (109) (68) HH (16) -CH- -NHCO- -CH (Me) -2-2376 (109) (68) 4-FH (16) -CH- -NH- -CH (Me)-2-2377 (109) (68) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2378 (109) (68) HH (16) N -NH- -CH (Me)-2-2379 (109) (72) HH (16) -CH- -NH- -CH (Me)-2-2380 (109) (73) HH (16) -CH- -NH- -CH (Me)-2-2381 (109) (74) HH (16) -CH- -NH- -CH (Me)-2-2382 (109) (75) HH (16) -CH- -NH- -CH (Me)-2-2383 (109) (76) HH (16) -CH- -NH- -CH (Me)-2-2384 (109) (77) HH (16) -CH- -NH- -CH (Me)-2-2385 (109) (109) HH (16) -CH- -NH- single bond 2-2386 (109) (109) HH (16) -CH- -NH- -CH_Two-2-2387 (109) (109) HH (16) -CH- -NH- -CH (Me)-2-2388 (109) (109) HH (16) -CH- -NH- -CH (Et) -2-2389 (109) (109) HH (16) -CH- -O- -CH (Me)-2-2390 (109) (109) HH (16) -CH- -S- -CH (Me) -2-2391 (109) (109) HH (16) -CH- -NHCO- -CH (Me)-2-2392 (109) (109) 4-FH (16) -CH- -NH- -CH ( (Me)-2-2393 (109) (109) 5-FH (16) -CH- -NH- -CH (Me)-2-2394 (109) (109) 4-Cl H (16) -CH-- NH- -CH (Me)-2-2395 (109) (109) 4-MeO H (16) -CH- -NH- -CH (Me)-2-2396 (109) (109) 5-MeO H ( 16) -CH- -NH- -CH (Me)-2-2397 (109) (109) 4-MeO 5-MeO (16) -CH- -NH- -CH (Me)-2-2398 (109) (109) HH (16) N -NH- -CH (Me)-2-2399 (109) (109) HH (16) N -O- -CH (Me)-2-2400 (109) (109) HH (16) N -S- -CH (Me)-2-2401 (109) (109) HH (16) N -NHCO- -CH (Me)-2-2402 (64) (64) HH (17)- CH- -NH- -CH (Me)-2-2403 (64) (109) HH (17) -CH- -NH- -CH (Me)-2-2404 (109) (64) HH (17)- CH- -NH- -CH (Me)-2-2405 (109) (109) HH (17) -CH- -NH- -CH (Me)-2-2406 (45) (109) HH (18)- CH- -NH- -CH (Me)-2-2407 (46) (109) HH (18) -CH- -NH- -CH (Me)-2-2408 (52) (109) HH (18) -CH- -NH- -CH (Me)-2-2409 (64) (64) HH (18) -CH- -NH- -CH (Me)-2-2410 (64) (109) HH (18) -CH- -NH- -CH (Me)-2-2411 (108) (109) HH (18) -CH- -NH- -CH (Me)-2-2412 (109) (64) HH (18) -CH- -NH- -CH (Me)-2-2413 (109) (109) HH (18) -CH- -NH- -CH (Me)-2-2414 (38) (109) HH (19) -CH- -NH- -CH (Me)-2-2415 (44) (109) HH (19) -CH- -NH- -CH (Me)-2-2416 (45) (46) HH (19) -CH- -NH- -CH (Me)-2-2417 (45) (64) HH (19) -CH- -NH- -CH (Me)-2-2418 (45) (109) HH (19) -CH- -NH- -CH (Me)-2-2419 (45) (64) HH (19) N -NH- -CH (Me)-2-2420 (46 ) (46) HH (19) -CH- -NH- -CH (Me)-2-2421 (46) (64) HH (19) -CH- -NH- -CH (Me)-2-2422 (46 ) (109) HH (19) -CH- -NH- -CH (Me)-2-2423 (46) (64) HH (19) N -NH- -CH (Me)-2-2424 (46) ( 109) HH (19) N -NH- -CH (Me)-2-2425 (48) (109) HH (19) -CH- -NH- -CH (Me)-2-2426 (49) (64) HH (19) -CH- -NH- -CH (Me)-2-2427 (49) (109) HH (19) -CH- -NH- -CH (Me)-2-2428 (50) (109) HH (19) -CH- -NH- -CH (Me)-2-2429 (51) (64) HH (19) -CH- -NH- -CH (Me)-2-2430 (51 ) (109) HH (19) -CH- -NH- -CH (Me)-2-2431 (52) (46) HH (19) -CH- -NH- -CH (Me)-2-2432 (52 ) (64) HH (19) -CH- -NH- -CH (Me)-2-2433 (52) (109) HH (19) -CH- -NH- -CH (Me)-2-2434 (52 ) (64) HH (19) N -NH- -CH (Me)-2-2435 (52) (109) HH (19) N -NH- -CH (Me)-2-2436 (53) (109) HH (19) -CH- -NH- -CH (Me)-2-2437 (55) (64) HH (19) -CH- -NH- -CH (Me)-2-2438 (55) (109) HH (19) -CH- -NH- -CH (Me)-2-2439 (59) (109) HH (19) -CH- -NH- -CH (Me)-2-2440 (62) (109) HH (19) -CH- -NH- -CH (Me)-2-2441 (63) (64) HH (19) -CH- -NH- -CH (Me)-2-2442 (63) (109) HH (19) -CH- -NH- -CH (Me)-2-2443 (64) (46) HH (19) -CH- -NH- -CH (Me)-2-2444 (64) (64) HH (19) -CH- -NH- -CH (Me)-2-2445 (64) (109) HH (19) -CH- -NH- -CH (Me)-2-2446 (64) (64) HH (19) N -NH- -CH (Me)-2-2447 (64) (109) HH (19) N -NH- -CH (Me)-2-2448 (66) (109) HH (19) -CH- -NH- -CH (Me)-2-2449 (68) (64) HH (19) -CH- -NH- -CH (Me)-2-2450 (68) (109) HH (19) -CH- -NH- -CH (Me)-2-2451 (70) (64) HH (19) -CH- -NH- -CH (Me)-2-2452 (70) (109) H H (19) -CH- -NH- -CH (Me)-2-2453 (86) (64) HH (19) -CH- -NH- -CH (Me)-2-2454 (86) (109) HH (19) -CH- -NH- -CH (Me)-2-2455 (101) (109) HH (19) -CH- -NH- -CH (Me)-2-2456 (102) (109) HH (19) -CH- -NH- -CH (Me)-2-2457 (103) (64) HH (19) -CH- -NH- -CH (Me)-2-2458 (103) (109) HH (19) -CH- -NH- -CH (Me)-2-2459 (106) (109) HH (19) -CH- -NH- -CH (Me)-2-2460 (108) (46) HH (19) -CH- -NH- -CH (Me)-2-2461 (108) (64) HH (19) -CH- -NH- -CH (Me)-2-2462 (108) (109) HH (19) -CH- -NH- -CH (Me)-2-2463 (108) (64) HH (19) N -NH- -CH (Me)-2-2464 (108) (109) HH ( 19) N -NH- -CH (Me)-2-2465 (109) (46) HH (19) -CH- -NH- -CH (Me)-2-2466 (109) (64) HH (19) -CH- -NH- -CH (Me)-2-2467 (109) (109) HH (19) -CH- -NH- -CH (Me)-2-2468 (109) (64) HH (19) N -NH- -CH (Me)-2-2469 (109) (109) HH (19) N -NH- -CH (Me)-2-2470 (64) (64) HH (20) -CH-- NH- -CH (Me)-2-2471 (64) (109) HH (20) -CH- -NH- -CH (Me)-2-2472 (109) (64) HH (20) -CH-- NH- -CH (Me)-2-2473 (109) (109) HH (20) -CH- -NH- -CH (Me)-2-2474 (64) ( 64) HH (21) -CH- -NH- -CH (Me)-2-2475 (64) (109) HH (21) -CH- -NH- -CH (Me)-2-2476 (109) ( 64) HH (21) -CH- -NH- -CH (Me)-2-2477 (109) (109) HH (21) -CH- -NH- -CH (Me)-2-2478 (45) ( 109) HH (22) -CH- -NH- -CH (Me)-2-2479 (46) (109) HH (22) -CH- -NH- -CH (Me)-2-2480 (52) ( 109) HH (22) -CH- -NH- -CH (Me)-2-2481 (64) (64) HH (22) -CH- -NH- -CH (Me)-2-2482 (64) ( 109) HH (22) -CH- -NH- -CH (Me)-2-2483 (108) (109) HH (22) -CH- -NH- -CH (Me)-2-2484 (109) ( 64) HH (22) -CH- -NH- -CH (Me)-2-2485 (109) (109) HH (22) -CH- -NH- -CH (Me)-2-2486 (64) ( 64) HH (23) -CH- -NH- -CH (Me)-2-2487 (64) (109) HH (23) -CH- -NH- -CH (Me)-2-2488 (109) ( 64) HH (23) -CH- -NH- -CH (Me)-2-2489 (109) (109) HH (23) -CH- -NH- -CH (Me)-2-2490 (38) ( 109) HH (24) -CH- -NH- -CH (Me)-2-2491 (44) (109) HH (24) -CH- -NH- -CH (Me)-2-2492 (45) ( 46) HH (24) -CH- -NH- -CH (Me)-2-2493 (45) (64) HH (24) -CH- -NH- -CH (Me)-2-2494 (45) ( 109) HH (24) -CH- -NH- -CH (Me)-2-2495 (45) (64) HH (24) N -NH- -CH (Me)-2-2496 (45) (109) HH (24) N -NH- -CH (Me)-2-2497 (46) (46) HH (24) -CH- -NH- -CH (Me)-2-2498 (46 ) (64) HH (24) -CH- -NH- -CH (Me)-2-2499 (46) (109) HH (24) -CH- -NH- -CH (Me)-2-2500 (46 ) (64) HH (24) N -NH- -CH (Me)-2-2501 (46) (109) HH (24) N -NH- -CH (Me)-2-2502 (48) (109) HH (24) -CH- -NH- -CH (Me)-2-2503 (49) (64) HH (24) -CH- -NH- -CH (Me)-2-2504 (49) (109) HH (24) -CH- -NH- -CH (Me)-2-2505 (50) (109) HH (24) -CH- -NH- -CH (Me)-2-2506 (51) (64) HH (24) -CH- -NH- -CH (Me)-2-2507 (51) (109) HH (24) -CH- -NH- -CH (Me)-2-2508 (52) (46) HH (24) -CH- -NH- -CH (Me)-2-2509 (52) (64) HH (24) -CH- -NH- -CH (Me)-2-2510 (52) (109) HH (24) -CH- -NH- -CH (Me)-2-2511 (52) (64) HH (24) N -NH- -CH (Me)-2-2512 (52) (109) HH ( 24) N -NH- -CH (Me)-2-2513 (53) (109) HH (24) -CH- -NH- -CH (Me)-2-2514 (55) (64) HH (24) -CH- -NH- -CH (Me)-2-2515 (55) (109) HH (24) -CH- -NH- -CH (Me)-2-2516 (59) (109) HH (24) -CH- -NH- -CH (Me)-2-2517 (62) (109) HH (24) -CH- -NH- -CH (Me)-2-2518 (63) (64) H H (24) -CH- -NH- -CH (Me)-2-2519 (63) (109) HH (24) -CH- -NH- -CH (Me)-2-2520 (64) (46) HH (24) -CH- -NH- -CH (Me)-2-2521 (64) (64) HH (24) -CH- -NH- -CH (Me)-2-2522 (64) (109) HH (24) -CH- -NH- -CH (Me)-2-2523 (64) (64) HH (24) N -NH- -CH (Me)-2-2524 (64) (109) HH ( 24) N -NH- -CH (Me)-2-2525 (66) (109) HH (24) -CH- -NH- -CH (Me)-2-2526 (68) (64) HH (24) -CH- -NH- -CH (Me)-2-2527 (68) (109) HH (24) -CH- -NH- -CH (Me)-2-2528 (70) (64) HH (24) -CH- -NH- -CH (Me)-2-2529 (70) (109) HH (24) -CH- -NH- -CH (Me)-2-2530 (86) (64) HH (24) -CH- -NH- -CH (Me)-2-2531 (86) (109) HH (24) -CH- -NH- -CH (Me)-2-2532 (101) (109) HH (24) -CH- -NH- -CH (Me)-2-2533 (102) (109) HH (24) -CH- -NH- -CH (Me)-2-2534 (103) (64) HH (24) -CH- -NH- -CH (Me)-2-2535 (103) (109) HH (24) -CH- -NH- -CH (Me)-2-2536 (106) (109) HH (24) -CH- -NH- -CH (Me)-2-2537 (108) (46) HH (24) -CH- -NH- -CH (Me)-2-2538 (108) (64) HH (24) -CH- -NH- -CH (Me)-2-2539 (108) (109) HH (24) -CH- -NH- -CH (Me)-2-2540 (108) ( 64) HH (24) N -NH- -CH (Me)-2-2541 (108) (109) HH (24) N -NH- -CH (Me)-2-2542 (109) (46) HH ( 24) -CH- -NH- -CH (Me)-2-2543 (109) (64) HH (24) -CH- -NH- -CH (Me)-2-2544 (109) (109) HH ( 24) -CH- -NH- -CH (Me)-2-2545 (109) (64) HH (24) N -NH- -CH (Me)-2-2546 (109) (109) HH (24) N -NH- -CH (Me)-2-2547 (64) (64) HH (25) -CH- -NH- -CH (Me)-2-2548 (64) (109) HH (25) -CH --NH- -CH (Me)-2-2549 (109) (64) HH (25) -CH- -NH- -CH (Me)-2-2550 (109) (109) HH (25) -CH --NH- -CH (Me)-2-2551 (38) (109) HH (26) -CH- -NH- -CH (Me)-2-2552 (44) (109) HH (26) -CH --NH- -CH (Me)-2-2553 (45) (46) HH (26) -CH- -NH- -CH (Me)-2-2554 (45) (64) HH (26) -CH --NH- -CH (Me)-2-2555 (45) (109) HH (26) -CH- -NH- -CH (Me)-2-2556 (45) (64) HH (26) N- NH- -CH (Me)-2-2557 (45) (109) HH (26) N -NH- -CH (Me)-2-2558 (46) (46) HH (26) -CH- -NH- -CH (Me)-2-2559 (46) (64) HH (26) -CH- -NH- -CH (Me)-2-2560 (46) (109) HH (26) -CH- -NH- -CH (Me)-2-2561 (46) (64) HH (26) N -NH- -CH (Me)-2-2562 (46) (109) HH (26) N -NH- -CH (Me)-2-2563 (48) (109) HH (26) -CH- -NH- -CH (Me)-2-2564 (49) (64) HH (26) -CH --NH- -CH (Me)-2-2565 (49) (109) HH (26) -CH- -NH- -CH (Me)-2-2566 (50) (109) HH (26) -CH --NH- -CH (Me)-2-2567 (51) (64) HH (26) -CH- -NH- -CH (Me)-2-2568 (51) (109) HH (26) -CH --NH- -CH (Me)-2-2569 (52) (46) HH (26) -CH- -NH- -CH (Me)-2-2570 (52) (64) HH (26) -CH --NH- -CH (Me)-2-2571 (52) (109) HH (26) -CH- -NH- -CH (Me)-2-2572 (52) (64) HH (26) N- NH- -CH (Me)-2-2573 (52) (109) HH (26) N -NH- -CH (Me)-2-2574 (53) (109) HH (26) -CH- -NH- -CH (Me)-2-2575 (55) (64) HH (26) -CH- -NH- -CH (Me)-2-2576 (55) (109) HH (26) -CH- -NH- -CH (Me)-2-2577 (59) (109) HH (26) -CH- -NH- -CH (Me)-2-2578 (62) (109) HH (26) -CH- -NH- -CH (Me)-2-2579 (63) (64) HH (26) -CH- -NH- -CH (Me)-2-2580 (63) (109) HH (26) -CH- -NH- -CH (Me)-2-2581 (64) (46) HH (26) -CH- -NH- -CH (Me)-2-2582 (64) (64) HH (26) -CH- -NH- -CH (Me)-2-2583 (64) (109) HH (26) -CH- -NH- -CH (Me)-2-2584 (64) (64) HH (26) N -NH- -CH (Me)-2-2585 (64) (109) HH (26) N -NH- -CH (Me)-2-2586 (66) (109) HH (26) -CH- -NH- -CH (Me)-2-2587 (68) (64) HH (26) -CH- -NH- -CH (Me)-2-2588 (68) (109) HH (26) -CH- -NH- -CH (Me)-2-2589 (70) (64) HH (26) -CH- -NH- -CH (Me)-2-2590 (70) (109) HH (26) -CH- -NH- -CH (Me)-2-2591 (86) (64) HH (26) -CH- -NH- -CH (Me)-2-2592 (86) (109) HH (26) -CH- -NH- -CH (Me)-2-2593 (101) (109) HH (26) -CH- -NH- -CH (Me)-2-2594 (102) (109) HH (26) -CH- -NH- -CH (Me)-2-2595 (103) (64) HH (26) -CH- -NH- -CH (Me)-2-2596 (103) (109) HH (26) -CH- -NH- -CH (Me)-2-2597 (106) (109) HH (26) -CH- -NH- -CH (Me)-2-2598 (108) (46) HH (26) -CH- -NH- -CH (Me)-2-2599 (108) (64) HH (26) -CH- -NH- -CH (Me)-2-2600 (108) (109) HH (26) -CH- -NH- -CH (Me)-2-2601 (108) (64) HH (26) N -NH- -CH (Me)-2-2602 (108) (109) HH (26) N -NH- -CH (Me)- 2-2603 (109) (46) HH (26) -CH- -NH- -CH (Me)-2-2604 (109) (64) HH (26) -CH- -NH- -CH (Me)- 2-2605 (109) (109) HH (26) -CH- -NH- -CH (Me)-2-2606 (109) (64) HH (26) N -NH- -CH (Me)-2-2607 (109) (109) HH (26) N -NH- -CH (Me)-2-2608 (64) (64) HH (27) -CH- -NH --CH (Me)-2-2609 (64) (109) HH (27) -CH- -NH- -CH (Me)-2-2610 (109) (64) HH (27) -CH- -NH --CH (Me)-2-2611 (109) (109) HH (27) -CH- -NH- -CH (Me)-2-2612 (45) (64) HH (28) -CH- -NH --CH (Me)-2-2613 (45) (109) HH (28) -CH- -NH- -CH (Me)-2-2614 (46) (64) HH (28) -CH- -NH --CH (Me)-2-2615 (46) (109) HH (28) -CH- -NH- -CH (Me)-2-2616 (49) (109) HH (28) -CH- -NH --CH (Me)-2-2617 (51) (109) HH (28) -CH- -NH- -CH (Me)-2-2618 (52) (64) HH (28) -CH- -NH --CH (Me)-2-2619 (52) (109) HH (28) -CH- -NH- -CH (Me)-2-2620 (55) (109) HH (28) -CH- -NH --CH (Me)-2-2621 (63) (109) HH (28) -CH- -NH- -CH (Me)-2-2622 (64) (64) HH (28) -CH- -NH --CH (Me)-2-2623 (64) (109) HH (28) -CH- -NH- -CH (Me)-2-2624 (68) (109) HH (28) -CH- -NH --CH (Me)-2-2625 (70) (109) HH (28) -CH- -NH- -CH (Me)-2-2626 (86) (109) HH (28) -CH- -NH --CH (Me)-2-2627 (103) (109) HH (28) -CH- -NH- -CH (Me)-2-2628 (108) (64) HH (28 ) -CH- -NH- -CH (Me)-2-2629 (108) (109) HH (28) -CH- -NH- -CH (Me)-2-2630 (109) (64) HH (28 ) -CH- -NH- -CH (Me)-2-2631 (109) (109) HH (28) -CH- -NH- -CH (Me)-2-2632 (64) (64) HH (29 ) -CH- -NH- -CH (Me)-2-2633 (64) (109) HH (29) -CH- -NH- -CH (Me)-2-2634 (109) (64) HH (29 ) -CH- -NH- -CH (Me)-2-2635 (109) (109) HH (29) -CH- -NH- -CH (Me)-2-2636 (45) (109) HH (30 ) -CH- -NH- -CH (Me)-2-2637 (46) (109) HH (30) -CH- -NH- -CH (Me)-2-2638 (52) (109) HH (30 ) -CH- -NH- -CH (Me)-2-2639 (64) (64) HH (30) -CH- -NH- -CH (Me)-2-2640 (64) (109) HH (30 ) -CH- -NH- -CH (Me)-2-2641 (108) (109) HH (30) -CH- -NH- -CH (Me)-2-2642 (109) (64) HH (30 ) -CH- -NH- -CH (Me)-2-2643 (109) (109) HH (30) -CH- -NH- -CH (Me)-2-2644 (45) (64) HH (31 ) -CH- -NH- -CH (Me)-2-2645 (45) (109) HH (31) -CH- -NH- -CH (Me)-2-2646 (46) (64) HH (31 ) -CH- -NH- -CH (Me)-2-2647 (46) (109) HH (31) -CH- -NH- -CH (Me)-2-2648 (49) (109) HH (31 ) -CH- -NH- -CH (Me)-2-2649 (51) (109) HH (31) -CH- -NH- -CH (Me)-2-2650 (52) (64) HH (31) -CH- -NH- -CH (Me)-2-2651 (52) (109) HH (31) -CH- -NH- -CH (Me)-2-2652 (55) (109) HH (31) -CH- -NH- -CH (Me)-2-2653 (63) (109) HH (31) -CH- -NH- -CH (Me)-2-2654 (64) (64) HH (31) -CH- -NH- -CH (Me)-2-2655 (64) (109) HH (31) -CH- -NH- -CH (Me)-2-2656 (68) (109) HH (31) -CH- -NH- -CH (Me)-2-2657 (70) (109) HH (31) -CH- -NH- -CH (Me)-2-2658 (86) (109) HH (31) -CH- -NH- -CH (Me)-2-2659 (103) (109) HH (31) -CH- -NH- -CH (Me)-2-2660 (108) (64) HH (31) -CH- -NH- -CH (Me)-2-2661 (108) (109) HH (31) -CH- -NH- -CH (Me)-2-2662 (109) (64) HH (31) -CH- -NH- -CH (Me)-2-2663 (109) (109) HH (31) -CH- -NH- -CH (Me)-2-2664 (45) (64) HH (32) -CH- -NH- -CH (Me)-2-2665 (45) (109) HH (32) -CH- -NH- -CH (Me)-2-2666 (46) (64) HH (32) -CH- -NH- -CH (Me)-2-2667 (46) (109) HH (32) -CH- -NH- -CH (Me)-2-2668 (49) (109) HH (32) -CH- -NH- -CH (Me)-2-2669 (51) (109) HH (32) -CH- -NH- -CH (Me)-2-2670 (52) (64) HH (32) -CH- -NH- -CH (Me)-2-2671 (52) (109) HH (32) -CH- -NH- -CH (Me)-2- 2672 (55) (109) HH (32) -CH- -NH- -CH (Me)-2-2673 (63) (109) HH (32) -CH- -NH- -CH (Me)-2- 2674 (64) (64) HH (32) -CH- -NH- -CH (Me)-2-2675 (64) (109) HH (32) -CH- -NH- -CH (Me)-2- 2676 (68) (109) HH (32) -CH- -NH- -CH (Me)-2-2677 (70) (109) HH (32) -CH- -NH- -CH (Me)-2- 2678 (86) (109) HH (32) -CH- -NH- -CH (Me)-2-2679 (103) (109) HH (32) -CH- -NH- -CH (Me)-2- 2680 (108) (64) HH (32) -CH- -NH- -CH (Me)-2-2681 (108) (109) HH (32) -CH- -NH- -CH (Me)-2- 2682 (109) (64) HH (32) -CH- -NH- -CH (Me)-2-2683 (109) (109) HH (32) -CH- -NH- -CH (Me)-2- 2684 (64) (64) HH (33) -CH- -NH- -CH (Me)-2-2685 (64) (109) HH (33) -CH- -NH- -CH (Me)-2- 2686 (109) (64) HH (33) -CH- -NH- -CH (Me)-2-2687 (109) (109) HH (33) -CH- -NH- -CH (Me)-2- 2688 (64) (64) HH (34) -CH- -NH- -CH (Me)-2-2689 (64) (109) HH (34) -CH- -NH- -CH (Me)-2- 2690 (109) (64) HH (34) -CH- -NH- -CH (Me)-2-2691 (109) (109) HH (34) -CH- -NH- -CH (Me)-2- 2692 (38) (64) HH (10) -CH- -NH- -CH_Two-2-2693 (110) (64) H H (10) -CH- -NH- -CH_Two-  . [Table 3]

[0107]

Embedded image Compd. R ¹ R ² R ³ R ⁴ ADEF No. Substituent No. Substituent No. Substituent No. 3-1 (45) (64) HH (1) -CH- -NH- -CH (Me)-3-2 (45) (109) HH (1) -CH- -NH- -CH (Me)- 3-3 (46) (64) HH (1) -CH- -NH- -CH (Me)-3-4 (46) (109) HH (1) -CH- -NH- -CH (Me)- 3-5 (49) (109) HH (1) -CH- -NH- -CH (Me)-3-6 (51) (109) HH (1) -CH- -NH- -CH (Me)- 3-7 (52) (64) HH (1) -CH- -NH- -CH (Me)-3-8 (52) (109) HH (1) -CH- -NH- -CH (Me)- 3-9 (55) (109) HH (1) -CH- -NH- -CH (Me)-3-10 (63) (109) HH (1) -CH- -NH- -CH (Me)- 3-11 (64) (64) HH (1) -CH- -NH- -CH (Me)-3-12 (64) (109) HH (1) -CH- -NH- -CH (Me)- 3-13 (68) (109) HH (1) -CH- -NH- -CH (Me)-3-14 (70) (109) HH (1) -CH- -NH- -CH (Me)- 3-15 (86) (109) HH (1) -CH- -NH- -CH (Me)-3-16 (103) (109) HH (1) -CH- -NH- -CH (Me)- 3-17 (108) (64) HH (1) -CH- -NH- -CH (Me)-3-18 (108) (109) HH (1) -CH- -NH- -CH (Me)- 3-19 (109) (64) HH (1) -CH- -NH- -CH (Me)-3-20 (109) (109) HH (1) -CH- -NH- -CH (Me)- 3-21 (64) (64) HH (2) -CH- -NH- -CH (Me)-3-22 (64) (109) HH (2) -CH- -NH- -CH (Me)- 3-23 (109) (64) HH (2) -CH- -NH- -CH (Me)-3-24 (109) (109) HH (2) -CH- -NH- -CH (Me)- 3- 25 (46) (109) HH (3) -CH- -NH- -CH (Me)-3-26 (52) (109) HH (3) -CH- -NH- -CH (Me) -3- 27 (64) (64) HH (3) -CH- -NH- -CH (Me)-3-28 (64) (109) HH (3) -CH- -NH- -CH (Me) -3- 29 (108) (109) HH (3) -CH- -NH- -CH (Me)-3-30 (109) (64) HH (3) -CH- -NH- -CH (Me) -3- 31 (109) (109) HH (3) -CH- -NH- -CH (Me)-3-32 (109) (109) HH (4) -CH- -NH- -CH (Me) -3- 33 (109) (109) HH (5) -CH- -NH- -CH (Me)-3-34 (109) (109) HH (6) -CH- -NH- -CH (Me) -3- 35 (109) (109) HH (7) -CH- -NH- -CH (Me)-3-36 (109) (109) HH (8) -CH- -NH- -CH (Me) -3- 37 (45) (109) HH (9) -CH- -NH- -CH (Me) -3- 38 (46) (109) HH (9) -CH- -NH- -CH (Me) -3- 39 (52) (109) HH (9) -CH- -NH- -CH (Me)-3-40 (64) (64) HH (9) -CH- -NH- -CH (Me)-3- 41 (64) (109) HH (9) -CH- -NH- -CH (Me)-3-42 (108) (109) HH (9) -CH- -NH- -CH (Me) -3- 43 (109) (64) HH (9) -CH- -NH- -CH (Me)-3-44 (109) (109) HH (9) -CH- -NH- -CH (Me) -3- 45 (37) (109) HH (10) -CH- -NH- -CH (Me)-3-46 (38) (64) HH (10) -CH- -NH- -CH (Me) -3- 47 (38) (109) HH (10) -CH- -NH- -CH (Me)-3-48 (44) (64) HH (10) -CH- -NH- -CH (Me)-3-49 (44) (109) HH (10) -CH- -NH- -CH (Me)-3-50 (45) (45) HH (10) -CH- -NH- -CH (Me)-3-51 (45) (46) HH (10) -CH- -NH- -CH (Me)-3-52 (45) (49) HH (10) -CH- -NH- -CH (Me)-3-53 (45) (51) HH (10) -CH- -NH- -CH (Me)-3-54 (45) (63) HH (10) -CH- -NH- -CH (Me)-3-55 (45) (64) HH (10) -CH- -NH- -CH (Me)-3-56 (45) (66) HH (10) -CH- -NH- -CH (Me)-3-57 (45) (68) HH (10) -CH- -NH- -CH (Me)-3-58 (45) (109) HH (10) -CH- -NH- -CH (Me)-3-59 (45) (109) HH (10) N -NH- -CH (Me)-3-60 (46) (45) HH (10) -CH- -NH --CH (Me)-3-61 (46) (46) HH (10) -CH- -NH- -CH (Me)-3-62 (46) (49) HH (10) -CH- -NH --CH (Me)-3-63 (46) (51) HH (10) -CH- -NH- -CH (Me)-3-64 (46) (63) HH (10) -CH- -NH --CH (Me)-3-65 (46) (64) HH (10) -CH- -NH- -CH (Me)-3-66 (46) (66) HH (10) -CH- -NH --CH (Me)-3-67 (46) (68) HH (10) -CH- -NH- -CH (Me)-3-68 (46) (109) HH (10) -CH- -NH --CH (Me)-3-69 (46) (109) HH (10) N -NH- -CH (Me)-3-70 (47) (109) HH (10) -CH- -NH-- CH (Me)-3-71 (48) (64) HH (10) -CH- -NH- -CH (Me) -3-72 (48) (109) HH (10) -CH- -NH- -CH (Me)-3-73 (49) (46) HH (10) -CH- -NH- -CH (Me)-3-74 (49) (64) HH (10) -CH- -NH- -CH (Me)-3-75 (49) (109) HH (10) -CH- -NH- -CH (Me)-3-76 (49) (64) HH (10) N -NH- -CH (Me)-3-77 (49) (109) HH (10) N -NH- -CH (Me) -3-78 (50) (64) HH (10)- CH- -NH- -CH (Me)-3-79 (50) (109) HH (10) -CH- -NH- -CH (Me)-3-80 (51) (46) HH (10)- CH- -NH- -CH (Me)-3-81 (51) (64) HH (10) -CH- -NH- -CH (Me)-3-82 (51) (109) HH (10)- CH- -NH- -CH (Me)-3-83 (51) (64) HH (10) N -NH- -CH (Me) -3-84 (51) (109) HH (10) N -NH --CH (Me)-3-85 (52) (45) HH (10) -CH- -NH- -CH (Me)-3-86 (52) (46) HH (10) -CH- -NH --CH (Me)-3-87 (52) (49) HH (10) -CH- -NH- -CH (Me) -3-88 (52) (51) HH (10) -CH- -NH --CH (Me)-3-89 (52) (63) HH (10) -CH- -NH- -CH (Me)-3-90 (52) (64) HH (10) -CH- -NH --CH (Me)-3-91 (52) (66) HH (10) -CH- -NH- -CH (Me)-3-92 (52) (68) HH (10) -CH- -NH --CH (Me)-3-93 (52) (109) HH (10) -CH- -NH- -CH (Me)-3-94 (52) (109) HH (10) N -NH-- CH (Me)-3-95 (53) (64) HH (10) -CH- -NH- -CH (Me) -3-96 (53) (109) HH (10) -CH- -NH- -CH (Me)-3-97 (55) (46) HH (10) -CH- -NH- -CH (Me)-3-98 (55) (64) HH (10) -CH- -NH- -CH (Me)-3-99 (55) (109) HH (10) -CH- -NH- -CH (Me) -3-100 (55) (64) HH (10) N -NH- -CH (Me)-3-101 (55) (109) HH (10) N -NH- -CH (Me) -3-102 (57) (109) HH (10)- CH- -NH- -CH (Me)-3-103 (58) (109) HH (10) -CH- -NH- -CH (Me)-3-104 (59) (64) HH (10)- CH- -NH- -CH (Me)-3-105 (59) (109) HH (10) -CH- -NH- -CH (Me)-3-106 (62) (64) HH (10)- CH- -NH- -CH (Me)-3-107 (62) (109) HH (10) -CH- -NH- -CH (Me)-3-108 (63) (46) HH (10)- CH- -NH- -CH (Me)-3-109 (63) (64) HH (10) -CH- -NH- -CH (Me)-3-110 (63) (109) HH (10)- CH- -NH- -CH (Me)-3-111 (63) (64) HH (10) N -NH- -CH (Me)-3-112 (63) (109) HH (10) N -NH --CH (Me)-3-113 (64) (45) HH (10) -CH- -NH- -CH (Me)-3-114 (64) (46) HH (10) -CH- -NH --CH (Me)-3-115 (64) (49) HH (10) -CH- -NH- -CH (Me)-3-116 (64) (51) HH (10) -CH- -NH --CH (Me)-3-117 (64) (63) HH (10) -CH- -NH- -CH (Me)-3-118 (64) (64) HH (10) -CH- -NH --CH (Me)-3-119 (64) (66) HH (10) -CH- -NH- -C H (Me)-3-120 (64) (68) HH (10) -CH- -NH- -CH (Me)-3-121 (64) (109) HH (10) -CH- -NH-- CH (Me)-3-122 (64) (109) HH (10) N -NH- -CH (Me)-3-123 (66) (64) HH (10) -CH- -NH- -CH ( (Me)-3-124 (66) (109) HH (10) -CH- -NH- -CH (Me)-3-125 (68) (64) HH (10) -CH- -NH- -CH ( (Me)-3-126 (68) (109) HH (10) -CH- -NH- -CH (Me)-3-127 (68) (64) HH (10) N -NH- -CH (Me) -3-128 (68) (109) HH (10) N -NH- -CH (Me)-3-129 (69) (109) HH (10) -CH- -NH- -CH (Me) -3 -120 (70) (64) HH (10) -CH- -NH- -CH (Me)-3-121 (70) (109) HH (10) -CH- -NH- -CH (Me) -3 -122 (70) (64) HH (10) N -NH- -CH (Me)-3-123 (70) (109) HH (10) N -NH- -CH (Me)-3-124 (73 ) (109) HH (10) -CH- -NH- -CH (Me)-3-125 (75) (109) HH (10) -CH- -NH- -CH (Me)-3-126 (76 ) (109) HH (10) -CH- -NH- -CH (Me)-3-127 (85) (109) HH (10) -CH- -NH- -CH (Me)-3-128 (86 ) (64) HH (10) -CH- -NH- -CH (Me)-3-129 (86) (109) HH (10) -CH- -NH- -CH (Me)-3-130 (86 ) (64) HH (10) N -NH- -CH (Me)-3-131 (86) (109) HH (10) N -NH- -CH (Me)-3-132 (88) (109) HH (10) -CH- -NH- -CH (Me)-3-133 (90) (109) HH (10) -CH- -NH- -CH (Me)-3-134 (92) (109) HH (10) -CH- -NH- -CH (Me) -3-135 (95) (109) HH (10) -CH- -NH- -CH (Me)-3-136 (101) (64) HH (10) -CH- -NH- -CH (Me) -3-137 (101) (109) HH (10) -CH- -NH- -CH (Me)-3-138 (102) (64) HH (10) -CH- -NH- -CH (Me)-3-139 (102) (109) HH (10) -CH- -NH- -CH (Me)-3-140 (103) (64) HH (10) -CH- -NH- -CH (Me)-3-141 (103) (109) HH (10) -CH- -NH- -CH (Me)-3-142 (103) (64) HH (10) N -NH- -CH (Me)-3-143 (103) (109 ) HH (10) N -NH- -CH (Me)-3-144 (106) (64) HH (10) -CH- -NH- -CH (Me)-3-145 (106) (109) HH (10) -CH- -NH- -CH (Me)-3-146 (108) (45) HH (10) -CH- -NH- -CH (Me)-3-147 (108) (46) HH (10) -CH- -NH- -CH (Me) -3-148 (108) (49) HH (10) -CH- -NH- -CH (Me)-3-149 (108) (51) HH (10) -CH- -NH- -CH (Me)-3-150 (108) (63) HH (10) -CH- -NH- -CH (Me)-3-151 (108) (64) HH (10) -CH- -NH- -CH (Me)-3-152 (108) (66) HH (10) -CH- -NH- -CH (Me)-3-153 (108) (68) HH (10) -CH- -NH- -CH (Me)-3-154 (108) (109) HH (10) -CH- -NH- -CH (Me)-3-155 (108) (109) HH (10) N -NH- -CH (Me)- 3-156 (109) (45) HH (10) -CH- -NH- -CH (Me)-3-157 (109) (46) HH (10) -CH- -NH- -CH (Me)- 3-158 (109) (49) HH (10) -CH- -NH- -CH (Me)-3-159 (109) (51) HH (10) -CH- -NH- -CH (Me)- 3-160 (109) (63) HH (10) -CH- -NH- -CH (Me)-3-161 (109) (64) HH (10) -CH- -NH- -CH (Me)- 3-162 (109) (66) HH (10) -CH- -NH- -CH (Me)-3-163 (109) (68) HH (10) -CH- -NH- -CH (Me)- 3-164 (109) (109) HH (10) -CH- -NH- -CH (Me)-3-165 (109) (109) HH (10) N -NH- -CH (Me)-3- 166 (109) (109) HH (11) -CH- -NH- -CH (Me)-3-167 (46) (109) HH (12) -CH- -NH- -CH (Me) -3- 168 (52) (109) HH (12) -CH- -NH- -CH (Me)-3-169 (64) (64) HH (12) -CH- -NH- -CH (Me) -3- 170 (64) (109) HH (12) -CH- -NH- -CH (Me)-3-171 (108) (109) HH (12) -CH- -NH- -CH (Me) -3- 172 (109) (64) HH (12) -CH- -NH- -CH (Me)-3-173 (109) (109) HH (12) -CH- -NH- -CH (Me) -3- 174 (38) (109) HH (13) -CH- -NH- -CH (Me)-3-175 (44) (109) HH (13) -CH- -NH- -CH (Me) -3- 176 (45) (46) HH (13) -CH- -NH- -CH (Me)-3-177 (45) (64) HH (13) -CH- -NH- -CH (Me) -3- 178 (45) (109) HH (13) -CH- -NH --CH (Me)-3-179 (45) (64) HH (13) N -NH- -CH (Me)-3-180 (45) (109) HH (13) N -NH- -CH ( Me)-3-181 (46) (46) HH (13) -CH- -NH- -CH (Me)-3-182 (46) (64) HH (13) -CH- -NH- -CH ( Me)-3-183 (46) (109) HH (13) -CH- -NH- -CH (Me)-3-184 (46) (64) HH (13) N -NH- -CH (Me) -3-185 (46) (109) HH (13) N -NH- -CH (Me)-3-186 (48) (109) HH (13) -CH- -NH- -CH (Me) -3 -187 (49) (64) HH (13) -CH- -NH- -CH (Me)-3-188 (49) (109) HH (13) -CH- -NH- -CH (Me) -3 -189 (50) (109) HH (13) -CH- -NH- -CH (Me)-3-190 (51) (64) HH (13) -CH- -NH- -CH (Me) -3 -191 (51) (109) HH (13) -CH- -NH- -CH (Me)-3-192 (52) (46) HH (13) -CH- -NH- -CH (Me) -3 -193 (52) (64) HH (13) -CH- -NH- -CH (Me)-3-194 (52) (109) HH (13) -CH- -NH- -CH (Me) -3 -195 (52) (64) HH (13) N -NH- -CH (Me)-3-196 (52) (109) HH (13) N -NH- -CH (Me)-3-197 (53 ) (109) HH (13) -CH- -NH- -CH (Me)-3-198 (55) (64) HH (13) -CH- -NH- -CH (Me)-3-199 (55 ) (109) HH (13) -CH- -NH- -CH (Me)-3-200 (59) (109) HH (13) -CH- -NH- -CH (Me) -3-201 (62 ) (109) HH (13) -CH- -NH- -CH (Me)-3-202 (63) (64) HH (13) -CH- -NH- -CH (Me)-3-203 (63) (109) HH (13) -CH- -NH- -CH (Me) -3-204 (64) (46) HH (13) -CH- -NH- -CH (Me) -3-205 (64) (64) HH (13) -CH- -NH- -CH (Me) -3-206 (64) (109) HH (13) -CH- -NH- -CH (Me) -3-207 (64) (64) HH (13) N -NH- -CH (Me) -3-208 (64 ) (109) HH (13) N -NH- -CH (Me)-3-209 (66) (109) HH (13) -CH- -NH- -CH (Me)-3-210 (68) ( 64) HH (13) -CH- -NH- -CH (Me)-3-211 (68) (109) HH (13) -CH- -NH- -CH (Me)-3-212 (70) ( 64) HH (13) -CH- -NH- -CH (Me)-3-213 (70) (109) HH (13) -CH- -NH- -CH (Me) -3-214 (86) ( 64) HH (13) -CH- -NH- -CH (Me)-3-215 (86) (109) HH (13) -CH- -NH- -CH (Me)-3-216 (101) ( 109) HH (13) -CH- -NH- -CH (Me)-3-217 (102) (109) HH (13) -CH- -NH- -CH (Me)-3-218 (103) ( 64) HH (13) -CH- -NH- -CH (Me)-3-219 (103) (109) HH (13) -CH- -NH- -CH (Me)-3-220 (106) ( 109) HH (13) -CH- -NH- -CH (Me) -3-221 (108) (46) HH (13) -CH- -NH- -CH (Me) -3-222 (108) ( 64) HH (13) -CH- -NH- -CH (Me)-3-223 (108) (109) HH (13) -CH- -NH- -CH (Me) -3-224 (108) ( 64) HH (13) N -NH- -CH (Me)-3-22 5 (108) (109) HH (13) N -NH- -CH (Me)-3-226 (109) (46) HH (13) -CH- -NH- -CH (Me)-3-227 ( 109) (64) HH (13) -CH- -NH- -CH (Me)-3-228 (109) (109) HH (13) -CH- -NH- -CH (Me) -3-229 ( 109) (64) HH (13) N -NH- -CH (Me)-3-230 (109) (109) HH (13) N -NH- -CH (Me)-3-231 (109) (109 ) HH (14) -CH- -NH- -CH (Me)-3-232 (45) (109) HH (15) -CH- -NH- -CH (Me)-3-233 (46) (109 ) HH (15) -CH- -NH- -CH (Me)-3-234 (52) (109) HH (15) -CH- -NH- -CH (Me)-3-235 (64) (64 ) HH (15) -CH- -NH- -CH (Me)-3-236 (64) (109) HH (15) -CH- -NH- -CH (Me)-3-237 (108) (109 ) HH (15) -CH- -NH- -CH (Me)-3-238 (109) (64) HH (15) -CH- -NH- -CH (Me) -3-239 (109) (109 ) HH (15) -CH- -NH- -CH (Me)-3-240 (37) (109) HH (16) -CH- -NH- -CH (Me)-3-241 (38) (64 ) HH (16) -CH- -NH- -CH (Me)-3-242 (38) (109) HH (16) -CH- -NH- -CH (Me)-3-243 (44) (64 ) HH (16) -CH- -NH- -CH (Me)-3-244 (44) (109) HH (16) -CH- -NH- -CH (Me)-3-245 (45) (45) ) HH (16) -CH- -NH- -CH (Me)-3-246 (45) (46) HH (16) -CH- -NH- -CH (Me)-3-247 (45) (49) ) HH (16) -CH- -NH- -CH (Me)-3 -248 (45) (51) HH (16) -CH- -NH- -CH (Me)-3-249 (45) (63) HH (16) -CH- -NH- -CH (Me) -3 -250 (45) (64) HH (16) -CH- -NH- -CH (Me)-3-251 (45) (66) HH (16) -CH- -NH- -CH (Me) -3 -252 (45) (68) HH (16) -CH- -NH- -CH (Me)-3-253 (45) (109) HH (16) -CH- -NH- -CH (Me) -3 -254 (45) (109) HH (16) N -NH- -CH (Me)-3-255 (46) (45) HH (16) -CH- -NH- -CH (Me)-3-256 (46) (46) HH (16) -CH- -NH- -CH (Me)-3-257 (46) (49) HH (16) -CH- -NH- -CH (Me) -3-258 (46) (51) HH (16) -CH- -NH- -CH (Me) -3-259 (46) (63) HH (16) -CH- -NH- -CH (Me) -3-260 (46) (64) HH (16) -CH- -NH- -CH (Me)-3-261 (46) (66) HH (16) -CH- -NH- -CH (Me) -3-262 (46) (68) HH (16) -CH- -NH- -CH (Me) -3-263 (46) (109) HH (16) -CH- -NH- -CH (Me) -3-264 (46) (109) HH (16) N -NH- -CH (Me)-3-265 (47) (109) HH (16) -CH- -NH- -CH (Me)-3-266 (48 ) (64) HH (16) -CH- -NH- -CH (Me)-3-267 (48) (109) HH (16) -CH- -NH- -CH (Me)-3-268 (49 ) (46) HH (16) -CH- -NH- -CH (Me)-3-269 (49) (64) HH (16) -CH- -NH- -CH (Me)-3-270 (49 ) (109) HH (16) -CH- -NH- -CH (Me)-3-271 (49) (64) HH (16) N -NH- -CH (Me)-3-272 (49) (109) HH (16) N -NH- -CH (Me)-3-273 (50) (64) HH (16) -CH- -NH- -CH (Me)-3-274 (50) (109) HH (16) -CH- -NH- -CH (Me)-3-275 (51) (46) HH (16) -CH- -NH- -CH (Me)-3-276 (51) (64) HH (16) -CH- -NH- -CH (Me)-3-277 (51) (109) HH (16) -CH- -NH- -CH (Me)-3-278 (51) (64) HH (16) N -NH- -CH (Me)-3-279 (51) (109) HH (16 ) N -NH- -CH (Me)-3-280 (52) (45) HH (16) -CH- -NH- -CH (Me)-3-281 (52) (46) HH (16)- CH- -NH- -CH (Me)-3-282 (52) (49) HH (16) -CH- -NH- -CH (Me)-3-283 (52) (51) HH (16)- CH- -NH- -CH (Me)-3-284 (52) (63) HH (16) -CH- -NH- -CH (Me)-3-285 (52) (64) HH (16)- CH- -NH- -CH (Me)-3-286 (52) (66) HH (16) -CH- -NH- -CH (Me)-3-287 (52) (68) HH (16)- CH- -NH- -CH (Me)-3-288 (52) (109) HH (16) -CH- -NH- -CH (Me)-3-289 (52) (109) HH (16) N -NH- -CH (Me)-3-290 (53) (64) HH (16) -CH- -NH- -CH (Me)-3-291 (53) (109) HH (16) -CH- -NH- -CH (Me)-3-292 (55) (46) HH (16) -CH- -NH- -CH (Me)-3-293 (55) (64) HH (16) -CH- -NH- -CH (Me)-3-294 (55) (109) HH (16) -CH- -NH- -CH (Me)-3-295 (55) (64) HH (16) N -NH- -CH (Me)-3-296 (55) (109) HH (16) N -NH-- CH (Me)-3-297 (57) (109) HH (16) -CH- -NH- -CH (Me)-3-298 (58) (109) HH (16) -CH- -NH-- CH (Me)-3-299 (59) (64) HH (16) -CH- -NH- -CH (Me)-3-300 (59) (109) HH (16) -CH- -NH-- CH (Me)-3-301 (62) (64) HH (16) -CH- -NH- -CH (Me)-3-302 (62) (109) HH (16) -CH- -NH-- CH (Me)-3-303 (63) (46) HH (16) -CH- -NH- -CH (Me)-3-304 (63) (64) HH (16) -CH- -NH-- CH (Me)-3-305 (63) (109) HH (16) -CH- -NH- -CH (Me)-3-306 (63) (64) HH (16) N -NH- -CH ( Me)-3-307 (63) (109) HH (16) N -NH- -CH (Me)-3-308 (64) (45) HH (16) -CH- -NH- -CH (Me) -3-309 (64) (46) HH (16) -CH- -NH- -CH (Me)-3-310 (64) (49) HH (16) -CH- -NH- -CH (Me) -3-311 (64) (51) HH (16) -CH- -NH- -CH (Me)-3-312 (64) (63) HH (16) -CH- -NH- -CH (Me) -3-313 (64) (64) HH (16) -CH- -NH- -CH (Me)-3-314 (64) (66) HH (16) -CH- -NH- -CH (Me) -3-315 (64) (68) HH (16) -CH- -NH- -CH (Me)-3-316 (64) (109) HH (16) -CH- -NH- -CH (Me) -3-317 (64) (109) HH (16) N -NH- -CH (Me)-3-3 18 (66) (64) HH (16) -CH- -NH- -CH (Me)-3-319 (66) (109) HH (16) -CH- -NH- -CH (Me)-3- 320 (68) (64) HH (16) -CH- -NH- -CH (Me)-3-321 (68) (109) HH (16) -CH- -NH- -CH (Me) -3- 322 (68) (64) HH (13) N -NH- -CH (Me) -3- 323 (68) (109) HH (16) N -NH- -CH (Me)-3-324 (69) (109) HH (16) -CH- -NH- -CH (Me)-3-325 (70) (64) HH (16) -CH- -NH- -CH (Me) -3-326 (70) (109) HH (16) -CH- -NH- -CH (Me)-3-327 (70) (64) HH (16) N -NH- -CH (Me)-3-328 (70) (109 ) HH (16) N -NH- -CH (Me) -3-329 (73) (109) HH (16) -CH- -NH- -CH (Me) -3-330 (75) (109) HH (16) -CH- -NH- -CH (Me)-3-331 (76) (109) HH (16) -CH- -NH- -CH (Me) -3-332 (85) (109) HH (16) -CH- -NH- -CH (Me) -3-333 (86) (64) HH (16) -CH- -NH- -CH (Me) -3-334 (86) (109) HH (16) -CH- -NH- -CH (Me) -3-335 (86) (64) HH (16) N -NH- -CH (Me) -3-336 (86) (109) HH (16 ) N -NH- -CH (Me)-3-337 (88) (109) HH (16) -CH- -NH- -CH (Me)-3-338 (90) (109) HH (16)- CH- -NH- -CH (Me)-3-339 (92) (109) HH (16) -CH- -NH- -CH (Me)-3-340 (95) (109) HH (16)- CH- -NH- -CH (Me)-3-341 (101) (64) HH (16) -CH- -NH- -CH (Me)-3-342 (101) (109) HH (16) -CH- -NH- -CH (Me)-3-343 (102) (64) HH (16) -CH- -NH- -CH (Me) -3-344 (102) (109) HH (16) -CH- -NH- -CH (Me) -3-345 (103) (64) HH (16) -CH- -NH- -CH (Me)-3-346 (103) (109) HH (16) -CH- -NH- -CH (Me)-3-347 (103) (64) HH (16) N -NH- -CH (Me) -3-348 (103) (109) HH (16) N -NH- -CH (Me) -3-349 (106) (64) HH (16) -CH- -NH- -CH (Me)-3-350 (106) (109) HH (16) -CH- -NH- -CH (Me)-3-351 (108) (45) HH (16) -CH- -NH- -CH (Me)-3-352 (108) (46) HH (16) -CH- -NH- -CH (Me)-3-353 (108) (49) HH (16) -CH- -NH- -CH (Me)-3-354 (108) (51) HH (16) -CH- -NH- -CH (Me) -3-355 (108) (63) HH (16) -CH- -NH- -CH (Me)-3-356 (108) (64) HH (16) -CH- -NH- -CH (Me)-3-357 (108) (66) HH (16) -CH- -NH- -CH (Me)-3-358 (108) (68) HH (16) -CH- -NH- -CH (Me)-3-359 (108) (109) HH (16) -CH- -NH- -CH (Me)-3-360 (108) (109) HH (16) N -NH- -CH (Me) -3-361 (109) (45) HH (16) -CH --NH- -CH (Me)-3-362 (109) (46) HH (16) -CH- -NH- -CH (Me)-3-363 (109) (49) HH (16) -CH --NH- -CH (Me)-3-364 (109) (51) HH (16) -CH- -NH- -CH (Me) -3-365 (109) (63) HH (16) -CH- -NH- -CH (Me) -3-366 (109) (64) HH (16) -CH- -NH- -CH (Me)-3-367 (109) (66) HH (16) -CH- -NH- -CH (Me) -3-368 (109) (68) HH (16) -CH- -NH- -CH (Me)-3-369 (109) (109) HH (16) -CH- -NH- -CH (Me) -3-370 (109) (109) HH (16) N -NH- -CH (Me)-3-371 (109) (109) HH (17) -CH- -NH- -CH (Me)-3-372 (64 ) (64) HH (18) -CH- -NH- -CH (Me)-3-373 (64) (109) HH (18) -CH- -NH- -CH (Me)-3-374 (109 ) (64) HH (18) -CH- -NH- -CH (Me)-3-375 (109) (109) HH (18) -CH- -NH- -CH (Me)-3-376 (45 ) (64) HH (19) -CH- -NH- -CH (Me)-3-377 (45) (109) HH (19) -CH- -NH- -CH (Me)-3-378 (46 ) (64) HH (19) -CH- -NH- -CH (Me)-3-379 (46) (109) HH (19) -CH- -NH- -CH (Me)-3-380 (49 ) (109) HH (19) -CH- -NH- -CH (Me)-3-381 (51) (109) HH (19) -CH- -NH- -CH (Me) -3-382 (52 ) (64) HH (19) -CH- -NH- -CH (Me)-3-383 (52) (109) HH (19) -CH- -NH- -CH (Me)-3-384 (55 ) (109) HH (19) -CH- -NH- -CH (Me)-3-385 (63) (109) HH (19) -CH- -NH- -CH (Me)-3-386 (64 ) (64) HH (19) -CH- -NH- -CH (Me) -3-387 (64) (109) HH (19) -CH- -NH- -CH (Me)-3-388 (68) (109) HH (19) -CH- -NH- -CH (Me) -3-389 (70) (109) HH (19) -CH- -NH- -CH (Me)-3-390 (86) (109) HH (19) -CH- -NH- -CH (Me) -3-391 (103) (109) HH (19) -CH- -NH- -CH (Me)-3-392 (108) (64) HH (19) -CH- -NH- -CH (Me) -3-393 (108) (109) HH (19) -CH- -NH- -CH (Me)-3-394 (109) (64) HH (19) -CH- -NH- -CH (Me) -3-395 (109) (109) HH (19) -CH- -NH- -CH (Me)-3-396 (109) (109) HH (20) -CH- -NH- -CH (Me) -3-397 (109) (109) HH (21) -CH- -NH- -CH (Me)-3-398 (64) (64) HH (22) -CH- -NH- -CH (Me) -3-399 (64) (109) HH (22) -CH- -NH- -CH (Me)-3-400 (109) (64) HH (22) -CH- -NH- -CH (Me) -3-401 (109) (109) HH (22) -CH- -NH- -CH (Me)-3-402 (109) (109) HH (23) -CH- -NH- -CH (Me) -3-403 (45) (64) HH (24) -CH- -NH- -CH (Me)-3-404 (45) (109) HH (24) -CH- -NH- -CH (Me) -3-405 (46) (64) HH (24) -CH- -NH- -CH (Me)-3-406 (46) (109) HH (24) -CH- -NH- -CH (Me) -3-407 (49) (109) HH (24) -CH- -NH- -CH (Me)-3-408 (51) (109) HH (24) -CH- -NH- -CH (Me) -3-409 (52) (64) HH (24) -C H- -NH- -CH (Me)-3-410 (52) (109) HH (24) -CH- -NH- -CH (Me)-3-411 (55) (109) HH (24)- CH- -NH- -CH (Me)-3-412 (63) (109) HH (24) -CH- -NH- -CH (Me)-3-413 (64) (64) HH (24)- CH- -NH- -CH (Me)-3-414 (64) (109) HH (24) -CH- -NH- -CH (Me)-3-415 (68) (109) HH (24)- CH- -NH- -CH (Me)-3-416 (70) (109) HH (24) -CH- -NH- -CH (Me)-3-417 (86) (109) HH (24)- CH- -NH- -CH (Me)-3-418 (103) (109) HH (24) -CH- -NH- -CH (Me)-3-419 (108) (64) HH (24)- CH- -NH- -CH (Me)-3-420 (108) (109) HH (24) -CH- -NH- -CH (Me)-3-421 (109) (64) HH (24)- CH- -NH- -CH (Me)-3-422 (109) (109) HH (24) -CH- -NH- -CH (Me)-3-423 (109) (109) HH (25)- CH- -NH- -CH (Me)-3-424 (45) (64) HH (26) -CH- -NH- -CH (Me)-3-425 (45) (109) HH (26)- CH- -NH- -CH (Me)-3-426 (46) (64) HH (26) -CH- -NH- -CH (Me)-3-427 (46) (109) HH (26)- CH- -NH- -CH (Me)-3-428 (49) (109) HH (26) -CH- -NH- -CH (Me)-3-429 (51) (109) HH (26)- CH- -NH- -CH (Me)-3-430 (52) (64) HH (26) -CH- -NH- -CH (Me)-3-431 (52) (109) HH (26)- CH- -NH- -CH (Me)-3-432 (55) (109 ) HH (26) -CH- -NH- -CH (Me)-3-433 (63) (109) HH (26) -CH- -NH- -CH (Me) -3-434 (64) (64 ) HH (26) -CH- -NH- -CH (Me)-3-435 (64) (109) HH (26) -CH- -NH- -CH (Me) -3-436 (68) (109) ) HH (26) -CH- -NH- -CH (Me)-3-437 (70) (109) HH (26) -CH- -NH- -CH (Me)-3-438 (86) (109 ) HH (26) -CH- -NH- -CH (Me)-3-439 (103) (109) HH (26) -CH- -NH- -CH (Me)-3-440 (108) (64 ) HH (26) -CH- -NH- -CH (Me)-3-441 (108) (109) HH (26) -CH- -NH- -CH (Me)-3-442 (109) (64 ) HH (26) -CH- -NH- -CH (Me) -3-443 (109) (109) HH (26) -CH- -NH- -CH (Me) -3-444 (109) (109) ) HH (27) -CH- -NH- -CH (Me)-3-445 (45) (109) HH (28) -CH- -NH- -CH (Me) -3-446 (46) (109 ) HH (28) -CH- -NH- -CH (Me)-3-447 (52) (109) HH (28) -CH- -NH- -CH (Me)-3-448 (64) (64 ) HH (28) -CH- -NH- -CH (Me)-3-449 (64) (109) HH (28) -CH- -NH- -CH (Me) -3-450 (108) (109 ) HH (28) -CH- -NH- -CH (Me)-3-451 (109) (64) HH (28) -CH- -NH- -CH (Me) -3-452 (109) (109) ) HH (28) -CH- -NH- -CH (Me)-3-453 (109) (109) HH (29) -CH- -NH- -CH (Me)-3-454 (64) (64 ) HH (30) -CH- -NH- -CH (Me)- 3-455 (64) (109) HH (30) -CH- -NH- -CH (Me)-3-456 (109) (64) HH (30) -CH- -NH- -CH (Me)- 3-457 (109) (109) HH (30) -CH- -NH- -CH (Me)-3-458 (45) (109) HH (31) -CH- -NH- -CH (Me)- 3-459 (46) (109) HH (31) -CH- -NH- -CH (Me)-3-460 (52) (109) HH (31) -CH- -NH- -CH (Me)- 3-461 (64) (64) HH (31) -CH- -NH- -CH (Me)-3-462 (64) (109) HH (31) -CH- -NH- -CH (Me)- 3-463 (108) (109) HH (31) -CH- -NH- -CH (Me)-3-464 (109) (64) HH (31) -CH- -NH- -CH (Me)- 3-465 (109) (109) HH (31) -CH- -NH- -CH (Me)-3-466 (45) (109) HH (32) -CH- -NH- -CH (Me)- 3-467 (46) (109) HH (32) -CH- -NH- -CH (Me)-3-468 (52) (109) HH (32) -CH- -NH- -CH (Me)- 3-469 (64) (64) HH (32) -CH- -NH- -CH (Me)-3-470 (64) (109) HH (32) -CH- -NH- -CH (Me)- 3-471 (108) (109) HH (32) -CH- -NH- -CH (Me)-3-472 (109) (64) HH (32) -CH- -NH- -CH (Me)- 3-473 (109) (109) HH (32) -CH- -NH- -CH (Me)-3-474 (109) (109) HH (33) -CH- -NH- -CH (Me)- 3-475 (109) (109) HH (34) -CH- -NH- -CH (Me)- In the above Table 1-3, examples of suitable compounds include: Exemplified compound numbers: 1-29, 1-30, 1-38, 1-70, 1-78, 1-9
9, 1-100, 1-140, 1-141,1-149, 1-150, 2-5, 2-21, 2-
46, 2-56, 2-72, 2-77, 2-89, 2-117, 2-126, 2-133, 2
-158, 2-162, 2-167, 2-205, 2-217, 2-221, 2-265, 2-
267, 2-268, 2-269, 2-270, 2-271, 2-272, 2-273, 2-2
74, 2-275, 2-279, 2-298, 2-308, 2-320,2-325, 2-32
6, 2-327, 2-328, 2-329, 2-330, 2-337, 2-341, 2-34
2, 2-343, 2-344, 2-345, 2-346, 2-347, 2-413, 2-50
4, 2-506, 2-515, 2-553, 2-600, 2-604, 2-605, 2-60
6, 2-608, 2-609, 2-614, 2-642, 2-654, 2-671, 2-67
6, 2-677, 2-679, 2-680, 2-691, 2-804, 2-809, 2-81
0, 2-812, 2-813, 2-814, 2-857, 2-878, 2-907, 2-964,
2-1009, 2-1013, 2-1027, 2-1059, 2-1073, 2-1106, 2
-1110, 2-1111, 2-1112, 2-1113, 2-1114, 2-1115, 2-1
116, 2-1192, 2-1203, 2-1217, 2-1251, 2-1255, 2-125
6, 2-1257, 2-1259, 2-1260, 2-1261, 2-1259, 2-1292,
2-1321, 2-1325, 2-1498, 2-1514, 2-1539, 2-1543, 2
-1548, 2-1566, 2-1578, 2-1582, 2-1583, 2-1584, 2-1
585, 2-1586, 2-1587, 2-1588, 2-1626, 2-1628, 2-162
9, 2-1630, 2-1631, 2-1632, 2-1633, 2-1634, 2-1635,
2-1636, 2-1659, 2-1664, 2-1665, 2-1670, 2-1671, 2
-1672, 2-1673, 2-1674, 2-1675, 2-1676, 2-1677, 2-1
678, 2-1688, 2-1744, 2-1748, 2-1749, 2-1750, 2-180
4, 2-1813, 2-1845, 2-1849, 2-1850, 2-1851, 2-1852,
2-1853, 2-1854, 2-1855, 2-1892, 2-1896, 2-1897, 2
-1898, 2-1899, 2-1900, 2-1901, 2-1902, 2-1938, 2-1
939, 2-1940, 2-1941, 2-1942, 2-1943, 2-2046, 2-205
1, 2-2052, 2-2053, 2-2054, 2-2055, 2-2056, 2-2086,
2-2091, 2-2092, 2-2093, 2-2094, 2-2095, 2-2096, 2
-2151, 2-2163, 2-2186, 2-2190, 2-2191, 2-2192, 2-2
193, 2-2194, 2-2195, 2-2196, 2-2233, 2-2238, 2-223
9, 2-2240, 2-2241, 2-2242, 2-2243, 2-2347, 2-2351,
2-2352, 2-2353, 2-2354, 2-2355, 2-2356, 2-2357, 2
-2387, 2-2391, 2-2476, 2-2477, 2-2481, 2-2484, 2-2
485, 3-55, 3-90, 3-250 and 3-345. More preferred compounds are exemplified compound numbers: 2-5, 2-21, 2-46, 2-56, 2-72, 2-77,
2-89, 2-117, 2-126, 2-133, 2-158, 2-162, 2-167, 2
-205, 2-221, 2-217, 2-265, 2-267, 2-268, 2-269, 2-
275, 2-279, 2-298, 2-308, 2-320, 2-325, 2-326, 2-3
27, 2-328, 2-329, 2-330, 2-337, 2-341, 2-342, 2-34
3, 2-344, 2-345, 2-346, 2-347, 2-413, 2-504, 2-506,
2-515, 2-553, 2-600, 2-604, 2-605, 2-606, 2-608,
2-609, 2-614, 2-642, 2-654, 2-671, 2-676, 2-677, 2
-679, 2-680, 2-691, 2-804, 2-809, 2-810, 2-812, 2-
813, 2-814, 2-857, 2-878, 2-907, 2-964, 2-1009, 2-
1013, 2-1027, 2-1059, 2-1073, 2-1106, 2-1110, 2-11
11, 2-1112, 2-1113, 2-1114, 2-1115, 2-1116, 2-119
2, 2-1203, 2-1217, 2-1251, 2-1255, 2-1256, 2-1257,
2-1259, 2-1260, 2-1261, 2-1259, 2-1292, 2-1321, 2
-1325, 2-1498, 2-1514, 2-1539, 2-1543, 2-1548, 2-1
566, 2-1578, 2-1582, 2-1583, 2-1584, 2-1585, 2-158
6, 2-1587, 2-1588, 2-1626, 2-1628, 2-1629, 2-1630,
2-1636, 2-1659, 2-1664, 2-1665, 2-1670, 2-1671, 2
-1672, 2-1673, 2-1674, 2-1675, 2-1676, 2-1677, 2-1
678, 2-1688, 2-1744, 2-1748, 2-1749, 2-1750, 2-180
4, 2-1813, 2-1845, 2-1849, 2-1850, 2-1851, 2-1852,
2-1853, 2-1854, 2-1855, 2-1892, 2-1896, 2-1897, 2
-1898, 2-1899, 2-1900, 2-1901, 2-1902, 2-1938, 2-1
939, 2-1940, 2-1941, 2-1942, 2-1943, 2-2046, 2-205
1, 2-2052, 2-2053, 2-2054, 2-2055, 2-2056, 2-2086,
2-2091, 2-2092, 2-2093, 2-2094, 2-2095, 2-2096, 2
-2151, 2-2163, 2-2186, 2-2190, 2-2191, 2-2192, 2-2
193, 2-2194, 2-2195, 2-2196, 2-2233, 2-2238, 2-223
9, 2-2240, 2-2241, 2-2242, 2-2243, 2-2347, 2-2351,
2-2352, 2-2353, 2-2354, 2-2355, 2-2356, 2-2357, 2
-2387, 2-2391, 2-2476, 2-2477, 2-2481, 2-2284 and 2
-2285, and more preferable compounds are exemplified compound numbers: 2-217, 2-221, 2-265, 2-269, 2-275,
2-298, 2-308, 2-320,2-337, 2-341, 2-413, 2-504, 2
-506, 2-515, 2-553, 2-600, 2-604, 2-608, 2-614, 2-
642, 2-654, 2-671, 2-676, 2-677, 2-679, 2-680, 2-6
91, 2-804, 2-809, 2-810, 2-812, 2-813, 2-814, 2-85
7, 2-878, 2-907, 2-964, 2-1009, 2-1013, 2-1027, 2-
1059, 2-1073, 2-1106, 2-1110, 2-1192, 2-1203, 2-12
55, 2-1256, 2-1257, 2-1297, 2-1321, 2-1325, 2-157
8, 2-1626, 2-1630, 2-1636, 2-1688, 2-1744, 2-1748,
2-1804, 2-1813, 2-1845, 2-1849, 2-1892, 2-1896, 2
-1897, 2-1898, 2-1899, 2-1900, 2-1901, 2-1902, 2-1
938, 2-1939, 2-1940, 2-1941, 2-1942, 2-1943, 2-204
6, 2-2051, 2-2052, 2-2053, 2-2054, 2-2055, 2-2056,
2-2086, 2-2151, 2-2163, 2-2186, 2-2190, 2-2191, 2
-2192, 2-2193, 2-2194, 2-2195, 2-2196, 2-2233, 2-2
347, 2-2351, 2-2352, 2-2353, 2-2354, 2-2355, 2-235
6, 2-2357, 2-2387 and 2-2391. Particularly preferred compounds are exemplified compound No. 2-265: 5- [3-((1- (3-fluorophenyl) ethylamino). )-(4-Methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione, Exemplified Compound No. 2-413: 5- [3-((1- (4-fluorophenyl) ethylamino)-(4-methoxy) Phenyl) methyl) benzyl] thiazolidine-2,4-dione, Exemplified Compound No. 2-504: 5- [3-((1- (3-chlorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine -2,4-dione, Exemplified Compound No. 2-515: 5- [3-((1- (4-chlorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione, Example Compound number 2-600: 5- [3-((1- (3,4-
Difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-
Dione, Exemplified Compound No. 2-604: 5- [3-((2- (3,4-
Difluorophenyl) propionylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-
2,4-dione, Exemplified Compound No. 2-1013: 5- [3-((-1- (1-naphthyl) ethylamino) -phenylmethyl) benzyl]
Thiazolidine-2,4-dione, Exemplified Compound No. 2-1027: 5- [3-((1- (2-thienyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione Exemplified Compound No. 2-1059: 5- [3-((1- (4-pyridyl) ethylamino)-(4-fluorophenyl) methyl) benzyl] thiazolidine-2,4-dione, Exemplified Compound No. 2-1106 : 5- [3-((1- (4-pyridyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione, Exemplified Compound No. 2-1321: 5- [3- ( Phenyl- (1-
Phenylethylamino) methyl) benzyl] thiazolidine-2,4-dione, Exemplified Compound No. 2-1325: 5- [3-((2-phenylpropionylamino) -phenylmethyl) benzyl] thiazolidine-2,4-dione; Exemplified Compound No. 2-1626: 5- [3-((1- (3-fluorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] -2-thioxothiazolidine-
4-one, Exemplified Compound No. 2-1744: 5- [3-((1- (4-fluorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] -2-thioxothiazolidine-
4-one, Exemplified Compound No. 2-1804: 5- [3-((1- (3-chlorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] -2-thioxothiazolidine-
4-one, Exemplified Compound No. 2-1813: 5- [3-((1- (4-chlorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] -2-thioxothiazolidine-
4-one, Exemplified Compound No. 2-1892: 5- [3-((1- (3,4-
Difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] -2-thioxothiazolidine-4-one, Exemplified Compound No. 2-1896: 5- [3-((2- (3,4-
Difluorophenyl) propionylamino)-(4-methoxyphenyl) methyl) benzyl] -2-thioxothiazolidine-4-one, Exemplified Compound No. 2-2151: 5- [3-((-1- (1-naphthyl) Ethylamino) -phenylmethyl) benzyl
-2-thioxothiazolidine-4-dione, Exemplified Compound No. 2-2163: 5- [3-((1- (2-thienyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] -2-thio Oxothiazolidine-4-one, Exemplified Compound No. 2-2233: 5- [3-((1- (4-pyridyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] -2-thioxothiazolidine-4 -One, Exemplified Compound No. 2-2387: 5- [3-((1-phenylethylamino) -phenylmethyl) benzyl] -2-thioxothiazolidine-4-one, and Exemplified Compound No. 2-2391: 5- [3-((2-phenylpropionylamino) -phenylmethyl) benzyl] -2
-Thioxothiazolidine-4-one.

[0108]

BEST MODE FOR CARRYING OUT THE INVENTION The compound having the general formula (II) of the present invention can be produced according to the method described below. Further, the compound having the general formula (I) of the present invention can be produced by the same method as the method for producing the compound having the general formula (II).

In the method A, in the compound (II), A is
Compound (IIf) which is a group having the formula (A-1) or A
There is a group having the formula (A-2), a method B to Compound C ₁ -C ₆ alkylene group and (IIg).

[0110]

Embedded imageIn the above formula, R¹, R^Two, R^Three, R^Four, B, D, E, F,
Ring Ar₁And Ar_TwoHas the same meaning as described above, and R
^1aIs R¹Amino, hydr
Roxy and / or carboxy groups)
Amino, hydroxy and / or carboxy groups "
Other R¹A group similar to the group in the definition of the group^2a,
R^3aAnd R^4aIs R^Two, R^ThreeAnd R^FourA included in the group of
Mino is an amino which may be protected.^Two, R^ThreePassing
And R^FourA group similar to the group in the definition of the group
^FiveRepresents a protecting group for a hydrogen atom or a carboxy group;
r_1aIs a ring Ar₁Imino groups included in the definition of
Other ring Ar which is an imino group which may be protected₁In the definition of the group
And Ba represents a single bond or C₁−
C _FiveShows an alkylene group.

In the above, R^1a, R^2a, R^3aAnd R^4a
"Optionally protected amino group" in the definition of
Ar_1aDefinition of "optionally protected imino group"
"Protecting group" is an amino group used in the field of synthetic organic chemistry.
Is not particularly limited as long as it is a protecting group for a group or an imino group
Is, for example, the C₁-C₇Aliphatic acyl group, chloroacetate
Chill, dichloroacetyl, trichloroacetyl, torif
Halogeno C such as Luoroacetyl_Two-C₇Alkyl cal
Bonyl group, C such as methoxyacetyl₁-C₆Alkoki
C replaced with C_Two-C₇"Fats" such as alkylcarbonyl groups
Aliphatic acyls "; C₆-C_TenAryl to carbonyl
C to which the group is attached₇-C₁₁Aromatic acyl group, 2-bromobe
Halogeno C such as nzoyl, 4-chlorobenzoyl₇
-C₁₁Aromatic acyl group, 2,4,6-trimethylbenzo
Il, C like 4-tor oil₁-C₆Substitute with alkyl
Done C₇-C₁₁Aromatic acyl group, like 4-anisoyl
Una C ₁-C₆C substituted with alkoxy₇-C₁₁Aromatic
Acyl group, 4-nitrobenzoyl, 2-nitrobenzoy
C substituted with nitro, such as₇-C₁₁Aromatic acyl
Group, C such as 2- (methoxycarbonyl) benzoyl
_Two-C₇C substituted with alkoxycarbonyl₇-C₁₁Good
Aromatic acyl groups, C such as 4-phenylbenzoyl₆−
C_TenC substituted with aryl₇-C₁₁Aromatic acyl group, etc.
"Aromatic acyls";_Two-C₇Alkoxycarbo
A nyl group, 2,2,2-trichloroethoxycarbonyl,
Halo such as 2-trimethylsilylethoxycarbonyl
Gen or bird C₁-C₆C substituted with alkylsilyl_Two
-C₇"Alkoxy carboxy group"
Nyls ”; vinyloxycarbonyl, allyloxycar
"Alkenyloxycarbonyls" such as bonyl;
Benzyloxycarbonyl, 4-methoxybenzyloxy
Carbonyl, 3,4-dimethoxybenzyloxycarbo
Nyl, 2-nitrobenzyloxycarbonyl, 4-nitto
Such as 1 to 2
C₁-C₆Aryl ring substituted by alkoxy or nitro
Aralkyloxycarbonyls which may be
Tylsilyl, triethylsilyl, isopropyldimethyl
Silyl, t-butyldimethylsilyl, methyldiisopro
Pyrsilyl, methyl di-t-butylsilyl, triisoprop
Tri C like ropirsilyl₁-C₆Alkylsilyl group,
Diphenylmethylsilyl, diphenylbutylsilyl, di
Phenylisopropylsilyl, phenyldiisopropyl
Aryls such as silyl and C₁-C₆Choose from alkyl
"Silyls" such as a silyl group substituted three times with a substituted group;
Benzyl, phenethyl, 3-phenylpropyl, α-na
Futylmethyl, β-naphthylmethyl, diphenylmethyl
, Triphenylmethyl, α-naphthyldiphenylmethyl
1 to 3 ants, such as 9-anthrylmethyl
C substituted with₁-C₆Alkyl group, 4-methylben
Jill, 2,4,6-trimethylbenzyl, 3,4,5-
Trimethylbenzyl, 4-methoxybenzyl, 4-metho
Xyphenyldiphenylmethyl, 2-nitrobenzyl,
4-nitrobenzyl, 4-chlorobenzyl, 4-bromo
Benzyl, 4-cyanobenzyl, 4-cyanobenzyldi
Phenylmethyl, bis (2-nitrophenyl) methyl,
C like piperonyl₁-C₆Alkyl, C₁-C₆Arco
Aryl ring substituted with xy, nitro, halogen, cyano
Substituted with one to three aryl groups₁-C₆Al
"Aralkyls" such as a kill group; or N, N-dimethyla
Minomethylene, benzylidene, 4-methoxybenzylidene
4-nitrobenzylidene, salicylidene, 5-chloro
Rosalicylidene, diphenylmethylene, (5-chloro-
Like 2-hydroxyphenyl) phenylmethylene
A "substituted methylene group forming a Schiff base";
And preferably C₁-C₇Aliphatic acyl group, C₇-C₁₁Good
An aromatic acyl group or an alkoxycarbonyl group,
Preferably C_Two-C₇An alkoxycarbonyl group, especially
Preferably, it is a t-butoxycarbonyl group.

In the above, R^1a"Protection" in the definition of
The "protecting group" of the "hydroxyl group which may be
If it is a protecting group for hydroxy group used in the field of chemistry
Although not particularly limited, for example, the C₁-C₇Aliphatic
Sil group, succinoyl, glutaroyl, adipoyl
C substituted with carboxy_Two-C₇Alkyl carboni
Group, chloroacetyl, dichloroacetyl, trichloro
Halogeno C such as acetyl and trifluoroacetyl_Two
-C₇Alkylcarbonyl group, like methoxyacetyl
Na C₁-C₆C substituted with alkoxy_Two-C₇Alkylka
"Aliphatic acyls" such as a rubonyl group;₇-C₁₁Good
Aromatic acyl group, 2-bromobenzoyl, 4-chloroben
Halogeno C like Zoyl₇-C₁₁Aromatic acyl group,
2,4,6-trimethylbenzoyl, 4-toluoyl
Like C₁-C₆C substituted with alkyl₇-C₁₁Aromatic
Acyl group, C such as 4-anisoyl₁-C₆Alkoxy
C substituted with₇-C₁₁Aromatic acyl group, 2-carboxy
Cibenzoyl, 3-carboxybenzoyl, 4-carbo
C substituted with a carboxy such as xybenzoyl₇−
C₁₁Aromatic acyl group, 4-nitrobenzoyl, 2-nitro
C substituted with a nitro such as lobenzoyl₇-C₁₁Good
Aromatic acyl group, 2- (methoxycarbonyl) benzoyl
Like C_Two-C₇C substituted with alkoxycarbonyl
₇-C₁₁Aromatic acyl group, 4-phenylbenzoyl
Una C₆-C_TenC substituted with aryl₇-C₁₁Aromatic
"Aromatic acyls" such as a sil group; tetrahydropyran-
2-yl, 3-bromotetrahydropyran-2-yl,
4-methoxytetrahydropyran-4-yl, tetrahi
Dorothiopyran-2-yl, 4-methoxytetrahydro
"Tetrahydropyranyl" such as thiopyran-4-yl
Or tetrahydrothiopyranyls "; tetrahydrofura
2--2-yl and tetrahydrothiofuran-2-yl
"Tetrahydrofuranyl or tetrahydrothiofura
Nyls ”; trimethylsilyl, triethylsilyl, iso
Propyldimethylsilyl, t-butyldimethylsilyl,
Methyldiisopropylsilyl, methyldi-t-butylsilyl
Ril, tri-C such as triisopropylsilyl₁-C₆A
Lucylsilyl group, diphenylmethylsilyl, diphenyl
Butylsilyl, diphenylisopropylsilyl, phenyl
Aryls such as rudiisopropylsilyl and C₁-C₆
Silyl group substituted by three groups selected from alkyl, etc.
"Silyls"; methoxymethyl, 1,1-dimethyl-
1-methoxymethyl, ethoxymethyl, propoxymethi
, Isopropoxymethyl, butoxymethyl, t-but
(C₁-C₆Alkoxy) methyl group,
C such as 2-methoxyethoxymethyl₁-C₆Alkoki
(C ₁-C₆An alkoxy) methyl group, 2,
2,2-trichloroethoxymethyl, bis (2-chloro
Halogeno (C) such as ethoxy) methyl₁-C₆Alkoki
C) "Alkoxymethyls" such as methyl; 1-ethoxy
Ethyl, 1- (isopropoxy) ethyl (C₁−
C₆Alkoxy) ethyl group, 2,2,2-trichloroe
"Substituted ethyl" such as ethyl halide such as tyl
"; Benzyl, α-naphthylmethyl, β-naphthylme
Tyl, diphenylmethyl, triphenylmethyl, α-na
Like phthyldiphenylmethyl, 9-anthrylmethyl
Substituted with 1 to 3 aryl groups₁-C₆Archi
Group, 4-methylbenzyl, 2,4,6-trimethylbe
Benzyl, 3,4,5-trimethylbenzyl, 4-methoxy
Cibenzyl, 4-methoxyphenyldiphenylmethyl,
2-nitrobenzyl, 4-nitrobenzyl, 4-chloro
Benzyl, 4-bromobenzyl, 4-cyanobenzyl,
C such as methyl, piperonyl₁-C₆Alkyl, C₁−
C₆Aryl ring substituted by alkoxy, halogen, cyano
Substituted with one to three aryl groups₁-C₆A
"Aralkyls" such as alkyl groups;_Two-C₇Alkoki
Cicarbonyl group, 2,2,2-trichloroethoxy
Bonyl, 2-trimethylsilylethoxycarbonyl
Uno halogen or tri-C₁-C₆Substituted with alkylsilyl group
Done C_Two-C₇"Alkoxy" such as alkoxycarbonyl group
Cycarbonyls "; vinyloxycarbonyl, allylo
"Alkenyloxycarbonyl, such as xycarbonyl
"; Benzyloxycarbonyl, 4-methoxybenzyl
Ruoxycarbonyl, 3,4-dimethoxybenzyloxy
Cicarbonyl, 2-nitrobenzyloxycarbonyl,
1 to 4 such as 4-nitrobenzyloxycarbonyl
Two C₁-C₆Aryl ring is substituted by alkoxy or nitro
"Aralkyloxycarbonyls" which may be replaced
And preferably C₁-C₇Aliphatic acyl group, C₇-C
₁₁Aromatic acyl group, C_Two-C₇Alkoxycarbonyl group or
Is (C₁-C₆Alkoxy) methyl group, more preferably
Is C₇-C₁₁An aromatic acyl group or (C₁-C₆Alkoki
B) a methyl group, particularly preferably a benzoyl group or
It is a toxicoxy group.

In the above, the “protecting group” of the “optionally protected carboxy group” in the definition of R ^1a and the “protecting group of the carboxy group” in the definition of R ⁵ are carboxy groups used in the field of synthetic organic chemistry. The protecting group is not particularly limited as long as it is a protecting group for the group. For example, a C ₁ -C ₆ alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, benzyl, phenethyl, 3
-Phenylpropyl, 1-naphthylmethyl, diphenylmethyl, triphenylmethyl, 4-methylbenzyl,
_{1 to 3} optionally substituted by C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, nitro, halogen or cyano, such as -methoxybenzyl, 4-nitrobenzyl, 4-fluorobenzyl, 4-cyanobenzyl A C ₁ -C ₆ alkyl group substituted with a C ₆ -C ₁₀ aryl, and preferably a C ₁ -C ₆ alkyl group or a benzyl group.

The step A1 is a step for producing a compound having the general formula (IV), and is carried out by bringing the compound having the general formula (III) into contact with a reducing agent in an inert solvent.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate. Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol; Isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; nitriles such as acetonitrile and isobutyronitrile; formamide, dimethylformamide, dimethylacetamide, hexamethyl Amides such as phosphoric acid triamide;
Water; or a mixed solvent of the above solvents, and preferably ethers (particularly preferably tetrahydrofuran).

Examples of the reducing agent used in the above reaction include alkali metal borohydrides such as sodium borohydride, lithium borohydride, sodium cyanoborohydride; diisobutylaluminum hydride;
Aluminum hydride, such as lithium aluminum hydride and lithium triethoxide aluminum; and preferably an aluminum hydride compound (particularly preferably lithium aluminum hydride).

The reaction temperature varies depending on the starting compound, the catalyst used, the solvent and the like, but is usually from -50 ° C to 50 ° C.
(Preferably −20 ° C. to 20 ° C.).

The reaction time varies depending on the starting compound, the catalyst used, the solvent, the reaction temperature and the like, but is usually from 15 minutes to 50 hours (preferably from 30 minutes to 24 hours).

After completion of the reaction, the target compound (IV)
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. And dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and then the solvent is distilled off. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

The compound (V) can be directly produced by controlling the conditions.

Step A2 is a step for producing a compound having the general formula (V), which is carried out by bringing the compound (IV) into contact with an oxidizing agent in an inert solvent.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene , Toluene, xylene; aromatic hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether Ethers such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,
Alcohols such as diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve
Amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; acids such as acetic acid and propionic acid; sulfoxides such as dimethylsulfoxide; sulfolane; or a mixed solvent of the above solvents; , Preferably halogenated hydrocarbons (particularly preferably dichloromethane).

As the oxidizing agent used in the above reaction,
Usually, there is no particular limitation as long as it is used for the oxidation reaction.
But, for example, manganese oxides such as manganese dioxide;
Ruthenium oxides such as ruthenium tetroxide;
A selenium compound such as len; an iron compound such as iron chloride;
Osmium tetroxide, potassium osmate dihydrate (K _TwoO
sO_Four・ 2H_TwoOsmium compounds such as O); such as silver oxide
Silver compounds; mercury compounds such as mercury acetate; lead oxide, tetravinegar
Lead oxide compounds such as lead oxide; chromic acid-pyridine complex
Such as chromic acid compounds, ammonium cerium nitrite
Inorganic metal acids such as cerium compounds such as silica (CAN)
Agent: halogen such as chlorine molecule, bromine molecule and iodine molecule
Molecules; periodic acids such as sodium periodate;
Nitrous compounds such as nitrous acid;
Chlorous acid oxidation such as potassium citrate and sodium chlorite
Compounds: Persulfur such as potassium persulfate and sodium persulfate
Inorganic oxidizing agents such as acid compounds; trials used for DMSO oxidation
Drugs (dimethyl sulfoxide and dicyclohexyl carb
Diimide, oxalyl chloride, acetic anhydride or pentaacid
Complex with phosphorus hydride or pyridine-sulfuric anhydride complex);
Peroxides such as tyl hydroperoxide and banana
Combination with didium or molybdenum complex;
Stable cations such as tyl cation; N-bromoco
Succinimides such as succinimides and alkalis
Combination; oxiranes such as dimethyldioxirane;
Hypochlorous acid compounds such as t-butyl chlorite; azodi
Azodicarboxylic acid compounds such as carboxylic esters;
peracids such as m-chloroperbenzoic acid and perphthalic acid;
Methyl disulfide, diphenyl disulfide, dipyri
Disulfides such as zirdisulfide and triphenyl
Ruphosphine; nitrite such as methyl nitrite
And tetrahalogenated carbons such as methane tetrabromide, 2,
3-dichloro-5,6-dicyano-p-benzoquinone
Organic oxidizing agents such as quinone compounds such as (DDQ);
Manganese dioxide, chromic acid-pyridine complex
, Reagents used for DMSO oxidation or 2,3-dic
Rollo-5,6-dicyano-p-benzoquinone (DDQ)
And more preferably with manganese dioxide.
is there.

The reaction temperature varies depending on the starting compound, the oxidizing agent used, the solvent and the like, but is usually from 0 ° C. to 50 ° C. (preferably from 10 ° C. to 40 ° C.).

The reaction time varies depending on the starting compound, the oxidizing agent used, the solvent, the reaction temperature and the like, but is usually 1 hour to 50 hours (preferably 5 hours to 25 hours).

After completion of the reaction, the target compound (V) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step A3 is a step for producing a compound having the general formula (IIf), in which the compound (V) is reacted with a compound having the general formula (VI) in an inert solvent in the presence of an acid and a base. And then, if desired, R ^1a , R ^2a , R ^3a and R
^It is carried out by removing the protecting group for the amino, hydroxy and / or carboxy group in ^4a and the protecting group for the imino group in Ar _1a .

The acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a usual reaction. For example, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid,
Inorganic acids such as phosphoric acid; Bronsted acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, organic acids such as p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid; Tin chloride, boron trichloride, boron trifluoride,
A Lewis acid such as boron tribromide; an acidic ion exchange resin; preferably an organic acid (particularly preferably acetic acid).

Bases used in the above reaction include, for example, alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate; alkali metal bicarbonates such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium methoxide, sodium methoxide and sodium Alkali metal alkoxides such as ethoxide and potassium t-butoxide; piperidine, piperidinium acetate, piperidinium benzoate, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-di Chiruamino) pyridine, N, N
-Dimethylaniline, N, N-diethylaniline, 1,
5-diazabicyclo [4.3.0] non-5-ene,
1,4-diazabicyclo [2.2.2] octane (DA
BCO), 1,8-diazabicyclo [5.4.0] -7
Organic amines such as undecene (DBU); preferably organic amines (particularly preferably piperidine)
It is.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. For example, aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate. Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol; Isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; nitriles such as acetonitrile and isobutyronitrile; formamide, dimethylformamide, dimethylacetamide, hexamethyl Amides such as phosphoric acid triamide;
Or a mixed solvent of the above solvents, and is preferably an aromatic hydrocarbon (particularly preferably toluene).

The reaction temperature depends on the starting compound, the catalyst used, the solvent and the like, but is usually from 0 ° C. to 200 ° C.
(Preferably 10 ° C. to 150 ° C.).

The reaction time varies depending on the starting compound, the catalyst used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 50 hours (preferably 1 hour to 24 hours).

The removal of the protecting groups for the amino, imino, hydroxy and carboxy groups depends on the type thereof, but is generally carried out by methods well known in the art of synthetic organic chemistry, for example, T.I.
W. Green, (Protective Groups in Organic Synthesi
s), John Wiley & Sons: JFWMcOmis, (Protective G
roups in Organic Chemistry), Plenum Press.

When the protecting group for the amino or imino group is a silyl, it usually forms a fluoride anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine or potassium fluoride. By treatment with a compound of interest.

The solvent used in the above reaction is not particularly limited as long as it does not inhibit the reaction. Examples thereof include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether. Is preferred.

The reaction temperature and reaction time are not particularly limited, but the reaction is usually carried out at 0 ° C. to 50 ° C. for 10 hours to 18 hours.

When the protecting group for the amino or imino group is an aliphatic acyl, an aromatic acyl, an alkoxycarbonyl, or a substituted methylene group forming a Schiff base, the protecting group may be dissolved in the presence of an aqueous solvent in the presence of an acid. Alternatively, it can be removed by treating with a base.

The acid used in the above reaction is not particularly limited as long as it is one which is usually used as an acid and does not inhibit the reaction. Examples thereof include hydrobromic acid, hydrochloric acid, sulfuric acid, and the like.
Inorganic acids such as perchloric acid, phosphoric acid and nitric acid, preferably hydrochloric acid.

The base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound, but is preferably an alkali metal such as lithium carbonate, sodium carbonate and potassium carbonate. Carbonates; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; metal alkoxides such as lithium methoxide, sodium methoxide, sodium ethoxide and potassium-t-butoxide; ammonia water ,
Ammonia, such as concentrated ammonia-methanol.

The solvent used in the above reaction is not particularly limited as long as it is a solvent used in a usual hydrolysis reaction. Examples thereof include methanol, ethanol, n-propanol and isopropanol. Alcohols such as toluene, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve;
Ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether;
Water; a mixed solvent of water and the above organic solvent; and preferably ethers (particularly preferably dioxane).

The reaction temperature and the reaction time vary depending on the starting compound, the solvent and the acid or base to be used, and are not particularly limited. Let react for ~ 10 hours.

When the amino- or imino-protecting group is an aralkyl or aralkyloxycarbonyl, it is usually brought into contact with a reducing agent in an inert solvent (preferably at room temperature under a catalyst at room temperature). A method of removing by catalytic reduction) or a method of removing with an oxidizing agent is preferable.

The solvent used for the removal by catalytic reduction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as toluene, benzene, xylene; methyl acetate,
Esters such as ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n- Alcohols such as propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; Such organic acids; water; a mixed solvent of the above solvent and water; preferably alcohols, ethers,
Organic acids or water (particularly preferably, alcohols or organic acids).

The catalyst used for the removal by the catalytic reduction is not particularly limited as long as it is usually used for the catalytic reduction reaction.
Carbon, Raney-nickel, platinum oxide, platinum black, rhodium-
Aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate are used.

Although the pressure is not particularly limited, it is usually 1 to 1
It is performed at 0 atm.

The reaction temperature and the reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C. to 100 ° C.
For 5 minutes to 24 hours.

The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction, but is preferably a water-containing organic solvent.

Examples of such an organic solvent include halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; nitriles such as acetonitrile, diethyl ether, diisopropyl ether, tetrahydrofuran, and the like. Ethers such as dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; and sulfoxides such as dimethylsulfoxide; And preferably halogenated hydrocarbons, ethers or sulfoxides (particularly preferred are halogenated hydrocarbons or sulfoxides).

The oxidizing agent to be used is not particularly limited as long as it is a compound used for oxidation. Preferably, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3- Dichloro-5,6-
Dicyano-p-benzoquinone (DDQ) is used.

The reaction temperature and the reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C. to 150 ° C.
For 10 minutes to 24 hours.

When the protecting group for the amino or imino group is an aralkyl, the protecting group can be removed using an acid.

The acid used in the above reaction is not particularly limited as long as it is used as an acid catalyst in a usual reaction. For example, hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid,
Inorganic acids such as phosphoric acid; Bronsted acids such as acetic acid, formic acid, oxalic acid, methanesulfonic acid, organic acids such as p-toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid and trifluoromethanesulfonic acid; Tin chloride, boron trichloride, boron trifluoride,
A Lewis acid such as boron tribromide; an acidic ion exchange resin; preferably an inorganic or organic acid (particularly preferably hydrochloric acid, acetic acid or trifluoroacetic acid).

The inert solvent used in the first-stage reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin, and petroleum ether. Aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate, carbonic acid Esters such as diethyl; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, and n-butanol. , Isobutanol, t-butanol, Soamiruaruko - le, diethylene glycol, glycerin, octanol, cyclohexanol, alcohol such as methyl cellosolve - Le acids;
Amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; water; or water or a mixed solvent of the above solvents; preferably ethers, alcohols or water (particularly preferable). Is dioxane, tetrahydrofuran, ethanol or water.

The reaction temperature depends on the starting compound, the acid used,
Although it depends on the solvent and the like, it is usually from -20 ° C to the boiling point (preferably 0 ° C to 100 ° C).

The reaction time depends on the starting compound, the acid used,
The time is usually from 15 minutes to 48 hours (preferably from 30 minutes to 20 hours), although it depends on the solvent, the reaction temperature and the like.

When the protecting group for the amino or imino group is an alkenyloxycarbonyl, the protecting group for the amino is usually substituted with an aliphatic acyl, an aromatic acyl, an alkoxycarbonyl or a Schiff base. The reaction is carried out by treating with a base in the same manner as the conditions for the removal reaction in the case of a methylene group.

Incidentally, in the case of an allyloxycarbonyl group,
In particular, the removal method using palladium and triphenylphosphine or nickel tetracarbonyl is simple and can be performed with few side reactions.

When a silyl is used as a protecting group for the hydroxy group, a fluorine anion such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine, or potassium fluoride is usually formed. Treated with compounds or
Or an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid, phosphoric acid or acetic acid, formic acid, oxalic acid, methanesulfonic acid, p
-It can be removed by treatment with an organic acid such as toluenesulfonic acid, camphorsulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid.

In the case of removal by fluorine anion,
The reaction may be accelerated by adding organic acids such as formic acid, acetic acid, propionic acid.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Preferably, diethyl ether or diisopropyl ether is used.
Ethers such as ter, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; organic acids such as acetic acid; water;

The reaction temperature and the reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C. to 100 ° C.
(Preferably 10 ° C. to 50 ° C.) for 1 hour to 24 hours.

When the protecting group for the hydroxy group is an aralkyl or aralkyloxycarbonyl, it is usually brought into contact with a reducing agent in an inert solvent (preferably by catalytic reduction at room temperature under a catalyst at room temperature). ) A method of removing or using an oxidizing agent is preferred.

The solvent used for the removal by catalytic reduction is not particularly limited as long as it does not take part in the present reaction. Aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; toluene, benzene , Xylene and the like; aromatic hydrocarbons such as xylene; esters such as ethyl acetate and propyl acetate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol; Ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,
Alcohols such as diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve
Amides such as formamide, dimethylformamide, dimethylacetamide, N-methyl-2-pyrrolidone and hexamethylphosphoric triamide; fatty acids such as formic acid and acetic acid; water; a mixed solvent of the above solvents; Preferred are alcohols (particularly preferred is methanol).

As the catalyst used for the removal by the catalytic reduction, if it is usually used for the catalytic reduction reaction,
Although not particularly limited, for example, palladium-carbon, palladium-black, Raney-nickel, platinum oxide, platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate, preferably palladium- Carbon.

Although the pressure is not particularly limited, it is usually 1 to 1
It is performed at 0 atm.

The reaction temperature and the reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C. to 100 ° C.
(Preferably 20 ° C. to 70 ° C.) for 5 minutes to 48 hours (preferably 1 hour to 24 hours).

The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in this reaction, but is preferably a water-containing organic solvent.

Preferred as such organic solvents are ketones such as acetone; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; nitriles such as acetonitrile; diethyl ether, tetrahydrofuran; Ethers such as dioxane; amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; and sulfoxides such as dimethylsulfoxide.

The oxidizing agent to be used is not particularly limited as long as it is a compound used for oxidation. Preferably, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3- Dichloro-5,6-
Dicyano-p-benzoquinone (DDQ) is used.

The reaction temperature and reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually from 0 ° C. to 150 ° C.
For 10 minutes to 24 hours.

Further, in liquid ammonia or methano-
, Ethanol, n-propanol, isopropanol
, N-butanol, isobutanol, t-butanol
In alcohols such as alcohol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve at -78 ° C.
At ~ 0 ° C, it can also be removed by the action of alkali metals such as metallic lithium and metallic sodium.

Further, it can be removed by using an alkylsilyl halide such as aluminum chloride-sodium iodide or trimethylsilyl iodide in a solvent.

The solvent to be used is not particularly limited as long as it does not participate in the present reaction, but is preferably a halogenated hydrocarbon such as methylene chloride, chloroform or carbon tetrachloride; Nitriles;
A mixed solvent of the above solvents.

The reaction temperature and reaction time vary depending on the starting compound, solvent and the like, but are usually carried out at 0 ° C. to 50 ° C. for 5 minutes to 72 hours.

When the reaction substrate has a sulfur atom,
Preferably, aluminum chloride-sodium iodide is used.

When the protecting group for the hydroxy group is an aliphatic acyl, an aromatic acyl or an alkoxycarbonyl group, it is removed by treating with a base in a solvent.

The base used in the above reaction is not particularly limited as long as it does not affect the other parts of the compound. Examples thereof include alkali metal carbonates such as lithium carbonate, sodium carbonate and potassium carbonate. Alkali metal bicarbonates such as lithium bicarbonate, sodium bicarbonate and potassium bicarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium methoxide, sodium methoxide; Metal alkoxides such as sodium ethoxide and potassium-t-butoxide; ammonia such as aqueous ammonia and concentrated ammonia-methanol; preferably alkali metal hydroxides, metal alkoxides or ammonia (Particularly preferably, alkali metal hydroxides or metal alkoxides) It is the earth).

The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction, and examples thereof include diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether. Ethers; methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; water; mixed solvents of the above solvents are preferred.

The reaction temperature and reaction time vary depending on the starting compound, base used, solvent and the like, and are not particularly limited.
In order to suppress side reactions, usually -20 ° C to 150 ° C
For 1 to 10 hours.

When the protecting group for the hydroxy group is an alkoxymethyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl or substituted ethyl, it is usually used in a solvent. , By treatment with an acid.

The acid used is not particularly limited as long as it is usually used as a Bronsted acid or a Lewis acid, and is preferably hydrogen chloride; an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid; or Bronsted acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, and organic acids such as p-toluenesulfonic acid: Lewis acids such as boron trifluoride, but strongly acidic cations such as Dowex 50W Exchange resins can also be used.

The solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction.
Aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene,
Halogenated hydrocarbons such as dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether Such ethers; methanol, ethanol
Alcohols such as toluene, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve Ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; water; a mixed solvent of the above solvents; preferably ethers (particularly preferably tetrahydrofuran) or alcohols ( Particularly preferred is methanol).

The reaction temperature and the reaction time vary depending on the starting compound, the acid used, the solvent and the like, but are usually from -10 ° C to 200 ° C (preferably 0 ° C to 150 ° C) for 5 minutes to 48 hours (Preferably 30 minutes to 10 hours).

When the protecting group for the hydroxy group is an alkenyloxycarbonyl, the conditions for the removal reaction when the protecting group for the hydroxy group is the above-mentioned aliphatic acyl, aromatic acyl or alkoxycarbonyl are usually used. In the same manner as in the above, it is achieved by treating with a base.

In the case of an allyloxycarbonyl group,
In particular, the removal method using palladium and triphenylphosphine, or bis (methyldiphenylphosphine) (1,5-cyclooctadiene) iridium (I) hexafluorophosphate is simple and is carried out with few side reactions. Can be.

[0186] protecting groups for carboxy groups, C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, nitro, three 1 may be substituted by halogen or cyano C ₆ In the case of a C ₁ -C ₆ alkyl group substituted with —C ₁₀ aryl, the removal reaction is usually performed when the protecting group of the hydroxy group is the above-mentioned aliphatic acyl, aromatic acyl or alkoxycarbonyl. It is achieved by treating with a base in the same manner as the conditions.

The removal of the protecting group for the amino, imino group, hydroxy and / or carboxy group can be carried out in any order and in the desired order.

After completion of the reaction, the desired compound (II)
f) is collected from the reaction mixture in a conventional manner. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

The step A4 is a step for producing a compound having the general formula (VII). This step is performed in the same manner as in the step A3.

Step A5 is a step of producing a compound having the general formula (IIg). After contacting compound (VII) with a reducing agent in an inert solvent, if desired, R ^1a ,
Amino, hydroxy and / or R ^2a , R ^3a and R ^4a
Alternatively, it is carried out by removing the protecting group for the carboxy group and the protecting group for the imino group in Ar _1a .

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. For example, the same inert solvent as used in the step A1 may be mentioned. Preferably, it is a mixed solvent of alcohols and ethers (particularly preferably, tetrahydrofuran and ethanol).

As the reducing agent used in the above reaction, for example, those similar to the reducing agent used in Step A1 can be mentioned, and alkali metal borohydrides (particularly preferably, Sodium boron).

The reaction temperature varies depending on the starting compound, the catalyst used, the solvent and the like, but is usually from 0 ° C to 80 ° C (preferably from 10 ° C to 50 ° C).

The reaction time varies depending on the starting compound, the catalyst used, the solvent, the reaction temperature and the like, but is usually 30 minutes to 50 hours (preferably 1 hour to 24 hours).

Desired protecting groups for amino, hydroxy and / or carboxy groups at R ^1a , R ^2a , R ^3a and R ^4a ;
The reaction for removing the protecting group for the imino group in Ar _1a is carried out in the same manner as in the latter part of the above-mentioned Method A, Step A3.

After completion of the reaction, the desired compound (II)
g) is collected from the reaction mixture in a conventional manner. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the target compound obtained is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds, and applying chromatography. Can be separated and purified.

Method B is a method for producing a compound having the general formula (IIh).

[0198]

Embedded image In the above formula, R ¹ , R ^1a , R ² , R ^2a , R ³ , R ^3a ,
R ⁴ , R ^4a , R ⁵ , B, D, E and F have the same meanings as described above, X represents a halogen atom, and Y represents an oxygen atom or a sulfur atom.

Step B1 is a step of preparing a compound having the general formula (IX), and adding Meer to compound (VIII).
Achieved by performing a wein Arylation reaction.

That is, in an inert solvent, compound (VII)
The reaction is carried out by reacting I) with a nitrite and a strong acid, followed by a reaction with an acrylate and a copper halide.

The Meerwein Arylation reaction is described in
No. 22657 (US Pat. No. 4,258,193) and S.M.
Oae et al. [Bull. Chem. Soc. Jpn., 53, 1065 (198
0) etc. The method is performed according to the method described in [1].

The nitrite used in the above reaction is, for example, lithium nitrite, potassium nitrite, sodium nitrite, and preferably sodium nitrite.

The strong acid used in the above reaction includes, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid and phosphoric acid, and is preferably hydrobromic acid.

The inert solvent used for reacting the compound (VIII) with a nitrite and a strong acid is not particularly limited as long as it is inert to the present reaction. For example, methanol, ethanol , N-propanol, isopropanol
, N-butanol, isobutanol, t-butanol
Alcohols such as toluene, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; water; And preferably a mixed solvent of ketones or alcohols and water (particularly preferably acetone).

The reaction temperature for reacting compound (VIII) with nitrite and a strong acid varies depending on the starting compounds, reagents, solvents and the like, but is usually -50 ° C to 100 ° C (preferably -20 ° C to 50 ° C). ° C).

The reaction time for reacting compound (VIII) with nitrite and strong acid varies depending on the starting compound, solvent, reaction temperature and the like, but is usually from 10 minutes to 25 hours (preferably from 15 minutes to 10 hours). ).

The acrylate used in the above reaction includes, for example, methyl acrylate, ethyl acrylate and n-butyl acrylate, preferably n-butyl acrylate.

The copper halide used in the above reaction includes, for example, cuprous chloride, cupric chloride, cuprous bromide, cuprous bromide, cuprous iodide, and cupric iodide. And preferably cuprous bromide.

The inert solvent used for reacting the compound (VIII) with an acrylate ester and copper halide is not particularly limited as long as it is inert to this reaction. The same inert solvents as used in the reaction of (VIII) with nitrite and strong acid can be used.

Next, the reaction temperature at which the compound (VIII) is reacted with the acrylate ester and the copper halide varies depending on the starting compound, the reagent, the solvent and the like.
-20 ° C to 100 ° C (preferably 0 ° C to 50 ° C).

Next, the reaction time for reacting the compound (VIII) with an acrylate ester and copper halide varies depending on the starting compound, the solvent, the reaction temperature and the like, but is usually from 10 minutes to 25 hours (preferably, 15 minutes to 1
0 hours).

After completion of the reaction, the desired compound (IX) of this reaction
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. And dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and then the solvent is distilled off. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step B2 is a step of producing a compound having the general formula (IIh). After reacting the compound (IX) with a compound having the general formula (X), the resulting compound is hydrolyzed. And optionally R ^1a , R ^2a , R ^3a and R
^It is carried out by removing the protecting group of the amino, hydroxy and / or carboxy group in ^4a .

The inert solvent used for reacting the compound (IX) with the compound having the general formula (X) is not particularly limited as long as it is inert to the reaction.
Aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene,
Halogenated hydrocarbons such as dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether Such ethers; methanol, ethanol
Alcohols such as n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve And ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone and cyclohexanone; water; a mixed solvent of the above solvents; preferably alcohols (particularly preferably ethanol).

The reaction temperature at which the compound (IX) is reacted with the compound having the general formula (X) varies depending on the starting compound, the solvent and the like, but is usually from -10 ° C to 200 ° C (preferably 0 ° C). To 150 ° C.).

The reaction time for reacting the compound (IX) with the compound having the general formula (X) varies depending on the starting compound, the solvent, the reaction temperature and the like, but is usually from 15 minutes to 5 minutes.
0 hours (preferably 30 minutes to 25 hours).

The acid used in the above-mentioned hydrolysis reaction is not particularly limited as long as it is usually used as an acid and does not inhibit the reaction. It is an inorganic acid such as an acid, phosphoric acid or nitric acid, preferably hydrochloric acid.

The solvent used in the above hydrolysis reaction is not particularly limited as long as it is one used in a usual hydrolysis reaction. For example, methanol, ethanol, n-
Propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol
Alcohols such as toluene, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; water; A mixed solvent with a solvent; and preferably ethers (particularly preferably dioxane).

The reaction temperature and the reaction time vary depending on the starting compound, the solvent and the acid used, and are not particularly limited. However, in order to suppress a side reaction, the reaction is usually carried out at 0 ° C. to 150 ° C.
And react for 1 to 10 hours.

The method for removing the protecting group for the amino, hydroxy and / or carboxy group in R ^1a , R ^2a , R ^3a and R ^4a , which is carried out as desired, is as follows. It is performed in the same manner as the method of removing the protecting group.

After completion of the reaction, the desired compound (II)
h) is collected from the reaction mixture in a conventional manner. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

In Method C, Compound (IIh) is prepared separately from Method B.
It is a method of manufacturing.

[0223]

Embedded image In the above formula, R ¹ , R ^1a , R ² , R ^2a , R ³ , R ^3a ,
R ⁴ , R ^4a , R ⁵ , B, D, E, F and Y are as defined above, and R ⁶ is C ₁ -C ₆ alkyl, C ₁
A C ₆ -C ₁₀ aryl group substituted with —C ₆ haloalkyl or C ₁ -C ₆ alkyl;

Step C1 is a step of producing a compound having the general formula (XI), and converting compound (V) to tri (C ₁
(C ₆ alkyl) silyl cyanide and a Lewis acid, followed by hydrolysis.

As the Lewis acid used in the above reaction,
For example, zinc halides such as zinc iodide, zinc chloride;
Tin halides such as tin tetrachloride; boron halides such as boron trichloride, boron trifluoride, and boron tribromide; and preferred are zinc halides (particularly preferred zinc iodide). is there.

Compound (V) was converted to tri (C ₁ -C ₆ alkyl)
The reaction temperature when reacting with silyl cyanide and a Lewis acid varies depending on the starting compound, solvent and the like, but is usually from 0 ° C to 150 ° C (preferably from 20 ° C to 100 ° C).

Compound (V) was converted to tri (C ₁ -C ₆ alkyl)
The reaction time for the reaction with silyl cyanide and Lewis acid varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 15 minutes to 50 hours (preferably 30 minutes to 2 hours).
4 hours).

The hydrolysis reaction is carried out in the same manner as the hydrolysis reaction in the step B2.

After completion of the reaction, the desired compound (XI) of this reaction
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. And dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and then the solvent is distilled off. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step C2 is a step for producing a compound having the general formula (XIII), which is carried out by reacting the compound (XI) with a compound having the general formula (XII) in the presence of a base.

The base used in the above reaction is, for example, an alkali metal carbonate such as lithium carbonate, sodium carbonate and potassium carbonate; an alkali metal bicarbonate such as lithium hydrogen carbonate, sodium hydrogen carbonate and potassium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; lithium methoxide, sodium methoxide and sodium Alkali metal alkoxides such as ethoxide and potassium t-butoxide; triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-
Dimethylamino) pyridine, N, N-dimethylaniline, N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-
Diazabicyclo [5.4.0] -7-undecene (DB
Organic amines such as U); and preferably organic amines (particularly preferably triethylamine).

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate. Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol, Isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; formamide, dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric acid triamide; water;
Or a mixed solvent of water or the above-mentioned solvents; preferably a halogenated hydrocarbon (particularly preferably dichloromethane).

The reaction temperature varies depending on the starting compound, base, solvent and the like, but is usually from -50 ° C to 100 ° C (preferably from -20 ° C to 50 ° C).

The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually 5 minutes to 48 hours (preferably 30 minutes to 20 hours).

After completion of the reaction, the desired compound of the present reaction (XII
I) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

The step C3 is a step for producing the compound (IIh). The compound (XIII) is reacted with the compound (X), hydrolyzed, and if desired, R ^1a , R ^2a ,
This step is carried out by removing the protecting group for the amino, hydroxy and / or carboxy group in R ^3a and R ^4a , and this step is carried out in the same manner as the above-mentioned step B2.

Method D is a method for producing compounds having the general formulas (IIj), (IIk) and (IIm).

[0238]

Embedded image In the above formula, R ¹ , R ^1a , R ² , R ^2a , R ³ , R ^3a ,
R ⁴ , R ^4a , B, D, E and F have the same meanings as described above.

Step D1 is a step of preparing a compound having the general formula (XV), in which the compound having the general formula (XIV) is reacted with hydroxylamine or a hydrochloride thereof in an inert solvent in the presence of a base. This is done by letting

As the base used in the above reaction, for example, the same bases as those used in the above-mentioned Step C2 can be mentioned, and preferred are organic amines (particularly preferred is triethylamine).

The organic solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include ketones such as acetone; halogens such as methylene chloride, chloroform and carbon tetrachloride. Hydrocarbons; nitriles such as acetonitrile; diethyl ether
Ethers such as ter, tetrahydrofuran, dioxane; dimethylformamide, dimethylacetamide,
Examples thereof include amides such as hexamethylphosphoric acid triamide; and sulfoxides such as dimethyl sulfoxide; preferably sulfoxides (particularly preferably dimethyl sulfoxide).

The reaction temperature varies depending on the starting compound, base, solvent and the like, but is usually 0 ° C. to 200 ° C. (preferably
20 ° C to 100 ° C).

The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually 5 minutes to 48 hours (preferably 30 minutes to 20 hours).

After completion of the reaction, the desired compound (XV)
Is collected from the reaction mixture according to a conventional method. For example,
The reaction mixture is appropriately neutralized, and if insoluble matters are removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. And dried over anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc., and then the solvent is distilled off. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

The step D2 is a compound for producing the compound (IIj). After reacting the compound (XV) with a carbonylating agent in an inert solvent in the presence of a base, R ^1a and R ^{2a are} optionally added. , R ^3a and R ^4a by removing the protecting groups of the amino, hydroxy and / or carboxy groups.

The carbonylating agent used in the above reaction is, for example, phosgene, diphosgene, triphosgene, 1,1'-carbonyldiimidazole, diethyl carbonate, 2-ethylhexyl chloroformate,
Preferably, it is 2-ethylhexyl chloroformate.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include the same solvents as those used in the step D2. Are amides (particularly preferably dimethylformamide).

The reaction temperature varies depending on the starting compound, base, solvent and the like, but is usually -50 ° C to 100 ° C (preferably -20 ° C to 50 ° C).

The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually from 5 minutes to 48 hours (preferably from 30 minutes to 20 hours).

The method of removing the protecting group for the amino, hydroxy and / or carboxy group in R ^1a , R ^2a , R ^3a and R ^4a , which is carried out as desired, is as follows. It is performed in the same manner as the method for removing the protecting group.

After completion of the reaction, the desired compound (II)
j) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step D3 is a step of producing compound (IIk). After condensing compound (XV) with a thiocarbonylating agent and a Lewis acid in an inert solvent, if desired, R ^1a , It is carried out by removing the protecting groups of the amino, hydroxy and / or carboxy groups in R ^2a , R ^3a and R ^4a .

The thiocarbonylating agent used in the above reaction includes, for example, thiophosgene and 1,1′-thioxocarbonyldiimidazole,
1′-thioxocarbonyldiimidazole.

The Lewis acids used in the above reaction include:
For example, zinc halides such as zinc iodide, zinc chloride;
Tin halides such as tin tetrachloride; boron halides such as boron trichloride, boron trifluoride and boron tribromide; and preferred are zinc halides (particularly preferably boron trifluoride). is there.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate. Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol; Isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; formamide, dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric acid triamide; water;
Or water or a mixed solvent of the above-mentioned solvents; preferably ethers (particularly preferably tetrahydrofuran).

The reaction temperature varies depending on the starting compound, solvent and the like, but is usually -20 ° C to 100 ° C (preferably 0 ° C to 100 ° C).
° C to 50 ° C).

The reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 5 minutes to 48 hours (preferably 30 minutes to 20 hours).

The method for removing the protecting group for the amino, hydroxy and / or carboxy group in R ^1a , R ^2a , R ^3a and R ^4a , which is carried out as desired, is as follows. It is performed in the same manner as the method for removing the protecting group.

After completion of the reaction, the desired compound (II)
k) is collected from the reaction mixture in a conventional manner. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step D4 produces compound (IIm).
In an inert solvent in the presence of a base.
After reacting (XV) with a thiocarbonylating agent,
More R ^1a, R^2a, R^3aAnd R^4aAmino, hydro in
Removing the protecting groups of the xy and / or carboxy groups
Done by

The thiocarbonylating agent used in the above reaction is, for example, thiophosgene or 1,1′-thioxocarbonyldiimidazole,
1′-thioxocarbonyldiimidazole.

As the base used in the above reaction, for example, the same bases as those used in the above-mentioned Step C2 can be mentioned, and preferably, 1,5-diazabicyclo [4.3.
0] non-5-ene.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate. Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol; Isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; formamide, dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric acid triamide; nitriles such as acetonitrile; preferably nitriles (particularly preferably acetonitrile).

The reaction temperature varies depending on the starting compound, the solvent and the like, but is usually -20 ° C to 100 ° C (preferably 0 ° C to 100 ° C).
° C to 50 ° C).

The reaction time varies depending on the starting compound, solvent, reaction temperature and the like, but is usually 5 minutes to 48 hours (preferably 1 hour to 30 hours).

The method for removing the protecting group for the amino, hydroxy and / or carboxy group in R ^1a , R ^2a , R ^3a and R ^4a , which is carried out as desired, is described in the above step A3. It is performed in the same manner as the method for removing the protecting group.

The target compound (IIm) of this reaction was
The target compound (IIk) obtained in the step D3 can be obtained by reacting the compound (XV) with a thiocarbonylating agent in the presence of a base. It is obtained by reacting with an agent.

After completion of the reaction, the desired compound (II)
m) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

In the method E, the compound (II) in which D is-
A compound (IIn) in which E is a group having -NH-, a compound (IIo) in which D is a group having -CH- and E is an oxygen atom or a sulfur atom, and a compound (IIo) in which D is -CH- This is a method for producing a compound (IIp) in which-is a group having E and -E is a group having -NHCO-.

[0270]

Embedded image In the above formula, R ¹ , R ^1a , R ² , R ^2a , R ³ , R ^3a ,
R ⁴ , R ^4a , F, X and Y have the same meanings as described above, R ⁷ represents a formyl, carboxy or C ₂ -C ₇ alkoxycarbonyl group, and A ′ is included in the definition of A And the same imino group as the group in the definition of A other than the imino group which may be protected.

Step E1 is a step of producing a compound having the general formula (XVIII), and a compound having the general formula (XVI) and a compound having the general formula (XVII) or an acid addition salt thereof in an inert solvent. (E.g., steel salts such as hydrochloride, nitrate and sulfate), for example, by heat condensation using an organic sulfonic acid such as p-toluenesulfonic acid as a catalyst or titanium tetrachloride. The condensation is carried out by using such a Lewis acid.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane and carbon tetrachloride; methyl acetate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate. Esters such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-butanol; Isobutanol, t-
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, and methyl cellosolve; formamide, dimethylformamide, dimethylacetamide;
Amides such as hexamethylphosphoric acid triamide; water;
Or a mixed solvent of water or the above-mentioned solvents; preferably a halogenated hydrocarbon (particularly preferably dichloromethane).

In the above reaction, compound (XVI
When I) is an acid addition salt, the reaction can be carried out using a base. Examples of such a base are the same as those used in the above-mentioned Step C2.

The reaction temperature varies depending on the starting compound, base, solvent and the like, but is usually from -20 ° C to 200 ° C. When the condensation is carried out using a Lewis acid, it is preferably from 10 ° C to 40 ° C.
C. and 50 to 150.degree. C. when heat condensation is carried out using an organic sulfonic acid as a catalyst.

The reaction time varies depending on the starting compound, base, solvent, reaction temperature and the like, but is usually 15 minutes to 48 hours (preferably 1 hour to 30 hours).

After completion of the reaction, the desired compound (XVI
II) is collected from the reaction mixture in a conventional manner. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, and then an immiscible organic solvent such as water and ethyl acetate is added, and the organic layer containing the target compound is separated. After washing with water etc., after drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate, etc.,
It is obtained by distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

The step E2 is a step of producing the compound (IIn). After reducing the compound (XVIII) in an inert solvent, if necessary, R ^1a , R ^2a , R ^3a , R ^4a and A ′ It is carried out by removing the protecting groups of the amino, imino, hydroxy and / or carboxy groups.

The inert solvent used in the above reaction is not particularly limited as long as it does not participate in the reaction.
The same as those used in the above-mentioned Step E1, preferably alcohols or ethers (particularly preferably ethanol or tetrahydrofuran).

The reducing agent used in the above reaction is, for example,
Alkali metal borohydrides, such as sodium borohydride, lithium borohydride, sodium cyanoborohydride; aluminum hydride compounds, such as diisobutylaluminum hydride, lithium aluminum hydride, lithium triethoxyaluminum hydride; Yes,
Preferred are alkali metal borohydrides (particularly preferred are sodium cyanoborohydride).

The reaction temperature varies depending on the starting compound, the reducing agent used, the type of the solvent and the like, but is usually from -20 ° C to 150 ° C, preferably from 10 ° C to 80 ° C.

The reaction time varies depending on the starting compound, the reducing agent used, the solvent, the reaction temperature and the like, but is usually 15 minutes to 24 hours, preferably 30 minutes to 16 hours.

If desired, R ^1a , R ^2a , R ^3a , R
Amino, imino, hydroxy and / or ^4a and A '
Alternatively, the method of removing the protecting group of the carboxy group is the same as the method of the
It is carried out in the same manner as in the method of removing the protecting group for the amino, imino, hydroxy and / or carboxy groups in three steps.

After completion of the reaction, the desired compound (II)
n) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step E3 is a step of producing compound (IIo), in which a compound having the general formula (XIX) is reacted with a base in the presence or absence (preferably in the presence) of an inert solvent. Is then reacted with a compound having the general formula (XX) and, if desired, R ^1a , R ^2a , R ^3a , R ^4a and A ′
By removing the protecting group of the amino, imino, hydroxy and / or carboxy group in the above.

As the base used in the above reaction, for example, the same bases as those used in the above-mentioned Step C2 can be mentioned, and alkali metal hydrides (particularly preferably sodium hydride) are preferred. It is.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; dimethylformamide;
Amides such as dimethylacetamide and hexamethylphosphoric triamide; or a mixed solvent of the above solvents;
Preferably, they are amides (particularly preferably, dimethylformamide).

The reaction temperature for reacting compound (XIX) with a base varies depending on the starting compound, the base used, the solvent and the like, but is usually -50 ° C to 200 ° C (preferably
0 ° C to 120 ° C).

The reaction time for reacting compound (XIX) with a base varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually from 15 minutes to 24 hours (preferably 1 hour To 10 hours).

Next, the reaction temperature when reacting with the compound (XX) is usually -20 ° C to 200 ° C (preferably 0 ° C to 200 ° C).
° C to 150 ° C).

Next, the reaction time for the reaction with the compound (XX) is usually 15 minutes to 48 hours (preferably 3 minutes).
0 minute to 24 hours).

If desired, R ^1a , R ^2a , R ^3a , R
Amino, imino, hydroxy and / or ^4a and A '
Alternatively, the method of removing the protecting group of the carboxy group is the same as that of the above A
It is carried out in the same manner as in the method of removing the protecting group for the amino, imino, hydroxy and / or carboxy groups in three steps.

After completion of the reaction, the desired compound (II)
o) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step E4 is a step of producing a compound having the general formula (XXII), and using a reducing agent such as triphenylphosphine in an inert solvent to give compound (XII).
XI).

The inert solvent used in the above reaction is not particularly limited as long as it does not participate in the reaction.
It is the same as that used in the step E1, preferably a mixed solvent of ethers and water (particularly preferably a mixed solvent of tetrahydrofuran and water).

After completion of the reaction, the desired compound (XXI
I) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Step E5 is a step for producing a compound (IIp), which comprises the compound (XXII) and a compound of the general formula (XXII)
After reacting the compound having I), R ^1a ,
It is carried out by removing the protecting groups of the amino, imino, hydroxy and / or carboxy groups in R ^2a , R ^3a , R ^4a and A ′.

When R ⁷ in the compound (XXIII) is a formyl group, the compound (XXII) in an inert solvent
And compound (XXIII).

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene , Toluene, xylene and the like aromatic hydrocarbons; diethyl ether, diisopropyl ether, tetrahydrofuran,
Ethers such as dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n-propanol, isopropanol, n-
Butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin,
Alcohols such as octanol, cyclohexanol, and methyl cellosolve; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphoric triamide; acids such as acetic acid and propionic acid; and sulfoxides such as dimethyl sulfoxide. Sulfolane; or a mixed solvent of the above-mentioned solvents; and preferably ethers (particularly preferably tetrahydrofuran).

The reaction temperature varies depending on the starting compound, the base used, the solvent and the like, but is usually from 0 ° C. to 200 ° C.
(Preferably 10 ° C. to 120 ° C.).

The reaction time varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually 1 hour to 50 hours (preferably 5 hours to 24 hours).

When R ⁷ is a carboxy group in the compound (XXIII), the compound represented by the general formula (XXII) in an inert solvent
A compound having the formula I) or a reactive derivative thereof (acid halides, active esters or mixed acid anhydrides) and a compound having the general formula (XXII) or an acid addition salt thereof (for example, hydrochloride, nitrate, sulfate) (A mineral acid salt).

In the acid halide method, compound (XXIII) is converted into a halogenating agent (eg, oxalyl chloride, thionyl chloride, thionyl bromide, oxalic acid chloride,
Oxalic acid dichloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, etc.) to produce acid halides, and the acid halides and compound (XXII) or an acid addition salt thereof in an inert solvent with a base The reaction is carried out in the presence or absence (preferably in the presence) of

The base used in the above reaction can be, for example, the same as the one used in the above-mentioned Step C2, and is preferably an organic amine (particularly preferably, pyridine). .

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction.
Aliphatic hydrocarbons such as hexane, heptane, ligroin or petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogens such as dichloromethane, chloroform, 1,2-dichloroethane and carbon tetrachloride Hydrocarbons; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide Kind;
Sulfoxides such as dimethyl sulfoxide; sulfolane; and preferably halogenated hydrocarbons, ethers or amides (particularly preferably, dichloromethane, chloroform, tetrahydrofuran or dimethylformamide).

The reaction temperature varies depending on the starting compounds, reagents and the like, but the reaction of the halogenating agent with the compound (XXIII) and the reaction of the acid halides with the compound (XXII) or an acid addition salt thereof are usually -20 ° C To 150 ° C, preferably the reaction between the halogenating agent and the compound (XXIII) is from -10 ° C to 100 ° C, and the reaction between the acid halides and the compound (XXII) or the acid addition salt thereof is -2.
0 ° C to 100 ° C.

The reaction time varies depending on the starting compound, the reagent, the reaction temperature, etc., but the halogenating agent and the compound (XXII)
The reaction of I) and the reaction of the acid halides with the compound (XXII) or an acid addition salt thereof are usually carried out for 30 minutes to 8 minutes.
0 hours (preferably 1 hour to 48 hours).

In the active ester method, the compound (XXIII) is reacted with an active esterifying agent in an inert solvent to produce active esters, and then, in an inert solvent, in the presence or absence of a base (preferably). In the presence of), compound (XXII) or an acid addition salt thereof.

The active esterifying agent used in the above reaction is, for example, N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide or the like. Compounds; disulfide compounds such as dipyridyl disulfide; carbodiimides such as dicyclohexylcarbodiimide; carbonyldiimidazole; triphenylphosphine;

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether. Aromatic hydrocarbons such as benzene, toluene and xylene; dichloromethane,
Halogenated hydrocarbons such as 1,2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone; formamide, dimethylformamide Amides such as dimethylacetamide, hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; sulfolane;
And preferably ethers or amides (particularly preferred are dioxane, tetrahydrofuran or dimethylformamide).

The base used in the above reaction includes, for example, the same bases as those used in the above-mentioned acid halide method.

The reaction temperature varies depending on the starting compounds, reagents and the like, but is generally -70 ° C to 150 ° C (preferably -10 ° C to 100 ° C) in the active esterification reaction.
In the reaction of the active ester with the compound (XXII) or an acid addition salt thereof, the reaction is carried out at -20 ° C to 100 ° C (preferably 0
° C to 50 ° C).

The reaction time varies depending on the starting compound, the reagent, the reaction temperature and the like. The active esterification reaction and the reaction of the active ester with the compound (XXII) or the acid addition salt thereof are usually carried out for 30 minutes to 80 hours ( (1 hour to 48 hours).

In the mixed acid anhydride method, the compound (X) is prepared in an inert solvent in the presence or absence (preferably in the presence) of a base.
XIII) is reacted with a mixed acid anhydride agent to produce mixed acid anhydrides, followed by reacting the mixed acid anhydrides with compound (XXII) or an acid addition salt thereof in an inert solvent.

Examples of the base used in the above reaction include the same bases as those used in the above-mentioned acid halide method, and are preferably organic amines (particularly preferably, pyridine).

Examples of the mixed acid anhydride agent used in the above reaction include C ₁ -C ₄ alkyl halides such as ethyl chlorocarbonate and isobutyl chlorocarbonate; C ₁ -C ₅ alkanoyl such as pivaloyl chloride. Halide; di-C ₁ -C ₄ alkyl or di-C ₆ -C ₁₄ arylcyanophosphoric acid such as diethyl cyanophosphonate and diphenyl cyanophosphonate, preferably di-C ₁ -C ₄ alkyl or di-C ₆ —C ₁₄ arylcyanophosphate (particularly preferably diethyl cyanophosphonate).

The inert solvent used in producing the mixed acid anhydrides is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. For example, hexane, heptane, ligroin Aliphatic hydrocarbons such as petroleum ether; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride; diethyl ether Ethers such as, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; ketones such as acetone; amides such as formamide, dimethylformamide, dimethylacetamide, hexamethylphosphoric triamide; and dimethyl sulfoxide Sulfoxy S; sulfolane; are, preferably, ethers or amides (particularly preferably include tetrahydrofuran or dimethylformamide) it is.

The reaction temperature in the reaction for producing the mixed acid anhydrides varies depending on the starting compounds, reagents and the like.
It is 50 ° C to 100 ° C (preferably 0 ° C to 60 ° C).

The reaction time in the reaction for producing mixed acid anhydrides varies depending on the starting compounds, reagents, reaction temperature and the like, but is usually 30 minutes to 72 hours (preferably 1 hour to 24 hours). is there.

The reaction between the mixed acid anhydrides and the compound (XXII) or an acid addition salt thereof is carried out in an inert solvent in the presence or absence (preferably in the presence) of a base. The base and the inert solvent are the same as those used in the reaction for producing the mixed acid anhydrides described above.

The reaction temperature in the reaction of the mixed acid anhydrides with the compound (XXII) or an acid addition salt thereof varies depending on the starting compounds, reagents and the like, but is usually from -30 ° C to 100 ° C.
° C (preferably 0 ° C to 80 ° C).

The reaction time in the reaction of the mixed acid anhydrides with the compound (XXII) or an acid addition salt thereof varies depending on the starting compound, the reagent, the reaction temperature and the like, but is usually from 5 minutes to 24 hours (preferably from 5 minutes to 24 hours). , 30 minutes to 16 hours).

When diC ₁ -C ₄ alkylcyanophosphoric acid or diC ₆ -C ₁₄ arylcyanophosphoric acid is used in this reaction, the compound (XXI) is added in the presence of a base.
II) can be directly reacted with compound (XXII).

In the compound (XXIII), R ⁷ is C _2-
When it is a C ₇ alkoxycarbonyl group, the compound (XXIII) and the compound (XX) can be used in the presence or absence (preferably absence) of an inert solvent or in the presence or absence of a base.
This is carried out by reacting II).

Compound (XXIII) and compound (XXI)
Examples of the base used in the reaction for reacting I) include the same bases as those used in the above-mentioned Step C2, and are preferably organic amines (particularly preferably pyridine).

Compound (XXIII) and compound (XXI)
The inert solvent used in the reaction for reacting I) is not particularly limited as long as it is inert to the present reaction, and examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin, and petroleum ether; Aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol
Alcohols such as toluene, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve Amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; or a mixed solvent of the above solvents; preferably ethers or amides (particularly preferably tetrahydrofuran, dioxane or Dimethylformamide).

The reaction temperature varies depending on the starting compound, the base used, the solvent and the like, but is usually from 0 ° C. to 200 ° C.
(Preferably 50 ° C. to 150 ° C.).

The reaction time varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually 1 hour to 50 hours (preferably 5 hours to 24 hours).

R ^1a , R ^2a , R ^3a , R
Amino, imino, hydroxy and / or ^4a and A '
Alternatively, the method of removing the protecting group of the carboxy group is the same as the method of the
It is carried out in the same manner as in the method of removing the protecting group for the amino, imino, hydroxy and / or carboxy groups in three steps.

After completion of the reaction, the desired compound (II)
p) is collected from the reaction mixture in a conventional manner. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Starting compounds (III), (VI) and (VI
II), (X), (XII), (XIV), (XV
I), (XVII), (XIX), (XX), (XX
I) and (XXIII) are known or are easily prepared according to known methods or methods analogous thereto. [For example, J. Org. Chem., 56, 1445-1453 (1991), Organic R
eaction, vol.5, 301-330 (1991) etc.].

Starting compounds (III), (VIII),
(XIV), (XVI), (XIX) and (XXI)
Can also be produced, for example, by the following method.

Method F may be carried out using compounds (III) and (VIII)
Or (XIV), a compound (XXVI) in which D is a group having -CH- and E is a group having -NH-,
Compound (XXXI) in which D is a group having -CH- and E is a group having the formula -NHCO- and compound (XXXII) in which D is a group having -CH- and E is an oxygen atom or a sulfur atom It is a manufacturing method.

[0333]

Embedded image In the above formula, R ^1a , R ^2a , R ^3a , R ^4a , R ⁷ , B, F and Y have the same meanings as described above, and R ⁸ is —CO ₂ R
⁵ (R ⁵ has the same meaning as described above), an amino group or a cyano group, and Q is not particularly limited as long as it is a group which is usually eliminated as a nucleophilic residue. Is a halogen atom such as chlorine, bromine or iodine; a trihalogenomethyloxy group such as trichloromethyloxy; a lower alkanesulfonyloxy group such as methanesulfonyloxy or ethanesulfonyloxy; trifluoromethanesulfonyloxy or pentafluoroethanesulfonyl A halogeno lower alkanesulfonyloxy group such as oxy; benzenesulfonyloxy, p-toluenesulfonyloxy,
Examples thereof include arylsulfonyloxy groups such as p-nitrobenzenesulfonyloxy, and particularly preferred are a halogen atom and a lower alkanesulfonyloxy group.

Step F1 is a step for producing a compound having the general formula (XXV), and a compound having the general formula (XXIV) and a compound (XVII) or an acid addition salt thereof (for example, hydrochloric acid) in an inert solvent. Salts, nitrates, mineral salts such as sulfates).
-A method of heat condensation using an organic sulfonic acid such as toluenesulfonic acid as a catalyst or a method of condensation using a Lewis acid such as titanium tetrachloride, and this step is performed in the same manner as the above-mentioned step E1.

The step F2 is a step for producing the compound (XXVI), which is carried out by reducing the compound (XXV) in an inert solvent. This step is carried out in the same manner as the step E2.

Step F3 is a step for producing a compound having the general formula (XXVIII), and removing the hydroxyl group of the compound having the general formula (XXVII) in an inert solvent in the presence or absence of a base. It is carried out by converting to a leaving group Q.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction. For example, the same base as that used in the step C2 can be mentioned. And organic amines (preferably pyridine).

Examples of the reagent forming the leaving group Q include sulfonyl halides such as methanesulfonyl chloride and P-toluenesulfonyl chloride; thionyl halides such as thionyl chloride, thionyl bromide and thionyl iodide; Sulfuryl halides such as sulfuryl bromide and sulfuryl iodide; phosphorus trihalides such as phosphorus trichloride, phosphorus tribromide and phosphorus triiodide; such as phosphorus pentachloride, phosphorus pentabromide and phosphorus pentaiodide Phosphorus pentahalides; phosphorus oxychloride, phosphorus oxybromide,
Halogenating agents such as phosphorus oxyhalides such as phosphorus oxyiodide can be mentioned, and phosphorus trihalides (particularly preferably phosphorus tribromide) are preferable.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. For example, aliphatic hydrocarbons such as heptane, ligroin or petroleum ether; benzene Aromatic hydrocarbons such as, toluene, xylene; dichloromethane, 1,
Halogenated hydrocarbons such as 2-dichloroethane and carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone; formamide;
Amides such as dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; sulfoxides such as dimethylsulfoxide; sulfolane; and preferred are halogenated hydrocarbons (particularly preferably dichloromethane).

The reaction temperature varies depending on the starting compound, the reagent used, the solvent and the like, but is usually from -20 ° C to 100 ° C.
° C (preferably 0 ° C to 50 ° C).

The reaction time varies depending on the starting compound, the reagent used, the solvent, the reaction temperature and the like, but is usually from 15 minutes to 50 hours (preferably from 30 minutes to 12 hours).

Step F4 is a step for producing a compound having the general formula (XXIX), which is carried out by azide-forming the compound (XXVIII) in an inert solvent.
The inert solvent used in the above reaction is not particularly limited as long as it does not hinder the reaction and dissolves the starting material to some extent. For example, aromatic hydrocarbons such as benzene, toluene and xylene; methylene Halogenated hydrocarbons such as chloride and chloroform; ethers such as ether, tetrahydrofuran, dioxane and dimethoxyethane; amides such as formamide, dimethylformamide, dimethylacetamide and hexamethylphosphoric triamide; acetonitrile Nitriles such as;
And amides (particularly preferably dimethylformamide).

The reagent used in the above reaction is not particularly limited as long as it is usually used for azidation. For example, diarylphosphoric acid azide derivatives such as diphenylphosphoric acid azide; trimethylsilyl azide, triethylsilyl azide Trialkylsilyl azides; alkali metal azides such as sodium azide and potassium azide; and preferably alkali metal azides (particularly preferably sodium azide). .

A catalyst may be used in the above reaction,
Examples thereof include trialkylsilyl triflates such as trimethylsilyl triflate and triethylsilyl triflate, and Lewis acids such as trifluoroborane etherate, aluminum chloride and zinc chloride.

The reaction temperature varies depending on the starting compound, the reagent used, the solvent and the like, but is usually from -20 ° C to 100 ° C.
° C (preferably 0 ° C to 50 ° C).

The reaction time varies depending on the starting compound, the reagent used, the solvent, the reaction temperature and the like, but is usually from 15 minutes to 50 hours (preferably from 30 minutes to 12 hours).

Step F5 is a step for producing a compound having the general formula (XXX), and using a reducing agent such as triphenylphosphine in an inert solvent to prepare the compound (XX)
IX), and this step is carried out in the step E.
It is performed in the same manner as in the four steps.

Step F6 is a step of producing a compound (XXXI), which comprises the compound (XXXI) and a compound of the general formula (XXII)
This step is carried out by reacting the compound having I), and this step is carried out in the same manner as in the above-mentioned Step E5.

Step F7 is a step of producing compound (XXXII), which comprises reacting compound (XXVIII) with a base in the presence or absence (preferably in the presence) of an inert solvent, and then reacting compound (XXXVIII) with a base. (XX).

As the base used in the above reaction, for example, the same bases as those used in the above-mentioned Step C2 can be mentioned, and alkali metal hydrides (particularly preferably sodium hydride) are preferred. It is.

The inert solvent used in the above reaction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; benzene Aromatic hydrocarbons such as toluene, xylene; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; dimethylformamide;
Amides such as dimethylacetamide and hexamethylphosphoric triamide; or a mixed solvent of the above solvents;
Preferably, they are amides (particularly preferably, dimethylformamide).

The reaction temperature for reacting compound (XXVIII) with a base varies depending on the starting compound, the base used, the solvent and the like, but is usually from -50 ° C to 200 ° C (preferably 0 ° C to 120 ° C). is there.

The reaction time for reacting the compound (XXVIII) with a base varies depending on the starting compound, the base used, the solvent, the reaction temperature and the like, but is usually from 15 minutes to 2 minutes.
4 hours (preferably 1 hour to 10 hours).

Next, the reaction temperature when reacting with the compound (XX) is usually from -20 ° C to 200 ° C (preferably 0 ° C).
° C to 150 ° C).

Next, the reaction time for the reaction with the compound (XX) is usually 15 minutes to 48 hours (preferably 3 minutes).
0 minute to 24 hours).

After completion of the reaction, the target compound of each step is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Method G can be carried out using compounds (III) and (VIII)
Or (XIV), wherein D is a nitrogen atom and E is -N
A compound (XXXV) that is a group having HCO—, a compound (XXXVIII) in which D is a nitrogen atom and E is an oxygen atom or a sulfur atom, and a compound (XXXVIII) in which D is a nitrogen atom and E is —NH
This is a method for producing a compound (XXXXI) which is a group having-.

[0358]

Embedded imageIn the above formula, R^1a, R^2a, R^3a, R^4a, R⁷, R⁸, B,
F, X, Y and Q have the same meaning as described above,
a is C₁-C₆Represents an alkylene group, and Fb represents ₁-C_FiveA
It represents a alkylene group or a single bond.

Step G1 is a step for producing a compound (XXXV) in an inert solvent (preferably hexane,
Hydrocarbons such as cyclohexane, benzene, toluene and xylene, halogen hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride, ethers such as diethyl ether, tetrahydrofuran and dioxane), bases (preferably Is triethylamine, N-
In the presence or absence of an organic amine such as methylmorpholine, pyridine, 4-dimethylaminopyridine, 2,4,6-trimethylpyridine), the compound represented by the general formula (XXXI)
The compound having V) is represented by the general formula (XXXIII) or an acid addition salt thereof (preferably hydrochloride) at -20 ° C
0 ° C (preferably 0 ° C to 100 ° C) for 15 minutes to 2
The reaction is carried out for 4 hours (preferably 30 minutes to 16 hours).

Further, by reacting the compound having the general formula (XXIII) with the general formula (XXXIII) or an acid addition salt thereof (preferably hydrochloride), the compound (XXXV) can be separately produced, This step is performed in the same manner as in the E5 step.

Step G2 is a step of compound (XXXVIII)
Is carried out by reacting a compound having the general formula (XXXVI) with a compound having the general formula (XXXVII) in an inert solvent in the presence or absence of a base. This is performed in the same manner as in the F7th step.

In step G3, compound (XXXVIII)
Is separately produced in an inert solvent in the presence of an organic base (preferably triethylamine) in the presence of the general formula (X
XXIX) is reacted with a compound having the general formula (XXXX), and this step is performed in the same manner as in the above-mentioned Step E3.

Step G4 is a step of producing compound (XXXXI). Compound (XXXIII) is reacted with compound (XXXVI) in an inert solvent in the presence or absence of a base.
This step is carried out by reacting
It is performed in the same manner as the three steps.

Step G5 is a step for producing a compound having the general formula (XXXXXXII), and a compound having the general formula (XXIIIa) and a compound (XXXX) in an inert solvent.
III) or acid addition salts thereof (eg, hydrochloride, nitrate,
(A steel salt such as a sulfate), for example, a method of heat condensation using an organic sulfonic acid such as p-toluenesulfonic acid as a catalyst or a condensation using a Lewis acid such as titanium tetrachloride. Done in a way that
This step is performed in the same manner as the above-mentioned E1 step.

Step G6 is a step for producing compound (XXXXIa), which is carried out by reducing compound (XXXXXXII). This step is carried out in the same manner as in step E2.

Compound (XXXXIa) can also be produced by subjecting compound (XXXXII) to catalytic reduction.

The solvent used for removal by catalytic reduction is not particularly limited as long as it is inert to the present reaction. Examples thereof include aliphatic hydrocarbons such as hexane, heptane, ligroin and petroleum ether; Aromatic hydrocarbons such as toluene, benzene, xylene; methyl acetate,
Esters such as ethyl acetate, propyl acetate, butyl acetate, diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; methanol, ethanol, n- Alcohols such as propanol, isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and methyl cellosolve; Such organic acids; water; a mixed solvent of the above solvent and water; preferably alcohols, ethers,
Organic acids or water (particularly preferably, alcohols or organic acids).

The catalyst to be used for the removal by catalytic reduction is not particularly limited as long as it is generally used for the catalytic reduction reaction. , Platinum black, rhodium-aluminum oxide, triphenylphosphine-rhodium chloride, palladium-barium sulfate, and preferably palladium-carbon.

Although the pressure is not particularly limited, it is usually 1 to 1
It is performed at 0 atm.

The reaction temperature and the reaction time vary depending on the starting compound, catalyst, solvent and the like, but are usually 0 ° C to 100 ° C.
For 5 minutes to 24 hours.

In addition, starting compounds (XVI) and (XIX)
And (XXI) have the following general formula (XXXXIII)

[0372]

Embedded image [In the above formula, R ^2a , R ^3a , R ^4a , R ⁸ and B have the same meanings as those described above.
¹⁰ represents a halogen atom or azide, and when the broken line represents a single bond, R ¹⁰ represents an oxygen atom. ] In place of compounds (III), (VIII) and (XIV), in the same manner as in the methods described in the above methods A, B, C and D.

After completion of the reaction, the target compound of each step is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified. Method H is a method for producing compound (XXIV).

[0374]

Embedded image In the above formula, R ^2a , R ^3a , R ^4a , R ⁸ , B and X have the same meanings as described above, and R ^2b is a phenyl group, a 3- or 4-position substituent group a ′. (The amino group included in the definition of the group of the substituent group a is an amino group which may be protected, and has the same meaning as the group included in the definition of the group of the substituent group a.) 1 substituted phenyl group, or 3
A phenyl group substituted at the 2nd and 4th positions by the same or different two groups selected from the substituent group a ′, and R ⁹ is C ₁
—C _{6 represents} an alkyl group.

Step H1 is a step for producing a compound (XXIV). The compound having the general formula (XXXXXXIV) is reacted with an inert solvent (preferably hexane, cyclohexane, benzene, toluene, xylene or the like). Hydrocarbons), a compound having the general formula (XXXXV) and -20 ° C
The reaction is performed at a temperature of 200 to 200 ° C. (preferably 0 ° C. to 150 ° C.) for 15 minutes to 24 hours (preferably 30 minutes to 16 hours).

The step H2 is a step of separately preparing the compound (XXIV). The compound having the general formula (XXXVI) is dissolved in an inert solvent (preferably hexane, cyclohexane, benzene, toluene, xylene or the like). Hydrocarbons or ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether), bases (preferably n-butyllithium, t
And a compound having the general formula (XXXXXXVII) in the presence of -organic lithiums such as -butyllithium and phenyllithium;
15 ° C to 24 hours (preferably 30 ° C to 0 ° C).
(Minutes to 16 hours).
In order to supplement the acid generated with the progress of the reaction,
The reaction can also be performed in the presence of an organic amine or the like (preferably N, N, N ', N'-tetramethylethylenediamine).

Step H3 is a step for producing a compound having the general formula (XXIVa),
V) in an inert solvent (preferably, hydrocarbons such as hexane, cyclohexane, benzene, toluene, and xylene); (150 ° C. to 150 ° C.) for 15 minutes to 24 hours (preferably 30 minutes to 20 hours).

The compound (XXXXIV) was dissolved in an inert solvent (preferably, halogen hydrocarbons such as dichloromethane, 1,2-dichloroethane and carbon tetrachloride, and sulfoxides such as dimethyl sulfoxide). XXXXVIII) and a Lewis acid (preferably aluminum chloride, zinc chloride), and the condensation is carried out at 20 to 200 ° C (preferably 50 ° C
To 150 ° C. for 15 minutes to 24 hours (preferably 3
(0 minute to 16 hours).

After completion of the reaction, the target compound of each step is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and, if insolubles are present, they are removed by filtration. It is obtained by washing with water and the like, drying with anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous sodium hydrogen carbonate and the like, and distilling off the solvent. If necessary, the obtained target compound is eluted with an appropriate eluent by applying a conventional method, for example, recrystallization, reprecipitation, etc., by appropriately combining the methods commonly used for separation and purification of organic compounds as appropriate and applying chromatography. Can be separated and purified.

Starting compounds (XXIIIa) and (XXI
V), (XXVII), (XXXIII), (XXXI)
V), (XXXVI), (XXXVII), (XXXI
X), (XXXX), (XXXXIII), (XXXX
IV), (XXXXV), (XXXXVI), (XXX
XVII) and (XXXXXXVIII) are known or are easily produced according to known methods or methods analogous thereto [eg, Acta. Chim. Acad. Humg., 34, 75-76 (19
62), Chem. Ber., 28, 1625 (1895), Chem. Abstr., 7
1, 123951j (1969), etc.].

The compound of the present invention having the above general formula (I) or (II), a pharmaceutically acceptable salt thereof, an ester or other derivative thereof has an excellent ileal bile acid transporter inhibitory activity.

When the compound of the present invention having the above general formula (I), its pharmaceutically acceptable salt, its ester or other derivative is used as the above-mentioned therapeutic or prophylactic agent, it may be used as such or as appropriate. Pharmacologically acceptable,
It can be mixed with excipients, diluents and the like and orally administered, for example, as tablets, capsules, granules, powders or syrups, or parenterally as injections or suppositories.

These preparations contain excipients (eg, lactose,
Sugar derivatives such as sucrose, glucose, mannitol, sorbitol; corn starch, potato starch,
α-starch, starch derivatives such as dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; dextran; organic excipients such as pullulan: and light anhydrous silicic acid, synthetic aluminum silicate, calcium silicate, and metasilicate aluminate Inorganic excipients such as silicate derivatives such as magnesium; phosphates such as calcium hydrogen phosphate; carbonates such as calcium carbonate; sulfates such as calcium sulfate. ), Lubricants (eg, stearic acid metal salts such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as veegum, gay wax; boric acid; adipic acid; Sodium sulfate; DL leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; Derivatives can be mentioned.) Binders (for example, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, macrogol, and the same compounds as the above-mentioned excipients), disintegrants (for example, , Low-substituted hydroxypropyl Cellulose derivatives such as loin, carboxymethylcellulose, carboxymethylcellulose calcium, and internally cross-linked sodium carboxymethylcellulose; and chemically modified starch and celluloses such as carboxymethyl starch, sodium carboxymethyl starch, and cross-linked polyvinyl pyrrolidone.) Stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; alcohols such as chlorobutanol, benzyl alcohol and phenylethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal;
Dehydroacetic acid; and sorbic acid. ), Flavoring agents (for example, commonly used sweeteners, sour agents, flavors, etc.) and diluents can be used in a well-known method.

The dosage depends on symptoms, age, etc., but in the case of oral administration, the lower limit is 1 mg (preferably 10 mg) and the upper limit is 2000 mg (preferably 4 mg) per dose.
00 mg), in the case of intravenous administration, 0.1 mg (preferably 1 mg) per day, 500 mg per day
(Preferably 300 mg) per adult per day
It is desirable to administer from 6 to 6 times depending on the symptoms.

[0385]

The present invention will be described in more detail with reference to the following examples and test examples, but the scope of the present invention is not limited to these examples.

Example 1 5- [3- (phenyl-((1R) -1-phenyl-ethylamino) methyl) benzylidene] thiazolidine-
2,4-dione and its hydrochloride (Exemplary Compound No. 2-5
7) (1a) 3- [phenyl-((1R) -1-phenylethylamino) methyl] benzoic acid methyl ester 3.0 g of 3-benzoylbenzoic acid methyl ester,
After dissolving 3.2 ml of (R) -1-phenylethylamine and 1.4 ml of triethylamine in 60 ml of dichloromethane, 15 ml of a dichloromethane solution of 1.4 ml of titanium tetrachloride was added at 0 ° C., and the reaction solution was stirred at room temperature for 4 hours. . An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction mixture under ice cooling, and the precipitated insolubles were removed by filtration. After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in 50 ml of methanol, and acetic acid 1.
1 ml and 5.23 g of sodium cyanoborohydride were added, and the mixture was heated under reflux for 1 hour. After evaporating the solvent of the reaction solution under reduced pressure, the residue was diluted with ethyl acetate and washed with water and saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 19/1), and 850 mg of isomer A of the title compound was obtained as a pale yellow oily substance, and isomer B was obtained as a colorless crystal. 1 g was obtained. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J = 6.6H)
z), 3.60-3.68 (1H, m), 3.90 (3H, s), 4.68 (1H, s), 7.
21-7.42 (12H, m), 7.56 (1H, d, J = 7.6Hz), 7.92 (1H, d,
J = 7.7Hz), 8.02 (1H, s). Isomer B NMR spectrum (CDCl ₃ ) δppm: 1.38 (3H, d, J = 6.6H)
z), 3.61-3.71 (1H, m), 3.88 (3H, s), 4.67 (1H, s), 7.
21-7.36 (12H, m), 7.49 (1H, d, J = 7.8Hz), 7.85 (1H, d,
J = 7.7Hz), 8.00 (1H, s).

(1b) [3- (phenyl-((1R)-
1-phenylethylamino) methyl) phenyl] methanol 850 mg of isomer A of 3- [phenyl-((1R) -1-phenylethylamino) methyl] benzoic acid methyl ester of Example (1a) was dissolved in 10 ml of tetrahydrofuran. Thereafter, 5.0 ml of a 1 M solution of lithium aluminum hydride in tetrahydrofuran was added at 0 ° C, and the reaction solution was stirred at 0 ° C for 1 hour. 2.0 g of sodium sulfate decahydrate was added to the reaction solution, and after stirring for a while, insolubles were removed by filtration. The filtrate was diluted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 9 /
Separation and purification in 1) were performed to obtain 600 mg of the isomer A of the title compound as a colorless oil. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.7H)
z), 3.63-3.71 (1H, m), 4.65 (2H, s), 4.67 (1H, s), 7.
14-7.37 (14H, m).

The 3- [phenyl-((1
R) -1-Phenylethylamino) methyl] benzoic acid methyl ester is reacted with 1.10 g of isomer B in the same manner as in the method for producing isomer A of Example (1b),
780 mg of isomer B of the title compound was obtained as a colorless oil. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.7H)
z), 3.63-3.70 (1H, m), 4.61 (2H, s), 4.63 (1H, s), 7.
15-7.36 (14H, m).

(1c) 3- [phenyl-((1R) -1
-Phenylethylamino) methyl] benzaldehyde [3- (phenyl-((1R) -1-) of Example (1b)
600 mg of isomer A of phenylethylamino) methyl) phenyl] methanol was dissolved in 12 ml of dichloromethane, and 1.64 g of manganese dioxide was further added, followed by stirring at room temperature for 19 hours. Remove manganese dioxide by filtration,
The solvent of the filtrate was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate).
And 510 mg of isomer A of the title compound was obtained as a pale yellow oil. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.39 (3H, d, J = 6.7H)
z), 3.60-3.67 (1H, m), 4.72 (1H, s), 7.15-7.89 (14H,
m), 10.20 (1H, s). [3- (phenyl-((1R) -1-) of Example (1b)
Using 780 mg of isomer B of phenylethylamino) methyl) phenyl] methanol, the reaction was carried out in the same manner as in the method for producing isomer A of Example (1c), to give 500 mg of isomer B of the title compound as a colorless oil Obtained. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J = 6.6H)
z), 3.65-3.72 (1H, m), 4.69 (1H, s), 7.23-7.84 (14H,
m), 9.95 (1H, s).

(1d) 5- [3- (phenyl-((1
R) -1-Phenylethylamino) methyl) benzylidene] thiazolidine-2,4-dione and its hydrochloride Example of 3- [phenyl-((1R) -1-phenylethylamino) methyl] benzaldehyde of Example (1c) Dissolve 510 mg of isomer A in 10 ml of toluene,
80 mg of 2,4-thiazolidinedione, 0.03 ml
Was added and 0.02 ml of acetic acid was added, and the mixture was heated under reflux for 3 hours. After diluting the reaction solution with ethyl acetate, the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (elution solvent = cyclohexane / ethyl acetate = 9/1), and the free form of the isomer A of the title compound was obtained as a yellow oil (650 m).
g was obtained. 650 mg of this free form in ethyl acetate and 4
After mixing a normal hydrogen chloride-ethyl acetate solution, the solvent was distilled off under reduced pressure to obtain 530 mg of the hydrochloride salt of the isomer A of the title compound as a yellow powder. Isomer A hydrochloride Melting point: 189-191 ° C (decomposition) NMR spectrum (CDCl ₃ ) δ ppm: 1.55 (3H, d, J = 6.8H)
z), 4.01-4.11 (1H, m), 4.87 (1H, s), 7.18-7.85 (15H,
m). A method for producing isomer A of example (1d) using 500 mg of isomer B of 3- [phenyl-((1R) -1-phenylethylamino) methyl] benzaldehyde of example (1c). Reaction was carried out in the same manner to give isomer B of the title compound.
Was obtained as a yellow oil. This free body 68
After mixing 0 mg of the ethyl acetate solution and 4N hydrogen chloride-ethyl acetate solution, the solvent was distilled off under reduced pressure to obtain 630 mg of the hydrochloride of the isomer B of the title compound as a yellow powder. Isomer B hydrochloride Melting point: 241-243 ° C. (decomposition) NMR spectrum (CDCl ₃ ) δ ppm: 1.73 (3H, d, J = 6.6H)
z), 4.02-4.13 (1H, m), 4.78 (1H, s), 7.19-7.83 (15H,
m).

Example 2 5- [3- (phenyl-((1R) -1-phenylethylamino) methyl) benzyl] thiazolidine-2,4-
Dione and its hydrochloride (Exemplary Compound No. 2-1321) (2a) 5- [3- (phenyl-((1R) -1-phenylethylamino) methyl) benzylidene] -3- (triphenylmethyl) thiazolidine-2 , 4-Dione 620 mg of the isomer A of 5- [3- (phenyl-((1R) -1-phenylethylamino) -methyl) benzylidene] thiazolidine-2,4-dione of Example 1 was dissolved in 10 ml of dichloromethane, Further, 0.60 ml of triethylamine and 0.46 g of chlorotriphenylmethane were added, and the reaction solution was stirred at room temperature for 8 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the residue was diluted with ethyl acetate and washed with water and saturated saline. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 9/1) to obtain 800 mg of the title compound isomer A as a pale yellow oil. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J = 6.7H)
z), 3.60-3.67 (1H, m), 4.63 (1H, s), 7.17-7.55 (29H,
m), 7.76 (1H, s). Using 5-520 mg of the isomer B of 5- [3- (phenyl-((1R) -1-phenylethylamino) methyl) benzylidene] thiazolidine-2,4-dione of Example 1. hand,
The reaction was carried out in the same manner as in the method for producing isomer A of Example (2a), and purification was carried out to obtain 830 mg of isomer B of the title compound as a pale yellow oil. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.7H)
z), 3.63-3.71 (1H, m), 4.61 (1H, s), 7.17-7.46 (29H,
m), 7.68 (1H, s).

(2b) 5- [3- (phenyl-((1
R) -1-Phenylethylamino) methyl) benzyl]
-3- (Triphenylmethyl) thiazolidine-2,4-
Dione The 5- [3- (phenyl-((1R)-) of Example (2a)
1-phenylethylamino) methyl) benzylidene]-
800 mg of isomer A of 3- (triphenylmethyl) thiazolidine-2,4-dione was added to 10 m of tetrahydrofuran.
of sodium borohydride, and 46 mg of sodium borohydride and 10 ml of ethanol were further added thereto, followed by stirring at room temperature overnight. After evaporating the solvent of the reaction solution under reduced pressure, the residue was diluted with ethyl acetate and washed with water and saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 9/1) to give the isomer A of the title compound as a colorless oil.
0 mg was obtained. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.34-1.37 (3H, m),
2.97-3.07 (1H, m), 3.51-3.66 (2H, m), 4.35-4.41 (1H, m
m), 4.60 (1H, d, J = 2.9 Hz), 7.04-7.39 (29H, m) 5- [3- (phenyl-((1R)-) of Example (2a).
1-phenylethylamino) methyl) benzylidene]-
Using 820 mg of isomer B of 3- (triphenylmethyl) thiazolidine-2,4-dione, the reaction was carried out in the same manner as in the method for producing isomer A of Example (2b), and isomer B of the title compound was converted into a colorless oil. 360 mg were obtained. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 2.88-3.01 (1H, m), 3.46-3.69 (2H, m), 4.27-4.35
(1H, m), 4.60 (1H, s), 7.15-7.36 (29H, m).

(2c) 5- [3- (phenyl-((1
R) -1-Phenylethylamino) methyl) benzyl]
Thiazolidine-2,4-dione and its hydrochloride 5- [3- (phenyl-((1R)-] of Example (2b)
1-phenylethylamino) methyl) benzyl] -3-
300 mg of isomer A of (triphenylmethyl) thiazolidine-2,4-dione was dissolved in 6 ml of acetic acid, 2 ml of water was further added, and the mixture was stirred at 80 ° C. for 1 hour. The reaction solution was neutralized with sodium hydrogen carbonate and extracted with ethyl acetate.
The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (eluent: cyclohexane / ethyl acetate = 4/1) to give the free form of isomer A of the title compound as a colorless oil.
mg. After mixing an ethyl acetate solution of 160 mg of the free compound and a 4 N hydrogen chloride-ethyl acetate solution, the solvent was distilled off under reduced pressure to obtain 130 mg of the hydrochloride of the isomer A of the title compound as a colorless powder. Hydrochloride of isomer A Optical rotation: [α] _D ^23.5 = -16.0 (C = 0.1 EtOH) Melting point: 166-168 ° C. (decomposition) NMR spectrum (CDCl ₃ ) δ ppm: 1.42 (3H, d, J = 6.3H
z), 3.19-3.31 (1H, m), 3.63-3.70 (1H, m), 3.95-4.38
(1H, m), 4.76 (1H, s), 4.79-4.90 (1H, m), 7.14-7.94
(15H, m), 9.17-10.51 (2H, m).

In Example (2b), 5- [3- (phenyl-
((1R) -1-phenylethylamino) methyl) benzyl] -3- (triphenylmethyl) thiazolidine-
Using 360 mg of isomer B of 2,4-dione, the reaction was carried out in the same manner as in the method for producing isomer A of Example (2c),
The free form of isomer B of the title compound was converted to a colorless powder by 70
mg. Isomer B Optical rotation: [α] _D ^23.5 = + 76.1 (C = 1.0 EtOH) Melting point: 161-162 ° C. (decomposition) NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.7H)
z), 3.02-3.12 (1H, m), 3.42-3.49 (1H, m), 3.64-4.71
(1H, m), 4.40-4.47 (1H, m), 4.62 (1H, s), 7.00-7.37
(15H, m).

Example 3 5- [4- (phenyl-((1R) -1-phenylethylamino) methyl) benzylidene] thiazolidine-2,
4-Dione (Exemplified Compound No. 3-20) (3a) 4- [phenyl-((1R) -1-phenylethylamino) methyl] benzoic acid methyl ester 6.0 g of 4-benzoylbenzoic acid methyl ester and 6. The reaction was carried out in the same manner as in Example (1a) using 4 ml of (R) -1-phenylethylamine, and purified to obtain 8.36 g of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.6H)
z), 3.59-3.71 (1H, m), 3.87 and 3.90 (total 3H, each
s), 4.67 (1H, s), 7.16-7.46 (12H, m), 7.91 (1H, d, J =
8.4Hz), 8.00 (1H, d, J = 8.4Hz).

(3b) [4- (phenyl-((1R)-
1-phenylethylamino) methyl) phenyl] methanol Using 5.0 g of 4- [phenyl-((1R) -1-phenylethylamino) methyl] benzoic acid methyl ester of Example (3a), Example (1b) ) And silica gel column chromatography (eluent:
Separation and purification with cyclohexane / ethyl acetate = 9/1) gave isomer A of the title compound as a colorless oil in 1.57%.
and 1.48 g of isomer B as a pale yellow oil. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 3.63-3.70 (1H, m), 4.63 (1H, s), 4.67 (2H, s), 7.
13-7.41 (14H, m). Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 3.64-3.71 (1H, m), 4.61 (2H, s), 4.63 (1H, s), 7.
13-7.36 (14H, m).

(3c) 4- [phenyl-((1R) -1
-Phenylethylamino) methyl] benzaldehyde [4- (phenyl-((1R) -1-) of Example (3b)
The same reaction as in Example (1c) was carried out using 1.57 g of isomer A of phenylethylamino) methyl) phenyl] methanol and purified to obtain 1.50 g of isomer A of the title compound as a pale yellow oil. Was. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J = 6.7H)
z), 3.60-3.67 (1H, m), 4.69 (1H, s), 7.16-7.38 (12H,
m), 7.54 (1H, d, J = 8.1Hz), 7.84 (1H, d, J = 8.3Hz), 9.
99 (1H, s). [4- (phenyl-((1R) -1-) of Example (3b)
Using 1.48 g of isomer B of phenylethylamino) methyl) phenyl] methanol, the reaction was carried out in the same manner as in Example (1c), followed by purification to obtain 1.05 g of isomer B of the title compound as a pale yellow oil. Was. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J = 6.6H)
z), 3.65-3.72 (1H, m), 4.69 (1H, s), 7.15-7.39 (12H,
m), 7.47 (1H, d, J = 8.2Hz), 7.76 (1H, d, J = 8.3Hz), 9.
94 (1H, s).

(3d) 5- [4- (phenyl-((1
R) -1-Phenylethylamino) methyl) benzylidene] thiazolidine-2,4-dione 500 mg of isomer A of 4- [phenyl-((1R) -1-phenylethylamino) methyl] benzaldehyde of Example (3c). The reaction was carried out in the same manner as in Example (1d) and purified to obtain 580 mg of isomer A of the title compound as a pale yellow powder. Isomer A Melting point: 189-190 ° C. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.32 (3H, d, J = 6.6)
Hz), 3.52-3.57 (1H, m), 4.60 (1H, s), 7.16-7.56 (14H,
m), 7.74 (1H, s). Same as Example (1d) using 500 mg of isomer B of 4- [phenyl-((1R) -1-phenylethylamino) methyl] benzaldehyde of Example (3c). And purified to give 420 mg of isomer B of the title compound as a pale yellow powder. Isomer B Melting point: 218-220 ° C. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.31 (3H, d, J = 6.6)
Hz), 3.53-3.58 (1H, m), 4.60 (1H, s), 7.21-7.51 (14H,
m), 7.70 (1H, s).

Example 4 5- [4- (phenyl-((1R) -1-phenylethylamino) methyl) benzyl] thiazolidine-2,4-
Dione and its hydrochloride (Exemplified Compound No. 3-164) (4a) 5- [4- (phenyl-((1R) -1-phenylethylamino) methyl) benzylidene] -3- (triphenylmethyl) thiazolidine-2 Using 5-520-isomer A of 5- [4- (phenyl-((1R) -1-phenylethylamino) methyl) benzylidene] thiazolidine-2,4-dione of Example 3,
The reaction was carried out in the same manner as in Example (2a), and purification was performed to obtain 880 mg of isomer A of the title compound as a pale yellow oil. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.6H)
z), 3.59-3.66 (1H, m), 4.64 (1H, s), 7.15-7.47 (29H,
m), 7.74 (1H, s). Using 520 mg of isomer B of 5- [4- (phenyl-((1R) -1-phenylethylamino) methyl) benzylidene] thiazolidine-2,4-dione of Example 3. hand,
The reaction was carried out in the same manner as in Example (2a), and purification was performed to obtain 680 mg of isomer B of the title compound as a pale yellow oil. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.7H)
z), 3.63-3.70 (1H, m), 4.58 (1H, s), 7.14-7.46 (29H,
m), 7.68 (1H, s).

(4b) 5- [4- (phenyl-((1
R) -1-Phenylethylamino) methyl) benzyl]
-3- (Triphenylmethyl) thiazolidine-2,4-
Dione The 5- [4- (phenyl-((1R)-) of Example (4a)
1-phenylethylamino) methyl) benzylidene]-
Using 880 mg of the isomer A of 3- (triphenylmethyl) thiazolidine-2,4-dione, the reaction was carried out in the same manner as in Example (2b) and purification was carried out to obtain 410 mg of the isomer A of the title compound as a colorless oil. Was. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.34-1.38 (3H, m), 3.
03-3.12 (1H, m), 3.45-3.67 (2H, m), 4.37-4.41 (1H, m
m), 4.63 (1H, s), 7.13-7.42 (29H, m). The 5- [4- (phenyl-((1R)-
1-phenylethylamino) methyl) benzylidene]-
Using 680 mg of isomer B of 3- (triphenylmethyl) thiazolidine-2,4-dione, the reaction was carried out in the same manner as in Example (2b) and purification was performed to obtain 300 mg of isomer B of the title compound as a colorless oil. Was. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J = 6.7H)
z), 2.98-3.08 (1H, m), 3.37-3.45 (2H, m), 4.32-4.36
(1H, m), 4.59 (1H, s), 7.06-7.35 (29H, m).

(4c) 5- [4- (phenyl-((1
R) -1-Phenylethylamino) methyl) benzyl]
Thiazolidine-2,4-dione and its hydrochloride 5- [4- (phenyl-((1R)-] of Example (4b)
1-phenylethylamino) methyl) benzyl] -3-
The reaction was carried out in the same manner as in Example (2c) using 410 mg of (triphenylmethyl) thiazolidine-2,4-dione isomer A, followed by purification to give 210 mg of the free form of isomer A of the title compound as a colorless oil. Obtained. This free body 2
After mixing 10 mg of an ethyl acetate solution and a 4 N hydrogen chloride-ethyl acetate solution, the solvent was distilled off under reduced pressure to obtain 170 mg of the hydrochloride of the isomer A of the title compound as a pale yellow powder. Isomer A Melting point: 168-170 ° C (decomposition) NMR spectrum (CDCl ₃ ) δ ppm: 1.36-1.39 (3H, m),
3.16-3.27 (1H, m), 3.46-3.61 (1H, m), 3.99 (1H, s),
4.52-4.59 (1H, m), 4.73 (1H, s), 7.12-7.72 (14H, m), 1
0.57-10.71 (2H, m). 5- [4- (phenyl-((1R)-) of Example (4b)
1-phenylethylamino) methyl) benzyl] -3-
The same reaction as in Example (2c) was carried out and purified using 300 mg of isomer B of (triphenylmethyl) thiazolidine-2,4-dione to give 160 mg of a free form of isomer B of the title compound as a colorless oil. Obtained. This free form was treated with hydrogen chloride in the same manner as in the method for producing isomer A of Example (4c) to obtain 110 mg of the hydrochloride of isomer B of the title compound as a pale yellow powder. Isomer B Melting point: 166-168 ° C (decomposition) NMR spectrum (CDCl ₃ ) δ ppm: 1.45-1.47 (3H, m),
2.89-3.36 (1H, m), 3.45-3.51 (1H, m), 4.04 (1H, s),
4.29-4.34 (1H, m), 4.72 (1H, s), 7.09-7.72 (14H, m), 1
0.11-10.69 (2H, m).

Example 5 5- [3- (phenyl-((1R) -1-phenylethylamino) methyl) phenyl] thiazolidine-2,4-
Dione and its hydrochloride (Exemplified Compound No. 2-168) (5a) Hydroxy- [3- (phenyl-((1R)-
1-phenylethylamino) methyl) phenyl] acetic acid methyl ester To 1.0 g of the isomer A of 3- [phenyl-((1R) -1-phenylethylamino) methyl] benzaldehyde in Example (1c) was added cyanotrimethylsilane. .44ml
Then, 10 mg of zinc iodide was added, and the mixture was stirred at 75 ° C for 2 hours. After cooling the reaction solution, 2 ml of methanol and 4 ml of a 4N hydrogen chloride-dioxane solution were added, and the mixture was added at room temperature for 1.5 minutes.
Stirred for hours. The reaction solution was cooled to 0 ° C., 4 ml of tetrahydrofuran and 2 ml of water were added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium thiosulfate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (eluent: cyclohexane / ethyl acetate = 4/1) to obtain 790 mg of the isomer A of the title compound as a pale yellow oil. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 3.60-3.67 (1H, m), 3.75 (3H, s), 4.64 (1H, s), 5.
18 (1H, s), 7.20-7.40 (14H, m). Performed using 950 mg of isomer B of 3- [phenyl-((1R) -1-phenylethylamino) methyl] benzaldehyde in Example (1c). The reaction and purification were conducted in the same manner as in the method for producing isomer A of Example (5a), and 690 mg of the title compound isomer B was obtained as a pale yellow oil. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.8H)
z), 3.62-3.70 (1H, m), 3.71 (3H, s), 4.62 (1H, s), 5.
11 (1H, s), 7.22-7.36 (14H, m).

(5b) Methylsulfonyloxy- [3-
(Phenyl-((1R) -1-phenylethylamino)
Methyl) phenyl] acetic acid methyl ester Hydroxy- [3- (phenyl-) of Example (5a)
((1R) -1-phenylethylamino) methyl) phenyl] acetic acid methyl ester isomer A (790 mg) and triethylamine (0.6 ml) in dichloromethane (20 m)
To 0, 730 mg of methanesulfonic anhydride was added at 0 ° C.
Stirred at 0 ° C. for 30 minutes. After the reaction solution was washed with water and saturated saline, it was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 1.09 g of isomer A of the title compound as a pale yellow oil. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.54 (3H, d, J = 6.1H)
z), 3.08 and 3.10 (total3H, each s), 3.77 and 3.79
(total 3H, each s), 3.71-3.84 (1H, m), 4.70 (1H, s),
5.96 and 5.98 (total 1H, each s), 7.19-7.53 (14H,
m). The hydroxy- [3- (phenyl-) of Example (5a)
Using (690 mg) of isomer B of ((1R) -1-phenylethylamino) methyl) phenyl] acetic acid methyl ester, the reaction was carried out in the same manner as in the method for producing isomer A of Example (5b), followed by purification. 760 mg of isomer B of the title compound was obtained as a pale yellow oil. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.6H)
z), 2.99 and 3.00 (total3H, each s), 3.65-3.67 (1H,
m), 3.73 and 3.74 (total 3H, each s), 4.63 (1H, s),
5.88 (1H, s), 7.23-7.65 (14H, m).

(5c) 2-imino-5- [3- (phenyl-((1R) -1-phenylethylamino) methyl)
Phenyl] thiazolidine-4-one Isomer A950 of methylsulfonyloxy- [3- (phenyl-((1R) -1-phenylethylamino) methyl) phenyl] acetic acid methyl ester of Example (5b)
After dissolving mg in 20 ml of ethanol, 0.19 g of thiourea was added, and the mixture was heated under reflux for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 620 mg of isomer A of the title compound as a pale yellow oil. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.5H)
z), 3.58-3.65 (1H, m), 4.60 (1H, s), 5.17 and 5.18 (t
otal 1H, each s), 7.13-7.46 (17H, m). Methylsulfonyloxy- [3- (phenyl-((1R) -1-phenylethylamino) methyl) phenyl] acetic acid methyl ester of Example (5b) Isomer B of 760m
Using g, a reaction was conducted in the same manner as in the method for producing isomer A of Example (5c), followed by purification to obtain 450 mg of isomer B of the title compound as a pale yellow oil. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J = 6.6H)
z), 3.60-3.72 (1H, m), 4.59 (1H, s), 5.12 and 5.13 (t
otal 1H, each s), 7.05-7.34 (17H, m).

(5d) 5- [3- (phenyl-((1
R) -1-Phenylethylamino) methyl) phenyl]
Thiazolidine-2,4-dione and its hydrochloride 2-imino-5- [3- (phenyl-) of Example (5c)
12 ml of 2N hydrochloric acid was added to 12 ml of an ethanol solution of 620 mg of ((1R) -1-phenylethylamino) methyl) phenyl] thiazolidine-4-one isomer A, and the mixture was heated under reflux for 5 hours. The solvent of the reaction solution was evaporated under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (eluent:
Cyclohexane / ethyl acetate = 4/1).
530 mg of a free form of isomer A of the title compound was obtained as a pale yellow oil. A solution of 530 mg of this free form in ethyl acetate and a 4 N hydrogen chloride-ethyl acetate solution were mixed, and the solvent was distilled off under reduced pressure to obtain 480 mg of the title compound, isomer A hydrochloride as a pale yellow powder. Isomer A Melting point: 184-186 ° C. (decomposition) NMR spectrum (CDCl ₃ ) δ ppm: 1.30 (3H, d, J = 6.8H)
z), 3.83-3.96 (1H, m), 4.72 (1H, s), 5.36 and 5.42 (t
otal 1H, each s), 7.12-7.47 (14H, m). The 2-imino-5- [3- (phenyl-) of Example (5c)
Using ((1R) -1-phenylethylamino) methyl) phenyl] thiazolidine-4-one isomer B (450 mg), the reaction was carried out in the same manner as in the method for producing isomer A of Example (5d), followed by purification. 190 mg of a free form of isomer B of the title compound was obtained as a pale yellow oil. This free form was treated with hydrogen chloride in the same manner to obtain 120 mg of the hydrochloride of isomer B as a pale yellow powder as the title compound. Isomer B Melting point: 219-221 ° C (decomposition) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.67 (3H, br.s),
4.04-4.06 (1H, m), 5.16 (1H, br.s), 5.77 (1H, s), 7.3
1-7.83 (14H, m).

Example 6 5- [4- (phenyl-((1R) -1-phenylethylamino) methyl) phenyl] thiazolidine-2,4-
Dione and its hydrochloride (Exemplified Compound No. 3-44) (6a) Hydroxy- [4- (phenyl-((1R)-
1-phenylethylamino) methyl) phenyl] acetic acid methyl ester Example (5a) was prepared using 500 mg of isomer A of 4- [phenyl-((1R) -1-phenylethylamino) methyl] benzaldehyde of Example (2c). ), And purified to give 430 mg of isomer A of the title compound as a pale yellow oil. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.7H)
z), 3.61-3.69 (1H, m), 3.77 (3H, s), 4.63 (1H, s), 5.
16 (1H, s), 7.20-7.59 (14H, m). Performed using 550 mg of isomer B of 4- [phenyl-((1R) -1-phenylethylamino) methyl] benzaldehyde in Example (2c). The reaction and purification were conducted in the same manner as in the method for producing isomer A of Example (5a), and 470 mg of isomer B of the title compound was obtained as a pale yellow oil. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.7H)
z), 3.62-3.70 (1H, m), 3.73 (3H, s), 4.62 (1H, s), 5.
11 (1H, s), 7.22-7.38 (14H, m).

(6b) Methylsulfonyloxy- [4-
(Phenyl-((1R) -1-phenylethylamino)
Methyl) phenyl] acetic acid methyl ester Hydroxy- [4- (phenyl-) of Example (6a)
Using (790 mg) of isomer A of ((1R) -1-phenylethylamino) methyl) phenyl] acetic acid methyl ester, the reaction was carried out in the same manner as in Example (5b), purification was carried out, and isomer A of the title compound was pale yellow. 530 mg were obtained as an oil. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.77 (3H, d, J = 7.3H)
z), 3.13 (3H, s), 3.74-3.86 (1H, m), 3.79 (3H, s), 4.
70 (1H, s), 5.94 (1H, s), 7.19-7.88 (14H, m). The hydroxy- [4- (phenyl-
Using (470 mg of isomer B of ((1R) -1-phenylethylamino) methyl) phenyl] acetic acid methyl ester, the reaction was carried out in the same manner as in Example (5b), purification was performed, and isomer B of the title compound was pale yellow. 660 mg were obtained as an oil. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.76 (3H, d, J = 6.4H)
z), 2.99 and 3.00 (total3H, each s), 3.60 and 3.61
(total 3H, each s), 4.11-4.17 (1H, m), 4.78 (1H, s),
5.87 (1H, s), 7.31-7.80 (14H, m).

(6c) 2-imino-5- [4- (phenyl-((1R) -1-phenylethylamino) methyl)
Phenyl] thiazolidine-4-one Isomer A of methylsulfonyloxy- [4- (phenyl-((1R) -1-phenylethylamino) methyl) phenyl] acetic acid methyl ester of Example (6b) A500m
g, and purified in the same manner as in Example (5c), to give 290 of the title compound as a pale yellow oil.
mg. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.6H)
z), 3.59-3.67 (1H, m), 4.60 (1H, s), 5.23 and 5.25 (t
otal 1H, each s), 6.92-7.40 (16H, m). Methylsulfonyloxy- [4- (phenyl-((1R) -1-phenylethylamino) methyl) phenyl] acetic acid methyl ester of Example (6b) Isomer B of 570m
g, and purified in the same manner as in Example (5c) to give 370 of isomer B of the title compound as a pale yellow oil.
mg. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J = 6.7H)
z), 3.60-3.68 (1H, m), 4.58 (1H, s), 5.17 (1H, s), 6.
94-7.41 (16H, m).

(6d) 5- [4- (phenyl-((1
R) -1-Phenylethylamino) methyl) phenyl]
Thiazolidine-2,4-dione and its hydrochloride 2-imino-5- [4- (phenyl-) of Example (6c)
Using (290 mg) of ((1R) -1-phenylethylamino) methyl) phenyl] thiazolidine-4-one isomer A, the reaction was carried out in the same manner as in Example (5d), followed by purification.
130 mg of a free form of isomer A of the title compound was obtained as a pale yellow oil. 130 mg of this free body was prepared in Example (5
The mixture was treated with hydrogen chloride in the same manner as in d) to give 95 mg of the hydrochloride of isomer A as the title compound as a white powder. Isomer A Melting point: 187-189 ° C (decomposition) NMR spectrum (CDCl ₃ ) δ ppm: 1.42 (3H, d, J = 6.9H)
z), 4.02 (1H, br.s), 4.77 (1H, s), 5.42 and 5.45 (tot
al 1H, each s), 7.11-7.78 (15H, m). The 2-imino-5- [4- (phenyl-
Using (370 mg of ((1R) -1-phenylethylamino) methyl) phenyl] thiazolidine-4-one isomer B, the reaction was carried out in the same manner as in Example (5d), followed by purification.
The free form of the isomer B of the title compound was converted into a colorless oily substance 2
20 mg were obtained. 220 mg of this free body was prepared in Example (5
The mixture was treated with hydrogen chloride in the same manner as in d) to give 180 mg of the hydrochloride of the title compound, isomer B as a colorless powder. Isomer B Melting point: 219-220 ° C (decomposition) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.70 (3H, d, J = 5.7)
Hz), 4.10 (1H, s), 5.04 (1H, br.s), 5.80 (1H, s), 7.3
2-7.72 (14H, m).

Example 7 5- [3- (phenyl-((1R) -1-phenylethylamino) methyl) benzylidene] -2-thioxothiazolidine-4-one and its hydrochloride (Exemplified Compound No. 2)
-90) After dissolving 500 mg of the isomer A of 3- [phenyl-((1R) -1-phenylethylamino) methyl] benzaldehyde of Example (1c) in 10 ml of toluene, 3
20 mg of rhodanin, 0.03 ml of piperidine and 0.02 ml of acetic acid were added, and the mixture was heated under reflux for 20 minutes. After diluting the reaction solution with ethyl acetate, the organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (elution solvent = cyclohexane / ethyl acetate = 9/1) to obtain 310 mg of a free form of isomer A of the title compound as a yellow oil. After mixing an ethyl acetate solution of 100 mg of this free form and a 4 N hydrogen chloride-ethyl acetate solution, the solvent was distilled off under reduced pressure to obtain 82 mg of the hydrochloride of isomer A of the title compound as a yellow powder.
Obtained. Isomer A Melting point: 188-190 ° C (decomposition) NMR spectrum (CDCl ₃ ) δ ppm: 1.43-1.51 (3H, m),
3.97-4.12 (1H, m), 4.86 (1H, s), 7.15-8.34 (15H, m). 3- [phenyl-((1R) -1-phenylethylamino) methyl] benzaldehyde of Example (1c) Using 1.0 g of isomer B of Example 7, the reaction was carried out in the same manner as in the method for producing isomer A of Example 7, and purification was performed to obtain 1.13 g of isomer B of the title compound as a yellow oil. This free body 2
00 mg was treated with hydrogen chloride in the same manner as in Example (5d).
The hydrochloride salt of isomer B of the title compound was obtained as a tan powder in 12
0 mg was obtained. Isomer B Melting point: 234-236 ° C. (decomposition) NMR spectrum (CDCl ₃ ) δ ppm: 1.71 (3H, d, J = 6.7H)
z), 4.11-4.16 (1H, m), 5.23 (1H, s), 7.38-7.84 (15H,
m).

Example 8 5- [3- (phenyl-((1R) -1-phenylethylamino) methyl) benzyl] 2-thiooxothiazolidine-4-one and its hydrochloride (Exemplified Compound No. 2-23)
87) After dissolving 500 mg of the isomer A of 5- [3- (phenyl-((1R) -1-phenylethylamino) methyl) benzylidene] -2-thioxothiazolidine-4-one of Example 7 in ethanol. , 290 mg of sodium cyanoborohydride and 0.1 ml of acetic acid were added, and the mixture was heated under reflux for 3 hours. The solvent of the reaction solution was distilled off under reduced pressure, diluted with ethyl acetate, and washed with water and saturated saline. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: ethyl acetate / cyclohexane = 1 /
The product was separated and purified in 4) to give 440 mg of a free form of the title compound as a pale yellow oil. After mixing an ethyl acetate solution of 420 mg of the free form and a 4 N hydrogen chloride-ethyl acetate solution, the solvent was distilled off under reduced pressure to obtain 320 mg of the title compound, isomer A hydrochloride as a pale yellow powder. Isomer A Melting point: 215-217 ° C. (decomposition) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.72 (3H, d, J = 5.9)
Hz), 3.13-3.41 (2H, m), 4.07 (1H, d, J = 4.7Hz), 4.94-
5.12 (2H, m), 7.23-7.65 (14H, m). 5- [3- (phenyl-((1R) -1-phenylethylamino) methyl) benzylidene] -2-thioxothiazolidine of Example 7 Using 800 mg of 4-one isomer B, the reaction was carried out in the same manner as in the method for producing isomer A of Example 8, followed by purification to obtain 690 mg of a free form of isomer B of the title compound as a pale yellow oil. . This free body 40
0 mg was treated with hydrogen chloride in the same manner as in Example (5d) to give the hydrochloride of the title compound, Isomer B, as a pale yellow powder in 3 mg.
40 mg were obtained. Isomer B Melting point: 178-180 ° C (decomposition) NMR spectrum (CDCl ₃ ) δ ppm: 1.26-1.33 (3H, m),
3.04-3.15 (1H, m), 3.40-3.51 (1H, m), 4.05 (1H, s),
4.73-4.93 (2H, m), 7.00-7.63 (14H, m).

Example 9 5- [3-(((1R) -1- (1-naphthyl) ethylamino) -phenylmethyl) benzyl] thiazolidine
2,4-dione and its hydrochloride (Exemplary Compound No. 2-1)
013) (9a) 3- (3-Benzoylphenyl) -2-bromopropionic acid butyl ester After dissolving 10.3 g of 3-aminobenzophenone and 24.3 ml of 47% hydrogen bromide in 200 ml of acetone,
At 3 ° C., 12 ml of an aqueous solution of 3.96 g of sodium nitrite was added, and the mixture was stirred at the same temperature for 40 minutes. Acrylic acid n
After adding -butyl and stirring at room temperature for 15 minutes, 0.75 g of cuprous bromide was added and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into ice water, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 19 /
The compound was separated and purified in 1) to give the title compound as a yellow oil.
6.6 g were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 0.90 (3H, t, J = 7.4H)
z), 1.26-1.39 (2H, m), 1.53-1.64 (2H, m), 3.31 (2H, d
d, J = 7.4, 14.3Hz), 3.52 (2H, dd, J = 8.0, 14.1Hz), 4.
13 (2H, t, J = 6.5Hz), 4.42 (1H, t, J = 7.6Hz), 7.40-7.8
4 (9H, m).

(9b) 5- (3-benzoylbenzyl)
-2-Iminothiazolidine-4-one 3- (3-benzoylphenyl) -2 of Example (9a)
After dissolving 16.6 g of bromopropionic acid butyl ester in 260 ml of dimethylformamide, 9.6 g of thiourea and 6.9 g of sodium acetate were added, and the mixture was heated at 60 ° C.
For 2.5 hours. The solvent was distilled off under reduced pressure, an aqueous sodium hydrogen carbonate solution was added to the residue, and the mixture was extracted with ethyl acetate.
The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The precipitated solid was suspended in hexane and collected by filtration to obtain 8.5 g of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.08 (1H, dd, J = 8.7,
14.1Hz), 3.42 (1H, dd, J = 4.4, 14.1Hz), 4.61-4.66 (1
H, m), 7.49-7.75 (9H, m), 8.71 (1H, br.s), 8.93 (1H,
br.s).

(9c) 5- (3-benzoylbenzyl)
Thiazolidine-2,4-dione 5- (3-benzoylbenzyl) -2 of Example (9b)
After dissolving 8.49 g of -iminothiazolidine-4-one in 80 ml of methanol, 80 ml of 6N hydrochloric acid was added, and the mixture was heated under reflux for 10 hours. After distilling off the solvent under reduced pressure,
The residue was neutralized with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. After washing the organic layer with water and saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 3/1).
And purified. The precipitated solid is suspended in hexane,
Filtration yielded 7.7 g of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.24 (1H, dd, J = 9.4,
14.1Hz), 3.58 (1H, dd, J = 4.0, 14.1Hz), 4.56-4.60 (1
H, m), 7.43-7.80 (9H, m), 8.91 (1H, br.s).

(9d) 5- [3-(((1R) -1-
(1-Naphthyl) ethylamino) phenylmethyl) benzyl] -thiazolidine-2,4-dione 500 mg of 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c), (R) -1-
After dissolving 0.5 ml of (1-naphthyl) ethylamine and 2.2 ml of triethylamine in 10 ml of dichloromethane, 5 ml of a dichloromethane solution of 0.35 ml of titanium tetrachloride was added at 0 ° C., and the reaction solution was stirred at room temperature for 12 hours. An aqueous solution of sodium hydrogen carbonate and ethyl acetate were added to the reaction mixture under ice cooling, and the precipitated insolubles were removed by filtration.
After separating the organic layer of the filtrate, the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. 10 residues
dissolved in ethanol, and 0.14 ml of acetic acid and 402 mg of sodium cyanoborohydride were added thereto.
The mixture was heated under reflux for 3 hours. The solvent of the reaction solution was distilled off under reduced pressure.
The obtained residue was diluted with ethyl acetate, and washed with water and saturated saline. After drying the organic layer over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 4/1) and reverse phase chromatography (elution solvent: acetonitrile / water / acetic acid / triethylamine =
70/30 / 0.06 / 0.06) to give 241 mg of a free form of the title compound as a pale yellow foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.50 (3H, d, J = 6.6H)
z), 2.99-3.15 (1H, m), 3.40-3.49 (1H, m), 4.25-4.60
(2H, m), 4.72 and 4.74 (total 1H, each s), 7.00-7.9
1 (16H, m).

(9e) 5- [3-(((1R) -1-
(1-Naphthyl) ethylamino) phenylmethyl) benzyl] -thiazolidine-2,4-dione hydrochloride After mixing a hydrogen chloride-ethyl acetate solution with an ethyl acetate solution of 241 mg of the free form obtained in Example (9d). The solvent was distilled off under reduced pressure to obtain 105 mg of the hydrochloride as the title compound as a white solid. Melting point: 162-170 ° C NMR spectrum (CDCl ₃ ) δ ppm: 1.51 (3H, br.s), 3.0
2-3.55 (2H, m), 4.55-5.15 (3H, m), 6.75-7.95 (16H,
m).

Example 10 5- [3-((1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (exemplified) Compound No. 2-600) (10a) 2-bromo-3- [3- (4-methoxybenzoyl) phenyl] propionic acid butyl ester 3-amino-4'-methoxybenzophenone 23.6 g
And purified in the same manner as in Example (9a) to give 43.0 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 0.90 (3H, t, J = 7.4H)
z), 1.24-1.37 (2H, m), 1.53-1.64 (2H, m), 3.31 (1H, d
d, J = 7.4, 14.3Hz), 3.52 (1H, dd, J = 8.0, 14.1Hz), 3.
90 (3H, s), 4.14 (2H, m), 4.42 (1H, t, J = 7.7Hz), 6.97
(2H, d, J = 8.7Hz), 7.42-7.43 (2H, m), 7.61 (1H, s), 7.
65-7.68 (1H, m), 7.82 (2H, d, J = 8.7Hz).

(10b) 2-imino-5- [3- (4-
Methoxybenzoyl) benzyl] thiazolidine-4-one Using 43.0 g of butyl 2-bromo-3- [3- (4-methoxybenzoyl) phenyl] propionate of Example (10a), React and purify in the same manner to give 25.5 g of the title compound as a white solid.
Obtained. NMR spectrum (DMSO-d ₆ ) δ ppm: 3.07 (1H, dd, J = 8.
8, 14.0Hz), 3.39-3.44 (1H, m), 3.87 (3H, s), 4.63 (1
H, dd, J = 4.3,8.7Hz), 7.11 (2H, d, J = 8.8Hz), 7.45-7.
57 (4H, m), 7.75 (2H, d, J = 8.8Hz), 8.73 (1H, br.s),
8.95 (1H, br.s).

(10c) 5- [3- (4-Methoxybenzoyl) benzyl] thiazolidine-2,4-dione 2-Imino-5- [3- (4-methoxybenzoyl) benzyl] thiazolidine of Example (10b) -4-one 2
Using 4.8 g, the reaction was carried out in the same manner as in Example (9c).
Purification gave 24.5 g of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.25 (1H, dd, J = 9.5,
14.1Hz), 3.58 (1H, dd, J = 4.0, 14.1Hz), 3.90 (3H, s),
4.59 (1H, dd, J = 4.3, 9.5Hz), 6.98 (2H, d, J = 8.8Hz),
7.43-7.48 (2H, m), 7.63 (1H, s), 7.68-7.70 (1H, m),
7.82 (2H, d, J = 9.0Hz), 8.27 (1H, br.s).

(10d) 5- [3-((1- (3,4-
Difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-
Dione and its hydrochloride 5-64- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione 6.64 of Example (10c)
g and 6.38 g of 1- (3,4-difluorophenyl) ethylamine were reacted and purified in the same manner as in Example (9d) to obtain a free form of the title compound as a pale yellow foam. After mixing an ethyl acetate solution of this free form with a 4 N hydrogen chloride-ethyl acetate solution, the solvent was distilled off under reduced pressure to obtain 2.90 g of the title compound, hydrochloride, as a pale yellow solid. Melting point: 153-158 ° C NMR spectrum (DMSO-d ₆ ) δppm: 1.61-1.70 (3H, m),
3.04-3.18 (1H, m), 3.25-3.44 (1H, m), 3.73 and 3.76
(total 3H, each s), 4.13-4.16 (1H, m), 4.90-4.94 (1
H, m), 5.15-5.20 (1H, m), 6.91-7.61 (11H, m), 9.9-1
0.1 (1H, m), 10.4-10.5 (1H, m), 12.1 (1H, br.s).

Example 11 5- [3-((1- (4-methoxyphenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl]
Thiazolidine-2,4-dione hydrochloride (Exemplary Compound No. 2-804) 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione of Example (10c) 500 m
g and 1- (4-methoxyphenyl) ethylamine 28
Using 0 mg, the reaction was carried out in the same manner as in Example (9d), followed by purification to obtain 115 mg of the title compound as a pale yellow solid. Melting point: 185-188 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.64-1.68 (3H, m),
3.04-3.18 (1H, m), 3.25-3.45 (1H, m), 3.73 and 3.76
(total 3H, each s), 3.78 (3H, s), 3.96-4.02 (1H, m),
4.90-5.07 (2H, m), 6.94-7.00 (4H, m), 7.21 (1H, d, J
= 8.7Hz), 7.26-7.29 (2H, m), 7.35-7.39 (1H, m), 7.48-
7.57 (4H, m), 9.78-9.82 (1H, br.s), 10.26-10.32 (1H,
br.s), 12.08-12.13 (1H, br.s).

Example 12 5- [3-((1- (4-fluorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl]
Thiazolidine-2,4-dione hydrochloride (Exemplary Compound No. 2-413) 1.0 g of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione of Example (10c)
And 1- (4-fluorophenyl) ethylamine 850
The reaction was carried out and purified in the same manner as in Example (9d) using mg, to obtain 390 mg of the title compound as a pale yellow solid. Melting point: 215-217 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.68 (3H, br), 3.0
2-3.17 (1H, m), 3.34-3.43 (1H, m), 3.73 and 3.76 (tot
al 3H, each s), 4.05-4.15 (1H, m), 4.92-5.04 (2H,
m), 6.92-6.98 (2H, m), 7.20-7.66 (10H, m), 10.00 (1H,
br.s), 10.65 (1H, br.s), 12.10 (1H, br.s).

Example 13 5- [3-((1- (3,4-Dimethoxyphenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (exemplified) (Compound No. 2-892) (13a) 5- [3-((1- (3,4-dimethoxyphenyl) ethylamino)-(4-methoxyphenyl)
Methyl) benzyl] thiazolidine-2,4-dione 934m of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione of Example (10c)
g and 1- (3,4-dimethoxyphenyl) ethylamine using 816 mg, and reacted in the same manner as in Example (9d).
Purify to give the free form of the title compound as a colorless foam.
30 mg were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 3.03-3.21 (1H, m), 3.41-3.49 (1H, m), 3.52-3.70
(1H, m), 3.76 and 3.81 (total 3H, each s), 3.86 (3H,
s), 3.89 (3H, s), 4.42-4.56 (2H, m), 6.71-7.28 (11H,
m).

(13b) 5- [3-((1- (3,4
-Dimethoxyphenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4
-Dione hydrochloride 530 mg of the free compound obtained in Example (13a) was treated with hydrogen chloride in the same manner as in Example (9d) to obtain 425 mg of the hydrochloride as the title compound as a white solid. Melting point: 183 ° C (decomposition) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.66 (1H, br.s), 3.
03-3.19 (1H, m), 3.37-3.48 (1H, m), 3.70-3.87 (9H,
m), 3.91-3.99 (1H, br.s), 4.91-5.01 (2H, m), 6.68-7.
70 (11H, m), 9.90 (1H, br.s), 10.42 (1H, br.s), 12.10
(1H, br.s).

Example 14 5- [3-((1- (3-fluoro-4-methoxyphenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2-918) 1.0 g of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione of Example (10c)
Using 744 mg of 1- (3-fluoro-4-methoxyphenyl) ethylamine and 1- (3-fluoro-4-methoxyphenyl) ethylamine, the reaction was carried out in the same manner as in Example (9d) and purified to obtain 335 mg of a free form of the title compound as a colorless foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.6H
z), 3.03-3.21 (1H, m), 3.43-3.69 (2H, m), 3.76 and
3.81 (total 3H, each s), 3.90 (3H, s), 4.43-4.54 (2H,
m), 6.71-7.38 (11H, m). This free form was treated with hydrogen chloride in the same manner as in Example (9d) to give the hydrochloride of the title compound as a pale yellow solid in the form of 335.
mg. Melting point: 134-136 ° C NMR spectrum (DMSO-d ₆ ) δppm: 1.61 (3H, br.s),
3.03-3.18 (1H, m), 3.26-3.43 (1H, m), 3.71and3.73 (to
tal 3H, each s), 3.76-3.86 (3H, m), 4.00-4.06 (1H,
m), 4.91-4.95 (1H, m), 5.08 (1H, br.s), 6.93-7.70 (11
H, m), 9.86 (1H, br.s), 10.35 (1H, br.s), 12.09 (1H,
br.s).

Example 15 5- [3-((1- (3,4,5-trimethoxyphenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloric acid Salt (Exemplified Compound No. 2-907) 1.0 g of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione of Example (10c)
Using 951 mg of 1- (3,4,5-trimethoxyphenyl) ethylamine and 1- (3,4,5-trimethoxyphenyl) ethylamine, the reaction was carried out in the same manner as in Example (9d) and purified to obtain 354 mg of a free form of the title compound as a colorless foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H
z), 3.05-3.24 (1H, m), 3.39-3.65 (2H, m), 3.76-3.86
(12H, m), 4.44-4.60 (2H, m), 6.41-6.49 (2H, m), 6.80
and 6.88 (total 2H, each d, J = 8.6Hz), 7.02-7.32 (6
H, m). This free form was treated with hydrogen chloride in the same manner as in Example (9d) to give the hydrochloride as the title compound as a pale yellow solid in the form of 307.
mg. Melting point: 172-176 ° C. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.66 (3H, d, J = 5.5)
Hz), 3.05-3.19 (1H, m), 3.25-3.44 (1H, m), 3.65-3.75
(12H, m), 3.96-4.06 (1H, m), 4.90-4.97 (1H, m), 5.13
-5.18 (1H, m), 6.92-7.01 (2H, m), 7.21-7.68 (6H, m),
9.88 (1H, br.s), 10.24 (1H, br.s), 12.08 (1H, br.s).

Example 16 5- [3-((1- (3,5-Dibenzyloxyphenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2-994) 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione of Example (10c) 500 m
g and 725 mg of 1- (3,5-dibenzyloxyphenyl) ethylamine were reacted and purified in the same manner as in Example (9d), to give 333 mg of the title compound as a colorless foam as a free form of the title compound. NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.5H
z), 3.06-3.60 (3H, m), 3.74 and 3.80 (total 3H, each
s), 4.41-4.58 (2H, m), 5.03-5.04 (4H, m), 6.44-6.5
5 (3H, m), 6.76-6.87 (2H, m), 7.00-7.44 (16H, m). This free form was treated with hydrogen chloride in the same manner as in Example (9d) to give the hydrochloride salt of the title compound. 333 as a pale yellow solid
mg. Mp: 159-163 ° C. NMR Spectrum _{(DMSO-d 6) δppm:} 1.63 (3H, br.s),
3.05-3.16 (1H, m), 3.38-3.44 (1H, m), 3.74and3.75 (to
tal 3H, eachs), 3.99 (1H, br.s), 4.88-4.95 (1H, m),
5.03-5.18 (5H, m), 6.62-6.73 (3H, m), 6.94-6.99 (2H, m
m), 7.22-7.64 (16H, m), 9.85-9.92 (1H, m), 10.28-10.
38 (1H, m), 12.08-12.11 (1H, m).

Example 17 5- [3-(((1R) -1- (4-nitrophenyl)
Ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplary Compound No. 2-964) 5- [3- (4-methoxybenzoyl) of Example (10c) Benzyl] thiazolidine-2,4-dione 1.0 g
And 892 mg of (1R) -1- (4-nitrophenyl) ethylamine were reacted in the same manner as in Example (9d) and purified to obtain a free form of the title compound. This free form was treated with hydrogen chloride in the same manner as in Example (9d) to give 262 mg of the hydrochloride as the title compound as a pale yellow solid. Melting point: 160-162 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.70 (3H, br.s),
3.02-3.17 (1H, m), 3.35-3.45 (1H, m), 3.73 and 3.76
(total 3H, each s), 4.30 (1H, br.s), 4.91-4.96 (1H,
m), 5.14 (1H, br.s), 6.91-6.99 (2H, m), 7.20-7.72 (8
H, m), 8.27-8.32 (2H, m).

Example 18 5- [3-((1- (4-phenyloxyphenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (exemplary compound) No. 2-988) 1.0 g of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione of Example (10c)
Using 928 mg of 1- (4-phenyloxyphenyl) ethylamine and 1- (4-phenyloxyphenyl) ethylamine, the reaction was carried out in the same manner as in Example (9d) and purified to obtain 702 mg of a free form of the title compound as a colorless foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 3.03-3.21 (1H, m), 3.42-3.71 (2H, m), 3.76 and
3.81 (total 3H, each s), 4.43-4.50 (1H, m), 4.58 (1
H, s), 6.80 and 6.88 (total 2H, each d, J = 8.6Hz),
6.95-7.40 (15H, m). This free product was treated with hydrogen chloride in the same manner as in Example (9d) to give the hydrochloride as the title compound as a white solid in 192 m.
g was obtained. Melting point: 149-152 ° C. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.67 (3H, br.s),
3.04-3.14 (1H, m), 3.30-3.40 (1H, m), 3.73 and 3.75
(total 3H, each s), 4.07 (1H, br.s), 4.87-4.95 (1H,
m), 5.05-5.15 (1H, m), 6.86-7.63 (17H, m).

Example 19 5- [3-((1- (4-cyclohexylphenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2-975) 1.0 g of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione of Example (10c)
Using 895 mg of 1- (4-cyclohexylphenyl) ethylamine and 1- (4-cyclohexylphenyl) ethylamine, the reaction was carried out in the same manner as in Example (9d) and purified to obtain 674 mg of a free form of the title compound as a pale yellow foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.20-1.50 (5H, m),
1.70-2.40 (8H, m), 2.43-2.53 (1H, m), 3.00-3.20 (1H,
m), 3.40-3.67 (2H, m), 3.76 and 3.80 (total 3H, each
s), 4.42-4.56 (1H, m), 4.60 (1H, s), 6.79 and 6.87 (t
otal 2H, each d, J = 8.6Hz), 7.00-7.35 (10H, m). This free form was treated with hydrogen chloride in the same manner as in Example (9d) to give the hydrochloride as the title compound as a white solid (651 m).
g was obtained. Melting point: 128-136 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.19-1.46 (5H, m),
1.65-1.85 (8H, m), 2.50-2.60 (1H, m), 3.05-3.16 (1H,
m), 3.35-3.45 (1H, m), 3.74 and 3.75 (total 3H, eac
hs), 4.00 (1H, br.s), 4.88-4.97 (1H, m), 5.14-5.19
(1H, m), 6.94-6.98 (2H, m), 7.21-7.60 (10H, m).

Example 20 5- [3-((1- (4-biphenyl) ethylamino)
-(4-Methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplary Compound No. 2-980) 5- [3- (4-Methoxybenzoyl) benzyl] thiazolidine of Example (10c) 1.0 g of -2,4-dione
And 868 mg of 1- (4-biphenyl) ethylamine were reacted in the same manner as in Example (9d) and purified.
A free form of the title compound was obtained. This free product was treated with hydrogen chloride in the same manner as in Example (9d) to obtain 700 mg of the hydrochloride as the title compound as a pale yellow solid. Melting point: 188-191 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.70 (3H, br.s),
3.05-3.18 (1H, m), 3.35-3.45 (1H, m), 3.74 and 3.76
(total 3H, each s), 4.12 (1H, br.s), 4.90-4.96 (1H,
m), 5.13-5.23 (1H, m), 6.90-7.80 (17H, m).

Example 21 5- [3-((1- (3,4-dichlorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione hydrochloride (Exemplary Compound No. 2) -699) 1.0 g of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione of Example (10c)
And 1- (3,4-dichlorophenyl) ethylamine 8
Using 36 mg, the reaction was carried out in the same manner as in Example (9d).
Purification afforded the free form of the title compound. This free product was treated with hydrogen chloride in the same manner as in Example (9d) to give the hydrochloride salt of the title compound as a white solid (208 mg). Melting point: 168-173 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65 (3H, d, J = 4.9)
Hz), 3.06-3.17 (1H, m), 3.33-3.45 (1H, m), 3.73 and
3.76 (total 3H, each s), 4.17 (1H, br.s), 4.90-4.94
(1H, m), 5.19-5.26 (1H, m), 6.93-7.71 (11H, m).

Example 22 5- [3-((1- (2,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (exemplified) Compound number 2-687) 1.0 g of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione of Example (10c)
And 1.12 g of 1- (2,4-difluorophenyl) ethylamine hydrochloride were reacted and purified in the same manner as in Example (9d) to obtain 794 mg of a free form of the title compound as a pale yellow foam. Was. NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J = 6.7H
z), 3.03-3.20 (1H, m), 3.43-3.53 (1H, m), 3.76 and
3.80 (total 3H, each s), 3.85-3.96 (1H, m), 4.41-4.5
5 (2H, m), 6.73-7.31 (11H, m). This free compound was treated with hydrogen chloride in the same manner as in Example (9d) to give the hydrochloride as the title compound as a pale yellow solid in 736.
mg. Melting point: 210-213 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.67 (3H, br.s),
3.04-3.14 (1H, m), 3.35-3.47 (1H, m), 3.75 (3H, s),
4.35 (1H, br.s), 4.88-4.95 (1H, m), 5.33 (1H, br.s),
6.96-7.84 (11H, m).

Example 23 5- [3-((1- (3-fluorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl]
Thiazolidine-2,4-dione and its hydrochloride (Exemplary Compound No. 2-265) 1.0 g of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione of Example (10c)
Using 1.02 g of 1- (3-fluorophenyl) ethylamine hydrochloride and 1- (3-fluorophenyl) ethylamine hydrochloride, the reaction was carried out in the same manner as in Example (9d), followed by purification to obtain 352 mg of a free form of the title compound as a pale yellow foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J = 6.8H
z), 3.01-3.20 (1H, m), 3.42-3.70 (2H, m), 3.75 and
3.81 (total 3H, each s), 4.40-4.56 (2H, m), 6.77-7.3
3 (12H, m). This free form was treated with hydrogen chloride in the same manner as in Example (9d) to give the hydrochloride as the title compound as a white solid in a yield of 333 m.
g was obtained. Melting point: 201-203 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.67 (3H, br.s),
3.04-3.18 (1H, m), 3.30-3.44 (1H, m), 3.74 and 3.76
(total 3H, each s), 4.13 (1H, br.s), 4.90-4.95 (1H,
m), 5.10-5.19 (1H, m), 6.90-7.65 (12H, m).

Example 24 5- [3-((1- (3,4-dimethylphenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (exemplified) Compound No. 2-723) 1.0 g of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione of Example (10c)
Using 1.08 g of 1- (3,4-dimethylphenyl) ethylamine hydrochloride and 1.08 g of 1- (3,4-dimethylphenyl) ethylamine hydrochloride, purification was carried out in the same manner as in Example (9d) to obtain 719 mg of the free form of the title compound as a colorless foam. .

NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H,
d, J = 6.7Hz), 2.26 (6H, s), 2.97-3.15 (1H, m), 3.42-
3.65 (2H, m), 3.75 and 3.80 (total 3H, each s), 4.39
-4.52 (1H, m), 4.60 (1H, br.s), 6.79 and 6.87 (total
2H, each d, J = 8.6 Hz), 6.90-7.30 (9H, m). The free form was treated with hydrogen chloride in the same manner as in Example (9d) to give the hydrochloride as the title compound as a pale yellow solid, 674.
mg. Melting point: 202-204 ° C NMR spectrum (DMSO-d ₆ ) δppm: 1.64 (3H, br.s),
2.21-2.24 (6H, m), 3.04-3.18 (1H, m), 3.30-3.43 (1H,
m), 3.74 and 3.76 (total 3H, each s), 3.95 (1H, br.
s), 4.90-4.96 (1H, m), 5.02-5.11 (1H, m), 6.94-7.60
(11H, m).

Example 25 5- [3-(((1R) -1- (4-bromophenyl)
Ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione (Exemplary Compound No. 2-534) 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine of Example (10c) 1.0 g of 2,4-dione
And 880 mg of (1R) -1- (4-bromophenyl) ethylamine were reacted in the same manner as in Example (9d), and purified to obtain 357 mg of the title compound as a white solid.
Obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 6.6H
z), 3.04-3.70 (3H, m), 3.79 and 3.84 (total 3H, each
s), 4.44-4.54 (1H, m), 4.55 (1H, s), 6.83 and 6.90
(total 2H, d, J = 8.6Hz), 7.03-7.35 (8H, m), 7.48 (2H,
d, J = 8.0Hz).

Example 26 5- [3-((1- (4-chlorophenyl) ethylamino) -phenylmethyl) benzyl] -thiazolidine-
2,4-dione (Exemplary Compound No. 2-520) Using 500 mg of 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c) and 0.45 ml of 1- (4-chlorophenyl) ethylamine. The reaction was carried out and purified in the same manner as in Example (9d), to give 207 mg of the title compound as a white solid. Melting point: 150-170 ° C NMR spectrum (CDCl ₃ ) δppm: 1.35 (3H, d, J = 6.6H)
z), 3.06-3.21 (1H, m), 3.46-3.50 (1H, m), 3.60-3.70
(1H, m), 4.42-4.60 (2H, m), 7.00-7.38 (13H, m).

Example 27 5- [3- (phenyl- (2-phenyl- (2-phenylcyclopropylamino) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2-174) 500 mg of 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c) and trans-2-
The reaction was carried out in the same manner as in Example (9d) using 543 mg of phenylcyclopropylamine hydrochloride, and purified to obtain 210 mg of a free form of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 0.85-1.01 (1H, m),
1.06-1.13 (1H, m), 1.83-1.96 (1H, m), 2.17-2.30 (1H, m
m), 3.00-3.16 (1H, m), 3.37-3.49 (1H, m), 4.28-4.47
(1H, m), 4.94 (1H, s), 6.80-6.88 (2H, m), 7.01-7.47
(12H, m). 210 mg of this free compound was treated with hydrogen chloride in the same manner as in Example (9d) to obtain 82 mg of the hydrochloride salt of the title compound as a white solid. Melting point: 128-140 ° C NMR spectrum (CDCl ₃ ) δ ppm: 0.82-0.92 (1H, m),
1.60 (1H, br.s), 2.56 (2H, br.s), 3.16-3.40 (2H, m),
4.55-4.64 (1H, m), 5.24-5.34 (1H, m), 6.85-6.89 (2H,
m), 6.94-7.66 (12H, m).

Example 28 5- [3-((2- (3,4-Dibenzyloxyphenyl) ethylamino) -phenylmethyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2) -1001) 500 mg of 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c) and 2- (3,4
-Dibenzyloxyphenyl) ethylamine hydrochloride
Using 18 g, the reaction was carried out in the same manner as in Example (9d) and purification was carried out to obtain a free form of the title compound as a colorless foam.
5 mg were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 2.51-2.80 (4H, m),
3.01-3.12 (1H, m), 3.39-3.47 (1H, m), 4.37-4.44 (1H, m
m), 4.77 (1H, s), 5.09-5.11 (4H, m), 6.66-6.89 (3H,
m), 7.01-7.05 (1H, m), 7.16-7.49 (19H, m). This free form was treated with hydrogen chloride in the same manner as in Example (9d) to give the hydrochloride salt of the title compound as a white solid (397 m).
g was obtained. Melting point: 178-184 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 2.91-2.97 (4H, m),
3.07-3.17 (1H, m), 3.40-3.47 (1H, m), 4.92-4.99 (1H, m
m), 5.07-5.08 (4H, m), 5.56 (1H, s), 6.68 (1H, d, J =
8.3Hz), 6.86 (1H, s), 6.97 (1H, d, J = 8.3Hz), 7.25-7.
46 (15H, m), 7.57-7.69 (4H, m).

Example 29 5- [3-(((1S) -1- (1-naphthyl) ethylamino) -phenylmethyl) benzyl] thiazolidine-
2,4-dione and its hydrochloride (Exemplary Compound No. 2-1)
013) 500 mg of 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c) and (S) -1-
The reaction was carried out in the same manner as in Example (9d) using 0.51 ml of (1-naphthyl) ethylamine, followed by purification to obtain 242 mg of a free form of the title compound as a pale yellow foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.50 (3H, d, J = 6.6H)
z), 2.99-3.15 (1H, m), 3.40-3.49 (1H, m), 4.25-4.60
(2H, m), 4.72 and 4.74 (total 1H, each s), 7.00-7.9
1 (16H, m). This free compound was treated with hydrogen chloride in the same manner as in Example (9d) to give the hydrochloride as the title compound as a white solid (135 m).
g was obtained. Melting point: 162-170 ° C NMR spectrum (CDCl ₃ ) δ ppm: 1.51 (3H, br.s), 3.0
2-3.55 (2H, m), 4.55-5.15 (3H, m), 6.75-7.95 (16H,
m).

Example 30 5- [3-(((1R) -1-phenylpropylamino) -phenylmethyl) -benzyl] thiazolidine-
2,4-dione and its hydrochloride (Exemplary Compound No. 2-1)
322) 2.09 g of 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c) and (R) -1-
Example (9) using 2.0 g of phenylpropylamine
The reaction was conducted in the same manner as in d), and purification was performed to obtain 1.35 g of a free form of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 0.78-0.86 (3H, m),
1.56-1.83 (2H, m), 2.99-3.18 (1H, m), 3.33-3.54 (2H, m
m), 4.38-4.57 (1H, m), 4.58 (1H, s), 7.00-7.40 (14H,
m). This free compound was treated with hydrogen chloride in the same manner as in Example (9d) to give the hydrochloride as the title compound as a white solid in 1.02%
g was obtained. Melting point: 217-223 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 0.53-0.59 (3H, m),
1.91-2.00 (1H, m), 2.46-2.53 (1H, m), 3.03-3.18 (1H, m
m), 3.35-3.45 (1H, m), 3.80 (1H, br.s), 4.90-5.10 (2
H, m), 7.20-7.63 (14H, m).

Example 31 5- [3-((1- (4-methoxyphenyl) ethylamino) -phenylmethyl) benzyl] thiazolidine-
2,4-dione and its hydrochloride (Exemplary Compound No. 2-8
74) Using 934 mg of 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c) and 901 mg of 1- (4-methoxyphenyl) ethylamine, the reaction was carried out in the same manner as in Example (9d). Purification gave a free form of the title compound. The free form was treated with hydrogen chloride in the same manner as in Example (9d) to obtain 805 mg of the hydrochloride as the title compound as a white solid. Melting point: 115-116 ° C NMR spectrum (CDCl ₃ ) δ ppm: 1.67-1.70 (3H, m),
3.02-3.18 (1H, m), 3.25-3.44 (1H, m), 3.78 and 3.79
(total 3H, each s), 4.00-4.06 (1H, m), 4.90-5.08 (2
H, m), 6.97-7.09 (2H, m), 7.17-7.74 (11H, m), 9.92-1
0.05 (1H, br), 10.64-10.75 (1H, br), 12.12 (1H, br.
s).

Example 32 5- [3-((1- (3,4-Dimethoxyphenyl) ethylamino) -phenylmethyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2)
-895) 934 mg of 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c) and 1- (3,4
The same reaction as in Example (9d) was carried out using 1.09 g of -dimethoxyphenyl) ethylamine, followed by purification to obtain a free form of the title compound. The free body is described in Example (9)
The mixture was treated with hydrogen chloride in the same manner as in d) to obtain 789 mg of the hydrochloride salt of the title compound as a white solid. Melting point: 119-122 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.69 (3H, d, J = 5.8)
Hz), 3.02-3.19 (1H, m), 3.27-3.47 (1H, m), 3.721 and
3.724 (total 3H, each s), 3.78 (3H, s), 3.98-4.09 (1
H, m), 4.91-5.15 (2H, m), 6.68-6.80 (1H, m), 6.95-7.
08 (2H, m), 7.19-7.67 (9H, m), 9.90-10.12 (1H, br), 1
0.51-10.75 (1H, br), 12.03-12.17 (1H, br).

Example 33 5- [3-((1- (3,4,5-trimethoxyphenyl) ethylamino) -phenylmethyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2-910) 934 mg of 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c) and 1- (3
4,5-trimethoxyphenyl) ethylamine 1.27
Using g, the reaction was carried out in the same manner as in Example (9d), followed by purification to obtain a free form of the title compound. The free compound was treated with hydrogen chloride in the same manner as in Example (9d) to give 838 mg of the hydrochloride salt of the title compound as a white solid. Melting point: 113-114 ° C. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.70 (3H, d, J = 6.4)
Hz), 3.02-3.19 (1H, m), 3.28-3.45 (1H, m), 3.67 (3H,
s), 3.72 (3H, s), 3.73 (3H, s), 4.00-4.06 (1H, m), 4.8
6-5.00 (1H, m), 5.10-5.18 (1H, br.m), 6.66-6.74 (2H,
m), 7.06-7.77 (9H, m), 9.99-10.23 (1H, br), 10.50-1
0.77 (1H, br), 12.00-12.21 (1H, br).

Example 34 5- [3-((1- (4-fluorophenyl) ethylamino) -phenylmethyl) benzyl] thiazolidine-
2,4-dione and its hydrochloride (Exemplary Compound No. 2-4)
85) Using 5- (3-benzoylbenzyl) thiazolidine-2,4-dione 623 mg and 1- (4-fluorophenyl) ethylamine 557 mg of Example (9c), the reaction was carried out in the same manner as in Example (9d). Purification gave a free form of the title compound. The free compound was treated with hydrogen chloride in the same manner as in Example (9d) to give 397 mg of the hydrochloride as the title compound as a white solid. Melting point: 122-124 ° C. NMR spectrum (CDCl ₃ ) δ ppm: 1.71 (3H, br), 3.01-
3.17 (1H, m), 3.34-3.44 (1H, m), 4.08-4.22 (1H, br),
4.93-5.13 (2H, m), 7.20-7.47 (9H, m), 7.54-7.72 (4H, m
m), 10.04-10.40 (1H, br), 10.78-11.02 (1H, br), 12.1
2 (1H, br.s).

Example 35 5- [3-((1- (3,4-Difluorophenyl) ethylamino) -phenylmethyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2)
-671) 934 mg of 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c) and 1- (3,4
-Difluorophenyl) ethylamine was reacted in the same manner as in Example (9d) using 913 mg, and purified to obtain a free form of the title compound. The free body is described in Example (9)
The mixture was treated with hydrogen chloride in the same manner as in d) to obtain 656 mg of the hydrochloride salt of the title compound as a white solid. Melting point: 114-115 ° C NMR spectrum (DMSO-d ₆ ) δppm: 1.69 (3H, d, J = 5.6)
Hz), 3.02-3.29 (1H, m), 3.32-3.44 (1H, m), 4.12-4.28
(1H, br), 4.92-4.97 (1H, m), 5.14-5.23 (1H, br), 7.0
7-7.73 (12H, m), 10.12-10.37 (1H, br), 10.68-10.91 (1
H, br), 12.11 (1H, br.s).

Example 36 5- [3-((1- (3-fluoro-4-methoxyphenyl) -ethylamino) -phenylmethyl) benzyl]
-Thiazolidine-2,4-dione and its hydrochloride (Exemplary Compound No. 2-923) 934 mg of 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c) and 1- (3-fluoro- 4-methoxyphenyl) ethylamine 1.02
Using g, the reaction was carried out in the same manner as in Example (9d), followed by purification to obtain a free form of the title compound. The free compound was treated with hydrogen chloride in the same manner as in Example (9d) to obtain 652 mg of the hydrochloride as the title compound as a white solid. Melting point: 111-113 ° C. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.69 (3H, br.d, J
= 2.8Hz), 3.01-3.18 (1H, m), 3.25-3.47 (1H, m), 3.86 (3
H, s), 4.00-4.16 (1H, br), 4.94-5.66 (2H, m), 6.96-7.
41 (12H, m), 10.03-10.25 (1H, br), 10.72-10.95 (1H,
br), 12.12 (1H, br.s).

Example 37 5- [3-((1- (4-Cyclohexylphenyl) ethylamino) phenyl-methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2)
-977) In the same manner as in Example (9d), using 934 mg of 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c) and 1.22 g of 1- (4-cyclohexylphenyl) ethylamine. The mixture was reacted and purified to obtain a free form of the title compound. The free body is described in Example (9)
The mixture was treated with hydrogen chloride in the same manner as in d) to give 150 mg of the hydrochloride salt of the title compound as a white solid. Melting point: 118-120 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.25-1.88 (13H,
m), 2.47-2.59 (1H, m), 3.05-3.17 (1H, m), 3.26-3.44
(1H, m), 3.97-4.12 (1H, br), 4.89-4.97 (1H, m), 5.10
-5.31 (1H, br), 7.22-7.65 (13H, m), 9.88-10.06 (1H, b
r), 10.42-10.68 (1H, br), 12.11 (1H, br.s).

Example 38 5- [3-((1- (4-biphenyl) ethylamino)
-Phenylmethyl) benzyl] thiazolidine-2,4-
Dione and its hydrochloride (Exemplified Compound No. 2-983) Using 934 mg of 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c) and 1.18 g of 1- (4-biphenyl) ethylamine The reaction was carried out and purified in the same manner as in Example (9d).
I got (YMC reverse phase HPLC column: JH08S04
−1546WD, 150 × 4.6 mm, eluent: acetonitrile / acetic acid-triethylamine buffer (water: acetic acid: triethylamine = 1000: 2: 2) = 60/40, flow rate: 1 ml / m
in, isomers A and B were 22.41 min and 25.11 min, respectively.
Is detected. ) The free form was treated with hydrogen chloride in the same manner as in Example (9d) to give 158 mg of isomer A and 1 of isomer B as hydrochloride salts of the title compounds as white solids, respectively.
10 mg were obtained. Isomer A Melting point: 122-125 ° C NMR spectrum (DMSO-d ₆ ) δppm: 1.74 (3H, d, J = 6.3)
0Hz), 3.10-3.17 (1H, m), 3.28-3.46 (1H, m), 4.09-4.2
1 (1H, br), 4.92-4.98 (1H, m), 5.12-5.23 (1H, br), 7.
22-7.79 (18H, m), 10.04-10.16 (1H, br), 10.64-77 (1H,
br), 12.12 (1H, br.s). Isomer B Melting point: 152-154 ° C. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.73 (3H, d, J = 6.3)
3Hz), 3.05-3.13 (1H, m), 3.27-3.47 (1H, m), 4.09-4.2
1 (1H, br), 4.93-4.97 (1H, m), 5.25-5.28 (1H, br), 7.
24-7.51 (10H, m), 7.55-7.75 (8H, m), 10.09-10.18 (1H,
br), 10.60-10.72 (1H, br), 12.09 and 12.12 (total
1H, each s).

Example 39 5- [3-((1- (4-phenoxyphenyl) ethylamino) -phenylmethyl) -benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2-
987) Using 934 mg of 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c) and 1.28 g of 1- (4-phenoxyphenyl) ethylamine,
The reaction was conducted and purified in the same manner as in Example (9d) to obtain a free form of the title compound. The free form was treated with hydrogen chloride in the same manner as in Example (9d) to give 885 mg of the hydrochloride as the title compound as a white solid. Melting point: 130-131 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.71 (3H, d, J = 4.6)
Hz), 3.02-3.15 (1H, m), 3.30-3.47 (1H, m), 4.03-4.19
(1H, br), 4.89-5.07 (1H, m), 5.11-5.16 (1H, m), 6.96
-7.08 (4H, m), 7.17-7.47 (10H, m), 7.53-7.74 (4H, m),
10.11-10.20 (1H, br), 10.77-10.94 (1H, br), 12.11 (1
H, br.s).

Example 40 5- [3-((1- (3,5-Dibenzyloxyphenyl) ethylamino) -phenylmethyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2) -996) 934 mg of 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c) and 1- (3,5
The reaction was carried out in the same manner as in Example (9d) using 2.00 g of -dibenzyloxyphenyl) ethylamine, followed by purification to obtain a free form of the title compound. The free body is described in Example (9)
Hydrochloride treatment was carried out in the same manner as in d) to obtain 561 mg of the hydrochloride as the title compound as a white solid. Melting point: 102-103 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.68 (3H, d, J = 6.3)
Hz), 3.02-3.15 (1H, m), 3.25-3.47 (1H, m), 3.95-4.08
(1H, m), 4.88-5.24 (6H, m), 6.60-6.73 (3H, m), 7.21-
7.74 (19H, m), 10.02-10.25 (1H, br), 10.71-10.92 (1H,
br), 12.06-12.17 (1H, br).

Example 41 5- [3-(((1R) -1- (4-nitrophenyl)
Ethylamino) -phenylmethyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplary Compound No. 2-971) 623 mg of 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c) And (R) -1-
The same reaction as in Example (9d) was carried out using 811 mg of (4-nitrophenyl) ethylamine, followed by purification to obtain a free form of the title compound. The free body is described in Example (9)
The mixture was treated with hydrogen chloride in the same manner as in d) to give 625 mg of the hydrochloride salt of the title compound as a white solid. Melting point: 110-111 ° C NMR spectrum (DMSO-d ₆ ) δppm: 1.65-1.71 (3H, b
r), 3.01-3.17 (1H, m), 3.35-3.47 (1H, m), 4.26-4.38
(1H, br), 4.92-5.00 (1H, m), 5.13-5.22 (1H, br), 7.21
-7.47 (5H, m), 7.51-7.81 (6H, m), 8.23-8.29 (2H, m),
10.33-10.58 (1H, br), 10.92-11.15 (1H, br), 12.12 (1
H, br.s).

Example 42 5- [3-(((1R) -1- (4-bromophenyl)
Ethylamino) -phenylmethyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplary Compound No. 2-539) 5- (3-benzoylbenzyl) thiazolidine-2,4-dione of Example (9c) 623 mg And (R) -1-
The same reaction as in Example (9d) was carried out using 800 mg of (4-bromophenyl) ethylamine, followed by purification to obtain a free form of the title compound. The free body is described in Example (9)
The mixture was treated with hydrogen chloride in the same manner as in d) to obtain 328 mg of the hydrochloride salt of the title compound as a white solid. Melting point: 128-130 ° C NMR spectrum (DMSO-d ₆ ) δppm: 1.61-1.79 (3H, b
r), 3.01-3.17 (1H, m), 3.27-3.48 (1H, m), 4.02-4.20
(1H, br), 4.92-5.18 (2H, m), 7.18-7.44 (7H, m), 7.52
-7.75 (6H, m), 10.10-10.34 (1H, br), 10.81-11.03 (1H,
br), 12.15 (1H, br.s).

Example 43 5- [3-((1- (3,4-Difluorophenyl) ethylamino)-(3,4-dimethoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2-617) (43a) 2-bromo-3- [3- (3,4-dimethoxybenzoyl) phenyl] propionic acid butyl ester 3-amino-3 ′, 4′-dimethoxybenzophenone 3
Using 70 mg, the reaction was carried out in the same manner as in Example (9a).
Purification gave 521 mg of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 0.90 (3H, t, J = 7.5H)
z), 1.28-1.38 (2H, m), 1.57-1.63 (2H, m), 3.31 (1H, d
d, J = 7.4, 14.2Hz), 3.52 (1H, dd, J = 7.9, 14.3Hz), 3.
95 (3H, s), 3.97 (3H, s), 4.09-4.19 (2H, m), 4.43 (1
H, t, J = 7.7Hz), 6.90 (1H, d, J = 8.5Hz), 7.36 (1H, m),
7.43 (2H, d, J = 5.0Hz), 7.49 (1H, d, J = 1.7Hz), 7.62
(1H, s), 7.66-7.69 (1H, m).

(43b) 2-imino-5- [3- (3,
4-dimethoxybenzoyl) benzyl] thiazolidine-
4-one The 2-bromo-3- [3- (3,4-
Dimethoxybenzoyl) phenyl] propionic acid butyl ester (29.1 g) was reacted and purified in the same manner as in Example (9b) to give the title compound as a white solid.
6.6 g were obtained. NMR spectrum (DMSO-d ₆ ) δ ppm: 3.07 (1H, dd, J = 8.
8, 14.1Hz), 3.42 (1H, dd, J = 4.3, 14.1Hz), 3.83 (3H,
s), 3.87 (3H, s), 4.64 (1H, dd, J = 4.3, 8.8Hz), 7.11 (1
H, d, J = 8.5Hz), 7.31 (1H, m), 7.37 (1H, d, J = 2.0Hz),
7.45-7.58 (4H, m), 8.72 (1H, br.s), 8.94 (1H, br.s).

(43c) 5- [3- (3,4-Dimethoxybenzoyl) benzyl] thiazolidine-2,4-dione The 2-imino-5- [3- (3,4-diene) of Example (43b)
Dimethoxybenzoyl) benzyl] thiazolidine-4-
Using 16.6 g of ON, the reaction was carried out in the same manner as in Example (9c) and the mixture was purified to obtain 11.8 g of the title compound as a white solid.
Obtained. NMR spectrum (CDCl ₃ ) δ ppm: 3.27 (1H, dd, J = 8.6,
14.1Hz), 3.46 (1H, dd, J = 4.7, 14.1Hz), 3.82 (3H, s),
3.87 (3H, s), 4.98 (1H, dd, J = 4.5, 8.6Hz), 7.10 (1H,
d, J = 8.3Hz), 7.30 (1H, dd, J = 2.0, 8.1Hz), 7.37 (1H,
d, J = 2.0Hz), 7.49-7.62 (4H, m), 12.06 (1H, br.s).

(43d) 5- [3-((1- (3,4-
Difluorophenyl) ethylamino)-(3,4-dimethoxyphenyl) methyl) benzyl] thiazolidine-
2,4-dione and its hydrochloride 5- [3- (3,4-dimethoxybenzoyl) benzyl] thiazolidine-2,4-dione 5 of Example (43c)
Using 00 mg and 423 mg of 1- (3,4-difluorophenyl) ethylamine, the reaction was carried out in the same manner as in Example (9d), followed by purification to obtain a free form of the title compound as a pale yellow foam. Ethyl acetate solution of this free form and 4
After a normal hydrogen chloride-ethyl acetate solution was mixed, the solvent was distilled off under reduced pressure to obtain 251 mg of the hydrochloride as the title compound as a pale yellow solid. Melting point: 140-143 ° C NMR spectrum (DMSO-d ₆ ) δppm: 1.68 (3H, m), 3.01
-3.16 (1H, m), 3.36-3.46 (1H, m), 3.72 and 3.75 (tota
l 3H, each s), 3.78 (3H, s), 4.12-4.22 (1H, m), 4.91
-5.12 (2H, m), 6.90-7.72 (10H, m), 10.05-10.20 (1H,
m), 10.65-10.85 (1H, m), 12.11 (1H, br.s).

Example 44 5- [3-((1- (4-methoxyphenyl) ethylamino)-(3,4-dimethoxyphenyl) methyl) -benzyl] -thiazolidine-2,4-dione hydrochloride (exemplified) Compound number 2-821) 5- [3- (3,4-Dimethoxybenzoyl) benzyl] thiazolidine-2,4-dione 5 of Example (43c)
Using 00 mg and 1- (4-methoxyphenyl) ethylamine 404 mg, the reaction was carried out in the same manner as in Example (9d), and the title compound was purified as a pale yellow solid by 105 m
g was obtained. Melting point: 114-117 ° C NMR spectrum (DMSO-d ₆ ) δppm: 1.55-1.75 (3H, m),
3.05-3.17 (1H, m), 3.36-3.45 (1H, m), 3.72, 3.75,
3.77 and 3.78 (total 9H, each s), 3.95-4.05 (1H, m),
4.89-5.00 (2H, m), 6.91-7.16 (4H, m), 7.20-7.69 (7H,
m), 9.8-9.9 (1H, br.), 10.3-10.6 (1H, br.), 11.95-1
2.25 (1H, br.).

Example 45 5- [3-((1- (3,4-dimethoxyphenyl) ethylamino)-(3,4-dimethoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione hydrochloride (exemplified) Compound number 2-893) 5- [3- (3,4-Dimethoxybenzoyl) benzyl] thiazolidine-2,4-dione 5 of Example (43c)
Using 00 mg and 1- (3,4-dimethoxyphenyl) ethylamine 488 mg, the reaction was carried out in the same manner as in Example (9d) and purified to give the title compound as a white solid (97%).
mg. Melting point: 138-142 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.60-1.75 (3H, m),
3.02-3.18 (1H, m), 3.36-3.45 (1H, m), 3.72, 3.73,
3.74, 3.75, 3.77, 3.78 and 3.79 (total 12H, each
s), 3.95-4.05 (1H, m), 4.91-5.00 (2H, m), 6.69-7.67
(10H, m), 9.85-9.90 (1H, br.s), 10.40-10.60 (1H, br.
s), 12.05-12.15 (1H, br.s).

Example 46 5- [3-((1- (3,4,5-trimethoxyphenyl) ethylamino)-(3,4-dimethoxyphenyl)
Methyl) benzyl] thiazolidine-2,4-dione hydrochloride (Exemplary Compound No. 2-908) 5- [3- (3,4-dimethoxybenzoyl) benzyl] thiazolidine-2,4-dione 5 of Example (43c)
Example 9 (00 mg) and 569 mg of 1- (3,4,5-trimethoxyphenyl) -ethylamine.
The reaction was conducted in the same manner as in d), and purification was performed to obtain 89 mg of the title compound as a white solid. Melting point: 135-140 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.60-1.75 (3H, m),
3.04-3.18 (1H, m), 3.36-3.45 (1H, m), 3.66, 3.68,
3.72, 3.73, 3.75 and 3.78 (total 15H, each s), 3.98-
4.06 (1H, m), 4.90-5.00 (1H, m), 5.05-5.20 (1H, m),
6.67-6.74 (2H, m), 6.90-7.72 (7H, m), 9.80-9.95 (1H, b
rs), 10.25-10.45 (1H, m), 12.0-12.15 (1H, br.s).

Example 47 5- [3-((1- (4-biphenyl) ethylamino)
-(3,4-dimethoxyphenyl) methyl) benzyl]
Thiazolidine-2,4-dione hydrochloride (Exemplary Compound No. 2-981) 5- [3- (3,4-Dimethoxybenzoyl) benzyl] thiazolidine-2,4-dione 5 of Example (43c)
00 mg and 1- (4-biphenyl) ethylamine 53
Using 1 mg, the reaction was carried out in the same manner as in Example (9d) and purified to obtain 274 mg of the title compound as a white solid. Melting point: 148 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65-1.80 (3H, m),
3.03-3.18 (1H, m), 3.36-3.46 (1H, m), 3.72 and 3.76
(total 3H, each s), 3.79 (3H, s), 4.10-4.20 (1H, m),
4.92-5.01 (1H, m), 5.07-5.13 (1H, m), 6.92-7.76 (16
H, m), 9.90-10.10 (1H, m), 10.60-10.80 (1H, m), 12.0
5-12.15 (1H, br.s).

Example 48 5- [3-((1- (3,4-difluorophenyl) ethylamino)-(3,4,5-trimethoxyphenyl)
Methyl) benzyl] thiazolidine-2,4-dione hydrochloride (Exemplified Compound No. 2-626) (48a) [3- (3,4,5-trimethoxybenzoyl) phenyl] -2-bromopropionic acid butyl ester 3- Using 1.32 g of amino-3 ', 4', 5'-trimethoxybenzophenone hydrochloride, the reaction was carried out in the same manner as in Example (9a), followed by purification to obtain 1.60 g of the title compound. NMR spectrum (CDCl ₃ ) δ ppm: 0.91 (3H, t, J = 7.4H)
z), 1.25-1.38 (2H, m), 1.56-1.63 (2H, m), 3.31 (1H, d
d, J = 7.6, 14.3Hz), 3.53 (1H, dd, J = 7.8, 14.3Hz), 3.
89 (6H, s), 3.95 (3H, s), 4.14 (2H, dt, J = 4.1, 6.6H
z), 4.44 (1H, t, J = 7.7Hz), 7.06 (2H, s), 7.45-7.46 (2
H, m), 7.65 (1H, s), 7.69-7.73 (1H, s).

(48b) 5- [3- (3,4,5-trimethoxybenzoyl) benzyl] -2-iminothiazolidin-4-one [3- (3,4,5-trimethoxy)] of Example (48a) [Methoxybenzoyl) phenyl] -2-bromopropionic acid butyl ester (1.59 g) was reacted and purified in the same manner as in Example (9b) to give the title compound as a white solid.
12 g were obtained. Melting point: 114-116 ° C NMR spectrum (CDCl ₃ ) δppm: 3.07 (1H, dd, J = 8.9,
14.1Hz), 3.43 (1H, dd, J = 4.4, 14.1Hz), 3.78 (3H, s),
3.83 (6H, s), 4.63-4.66 (1H, m), 7.01 (2H, s), 7.47-
7.65 (4H, m), 8.82 (2H, br.s).

(48c) 5- [3- (3,4,5-trimethoxybenzoyl) benzyl] thiazolidine-2,4
-Dione In the same manner as in Example (9c), using 1.10 g of 5- [3- (3,4,5-trimethoxybenzoyl) benzyl] -2-iminothiazolidine-4-one of Example (48b). React and purify the title compound as a white solid in 65%.
9 mg were obtained. Melting point: 161-163 ° C NMR spectrum (CDCl ₃ ) δ ppm: 3.26 (1H, dd, J = 9.3,
14.2Hz), 3.59 (1H, dd, J = 4.2, 14.1Hz), 3.89 (6H, s),
3.96 (3H, s), 4.58-4.61 (1H, m), 7.05 (2H, s), 7.44-
7.53 (2H, m), 7.72-7.75 (1H, s), 7.66 (1H, m), 8.36
(1H, br.s).

(48d) 5- [3-((1- (3,4-
Difluorophenyl) ethylamino)-(3,4,5-
Trimethoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione hydrochloride 567 mg of 5- [3- (3,4,5-trimethoxybenzoyl) benzyl] thiazolidine-2,4-dione of Example (48c), 1- (3,4-difluorophenyl)
The reaction was carried out in the same manner as in Example (9d) using 472 mg of ethylamine, and the residue was purified to give the title compound as a white solid.
59 mg were obtained. Melting point: 128-131 ° C (decomposition) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.71-1.72 (3H, br.
s), 3.02-3.17 (1H, m), 3.34-3.46 (1H, m), 3.60 and 3.
65 (total 3H, each s), 3.78 and 3.82 (total 6H, each
s), 4.13-4.31 (1H, br.m), 4.90-5.18 (2H, br.m), 7.1
0 (9H, br.s), 10.04-10.38 (1H, br.m), 10.71-11.06 (1
H, br.m), 12.11 (1H, br.s).

Example 49 5- [3-(((1R) -1-phenylethylamino)
-(3-Bromophenyl) methyl) benzyl] -thiazolidine-2,4-dione and its hydrochloride (Exemplary Compound No. 2-1231) (49a) 2-bromo-3- [3- (3-bromobenzoyl) phenyl ] Propionic acid butyl ester 3,3'-diaminobenzophenone 5.0 g and 47%
After dissolving 20.8 ml of hydrogen bromide in 100 ml of acetone, an aqueous solution of 3.4 g of sodium nitrite 30 was added under ice cooling.
Then, the mixture was stirred for 1 hour under ice cooling. After adding n-butyl acrylate to the reaction solution and stirring at room temperature for 30 minutes, 0.32 g of cuprous bromide was added and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water, neutralized with sodium hydrogen carbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 2).
0/1) to give 2.05 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 0.91 (3H, t, J = 7.4H)
z), 1.33 (2H, m), 1.55-1.69 (2H, m), 3.31 (1H, dd, J =
7.5, 14.2Hz), 3.53 (1H, dd, J = 7.8, 14.3Hz), 4.15 (2
H, m), 4.42 (1H, t, J = 7.6Hz), 7.35-7.93 (8H, m).

(49b) 2-imino-5- [3- (3-
Bromobenzoyl) benzyl] thiazolidine-4-one Using 3.42 g of butyl 2-bromo-3- [3- (3-bromobenzoyl) phenyl] propionate of Example (49a), React and purify similarly, 2.34 g of the title compound as a white solid
Obtained. NMR spectrum (DMSO-d ₆ ) δ ppm: 3.07 (1H, dd, J = 8.
9, 14.1Hz), 3.43 (1H, dd, J = 4.3, 14.1Hz), 4.63 (1H,
m), 7.47-7.91 (8H, m), 8.70 (1H, br.s), 8.94 (1H, br.
s).

(49c) 5- [3- (3-Bromobenzoyl) benzyl] thiazolidine-2,4-dione 2-imino-5- [3- (3-bromobenzoyl) benzyl] thiazolidine of Example (49b) -4-one 2.
Using 33 g, the reaction was carried out in the same manner as in Example (9c) and purification was performed to obtain 2.09 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 3.28 (1H, dd, J = 9.0,
14.1Hz), 3.57 (1H, dd, J = 4.2, 14.1Hz), 4.59 (1H, m),
7.37-7.81 (7H, m), 7.92 (1H, t, J = 1.5Hz), 8.23 (1H,
br.s).

(49d) 5- [3-(((1R) -1-
Phenyl) ethylamino)-(3-bromophenyl) methyl) benzyl] -thiazolidine-2,4-dione and its hydrochloride 5- [3- (3-bromobenzoyl) benzyl] thiazolidine-2 of Example (49c) , 4-dione 500m
g and (R) -1-phenylethylamine 0.33 ml
And purified in the same manner as in Example (9d) to give a free form of the title compound as a pale yellow oily substance. 4N hydrogen chloride in ethyl acetate solution of this free form
After mixing the ethyl acetate solution, the solvent was distilled off under reduced pressure,
110 mg of the hydrochloride salt of the title compound was obtained as a white solid. Melting point: 136-139 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.60-1.80 (3H, m),
3.06-3.18 (1H, m), 3.35-3.47 (1H, m), 4.02-4.09 (1H,
m), 4.89-4.95 (1H, m), 5.05-5.36 (1H, m), 7.25-7.93
(13H, m), 10.0-10.25 (1H, m), 10.5-10.9 (1H, m), 12.
1 (1H, br.s).

Example 50 5- [3-((1- (3,4-difluorophenyl) ethylamino)-(4-fluorophenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (exemplified) Compound No. 2-553) (50a) 2-bromo-3- [3- (4-fluorobenzoyl) phenyl] propionic acid butyl ester 3-amino-4′-fluorobenzophenone 11.5 g
And purified in the same manner as in Example (9a) to obtain 19.2 g of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 0.90 (3H, t, J = 7.3H)
z), 1.33 (2H, m), 1.55-1.63 (2H, m), 3.31 (1H, dd, J =
7.5, 14.3Hz), 3.52 (1H, dd, J = 7.8, 14.2Hz), 4.14 (2
H, m), 4.42 (1H, t, J = 7.5Hz), 7.17 (2H, q, J = 8.7Hz),
7.42-7.48 (2H, m), 7.63 (1H, s), 7.67 (1H, dd, J = 2.2,
6.5Hz), 7.84 (2H, dd, J = 5.5, 8.9Hz).

(50b) 2-imino-5- [3- (4-
Fluorobenzoyl) benzyl] thiazolidine-4-one Using 19.1 g of butyl 2-bromo-3- [3- (4-fluorobenzoyl) phenyl] propionate of Example (50a), the procedure of Example 9b was followed. React and purify in the same manner to give 9.44 g of the title compound as a white solid.
Obtained. NMR spectrum (DMSO-d ₆ ) δ ppm: 3.09 (1H, dd, J = 8.
6, 14.1Hz), 3.41 (1H, dd, J = 4.3, 14.0Hz), 4.64 (1H,
dd, J = 4.4, 8.6Hz), 7.41 (2H, q, J = 8.9Hz), 7.48-7.61
(4H, m), 7.83 (2H, dd, J = 2.0, 8.8Hz), 8.72 (1H, br.
s), 8.95 (1H, br.s).

(50c) 5- [3- (4-Fluorobenzoyl) benzyl] thiazolidine-2,4-dione 2-Imino-5- [3- (4-fluorobenzoyl) benzyl] thiazolidine of Example (50b) Using 9.40 g of -4-one, the reaction was carried out in the same manner as in Example (9c), followed by purification to obtain 8.97 g of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.27 (1H, dd, J = 9.4,
14.2Hz), 3.57 (1H, dd, J = 4.0, 14.1Hz), 4.59 (1H, dd,
J = 3.8, 9.0Hz), 7.18 (2H, dd, J = 8.7, 8.7Hz), 7.47-7.
50 (2H, m), 7.65 (1H, s), 7.68-7.71 (1H, m), 7.82-7.8
6 (2H, m), 8.20 (1H, br.s).

(50d) 5- [3-((1- (3,4-
Difluorophenyl) ethylamino)-(4-fluorophenyl) methyl) benzyl] thiazolidine-2,4-
Dione and its hydrochloride 500 m of 5- [3- (4-fluorobenzoyl) benzyl] thiazolidine-2,4-dione of Example (50c)
g and 477 mg of 1- (3,4-difluorophenyl) ethylamine were reacted in the same manner as in Example (9d) and purified to obtain a free form of the title compound as a colorless foam. After a 4N hydrogen chloride-ethyl acetate solution was mixed with the ethyl acetate solution of the free form, the solvent was distilled off under reduced pressure to give the hydrochloride salt of the title compound as a white solid in 450 mL.
mg. Melting point: 134-137 ° C NMR spectrum (DMSO-d ₆ ) δppm: 1.60-1.80 (3H, m),
3.03-3.18 (1H, m), 3.30-3.50 (1H, m), 4.10-4.25 (1H, m
m), 4.91-4.96 (1H, m), 5.20-5.28 (1H, m), 7.05-7.81
(11H, m), 10.15-10.4 (1H, m), 10.75-11.00 (1H, m), 1
2.1 (1H, br.s).

Example 51 5- [3-(((1R) -1-phenylethylamino)
-Cyclohexylmethyl) benzylidene] thiazolidine-2,4-dione hydrochloride (Exemplified Compound No. 2-54) (51a) 3-[((1R) -1-phenylethylimino) -cyclohexylmethyl] benzoic acid methyl ester 3- Cyclohexylcarbonylbenzoic acid methyl ester 1.77 g, (R) -1-phenylethylamine 1.8
After 3 ml and 4.01 ml of triethylamine were dissolved in 10 ml of anhydrous methylene chloride, 10 ml of an anhydrous methylene chloride solution of 0.95 ml of titanium tetrachloride was added under ice cooling, followed by stirring at room temperature for 2 hours. Add absolute ethanol 2 to the reaction mixture.
5 ml and 1.90 g of sodium cyanoborohydride were added, and the mixture was heated under reflux for 2 hours. After diluting the reaction solution with ethyl acetate, the precipitated insoluble material was separated by filtration. The filtrate was washed with water and saturated saline and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (eluent: cyclohexane / ethyl acetate = 40/1) to give 1.95 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 0.8-2.1 (14H, m),
3.51-3.58 (1H, m), 3.91and 3.92 (total 3H, each s),
7.16-7.93 (9H, m).

(51b) 3-[((1R) -1-phenylethylamino) -cyclohexylmethyl) phenyl]
Methanol 1.95 g of 3-[((1R) -1-phenylethylimino) -cyclohexylmethyl] benzoic acid methyl ester of Example (51a) was added to 50 ml of anhydrous tetrahydrofuran.
After adding 8.4 ml of a 1M solution of lithium aluminum hydride in tetrahydrofuran under ice-cooling,
Stirred at 0 ° C. for 6 hours. The reaction solution was poured into ice water and extracted with ethyl acetate, and the combined organic layers were washed with saturated saline.
After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to give the title compound as a colorless oil (1.66 g).
Obtained. NMR spectrum (CDCl ₃ ) δ ppm: 0.8-2.1 (14H, m),
3.81-3.61 (2H, m), 4.64-4.71 (3H, m), 7.03-7.40 (9H,
m).

(51c) 3-[((1R) -1-phenyl-ethylamino) -cyclohexylmethyl] benzaldehyde 3-[((1R) -1-phenyl-) of Example (51b)
Using 1.66 g of [ethylamino) -cyclohexylmethyl) phenyl] methanol, the reaction was carried out in the same manner as in Example (1c), and silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 20/1 to 10 /
Separation and purification in 1), 680 mg of isomer A of the title compound as a yellow oil and 41 mg of isomer B as a yellow oil.
0 mg was obtained. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 0.80-1.80 (13H, m),
1.95-2.05 (1H, m), 3.49-3.59 (2H, m), 7.12-7.72 (9H,
m), 9.96 (1H, s). Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 0.70-2.05 (14H, m),
3.14 (1H, d, J = 7.5Hz), 3.36 (1H, q, J = 6.6Hz), 7.13-
7.89 (9H, m), 10.03 and 10.04 (total 1H, eachs).

(51d) 5- [3-(((1R) -1-
Phenylethylamino) -cyclohexylmethyl) benzylidene] thiazolidine-2,4-dione hydrochloride Using 670 mg of isomer A of 3-[((1R) -1-phenylethylamino) -cyclohexylmethyl] benzaldehyde of Example (51c). Then, the reaction was conducted and purified in the same manner as in Example (1d) to obtain 690 mg of isomer A of the title compound as a pale yellow solid. Isomer A Melting point: 178-181 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 0.60-1.30 (5H,
m), 1.50-1.75 (7H, m), 1.80-1.90 (1H, m), 2.10-2.25
(1H, m), 4.10-4.20 (2H, m), 7.30-7.65 (9H, m), 7.74
(1H, s), 9.15-9.55 (1H, br), 9.70-9.95 (1H, br), 12.
50-12.80 (1H, br).

In Example (51c), 3-[((1R) -1
-Phenylethylamino) -cyclohexylmethyl] benzaldehyde isomer B (410 mg) was reacted and purified in the same manner as in Example (1d) to give 25 mg of the title compound isomer B as a yellow solid. Isomer B Melting point: 165-168 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 0.60-2.10 (14H,
m), 3.55-3.65 (1H, m), 3.90-4.00 (1H, m), 7.28-7.80
(10H, m), 9.20-9.70 (1H, br), 9.90-10.30 (1H, br), 1
2.50-12.80 (1H, br).

Example 52 5- [3-(((1R) -1-phenylethylamino)
-Cyclohexylmethyl) benzyl] thiazolidine-
2,4-dione hydrochloride (Exemplary Compound No. 2-119)
2) (52a) 5- [3-(((1R) -1-phenylethylamino) -cyclohexylmethyl) benzylidene]-
3- (Triphenylmethyl) thiazolidine-2,4-dione 5- [3-(((1R) -1-phenylethylamino) -cyclohexylmethyl) benzylidene] of Example 51
Isomer A50 of thiazolidine-2,4-dione hydrochloride
Using 0 mg, the reaction was carried out and purified in the same manner as in Example (2a), to give Isomer A of the title compound as a white solid in 350 mg
mg. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 0.80-1.80 (13H, m),
1.91-2.01 (1H, m), 3.47-3.58 (2H, m), 7.11-7.39 (18
H, m), 7.46 (6H, d, J = 7.1 Hz), 7.73 (1H, s).

In Example 51, 5- [3-(((1R) -1)
-Phenylethylamino) -cyclohexylmethyl) benzylidene] thiazolidine-2,4-dione Hydrochloride isomer B is reacted with 187 mg in the same manner as in Example (2a) and purified to give the title compound isomer B 258 mg were obtained as a colorless foam. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 0.70-2.10 (14H, m),
3.05 (1H, d, J = 7.3Hz), 3.36 (1H, q, J = 6.6Hz), 7.12-
7.79 (25H, m).

(52b) 5- [3-(((1R) -1-
Phenylethylamino) -cyclohexylmethyl) benzyl] -3- (triphenylmethyl) thiazolidine-
2,4-dione 5- [3-(((1R) -1-phenylethylamino) -cyclohexylmethyl) benzylidene] -3- (triphenylmethyl) thiazolidine of Example (52a)
The reaction was carried out and purified in the same manner as in Example (2b) using isomer A of 2,4-dione (500 mg) to obtain 255 mg of the isomer A of the title compound as a colorless foam. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 0.80-1.78 (13H, m),
1.95-2.05 (1H, m), 2.89-2.99 (1H, m), 3.43-3.58 (3H,
m), 4.26-4.38 (1H, m), 7.01-7.32 (18H, m), 7.38 (6H,
m). 5- [3-(((1R) -1-phenylethylamino) -cyclohexylmethyl) benzylidene] -3- (triphenylmethyl) thiazolidine of Example (52a)
The reaction was carried out and purified in the same manner as in Example (2b) using 258 mg of 2,4-dione isomer B to obtain 100 mg of the title compound isomer B as a colorless oil. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 0.68-2.05 (14H, m),
2.97-3.06 (2H, m), 3.35-3.59 (2H, m), 4.39 (1H, dd,
J = 3.8, 10.0Hz), 6.97-7.39 (24H, m).

(52c) 5- [3-(((1R) -1-
Phenylethylamino) -cyclohexylmethyl) benzyl] thiazolidine-2,4-dione hydrochloride 5- [3-(((1R) -1-phenylethylamino) -cyclohexylmethyl) benzyl] -3 of Example (52b) -(Triphenylmethyl) thiazolidine-2,
Using 250 mg of isomer A of 4-dione, Example (2)
The reaction was carried out in the same manner as in c) and purification was carried out to obtain 90 mg of isomer A of the title compound as a white solid. Isomer A Melting point: 150-153 ° C. NMR spectrum (DMSO-d ₆ ) δ ppm: 0.67-1.24 (5H,
m), 1.46-1.85 (8H, m), 1.99-2.10 (1H, m), 3.17 (1H,
dd, J = 8.5, 14.1Hz), 3.32-3.42 (1H, m), 3.95-4.10 (2
H, m), 4.91 (1H, dd, J = 4.5, 8.5Hz), 7.22-7.40 (9H,
m), 9.10-9.50 (2H, br), 11.9-12.1 (1H, br).

In Example (52b), 5- [3-((((1
R) -1- (Phenylethylamino) -cyclohexylmethyl) benzyl] -3- (triphenylmethyl) thiazolidine-2,4-dione Isomer B (100 mg) was reacted and purified in the same manner as in Example (2c). Thus, 19 mg of isomer B of the title compound was obtained as a pale yellow solid. Isomer B Melting point: 138-141 ° C. NMR spectrum (DMSO-d ₆ ) δ ppm: 0.64-1.99 (14H,
m), 3.12-3.26 (1H, m), 3.35-3.48 (2H, m), 3.85-3.93
(1H, m), 4.86-4.97 (1H, m), 7.06-7.42 (9H, m), 9.10-
9.20 (1H, br), 9.70-9.80 (1H, br), 12.00-12.10 (1H, b
r).

Example 53 5- [3-(((1R) -1-cyclohexylethylamino) -cyclohexylmethyl) benzylidene] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2-1) (53a ) 3-[((1R) -1-cyclohexylethylimino) -cyclohexylmethyl] benzoic acid methyl ester Using 1.77 g of 3-cyclohexylcarbonylbenzoic acid methyl ester and 2.18 ml of (R) -1-cyclohexylethylamine, The reaction was conducted in the same manner as in Example (51a) and purified to give the title compound as a yellow oil (1.8).
5 g were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 0.75-2.30 (25H, m),
3.44-3.52 (1H, m), 3.91 and 3.96 (total 3H, each
s), 7.33-7.48 (2H, m), 7.88-7.90 (2H, m).

(53b) [3-(((1R) -1-cyclohexylethylamino) -cyclohexylmethyl) phenyl] methanol 3-[((1R) -1-cyclohexylethylimino) -cyclohexyl of Example (53a) Example 1 (51b) using 1.85 g of methyl] benzoic acid methyl ester
And purified to give 1.53 g of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 0.70-2.20 (26H, m),
3.41-3.48 (1H, m), 4.69-4.72 (2H, m), 7.16-7.40 (4H,
m).

(53c) 3-[((1R) -1-cyclohexylethylamino) -cyclohexylmethyl] benzaldehyde [3-(((1R) -1-cyclohexylethylamino) -cyclohexylmethyl) of Example (53b) [Phenyl] methanol was reacted and purified in the same manner as in Example (1c) using 1.53 g of silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate =
20/1 to 10/1) to give 780 mg of isomer A of the title compound as a yellow oil and 267 mg of isomer B as a yellow oil. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 0.80-1.80 (24H, m),
1.84-1.94 (1H, m), 2.05 (1H, m), 3.55 (1H, d, J = 7.0H
z), 7.46 (1H, dd, J = 7.3, 7.6Hz), 7.55 (1H, d, J = 7.5H
z), 7.72-7.75 (2H, m), 10.02 (1H, s). Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 0.73-1.80 (24H, m),
1.92-1.97 (1H, m), 2.26 (1H, m), 3.50 (1H, d, J = 7.0H
z), 7.46 (1H, dd, J = 7.4, 7.5Hz), 7.55 (1H, d, J = 7.7H
z), 7.72-7.76 (2H, m), 10.02 (1H, s).

(53d) 5- [3-(((1R) -1-
Cyclohexylethylamino) -cyclohexylmethyl) benzylidene] thiazolidine-2,4-dione and its hydrochloride Isomer A of 3-[((1R) -1-cyclohexylethylamino) -cyclohexylmethyl] benzaldehyde of Example (53c) A780 mg Example (1)
The reaction was carried out in the same manner as in d), and purification was performed to obtain 760 mg of the hydrochloride salt of the isomer A of the title compound as a yellow solid. Isomer A Melting point: 266-268 ° C. NMR spectrum (DMSO-d ₆ ) δ ppm: 0.65-1.85 (23H,
m), 2.01-2.25 (2H, m), 2.50-2.65 (1H, m), 4.24-4.35
(1H, m), 7.59-7.76 (5H, m), 8.60-8.85 (2H, br), 12.59
-12.77 (1H, br).

In Example (53c), 3-[((1R) -1
-Cyclohexylethylamino) -cyclohexylmethyl] benzaldehyde isomer B (260 mg)
The reaction was carried out and purified in the same manner as in Example (1d) to obtain 270 mg of a free form of isomer B of the title compound as a yellow solid. Isomer B Melting point: 99-102 ° C NMR spectrum (CDCl ₃ ) δ ppm: 0.81-1.82 (24H, m),
1.95-2.00 (1H, m), 2.31-2.39 (1H, m), 3.51 (1H, d, J
= 7.1Hz), 7.30-7.45 (3H, m), 7.51 (1H, s), 7.87 (1H,
s).

Example 54 5- [3-(((1R) -1-cyclohexyl-ethylamino) -cyclohexyl-methyl) -benzyl] -thiazolidine-2,4-dione hydrochloride (Exemplified Compound No. 2-179) (54a) 5- [3-(((1R) -1-cyclohexylethylamino) -cyclohexylmethyl) benzylidene] -3- (triphenylmethyl) thiazolidine-2,
4-Dione Using 580 mg of the isomer A of 5- [3-(((1R) -1-cyclohexylethylamino) -cyclohexylmethyl) benzylidene] thiazolidine-2,4-dione hydrochloride of Example 53, Example The reaction was carried out in the same manner as in 2a) and purification was performed to obtain 421 mg of isomer A of the title compound as a white solid. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 0.77-1.78 (24H, m),
1.87-1.92 (1H, m), 2.01-2.09 (1H, m), 3.47 (1H, d, J
= 6.8Hz), 7.17-7.39 (13H, m), 7.45-7.48 (6H, m), 7.77
(1H, s).

In Example 53, 5- [3-(((1R) -1)
-Cyclohexylethylamino) -cyclohexylmethyl) benzylidene] thiazolidine-2,4-dione isomer B was reacted and purified in the same manner as in Example (2a) using 156 mg of isomer B to give isomer B of the title compound in pale yellow color 230 mg were obtained as a foam. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 0.71-1.78 (24H, m),
1.80-1.94 (1H, m), 2.21-2.30 (1H, m), 3.43 (1H, d, J
= 6.8Hz), 7.17-7.48 (19H, m), 7.77 (1H, s).

(54b) 5- [3-(((1R) -1-
Cyclohexylethylamino) -cyclohexylmethyl) benzyl] -3- (triphenylmethyl) thiazolidine-2,4-dione 5- [3-(((1R) -1-cyclohexylethylamino) -cyclohexyl of Example (54a)) Methyl) benzylidene] -3- (triphenylmethyl) thiazolidine-2,4-dione isomer A was reacted in the same manner as in Example (2b) using 410 mg of isomer A, and purified to give isomer A of the title compound in colorless form. 310 mg were obtained as a foam. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 0.77-1.78 (24H, m),
1.89-1.94 (1H, m), 2.05-2.09 (1H, m), 2.96 (1H, dd,
J = 10.6, 13.8Hz), 3.41 (1H, d, J = 7.1Hz), 3.56 (1H, d
d, J = 10.5, 13.8Hz), 4.08-4.42 (1H, m), 7.00-7.41 (19
H, m). The 5- [3-(((1R) -1-cyclohexylethylamino) -cyclohexylmethyl)-of Example (54a)
Benzylidene] -3- (triphenylmethyl) thiazolidine-2,4-dione isomer B (230 mg) was reacted in the same manner as in Example (2b) and purified to give the title compound isomer B as a colorless foam 90 mg was obtained. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 0.72-1.78 (24H, m),
1.90-2.01 (1H, m), 2.20-2.30 (1H, m), 2.95-3.10 (1H, m
m), 3.30-3.40 (1H, m), 3.55-3.65 (1H, m), 4.35-4.45
(1H, m), 7.00-7.40 (19H, m).

(54c) 5- [3-(((1R) -1-
Cyclohexylethylamino) -cyclohexylmethyl) benzyl] thiazolidine-2,4-dione hydrochloride 5- [3-(((1R) -1-cyclohexylethylamino) -cyclohexylmethyl) benzyl] -3 of Example (54b) -(Triphenylmethyl) thiazolidine-
Using 300 mg of 2,4-dione isomer A, the reaction was carried out in the same manner as in Example (2c), followed by purification to obtain 114 mg of isomer A of the title compound as a pale yellow solid. Isomer A Melting point: 164-168 ° C. NMR spectrum (DMSO-d ₆ ) δ ppm: 0.65-1.69 (23H,
m), 1.99-2.05 (2H, m), 2.45-2.55 (1H, m), 3.10-3.29
(1H, m), 3.36-3.42 (1H, m), 4.13-4.18 (1H, m), 4.89-
4.95 (1H, m), 7.22-7.42 (4H, m), 8.30-8.51 (2H, br),
12.03 (1H, brs) 5- [3-(((1R) -1-cyclohexylethylamino) -cyclohexylmethyl) benzyl] -3- (triphenylmethyl) thiazolidine of Example (54b)
Using 90 mg of 2,4-dione isomer B, the reaction was carried out in the same manner as in Example (2c), followed by purification to obtain 13 mg of isomer B of the title compound as a pale yellow solid. Isomer B Melting point: 121 ° C. NMR spectrum (DMSO-d ₆ ) δ ppm: 0.74-1.79 (23H,
m), 1.89-2.07 (2H, m), 2.70-2.75 (1H, m), 3.11-3.43
(2H, m), 4.07-4.13 (1H, m), 4.88-4.94 (1H, m), 7.26-
7.45 (4H, m), 8.00-8.20 (1H, br), 8.70-8.90 (1H, br),
11.99-12.05 (1H, br).

Example 55 5- [3-(((1S) -1- (4-bromophenyl)
Ethylamino) -phenylmethyl) benzylidene] thiazolidine-2,4-dione (Exemplary Compound No. 2-19) (55a) 3-[((1S) -1- (4-bromophenyl) ethylamino) -phenylmethyl] Benzoic acid methyl ester Using 2.4 g of 3-benzoylbenzoic acid methyl ester and 4.0 g of (S) -1- (4-bromophenyl) ethylamine, reacted and purified in the same manner as in Example (1a). To give the isomer A of the title compound as a colorless oil.
27 g and 1.25 g of isomer B were obtained as a white powder. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J = 6.7H)
z), 3.61 (1H, q, J = 6.7Hz), 3.91 (3H, s), 4.64 (1H,
s), 7.11 (2H, d, J = 8.4Hz), 7.14-7.57 (10H, m), 7.92
(1H, d, J = 7.6 Hz), 7.99 (1H, s). Isomer B Melting point: 101-102 ° C. NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J = 6.7H)
z), 3.65 (1H, q, J = 6.7Hz), 3.89 (3H, s), 4.63 (1H,
s), 7.13 (2H, d, J = 8.4Hz), 7.20-7.50 (10H, m), 7.85
(1H, d, J = 7.7Hz), 7.99 (1H, s).

(55b) [3-(((1S) -1- (4
-Bromophenyl) ethylamino) -phenylmethyl)
Phenyl] methanol 1.27 g of isomer A of methyl 3-[((1S) -1- (4-bromophenyl) ethylamino) -phenylmethyl] benzoate of Example (55a) was dissolved in 12 ml of anhydrous tetrahydrofuran. Thereafter, 284 mg of sodium borohydride was added, and 2.4 ml of anhydrous methanol was added dropwise over 1 hour while heating and refluxing the reaction solution. 284 mg of sodium borohydride was added to the reaction solution, 2.4 ml of anhydrous methanol was added dropwise over 20 minutes, and the mixture was refluxed for 1 hour. After the same operation was repeated twice to complete the reaction, 5 ml of acetone was added and the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate, and insolubles were filtered off. After adding water to the filtrate and separating an organic layer, the aqueous layer was extracted with ethyl acetate. Wash the organic layer with saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 4 /
Separation and purification in 1) were performed to obtain 922 mg of isomer A of the title compound as a colorless oil. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J = 6.7H)
z), 3.64 (1H, q, J = 6.7Hz), 4.61 (1H, s), 4.68 (2H,
s), 7.10-7.35 (11H, m), 7.45 (2H, d, J = 8.1 Hz). 3-[((1S) -1- (4-bromophenyl) ethylamino)-of Example (55a) Phenylmethyl] benzoic acid methyl ester isomer B (1.25 g) was dissolved in anhydrous tetrahydrofuran (14 ml).
0 ml was added, and 1.63 g of calcium chloride was further added at 0 ° C., followed by stirring for 1 hour. Sodium borohydride 556
mg was added at 0 ° C., and the mixture was stirred at 0 ° C. for 30 minutes.
Stirred for hours. 1.63 g of calcium chloride was added again at 0 ° C., and the mixture was stirred for 10 minutes.
6 mg was added and left overnight. 0 to complete the reaction
1.63 g of calcium chloride was added at ℃, and after stirring for 10 minutes, 556 mg of sodium borohydride was added. After quenching the excess reagent by adding 5 ml of acetone, the reaction solution was diluted with ethyl acetate, and the insoluble matter was filtered off. Water was added to the filtrate, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 4/1) to give the isomer B of the title compound as a colorless oily substance in an amount of 1.05.
g was obtained. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J = 6.7H)
z), 3.64 (1H, q, J = 6.7Hz), 4.59 (1H, s), 4.63 (2H,
s), 7.13 (2H, d, J = 8.3Hz), 7.15-7.38 (9H, m), 7.44 (2
H, d, J = 8.3Hz).

(55c) 3- [phenyl-((1S)-
1- (4-Bromophenyl) -ethylamino) -methyl] -benzaldehyde [3-(((1S) -1- (4-bromophenyl) ethylamino) -phenylmethyl) phenyl] methanol of Example (55b) Using 900 mg of isomer A of the above, the reaction was carried out in the same manner as in Example (1c), and purification was performed to obtain 635 mg of isomer A of the title compound as a colorless oil. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 3.61 (1H, q, J = 6.6Hz), 4.68 (1H, s), 7.08-8.00 (1
3H, m), 10.01 (1H, s). Isomer of [3-(((1S) -1- (4-bromophenyl) ethylamino) -phenylmethyl) phenyl] methanol of Example (55b) B1. The reaction was carried out in the same manner as in Example (1c) using 05 g and purified to obtain 670 mg of isomer B of the title compound as a colorless oil. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J = 6.6H)
z), 3.65 (1H, q, J = 6.6Hz), 4.64 (1H, s), 7.05-7.90 (1
3H, m), 9.95 (1H, s).

(55d) 5- [3-(((1S) -1-
(4-bromophenyl) ethylamino) -phenylmethyl) benzylidene] thiazolidine-2,4-dione 3-[((1S) -1- (4-bromophenyl) ethylamino) -phenylmethyl of Example (55c) Example (1) was prepared using 630 mg of isomer A of benzaldehyde.
The reaction was carried out in the same manner as in d), and purification was performed to obtain 768 mg of isomer A of the title compound as a yellow oil. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J = 6.7H)
z), 3.63 (1H, q, J = 6.7Hz), 4.63 (1H, s), 7.04-7.58 (1
3H, m), 7.86 (1H, s). Using 650 mg of the isomer B of 3-[((1S) -1- (4-bromophenyl) ethylamino) -phenylmethyl] benzaldehyde of Example (55c), Example (1)
The reaction was carried out in the same manner as in d) and purification was performed to obtain 789 mg of isomer B of the title compound as a yellow oil. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (1H, d, J = 6.6H)
z), 3.66 (1H, q, J = 6.6Hz), 4.60 (1H, s), 7.10-7.50 (1
3H, m), 7.80 (1H, s).

Example 56 5- [3-(((1S) -1- (4-bromophenyl)
Ethylamino) -phenylmethyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplary Compound No. 2-539) (56a) 5- [3-(((1S) -1- (4-bromophenyl) Ethylamino) -phenylmethyl) benzylidene] -3- (triphenylmethyl) thiazolidine-
2,4-dione Isomer A75 of 5- [3-(((1S) -1- (4-bromophenyl) ethylamino) -phenylmethyl) benzylidene] thiazolidine-2,4-dione of Example 55
Using 7 mg, the reaction was carried out in the same manner as in Example (2a) and purified to give isomer A of the title compound as a colorless foam.
1 mg was obtained. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J = 6.8H)
z), 3.61 (1H, q, J = 6.8Hz), 4.59 (1H, s), 7.09-7.76 (2
9H, m). Isomer B67 of 5- [3-(((1S) -1- (4-bromophenyl) ethylamino) -phenylmethyl) benzylidene] thiazolidine-2,4-dione of Example 55
Using 6 mg, the reaction was carried out in the same manner as in Example (2a) and purification was carried out to give Isomer B of the title compound as a colorless foam.
8 mg were obtained. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.6H)
z), 3.64 (1H, q, J = 6.6Hz), 4.57 (1H, s), 7.07-7.68 (2
9H, m), 7.68 (1H, s).

(56b) 5- [3-(((1S) -1-
(4-Bromophenyl) ethylamino) -phenylmethyl) benzyl] -3- (triphenylmethyl) thiazolidine-2,4-dione 5- [3-(((1S) -1- ( 4
-Bromophenyl) ethylamino) -phenylmethyl)
Benzylidene] -3- (triphenylmethyl) thiazolidine-2,4-dione isomer A using 876 mg,
The reaction was conducted and purified in the same manner as in Example (2b) to give 208 mg of isomer A of the title compound as a colorless foam. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.28-1.36 (3H, m),
3.15-3.22 (1H, m), 3.45-3.64 (2H, m), 4.38-4.41 (1H, m
m), 4.55 (1H, d, J = 8.3 Hz), 7.03-7.47 (28H, m). The 5- [3-(((1S) -1- (4
-Bromophenyl) ethylamino) -phenylmethyl)
Benzylidene] -3- (triphenylmethyl) thiazolidine-2,4-dione isomer B using 875 mg,
The reaction was carried out and purified in the same manner as in Example (2b), to give 384 mg of isomer B of the title compound as a colorless foam. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, d, J = 6.6H)
z), 2.92-3.00 (1H, m), 3.48 (1H, dd, J = 3.7, 13.9Hz),
3.59-3.66 (1H, m), 4.29-4.35 (1H, m), 4.56 (1H, d, J =
3.9Hz), 7.00-7.46 (28H, m).

(56c) 5- [3-(((1S) -1-
(4-Bromophenyl) ethylamino) -phenylmethyl) benzyl] thiazolidine-2,4-dione and its hydrochloride 5- [3-(((1S) -1- (4
-Bromophenyl) ethylamino) -phenylmethyl)
Using 208 mg of the isomer A of benzyl] -3- (triphenylmethyl) thiazolidine-2,4-dione, the reaction was carried out in the same manner as in Example (2c), purification was carried out, and the free form of the isomer A of the title compound was obtained. 71 mg were obtained as a colorless oil.
After mixing a solution of 61 mg of this free compound in ethyl acetate and a 4N hydrogen chloride-ethyl acetate solution, the solvent was distilled off under reduced pressure to give the hydrochloride of isomer A of the title compound as a white powder.
0 mg was obtained. Isomer A Melting point: 157-159 ° C NMR spectrum (CDCl ₃ ) δ ppm: 1.33 (3H, br.s), 3.3
3-3.49 (1H, m), 3.63 (1H, br.s), 4.02-4.10 (1H, m),
4.73-4.90 (2H, m), 7.05-7.60 (12H, m), 7.93-7.96 (1H,
m). The 5- [3-(((1S) -1- (4
-Bromophenyl) ethylamino) -phenylmethyl)
Using 377 mg of the isomer B of benzyl] -3- (triphenylmethyl) thiazolidine-2,4-dione, the reaction was carried out in the same manner as in Example (2c) and purification was performed to obtain a free form of the isomer B of the title compound 195 mg were obtained as a white powder. Isomer B Melting point: 171-173 ° C. NMR spectrum (CDCl ₃ ) δ ppm: 1.34 (3H, d, J = 6.6H)
z), 3.09 (1H, dd, J = 9.6,14.0Hz), 3.45 (1H, dd, J = 3.
9, 14.0Hz), 3.61-3.68 (1H, m), 4.42-4.48 (1H, m), 4.
56 and 4.57 (total 1H, each s), 7.03-7.06 (1H, m),
7.12-7.36 (10H, m), 7.45 (2H, d, J = 8.2Hz).

Example 57 5- [3-(((1R) -1-cyclohexylethylamino) -phenylmethyl) benzylidene] thiazolidine-2,4-dione (Exemplary Compound No. 2-2) (57a) 3- [ ((1R) -1-cyclohexylethylamino) -phenylmethyl] benzoic acid methyl ester Example using 3.41 g of 3-benzoylbenzoic acid methyl ester and 3.62 g of (R) -1-cyclohexylethylamine. The reaction was carried out in the same manner as in 1a) and purification was carried out to obtain 4.97 g of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 0.92-1.49 (9H, m),
1.51-1.79 (5H, m), 2.31-2.45 (1H, m), 3.90 (3H, s),
5.01 (1H, s), 7.16-7.41 (6H, m), 7.61-7.69 (1H, m),
7.85-7.92 (1H, m), 8.08-8.12 (1H, m).

(57b) [3-(((1R) -1-cyclohexylethylamino) -phenylmethyl) phenyl] methanol 3- [phenyl-((1R) -1-) of Example (57a)
The reaction was carried out in the same manner as in Example (1b) using 4.97 g of cyclohexylethylamino) methyl] benzoic acid methyl ester, and purified to obtain 4.4 g of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.00 (3H, d, J = 6.2H)
z), 0.75-1.40 (6H, m), 1.56-1.76 (5H, m), 2.35-2.44
(1H, m), 4.66 (2H, s), 4.97 (1H, s), 7.16-7.64 (9H,
m).

(57c) 3- [phenyl-((1R)-
1-cyclohexylethylamino) methyl] benzaldehyde [3- (phenyl-((1R) -1) of Example (57b)
-Cyclohexylethylamino) methyl) phenyl] Using 4.4 g of methanol, the reaction was carried out and purified in the same manner as in Example (1c) to give 1.5 g of isomer A of the title compound as a colorless oil, and isomer B 1.9 g as a colorless oil
Obtained. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.03 (3H, d, J = 6.5H)
z), 0.78-1.85 (11H, m), 2.33-2.43 (1H, m), 5.06 (1H,
s), 7.19-7.59 (6H, m), 7.71-7.79 (2H, m), 7.96 (1H,
isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.01 (3H, d, J = 6.3H)
z), 1.00-2.00 (11H, m), 2.37-2.46 (1H, m), 5.05 (1H,
s), 7.19-7.90 (8H, m), 7.94 (1H, s), 10.07 (1H, s).

(57d) 5- [3- (phenyl-((1
R) -1-cyclohexylethylamino) methyl) benzylidene] thiazolidine-2,4-dione 3- [phenyl-((1R) -1-) of Example (57c)
Using 1.32 g of isomer A of cyclohexylethylamino) methyl] benzaldehyde, the reaction was carried out in the same manner as in Example (1d), followed by purification to obtain 1.16 g of isomer A of the title compound as a yellow foam. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.03 (3H, d, J = 6.5H)
z), 0.86-1.48 (6H, m), 1.58-1.78 (5H, m), 2.34-2.43
(1H, m), 5.01 (1H, s), 6.83-7.51 (8H, m), 7.61 (1H,
s), 7.84 (1H, s). The 3- [phenyl-((1R) -1-) of Example (57c).
Cyclohexylethylamino) methyl] benzaldehyde (800 mg) was reacted in the same manner as in Example (1d) and purified to obtain 940 mg of the title compound (Isomer B) as a yellow powder. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.03 (3H, d, J = 6.5H)
z), 0.77-1.41 (6H, m), 1.59-1.77 (5H, m), 2.39-2.48
(1H, m), 5.01 (1H, s), 7.05-7.63 (8H, m), 7.65 (1H,
s), 7.83 (1H, s).

Example 58 5- [3- (phenyl-((1R) -1-cyclohexylethylamino) methyl) benzyl] thiazolidine-
2,4-dione (Exemplified Compound No. 2-183) (58a) 5- [3- (phenyl-((1R) -1-cyclohexylethylamino) methyl) benzylidene]-
3- (Triphenylmethyl) thiazolidine-2,4-dione 5- [3- (phenyl-((1R) -1-) of Example 57
Cyclohexylethylamino) methyl) benzylidene]
Using 1.16 g of the thiazolidine-2,4-dione isomer A, the reaction was carried out in the same manner as in Example (2a), followed by purification.
1.82 g of isomer A of the title compound were obtained as a colorless foam. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.00 (3H, d, J = 6.5H)
z), 0.90-1.80 (11H, m), 2.31-2.39 (1H, m), 4.97 (1H,
s), 7.13-7.53 (24H, m), 7.73 (1H, s). 5- [3- (phenyl-((1R) -1-
Cyclohexylethylamino) methyl) benzylidene]
Using 566 mg of the isomer B of thiazolidine-2,4-dione, the reaction was carried out in the same manner as in Example (2a), followed by purification.
965 mg of isomer B of the title compound was obtained as a colorless foam. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 0.99 (3H, d, J = 6.5H)
z), 0.90-1.80 (11H, m), 2.36-2.45 (1H, m), 4.96 (1H,
s), 7.15-7.60 (24H, m), 7.73 (1H, s).

(58b) 5- [3- (phenyl-((1
R) -1-Cyclohexylethylamino) methyl) benzyl] -3- (triphenylmethyl) thiazolidine-
2,4-dione 5- [3- (phenyl-((1R)) of Example (58a)
-1-cyclohexylethylamino) methyl) benzylidene] -3- (triphenylmethyl) thiazolidine-
Using 1.82 g of isomer A of 2,4-dione, the reaction was carried out in the same manner as in Example (2b) and purification was carried out to obtain 1.64 g of isomer A of the title compound as a colorless foam. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.00 (3H, d, J = 6.5H)
z), 1.08-1.33 (6H, m), 1.56-1.75 (5H, m), 2.34-2.39
(1H, m), 2.90-2.95 (1H, m), 3.54-3.58 (1H, m), 4.33-
4.37 (1H, m), 4.94 (1H, m), 7.03-7.38 (24H, m). The 5- [3- (phenyl-((1R)) of Example (58a)
-1-cyclohexylethylamino) methyl) benzylidene] -3- (triphenylmethyl) thiazolidine-
Using 960 mg of 2,4-dione isomer B, the reaction was carried out in the same manner as in Example (2b) and purification was performed to obtain 508 mg of isomer B of the title compound as a colorless foam. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 0.83-1.43 (9H, m),
1.45-1.74 (5H, m), 2.34-2.41 (1H, m), 2.93-3.02 (1H,
m), 3.51-3.57 (1H, m), 4.35 (1H, dd, J = 3.8, 10.1Hz),
4.94 (1H, s), 6.98-7.38 (24H, m).

(58c) 5- [3- (phenyl-((1
R) -1-Cyclohexylethylamino) methyl) benzyl] thiazolidine-2,4-dione 5- [3- (phenyl-((1R)) of Example (58b)
-1-cyclohexylethylamino) methyl) benzyl] -3- (triphenylmethyl) thiazolidine-2,
Using 1.64 g of isomer A of 4-dione, Example (2)
The reaction was carried out in the same manner as in c) and purification was carried out to obtain 106 mg of a free form of isomer A of the title compound as a white powder. Isomer A Melting point: 125-128 ° C NMR spectrum (CDCl ₃ ) δppm: 1.01 (3H, d, J = 6.6H)
z), 0.86-1.26 (5H, m), 1.27-1.37 (1H, m), 1.62-1.77
(5H, m), 2.33-2.39 (1H, m), 3.12 (1H, dd, J = 9.7,14.0
Hz), 3.50 (1H, dd, J = 9.8, 14.0Hz), 4.49 (1H, dd, J =
4.1, 10.0Hz), 4.95 (1H, s), 7.05 (1H, d, J = 7.5Hz),
7.18-7.39 (8H, m). 5- (3- (phenyl-((1R)) of Example (58b)
-1-cyclohexylethylamino) methyl) benzyl] -3- (triphenylmethyl) thiazolidine-2,
Example 5 (500 mg) using isomer B of 4-dione (500 mg)
The reaction was carried out in the same manner as in c) and purification was carried out to obtain 248 mg of a free form of isomer B of the title compound as a white powder. Isomer B Melting point: 153-156 ° C. NMR spectrum (CDCl ₃ ) δ ppm: 1.00 (3H, d, J = 6.6H)
z), 0.83-1.27 (5H, m), 1.31-1.39 (1H, m), 1.65-1.75
(5H, m), 2.37-2.43 (1H, m), 3.11 (1H, dd, J = 9.7,14.0
Hz), 3.49 (1H, dd, J = 3.8, 14.0Hz), 4.48 (1H, dd, J =
3.8, 9.7Hz), 4.95 (1H, s), 7.05 (1H, d, J = 7.4Hz), 7.
19-7.38 (8H, m).

Example 59 5- [3-(((2R) -2-phenylpropionylamino) -phenylmethyl) benzyl] thiazolidine-
2,4-dione (Exemplified Compound No. 2-1325) (59a) 3- (bromo-phenylmethyl) benzoic acid methyl ester 1.2 g of 3- (hydroxy-phenylmethyl) benzoic acid methyl ester is dissolved in 20 ml of anhydrous dichloromethane. After that, 0.16 ml of phosphorus tribromide was added dropwise under ice cooling.
After stirring at room temperature for 1 hour, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (eluent: cyclohexane / ethyl acetate = 20/1) to give 990 mg of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 3.91 (3H, s), 6.30 (1
H, s), 7.28-7.45 (6H, m), 7.67 (1H, d, J = 7.8Hz), 7.9
6 (1H, d, J = 7.7Hz), 8.14 (1H, s).

(59b) 3- (azido-phenylmethyl) benzoic acid methyl ester 2.0 g of 3- (bromo-phenylmethyl) benzoic acid methyl ester of Example (59a) was dissolved in 50 ml of anhydrous N, N-dimethylformamide. After that, 469 mg of sodium azide was added at room temperature, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the title compound as a colorless oil.
7 g were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 3.91 (3H, s), 5.76 (1
H, s), 7.27-7.53 (7H, m), 7.96-8.02 (2H, m).

(59c) [3- (Azido-phenylmethyl) phenyl] methanol 1.7 g of 3- (azido-phenylmethyl) benzoic acid methyl ester of Example (59b) was dissolved in 10 ml of methanol and hydrogenated. 3.5 g of sodium borohydride was added at room temperature, and the reaction solution was stirred at 50 ° C. for 8 hours. The reaction solution was diluted with ethyl acetate, and the organic layer was washed with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 1.36 g of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 4.69 (2H, s), 5.72 (1
H, s), 7.23-7.40 (9H, m).

(59d) 3- (azido-phenylmethyl) benzaldehyde [3- (azido-phenylmethyl) of Example (59c)
Example 1 (1.
The reaction was carried out in the same manner as in c) and purification was carried out to obtain 920 mg of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 5.80 (1H, s), 7.29-
7.44 (5H, m), 7.49-7.62 (2H, m), 7.81-7.86 (2H, m), 1
0.01 (1H, s).

(59e) 5- [3- (Azido-phenylmethyl) benzylidene] thiazolidine-2,4-dione Example (1d) was prepared using 920 mg of 3- (azido-phenylmethyl) benzaldehyde of Example (59d). ) And purified to give 990 mg of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 5.76 (1H, s), 7.30-
7.65 (9H, m), 7.83 (1H, s), 8.38-8.51 (1H, br).

(59f) 5- [3- (azido-phenylmethyl) benzylidene] -3- (triphenylmethyl)
Thiazolidine-2,4-dione 5- [3- (azido-phenylmethyl) benzylidene] thiazolidine-2,4-dione of Example (59e) 98
Using 0 mg, the reaction was carried out in the same manner as in Example (2a), followed by purification to obtain 1.43 g of the title compound as a colorless foam. NMR spectrum (CDCl ₃ ) δ ppm: 5.72 (1H, s), 7.17-
7.46 (24H, m), 7.71 (1H, s).

(59 g) 5- [3- (azido-phenylmethyl) benzyl] -3- (triphenylmethyl) thiazolidine-2,4-dione 5- [3- (azido-phenylmethyl) of Example (59f) ) Benzylidene] -3- (triphenylmethyl) thiazolidine-2,4-dione, 1.43 g, reacted in the same manner as in Example (2b), and purified to obtain 380 mg of the title compound as a colorless foam. Was. NMR spectrum (CDCl ₃ ) δ ppm: 2.95-3.10 (1H, m),
3.48-3.56 (1H, m), 4.35-4.41 (1H, m), 5.69 (1H, s),
7.10-7.40 (24H, m).

(59h) 5- [3- (Amino-phenylmethyl) benzyl] -3- (triphenylmethyl) thiazolidine-2,4-dione 5- [3- (azido-phenylmethyl) of Example (59 g) ) Benzyl] -3- (triphenylmethyl) thiazolidine-2,4-dione (203 mg) was dissolved in tetrahydrofuran (5 ml), water (0.1 ml) and triphenylphosphine (110 mg) were added at room temperature, and the mixture was stirred for 2 days. The solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by silica gel column chromatography (elution solvent: ethyl acetate) to obtain 65 mg of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 2.96-3.06 (1H, m),
3.57 (1H, dd, J = 3.9, 13.9Hz), 4.37 (1H, dd, J = 3.8,
9.8Hz), 5.19 (1H, s), 7.05 (1H, d, J = 7.0Hz), 7.09-7.
71 (23H, m).

(59i) 5- [3-(((2R) -2-
Phenylpropionylamino) -phenylmethyl) benzyl] -3- (triphenylmethyl) thiazolidine-
0.48 ml of 2,4-dione (R) -2-phenylpropionic acid and 0.92 ml of oxalyl chloride were mixed in 1 ml of dichloromethane to prepare an acid chloride. This solution was prepared in Example (59).
h) 5- [3- (amino-phenylmethyl) benzyl] -3- (triphenylmethyl) thiazolidine-2,
To a solution of 60 mg of 4-dione in 2 ml of anhydrous pyridine was added dropwise under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Ethyl acetate 1
The mixture was diluted to 00 ml, and the organic layer was washed with an aqueous citric acid solution, a saturated aqueous sodium bicarbonate solution, and a saturated saline solution. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (eluent: cyclohexane / ethyl acetate = 4/1) to obtain 80 mg of the title compound as a pale yellow foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.53 (3H, J = 6.6 Hz),
2.61-3.02 (1H, m), 3.43-3.68 (2H, m), 4.15-4.35 (1H,
m), 5.82-5.87 (1H, m), 6.18 and 6.21 (total 1H, each
s), 6.73-7.41 (29H, m).

(59j) 5- [3-(((2R) -2-phenylpropionylamino) -phenylmethyl) benzyl] thiazolidine-2,4-dione 5- [3-((( 2R) -2-phenylpropionylamino) -phenylmethyl) benzyl] -3- (triphenylmethyl) thiazolidine-2,
Using 80 mg of 4-dione, the reaction was carried out in the same manner as in Example (2c) and the compound was purified to give the title compound as a pale yellow solid (1).
5 mg were obtained. Melting point: 65-68 ° C NMR spectrum (CDCl ₃ ) δ ppm: 1.52-1.56 (3H, m),
2.96-3.20 (1H, m), 3.29-3.42 (1H, m), 3.59-3.71 (1H, m
m), 4.31-4.48 (1H, m), 5.77-5.90 (1H, m), 6.12-6.18
(1H, m), 6.79-7.41 (14H, m), 7.95-8.10 (1h, br).

Example 60 5- [3-(((1R) -1-phenylethyloxy)
-Phenylmethyl) benzylidene] thiazolidine-2,
4-Dione (Exemplified Compound No. 2-58) (60a) 3-[((1R) -1-phenylethyloxy) -phenylmethyl] benzoic acid methyl ester 55% sodium hydride 157 mg in anhydrous N, N-dimethylformamide After dissolving in 20 ml, under ice cooling,
0.44 ml of (R) -1-phenylethyl alcohol was added dropwise, and the mixture was stirred at room temperature for 1 hour. Example (59)
5 ml of a solution of 1.0 g of 3- (bromo-phenylmethyl) benzoic acid methyl ester of a) in anhydrous N, N-dimethylformamide was added dropwise under ice-cooling. The reaction was left at 0 ° C. for 30 minutes,
The mixture was further stirred at room temperature for 1 hour. The reaction solution was poured into 50 ml of water and extracted with ethyl acetate. The ethyl acetate layer was washed with 3N-hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 20/1 to 10 /
1) to give the title compound and by-product 3-[((1
R) -1-Phenylethyloxy) -phenylmethyl]
320 mg of a mixture of benzoic acid- (1R) -1-phenylethyl ester (title compound / by-product = 6 / 3.5) was obtained as a colorless oil. NMR spectrum (CDCl ₃ ) δppm of the title compound of Example (60a): 1.49 (3H, d, J = 6.5H)
z), 3.88 and 3.91 (total 3H, each s), 4.39-4.49 (1H,
m), 5.27 and 5.32 (total 1H, each s), 7.18-8.07 (14
H, m). By-product NMR spectrum (CDCl ₃ ) δ ppm: 1.48-1.54 (3H, m),
1.62-1.69 (3H, m), 4.33-4.44 (1H, m), 5.27-5.32 (1H,
m), 6.05-6.15 (1H, m), 7.18-8.07 (19H, m).

(60b) 3-[((1R) -1-phenylethyloxy) -phenylmethyl] -phenyl-methanol 3- [1-((1R) -1-phenylethyloxy) of Example (60a) -Phenylmethyl] benzoic acid methyl ester and by-product 3- [1-((1R) -1-phenylethyloxy) -phenylmethyl] -benzoic acid-
The reaction was carried out in the same manner as in Example (1b) using 320 mg of a mixture of (1R) -1-phenylethyl ester (ratio = 6 / 3.5), followed by purification to obtain 203 mg of the title compound as a colorless oil. . NMR spectrum (CDCl ₃ ) δ ppm: 1.48 (3H, d, J = 6.5H
z), 4.42-4.48 (1H, m), 4.62 (1H, d, J = 5.8Hz), 4.69 (1
H, d, J = 5.6Hz), 5.25 and 5.27 (total 1H, eachs), 7.
17-7.52 (14H, m).

(60c) 3-[((1R) -1-phenylethyloxy) -phenylmethyl] -benzaldehyde [3-(((1R) -1-phenylethyloxy) -phenylmethyl) of Example (60b) ) Phenyl] methanol was reacted and purified in the same manner as in Example (1c) using 1.17 g of the title compound to give the title compound as a yellow oil (513 m).
g was obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.50 and 1.51 (total
3H, each d, J = 6.5, 6.4Hz), 4.43-4.47 (1H, m), 5.28
and 5.36 (total 1H, each s), 7.22-7.86 (12H, m), 7.9
7 (2H, d, J = 7.1Hz), 9.96 and 10.02 (total 1H, each
s).

(60d) 5- [3-(((1R) -1-
Phenylethyloxy) -phenylmethyl) benzylidene] thiazolidine-2,4-dione 3-[((1R) -1-phenylethyl-oxy) -phenylmethyl] benzaldehyde 5 of Example (60c)
The reaction was carried out in the same manner as in Example (1d) using 10 mg,
Purification provided 375 mg of the title compound as a yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.49-1.53 (3H, m),
4.43-4.49 (1H, m), 5.25and 5.31 (total 1H, each s),
7.20-7.53 (14H, m), 7.81 and 7.87 (total 1H, each
s), 8.34 (1H, br) IR spectrum (KBr) ν (cm ^-1 ): 1745 (s), 1610 (m),
1331 (m), 701 (m).

Example 61 5- [3-(((1R) -1-phenylethyloxy)
-Phenylmethyl) benzyl] thiazolidine-2,4-
Dione (Exemplified Compound No. 2-1323) 900 mg of 5- [3-(((1R) -1-phenylethyloxy) -phenylmethyl) benzylidene] thiazolidine-2,4-dione of Example 60, sodium borohydride 5 0.57 g and 1.71 ml of acetic acid were dissolved in 170 ml of anhydrous ethanol solution, and the mixture was refluxed for 48 hours.
The solvent was distilled off under reduced pressure, and the residue was diluted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by reversed-phase silica gel thin-layer chromatography (eluent: acetonitrile / water = 2/1).
75 mg of the title compound were obtained as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.48-1.51 (3H, m),
3.04-3.23 (1H, m), 3.43-3.54 (1H, m), 4.40-4.55 (2H,
m), 5.23-5.24 (1H, m), 7.04-7.40 (14H, m), 7.89 (1H,
br). IR spectrum (KBr) ν (cm ^-1 ): 1755 (m), 1694 (s),
1328 (m), 1156 (m), 1086 (m), 701 (m).

Example 62 5- [3-(((1R) -1-phenylethyloxy)
-Phenylmethyl) benzylidene] -2-thioxothiazolidine-4-one (Exemplary Compound No. 2-91) 3-[((1R) -1-phenylethyloxy) -phenylmethyl] benzaldehyde 72 of Example (60c)
6 mg, 631 mg of rhodanin, 0.036 ml of acetic acid and 0.063 ml of piperidine were dissolved in 20 ml of anhydrous toluene, and the mixture was refluxed for 3 hours. The reaction solution was diluted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 10 /
1-2 / 1) to give 500 mg of the title compound as a yellow foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.50-1.54 (3H, m),
4.43-4.49 (1H, m), 5.26and 5.32 (total 1H, each s),
7.20-7.51 (14H, m), 7.63 and 7.69 (total 1H, each
s), 9.57 (1H, br) IR spectrum (KBr) ν (cm ^-1 ): 1726 (m), 1699 (s),
1602 (m), 1435 (s), 1204 (s), 1070 (m), 701 (s).

Example 63 5- [3-(((1R) -1-phenylethyloxy)
-Phenylmethyl) benzyl] -2-thioxothiazolidine-4-one (Exemplified Compound No. 2-2389) 5- [3-(((1R) -1-phenylethyloxy) -phenylmethyl) benzylidene of Example 62 ] -2-
Using 300 mg of thioxothiazolidine-4-one,
The reaction was carried out and purified in the same manner as in Example (2b) to give 279 mg of the title compound as a yellow foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.48-1.51 (3H, m),
3.08-3.28 (1H, m), 3.42-3.50 (1H, m), 4.40-4.63 (2H,
m), 5.23-5.24 (1H, m), 7.03-7.40 (14H, m), 8.80 (1H,
br). IR spectrum (KBr) ν (cm ^-1 ): 1735 (s), 1437 (s),
1218 (s), 1186 (s), 1075 (s), 701 (s).

Example 64 5- [3-((1- (2-thienyl) ethylamino)-
(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2-1027) 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine of Example (10c) 1 g of 2,4-dione and 949 mg of 1- (2-thienyl) ethylamine hydrochloride
And purified in the same manner as in Example (9d) using
656 mg of the free form of the title compound as a pale yellow foam
Obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.48 (3H, d, J = 6.6H)
z), 3.01-3.20 (1H, m), 3.44-3.72 (1H, m), 3.75 and
3.80 (total 3H, each s), 3.88-3.98 (1H, m), 4.44-4.5
5 (1H, m), 4.76 (1H, s), 6.78-7.29 (11H, m). This free form was treated with hydrogen chloride-ethyl acetate solution,
551 mg of the hydrochloride of the title compound was obtained as a white solid. Mp: 187-189 ° C. NMR Spectrum _{(DMSO-d 6) δppm:} 1.63-1.81 (3H, m),
3.02-3.20 (1H, m), 3.28-3.70 (1H, m), 3.73 and 3.76
(total 3H, each s), 4.40-4.48 (1H, m), 4.92-4.99 (1
H, m), 5.05-5.19 (1H, m), 6.94-7.82 (11H, m).

Example 65 5- [3-((1- (4-pyridyl) ethylamino)-
(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplary Compound No. 2-1106) 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine- of Example (10c) The reaction was purified in the same manner as in Example (9d) using 1 g of 2,4-dione and 709 mg of 1- (4-pyridyl) ethylamine to obtain 559 mg of a free form of the title compound as a white foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 3.01-3.52 (1H, m), 3.58-3.71 (1H, m), 3.76 and
3.81 (total 3H, each s), 4.42-4.56 (2H, m), 6.80 (1H,
d, J = 8.5Hz), 6.87 (1H, d, J = 8.5Hz), 7.05-7.32 (8H,
m), 8.56 (2H, d, J = 4.9Hz). This free form is treated with hydrogen chloride-ethyl acetate solution,
369 mg of the hydrochloride salt of the title compound was obtained as a white solid. Mp: 161-163 ° C. NMR Spectrum _{(DMSO-d 6) δppm:} 1.70 (3H, d, J = 5.6
Hz), 3.02-3.16 (1H, m), 3.36-3.44 (1H, m), 3.73 and
3.76 (total 3H, each s), 4.31-4.32 (1H, m), 4.91-4.9
8 (1H, m), 5.23 (1H, br.s), 6.90-6.99 (2H, m), 7.20-
7.40 (2H, m), 7.55-7.69 (4H, m), 7.81-7.88 (2H, m),
8.82-8.86 (2H, m).

Example 66 5- [3-(((1R) -1- (2-naphthyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride ( Exemplified Compound No. 2-1011) 1 g of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione of Example (10c) and 1- (1R)-(2-naphthyl) ethylamine 993
The same reaction as in Example (9d) was carried out and purified using the mg compound to give a free form of the title compound as a white foam as a solid (729).
mg. NMR spectrum (CDCl ₃ ) δ ppm: 1.44 (3H, d, J = 6.7H
z), 3.03-3.19 (1H, m), 3.42-3.53 (1H, m), 3.73-3.86
(1H, m), 3.78 and 3.82 (total 3H, each s), 4.36-4.5
5 (1H, m), 4.58-4.60 (1H, m), 6.78 (1H, d, J = 8.5Hz),
6.89 (1H, d, J = 8.5Hz), 7.00-7.31 (6H, m), 7.42-7.52
(3H, m), 7.60 (1H, dd, J = 5.6, 15.5Hz), 7.79-7.86 (3
H, m). This free product was treated with a hydrogen chloride-ethyl acetate solution in the same manner to obtain 621 mg of the hydrochloride salt of the title compound as a white solid. Melting point: 155-157 ° C NMR spectrum (DMSO-d ₆ ) δppm: 1.71-1.77 (3H, b
r), 3.03-3.18 (1H, m), 3.25-3.43 (1H, m), 3.73 and
3.77 (total 3H, each s), 4.25 (1H, br.s), 4.89-4.96
(1H, m), 5.13-5.19 (1H, m), 6.94-7.00 (2H, m), 7.23-
8.03 (13H, m). Optical rotation: [α] _D ²⁴ = + 31.7 C = 1.0 EtOH.

Example 67 5- [3-(((1S) -1- (2-naphthyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride ( Exemplified Compound No. 2-1011) 1 g of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione of Example (10c) and 993 m of 1- (S)-(2-naphthyl) ethylamine
Using g, the reaction was carried out in the same manner as in Example (9d), followed by purification to obtain a free form of the title compound.

This free compound was treated with a hydrogen chloride-ethyl acetate solution in the same manner to obtain 453 mg of the hydrochloride as the title compound as a white solid. Melting point: 155-157 ° C. Optical rotation: [α] _D ²⁴ = −34.0 C = 1.0 EtOH.

Example 68 5- [3- (phenyl-((1S) -1-phenylethylamino) methyl) benzylidene] thiazolidine-2,
4-dione and its hydrochloride (Exemplary Compound No. 2-16
8) Using 10 g of 3-benzoylbenzoic acid methyl ester and 10.6 ml of (S) -1-phenylethylamine, reacted in the same manner as in Example 1 (a) -1 (d), purified and purified to give the title compound. 3.08 g of isomer A was obtained as a free form of a yellow foam, and 2.63 g of isomer B was obtained as a free form of a yellow foam.

Example 69 5- [3- (phenyl-((1R) -1-phenylethylamino) methyl) benzyl] thiazolidine-2,4-
Dione hydrochloride (Exemplified Compound No. 2-1321) 150 mg of isomer B of 5- [3- (phenyl-((1R) -1-phenylethylamino) methyl) benzyl] thiazolidine-2,4-dione of Example 2 A hydrogen chloride-ethyl acetate solution was added to 3 ml of the ethyl acetate solution, and the mixture was stirred to make the mixture uniform, and then the solvent was distilled off under reduced pressure. The precipitated white solid was further dried to obtain 165 mg of the title compound. Melting point: 200-205 ° C NMR spectrum (DMSO-d ₆ ) δppm: 1.69 (3H, d, J = 6.4)
Hz), 3.04-3.14 (1H, m), 3.35-3.50 (1H, m), 4.00-4.14
(1H, br), 4.91-4.97 (1H, m), 5.14-5.18 (1H, m), 7.20
-7.69 (14H, m).

Example 70 5- [3- (phenyl-((1R) -1-phenylethylamino) methyl) benzyl] thiazolidine-2,4-
Dione acetate (Exemplary Compound No. 2-1321) 150 mg of isomer B of 5- [3- (phenyl-((1R) -1-phenylethylamino) methyl) benzyl] thiazolidine-2,4-dione of Example 2 Acetic acid 24mg
The reaction was carried out in the same manner as in Example 69 and purified to obtain 176 mg of the title compound as a white solid. Melting point: 160-161 ° C. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.29 (3H, d, J = 6.7)
Hz), 1.91 (3H, s), 3.00-3.09 (1H, m), 3.20-3.40 (1H,
m), 3.47-3.53 (1H, m), 4.50 (1H, s), 4.80-4.88 (1H, b
r), 7.03-7.35 (14H, m).

Example 71 5- [3- (phenyl-((1R) -1-phenylethylamino) methyl) benzyl] thiazolidine-2,4-
Dione ascorbate (Exemplary Compound No. 2-132)
1) Example using 150 mg of isomer B of 5- [3- (phenyl-((1R) -1-phenylethylamino) methyl) benzyl] thiazolidine-2,4-dione of Example 2 and 63 mg of ascorbic acid. Reaction similar to 69,
Purification provided 213 mg of the title compound as a white solid. Melting point: 145-150 ° C (decomposition) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.31 (3H, d, J = 6.5)
Hz), 3.00-3.08 (1H, m), 3.16-3.60 (3H, m), 3.70-3.75
(1H, m), 4.53 (1H, br), 4.71 (1H, s), 4.81-4.93 (2H,
m), 7.05-7.40 (14H, m).

Example 72 5- [5-((1- (3,4-Difluorophenyl) ethylamino) -phenylmethyl) -2-methoxybenzyl] thiazolidine-2,4-dione and its hydrochloride (exemplary compound) No. 2-679) (72a) 3- (5-benzoyl-2-methoxyphenyl) -2-bromopropionic acid butyl ester 3-amino-4-methoxybenzophenone hydrochloride3.
The reaction was carried out in the same manner as in Example (9a) using 5 g to obtain 4.1 g of the title compound as a pale purple oil. NMR spectrum (CDCl ₃ ) δ ppm: 0.90 (3H, t, J = 7.3H)
z), 1.26-1.40 (2H, m), 1.56-1.62 (2H, m), 3.30 (1H, d
d, J = 7.7, 13.9Hz), 3.45 (1H, dd, J = 7.8, 13.9Hz), 3.
94 (3H, s), 4.13 (2H, m), 4.59 (1H, t, J = 7.9Hz), 6.94
(1H, d, J = 8.6 Hz), 7.46-7.88 (7H, m) (72b) 2-Imino-5- (5-benzoyl-2-methoxybenzyl) thiazolidine-4-one 3 of Example (72a) Using-(5-benzoyl-2-methoxyphenyl) -2-bromopropionic acid butyl ester (4.0 g), the reaction was conducted in the same manner as in Example (9b), and the title compound was purified as a white solid (2.2 g). Obtained. NMR spectrum (DMSO-d ₆ ) δ ppm: 2.80 (1H, dd, J = 1)
0.1, 14.0Hz), 3.54 (1H, dd, J = 4.3, 13.9Hz), 3.92 (3H,
s), 4.55 (1H, dd, J = 4.3, 10.2Hz), 7.16 (1H, d, J = 8.
7Hz), 7.54-7.71 (7H, m), 8.74 (1H, br.s), 9.00 (1H, b
rs).

(72c) 5- (5-Benzoyl-2-methoxybenzyl) thiazolidine-2,4-dione 2-Imino-5- (5-benzoyl-2-methoxybenzyl) thiazolidine-4 of Example (72b) -ON2.
Using 1 g, the reaction was carried out in the same manner as in Example (9c), followed by purification to obtain 1.8 g of the title compound as colorless crystals. NMR spectrum (DMSO-d ₆ ) δ ppm: 3.09 (1H, dd, J = 9.
5, 14.0Hz), 3.52 (1H, dd, J = 4.8, 13.9Hz), 3.91 (3H,
s), 4.87 (1H, dd, J = 4.7, 9.5Hz), 7.18 (1H, d, J = 8.7H
z), 7.54-7.74 (7H, m), 12.09 (1H, br.s).

(72d) 5- [5-((1- (3,4-
Difluorophenyl) ethylamino) -phenylmethyl) -2-methoxybenzyl] thiazolidine-2,4-
Dione hydrochloride 500 mg of 5- (5-benzoyl-2-methoxybenzyl) thiazolidine-2,4-dione of Example (72c)
Using 567 mg of 1- (3,4-difluorophenyl) ethylamine hydrochloride and 1- (3,4-difluorophenyl) ethylamine hydrochloride, the reaction was conducted in the same manner as in Example (9d) and purified to obtain a free form of the title compound as a colorless oily substance. To this ethyl acetate solution of the free form was added a 4N solution of hydrogen chloride in ethyl acetate, and the solvent was distilled off under reduced pressure.
g was obtained. Melting point: 190-194 ° C NMR spectrum (DMSO-d ₆ ) δppm: 1.60-1.80 (3H, m),
2.84-3.01 (1H, m), 3.42-3.52 (1H, m), 3.78, 3.80 an
d 3.81 (total 3H, each s), 4.16-4.22 (1H, m), 4.79-4.
89 (1H, m), 5.04 and 5.18 (total 1H, each br.s), 7.0
0-7.65 (11H, m), 10.11-10.22 (1H, m), 10.66-10.87 (1H,
m), 12.1 (1H, br.s).

Example 73 3- [3-(((1- (3,4-difluorophenyl)
Ethylamino)-(4-methoxyphenyl) methyl) phenyl) -4H- [1,2,4] oxadiazole-5
-One and its hydrochloride (Exemplified Compound No. 2-2509) (73a) 3-[(1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] benzonitrile 3-cyano-4 Using 1.0 g of '-methoxybenzophenone and 1.32 g of 1- (3,4-difluorophenyl) ethylamine, the reaction was carried out in the same manner as in Example (9d), and the title compound was purified as a yellow-green oily substance. .
50 g were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.33 and 1.34 (total
3H, each d, J = 6.8Hz), 3.57 and 3.64 (total 1H, each
q, J = 6.6Hz), 3.77 and 3.82 (total 3H, eachs), 4.52
and 4.58 (total 1H, each s), 6.80-7.54 (10H, m), 7.
63 and 7.69 (total 1H, each s).

(73b) 3-[(1- (3,4-Difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl] -N-hydroxybenzamidine 3-[(1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl)
8.62 g of [methyl] benzonitrile and 7.91 g of hydroxylamine hydrochloride in dimethyl sulfoxide 5
0 ml, triethylamine 16.2 ml was added, and 80 ml was added.
Stirred at C for 3 hours. The reaction was diluted with water and extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 9.52 g of the title compound as a pale green oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.32 (3H, d, J = 6.6H)
z), 3.63 (1H, m), 3.75 and 3.80 (total 3H, each s),
4.56 and 4.58 (total 1H, each s), 4.82 and 4.86 (tot
al 1H, each br s), 6.79 and 6.86 (total 2H, each d,
J = 8.7Hz), 6.88-6.96 (1H, m), 7.06-7.53 (7H, m), 7.5
8 (1H, s), 7.65-7.90 (1H, br). (73c) 3- [3-(((1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl)
Methyl) phenyl) -4H- [1,2,4] oxadiazol-5-one hydrochloride 3-[(1- (3,4-difluorophenyl) ethylamino)-(4- Methoxyphenyl)
To a solution of 1.0 g of [methyl] -N-hydroxybenzamidine and 0.22 ml of pyridine in 10 ml of anhydrous N, N-dimethylformamide was added dropwise 0.47 ml of 2-ethylhexyl chloroformate under ice cooling. After the dropwise addition, the mixture was stirred at 0 ° C for 1.5 hours, poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 40 ml of xylene,
Heated to reflux for an hour. After evaporating the solvent under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent: cyclohexane / ethyl acetate = 3 / 1-3 / 2) to obtain a free form of the title compound as an oil. A 4N hydrogen chloride-ethyl acetate solution was added to the ethyl acetate solution of the free compound, and the solvent was distilled off under reduced pressure to obtain 675 mg of the hydrochloride as the title compound as a yellow solid. Melting point: 145-149 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.60-1.80 (3H, m),
3.74 and 3.76 (total 3H, each s), 4.10-4.30 (1H,
m), 5.22 and 5.34 (total 1H, each br s), 6.95-7.00
(2H, m), 7.15-7.20 (1H, m), 7.44-7.79 (6H, m), 8.01-
8.12 (2H, m), 10.1-10.55 (1H, br), 10.65-11.05 (1H, b
r), 12.9-13.2 (1H, br).

Example 74 3- [3-(((1- (3,4-difluorophenyl)
Ethylamino)-(4-methoxyphenyl) methyl) phenyl) -4H- [1,2,4] thiadiazole-5
On and its hydrochloride (Exemplified Compound No. 2-2570) 3-[(1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) of Example (73b)
To a solution of 1.0 g of [methyl] -N-hydroxybenzamidine in 20 ml of anhydrous tetrahydrofuran was added 578 mg of 1,1'-thiocarbonyldiimidazole.
Stirred for hours. The reaction solution was diluted with ethyl acetate, washed with saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 20 ml of anhydrous tetrahydrofuran, 1.53 ml of boron trifluoride-diethyl ether complex was added, and the mixture was stirred at room temperature for 6 hours. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (eluent: cyclohexane / ethyl acetate = 3 / 1-5 / 2) to give the free form of the title compound as a yellow oil. A 4N hydrogen chloride-ethyl acetate solution was added to a diethyl ether solution of this free form, and the solvent was distilled off under reduced pressure to give the title compound hydrochloride as a yellow solid in 645 m
g was obtained. Mp: 194-197 ° C. NMR Spectrum _{(DMSO-d 6) δppm:} 1.60-1.80 (3H, m),
3.74 and 3.76 (total 3H, each s), 4.10-4.30 (1H,
m), 5.21 and 5.32 (total 1H, each br s), 6.94-7.00
(2H, m), 7.15-7.20 (1H, m), 7.44-7.63 (5H, m), 7.83-
8.00 (2H, m), 8.20 (1H, s), 10.1-10.5 (1H, br), 10.7-
11.0 (1H, br), 13.35-13.55 (1H, br).

Example 75 3- [3-(((1- (3,4-difluorophenyl)
Ethylamino)-(4-methoxyphenyl) methyl) phenyl) -4H- [1,2,4] oxadiazole-5
-Thione and its hydrochloride (Exemplary Compound No. 2-261)
8) 3-[(1- (3,4-Difluorophenyl) ethylamino)-(4-methoxyphenyl) of Example (74b)
Methyl] -N-hydroxybenzamidine 1.0 g,
A solution of 529 mg of 1,1'-thiocarbonyldiimidazole and 1.16 ml of 1,5-diazabicyclo [4.3.0] non-5-ene in 20 ml of acetonitrile was added at room temperature.
Stirred for 16 hours. The reaction solution was adjusted to pH 1 with dilute hydrochloric acid, and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 3 / 1-2)
/ 1), and reversed-phase silica gel column chromatography (elution solvent: acetonitrile / acetic acid buffer = 40 /
60 (acetic acid buffer; water: acetic acid: triethylamine = 1000: 2: 2 (volume ratio))) to obtain a free form of the title compound as a colorless oil. The ethyl acetate solution of the free form was washed with dilute hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was triturated from a mixed solvent of ethyl acetate-n-hexane to give the hydrochloride (95 mg) as the title compound as a white solid. Melting point: 132-134 ° C NMR spectrum (DMSO-d ₆ ) δppm: 1.60-1.75 (3H, m),
3.74 and 3.76 (total 3H, each s), 4.10-4.30 (1H,
m), 5.29 and 5.47 (total 1H, each br s), 6.98-7.03
(2H, m), 7.17-7.19 (1H, m), 7.46-7.60 (5H, m), 7.74-
7.87 (2H, m), 8.17-8.18 (1H, m), 9.90-10.5 (1H, br).

Example 76 5- [3- (Phenyl-((1S) -1-phenylethylamino) methyl) benzyl] thiazolidine-2,4-
Dione and its hydrochloride (Exemplified Compound No. 2-1321) 5- [3- (phenyl-((1S) -1-) of Example 68
Phenylethylamino) methyl) benzylidene] A reaction and purification were conducted in the same manner as in Examples (2a)-(2c) using 3.08 g of isomer A of thiazolidine-2,4-dione and 2.63 g of isomer B. 814 mg of isomer A of the title compound was obtained as a hydrochloride of a white solid, and 280 mg of isomer B was obtained as a free form of a white solid. Isomer A Optical rotation: [α] _D ^23.5 = +42.3 C = 1.0 EtOH Isomer B Optical rotation: [α] _D ²⁴ = -50.7 C = 1.0 EtOH.

Example 77 5- [3-(((1R) -1-phenylethylamino)
-(2-thienyl) methyl) benzyl] thiazolidine-
2,4-dione and its hydrochloride (Exemplary Compound No. 2-1)
292) (77a) 2-Bromo-3- [3- (2-thenoyl) phenyl] propionic acid butyl ester Using 7.06 g of 2- (3-aminobenzoyl) thiophene, the reaction was carried out in the same manner as in Example (9a). Purification gave 14.0 g of the title compound as a yellow liquid. NMR spectrum (CDCl ₃ ) δ ppm: 0.89 (3H, t, J = 7.4H
z), 1.28-1.37 (2H, m), 1.55-1.62 (2H, m), 3.33 (1H, d
d, J = 7.4, 14.2Hz), 3.54 (1H, dd, J = 8.0, 14.3Hz), 4.
09-4.19 (2H, m), 4.44 (1H, t, J = 7.7Hz), 7.17-7.20 (1
H, m), 7.40-7.52 (2H, m), 7.64-7.65 (1H, m), 7.68-7.
83 (3H, m).

(77b) 2-imino-5- [3- (2-
[Thenoyl) benzyl] thiazolidine-4-one 2-bromo-3- [3- (2-thenoyl) phenyl] propionic acid butyl ester of Example (77a) 14.0
Using g, the reaction was carried out in the same manner as in Example (9b) and purification was carried out to obtain 6.53 g of the title compound as a white solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 3.11 (1H, dd, J = 8.
6, 14.1Hz), 3.43 (1H, dd, J = 4.4, 14.1Hz), 4.67 (1H,
dd, J = 4.4, 8.6Hz), 7.29-7.31 (1H, m), 7.48-7.55 (2H,
m), 7.63-7.75 (3H, m), 8.13 (1H, d, J = 5.4Hz).

(77c) 5- [3- (2-Thenoyl) benzyl] thiazolidine-2,4-dione 2-imino-5- [3- (2-thenoyl) benzyl] thiazolidine-4 of Example (77b) Using 6.53 g of -one, the reaction was carried out in the same manner as in Example (9c), followed by purification to obtain 5.12 g of the title compound as a white solid. NMR spectrum (CDCl ₃ ) δ ppm: 3.27 (1H, dd, J = 9.4,
14.1Hz), 3.60 (1H, dd, J = 4.1, 14.2Hz), 4.60 (1H, dd,
J = 3.8, 9.5Hz), 7.18-7.20 (1H, m), 7.44-7.52 (2H,
m), 7.65-7.69 (1H, m), 7.74-7.78 (2H, m), 7.79-7.83
(1H, m).

(77d) 5- [3-(((1R) -1-
Phenylethylamino)-(2-thienyl) methyl)-
Benzyl] thiazolidine-2,4-dione and its hydrochloride 1.5 g of 5- [3- (2-thenoyl) benzyl] thiazolidine-2,4-dione of Example (77c) and (R)
The reaction was carried out in the same manner as in Example (9d) using 0.81 ml of -1-phenylethylamine, and purification was performed to obtain a free form of the title compound as a pale yellow foam. After mixing the ethyl acetate solution of the free form with a 4N hydrogen chloride-ethyl acetate solution, the solvent was distilled off under reduced pressure to obtain 905 mg of the hydrochloride as the title compound as a pale yellow solid. Melting point: 144-146 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.68 (3H, br.s), 3.
09-3.19 (1H, m), 3.25-3.45 (1H, m), 4.02-4.12 (1H, m
m), 4.89-4.97 (1H, m), 5.33-5.54 (1H, m), 7.08-7.70
(12H, m).

Example 78 5- [3-(((1R) -1-phenylethylamino)
-(4-pyridyl) methyl) benzyl] thiazolidine-
2,4-dione and its hydrochloride (Exemplary Compound No. 2-1)
304) (78a) 2-Bromo-3- (3-isonicotinoylphenyl) propionic acid butyl ester The reaction was carried out in the same manner as in Example (9a) using 6.0 g of 4- (3-aminobenzoyl) pyridine, and purified. Thus, 3.73 g of the title compound was obtained as a yellow liquid. NMR spectrum (CDCl ₃ ) δ ppm: 0.84-0.97 (3H, m), 1.
23-1.41 (2H, m), 1.50-1.63 (2H, m), 4.03-4.24 (2H, m
m), 4.42 (1H, t, J = 7.6Hz), 7.29-7.73 (4H, m), 7.77-
7.89 (2H, m), 8.82-8.92 (2H, m).

(78b) 2-Imino-5- (3-isonicotinoylbenzyl) thiazolidine-4-one butyl 2-bromo-3- (3-isonicotinoylphenyl) propionate of Example (78a) .73
Using g, the reaction was carried out in the same manner as in Example (9b) and purification was performed to obtain 1.09 g of the title compound as a white solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 3.09 (1H, dd, J = 8.
6, 1.41Hz), 3.42 (1H, dd, J = 4.4, 14.1Hz), 4.64 (1H,
dd, J = 4.4, 8.6Hz), 7.50-7.56 (1H, m), 7.59-7.62 (3H,
m), 7.65-7.67 (2H, m), 8.82-8.84 (2H, m).

(78c) 5- (3-Isonicotinoylbenzyl) thiazolidine-2,4-dione 2-Imino-5- (3-isonicotinoylbenzyl) thiazolidine-4-one of Example (78b) The reaction was carried out in the same manner as in Example (9c) using 09 g, and purified to give 1.12 g of the title compound as a white solid. NMR spectrum (DMSO-d ₆ ) δ ppm: 2.89 (1H, dd, J = 9.
5, 13.9Hz), 3.39 (1H, dd, J = 3.8, 13.9Hz), 4.22 (1H,
dd, J = 3.8, 9.5Hz), 7.47-7.51 (2H, m), 7.56-7.63 (4H,
m), 8.80-8.82 (2H, m).

(78d) 5- [3-(((1R) -1-
Phenylethylamino)-(4-pyridyl) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride 500 mg of 5- (3-isonicotinoylbenzyl) thiazolidine-2,4-dione of Example (78c) and The reaction was carried out in the same manner as in Example (9d) using 0.48 ml of (R) -1-phenylethylamine, followed by purification to obtain a free form of the title compound as a pale yellow foam. After mixing an ethyl acetate solution of this free form with a 4 N hydrogen chloride-ethyl acetate solution, the solvent was distilled off under reduced pressure to obtain 81 mg of the hydrochloride as the title compound as a pale yellow solid. Melting point: 142-145 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.65-1.77 (3H, m),
3.04-3.19 (1H, m), 3.35-3.45 (1H, m), 3.99-4.26 (1H,
m), 4.87-4.99 (1H, m), 5.24-5.38 (1H, m), 7.24-7.71
(9H, m), 7.88-7.99 (2H, m), 8.67-8.80 (2H, m).

Example 79 5- [3-((4-methoxyphenyl)-((1R) -1]
-Phenylethylamino) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2-1251) Example (79a) 3-[(4-methoxyphenyl)-
((1R) -1-phenylethylamino) methyl] benzoic acid ethyl ester Using 3.58 g of 3- (4-methoxybenzoyl) benzoic acid ethyl ester and 3.2 ml of (R) -1-phenylethylamine, Purified by reacting in the same manner as in Example (1a) to give the title compound as a pale yellow oil.
57 g were obtained. NMR spectrum (CDCl ₃ ) δ ppm: 1.34-1.41 (6H, m),
3.60-3.69 (1H, m), 3.75and 3.80 (total 3H, each s),
4.32-4.40 (2H, m), 4.631 and 4.636 (total 1H, each
s), 6.77-6.88 (2H, m), 7.15-7.83 (9H, m), 7.84-8.00
(2H, m).

(79b) [3-((4-Methoxyphenyl)-((1R) -1-phenylethylamino) methyl) phenyl] methanol 3-[(4-methoxyphenyl) -methanol of Example (79a)
Using 4.57 g of ((1R) -1-phenylethylamino) methyl] benzoic acid ethyl ester, Example (1)
The reaction was carried out in the same manner as in b) and purification was carried out to obtain 3.72 g of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 6.6H)
z), 3.61-3.68 (1H, m), 3.74 and 3.49 (total 3H, each
s), 4.58 and 4.60 (total 2H, each s), 4.66 (1H, s),
6.76-6.87 (2H, m), 7.16-7.34 (11H, m).

(79c) 3-[(4-methoxyphenyl)-((1R) -1-phenylethylamino) methyl] benzaldehyde [3-((4-methoxyphenyl)] of Example (79b)
-((1R) -1-phenylethylamino) methyl) phenyl] methanol (3.72 g) was used to prepare Example (1).
The reaction was carried out in the same manner as in c) and purification was carried out to obtain 3.11 g of the title compound as a pale yellow oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.36-1.39 (3H, m),
3.57-3.73 (1H, m), 3.75and 3.80 (total 3H, each s),
4.63 and 4.66 (total 1H, each s), 6.77-6.89 (2H, m),
7.15-7.88 (11H, m), 9.95 and 10.00 (total 1H, each
s).

(79d) 5- [3-((4-methoxyphenyl)-((1R) -1-phenylethylamino) methyl) benzylidene] thiazolidine-2,4-dione 3- [of Example (79c) (4-methoxyphenyl)-
Using ((1R) -1-phenylethylamino) methyl] benzaldehyde (1.5 g), the reaction was carried out in the same manner as in Example (1d), followed by purification to obtain 1.66 g of the title compound as a pale yellow foam. . NMR spectrum (CDCl ₃ ) δ ppm: 1.37-1.43 (3H, m),
3.57-3.73 (1H, m), 3.76and 3.82 (total 3H, each s),
4.60 and 4.61 (total 1H, each s), 6.78-6.92 (2H, m),
7.15-7.44 (10H, m), 7.47 and 7.59 (total 1H, each
s), 7.80 and 7.87 (total 1H, each s).

(79e) 5- [3-((4-methoxyphenyl)-((1R) -1-phenylethylamino) methyl) benzylidene] -3- (triphenylmethyl) thiazolidine-2,4-dione Example (79d) 5- [3-((4-methoxyphenyl)-((1R) -1-phenylethylamino) methyl) benzylidene] thiazolidine-2,4-dione
The reaction was carried out in the same manner as in Example (1e) using 66 g, and purified to give 1.79 g of the title compound as a colorless foam. NMR spectrum (CDCl ₃ ) δ ppm: 1.34-1.38 (3H, m),
3.59-3.69 (1H, m), 3.75and 3.81 (total 3H, each s),
4.568 and 4.574 (total 1H, each s), 6.76-6.90 (2H,
m), 7.12-7.54 (26H, m), 7.69 and 7.76 (total 1H, eac
hs).

(79f) 5- [3-((4-methoxyphenyl)-((1R) -1-phenylethylamino) methyl) benzyl] -3- (triphenylmethyl) thiazolidine-2,4-dione Example (79e) 5- [3-((4-methoxyphenyl)-((1R) -1-phenylethylamino) methyl) benzylidene] -3- (triphenylmethyl) thiazolidine-2,4-dione Using 79 g, the reaction was carried out in the same manner as in Example (1f) and purification was performed to obtain 0.81 g of the title compound as a colorless oil. NMR spectrum (CDCl ₃ ) δ ppm: 1.34-1.35 (3H, m),
2.91-3.06 (1H, m), 3.47-3.79 (5H, m), 4.31-4.41 (1H, m
m), 4.55-4.62 (1H, m), 6.70-7.37 (28H, m).

(79 g) 5- [3-((4-dimethoxyphenyl)-((1R) -1-phenylethylamino)
Methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride 5- [3-((4-dimethoxyphenyl)-((1R) -1-phenylethylamino) methyl] benzyl]-of Example (79f) Example (1) was prepared using 0.81 g of 3- (triphenylmethyl) thiazolidine-2,4-dione.
The same reaction as in g) was carried out and purification was performed to obtain 160 mg of a free form of the title compound as a colorless foam. This free body 1
After mixing 52 mg of an ethyl acetate solution and a 4 N hydrogen chloride-ethyl acetate solution, the solvent was distilled off under reduced pressure to obtain 130 mg of the hydrochloride of the title compound as a white powder. Melting point: 212-215 ° C (decomposition) NMR spectrum (DMSO-d ₆ ) δ ppm: 1.67 (3H, br.s),
3.05-3.18 (1H, m), 3.36-3.45 (1H, m), 3.74 and 3.76
(total 3H, each s), 4.00-4.06 (1H, m), 4.90-4.96 (1
H, m), 5.02-5.14 (1H, m), 6.92-6.99 (2H, m), 7.24-7.
62 (11H, m).

Example 80 5- [3-((3,4-dimethoxyphenyl)-((1
R) -1-Phenylethylamino) methyl) benzyl]
Thiazolidine-2,4-dione and hydrochloride (Exemplary Compound No. 2-1681) (80a) 3-[(3,4-dimethoxyphenyl)-
((1R) -1-phenylethylamino) methyl] benzoic acid methyl ester 12.9 g of 3- (3,4-dimethoxybenzoyl) benzoic acid ethyl ester and 10.4 ml of (R)-
The reaction was carried out in the same manner as in Example (1a) using 1-phenylethylamine and purified. 6.48 g of isomer A of the title compound as a colorless oil and 8.56 g of isomer B as a pale yellow oil Obtained. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.36-1.41 (6H, m),
3.68 (1H, q, J = 7Hz), 3.85 (3H, s), 3.87 (3H, s), 4.35
(2H, q, J = 7Hz), 4.61 (1H, s), 6.81-6.88 (3H, m), 7.2
3-7.35 (6H, m), 7.48 (1H, d, J = 8Hz), 7.86 (1H, d, J = 8
Hz), 8.00 (1H, s). Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.37-1.41 (6H, m),
3.63 (1H, q, J = 7Hz), 3.80 (3H, s), 3.82 (3H, s), 4.37
(2H, q, J = 7Hz), 4.63 (1H, s), 6.73-6.82 (3H, m), 7.2
1-7.42 (6H, m), 7.56 (1H, d, J = 8Hz), 7.92 (1H, d, J = 8
Hz), 8.01 (1H, s).

(80b) [3-((3,4-dimethoxyphenyl)-((1R) -1-phenylethylamino)
Methyl) phenyl] methanol Isomer A of 3-[(3,4-dimethoxyphenyl)-((1R) -1-phenylethylamino) methyl] benzoic acid ethyl ester of Example (80a), 6.48 g
And purified in the same manner as in Example (1b), using isomer A of the title compound as a colorless oil (5.84).
g was obtained. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 7 Hz),
3.67 (1H, q, J = 7Hz), 3.85 (3H, s), 3.87 (3H, s), 4.5
6 (1H, s), 4.62 (2H, s), 6.81-6.88 (3H, m), 7.17-7.36
(9H, m). Isomer B of 3-[(3,4-dimethoxyphenyl)-((1R) -1-phenylethylamino) methyl] benzoic acid ethyl ester of Example (80a), 8.56 g
And purified in the same manner as in Example (1b) using
7.54 g of isomer B of the title compound was obtained as a colorless oil. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.37 (3H, d, J = 7 Hz),
3.66 (1H, q, J = 7Hz), 4.61 (1H, s), 4.68 (2H, s), 6.7
3-6.88 (3H, m), 7.17-7.36 (9H, m).

(80c) 3-[(3,4-Dimethoxyphenyl)-((1R) -1-phenylethylamino) methyl] benzaldehyde 3-[(3,4-dimethoxyphenyl)-of Example (80b) Using 7.54 g of isomer A of ((1R) -1-phenylethylamino) methyl] phenylmethanol, the reaction was carried out in the same manner as in Example (1c), purification was carried out, and isomer A of the title compound was obtained in pale color. 6.39 g were obtained as a yellow oil. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J = 7 Hz),
3.69 (1H, q, J = 7Hz), 3.85 (3H, s), 3.88 (3H, s), 4.6
2 (1H, s), 6.82-6.87 (3H, m), 7.20-7.43 (6H, m), 7.56
(1H, d, J = 8Hz), 7.69 (1H, d, J = 7Hz), 7.85 (1H, s),
9.96 (1H, s). Using 5.84 g of isomer B of 3-[(3,4-dimethoxyphenyl)-((1R) -1-phenylethylamino) methyl] phenylmethanol of Example (80b). Then, the reaction was carried out and purified in the same manner as in Example (1c) to give 4.45 g of isomer B of the title compound as a pale yellow oil. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.39 (3H, d, J = 7 Hz),
3.62 (1H, q, J = 7Hz), 3.80 (3H, s), 3.83 (3H, s), 4.6
7 (1H, s), 6.73-6.85 (3H, m), 7.19-7.89 (9H, m), 10.0
1 (1H, m).

(80d) 5- [3-((3,4-dimethoxyphenyl)-((1R) -1-phenylethylamino) methyl) benzylidene] thiazolidine-2,4-dione Example 3 (80c) Using 4.45 g of isomer A of-[(3,4-dimethoxyphenyl)-((1R) -1-phenylethylamino) methyl] benzaldehyde, the reaction was carried out in the same manner as in Example (1d), followed by purification. Thus, 5.78 g of isomer A of the title compound was obtained as a pale yellow solid. Isomer A Melting point: 97-100 ° C NMR spectrum (CDCl ₃ ) δ ppm: 1.39 (3H, d, J = 7 Hz),
3.70 (1H, q, J = 7Hz), 3.86 (3H, s), 3.89 (3H, s), 4.5
8 (1H, s), 6.82 (1H, s), 6.87 (2H, s), 7.21-7.41 (9H,
m), 7.49 (1H, s), 7.80 (1H, s). of 3-[(3,4-dimethoxyphenyl)-((1R) -1-phenylethylamino) methyl] benzaldehyde of Example (80c) The same reaction as in Example (1d) was carried out using 6.39 g of isomer B, followed by purification to obtain 8.92 g of isomer B of the title compound as a pale yellow foam. Isomer B NMR spectrum (CDCl3) δ ppm: 1.41 (3H, d, J = 7 Hz),
3.64 (1H, q, J = 7Hz), 3.81 (3H, s), 3.83 (3H, s), 4.6
1 (1H, s), 6.74-6.85 (3H, m), 7.20-7.45 (9H, m), 7.60
(1H, s), 7.87 (1H, s).

(80e) 5- [3-((3,4-dimethoxyphenyl)-((1R) -1-phenylethylamino) methyl) benzylidene] -3- (triphenylmethyl) thiazolidine-2,4- Dione 5- [3-((3,4-dimethoxyphenyl)-((1R) -1-phenylethylamino) of Example (80d)
Methyl) benzylidene] thiazolidine-2,4-dione isomer A was reacted with 5.78 g, and purified in the same manner as in Example (1e) to give the title compound isomer A as a pale yellow foam. 8.42 g was obtained. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.36 (3H, d, J = 7 Hz),
3.60-3.70 (1H, m), 3.84 (3H, m), 3.88 (3H, s), 4.55
(1H, s), 6.80 (1H, s), 6.85 (2H, s), 7.15-7.50 (24H,
m), 7.70 (1H, s), 1.38 (3H, d, J = 7Hz), 3.59-3.68 (1H,
m), 3.79 (3H, m), 3.82 (3H, s), 4.57 (1H, s), 6.72-6.
79 (3H, m), 7.18-7.55 (24H, m), 7.77 (1H, s). In Example (80d), 5- [3-((3,4-dimethoxyphenyl)-((1R) -1 -Phenylethylamino)
[Methyl) benzylidene] thiazolidine-2,4-dione isomer B, 1.5 g, reacted in the same manner as in Example (1e) and purified to give the title compound isomer B as a pale yellow solid. .56 g were obtained. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.38 (3H, d, J = 7 Hz),
3.59-3.68 (1H, m), 3.79 (3H, m), 3.82 (3H, s), 4.57
(1H, s), 6.72-6.79 (3H, m), 7.18-7.55 (24H, m), 7.77
(1H, s).

(80f) 5- [3-((3,4-dimethoxyphenyl)-((1R) -1-phenylethylamino) methyl) benzyl] -3- (triphenylmethyl)
Thiazolidine-2,4-dione and its hydrochloride 5- [3-((3,4-dimethoxyphenyl)-((1R) -1-phenylethylamino) of Example (80e)]
Methyl) benzylidene] -3- (triphenylmethyl)
Using 6.0 g of isomer A of thiazolidine-2,4-dione, the reaction was carried out in the same manner as in Example (1f), followed by purification.
3.81 g of isomer A of the title compound was obtained as a colorless oil. Isomer A NMR spectrum (CDCl ₃ ) δ ppm: 1.35-1.37 (3H, m),
2.90-3.01 (1H, m), 3.47-3.54 (1H, m), 3.63-3.69 (1H, m
m), 3.79 and 3.82 (total 3H, each s), 3.87 (3H, s),
4.29-4.35 (1H, m), 4.536 and 4.543 (total 1H, each.
s), 6.80-6.85 (3H, m), 7.00-7.40 (24H, m). 5- [3-((3,4-dimethoxyphenyl)-((1R) -1-phenyl) of Example (80e) Ethylamino)
Methyl) benzylidene] -3- (triphenylmethyl)
Isomer B of thiazolidine-2,4-dione, 1.56 g
And purified in the same manner as in Example (1f), using 958 mg of isomer B of the title compound as a white solid.
Obtained. Isomer B NMR spectrum (CDCl ₃ ) δ ppm: 1.35-1.37 (3H, m),
2.98-3.05 (1H, m), 3.52-3.69 (2H, m), 3.77-3.85 (3H,
m), 3.87 (3H, m), 4.37-4.41 (1H, m), 4.549 and4.558
(total 1H, each.s), 6.72-6.80 (3H, m), 7.05-7.41 (24
H, m).

(80 g) 5- [3-((3,4-dimethoxyphenyl)-((1R) -1-phenylethylamino) methyl) benzyl] thiazolidine-2,4-dione 5 of Example (80f) -[3-((3,4-dimethoxyphenyl)-((1R) -1-phenylethylamino)
Methyl) benzyl] -3- (triphenylmethyl) thiazolidine-2,4-dione isomer A, 3.81 g, was reacted in the same manner as in Example (1 g), purified and purified to give the isomer of the title compound. 1. Free form of Form A as colorless oil
34 g were obtained. A mixture of 2.34 g of the free compound in ethyl acetate and a 4 N hydrogen chloride-ethyl acetate solution was mixed, and the solvent was distilled off under reduced pressure to obtain 2.05 g of the hydrochloride of isomer A of the title compound as a pale white powder. Isomer A Melting point: 146-148 ° C. (decomposition) NMR spectrum (CDCl ₃ ) δ ppm: 1.19-1.45 (3H, m),
3.05-3.32 (2H, m), 3.89,3.94, 3.98 and 4.04 (total 6
H, each s), 4.05-4.15 (1H, m), 4.04-4.75 (2H, m), 6.2
0-7.75 (12H, m). 5- [3-((3,4-dimethoxyphenyl)-((1R) -1-phenylethylamino) of Example (80f)]
Using 950 mg of isomer B of methyl) benzyl] -3- (triphenylmethyl) thiazolidine-2,4-dione, the reaction was carried out in the same manner as in Example (1 g), followed by purification to obtain isomer B of the title compound. 56 as a colorless foam
6 mg were obtained. This free form was treated with hydrogen chloride in the same manner as described above to obtain 370 mg of the hydrochloride salt of isomer B of the title compound as a white powder. Isomer B Melting point: 118-123 ° C (decomposition) NMR spectrum (CDCl ₃ ) δ ppm: 1.35 (3H, d, J = 6.6H)
z), 3.24 (1H, br.s), 3.59-4.05 (8H, m), 4.60-4.86 (2
H, br), 6.71-7.86 (12H, m).

Example 81 5- [3-((4-methoxyphenyl)-(1- (3-methoxyphenyl) ethylamino) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2-738) (81a) 5- [3-((4-methoxyphenyl)-(1-
(3-methoxyphenyl) ethylamino) methyl) benzyl] thiazolidine-2,4-dione 1 g of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione and 1- (3-methoxyphenyl) 877 mg of ethylamine was dissolved in 20 ml of anhydrous dichloromethane, and 1.61 ml of triethylamine was added. The reaction solution was ice-cooled, and a solution of 0.38 ml of titanium tetrachloride in 5 ml of anhydrous dichloromethane was slowly added dropwise, followed by stirring at room temperature for 2.5 hours. An aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the imine compound as a pale pink foam, 1.7.
2 g were obtained.

The obtained foam was dissolved in 30 ml of ethanol, 729 mg of sodium borohydride cyanide and 0.25 ml of acetic acid were added, and the mixture was heated under reflux for 2 hours. The solvent of the reaction solution was concentrated under reduced pressure, the residue was neutralized with an aqueous solution of sodium hydrogen carbonate, and extracted three times with ethyl acetate. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was separated and purified by silica gel column chromatography (elution solvent: cyclohexane / ethyl acetate = 3/1) to obtain the title compound free form as a white foam.

(81b) 5- [3-((4-methoxyphenyl)-(1- (3-methoxyphenyl) ethylamino)
[Methyl) benzyl] thiazolidine-2,4-dione hydrochloride (exemplary compound number) 2 ml of ethyl acetate was obtained from the foam obtained in Example (81a).
In 4N hydrogen chloride-ethyl acetate solution 0.5 ml
Was added and stirred at room temperature for 1 hour. The precipitate was suspended in ether and collected by filtration to give 627 mg of the title compound. Melting point: 209-211 ° C. NMR spectrum (DMSO-d ₆ ) δ ppm: 1.66 (3H, br.d),
3.05-3.18 (1H, m), 3.23-3.44 (1H, m), 3.70-3.80 (6H,
m), 4.02-4.04 (1H, m), 4.91-4.96 (1H, m), 5.06-5.13
(1H, m), 6.80-7.05 (5H, m), 7.22-7.59 (7H, m).

Example 82 5- [3-((4-Methoxyphenyl)-(1- (3-trifluoromethylphenyl) ethylamino) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (exemplified) (Compound No. 2-927) (82a) 5- [3-((4-methoxyphenyl)-(1-
(3-trifluoromethylphenyl) ethylamino) methyl) benzyl] thiazolidine-2,4-dione 5- [3
-(4-methoxybenzoyl) benzyl] thiazolidine-
1 g of 2,4-dione, 1.1 g of 1- (3-trifluoromethylphenyl) ethylamine, 1.
The reaction was carried out in the same manner as in Example (81a) using 61 ml and 0.38 ml of titanium tetrachloride to obtain an imine compound. Using the obtained imine compound, 729 mg of sodium borohydride cyanide and 0.25 ml of acetic acid, a reduction reaction was carried out in the same manner as in Example (81a) to obtain a free form of the title compound as a white foam.

(82b) 5- [3-((4-Methoxyphenyl)-(1- (3-trifluoromethylphenyl) ethylamino) methyl) benzyl] thiazolidine-2,4-dione hydrochloride Example (82a) ) Was added to 3 ml of ethyl acetate.
, And 1 ml of a 4N hydrogen chloride-ethyl acetate solution was added, followed by stirring at room temperature for 1 hour. The precipitate was suspended in n-hexane and collected by filtration to give 845 mg of the title compound. Melting point: 185-187 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.70 (3H, d, J =
6.5Hz), 3.03-3.16 (1H, m), 3.25-3.46 (1H, m), 3.76 (3
H, s), 4.25 and 4.27 (total 1H, each br.s), 4.94 (1
H, dd, J = 4.3, 9.6Hz), 6.96 and 6.98 (total 1H, each
br.s), 6.97 (2H, d, J = 8.6Hz), 7.16-7.79 (10H, m).

Example 83 5- [3-((4-Methoxyphenyl)-(1- (3-chlorophenyl) ethylamino) methyl) benzyl] thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2) -504) (83a) 5- [3-((4-methoxyphenyl)-(1-
(3-chlorophenyl) ethylamino) methyl) benzyl] thiazolidine-2,4-dione 1 g of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione and 902 mg of 1- (3-chlorophenyl) ethylamine , Triethylamine 4.0
The reaction was carried out in the same manner as in Example (81a) using 3 ml and 0.77 ml of titanium tetrachloride to obtain an imine compound.

Using the obtained imine compound, 729 mg of sodium borohydride cyanide and 0.25 ml of acetic acid, a reduction reaction was carried out in the same manner as in Example (81a) to obtain a free form of the title compound as a white foam.

(83b) 5- [3-((4-methoxyphenyl)-(1- (3-chlorophenyl) ethylamino) methyl) benzyl] thiazolidine-2,4-dione hydrochloride obtained in Example (83a). 3 ml of ethyl acetate
, And 1 ml of a 4N hydrogen chloride-ethyl acetate solution was added, followed by stirring at room temperature for 1 hour. The precipitate was suspended in n-hexane and collected by filtration to give 775 mg of the title compound. Melting point: 166-168 ° C NMR spectrum (DMSO-d ₆ ) δppm: 1.60-1.74 (3H,
m), 3.04-3.17 (1H, m), 3.24-3.46 (1H, m), 3.74 and
3.76 (total 3H, each s), 4.12-4.18 (1H, m), 4.91-4.9
7 (1H, m), 5.10-5.18 (1H, m), 6.91-7.04 (2H, m), 7.16
-7.72 (10H, m).

Example 84 5- [3-((4-methoxyphenyl)-(3-fluorobenzylamino) methyl) benzyl] thiazolidine-2,4
-Dione and its hydrochloride (Exemplified Compound No. 2-264) (84a) 5- [3-((4-methoxyphenyl)-(3-
Fluorobenzylamino) methyl) benzyl] thiazolidine-2,4-dione 1 g of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione and 750 mg of 3-fluorobenzylamine, 4.03 ml of triethylamine and The reaction was carried out in the same manner as in Example (81a) using 0.77 ml of titanium chloride to obtain an imine compound.

Using the obtained imine compound, 729 mg of sodium borohydride cyanide and 0.25 ml of acetic acid, a reduction reaction was carried out in the same manner as in Example (81a) to obtain a free form of the title compound as a white foam.

(84b) 5- [3-((4-methoxyphenyl)-(3-fluorobenzylamino) methyl) benzyl] thiazolidine-2,4-dione hydrochloride Foam obtained in Example (84a) 2 ml of ethyl acetate
In 4N hydrogen chloride-ethyl acetate solution 0.5 ml
Was added and stirred at room temperature for 1 hour. The precipitate was suspended in ether and collected by filtration to give 479 mg of the title compound. Melting point: 212-215 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 3.09-3.19 (1H,
m), 3.38-3.47 (1H, m), 3.76 (3H, s), 4.01-4.09 (2H,
m), 4.94 (1H, dd, J = 4.0, 9.6Hz), 5.44-5.51 (1H, m),
6.99 (2H, dd, J = 2.7, 8.8Hz), 7.19-7.62 (10H, m).

Example 85 5- [3-((4-methoxyphenyl)-(cyclohexylmethylamino) methyl) benzyl] thiazolidine-2,4
-Dione and its hydrochloride (Exemplary Compound No. 2-269)
2) (85a) 5- [3-((4-methoxyphenyl)-(cyclohexylmethylamino) methyl) benzyl] thiazolidine-2,4-dione 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2 Using 1 g of 1,4-dione, 657 mg of cyclohexylmethylamine, 4.03 ml of triethylamine and 0.77 ml of titanium tetrachloride, the reaction was carried out in the same manner as in Example (81a) to obtain an imine compound.

Using the obtained imine compound, 729 mg of sodium borohydride cyanide and 0.25 ml of acetic acid, a reduction reaction was carried out in the same manner as in Example (81a) to obtain a free form of the title compound as a white foam.

(85b) 5- [3-((4-methoxyphenyl)-(cyclohexylmethylamino) methyl) benzyl] thiazolidine-2,4-dione hydrochloride The foam obtained in Example (85a) 3 ml of ethyl acetate
, And 1 ml of a 4N hydrogen chloride-ethyl acetate solution was added, followed by stirring at room temperature for 1 hour. The precipitate was suspended in n-hexane and collected by filtration to obtain 467 mg of the title compound. Melting point: 210-212 ° C NMR spectrum (DMSO-d ₆ ) δppm: 0.83-0.92 (2H,
m), 1.05-1.23 (3H, m), 1.57-1.82 (6H, m), 2.61-2.72
(2H, m), 3.08-3.16 (1H, m), 3.36-3.45 (1H, m), 3.75
(3H, s), 4.93-4.96 (1H, m), 5.48 (1H, br.s), 6.98 (2
H, dd, J = 2.5, 9.9Hz), 7.24 (1H, t, J = 6.2Hz), 7.38 (1
H, t, J = 7.7Hz), 7.53-7.63 (4H, m).

Example 86 5- [3-((4-methoxyphenyl)-(1-adamantanemethylamino) methyl) benzyl] thiazolidine-2,
4-dione and its hydrochloride (Exemplary Compound No. 2-269)
3) (86a) 5- [3-((4-methoxyphenyl)-(1-
Adamantanemethylamino) methyl) benzyl] thiazolidine-2,4-dione 1 g of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione and 960 mg of 1-adamantanemethylamine, 4.03 ml of triethylamine and Example (81a) using 0.77 ml of titanium chloride
The reaction was carried out in the same manner as in to obtain an imine compound.

Using the obtained imine compound, 729 mg of sodium borohydride cyanide and 0.25 ml of acetic acid, a reduction reaction was carried out in the same manner as in Example (81a) to obtain a free form of the title compound as a white foam.

(86b) 5- [3-((4-methoxyphenyl)-(1-adamantanemethylamino) methyl) benzyl] thiazolidine-2,4-dione hydrochloride Foam obtained in Example (86a) 3 ml of ethyl acetate
, And 1 ml of a 4N hydrogen chloride-ethyl acetate solution was added, followed by stirring at room temperature for 1 hour. The precipitate was suspended in n-hexane and collected by filtration to give 1.08 g of the title compound. Melting point: 167-169 ° C (decomposition) NMR spectrum (DMSO-d ₆ ) δppm: 1.55-1.71 (12H,
m), 1.99 (3H, br.s), 2.55-2.56 (2H, m), 3.04-3.17 (1
H, m), 3.34-3.46 (1H, m), 3.75 (3H, s), 4.94-4.98 (1
H, m), 5.43-5.46 (1H, m), 6.98 (2H, dd, J = 2.8, 8.8H
z), 7.25 (1H, t, J = 7.0Hz), 7.39 (1H, t, J = 7.7Hz), 7.
58-7.68 (4H, m).

Example 87 5- [3-((4-methoxyphenyl)-(1- (3,5-
Difluorophenyl) ethylamino) methyl) benzyl
Thiazolidine-2,4-dione and its hydrochloride (Exemplified Compound No. 2-691) (87a) 5- [3-((4-methoxyphenyl)-(1-
(3,5-difluorophenyl) ethylamino) methyl)
Benzyl] thiazolidine-2,4-dione 1 g of 5- [3- (4-methoxybenzoyl) benzyl] thiazolidine-2,4-dione, 1.12 g of 1- (3,5-difluorophenyl) ethylamine, 4.03 ml of triethylamine The reaction was carried out in the same manner as in Example (81a) using 0.77 ml of titanium tetrachloride, and an imine compound was obtained. Using the obtained imine compound, 729 mg of sodium borohydride cyanide and 0.25 ml of acetic acid, a reduction reaction was carried out in the same manner as in Example (81a) to obtain a free form of the title compound as a white foam.

(87b) 5- [3-((4-methoxyphenyl)-(1- (3,5-difluorophenyl) ethylamino) methyl) benzyl] thiazolidine-2,4-dione hydrochloride Example (87a) ) Was added to 3 ml of ethyl acetate.
, And 1 ml of a 4N hydrogen chloride-ethyl acetate solution was added, followed by stirring at room temperature for 1 hour. The precipitate was suspended in n-hexane and collected by filtration to obtain 451 mg of the title compound. Melting point: 210-212 ° C NMR spectrum (DMSO-d ₆ ) δ ppm: 1.66 (3H, d, J =
8.4Hz), 3.03-3.12 (1H, m), 3.35-3.45 (1H, m), 3.76 (3
H, s), 4.17-4.18 (1H, m), 4.92-4.97 (1H, m), 5.20 an
d 5.24 (total 1H, each br.s), 6.93-7.03 (2H, m), 7.1
2-7.40 (5H, m), 7.51-7.71 (4H, m).

Test Example 1 Measurement of Intestinal Bile Acid Transporter Inhibitory Activity Using Caco-2 Cells The measurement of ileal bile acid transporter inhibitory activity in this test example was performed according to [J. Biol. Chem., 269, 1340]. -1347 (199
4)], according to the method of Wong et al.

That is, as a cell expressing the bile acid transporter [Am. J. Physiol., 264, G1118-G1125 (1993)]
Caco-2 cells described in (1) were used.

[0591] 200 μl of 4 × 10 ⁴ / ml Caco-2 cells were added to each well of a collagen-coated 96-well culture plate (trade name: View plate, manufactured by Packard).
After sowing the culture medium, the medium was appropriately replaced for 15 days or more and cultured. After adding a specimen (compounds of Examples 1, 11 and 15) to the main culture system, 0.1 μCi of radioactive taur-
Luic acid ([ ³ H] -taurocholic acid: manufactured by NEN) was added, and the mixture was incubated at 37 ° C. for 1 hour in the presence of 5% CO ₂ to incorporate radioactive taurocholic acid into Caco-2 cells by an ileal bile acid transporter. I let you. Cac
The o-2 cells were ice-cold with 0.2% bovine serum albumin (bo
vine serum albumin), 1 mM taurocholic acid (cold)
Was washed 5 times with PBS (phosphate buffered saline) containing, and left to dry overnight. To each well of a 96-well culture plate, 250 μl of a liquid scintillation cocktail (trade name: Microscint 20, manufactured by Packard) was added, and a top count (manufactured by Packard), a type of liquid scintillation counter, was added. And radioactivity was measured. The inhibition rate (%) was determined from the radioactivity of the control obtained without using the test compound and the radioactivity when the test compound was used at a certain concentration, and the concentration of the test compound that inhibited the ileal bile acid transporter activity by 50%. Was examined. As a result, the compounds of the present invention exhibited excellent ileal bile acid transporter inhibitory activity.

[0586]

[Table 4] Example compound number IC ₅₀ (ug / ml) 2 (Isomer B) 0.59 .

Test Example 2 Hamster everted ileal ri
Measurement of ileal bile acid transporter inhibitory activity using ngs) The measurement of ileal bile acid transporter inhibitory activity in this test example is described in [Pharm. Res., 12, 693-699 (1995)]. This was performed according to the method of Stewart et al.

That is, a hamster inverted intestinal ring was used as a material for the ileal bile acid transporter. A 5-7 week old male Syrian hamster was anesthetized with ether, and the ileum was removed about 10 cm from the blind end and inverted. One rat inverted intestinal ring was obtained. In order to correct the difference in the expression level of the bile acid transporter depending on the site of the ileum, rings were appropriately selected from the upper and lower parts of the ileum, and three rings were used as a group to form a total of five groups. Each ring was placed in 1 ml of radioactive taurocholic acid solution at 37 ° C. for 3 hours.
The ring was loaded with radioactive taurocholic acid by the ileal bile acid transporter while shaking at 90 rpm for minutes. The composition of the radioactive taurocholic acid solution is
It consists of 1.0 μCi radioactive taurocholic acid, 0.037 mM taurocholic acid (cold), various analytes at appropriate concentrations and Ringer's buffer. Ring with Ringer's buffer 3
After washing twice, the wet weight was measured, and placed in a vial.
5 ml was added and left at 50 ° C. overnight to completely dissolve. Add 2.5 ml of liquid scintillation cocktail and add liquid scintillation counter (scintillation counter).
counter)).

The ileal-type bile acid transporter activity was obtained by correcting each radioactivity by wet weight, expressing it in dpm / mg (radioactivity per mg), and taking the average value of each group as its activity. The inhibition rate of the ileal bile acid transporter activity at a concentration of 100 μg / ml was determined.
As a result, the compound of the present invention exhibited excellent ileal bile acid transporter inhibitory activity.

[0590]

[Table 5] Example compound number Inhibition rate (%) 2 (Isomer B) 61.87 .

Formulation Example 1 Tablets Compound of Example 2 10 mg Lactose 68.5 Crystalline Cellulose 20 Carboxymethyl starch Sodium 5 Light Silicic Anhydride 0.5 Magnesium stearate 1 105 mg

[0592]

The compounds having the general formula (I) of the present invention are useful as ileal bile acid transporter inhibitors.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/4439 A61K 31/4439 A61P 3/06 A61P 3/06 9/10 101 9/10 101 43/00 111 43/00 111 C07D 249/12 506 C07D 249/12 506 271/06 271/06 277/36 277/36 285/08 285/08 413/06 413/06 417/06 417/06 417/10 417 / 10 417/12 417/12 (72) Inventor Koji Kurata 1-2-58 Hiromachi, Shinagawa-ku, Tokyo Inside Sankyo Co., Ltd. (72) Inventor Takafumi Kohama 1-2-2 Hiromachi, Shinagawa-ku, Tokyo No. 58 Sankyo Co., Ltd. (72) Inventor Keita Kono 1-258 Hiromachi, Shinagawa-ku, Tokyo

Claims (43)

[Claims] 1. A compound of the general formula (I) [In the formula, R ^1, C ₃ -C ₁₀ cycloalkyl group, C ₆ -C ₁₀ aryl group, a heterocyclic group, C ₃ to 1 is five substituted with a group selected from Substituent group a and b -C ₁₀ cycloalkyl group, C ₆ -C ₁₀ aryl group substituted with 1 to 5 groups selected from substituent groups a and b, or 1 to 5 groups selected from substituent groups a and b A 5-substituted heterocyclic group; and R ² is a group selected from a C ₃ -C ₁₀ cycloalkyl group, a C ₆ -C ₁₀ aryl group, a heterocyclic group, and a substituent group a. A substituted C ₃ -C ₁₀ cycloalkyl group, a C ₆ -C ₁₀ substituted with 1 to 3 substituents selected from a substituent group a
An aryl group or a heterocyclic group substituted by 1 to 3 groups selected from a substituent group a, wherein R ³ and R ⁴ are the same or different and are each a hydrogen atom or a substituent group a; A is a group represented by the following formula (A-1) or (A-2): Embedded image (Wherein, B represents a single bond or a C ₁ -C ₆ alkylene group, and rings Ar ₁ and Ar ₂ represent a heterocyclic group substituted with one or two oxo or thioxo groups). D represents a group having CH or a nitrogen atom, E represents an oxygen atom, a sulfur atom, a group having -NH- or-
And F represents a single bond or a C ₁ -C ₆ alkylene group. However,
A represents a group having the formula (A-2), E represents a sulfur atom,
When a group having -NH- or a group having -NHCO- is represented, B represents a single bond or a methylene group, A represents a group having the formula (A-2), and E represents an oxygen atom. And B represents a methylene group. ], Its pharmacologically acceptable salt, its ester or other derivatives. <Substituent group a> halogen atom, C ₁ -C ₆ alkyl group, C
₁ -C ₆ haloalkyl group, C ₁ -C ₆ alkoxy group, amino group, mono--C ₁ -C ₆ alkylamino group and a di -C ₁ -C ₆
Alkylamino group <substituent group b> hydroxy group, carboxy group, C ₁ -C ₆
Alkoxycarbonyl group, carbamoyl group, mono-C ₁
-C ₆ alkylcarbamoyl group, a di -C ₁ -C ₆ alkylcarbamoyl group, a nitro group, C ₃ -C ₁₀ cycloalkyl group, C ₆ -C ₁₀ aryl group, C ₆ -C _{1 0} aryloxy group, C ₇ -C ₁₆ aralkyloxy group, C ₆ -C ₁₀ arylthio group, and, 1 to have been three substituted with a group selected from substituent group a, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀
Aryl, C ₆ -C ₁₀ aryloxy, C ₇ -C ₁₆ aralkyloxy and C ₆ -C ₁₀ arylthio group. 2. The method according to claim 1, wherein the compound is represented by the general formula (Ia) or (Ib): Or a pharmaceutically acceptable salt thereof, an ester or other derivative thereof. 3. The compound according to claim 2, wherein the compound has the general formula (Ia), a pharmaceutically acceptable salt thereof, an ester or other derivative thereof. 4. One of the first to third aspects
In the above item, the compound wherein A is a group having the formula (A-1), a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. 5. The compound according to claim 4, wherein B is a single bond or a C ₁ -C ₂ alkyl group, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. 6. The compound according to claim 4, wherein B is a single bond or a methylene group, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. 7. The compound according to claim 4, wherein B is a single bond, a pharmaceutically acceptable salt thereof,
Esters or other derivatives thereof. 8. The compound according to claim 4, wherein A is a thiazolidine-2,4-dione-5-ylidenyl or 2-thioxothiazolidine-4-one-5-ylidenyl group, or a pharmaceutically acceptable salt thereof. , Its esters or other derivatives. 9. The compound according to claim 4, wherein A is a thiazolidine-2,4-dione-5-yridenyl group, a pharmacologically acceptable salt thereof, an ester thereof or another derivative thereof. 10. The compound according to any one of claims 1 to 3, wherein A is a group having the formula (A-2), a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. . 11. The compound according to claim 10, wherein B is a methylene group, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. 12. The compound according to claim 10, wherein B is a single bond, a pharmaceutically acceptable salt thereof,
Esters or other derivatives thereof. 13. A 5-membered heterocyclic ring containing at least one nitrogen atom, wherein one or two rings Ar ₂ are substituted with oxo or thioxo in any one selected from claims 10 to 12. A compound that is a group, a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. 14. The method according to claim 10, wherein the ring Ar ₂ is selected from the group consisting of thiazolidine-2,4-dione-5-yl and 2-thioxothiazolidine-4-one-5-yl. ,
Oxazolidin-2,4-dione-5-yl, 2-thioxooxazolidin-4-one-5-yl, [1,2,
4] oxadiazol-5-one-3-yl, [1,
2,4] oxadiazol-5-thion-3-yl,
[1,2,4] thiadiazol-5-one-3-yl,
[1,2,4] thiadiazol-5-thion-3-yl, [1,3,4] oxadiazol-2-one-5-
Yl, [1,3,4] oxadiazole-2-thione-
5-yl, [1,2,4] triazol-3-one-5
-Yl or [1,2,4] triazol-3-thione-
A compound that is a 5-yl group, a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. 15. The compound according to claim 10, wherein the ring Ar ₂ is selected from the group consisting of thiazolidine-2,4-dione-5-yl and 2-thioxothiazolidine-4-one-5-yl. A compound that is a group, a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. 16. The compound according to any one of claims 10 to 12, wherein the ring Ar ₂ is a thiazolidine-2,4-dione-5-yl group, a pharmacologically acceptable salt thereof, Esters or other derivatives. 17. The compound according to any one of claims 1 to 16, wherein D is a group having CH, a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. 18. The compound according to claim 1, wherein D is a nitrogen atom, a pharmaceutically acceptable salt thereof, an ester thereof, or another derivative thereof. 19. The compound according to any one of claims 1 to 18, wherein E is a group having -NH- or -NHCO-, a pharmaceutically acceptable salt thereof, an ester thereof or other Derivatives. 20. The compound according to any one of claims 1 to 18, wherein E is a group having -NH-, a pharmaceutically acceptable salt thereof, an ester thereof, or another derivative thereof. 21. The compound according to any one of claims 1 to 20, wherein F is a C ₁ -C ₄ alkylene group, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. 22. The compound according to any one of claims 1 to 20, wherein F is a methylene, methylmethylene or ethylmethylene group, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. 23. The compound according to any one of claims 1 to 20, wherein F is a methylmethylene group, a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. 24. The method according to any one of claims 1 to 23, wherein R ¹ is a C ₅ -C ₆ cycloalkyl group, a C ₆ -C ₁₀ aryl group, a heterocyclic group, a substituent group a and a C ₅ -C ₆ cycloalkyl group substituted by 1 to 3 groups selected from b, a C ₆ -C ₁₀ aryl group substituted by 1 to 5 groups by a group selected from substituent groups a and b, Or a compound which is a heterocyclic group substituted by 1 to 3 groups selected from substituent groups a and b, a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. 25. The method according to claim 1, wherein R ¹ is a C ₅ -C ₆ cycloalkyl group, a C ₆ -C ₁₀ aryl group, a heterocyclic group, a substituent group a and a C ₆ -C ₁₀ aryl group substituted by 1 to 3 groups selected from b, or a heterocyclic group substituted by 1 to 3 groups by a group selected from substituent groups a and b, A pharmacologically acceptable salt thereof, an ester or other derivative thereof. 26. The method according to claim 1, wherein R ¹ is a group selected from a C ₆ -C ₁₀ aryl group, a cyclohexyl group, a heterocyclic group, and substituent groups a and b. 1 to 3
An individually substituted C ₆ -C ₁₀ aryl group or substituent group a
And b) a compound which is a heterocyclic group substituted by 1 to 3 groups selected from b and b, a pharmacologically acceptable salt, an ester or another derivative thereof. 27. The method according to claim 1, wherein one or three R ¹ are substituted with a C ₆ -C ₁₀ aryl group or a group selected from substituent groups a and b. A C ₆ -C ₁₀ aryl group, a 5- or 6-membered aromatic heterocyclic group or a 5- or 6-membered aromatic heterocyclic group fused to a benzene ring, a pharmaceutically acceptable salt thereof, an ester thereof or Other derivatives. 28. The method according to any one of claims 1 to 23, wherein R ¹ is a C ₆ -C ₁₀ aryl group, 1 to 3 substituted C ₆ -C ₁₀ aryl groups (substituents the substituent group a, and, hydroxy group, nitro group, C ₃ -C ₁₀ cycloalkyl group, C ₆ -C ₁₀ aryl group, C ₆ -C ₁₀ aryloxy group, C ₇ -C ₁₆ aralkyloxy group, C ₃ -C ₁₀ cycloalkyl, C ₆ -C ₁₀ substituted with 1 to 3 C ₆ -C ₁₀ arylthio groups and a group selected from substituent group a
It is a group selected from the group consisting of aryl, C ₆ -C ₁₀ aryloxy, C ₇ -C ₁₆ aralkyloxy and C ₆ -C ₁₀ arylthio. A) a compound having a 5- or 6-membered aromatic heterocyclic group or a 5- or 6-membered aromatic heterocyclic group condensed with a benzene ring, a pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. 29. Any one selected from claims 1 to 23
Or in one, R¹But C₆-C_TenAryl group, 1 to 3 substituted
C₆-C_TenAn aryl group (the substituent is a halogen atom, C₁
-C₆Alkyl group, C₁-C₆Haloalkyl group, C ₁-C₆
Alkoxy group, nitro group, C_Three-C_TenCycloalkyl
Group, C₆-C_TenAryl group, C₆-C_TenAryloxy group
And C₆-C_TenSelected from the group consisting of arylthio groups
Group. ) A 5- or 6-membered aromatic heterocyclic group or
A 5- or 6-membered aromatic heterocyclic group fused to a benzene ring
Compound, its pharmacologically acceptable salt, its ester or its
Other derivatives. 30. The method according to any one of claims 1 to 23, wherein R ¹ is a C ₆ -C ₁₀ aryl group, 1 to 3 substituted C ₆ -C ₁₀ aryl groups (substituents Is a halogen atom, C ₁
-C ₆ alkoxy group, a group selected from the group consisting of nitro groups, and C ₆ -C ₁₀ aryl group. A) a thienyl group, a furyl group, a pyrrolyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a pyridyl group, or a compound condensed with a benzene ring, which is a thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl or pyridyl group, Pharmacologically acceptable salts, esters or other derivatives thereof. 31. The method according to any one of claims 1 to 23, wherein R ¹ is phenyl, 1-naphthyl, 2-naphthyl,
Fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4 Compounds which are 5-trimethoxyphenyl, 4-nitrophenyl, 2-biphenyl, thienyl or pyridyl groups, pharmacologically acceptable salts thereof, esters or other derivatives thereof. 32. The method according to any one of claims 1 to 23, wherein R ¹ is phenyl, 3-fluorophenyl, 3-chlorophenyl, 3,4-difluorophenyl, 3,4-dichlorophenyl, 1- A compound which is a naphthyl, 2-thienyl or 4-pyridyl group, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. 33. The method according to claim 1, wherein R ² is selected from the group consisting of a C ₅ -C ₆ cycloalkyl group, a C ₆ -C ₁₀ aryl group, a heterocyclic group and a substituent group a. A compound which is a C ₆ -C ₁₀ aryl group substituted with 1 to 3 substituents selected from a group selected or a heterocyclic group substituted with 1 to 3 substituents selected from a group selected from a substituent group a; Salts, esters or other derivatives thereof. 34. The method according to claim 1, wherein R ² is a cyclohexyl group, a 5- or 6-membered aromatic heterocyclic group, or a 5- or 6-membered aromatic heterocyclic ring condensed with a benzene ring. Group,
A C ₆ -C ₁₀ aryl group or 1 to 3 substituted C ₆
-C ₁₀ aryl group (the substituent is a halogen atom, C _1-
It is a group selected from the group consisting of a C ₆ alkyl group and a C ₁ -C ₆ alkoxy group. ), Pharmacologically acceptable salts thereof, esters or other derivatives thereof. 35. The method according to any one of claims 1 to 32, wherein R ² is a C ₆ -C ₁₀ aryl group, a thienyl group, a furyl group, a pyrrolyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, Pyridyl group, condensed with benzene ring, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl,
An imidazolyl or pyridyl group, or a monosubstituted C ₆ -C ₁₀ aryl group (the substituent is a halogen atom,
It is C ₁ -C ₆ alkyl group or a C ₁ -C ₆ alkoxy group. ), A pharmacologically acceptable salt thereof, an ester or other derivative thereof. 36. The method according to claim 1, wherein R ² is a C ₆ -C ₁₀ aryl group, a 2-thienyl group,
A compound which is a pyridyl group or a single-substituted C ₆ -C ₁₀ aryl group (the substituent is a halogen atom or a C ₁ -C ₆ alkoxy group), a pharmaceutically acceptable salt thereof,
Esters or other derivatives thereof. 37. The method according to any one of claims 1 to 32, wherein R ² is a phenyl group or a single-substituted phenyl group (the substituent is a halogen atom or C ₁ -C ₆ A pharmacologically acceptable salt thereof, an ester thereof, or another derivative thereof. 38. The compound according to any one of claims 1 to 32, wherein R ² is a phenyl, 4-fluorophenyl, 4-chlorophenyl or 4-methoxyphenyl group, or a pharmaceutically acceptable compound thereof. Salts, esters or other derivatives thereof. 39. The method according to claim 1, wherein R ³ and R ⁴ are the same or different and are each a hydrogen atom, a halogen atom, a C ₁ -C ₆ alkoxy group, an amino group, or a diamine. −C ₁
-C is ₆ alkylamino group compound, a pharmacologically acceptable salt, esters or other derivatives. 40. The compound according to any one of claims 1 to 38, wherein R ³ and R ⁴ are the same or different and are a hydrogen atom, a halogen atom or a C ₁ -C ₆ alkoxy group. Pharmacologically acceptable salts, esters or other derivatives thereof. 41. The compound according to any one of claims 1 to 38, wherein R ³ and R ⁴ are a hydrogen atom, a pharmaceutically acceptable salt thereof, an ester thereof or another derivative thereof. 42. The compound according to claim 1, wherein the compound is selected from the following, a pharmacologically acceptable salt thereof, an ester thereof and other derivatives thereof. 5- [3-((1- (3
-Fluorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-
Dione, 5- [3-((1- (4-fluorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl]
Thiazolidine-2,4-dione, 5- [3-((1- (3-chlorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione, 5- [3- ( (1- (4-chlorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione, 5- [3-((1- (3,4-difluorophenyl) ethylamino) -(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione, 5- [3-((2- (3,4-difluorophenyl) propionylamino)-(4-methoxyphenyl) methyl) benzyl] Thiazolidine-2,4-dione, 5- [3-((-1- (1-naphthyl) ethylamino)
-Phenylmethyl) benzyl] thiazolidine-2,4-
Dione, 5- [3-((1- (2-thienyl) ethylamino)-
(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione, 5- [3-((1- (4-pyridyl) ethylamino)-
(4-Fluorophenyl) methyl) benzyl] thiazolidine-2,4-dione, 5- [3-((1- (4-pyridyl) ethylamino)-
(4-methoxyphenyl) methyl) benzyl] thiazolidine-2,4-dione, 5- [3- (phenyl- (1-phenylethylamino)
Methyl) benzyl] thiazolidine-2,4-dione, 5- [3-((2-phenylpropionylamino) -phenylmethyl) benzyl] thiazolidine-2,4-dione 5- [3-((1- (3- Fluorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl
-2-thioxothiazolidine-4-one, 5- [3-((1- (4-fluorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl]
-2-thioxothiazolidine-4-one, 5- [3-((1- (3-chlorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl]-
2-thioxothiazolidine-4-one, 5- [3-((1- (4-chlorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl]-
2-thioxothiazolidine-4-one, 5- [3-((1- (3,4-difluorophenyl) ethylamino)-(4-methoxyphenyl) methyl) benzyl] -2-thioxothiazolidine-4- On, 5- [3-((2- (3,4-difluorophenyl) propionylamino)-(4-methoxyphenyl) methyl) benzyl] -2-thioxothiazolidine-4-one, 5- [3- ( (-1- (1-naphthyl) ethylamino)
-Phenylmethyl) benzyl] -2-thioxothiazolidine-4-dione, 5- [3-((1- (2-thienyl) ethylamino)-
(4-methoxyphenyl) methyl) benzyl] -2-thioxothiazolidine-4-one, 5- [3-((1- (4-pyridyl) ethylamino)-
(4-methoxyphenyl) methyl) benzyl] -2-thioxothiazolidine-4-one, 5- [3-((1-phenylethylamino) -phenylmethyl) benzyl] -2-thioxothiazolidine-4-
On, and 5- [3-((2-phenylpropionylamino) -phenylmethyl) benzyl] -2-thiooxothiazolidine-4-one. 43. A pharmaceutical composition comprising the substituted benzylamine according to any one of claims 1 to 42, a pharmaceutically acceptable salt thereof, an ester or other derivative thereof as an active ingredient.