JP3524133B2 - Nitrogen-containing fused heterocyclic compound, method for producing the same and agent - Google Patents

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention has excellent acyl-CoA:
Cholesterol acyltransferase (hereinafter "AC
The present invention relates to a novel nitrogen-containing fused heterocyclic compound having an inhibitory action.

[0002]

2. Description of the Related Art A non-aromatic 6-membered heterocyclic ring having a nitrogen atom at the 1-position and a condensed ring consisting of a benzene ring have -Z-CONH-Ph [Z is -NH-, -CH at the 3-position. ₂ - or conventional for compounds showing a -CH ₂ NH-] is substituted, for example, (1) Pharma Tze (Pharmazi
e), 34, pages 113-114 (issued in 1979), the formula

[Chemical 15] A compound represented by

(2) Chemical Abstract (Chemic
al Abstract) 69, 77223g (issued in 1968), the formula

[Chemical 16] The compound represented by and the like were known. Further, (3) Japanese Patent Laid-Open No. 56-2976 discloses that

[Chemical 17] [Wherein R ₁ is hydrogen or an optionally substituted hydrocarbon residue, at least one of R ₂ and R ₃ is an electronegative group, and the other is hydrogen or an optionally substituted hydrocarbon residue. R ₄ represents hydrogen or an optionally substituted hydrocarbon residue, X represents methylene, carbonyl or thiocarbonyl, and Ring A may have a substituent. ] In describes a benzoxazine derivative represented by, as electronegative groups represented by R ₂ and R _3, for example, the formula

[Chemical 18] [In the formula, R ₆ and R ₇ are the same or different and each represents hydrogen or lower alkyl, and may form a heterocyclic ring together with the nitrogen atom. ] The carbamoyl group etc. which are represented by these are described. In these known literatures, the literature of (1) includes certain 1-aryl-3- (substituted) alkyl-2,4-
It is described that the dioxo [1H, 3H] quinazoline compound has analgesic, central nervous system sedative and anti-inflammatory effects.
In the document of (2), it was described that the compound described in the document of (2) was not effective as an anticonvulsant, but in the document of (3), 3,
It is described that some 4-dihydro-2H-1,4-benzoxazine compounds are known to have anticonvulsant action and the like. However, these conventional compounds include A
Whether or not it has a CAT inhibitory effect, a blood cholesterol lowering effect, or an arteriosclerosis therapeutic effect has not been reported at all. Also, Japanese Patent Publication No. 48-6474 and Japanese Patent Publication No. 48-
23785, European Patent No. 354994, European Patent No. 421456, PCT Publication No. 9109017,

[Chemical 19] [In the formula, X represents -N =, -NR- (R represents a hydrogen atom or an alkyl group) or -N (O) _m- (m represents 0 or 1), and Y represents = CH-,-. CH ₂ -, - the CO- or -CS-, Z represents a -NH- or an alkylene group. ] The compound characterized in that the carbon atom on the quinoline ring represented by the above is substituted by a phenyl group and a side chain -NHCO-Z-Ph adjacently to each other Is described.

[0004]

Under such circumstances, it has an excellent ACAT inhibitory action and suppresses the absorption of cholesterol from the intestinal tract and the accumulation of cholesterol ester in the arterial wall in mammals, resulting in hypercholesterolemia. Of novel compounds useful as prophylactic / therapeutic agents for inflammatory disease, atherosclerosis and various diseases caused by these diseases (eg, ischemic heart disease such as myocardial infarction and cerebral infarction such as cerebral infarction, stroke) Was wanted.

[0005]

Means for Solving the Problems The present inventors have conducted various investigations on a compound having a nitrogen-containing condensed heterocyclic structure, and as a result, have shown that

[Chemical 20] The compound represented by

[Chemical 21] [The symbols in the formulas have the same meanings as described above. ] The compound represented by or its salt or reactive derivative, and a formula

[Chemical formula 22] [The symbols in the formulas have the same meanings as described above. ] The compound of formula (I _a ) contained in the compound of formula (I)

[Chemical formula 23] [In the formula, Z ′ represents —NH— or —CH ₂ NH—, and other symbols have the same meanings as described above. ] The compound or its salt represented by

[Chemical formula 24] [In the formula, n represents 0 or 1, and other symbols are as defined above. ] Or a salt thereof represented by the formula

[0006]

[Chemical 25] [The symbols in the formulas have the same meanings as described above. ] The compound of formula (I ′) containing the novel compound (I) obtained by reacting with a compound represented by

[Chemical formula 26] The compound represented by or its salt is unexpectedly strong AC
It has been found that it has an AT inhibitory effect and is useful as a safe cholesterol lowering agent and a therapeutic agent for arteriosclerosis, and based on these, the present invention was completed. That is, the present invention provides (1) compound (I) or a salt thereof, (2) ring A having (i) halogen, (ii) C _1-6 alkyl group optionally substituted with halogen, (iii) 1 to 4 substituents selected from C _1-6 alkoxy group, (iv) hydroxyl group, (v) amino group optionally substituted by C _1-4 alkyl group, and (vi) C _1-3 acyloxy group The compound according to (1) above, which is a benzene ring which may be substituted with a group, (3) ring A is halogen, C _1-4 alkyl group, C _1-4 alkoxy group and halogeno-C _1-4 alkyl The compound according to (1) above, which is a benzene ring optionally substituted with 1 to 4 substituents selected from the group:

(4) A ring has the formula

[Chemical 27] [In the formula, A ¹ and A ² are the same or different and each represents hydrogen, halogen, a C _1-4 alkyl group, a C _1-4 alkoxy group or a halogeno-C _1-4 alkyl group. ] The compound as described in (1) above, which is an optionally substituted benzene ring, (5) Ring B is (i) halogen, (ii) optionally substituted C _{1- 6} alkyl group, (iii) C _1-6 alkoxy group, (iv) hydroxyl group, (v) amino group optionally substituted by C _1-4 alkyl group, and (vi) C _1-3 acyloxy group The compound according to (1) above, which is an aromatic ring optionally substituted with 1 to 4 substituents, (6) ring B is halogen, C _1-4 alkyl group, C _1-4 alkoxy group The compound according to (1) above, which is an aromatic ring which may be substituted with 1 to 4 substituents selected from a di-C _1-4 alkylamino group, a C _1-3 acyloxy group and a hydroxyl group, 7) The aromatic ring is (1) benzene ring, (2) pyridine ring, (3) pyrazine ring, (4) pyrimidine ring or (5) pyridazine ring, as described in (1) and (5) above. Or the compound described in (6), (8) the ring B has the formula

[Chemical 28] [Wherein B ¹ , B ² and B ³ are the same or different and are hydrogen, halogen, a C _1-4 alkyl group, a C _1-4 alkoxy group,
A di-C _1-4 alkylamino group is shown. ] The compound according to (1) above, which is an optionally substituted benzene ring represented by the following:

(9) The compound described in (1) above, wherein R is an optionally substituted phenyl-C _1-4 alkyl group, (10) Formula

[Chemical 29] [In the formula, the B ′ ring is an optionally substituted benzene ring,
Other symbols have the same meanings as described above. ] The compound according to the above (1) represented by the formula (11):

[Chemical 30] [In the formula, the B ′ ring is an optionally substituted benzene ring,
X ¹ is —O— or —S—, Z ′ is —CH ₂ — or —
CH ₂ NH- and other symbols have the same meanings as described in (1) above. ] The compound of the above (1) represented by: (12) Formula

[Chemical 31] [In the formula, the B ′ ring is an optionally substituted benzene ring,
Z ′ represents —CH ₂ — or —CH ₂ NH—, and other symbols have the same meanings as described above. ] The compound of the above (1) represented by

Equation (13)

[Chemical 32] [In the formula, the B ′ ring is an optionally substituted benzene ring,
X ² represents —CH ₂ — or —CO—, and other symbols have the same meanings as described above. [14] The compound according to the above (1), (14) Compound (II) or a salt thereof or a reactive derivative thereof, and compound (III) or a salt thereof are reacted, or a compound (I) thereof preparation of salts, (15) compound (IV) or a salt thereof and the compound (V) or compound which comprises reacting a salt thereof (I _a)
Or a method for producing a salt thereof, (16) an acyl-CoA: cholesterol acyltransferase inhibitor containing compound (I ′) or a salt thereof.

In the above formula, the A ring and the B'ring each represent a benzene ring which may be substituted, and the B ring represents an aromatic ring which may be substituted. Examples of such a substituent on the benzene ring and aromatic ring include a halogen atom (for example,
Fluorine, chlorine, bromine, iodine, etc., preferably chlorine, fluorine, etc.), an alkyl group optionally substituted with halogen, an alkoxy group optionally substituted with halogen, an alkylthio optionally substituted with halogen Base,
C _1-7 acylamino group (for example, C _1-6 alkanoylamino group such as formylamino, acetylamino, propionylamino, butyrylamino group, benzoylamino group etc.), amino group optionally substituted by C _1-4 alkyl group (For example, mono- or di-C _1-4 alkylamino group such as methylamino, ethylamino, propylamino, dimethylamino, methylethylamino, methylpropylamino group), C _1-3 acyloxy group (eg formyloxy, acetoxy , Propionyloxy group, etc.), hydroxyl group,
A cyano group, a carboxyl group or the like is used.

The above-mentioned alkyl group which may be substituted with halogen is, for example, a linear or branched alkyl group having 1 to 6 carbon atoms or a halogen atom (for example, fluorine, chlorine, bromine and iodine). Etc., preferably, for example, chlorine, bromine, etc.) substituted with 1 to 5 are used, for example, methyl, chloromethyl, difluoromethyl, trichloromethyl, trifluoromethyl, ethyl, 2-bromoethyl, 2,2,2 -Trifluoroethyl, pentafluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl,
Isobutyl, sec-butyl, tert-butyl, pentyl,
Isopentyl, neopentyl, 5,5,5-trifluoropentyl, 4-trifluoromethylbutyl, hexyl,
6,6,6-trifluorohexyl, 5-trifluoromethylpentyl and the like are frequently used, preferably methyl,
Chloromethyl, difluoromethyl, trichloromethyl,
Trifluoromethyl, ethyl, 2-bromoethyl, 2,
2,2-trifluoroethyl, propyl, 3,3,3-trifluoropropyl, isopropyl, 2-trifluoromethylethyl, butyl, 4,4,4-trifluorobutyl, isobutyl, sec-butyl, tert-butyl And a straight-chain or branched alkyl group having 1 to 4 carbon atoms, or a group obtained by substituting 1 to 3 halogen atoms as described above.

As the alkoxy group optionally substituted with halogen and the alkylthio group optionally substituted with halogen, for example, an alkyl group substituted with the above alkyl group or halogen and an oxygen atom and a sulfur atom are respectively bonded. An alkoxy group optionally substituted with halogen, an alkylthio group optionally substituted with halogen, and the like are used. As the alkoxy group which may be substituted with halogen, for example, a linear or branched alkoxy group having 1 to 6 carbon atoms, or one in which 1 to 5 halogen atoms as described above are substituted is used. Such as methoxy, difluoromethoxy,
Trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4-trifluorobutoxy, isobutoxy,
sec-butoxy, pentoxy, hexyloxy and the like are widely used, and preferably, for example, methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4, 4, 4 -A straight-chain or branched alkoxy group having 1 to 4 carbon atoms such as trifluorobutoxy, isobutoxy, sec-butoxy, etc., or one having 1 to 3 halogen atoms as described above substituted thereto is used.

The alkylthio group which may be substituted with halogen is, for example, a straight-chain or branched alkylthio group having 1 to 6 carbon atoms, or one in which 1 to 5 halogen atoms as described above are substituted. Is used, for example, methylthio, difluoromethylthio, trifluoromethylthio, ethylthio, propylthio, isopropylthio, butylthio, 4,4,4-trifluorobutylthio, pentylthio, hexylthio and the like are commonly used, and preferably methylthio, difluoromethylthio,
Trifluoromethylthio, ethylthio, propylthio,
A linear or branched alkylthio group having 1 to 4 carbon atoms such as isopropylthio, butylthio, 4,4,4-trifluorobutylthio, etc., or one having 1 to 3 halogen atoms as described above substituted therein Is used. Hereinafter, "which may be substituted with halogen" means that 1 to 3 halogens as described above may be contained. Preferred as the substituents on the benzene ring and aromatic ring represented by A ring, B ′ ring and B ring are:
Substituted with (i) halogen atom, (ii) halogen-substituted C _1-6 alkyl group, (iii) C _1-6 alkoxy group, (iv) hydroxyl group, (v) C _1-4 alkyl group The optionally used amino group and (vi) C _1-3 acyloxy group and the like are used.
Each of the terms (i) to (vi) has the same meaning as described above. A ring,
The substituents of the benzene ring and the aromatic ring represented by the B ′ ring and the B ring may be substituted at any substitutable positions of the benzene ring and the aromatic ring, and when there are two or more substituents, they may be the same or different. Can be different, the number is 1
To 4, preferably 2 or 3. Also A
Adjacent carbons on the ring, B ′ ring or B ring are — (CH ₂ ) _q
It may be linked to a group represented by-(q represents an integer of 3 to 5) to form a 5- to 7-membered ring, and in such a case, the compound of interest (I) and compound (I ′) included.

The ring A is preferably, for example, halogen (eg chlorine), C _1-4 alkyl group _optionally substituted by 1 to 3 halogens (eg methyl, ethyl,
A benzene ring which may be substituted with 1 to 4 substituents selected from isopropyl, trifluoromethyl and the like) and C _1-4 alkoxy groups (eg, methoxy and the like) is used, and particularly one halogen ( A benzene ring optionally substituted with the same meaning as described above) or one C _1-4 alkyl group (eg, methyl, ethyl, isopropyl, etc.) is preferable. Specifically, more preferably, for example, the formula [A]

[Chemical 33] [In the formula, A ¹ and A ² are the same or different and each is hydrogen, halogen (eg chlorine), C _1-4 alkyl group (eg methyl, ethyl, isopropyl etc.), C _1-4 alkoxy group (eg methoxy etc.). ) Or a halogeno-C _1-4 alkyl group (eg trifluoromethyl etc.). ] An optionally substituted benzene ring or the like represented by the following is used. More preferred ring A is, for example, in the above formula [A], A ¹ and A ² are the same or different and are hydrogen, halogen (as defined above), C _1-4 alkyl (as defined above).
An optionally substituted benzene ring and the like are particularly preferable A rings, for example, in the above formula [A], A
^An optionally substituted benzene ring in which ¹ and A ² are the same or different and is hydrogen, chlorine, methyl or the like is used. The aromatic ring represented by ring B is, for example, a 5- or 6-membered aromatic ring which may have 1 to 4 oxygen atoms, sulfur atoms and nitrogen atoms other than carbon atoms, preferably 1 or 2 atoms. Is used, and preferably has, for example, 1 or 2 nitrogen atoms other than carbon atoms 5
Or, a 6-membered aromatic ring is more preferably used, for example, (1) benzene ring, (2) pyridine ring, (3) pyrazine ring, (4) pyrimidine ring, (5) pyridazine ring, etc., and further preferably For example, a benzene ring or a pyrimidine ring or the like, particularly preferably a benzene ring or the like is used.

Ring B and ring B'may be the same or different and each may have 1 to 4 substituents. Preferred examples of such a substituent include, for example, halogen (eg, fluorine, chlorine, etc.). A halogenated C _1-4 alkyl group (eg, methyl, ethyl, isopropyl, trifluoromethyl, etc.), a halogenated C _1-4 alkoxy group (eg, methoxy,
Ethoxy, isopropoxy, trifluoromethoxy etc.), di-C _1-4 alkylamino group (eg dimethylamino etc.), C _1-3 acyloxy group (eg acetoxy etc.) or hydroxyl group etc. are used, especially halogen (above-mentioned The same meaning), a C _1-4 alkyl group optionally substituted by halogen (the same meaning as described above), a C _1-4 alkoxy group optionally substituted by halogen (the same meaning as described above) and the like are widely used. It Preferred as the B ring and the B ′ ring are:
For example, the formula [B]

[Chemical 34] [Wherein B ¹ , B ² and B ³ are the same or different and are hydrogen, halogen (eg fluorine, chlorine etc.), and a C _1-4 alkyl group optionally substituted by halogen (eg methyl,
Ethyl, isopropyl, trifluoromethyl etc.), a C _1-4 alkoxy group which may be substituted with halogen (eg methoxy, ethoxy, isopropoxy, trifluoromethoxy etc.) or a di-C _1-4 alkylamino group (eg And an optionally substituted benzene ring represented by the formula]) is used. More preferred are, for example, in the formula [B], (1) B ¹ and B ²
And B ³ are identical or different, halogen, halogen optionally substituted C _1-4 alkyl group or halogen substituted C _{1 -4} alkoxy group, (2)
B ¹ and B ² are the same or different and each is halogen, a C _1-4 alkyl group optionally substituted with halogen or a C _1-4 alkoxy group optionally substituted with halogen, and B ³ is hydrogen. , (3) B ¹ and B ³ are the same or different and are halogen, or C _1-4 which may be substituted with halogen.
C optionally substituted with an alkyl group or halogen
_A substituted benzene ring in which _{1-4 is an} alkoxy group, B ² is hydrogen, or (4) B ¹ and B ³ are hydrogen and B ² is halogen is used. Each term in (1) to (4) has the same meaning as described above.

More preferred as the B ring and the B ′ ring are, for example, in the above formula [B], (a) B ¹ ,
B ² and B ³ are all fluorine, methyl group or methoxy group, (b) B ¹ and B ² are both chlorine, fluorine, isopropyl group or methoxy group, B ³ is hydrogen, (c) B ¹ and B ³ Are chlorine, fluorine, methyl group, ethyl group, isopropyl group or methoxy group, B ² is hydrogen, (d) B ¹
Is an isopropyl group, B ² is hydrogen, B ³ is a methyl group, or
(e) An optionally substituted benzene ring in which B ¹ and B ³ are hydrogen and B ² is chlorine is used.

In the above formula, R represents a hydrogen atom or an optionally substituted hydrocarbon group. Examples of such a hydrocarbon group include an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group and an aralkyl group. As the alkyl group, a linear or branched one having 1 to 6 carbon atoms is used, preferably, for example, methyl, ethyl, propyl, isopropyl, butyl,
Carbon number 1 such as isobutyl, sec-butyl, tert-butyl
A straight-chain or branched alkyl group of 4 to 4 is used. Examples of the alkenyl group include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, sec-
An alkenyl group having 2 to 6 carbon atoms such as butenyl is used, and preferably an alkenyl group having 2 to 4 carbon atoms such as ethenyl, propenyl, isopropenyl is used. Examples of the alkynyl group include ethynyl, propynyl, isopropynyl, butynyl, isobutynyl, s.
An alkenyl group having 2 to 6 carbon atoms such as ec-butynyl is used, preferably, for example, ethynyl, propynyl,
An alkynyl group having 2 to 4 carbon atoms such as isopropynyl is used. As the cycloalkyl group, for example, a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl is used, and preferably a cycloalkyl group having 3 to 6 carbon atoms such as cyclopropyl and cyclobutyl is used. To be
As the aryl group, an aryl group having 6 to 14 carbon atoms such as phenyl, naphthyl, anthryl and phenanthryl is used, and preferably an aryl group having 6 to 10 carbon atoms such as phenyl and naphthyl is used.

Examples of the aralkyl group include benzyl,
A C _6-10 aryl-C _1-4 alkyl group such as phenethyl, phenyl-propyl, naphthyl-methyl and the like is used, preferably phenyl-C such as benzyl and phenethyl.
_1-4 alkyl groups are used. As a preferable hydrocarbon group, for example, an alkyl, cycloalkyl, aryl or aralkyl group is used, more preferably an aralkyl group is used. The substituent of the optionally substituted hydrocarbon group may be, for example, (i) halogen, (ii) cycloalkyl group, (iii) alkyl, alkenyl, cycloalkyl, or aryl group as a substituent. A good amino group, (iv) hydroxyl group, (v) an optionally substituted alkoxy group with a halogen, (vi) an acyl group, (vii) an acyloxy group,
(viii) cyano group, (ix) optionally protected carboxyl group, (x) carbamoyl group, (xi) mercapto group, (xii) alkylthio group, (xiii) sulfo group, (xiv) alkylsulfonyl group and the like Used. The hydrocarbon group which may be substituted may have the same or different 1 depending on these substituents.
It may be substituted by 4 to 4, preferably 1 or 2. Regarding the substituents (i) to (xiv) of the hydrocarbon group, as the halogen, for example, fluorine, chlorine, bromine, iodine or the like is used, and preferably fluorine, chlorine or the like is used. Examples of the cycloalkyl group include C _3-6 such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
A cycloalkyl group is used. In the amino group which may have an alkyl, alkenyl, cycloalkyl or aryl group as a substituent, examples of the alkyl group include C such as methyl, ethyl, propyl and isopropyl.
_1-4 alkyl groups are used, examples of alkenyl groups include C _2-4 alkenyl groups such as ethenyl, propenyl, isopropenyl, butenyl, and examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl. C _3-6 cycloalkyl group such as, for example, phenyl,
A C _6-10 aryl group such as naphthyl is used. Preferred examples of the amino group include mono- or di-C _1-4 alkylamino groups such as amino, methylamino, ethylamino, dimethylamino and diethylamino groups.
Examples of the alkoxy group which may be substituted with halogen include methoxy, difluoromethoxy, trifluoromethoxy, ethoxy, 2,2,2-trifluoroethoxy, propoxy, isopropoxy, butoxy, 4,4,4.
-A C _1-4 alkoxy group such as trifluorobutoxy, isobutoxy, sec-butoxy or the like in which 1 to 3 halogen atoms (eg, fluorine, chlorine) are substituted is used. Examples of the acyl group include C _1-4 such as formyl, acetyl, propionyl, butyryl and isobutyryl.
An acyl group is used. As the acyloxy group, a C _1-4 acyloxy group such as formyloxy, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy group is used. Examples of the optionally protected carboxyl group protecting group include C _1-4 alkyl groups such as methyl, ethyl and t-butyl groups, and C _7-11 aralkyl groups such as benzyl. As the alkylthio group, for example, a C _1-4 alkylthio group such as methylthio, ethylthio, propylthio, isopropylthio and butylthio is used. As the alkylsulfonyl group, for example, a C _1-4 alkylsulfonyl group such as methylsulfonyl, ethylsulfonyl, propylsulfonyl, isopropylsulfonyl and butylsulfonyl group is used.

Preferred substituents for the optionally substituted hydrocarbon group are, for example, (i) halogen, (ii) cycloalkyl group and (ii) as defined above.
i) an alkyl group, an alkenyl group, a cycloalkyl group, an amino group which may have an aryl group as a substituent, (iv) a hydroxyl group, (v) an alkoxy group which may be substituted with a halogen, (vi) an acyl group, ( vii) acyloxy group, (viii) cyano group, (ix) optionally protected carboxyl group, (x)
A carbamoyl group or the like is used, and more preferably, for example, (a) C _3-6 cycloalkyl group, (b) mono- or di-
A C _1-4 alkylamino group, (c) a carboxyl group which may be substituted with a C _1-4 alkyl group and the like are used. Examples of preferable groups as R include (a) halogen such as chlorine,
(b) C _3-6 cycloalkyl group such as cyclohexyl group,
(c) _{1 to 4} C _1-4 alkoxy groups such as methoxy group and (d) carboxyl groups which may be protected by C _1-4 alkyl group such as t-butoxycarbonyl group, which may be the same or different. , Preferably 1 or 2 substituted C _1-6 alkyl, C _6-10 aryl, C _6-10 aryl-
A C _1-4 alkyl group is used, and more preferably, for example,
Halogen (eg fluorine, chlorine etc.) or alkoxy group (eg methoxy, ethoxy, isopropoxy etc.)
A phenyl-C _1-4 alkyl group (eg, benzyl etc.) which may be substituted with, etc. is used.

In the above formula, R ¹ represents a hydrogen atom or an aliphatic group. Examples of such an aliphatic group include an alkyl group, an alkenyl group, an alkynyl group and a cycloalkyl group. Alkyl group has 1 to 6 carbon atoms
The straight-chain or branched-chain of 1 to 4 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like are used. Alkyl groups of the form are used. Examples of the alkenyl group include ethenyl, propenyl, isopropenyl, butenyl, isobutenyl, se
An alkenyl group having 2 to 6 carbon atoms such as c-butenyl is used, and preferably an alkenyl group having 2 to 4 carbon atoms such as ethenyl, propenyl and isopropenyl is used. Examples of the alkynyl group include ethynyl,
An alkenyl group having 2 to 6 carbon atoms such as propynyl, isopropynyl, butynyl, isobutynyl and sec-butynyl is used, and preferably an alkynyl group having 2 to 4 carbon atoms such as ethynyl, propynyl and isopropynyl is used. As the cycloalkyl group, for example, a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl is used, and preferably a cycloalkyl group having 3 to 6 carbon atoms such as cyclopropyl and cyclobutyl is used. To be Preferable examples of R ¹ include, for example, an alkyl group and a cycloalkyl group, more preferably an alkyl group, and particularly preferably a linear group having 1 to 4 carbon atoms such as methyl, ethyl, propyl, and isopropyl group. A branched alkyl group is used. In the above formula, W is −
CH ₂ -, - CO- or -CS- indicates, preferably, -CH ₂ -, - CO- is generic.

[Chemical 35] In the formula, X is _{-CH 2 -, - O -,} - S -, - CO
—, —CS—, —NR ¹ — (R ¹ represents a hydrogen atom or an aliphatic group), and preferably —CH ₂ —, —O—,
—CO—, —NR ^1a — (R ^1a is, for example, methyl, ethyl, propyl, isopropyl, etc.) is used, and particularly —
CH ₂ -, - O- is generic. In the above formula, X ¹ is -O.
-, -S- is shown, and -O- is generally used. In the above formula, Z
Is _{-NH -, - CH 2 -,} - CH 2 NH- indicates, -NH
-, - CH ₂ - is universal. In the above formula, Z ¹ is —CH ₂
-, - CH ₂ NH- indicates, -CH ₂ - is universal.

The nitrogen-containing heterocyclic compound represented by the formula (I) or a salt thereof can be produced, for example, by the following method. That is: A compound (I) or a salt thereof is produced by reacting a carboxylic acid represented by the formula (II) or a salt thereof or a reactive derivative thereof with an amine represented by the formula (III) or a salt thereof. To do. A compound (I _a ) or a salt thereof is produced by reacting an amine represented by the formula (IV) or a salt thereof with a compound represented by the general formula (V) or a salt thereof. The method will be described in detail below. Method: The reaction of the carboxylic acid represented by the formula (II) or its salt or its reactive derivative with the compound (III) or its salt is an amide bond- or urea bond-forming reaction and can be carried out by various methods. For example, the compound (II
I) or a salt thereof (for example, a salt with an inorganic acid such as hydrochloric acid or sulfuric acid or a salt with an organic acid such as methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid), and a compound ( II) or a salt thereof (for example, a salt with an alkali metal such as sodium, potassium or magnesium, a salt with an alkaline earth metal, etc.),
Usually, an appropriate condensing agent is used, or compound (II) or a salt thereof is once converted into its reactive derivative and then compound (II
It is preferred to react with I) or a salt thereof. Examples of such condensing agents include dicyclohexylcarbodiimide,
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide, diethyl cyanophosphate, diphenylphosphoryl azide and the like are used. When using these condensing agents, it is usually a solvent (for example, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, dichloromethane,
1,2-dichloroethane, benzene, toluene, N, N
-Ethers such as dimethylformamide and dimethylsulfoxide, esters, halogenated hydrocarbons, hydrocarbons, amides, sulfoxides, etc.). This reaction may accelerate the reaction in the presence of a base,
The reaction is carried out at about -10 ° C to 100 ° C, preferably about 0 ° C to 60 ° C. Reaction time is usually 1 to 96
The time is preferably 1 to 72 hours. Compound (II
The amount of I) or a salt thereof and the condensing agent used is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to 1 mol of compound (II) or a salt thereof. As the base, for example, alkylamines such as triethylamine, cyclic amines such as N-methylmorpholine, pyridine and the like are used, and the amount thereof is 1 to 5 molar equivalents, preferably 1 to 5 molar equivalents relative to 1 mol of the compound (II) or a salt thereof. It is 1 to 3 molar equivalents.

Examples of the reactive derivative of the compound (II) include acid halides (eg chloride, bromide etc.), acid anhydrides, mixed acid anhydrides (eg methyl carbonate anhydride, ethyl carbonate anhydride, isobutyl carbonate). And the like), active ester (for example, ester with hydroxysuccinimide, ester with 1-hydroxybenzotriazole, ester with N-hydroxy-5-norbornene-2,3-dicarboximide, p-nitro Ester with phenol, ester with 8-oxyquinoline, etc.) and the like are used. When the compound (III) or a salt thereof and a reactive derivative of the compound (II) are reacted, a usual solvent (for example, chloroform, dichloromethane, 1,2-dichloroethane, ethyl ether, tetrahydrofuran, dioxane, dimethoxyethane, ethyl acetate, Halogenated hydrocarbons such as benzene, toluene, pyridine, N, N-dimethylformamide, ethers, esters, hydrocarbons, amides, etc.). This reaction may promote the reaction in the presence of a base. The reaction temperature is generally about -10 ° C to 120 ° C, preferably about 0 ° C to 100 ° C. The reaction time is usually 1 to 48 hours, preferably 1 to 24 hours. The amount of compound (III) or a salt thereof used is 1 to 5 per mol of the reactive derivative of compound (II).
It is a molar equivalent, preferably 1 to 3 molar equivalents. Examples of the base include alkylamines such as triethylamine, cyclic amines such as N-methylmorpholine and pyridine, aromatic amines such as N, N-dimethylaniline and N, N-diethylaniline, sodium carbonate and potassium carbonate. Alkali metal carbonates, alkali metal hydrogencarbonates such as sodium hydrogencarbonate, potassium hydrogencarbonate and the like are used, and the amount thereof is compound (II) or its reactive derivative 1
1 to 5 molar equivalents relative to moles, preferably 1 to 3
It is a molar equivalent. When a solvent immiscible with water is used in this reaction, water may be added to the reaction system to allow the reaction to proceed in a two-phase system.

Further, in the present method, Z of compound (II)
There The reactive derivative of -NH- or -CH ₂ NH-, compound formula (II-4)

[Chemical 36] [The symbols in the formulas have the same meanings as described above. ] The corresponding isocyanate compound represented by the following is preferably used. A urea derivative is produced by a reaction using these isocyanate compound and compound (III) or a salt thereof. In this reaction, compound (III) itself may be used as a solvent, but it can also be carried out in another solvent. Such other solvent may be any solvent as long as it does not interfere with the reaction, such as ethers (eg, diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, etc.), aromatic hydrocarbons (eg, benzene, toluene, xylene, etc.). ), Esters (eg, methyl acetate,
Ethyl acetate etc.), amides (eg N, N-dimethylformamide etc.), sulfoxides (eg dimethyl sulfoxide etc.) and the like are preferably used. Compound (II
When I) is used in the form of a salt, the reaction can be significantly advanced by adding a desalting agent if necessary.
In this case, as the desalting agent, for example, tertiary amines such as trimethylamine, triethylamine and N-methylmorpholine, aromatic amines such as pyridine, picoline and N, N-dimethylaniline are preferably used. The amount of these desalting agents used is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to 1 mole of the salt of compound (III).
The reaction temperature is generally -10 ° C to 180 ° C, preferably 0.
℃ to 120 ℃. The reaction time is usually 15 minutes to 40 hours, preferably 30 minutes to 20 hours.
The amount of compound (III) or a salt thereof used is compound (II)
Alternatively, the amount is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to 1 mol of the salt.

Method: This method comprises amine derivative (IV) or a salt thereof (for example, a salt with an inorganic acid such as hydrochloric acid or sulfuric acid, or methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid). Is a method of producing a urea derivative by the reaction of an isocyanate derivative (V) with a salt of such an organic acid). This method can be carried out in the same manner as the above-mentioned method of reacting compound (II-4) with compound (III). further,
formula

[Chemical 37] [In the formula, X ′ represents —CO— or —CH ₂ —, and other symbols have the same meanings as described above. ] The compound (I _b ) represented by

[Chemical 38] [The symbols in the formulas have the same meanings as described above. ] Or a salt thereof represented by the formula

[Chemical Formula 39] [In the formula, L represents a leaving group, and other symbols have the same meanings as described above. ] It can also be produced by reacting with a compound represented by the following or a salt thereof (as the salt, the same salt as the salt of the target compound (I) is used). In this reaction, the leaving group L of compound (XI) (eg, halogen atom such as chlorine, bromine, iodine or methanesulfonyloxy, p-toluenesulfonyloxy group, etc.) is reacted with -NH- group of compound (X). This is a reaction to give compound (I _b ) or a salt thereof.

The compound (X) may be used as it is in the free state, but may be used in the reaction as a salt, for example, an alkali metal salt such as lithium, sodium or potassium.
Compound (XI) per mole of compound (X) or salt thereof
1 to 10 mol, preferably 1 to 5 mol are reacted. Usually, the reaction is carried out in a solvent. As the solvent, for example, halogenated hydrocarbons such as dichloromethane and chloroform, nitriles such as acetonitrile, ethers such as dimethoxyethane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide, hexamethylphosphoramide and the like are preferably used. Addition of a base favors the reaction. Examples of such a base include, for example,
Sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, sodium amide, sodium methoxide, triethylamine, diisopropylethylamine, pyridine and the like are preferable. In this reaction, instead of using a base, the compound (X) is replaced with, for example, an alkali metal salt as described above,
It may be converted into an alkaline earth metal salt or the like and reacted with the compound (XI). The amount of the base used varies depending on the compounds (X) and (XI) used, the type of solvent and other reaction conditions, but is usually 1 per 1 mol of the compound (X).
To 10 mol, preferably 1 to 5 mol. The reaction temperature is about -50 ° C to 100 ° C, preferably -30.
It is carried out in the range of 80 ° C to 80 ° C. While the reaction time varies depending on the kind of compound (X) or a salt thereof, the kind of compound (XI), the reaction temperature, etc., it is 1 to 72 hours, preferably 1 to 24 hours. In addition, in the compound (I), a compound in which R is a hydrocarbon group which may be substituted is prepared by using a corresponding compound in which R is a hydrogen atom as a raw material and having the formula RL [where the symbols have the same meanings as described above]. ] The alkylating agent represented by the above can also be produced by reacting the compound (X) with the same method as the production of (I _b ) by the reaction of (XI).

Compound (I) produced by the above method
Alternatively, when the salt thereof contains a lower alkoxy group on the benzene ring in the ring A or the group represented by R or the aromatic ring represented by the ring B, a hydroxyl group may be optionally reacted with, for example, boron tribromide to give a hydroxyl group. It can also be converted to. This reaction is usually carried out in a solvent (for example, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, benzene and toluene, hydrocarbons etc.) at about -20 ° C to 80 ° C, preferably about 0 ° C to 30 ° C. Done at ℃,
The amount of boron tribromide used is 1 lower alkoxy group,
It is about 1 to 10 molar equivalents, preferably about 1 to 5 molar equivalents. The reaction time is usually 15 minutes to 24 hours,
It is preferably 30 minutes to 12 hours. In addition, the compound (I) or its salt produced by the above method is A
When the benzene ring in the ring or the group represented by R or the aromatic ring represented by B ring contains a hydroxyl group, it may be converted to an alkoxy or acyloxy group by alkylating or acylating, if necessary. You can The alkylation reaction is carried out by using a solvent (for example, alcohols such as methanol, ethanol and propanol,
In ethers such as dimethoxyethane, dioxane and tetrahydrofuran, ketones such as acetone, amides such as N, N-dimethylformamide, etc., a base (for example,
In the presence of an organic base such as trimethylamine, triethylamine, N-methylmorpholine, pyridine, picoline, N, N-dimethylaniline, an inorganic base such as potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide) Reacting with an alkylating agent such as an alkane halide (e.g., chloride, bromide, iodide, etc.) which may have, a sulfuric acid ester or a sulfonic acid ester (e.g., methane sulfonate, p-toluene sulfonate, benzene sulfonate, etc.) Done by. The reaction temperature is generally -10 ° C to 100 ° C, preferably about 0 ° C to 80 ° C. The amount of these alkylating agents used is about 1 to 5 molar equivalents, preferably about 1 to 3 molar equivalents, relative to 1 mol of the starting phenolic derivative. The reaction time is generally 15 minutes to 24 hours, preferably 30 minutes to 12 hours.

The acylation reaction is carried out by reacting the desired carboxylic acid or its reactive derivative. This reaction varies depending on the type of acylating agent and the type of raw material phenolic derivative, but is usually a solvent (for example, benzene, toluene, ethyl ether, ethyl acetate, chloroform,
Dichloromethane, dioxane, tetrahydrofuran,
N, N-dimethylformamide, hydrocarbons such as pyridine, ethers, esters, halogenated hydrocarbons,
Amides, aromatic amines, etc.) and an appropriate base for promoting the reaction (for example, hydrogen carbonate such as sodium hydrogen carbonate, potassium hydrogen carbonate, etc., carbonate such as sodium carbonate, potassium carbonate, etc., sodium acetate, etc. Of the above, tertiary amines such as triethylamine, and aromatic amines such as pyridine). Examples of the reactive derivative of carboxylic acid include acid anhydride, mixed acid anhydride, and acid halide.
(For example, chloride, bromide, etc.) and the like are used. The amount of these acylating agents used is 1 to 5 molar equivalents, preferably 1 to 3 molar equivalents, relative to 1 mol of the starting phenolic derivative. The reaction temperature is generally 0 ° C to 150 ° C, preferably about 10 ° C to 100 ° C. The reaction time is generally 15 minutes to 12 hours, preferably 30 minutes to 6 hours.

When the compound (I) is obtained in a free state by the above method, for example, a mineral acid (for example, hydrochloric acid, sulfuric acid, hydrobromic acid, etc.), an organic acid (for example, methanesulfone) can be used according to a conventional method. Acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.) and the like, and when the compound (I) is obtained in the form of a salt, according to a conventional method, It can also be converted to the free form or other salts. The target compound (I) or a salt thereof obtained by the above method is a separation and purification means known per se (for example, concentration, solvent extraction, column chromatography, recrystallization, etc.).
Can be used for purification and collection.

The starting material (II) or a salt thereof used for producing the compound (I) of the present invention or a salt thereof includes a part of known compounds. For example, the following methods 1) to 4) or modifications thereof It can be advantageously produced by the above method. 1) formula

[Chemical 40] [The symbols in the formulas have the same meanings as described above. The compound (II-1) represented by the following] can be produced by, for example, the following methods A), B), C) and D). A): Reaction formula using carboxylic acid derivative (XII) as a starting material

[Chemical 41] [Wherein R ′ and R ″ are carboxyl-protecting groups and the other symbols have the same meanings as defined above] to produce the compound (II-1). Examples of the protecting groups R ′ and R ″ of are methyl, ethyl, methoxymethyl, methoxyethoxymethyl, benzyloxymethyl, tert-butyl, benzyl,
Protecting groups of the ester-forming type such as p-methoxybenzyl, p-nitrobenzyl, o-nitrobenzyl, benzhydryl, trityl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl, allyl; for example, trimethylsilyl, triethyl. Examples thereof include silyl ester-forming protecting groups such as silyl, tert-butyldimethylsilyl, isopropyldimethylsilyl, and dimethylphenylsilyl.

In this method, the compound (XII) is first converted into the compound of the formula (XII
I) L-CH ₂ CO ₂ R ″ [wherein the symbols have the same meanings as defined above] is reacted with and alkylated. The alkylation reaction is usually carried out in a solvent (eg, tetrahydrofuran, dioxane). , Ethers such as dioxane, amides such as dimethylformamide, etc.) and a base (eg, sodium hydride, potassium hydride, sodium methylate, sodium ethylate, sodium amide, potassium, t-butoxy, etc.) It is preferred that the reaction is carried out in the presence of.
It can be carried out at a temperature of ° C. When the protecting group R'is removed from the alkyl compound and it is subjected to a decarboxylation reaction, the compound (II-1 ') is obtained.
Alternatively, it is converted to (II-1). The method for removing the protecting group R'depends on the type of the protecting group used, but when R'is a lower alkyl group such as methyl or ethyl, it is carried out by a hydrolysis reaction. This hydrolysis reaction is usually carried out (for example, alcohol such as methanol, ethanol, propanol, organic acid such as acetic acid) in a mineral acid (for example, hydrochloric acid,
The treatment is carried out in the presence of an aqueous solution of hydrobromic acid, sulfuric acid or the like) or a metal hydroxide (eg sodium hydroxide, potassium hydroxide or the like) at a temperature of about 15 ° C to 130 ° C. At this time, when R ″ is a lower alkyl group such as methyl and ethyl as in R ′, R ″ may be removed and isolated as a dicarboxylic acid. The carboxylic acid from which R'has been removed undergoes a decarboxylation reaction by heating to give the compound (II-
1 ') is obtained. At this time, in the case where R ′ and R ″ are both dicarboxylic acids removed, the compound (II-1) may be directly obtained by the decarboxylation reaction. , Pyridine, picoline,
Benzene, toluene, dimethylsulfoxide, dimethylformamide, acetic acid, etc.) at a temperature of about 40 ° C to 200 ° C. The compound (II-
R ′ of 1 ′) can be removed by a deprotection reaction depending on the type and converted to compound (II-1).

B): Formula in which the protective group for the carboxyl group of compound (XII) is removed

[Chemical 42] The reaction generally known as the Arndt-Eistert reaction from the carboxylic acid (XV) represented by the formula [F. Arndt et al., Chemish Berichte (Ch
emische Berichte), 68, p. 200 (published in 1935)], the carboxy group of (XV) is increased by 1 carbon by using diazomethane to obtain a compound (II-1 '). The protecting group for the carboxyl group of the compound (II-1 ′) is removed by a method similar to the method described in A) above,
A compound (II-1) is obtained.

C): The carboxyl group of the compound (XV) is increased by 1 carbon stepwise by the following method, and the compound (II-
This is a method of obtaining 1).

[Chemical 43] [The symbols in the formulas have the same meanings as described above. In this method, first, the carboxyl group is reduced to an alcohol. In this reduction, the carboxyl group is converted to its reactive derivative (eg, acid halide, mixed acid anhydride, active ester, ester, etc.), and the reducing agent (eg, sodium borohydride, lithium aluminum hydride, etc.) and solvent are used. (For example, ethers such as tetrahydrofuran and dimethoxyethane) at a reaction temperature of about 0 ° C to 100 ° C. The hydroxyl group of the alcohol thus obtained is converted into a leaving group (-OH → -L). Leaving group L
Is halogen (eg chlorine, bromine, iodine, etc.),
C _1-4 alkanesulfonyloxy group (e.g., methanesulfonyloxy, ethanesulfonyloxy, etc.), C _6-10
An arylsulfonyloxy group (eg, benzenesulfonyloxy, p-toluenesulfonyloxy, etc.) is preferably used. The conversion reaction is usually carried out in a solvent (for example, benzene, toluene, dichloromethane, 1,2-dichloroethane, chloroform, tetrahydrofuran, ethyl acetate, etc.), and for example, thionyl chloride, thionyl bromide, methanesulfonyl chloride, benzenesulfonyl chloride. Etc. at temperatures of about 0 ° C to 100 ° C. Then, the leaving group of the compound is converted to a nitrile group (-L → -CN).
To be done. This reaction is usually carried out by treating with a cyanide compound such as sodium cyanide, potassium cyanide, copper cyanide or the like in a solvent (eg, dimethylsulfoxide, dimethylformamide, acetone, etc.) at a temperature of 0 ° C to 100 ° C. The nitrile compound is hydrolyzed to give a compound (II-
The carboxylic acid of 1) is produced. This hydrolysis reaction is usually carried out in a solvent (eg alcohol such as methanol, ethanol, propanol, acetic acid etc.) with a mineral acid (eg hydrochloric acid, hydrobromic acid, sulfuric acid etc.) or a metal hydride (eg sodium hydride). , Potassium hydride, etc.) at a temperature of about 15 ° C. to 130 ° C.

D): formula

[Chemical 44] [The symbols in the formulas have the same meanings as described above. ] The compound (XVI) represented by this is subjected to an alkylation reaction using the compound (XIII). This reaction is carried out by a method similar to the conversion of compound (XII) to compound (XIV) described in A) above, and the resulting compound (II-1 ′) is also prepared by the same method as described in A). Converted to compound (II-1). The starting compounds (XI) used in A) to C) above
I) can be produced by various methods. For example, in the compound (XII), X is —CH ₂ —

[Chemical formula 45] [The symbols in the formulas have the same meanings as described above. ] It can manufacture by reducing the double bond of the 3rd and 4th positions of the compound represented by this.

This reaction can be carried out by various methods.
For example, a method of reduction in the presence of a metal catalyst for catalytic reduction is preferably used. Examples of catalysts used in this catalytic reduction method include platinum catalysts such as platinum black, platinum oxide and platinum carbon, palladium catalysts such as palladium black, palladium oxide, barium sulfate and palladium carbon, reduced nickel and nickel oxide. , Raney nickel, lacquer nickel, and other nickel catalysts. This reaction is usually carried out in a solvent, formic acid, acetic acid, using an organic acid such as propionic acid as a solvent, methanol, ethanol, propanol, alcohols such as isopropanol, tetrahydrofuran, ethers such as dioxane,
Esters such as ethyl acetate are used as a solvent in the presence of the above-mentioned organic acid or an inorganic acid such as phosphoric acid, sulfuric acid or hydrochloric acid. The reaction temperature is 0 ° C to 200 ° C, preferably 2
It is carried out at 0 ° C to 110 ° C. Reaction time is usually 0.
It is 5 to 48 hours, preferably 1 to 16 hours. The reaction is usually carried out under normal pressure, but if necessary, it is carried out under pressure (3 to 10 atm). The amount of the catalyst used varies depending on the kind of the catalyst, but is usually 0.1 to 10% (w / w) with respect to (XVII). The reduction reaction is also carried out using the metal hydride in an inert solvent. For example, lithium aluminum hydride or the like is preferably used. As the reaction solvent, for example, ethers such as dioxane and tetrahydrofuran, or hydrocarbons such as benzene and toluene can be used alone or as a mixture. The reaction temperature is generally about -100 ° C to 40 ° C, preferably about -80 ° C to 25 ° C. The reaction time is usually 5 minutes to 10 hours, preferably 10 minutes to 5
It's time. The amount of reducing agent used is usually 1 to 2 equivalents relative to compound (XVII). Further, among the compounds (XII), the compound in which X is —S— can be prepared by a known method [for example, Masahiro Kajino et al., Chemical Pharmaceutical Bulletin, Vol. 39, 2888-28].
95 (issued 1991)] or a method analogous thereto, and by the same method, X is -O- or-.
Compounds that are NR ¹ − can also be prepared.

2) In the compound (II-1), X is -O-.
Compounds and formulas that are

[Chemical formula 46] [The symbols in the formulas have the same meanings as described above. The compound represented by the formula [] is known in the art [for example, Yutaka Masuoka et al., Chem. Pharm. Bul.
l.), 34, 130-139 (issued in 1986)] or a method according thereto. 3) Expression

[Chemical 47] [The symbols in the formulas have the same meanings as described above. The compound represented by the formula [] is a known method [for example, MS Malamas (MS
Malamas) et al., Journal of Medicinal Chemistry (J. Med. Chem.), 34, 1492-15.
03 (published in 1991) or Shizuyoshi Fujimori et al., Japanese Patent Laid-Open Publication No. 3-181469 (published in 1991)] or a method according thereto.

4) In the isocyanate compound represented by the formula (II-4), Z is --NH-- or --CH ₂ NH in the formula (II).
-Corresponds to the compound being. Compound (II-4) is a compound having a corresponding skeleton

[Chemical 48] [The symbols in the formulas have the same meanings as described above. ] It can manufacture by the method of converting the carboxyl group of the carboxylic acid derivative represented by this to an isocyanate group. Various methods are known in the literature, and any method can be applied to the compound (II-5).

For example, the compound (II-5) is obtained by reacting an azidating agent [eg diphenylphosphoryl azide (hereinafter abbreviated as DPPA)] with the compound (II-5).
The acid azide compound can be produced. This reaction is usually
Solvents inert to the reaction (e.g. ethyl ether,
Ethers such as ropyl ether, dimethoxyethane, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as methyl acetate and ethyl acetate, ketones such as acetone and 2-butanone, pyridine and the like. Aromatic amines, amides such as N, N-dimethylformamide, and the like). The reaction may be allowed to proceed in the presence of a base (eg, trimethylamine, triethylamine, N-methylmorpholine, etc.). The reaction time is usually about 5 minutes to 12 hours,
It is preferably about 10 minutes to 6 hours. The reaction temperature is generally about -10 ° C to 150 ° C, preferably about -5 ° C to 120 ° C. Azidating agent (eg DPPA
Etc.) is used in an amount of 1 to 3 molar equivalents, preferably 1 to 2 molar equivalents, relative to compound (II-5). The generated acid azide can be isolated and purified by a means known per se, but usually the reaction solution is heated as it is without being isolated and converted into the isocyanate compound (II-4). For this conversion reaction, it is preferable to use the same solvent as used for the azidation, usually about 20 ° C to 200 ° C, preferably about 30 ° C.
To 150 ° C. The reaction time is usually about 5 minutes to 10 hours, preferably about 5 minutes to 6 hours. The obtained compound (II-4) is isolated by a method known per se, or the compound is isolated without isolation.
It can be used as a raw material for producing (I _a ).

The starting compound (IV) used for producing the compound ( _Ia ) contained in the compound (I) of the present invention or a salt thereof is the same as the above-mentioned compound (II-4) except that the isocyanate group is converted into an amino group. It can be manufactured by This step is usually performed under hydrolysis conditions. This reaction is performed, for example, in a solvent (for example, alcohols such as methanol, ethanol, propanol, butanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane, etc., or a mixed solvent thereof), for example, sodium hydroxide, water. It is carried out under alkaline conditions using an alkali or hydroxide of an alkaline earth metal such as barium oxide, or under acidic conditions using an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid. The reaction temperature is usually about 0 ° C to 1
20 ° C, preferably about 15 ° C to 100 ° C. The reaction time is about 30 minutes to 36 hours, preferably about 1
Hours to 20 hours. Of the raw material compound (II),
The compound in which W and / or X is -CS- can be produced by reacting the compound (II) in which W and / or X is -CO- with an appropriate sulfide.
Examples of the sulfide used in this reaction include phosphorus pentasulfide, Lowesson reagent and the like. This reaction is usually carried out under anhydrous conditions in a solvent such as dichloromethane, chloroform, dioxane, tetrahydrofuran, benzene, and toluene. The amount of sulfide used is
The amount is equimolar or more, preferably 2 to 5 mol, and the reaction temperature is 20 ° C to 120 ° C. The reaction time is usually 1 to 8 hours, varying depending on the kind of the raw material compound or sulfide, the reaction temperature and the like. In the method for producing the compounds (I), (I ′) of the present invention and the starting compounds thereof, when the starting compounds contain a reactive group such as an amino group, a hydroxyl group or a carboxyl group as a substituent, it may be necessary. Accordingly, it is also possible to use, as a raw material, one having a protective group introduced according to a conventional method. And the introduced protecting group is removed by subjecting it to a deprotection reaction according to a conventional method after the completion of the reaction, if necessary, to give the desired compound (I),
It is also possible to obtain (II) or a synthetic intermediate thereof or a salt thereof. As such a protecting group, for example, those used in the field of peptides are appropriately adopted, and among them, as the protecting group for an amino group, for example, formyl, chloroacetyl, tertiary butoxycarbonyl, benzyloxycarbonyl, p- Preferred are methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-trimethylsilylethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl and trityl. Examples of the protecting group for a hydrosyl group include chloroacetyl, benzyl, p-nitrobenzyl, methylthiomethyl, methoxymethyl, trimethylsilyl, tertiary butyldimethylsilyl, 2-tetrahydropyranyl, 4-methoxy-4-tetrahydropyranyl, p-Nitrobenzyloxycarbonyl, allyloxycarbonyl and the like are used. Examples of the protecting group for the carboxyl group include benzyl, benzhydryl, trityl, p-methoxybenzyl, p-nitrobenzyl, tertiary butyl, allyl and the like.

In the above-mentioned production method, when an amino group or a carboxyl group is contained in the starting compound or synthetic intermediate, etc., if necessary, for example, an inorganic acid (for example, hydrochloric acid, sulfuric acid, hydrogen bromide, etc.) can be prepared by a conventional method. Acid, etc.), organic acid (eg, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, oxalic acid, fumaric acid, maleic acid, tartaric acid, etc.), inorganic base (eg, alkali metal such as sodium, potassium, calcium, magnesium, etc.) Alkaline earth metal, aluminum or ammonium) or a salt with an organic base (eg trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N′-dibenzylethylenediamine) Can also . The compound obtained in each step may be purified and collected by a purification means known per se, such as concentration, liquid conversion, phase transfer, solvent extraction, column chromatography, crystallization, recrystallization, or the like, or a mixture of Alternatively, each may be used for the next step reaction.

The compound (I) or a pharmaceutically acceptable salt thereof (for example, a salt with the above-mentioned inorganic or organic base, or a salt with an inorganic or organic acid, etc.) is an excellent acyl-CoA:
It has an inhibitory effect on cholesterol acyltransferase (ACAT), is weak in both acute toxicity and toxicity by continuous administration, and is safe as a medicine. ACAT is an enzyme involved in higher fatty acid esterification of cholesterol in cells, and plays an important role in absorption as cholesterol ester and accumulation as cholesterol ester in peripheral organs, cells (eg, arterial wall, macrophage, etc.). Is known to play. Therefore AC
The AT inhibitory substance inhibits the absorption of dietary cholesterol from the intestinal tract, suppresses the increase of blood cholesterol level, suppresses the accumulation of intracellular cholesterol ester in the arteriosclerotic lesion, and may prevent the development of atherosclerosis. it can. Therefore, the compound (I) of the present invention or a salt thereof having an excellent ACAT inhibitory action is provided in mammals (for example, mouse,
Rat, hamster, rabbit, cat, dog, horse, cow, sheep, monkey, human etc.) hypercholesterolemia, atherosclerosis, and diseases caused by these (for example, ischemic heart disease such as myocardial infarction and It is useful as a safe preventive / therapeutic agent for cerebrovascular accidents such as cerebral infarction and stroke.

Further, the compound (I) or a salt thereof includes one having an action of suppressing the production of lipid peroxide (antioxidant action) (for example, in the formula (I), the ring A and the ring B are A compound in which one is a benzene ring substituted with an amino group or a hydroxyl group which may be substituted with a C _1-4 alkyl group). It is known that lipid peroxidation in the living body is closely related to the development of arteriosclerosis and ischemic diseases in the brain and cardiovascular system. Therefore, the compound (I) or its salt having both ACAT inhibitory action and antioxidant action is
Since both blood cholesterol and lipid peroxide can prevent and treat various vascular lesions caused by these, they are highly useful as pharmaceuticals.

When the compound represented by the formula (I) or a pharmaceutically acceptable salt thereof is used as the above-mentioned medicine, an appropriate pharmacologically acceptable carrier or excipient (eg starch, lactose, sucrose, Calcium carbonate, calcium phosphate, etc.), binders (eg starch, arabic gum, carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, alginic acid, gelatin, polyvinylpyrrolidone etc.), lubricants (eg stearic acid, magnesium stearate, calcium stearate talc) Etc.), a disintegrant (eg calcium carboxymethyl cellulose, talc etc.), a diluent (eg physiological saline etc.) and the like, and powders, fine granules, granules, tablets, capsules or injections etc. are prepared by a conventional method. Administered in oral form orally or parenterally Possible, when used for the purpose of absorption inhibition of cholesterol is more preferably administered orally. The dose varies depending on the type of compound (I) or its salt, administration route, symptoms, age of the patient, etc., but when administered orally to an adult patient with hypercholesterolemia, the daily dose is 1 kg body weight. About 0.005 to 5
0 mg, preferably about 0.05 to 10 mg, more preferably about 0.2 to 4 mg, this amount being 1 to 3 per day.
It is preferable to administer in divided doses.

[0043]

The compound (I) of the present invention or a salt thereof has excellent A
Although it has a CAT inhibitory action, the results of its pharmacological tests are shown below. (1) Inhibition of acyl-CoA: cholesterol acyltransferase (ACAT) [Experimental method] The enzyme preparation ACAT was prepared by Heider et al., Journal of Lipid Research [Journal of L
ipid Research], 24, 1127 (1982), and prepared from the small intestinal mucosal microsome fraction of 6-week-old male Sprague-Dawley rats fasted for 20 hours. The ACAT activity is determined by the method of Helgerud et al. (Journal of Lipid Research, Vol. 22, 271).
Page, according to 1981), [1- ¹⁴ C] oleoyl -
It was calculated by measuring the amount of labeled cholesterol ester produced from CoA and endogenous cholesterol.

[Results] (1) [Table 1] shows the test compounds (Examples 1 and 2 below).
The inhibitory rate (%) of labeled cholesterol ester formation when 10 ⁻⁶ M of the compound obtained in 9) was added is shown as an index of the ACAT inhibitory effect.

[Table 1] [Table 1] shows that the compound (I) or a salt thereof has excellent ACA
It is shown to have a T inhibitory effect.

[0045]

The present invention will be further described in detail in the following reference examples and examples, but these examples are merely illustrative and do not limit the present invention, and do not depart from the scope of the present invention. You may change with. Elution by column chromatography in Reference Examples and Examples was carried out under observation by TLC (Thin Layer Chromatography) unless otherwise specified. In TLC observation, 60F ₂₅₄ manufactured by Merck Co. as a TLC plate, a solvent used as an elution solvent in column chromatography as a developing solvent, and U as a detection method were used.
A V detector was adopted. The silica gel for column chromatography is silica gel 60 (70-230, manufactured by Merck & Co., Inc.).
Mesh) was used. Room temperature usually means about 10 ° C to 35 ° C. Sodium sulfate or magnesium sulfate was used for drying the extract. Abbreviations in Examples and Reference Examples mean the following. DMF: dimethylformamide, THF: tetrahydrofuran, Hz: Hertz, J: coupling constant, m: multiplet, q: quartet, t: triplet, d: doublet, s: singlet, b: broad, brs: broad singlet.

Example 1 N- [2,6-bis (1-methylethyl) phenyl]-
N '-(1,2,3,4-tetrahydro-2-oxo-
1-Phenyl-3-quinolyl) urea 1,2,3,4-tetrahydro-2-oxo-1-phenyl-3-quinolinecarboxylic acid (250 mg) in anhydrous benzene (10 ml) was suspended in diphenylphosphoryl azide (0 .262 ml) and triethylamine (0.143
ml) was added, and the mixture was stirred at room temperature for 1 hour and then with heating under reflux for 2 hours. This reaction solution (containing 1,2,3,4-tetrahydro-2-oxo-1-phenylquinoline-3-isocyanate) contained 2,6-diisopropylaniline (0.
(212 ml) was added and the mixture was stirred with heating under reflux for 10 hours. The solvent was evaporated, ethyl acetate was added to the residue, water, diluted hydrochloric acid,
The title compound was colorless crystals (138 mg) when the solvent was distilled off after washing with water, aqueous sodium hydrogen carbonate and water successively.
Was obtained as. Melting point 246-247 ° C (recrystallized from ethyl acetate-methanol) NMR (200MHz, CDCl ₃ ) ppm: 1.14-1.32 (m, 12H), 2.87
(t, 1H, J = 14.0Hz), 3.26-3.40 (m, 2H), 3.60 (dd, 1H, J = 5.
8,14.8Hz), 4.68 (dt, 1H, J = 4.4,13.2Hz), 5.44 (brs, 1H),
5.80 (brs, 1H), 6.36 (dd, 1H, J = 2.8,6.8Hz), 7.02-7.52
(m, 12H) Elemental analysis _{C 28 H 31 N 3 O 2} · 0.25H 2 O Calculated C, 75.39; H, 7.00; N, 9.4
2 Found C, 75.41; H, 6.82; N, 9.7.
5 1,2,3,4-Tetrahydro having the corresponding substituents instead of 1,2,3,4-tetrahydro-2-oxo-1-phenyl-3-quinoline-3-carboxylic acid of Example 1. By using 2-oxo-3-quinoline-3-carboxylic acid in the same manner as in Example 1, the compounds of Examples 2 to 8 were obtained.

Example 2 N- [2,6-bis (1-methylethyl) phenyl]-
N '-(1,2,3,4-tetrahydro-2-oxo-
1-Phenylmethyl-3-quinolyl) urea Melting point 198-199 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 1.07-1.39 (m, 12H), 2.76
(t, 1H, J = 14.4Hz), 3.29-3.42 (m, 2H), 3.51 (dd, 1H, J = 6.
2,15.2Hz), 4.56-4.70 (m, 1H), 4.87 (d, 1H, J = 16.0Hz),
5.33 (d, 1H, J = 16.6Hz), 5.51 (brs, 1H), 6.02 (brs, 1H),
6.85 (d, 1H, J = 8.0Hz), 6.94-7.40 (m, 11H) Elemental analysis C ₂₉ H ₃₃ N ₃ O ₂ Calculated C, 76.45; H, 7.30; N, 9. Two
2 Found C, 76.45; H, 7.10; N, 9.4.
3 Example 3 N- [2,6-bis (1-methylethyl) phenyl]-
N '-[1- (2-chlorophenyl) methyl-1,2,
3,4-Tetrahydro-2-oxo-3-quinolyl] urea Melting point 230-232 ° C (recrystallized from ethyl acetate) NMR (200MHz, CDCl ₃ ) ppm: 1.24 (d, 12H, J = 6.8Hz), 2.
80 (t, 1H, J = 14.6Hz), 3.28-3.45 (m, 2H), 3.53 (dd, 1H, J =
5.8,13.4Hz), 4.69 (dt, 1H, J = 4.0,14.4Hz), 4.91 (d, 1H, J
= 17.2Hz), 5.46 (d, 1H, J = 17.4Hz), 5.91 (brs, 1H), 5.93
(brs, 1H), 6.68 (d, 1H, J = 8.4Hz), 6.86 (d, 1H, J = 6.6Hz),
7.02-7.44 (m, 9H) Elemental analysis value Calculated value as C ₂₉ H ₃₂ N ₃ O ₂ Cl · 0.25H ₂ O C, 70.43; H, 6.52; N, 8.5
0 Found C, 70.30; H, 6.48; N, 8.4
1 Example 4 N- [2,6-bis (1-methylethyl) phenyl]-
N '-[1- (3-chlorophenyl) methyl-1,2,
3,4-Tetrahydro-2-oxo-3-quinolyl] urea Melting point 194-195 ° C. (recrystallized from ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.12-1.38 (m, 12H), 2.76
(t, 1H, J = 14.2Hz), 3.27-3.40 (m, 2H), 3.50 (dd, 1H, J = 6.
0,14.8Hz), 4.63 (dt, 1H, J = 5.8,13.4Hz), 4.82 (d, 1H, J = 1
6.2Hz), 5.29 (d, 1H, J = 16.2Hz), 5.46 (brs, 1H), 6.00 (br
s, 1H), 6.79 (d , 1H, J = 8.0Hz), 6.96-7.40 (m, 10H) Elemental analysis C ₂₉ H ₃₂ N ₃ O ₂ Calculated as Cl C, 71.08; H, 6 . 58; N, 8.5
7 Found C, 71.04; H, 6.70; N, 8.4.
1

Example 5 N- [2,6-bis (1-methylethyl) phenyl]-
N '-[1- (4-chlorophenyl) methyl-1,2,
3,4-Tetrahydro-2-oxo-3-quinolyl] urea Melting point 212-214 ° C. (recrystallized from ethyl acetate-methanol) NMR (200 MHz, CDCl ₃ ) ppm: 1.12-1.38 (m, 12H), 2.75
(t, 1H, J = 14.8Hz), 3.23-3.42 (m, 2H), 3.49 (dd, 1H, J = 5.
6,14.4Hz), 4.62 (dt, 1H, J = 5.2,14.0Hz), 4.86 (d, 1H, J = 1
6.0Hz), 5.26 (d, 1H, J = 16.2Hz), 5.45 (brs, 1H), 5.91 (br
s, 1H), 6.80 (d, 1H, J = 7.4Hz), 6.98-7.40 (m, 10H) Elemental analysis value C ₂₉ H ₃₂ N ₃ O ₂ Cl Calculated value C, 71.08; H, 6. 58; N, 8.5
7 Found C, 70.75; H, 6.58; N, 8.3
7 Example 6 N- [2,6-bis (1-methylethyl) phenyl]-
N '-(1,2,3,4-tetrahydro-6-methyl-
2-Oxo-1-phenylmethyl-3-quinolyl) urea melting point 205-206 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 1.12-1.38 (m, 12H), 2.25
(s, 3H), 2.72 (t, 1H, J = 14.4Hz), 3.28-3.52 (m, 3H), 4.58
(dt, 1H, J = 5.4,13.4Hz), 4.88 (d, 1H, J = 16.2Hz), 5.27 (d,
1H, J = 16.2Hz), 5.51 (brs, 1H), 5.85 (brs, 1H), 6.73 (d, 1
H, J = 8.4Hz), 6.91 (d, 1H, J = 7.4Hz), 7.01 (s, 1H), 7.08-
7.40 (m, 8H) Elemental analysis C ₃₀ H ₃₅ N ₃ O ₂ Calculated C, 76.73; H, 7.51; N, 8.9
5 Found C, 76.38; H, 7.50; N, 8.9.
6

Example 7 N- [2,6-bis (1-methylethyl) phenyl]-
N '-(6-chloro-1,2,3,4-tetrahydro-
2-oxo-1-phenylmethyl-3-quinolyl) urea melting point 217-220 ° C. (recrystallized from ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.24 (d, 12H, J = 7.2 Hz), 2.
73 (t, 1H, J = 14.6Hz), 3.24-3.51 (m, 3H), 4.59 (dt, 1H, J =
5.2,14.0Hz), 4.88 (d, 1H, J = 16.0Hz), 5.26 (d, 1H, J = 16.6
Hz), 5.42 (brs, 1H), 6.21 (brs, 1H), 6.76 (d, 1H, J = 8.8H
z), 7.02-7.19 (m, 10H) Elemental analysis value C ₂₉ H ₃₂ N ₃ O ₂ Cl
Calculated as C, 71.08; H, 6.58; N, 8.5
7 Found C, 70.96; H, 6.44; N, 8.6.
6 Example 8 N- [2,6-bis (1-methylethyl) phenyl]-
N '-(7-chloro-1,2,3,4-tetrahydro-
2-oxo-1-phenylmethyl-3-quinolyl) urea melting point 247-248 ° C. (recrystallized from ethyl acetate-methanol) NMR (200 MHz, CDCl ₃ ) ppm: 1.11-1.38 (m, 12H), 2.70
(t, 1H, J = 13.8Hz), 3.24-3.40 (m, 2H), 3.49 (dd, 1H, J = 6.
0,14.8Hz), 4.59 (dt, 1H, J = 5.0,14.2Hz), 4.87 (d, 1H, J = 1
6.8Hz), 5.26 (d, 1H, J = 16.4Hz), 5.44 (brs, 1H), 5.79 (br
s, 1H), 6.85 (d, 1H, J = 1.8Hz), 6.97 (dd, 1H, J = 1.8,8.0H
z), 7.10-7.38 (m, 9H) Elemental analysis value Calculated value as C ₂₉ H ₃₂ N ₃ O ₂ Cl C, 71.08; H, 6.58; N, 8.5
7 Found C, 70.97; H, 6.54; N, 8.4
7

Example 9 N- [2,6-bis (1-methylethyl) phenyl]-
1,2,3,4-tetrahydro-2-oxo-1-phenyl-3-quinoline acetamide 1,2,3,4-tetrahydro-2-oxo-1-phenyl-3-quinolineacetic acid (250 mg) Anhydrous THF (1
0 ml) solution to oxalyl chloride (0.111 ml) and D
MF (1 drop) was added at room temperature and stirred for 1 hour. The solvent was distilled off and the residue was dissolved in anhydrous THF (8 ml). 2,6-diisopropylaniline (0.184 m
l) and triethylamine (0.186 ml) anhydrous T
An HF (20 ml) solution was added and the mixture was stirred at room temperature for 15 hours. The solvent was distilled off, ethyl acetate was added to the residue, and the mixture was washed successively with water, diluted hydrochloric acid, water, aqueous sodium hydrogencarbonate and water, dried and the solvent was distilled off to give the title compound as colorless crystals (1
76 mg). Melting point 198-200 ° C. (recrystallized from ethyl acetate-methanol) NMR (200 MHz, CDCl ₃ ) ppm: 1.17 (d, 6H, J = 6.8 Hz), 1.1
8 (d, 6H, J = 6.8Hz), 2.82 (dd, 1H, J = 3.4,13.8Hz), 3.00-3.
38 (m, 6H), 6.38-6.43 (m, 1H), 7.00-7.30 (m, 8H), 7.38-7.
58 (m, 3H), 8.00 (brs, 1H) Elemental analysis value Calculated value as C ₂₉ H ₃₂ N ₂ O ₂ C, 79.06; H, 7.32; N, 6.3
6 Found C, 78.81; H, 7.48; N, 6.3.
7

Example 10 N- [2,6-bis (1-methylethyl) phenyl]-
1,2,3,4-Tetrahydro-2-oxo-1-phenylmethyl-3-quinoline acetamide N- [2,6-bis (1-methylethyl) phenyl]-
Sodium hydride (60% oily) (28.5 mg) was added to a solution of 1,2,3,4-tetrahydro-2-oxo-3-quinoline acetamide (200 mg) in DMF (5 ml), and the mixture was stirred at room temperature for 30 minutes. Stir it. Benzyl bromide (0.085 ml) was added to this mixture under ice-water cooling, and the mixture was stirred at room temperature for 2.5 hr. The reaction solution was concentrated, ethyl acetate was added to the residue, washed with water and dried, and then the solvent was distilled off. The residue was separated and purified by column chromatography (hexane-ethyl acetate = 5: 1) using silica gel (20 g) to give the title compound as colorless crystals (132 mg). Melting point 184-185 ° C NMR (200MHz, CDCl ₃ ) ppm: 1.18 (d, 12H, J = 7.0Hz), 2.
77 (dd, 1H, J = 3.8,13.8Hz), 3.00-3.42 (m, 6H), 4.88 (d, 1
H, J = 16.6Hz), 5.52 (d, 1H, J = 16.6Hz), 6.90 (d, 1H, J = 8.0H
z), 6.98-7.38 (m, 11H), 7.99 (brs, 1H) Elemental analysis value Calculated as C ₃₀ H ₃₄ N ₂ O ₂ C, 79.26; H, 7.54; N, 6.1
6 Found C, 79.27; H, 7.71; N, 6.3.
3 Instead of 1,2,3,4-tetrahydro-2-oxo-1-phenylquinoline-3-acetic acid of Example 9, 1,2,3,4-tetrahydro-2- having the corresponding substituents
Using oxoquinoline-3-acetic acid, the procedure of Example 9 was repeated to give compounds of Examples 11-14. Example 11 N- [2,6-bis (1-methylethyl) phenyl]-
1,2,3,4-Tetrahydro-1- (4-methoxyphenyl) methyl-2-oxo-3-quinoline acetamide Melting point 144-146 ° C. (recrystallized from isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm : 1.18 (d, 12H, J = 6.8Hz), 2.
76 (dd, 1H, J = 3.8,14.0Hz), 3.00-3.34 (m, 6H), 3.78 (s, 3
H), 4.85 (d, 1H, J = 16.0Hz), 5.44 (d, 1H, J = 16.0Hz), 6.85
(d, 2H, J = 8.8Hz), 6.90 (d, 1H, J = 8.4Hz), 7.04 (d, 1H, J = 7.
4Hz), 7.10-7.38 (m, 7H), 7.99 (brs, 1H) Elemental analysis value Calculated value as C ₃₁ H ₃₆ N ₂ O ₃ C, 76.83; H, 7.49; N, 5.7
8 Found C, 76.57; H, 7.38; N, 5.9.
0

Example 12 N- [2,6-bis (1-methylethyl) phenyl]-
1,2,3,4-Tetrahydro-6-methyl-2-oxo-1-phenylmethyl-3-quinoline acetamide Melting point 128-130 ° C. (recrystallized from ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.17 (d, 12H, J = 7.0Hz), 2.
25 (s, 3H), 2.70-2.84 (m, 1H), 2.96-3.30 (m, 6H), 4.88
(d, 1H, J = 16.0Hz), 5.48 (d, 1H, J = 16.6Hz), 6.78 (d, 1H, J =
8.2Hz), 6.90-7.38 (m, 10H), 8.10 (brs, 1H) Elemental analysis value Calculated value as C ₃₁ H ₃₆ N ₂ O ₂ C, 79.45; H, 7.74; N, 5.9
8 Found C, 79.47; H, 7.99; N, 5.7.
7 Example 13 N- [2,6-bis (1-methylethyl) phenyl]-
6-chloro-1,2,3,4-tetrahydro-2-oxo-1-phenylmethyl-3-quinoline acetamide Melting point 194-196 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 1.18 (d, 12H, J = 7.0Hz), 2.
75 (dd, 1H, J = 4.2,14.0Hz), 2.99-3.26 (m, 6H), 4.90 (d, 1
H, J = 16.6Hz), 5.46 (d, 1H, J = 16.4Hz), 6.81 (d, 1H, J = 8.8H
z), 7.08-7.39 (m, 11H), 7.76 (brs, 1H) Elemental analysis value Calculated value as C ₃₀ H ₃₃ N ₂ O ₂ Cl C, 73.68; H, 6.80; N, 5.7
3 Found C, 73.60; H, 6.66; N, 5.9.
9

Example 14 N- [2,6-bis (1-methylethyl) phenyl]-
1-Cyclohexylmethyl-1,2,3,4-tetrahydro-2-oxo-3-quinoline acetamide Melting point 192-193 ° C. (recrystallized from isopropyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 0.98-1.80 ( m, 11H), 1.19
(d, 12H, J = 6.8Hz), 2.60-2.78 (m, 1H), 2.91-3.18 (m, 6H),
3.76-3.98 (m, 2H), 6.97-7.35 (m, 7H), 8.03 (brs, 1H) Elemental analysis C ₃₀ H ₄₀ N ₂ O ₂ Calculated C, 78.22; H, 8.75; N, 6.0
8 Found C, 78.18; H, 8.50; N, 6.3.
6 Example 15 N- [2,6-bis (1-methylethyl) phenyl]-
1-[(1,1-dimethylethoxy) carbonylmethyl] -1,2,3,4-tetrahydro-2-oxo-3
-Quinoline acetamide 1-[(1,1-dimethylethoxy) carbonylmethyl] -1,2,3,4-tetrahydro-2-oxoquinoline-3-acetic acid (221 mg), 2,6-diisopropylaniline (0 0.092 ml) and 1-hydroxy-1H
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (146 mg) in a solution of benzotriazole hydrate (116 mg) in anhydrous acetonitrile (6 ml)
A suspension of triethylamine (0.125 ml) in anhydrous acetonitrile (4 ml) was added at 0 ° C., and the mixture was stirred at room temperature for 16 hr. Ethyl acetate was added to the reaction solution, washed with water, dried and the solvent was distilled off. The residue was separated and purified by column chromatography using silica gel (20 g) (hexane-ethyl acetate = 5: 1) to give the title compound as colorless crystals (46 mg). Melting point 121-124 ° C. (recrystallized from ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.18 (d, 12H, J = 7.0 Hz), 2.
18 (s, 9H), 2.66-2.79 (m, 1H), 2.98-3.24 (m, 6H), 4.47
(d, 1H, J = 17.2Hz), 4.73 (d, 1H, J = 17.4Hz), 6.78 (d, 1H, J =
8.4Hz), 7.00-7.39 (m, 6H ), 7.79 (brs, 1H) Elemental analysis _{C 29 H 38 N 2 O 4} · 0.5H 2 O Calculated C, 71.42; H, 7.85 ; N, 5.7
4 Found C, 71.62; H, 8.07; N, 5.7.
6

Example 16 N- [2,6-bis (1-methylethyl) phenyl]-
N '-(1,2,3,4-tetrahydro-2-oxo-
1-Phenyl-3-quinolylmethyl) urea 1,2,3,4-tetrahydro-2-oxo-1-phenyl-3-quinoline-3-acetic acid (250 mg) in anhydrous benzene (10 ml) was suspended in diphenylphosphoryl azide. (0.249 ml) and triethylamine (0.136
ml) was added, and the mixture was stirred at room temperature for 1 hour and then with heating under reflux for 2 hours. 2,6-Diisopropylaniline (0.201 ml) was added to this reaction solution (containing 1,2,3,4-tetrahydro-2-oxo-1-phenyl-3-quinolylmethylisocyanate), and the mixture was heated under reflux to give 10 Stir the time. The solvent was distilled off, ethyl acetate was added to the residue, and the mixture was washed successively with water, diluted hydrochloric acid, water, aqueous sodium hydrogencarbonate and water, dried and the solvent was distilled off to give the title compound as colorless crystals (1
72 mg). Melting point 241-243 ° C. (recrystallized from ethyl acetate-methanol) NMR (200 MHz, CDCl ₃ ) ppm: 1.17 (d, 12H, J = 7.0 Hz), 2.
79-2.94 (m, 1H), 2.99-3.08 (m, 2H), 3.16-3.32 (m, 2H),
3.50-3.84 (m, 2H), 5.03 (brs, 1H), 5.65 (brs, 1H), 6.32 (d
d, 1H, J = 2.2,7.0Hz), 6.98-7.52 (m, 11H) Elemental analysis value Calculated value as C ₂₉ H ₃₃ N ₃ O ₂ C, 76.45; H, 7.30; N, 9. Two
2 Found C, 76.32; H, 7.69; N, 9.1.
8 Example 17 N- [2,6-bis (1-methylethyl) phenyl]-
3,4-dihydro-3-oxo-4-phenylmethyl-
2H-1,4-benzothiazine-2-acetamide 3,4-dihydro-3-oxo-4-phenylmethyl-
The title compound was obtained by the same procedure as in Example 9 using 2H-1,4-benzothiazine-2-acetic acid and 2,6-diisopropylaniline. Melting point 219-220 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 1.16 (d, 6H, J = 4.2 Hz), 1.1
9 (d, 6H, J = 4.4Hz), 2.80-3.04 (m, 2H), 3.06-3.30 (m, 2H),
4.14 (dd, 1H, J = 5.4,7.6Hz), 5.08 (d, 1H, J = 16.4Hz), 5.4
2 (d, 1H, J = 16.2Hz), 6.82 (t, 2H, J = 7.4Hz), 6.90-7.47 (m,
11H) Elemental analysis _{C 29 H 32 N 2 O 2} S · 0.2H 2 O Calculated C, 73.14; H, 6.77; N, 5.8
8 Found C, 73.15; H, 6.90; N, 6.1
Four

Example 18 N- [2,6-bis (1-methylethyl) phenyl]-
3,4-Dihydro-6-methyl-3-oxo-4-phenylmethyl-2H-1,4-benzothiazine-2-acetamide 3,4-dihydro-6-methyl-3-oxo-4-phenylmethyl-2H Example 9 using -1,4-benzothiazine-2-acetic acid and 2,6-diisopropylaniline
The title compound was obtained in a similar manner to the above. Melting point 183-184 ° C. (recrystallized from ethyl ether) NMR (200 MHz, CDCl ₃ ) ppm: 1.16 (d, 6H, J = 6.6 Hz), 1.1
8 (d, 6H, J = 6.6Hz), 2.24 (s, 3H), 2.83 (dd, 1H, J = 5.4,11.6
Hz), 3.03-3.27 (m, 3H), 4.04-4.16 (m, 1H), 5.08 (d, 1H, J
= 18.6Hz), 5.37 (d, 1H, J = 16.6Hz), 6.78-6.90 (m, 2H), 7.
10-7.43 (m, 10H) Elemental analysis C ₃₀ H ₃₄ N calc C as _{2 O 2 S, 74.04; H} , 7.04; N, 5.7
6 Found C, 73.92; H, 7.11; N, 6.0.
4 Example 19 N- [2,6-bis (1-methylethyl) phenyl]-
N '-(3,4-dihydro-3-oxo-4-phenylmethyl-2H-1,4-benzoxazinylmethyl) urea 3,4-dihydro-3-oxo-4-phenylmethyl-
2H-1,4-benzoxazine-2-acetic acid and 2,6-
The title compound was obtained by the same procedure as in Example 16 using diisopropylaniline. Melting point 185-187 ° C. (recrystallized from ethyl acetate-methanol) NMR (200 MHz, CDCl ₃ ) ppm: 1.17 (d, 12H, J = 6.8 Hz), 3.
18-3.38 (m, 2H), 3.65-3.80 (m, 1H), 3.90-4.08 (m, 1H),
4.58 (t, 1H, J = 5.4Hz), 4.80 (brs, 1H), 4.88 (d, 1H, J = 16.0
Hz), 5.24 (d, 1H, J = 16.0Hz), 5.77 (brs, 1H), 6.79-6.92
(m, 4H), 7.12-7.38 (m, 8H) Elemental analysis value Calculated value as C ₂₉ H ₃₃ N ₃ O ₃ C, 73.86; H, 7.05; N, 8.9
1 Found C, 73.87; H, 6.83; N, 9.1.
5

Example 20 N- [2,6-bis (1-methylethyl) phenyl]-
3,4-dihydro-4-phenylmethyl-2H-1,4
-Benzoxazine-2-acetamide 3,4-dihydro-4-phenylmethyl-2H-1,4
The title compound was obtained by the same procedure as in Example 9 using -benzoxazine-2-acetic acid and 2,6-diisopropylaniline. Melting point 153-154 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 1.20 (d, 12H, J = 7.0 Hz), 2.
70 (dd, 1H, J = 3.6,14.6Hz), 2.84 (dd, 1H, J = 8.6,14.2Hz),
3.07-3.24 (m, 2H), 3.25 (dd, 1H, J = 7.4,12.4Hz), 3.41 (d
d, 1H, J = 2.8,12.0Hz), 4.47 (s, 2H), 4.66-4.80 (m, 1H),
6.62-6.88 (m, 4H), 7.14-7.40 (m, 8H) Elemental analysis value Calculated value as C ₂₉ H ₃₄ N ₂ O ₂ C, 78.70; H, 7.74; N, 6.3
3 Found C, 78.42; H, 7.71; N, 6.5.
5 As in Example 20, 2H- having the corresponding substituents
Using 1,4-benzoxazine-2-acetic acid and an aniline derivative in the same manner as in Example 9 described in Example 2 below.
1 to 24 compounds are obtained. Example 21 N- [2,6-bis (1-methylethyl) phenyl]-
6-chloro-3,4-dihydro-4-phenylmethyl-
2H-1,4-benzoxazine-2-acetamide Melting point 188-189 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 1.20 (d, 12H, J = 7.0 Hz), 2.
69 (dd, 1H, J = 4.0,15.9Hz), 2.80 (dd, 1H, J = 7.8,14.8Hz),
3.05-3.21 (m, 2H), 3.28 (dd, 1H, J = 7.6,11.8Hz), 3.41 (d
d, 1H, J = 2.8,12Hz), 4.46 (s, 2H), 4.62-4.78 (m, 1H), 6.5
8-6.78 (m, 3H), 7.16-7.40 (m, 8H) Elemental analysis value Calculated as C ₂₉ H ₃₃ N ₂ O ₂ Cl C, 73.02; H, 6.97; N, 5.8
7 Found C, 72.70; H, 6.89; N, 6.1.
Two

Example 22 6-Chloro-3,4-dihydro-4-phenylmethyl-
N- (2,4,6-trimethoxyphenyl) -2H-
1,4-benzoxazine-2-acetamide melting point 148-150 ° C (recrystallized from ethyl acetate-methanol) NMR (200MHz, CDCl ₃ ) ppm: 2.69 (dd, 1H, J = 6.2,15.0H
z), 2.82 (dd, 1H, J = 6.8,14.8Hz), 3.34 (dd, 1H, J = 6.4,12.
0Hz), 3.48 (dd, 1H, J = 2.2,12.4Hz), 3.75 (s, 6H), 3.80
(s, 3H), 4.46 (s, 2H), 4.55-4.68 (m, 1H), 6.14 (s, 2H),
6.52-6.78 (m, 3H), 6.88 (brs, 1H), 7.18-7.40 (m, 5H) Elemental analysis C ₂₆ H ₂₇ N ₂ O ₅ Calculated C as Cl, 64.66; H, 5.63 ; N, 5.8
0 Found C, 64.11; H, 5.59; N, 6.0
5 Example 23 6-chloro-N- (2,4-difluorophenyl)-
3,4-dihydro-4-phenylmethyl-2H-1,4
- benzoxazine-2-acetamido mp 124-125 ° C. (recrystallized from diisopropyl _{ether) NMR (200MHz, CDCl 3)} ppm: 2.65 (dd, 1H, J = 4.4,15.2H
z), 2.81 (dd, 1H, J = 8.2,15.2Hz), 3.23 (dd, 1H, J = 7.4,12.
4Hz), 3.37 (dd, 1H, J = 2.6,12.0Hz), 4.44 (s, 2H), 4.58-
4.68 (m, 1H), 6.60-6.75 (m, 2H), 6.75-6.95 (m, 3H), 7.20
-7.42 (m, 5H), 8.14 (brs, 1H), 8.15-8.35 (m, 1H) Elemental analysis value C ₂₃ H ₁₉ N ₂ O ₂ Cl ₂ Calculated value C, 64.41; H, 4.47 ; N, 6.5
3 Found C, 64.23; H, 4.40; N, 6.3.
Four

Example 24 N- [2,6-bis (1-methylethyl) phenyl]-
3,4-dihydro-6-methyl-4-phenylmethyl-
2H-1,4-benzoxazine-2-acetamide Melting point 160-163 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 1.20 (d, 12H, J = 6.8 Hz), 2.
22 (s, 3H), 2.66 (dd, 1H, J = 3.4,14.6Hz), 2.83 (dd, 1H, J =
8.6,15.0Hz), 3.06-3.29 (m, 3H), 3.37 (dd, 1H, J = 2.6,11.
6Hz), 4.46 (s, 2H), 4.60-4.78 (m, 1H), 6.48 (d, 1H, J = 7.6
Hz), 6.58 (s, 1H), 6.72 (d, 1H, J = 7.8Hz), 7.14-7.40 (m, 9
H) Elemental analysis value C ₃₀ H ₃₆ N ₂ O ₂ .0.5H ₂ O calculated value C, 77.38; H, 7.79; N, 6.0
2 Found C, 77.25; H, 7.74; N, 6.0.
3 Example 25 N- [2,6-bis (1-methylethyl) phenyl]-
N '-(6-chloro-3,4-dihydro-4-phenylmethyl-2H-1,4-benzoxazinylmethyl) urea 6-chloro-3,4-dihydro-4-phenylmethyl-
2H-1,4-benzoxazine-2-acetic acid and 2,6-
The title compound was obtained by the same procedure as in Example 16 using diisopropylaniline. Melting point 198-200 ° C (recrystallized from ethyl acetate-methanol) NMR (200MHz, CDCl ₃ ) ppm: 1.15 (d, 12H,
J = 7.0 Hz), 3.08-3.38 (m, 5
H), 3.52-3.70 (m, 1H), 4.10
-4.24 (m, 1H), 4.38 (s, 2H),
4.62 (brs, 1H), 5.74 (brs, 1)
H), 6.52 (s, 2H), 6.61 (s, 1
H), 7.18-7.40 (m, 8H) Elemental analysis value Calculated value as C ₂₉ H ₃₄ N ₃ O ₂ Cl C, 70.79; H, 6.96; N, 8.5
4 Found C, 70.64; H, 7.08; N, 8.4
Four

Example 26 N- [2,6-bis (1-methylethyl) phenyl]-
1,4-dihydro-2-oxo-1-phenylmethyl-
3 (2H) -quinazoline acetamide 1,4-dihydro-2-oxo-1-phenylmethyl-
The title compound was obtained by the same procedure as in Example 9 using 3 (2H) -quinazolineacetic acid and 2,6-diisopropylaniline. Melting point 212-217 ° C. (recrystallized from ethyl acetate-methanol) NMR (200 MHz, CDCl ₃ ) ppm: 1.17 (d, 12H, J = 6.8 Hz), 2.
99-3.15 (m, 2H), 4.34 (s, 2H), 4.68 (s, 2H), 5.19 (s, 2H),
6.79 (d, 1H, J = 8.0Hz), 6.98-7.38 (m, 11H), 8.18 (brs, 1
H) Elemental analysis value C ₂₉ H ₃₃ N ₃ O ₂ calculated value C, 76.45; H, 7.30; N, 9.2
2 Found C, 76.65; H, 7.19; N, 8.9.
3 Example 27 N- [2,6-bis (1-methylethyl) phenyl]-
6-chloro-1,4-dihydro-2-oxo-1-phenylmethyl-3 (2H) -quinazoline acetamide 6-chloro-1,4-dihydro-2-oxo-1-phenylmethyl-3 (2H ) -Quinazolineacetic acid and 2,6-diisopropylaniline were used in the same manner as in Example 9 to obtain the title compound. Mp _{222-223 ℃ NMR (200MHz, CDCl 3} ) ( recrystallized from ethyl acetate) ppm: 1.18 (d, 12H , J = 7.0Hz), 2.
98-3.14 (m, 2H), 4.31 (s, 2H), 4.65 (s, 2H), 5.16 (s, 2H),
6.69 (d, 1H, J = 9.2Hz), 7.06-7.39 (m, 10H), 8.07 (brs, 1
H) Elemental analysis value C ₂₉ H ₃₂ N ₃ O ₂ Cl calculated value C, 71.08; H, 6.58; N, 8.5
7 Found C, 70.90; H, 6.59; N, 8.6.
0

Example 28 6-Chloro-1,4-dihydro-N- (2,6-dimethoxyphenyl) -2-oxo-1-phenylmethyl-3
(2H) -Quinazoline Acetamide 6-Chloro-1,4-dihydro-2-oxo-1-phenylmethyl-3 (2H) -quinazolineacetic acid and 2,6-dimethoxyaniline were used as in Example 9. The title compound was obtained by any other method. Melting point 173-175 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 3.79 (s, 6H), 4.31 (s, 2H),
4.60 (s, 2H), 5.14 (s, 2H), 6.58 (d, 2H, J = 8.4Hz), 6.65
(d, 1H, J = 8.0Hz), 7.00-7.32 (m, 8H), 7.59 (brs, 1H) Elemental analysis value C ₂₅ H ₂₄ Calculated value as N ₃ O ₄ Cl C, 64.45; H, 5 .19; N, 9.0
2 Found C, 64.22; H, 5.20; N, 9.2.
8 Example 29 N- [2,6-bis (1-methylethyl) phenyl]-
6-chloro-1,4-dihydro-2,4-dioxo-1
-Phenylmethyl-3 (2H) -quinazoline acetamide 6-chloro-1,4-dihydro-2,4-dioxo-1
-Phenylmethyl-3 (2H) -quinazoline acetic acid and 2,
The title compound was obtained by the same procedure as in Example 9 using 6-diisopropylaniline. Melting point 290-291 ° C (recrystallized from ethyl acetate) NMR (200MHz, CDCl ₃ ) ppm: 1.16 (d, 12H, J = 5.0Hz), 3.
10-3.25 (m, 2H), 5.04 (s, 2H), 5.38 (s, 2H), 6.79-7.52
(m, 10H), 8.22 (d, 1H, J = 2.6Hz) Elemental analysis value Calculated value as C ₂₉ H ₃₀ N ₃ O ₃ Cl C, 69.11; H, 6.00; N, 8.3
4 Found C, 68.85; H, 6.15; N, 8.4.
4 In Examples 30 to 40, 1,4-dihydro-2-oxo- having a substituent corresponding to each Example compound
Using 3 (2H) -quinazoline acetic acid and aniline as starting materials, the reaction and treatment were carried out in the same manner as in Example 9 to obtain the target compound. Example 30 6-Chloro-N- (2,6-diethoxyphenyl)-
1,4-dihydro-2-oxo-1-phenylmethyl-
3 (2H) -quinazoline acetamide melting point 205-209 ° C (recrystallized from ethyl acetate-methanol) NMR (200MHz, CDCl ₃ ) ppm: 1.34 (t, 6H, J = 6.6Hz), 4.0
3 (q, 4H, J = 7.0Hz), 4.32 (s, 2H), 4.61 (s, 2H), 5.14 (s, 2
H), 6.54 (d, 2H, J = 8.4Hz), 6.64 (d, 2H, J = 10.0Hz), 7.00-
7.30 (m, 8H), 7.59 (bs, 1H) Example 31 6-chloro-1,4-dihydro-2-oxo-1-phenylmethyl-N- (2,4,6-trifluorophenyl) -3 (2H) -Quinazoline acetamide Melting point 199-202 ° C (recrystallized from ethyl acetate-methanol) NMR (200MHz, CDCl ₃ ) ppm: 4.30 (s, 2H), 4.59 (s, 2H),
5.15 (s, 2H), 6.66-6.80 (m, 3H), 7.04-7.12 (m, 2H), 7.1
8-7.38 (m, 5H), 8.20 (bs, 1H) Example 32 N- [2,6-bis (1-methylethyl) phenyl]-
7-chloro-1,4-dihydro-2-oxo-1-phenylmethyl-3 (2H) -quinazoline acetamide Melting point 252-253 ° C. (recrystallized from ethyl acetate) NMR (200 MHz, CDCl ₃ ) ppm: 1.17 (d, 12H, J = 6.8Hz), 2.
94-3.16 (m, 2H), 4.32 (s, 2H), 4.65 (s, 2H), 5.15 (s, 2H),
6.78 (s, 1H), 6.96-7.08 (m, 2H), 7.13-7.38 (m, 8H), 8.0
7 (bs, 1H) Example 33 N- [2,6-bis (1-methylethyl) phenyl]-
6-Chloro-1,4-dihydro-1- (4-methylphenyl) methyl-2-oxo-1-3 (2H) -quinazoline acetamide Melting point 263-265 ° C. (recrystallized from ethyl acetate) NMR (200 MHz , CDCl ₃ ) ppm: 1.18 (d, 12H, J = 6.8Hz), 2.
30 (s, 3H), 2.96-3.12 (m, 2H), 4.31 (s, 2H), 4.63 (s, 2H),
5.11 (s, 2H), 6.70 (d, 1H, J = 9.4Hz), 7.00-7.32 (m, 9H),
8.10 (bs, 1H) Example 34 6-chloro-1,4-dihydro-N- (2,6-dimethoxyphenyl) -1- (4-methylphenyl) methyl-
2-oxo-3 (2H) -quinazoline acetamide Melting point 182-184 ° C (recrystallized from ethyl acetate-methanol) NMR (200MHz, CDCl ₃ ) ppm: 2.30 (s, 3H), 3.80 (s, 6H),
4.32 (s, 2H), 4.59 (s, 2H), 5.11 (s, 2H), 6.59 (d, 2H, J =
8.4Hz), 6.68 (d, 1H, J = 9.2Hz), 7.04-7.25 (m, 7H), 7.61 (b
s, 1H) Example 35 6-chloro-N- (2,6-diethoxyphenyl)-
1,4-Dihydro-1- (4-methylphenyl) methyl-2-oxo-3 (2H) -quinazoline acetamide Melting point 222-223 ° C. (recrystallized from ethyl acetate-methanol) NMR (200 MHz, CDCl ₃ ). ppm: 1.34 (t, 6H, J = 7.0Hz), 2.3
0 (s, 3H), 4.04 (q, 4H, J = 7.0Hz), 4.32 (s, 2H), 4.61 (s, 2
H), 5.10 (s, 2H), 6.55 (d, 2H, J = 8.4Hz), 6.67 (d, 1H, J = 9.
2Hz), 7.02-7.18 (m, 7H), 7.60 (bs, 1H) Example 36 6-chloro-1,4-dihydro-1- (4-methylphenyl) methyl-2-oxo-N- (2,2 4,6-Trifluorophenyl) -3 (2H) -quinazoline acetamide Melting point 237-238 ° C (recrystallized from ethyl acetate-methanol) NMR (200MHz, CDCl ₃ ) ppm: 2.31 (s, 3H), 4.29 ( s, 2H),
4.58 (s, 2H), 5.11 (s, 2H), 6.68-6.80 (m, 3H), 7.04-7.1
4 (m, 6H), 8.22 (bs, 1H) Example 37 N- [2,6-bis (1-methylethyl) phenyl]-
6-chloro-1- (4-chlorophenyl) methyl-1-
1,4-Dihydro-3 (2H) -quinazoline acetamide Melting point 285-287 ° C (recrystallized from ethyl acetate) NMR (200MHz, CDCl ₃ ) ppm: 1.18 (d, 12H, J = 7.0Hz), 2.
96-3.12 (m, 2H), 4.31 (s, 2H), 4.65 (s, 2H), 5.12 (s, 2H),
6.64 (d, 1H, J = 9.4Hz), 7.18-7.32 (m, 9H), 8.00 (bs, 1H) Example 38 6-chloro-1- (4-chlorophenyl) methyl-1,
4-dihydro-N- (2,6-dimethoxyphenyl)-
2-oxo-3 (2H) -quinazoline acetamide Melting point 230-232 ° C (recrystallized from ethyl acetate) NMR (200MHz, CDCl ₃ ) ppm: 3.80 (s, 6H), 4.31 (s, 2H),
4.60 (s, 2H), 5.10 (s, 2H), 6.52-6.60 (m, 3H), 7.02-7.3
0 (m, 7H), 7.52 (bs, 1H) Example 39 6-Chloro-1- (4-chlorophenyl) methyl-N-
(2,6-diethoxyphenyl) -1,4-dihydro-
2-oxo-3 (2H) -quinazoline acetamide Melting point 216-218 ° C (recrystallized from ethyl acetate) NMR (200MHz, CDCl ₃ ) ppm: 1.34 (t, 6H, J = 7.0Hz), 4.0
4 (q, 4H, J = 7.0Hz), 4.30 (s, 2H), 4.61 (s, 2H), 5.09 (s, 2
H), 6.50-6.62 (m, 3H), 7.04-7.28 (m, 7H), 7.54 (bs, 1H) Example 40 6-chloro-1- (4-chlorophenyl) methyl-1,
4-dihydro-2-oxo-N- (2,4,6-trifluorophenyl) -3-3 (2H) -quinazoline acetamide Melting point 206-207 ° C (recrystallized from ethyl acetate) NMR (200MHz, CDCl ₃ ) ppm: 4.28 (s, 2H),
4.59 (s, 2H), 5.10 (s, 2H),
6.60-6.80 (m, 3H), 7.08-7.2
0 (m, 4H), 7.24-7.32 (m, 2H),
7.54 (bs, 1H)

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI A61P 43/00 111 A61P 43/00 111 C07D 215/22 C07D 215/22 239/80 239/80 239/88 239/88 (56 References US Pat. No. 2863864 (US, A) J. Am. Prakt. Chem. , 1985, Vol. 327, No. 5, p. 789-798 Tetrahedron, 1986, Vol. 42, No. 10, p. 2731-2738 Indian J. Chem. , Se ct. B, 1991, Vol. 30B, No. 5, p. 535-536 J. Am. Chem. Soc. , 1959, Vol. 81, p. 1721-1726 Izv. Vyssh. Ucheb. Z aved. , Khim. Tekhno l. , 1972, Vol. 15, No. 9, p. 1361-1363 Khim. Geterotsikl. Soedin. , 1973, No. 2, p. 264-266 (58) Fields surveyed (Int.Cl. ⁷ , DB name) C07D 215/12 C07D 215/22 C07D 239/80 C07D 239/88 A61K 31/47 A61K 31/505 CA (STN) CAOLD (STN) ) REGISTRY (STN)

Claims (16)

(57) [Claims] 1. The formula: Or a salt thereof. 2. A ring A has (i) halogen, (ii) halogen-substituted C _1-6 alkyl group, (iii) C _1-6 alkoxy group, (iv) hydroxyl group, (v) A benzene ring optionally substituted with 1 to 4 substituents selected from an amino group optionally substituted with a C _1-4 alkyl group and (vi) a C _1-3 acyloxy group. The described compound. 3. Ring A is halogen, C _1-4 alkyl group, C
The compound according to claim 1, which is a benzene ring which may be substituted with 1 to 4 substituents selected from _1-4 alkoxy group and halogeno-C _1-4 alkyl group. 4. The ring A has the formula: [In the formula, A ¹ and A ² are the same or different and each represents hydrogen, halogen, a C _1-4 alkyl group, a C _1-4 alkoxy group or a halogeno-C _1-4 alkyl group. ] The compound of Claim 1 which is an optionally substituted benzene ring represented by the following formula. 5. Ring B has (i) halogen, (ii) C _1-6 alkyl group optionally substituted with halogen, (iii) C _1-6 alkoxy group, (iv) hydroxyl group, (v) An amino group optionally substituted by a C _1-4 alkyl group and (vi) an aromatic ring optionally substituted by 1 to 4 substituents selected from a C _1-3 acyloxy group. The described compound. 6. Ring B is halogen, C _1-4 alkyl group, C
_1-4 alkoxy group, di-C _1-4 alkylamino group, C _1-3
An aromatic ring which may be substituted with 1 to 4 substituents selected from an acyloxy group and a hydroxyl group.
The described compound. 7. The aromatic ring is (1) benzene ring, (2) pyridine ring,
7. The compound according to claim 1, which is (3) pyrazine ring, (4) pyrimidine ring or (5) pyridazine ring. 8. The ring B has the formula: [Wherein B ¹ , B ² and B ³ are the same or different and are hydrogen, halogen, a C _1-4 alkyl group, a C _1-4 alkoxy group,
A di-C _1-4 alkylamino group is shown. ] The compound of Claim 1 which is an optionally substituted benzene ring represented by the following formula. 9. R-substituted phenyl-C
The compound according to claim 1, which is a _1-4 alkyl group. 10. The formula: [In the formula, the B ′ ring is an optionally substituted benzene ring,
Other symbols have the same meaning as in claim 1. ] The compound of Claim 1 which is a compound or its salt represented by these. 11. The formula: [In the formula, the B ′ ring is an optionally substituted benzene ring,
X ¹ is —O— or —S—, Z ¹ is —CH ₂ — or —
CH ₂ NH- and other symbols have the same meanings as in claim 1. ] The compound of Claim 1 which is a compound or its salt represented by these. 12. The formula: [In the formula, the B ′ ring is an optionally substituted benzene ring,
Z ¹ is —CH ₂ — or —CH ₂ NH—, and other symbols have the same meanings as in claim 1. ] The compound of Claim 1 which is a compound or its salt represented by these. 13. The formula: [In the formula, the B ′ ring is an optionally substituted benzene ring,
X ² is —CH ₂ — or —CO—, and the other symbols are claim 1.
It has the same meaning as described. ] The compound of Claim 1 which is a compound or its salt represented by these. 14. The formula: [The symbols in the formulas have the same meaning as in claim 1. ] Or a salt thereof or a reactive derivative of a carboxyl group thereof and a compound of the formula: [The symbols in the formulas have the same meaning as in claim 1. ] The compound represented by the formula or a salt thereof is reacted with a compound represented by the formula: [The symbols in the formulas have the same meaning as in claim 1. ] The manufacturing method of the compound or its salt represented by these. 15. The formula: [In the formula, n represents 0 or 1, and other symbols have the same meanings as in claim 1. ] The compound or its salt represented by these, and a formula [The symbols in the formulas have the same meaning as in claim 1. ] The compound represented by the formula or a salt thereof is reacted with the compound represented by the formula: [In the formula, Z ′ represents —NH— or —CH ₂ NH—, and other symbols have the same meanings as in claim 1. ] The manufacturing method of the compound or its salt represented by these. 16. The formula: Acyl-Co containing a compound represented by
A: Cholesterol acyltransferase inhibitor.