JPS61122296A - Novel 5-amino-4-hydroxyvaleryl derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a novel 5-amino-4-hydroxyvaleryl derivative, a process for its preparation, and a pharmaceutical formulation containing the derivative.

[Structure and effects of the invention]

The present invention relates to the general formula (I): [wherein R1 represents hydrogen or an acyl group other than an optionally N-substituted acyl group of a natural amino acid, A is bonded to R1 at the N-terminus, and represents an optionally N-alkylated α-amino acid group bonded to the group -NR2-, R2 represents hydrogen or a lower alkyl group, and R3 represents hydrogen, a lower alkyl group, optionally an etherified or ester hydroxy lower alkyl group, cycloalkyl group, cycloalkyl lower alkyl group, bicycloalkyl lower alkyl group, tricycloalkyl lower alkyl group, aryl group or aryl<g-class alkyl group,
R4 represents a hydroxy group or an etherified or esterified hydroxy group, and R5 represents a lower alkyl group having 2 or more carbon atoms, optionally an etherified or esterified hydroxy lower alkyl group, a cycloalkyl group, or a cycloalkyl lower group. Alkyl group, bicycloalkyl group, bicycloalkyl lower alkyl group, tricycloalkyl group, tricycloalkyl lower alkyl group, aryl group, aryl lower alkyl group, optionally substituted carbamoyl group, optionally substituted amino group, case represents a hydroxy group substituted by or an optionally substituted mercapto group, and R@ represents a substituted amino group excluding an amino group derived from an α-amino acid] and a salt of the compound having a salt-forming group; Processes for their preparation, pharmaceutical preparations containing these compounds and the use of these compounds as medicaments or for the manufacture of pharmaceutical preparations, as well as general formula (I)
The present invention relates to an intermediate for producing a compound of.

In this specification, the term "lower" used to define groups such as lower alkyl groups, lower alkoxy groups, lower alkanoyl groups, etc., means that these groups have 7 or less, preferably 4 or less, unless otherwise specified. This means that it contains carbon atoms.

The carbon atoms substituted by R, , R, and RS are R
-5S- or R,S-configuration, the general formula (
Compounds I) are preferred.

Common terms and expressions used herein preferably have the following meanings.

The acyl group R1 has, for example, up to 19 carbon atoms,
in particular acyl groups of carboxylic acids, carbonic acid half esters, optionally N-substituted carbamic or thiocarbamic acids, optionally N-substituted oxalamides, sulfonic acids or optionally N-substituted amidosulfonic acids, For example, the partial formula Rb-C0-1Ra -0-GO-
1(Rri) (Rb)N-CO-1(R” )(R”
)N-C5-1(Rb”)(Rb)N-GO-GO-
1Rb-3O2- or (R” ”) (Rb)N-3
02-(in the formula, Ra has 18 or less carbon atoms, preferably l
O or less unsubstituted or substituted, saturated or unsaturated aliphatic, alicyclic or alicyclic-aliphatic hydrocarbon group, or unsubstituted or substituted aromatic, heterocyclic group having up to 18 carbon atoms, preferably up to 10 carbon atoms represents an aromatic, araliphatic or heterocyclic aromatic-aliphatic hydrocarbon group, or an unsubstituted or substituted 5- or 6-membered saturated heterocycle, Rb represents hydrogen, or Evening definition.

In a group in which two Rb groups exist, the two groups Rb are the same -
or may be different.

Acyl groups of optionally substituted natural amino acids are not included in the acyl group R1.

The unsubstituted or substituted, saturated or unsaturated aliphatic, alicyclic or alicyclic-aliphatic hydrocarbon group Ra or Rb is
For example, unsubstituted or substituted alkyl groups, such as lower alkyl groups, lower alkenyl groups, low m alkynyl groups, mono-
, bi- or tricycloalkyl group, monocycloalkenyl group, bicycloalkenyl group, cycloalkyl lower alkyl group, cycloalkyl lower alkenyl group or cycloalkenyl lower alkyl group.

The alkyl group Ra or RI:I preferably has 1 to 10 carbon atoms, for example an optionally substituted lower alkyl group having 1 to 7 carbon atoms or n-octyl group, n-
It is a nonyl group or an n-decyl group.

Lower alkyl MRa or Rks preferably has 1 to 7 carbon atoms, for example methyl, ethyl) Ltd, n
-propyl group, isopropyl group, n-butyl group or t
ert-butyl group, which groups contain one or more functional groups, such as a hydroxy group, an etherified hydroxy group, such as a lower alkoxy group, such as a methoxy or ethoxy group, or a phenoxy group, an esterified hydroxy group,
For example, lower alkanoyloxy groups, such as acetoxy groups, halogens, such as chlorine or bromine, hydroxysulfonyloxy groups, carboxy groups, esterified carboxy groups, such as lower alkoxycarbonyl groups, such as methoxy- or ethoxycarbonyl groups, amidated carboxy groups, e.g. a carbamoyl group or a mono- or di-lower alkylcarbamoyl group, such as a methyl- or dimethylcarbamoyl group, a cyano group, a phosphono group, an esterified phosphono group, such as a di-lower alkoxyphosphoryl group,
For example, dimethoxy- or jetoxyphosphoryl groups,
It may be substituted with an amino group or an oxo group, and if the group is attached to the carbonyl group in the subformula R''--Co-, the substituent is present only in the 1-position of the lower alkyl group.

The monosubstituted lower alkyl group Ra or Rb is, for example, a hydroxy lower alkyl group, such as a 2-hydroxyethyl group,
lower alkoxy lower alkyl groups, such as lower alkoxymethyl groups or lower alkoxyethyl groups, such as methoxymethyl or 2-methoxyethyl groups, phenoxy lower alkyl groups, such as phenoxymethyl groups, naphthoxy lower alkyl groups, such as α- or β-naphtho. oxymethyl group, lower alkanoyloxy lower alkyl group,
For example, a lower alkanoyloxymethyl group or a lower alkanoyloxyethyl group, such as an acetoxymethyl group or a 2-acetoxyethyl group, a halogen lower alkyl group, such as a halogen methyl group or a halogen ethyl group, such as a 2-chloro- or 2-bromoethyl group,
Hydroxysulfonyloxy lower alkyl groups, such as hydroxysulfonyloxymethyl or 2-hydroxysulfonyloxyethyl groups, carboxy lower alkyl groups, such as carboxymethyl or 2-carboxyethyl groups, lower alkoxycarbonyl lower alkyl groups, such as lower alkoxycarbonylmethyl or lower alkoxycarbonylethyl groups, such as methoxycarbonylmethyl, 2-methoxycarbonylethyl, ethoxycarbonylmethyl or 2-ethoxycarbonylethyl, carbamoyl lower alkyl groups, such as carbamoylmethyl or 2-carbamoylethyl, lower Alkylcarbamoyl lower alkyl groups, such as methylcarbamoylmethyl groups, di-lower alkylcarbamoyl lower alkyl groups, such as dimethylcarbamoylmethyl groups, cyano-lower alkyl groups, such as cyanomethyl or 2-cyanoethyl groups, or oxo-lower alkyl groups,
For example, 2-oxopropyl group or 2-oxobutyl group.

A substituted lower alkyl group Ra or Rb having two or more substituents is, for example, a hydroxy-carboxy lower alkyl group, such as a hydroxy-carboxymethyl group or a 1-
hydroxy-2-carboxyethyl group, hydroxy-lower alkoxycarbonyl lower alkyl group, such as hydroxyethoxy- or monomethoxycarbonylethyl group,
Esterified hydroxy lower alkoxycarbonyl lower alkyl groups, such as acetoxy-methoxycarbonylmethyl groups, dihydroxy-carboxy lower alkyl groups, such as 1,2-dihydroxy-2-carboxyethyl groups, dihydroxy lower alkoxycarbonyl lower alkyl groups,
For example 1,2-dihydroxy-2-ethoxy- or monomethoxycarbonylethyl groups, esterified dihydroxy lower alkoxycarbonyl lower alkyl groups, e.g.
゜2-Diacetoxy-2-ethoxy- or -methoxycarbonylethyl group, α-naphthoxy-carboxy lower alkyl group, such as 1-α-naphthoxy-3-carboxypropyl group, α-naphthoxy-lower alkoxycarbonyl lower alkyl group groups, such as the α-naphthoxy-ethoxycarbonylmethyl group, the 1-α-naphthoxy-2-ethoxycarbonylethyl group or the 1-α-naphthoxy-3-tar t-butoxycarbonylprobyl group, α
-naphthoxybenzyloxycarbonyl lower alkyl group, such as 1-α-naphthoxy-2-benzyloxycarbonylethyl group, χ-naphthoxycarbamoyl lower alkyl group, such as 1-α-naphthoxy-3-carbamoylpropyl group, α-naphthoxy -cyano lower alkyl group, such as α-naphthoxy-cyanomethyl group or 1-
α-naphthoxy-3-cyanopropyl group, α-naphthoxy-dilower alkylamino lower alkyl group, e.g. 1-
α-naphthoxy-4-dimethylaminobutyl group, or α
-naphthoxy-oxo-lower alkyl group, e.g. 1-α
-naphthoxy-3-oxo-butyl group.

The lower alkenyl group Ra or RI:I contains, for example, 2 to 7, especially 2 to 4 carbon atoms and has the subformula R''-Co-
If that group in the carbonyl group is bonded to a carbonyl group, the double bond is present only in the 1-position of the lower alkenyl group, such as a vinyl group, an allyl group or a 2- or 3-butenyl group. Lower alkenyl 5Ra or R1:I has the same substituent as the lower alkyl group, such as a hydroxy group, an etherified hydroxy group, such as a methoxy group, an esterified hydroxy group, such as an acetoxy group, a halogen, such as chlorine or bromine, a carboxy group, esterified carboxy group,
For example, it may be substituted with a methoxycarbonyl group or an ethoxycarbonyl group, or an amidated carboxy group, such as a carbamoyl group.

A lower alkynyl group Ra or Rb contains, for example, 2 to 7, especially 2 to 4 carbon atoms, for example an ethynyl group, a 1-
It is a propynyl group or a 2-propynyl group.

Cycloalkyl radicals Ra or Rb contain, for example, 3 to 8, in particular 3 to 6 carbon atoms, and are, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

Bicycloalkyl radicals Ra or Rb contain, for example, 5 to 10, in particular 6 to 9 carbon atoms, for example bicyclohexyl, -hebutyl, -octyl, -nonyl or -decyl, for example bicyclo( 3,1,0) hexy-1
-1-2- or -3-yl group, bicyclo(4,1,
0) hept-1- or -4-yl group, bicyclo(2
,2,1) hept-2-yl group, e.g. endo- or exo-norbornyl group, bicyclo(3,2,13oct-2-yl group, bicyclo(3,,10)oct-3
-yl group or bicyclo(3,3,1)non-9-yl group, and also α- or β-decahydronaphthyl group.

Tricycloalkyl 5Ra or Rb is, for example, 8 to 10
carbon atoms, for example tricyclo(5,2,1,
0'') dec-8-yl or adamantyl group, e.g.
-Adamantyl group.

A cycloalkenyl group Ra or Rkl contains, for example, 3 to 8, in particular 3 to 6 carbon atoms, for example a cyclohexenyl group, such as a 1-cyclohexenyl group, or a cyclohexagenyl group, such as a 1°4-cyclo It is a hexagenyl group.

Bicycloalkenyl 5Ra or Rb is, for example, 5 to 10
, especially 7 to 10 carbon atoms, e.g. bicyclo(2,2,1)hept-5-en-yl, e.g. 5-
Norbornen-2-yl group, bicyclo(2,2,2)octen-2-yl group or hexahydro-4,7-methanoindo-1-en-6-yl group.

The cycloalkyl lower alkyl group Ra or Rb is, for example, 4
~10, especially 4 to 7 carbon atoms, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl or cyclohexylmethyl.

Cycloalkyl lower alkenyl radicals Ra or Rb contain, for example, 5 to 10, in particular 5 to 9 carbon atoms, and are, for example, cyclohexylvinyl or cyclohexylallyl.

Cycloalkenyl lower alkyl radicals Ra or Rb contain, for example, 4 to 10, in particular 4 to 7 carbon atoms, and are, for example, 1-cyclohexenylmethyl or 1,4-cyclohexagenylmethyl.

The alicyclic or alicyclic-aliphatic group may be substituted with the same substituent as the lower alkyl group RFa.

An optionally substituted aromatic or aromatic-aliphatic hydrocarbon group Ra or Rb is, for example, an unsubstituted or substituted aryl group, an aryl lower alkyl group or an aryl lower alkenyl group.

The aryl group Ra or Rb contains, for example, 6 to 14 carbon atoms, for example a phenyl group, an indenyl group, e.g. 2
- or 4-indenyl, 1- or 2-naphthyl, anthryl, such as 1- or 2-anthryl, phenanthryl, such as 9-phenanthryl, or acenaphthynyl, such as 1-acenaphthynyl.

The aryl group Ra or Rb is, for example, a lower alkyl group, such as a methyl group, a hydroxy group, a lower alkoxy group, such as a methoxy group, an acyloxy group, such as a lower alkanoyloxy group, such as an acetoxy group, an amino group, a lower alkylamino group. , methylamino group, di-lower alkylamino group, such as dimethylamino group, acylamino group,
For example, it is substituted with a tart-butoxycarbonylamino group, or with a halogen, such as chlorine, bromine or iodine, the substituent being at any position on the aryl group, such as on the phenyl group.

It may be present at the -1m- or p-position, and the aryl group may be substituted several times with the same or different substituents.

The aryl lower alkyl group Ra or Rb is, for example, 7 to 1
containing 5 carbon atoms, for example unsubstituted or substituted and optionally branched groups listed under the lower alkyl group Ra or Rb and unsubstituted or substituted groups listed under the aryl group Ra or Rb. include. Such aryl lower alkyl groups include, for example, a benzyl group, a lower alkylbenzyl group, such as a 4-methylbenzyl group, a lower alkoxybenzyl group, such as a 4-methoxybenzyl group, a substituted anilinobenzyl group, such as a 2- (o, o -dichloroanilino)
-benzyl group or 2-(o, o-dichloro-N-benzylanilino)-benzyl group, 2-phenylethyl i, 2-(p-hydroxyphenyl)-ethyl group, diphenylmethyl group, di(4-methoxy phenyl)
-Methyl group, trityl group, α- or β-naphthylmethyl group, 2-(α- or β-naphthyl)-ethyl group, as well as 2-phenylethyl group, 3-phenyl-2-propyl group, 4-phenyl- 3-7" thyl group, 2-α-naphthyl ethyl group, 3.α-naphthyl-2-propyl group, or 4-α-naphthyl-3-butyl group (respectively, the 1st position is a hydroxy group, a lower alkoxy group, e.g. neo Pentyloxy group, acyloxy group, such as acetoxy group, pivaloyloxy group, nityloxy group, 2
-benzyloxycarbonylamino-2-methylpropionoxy group, 2-amino-2-methylpropionoxy or acetoacetoxy group, carboxy group, esterified carboxy group, e.g. benzyloxycarbonyl 5, t
ert-butoxycarbonyl group or ethoxycarbonyl group, carbamoyl group, substituted carbamoyl group, such as tert-butylcarbamoyl group, carboxymethylcarbamoyl group, tart-butoxycarbonylmethylcarbamoyl group, 2-dimethylaminoethylcarbamoyl group, 3-hydroxy-2 -propylcarbamoyl group,
2.2-dimethoxyethylcarbamoyl group or 5-
amino-5-carboxypentylcarbamoyl group, cyano group, phosphono group, esterified phosphono group, such as monosubstituted with jetoxyphosphoryl group, dimethoxyphosphoryl group or hydroxymethoxyphosphoryl group or oxo group), furthermore 1-phenyl - or α-naphthyl-4-oxo-2-pentyl group, 1-phenyl- or α-naphthyl-5,5-dimethyl-4-oxo-2
-hexyl group, 1-phenyl- or α-naphthyl-
4,4-dimethyl-3-oxo-2-pentyl group, ■-
Phenyl-4-(2-benzofuranyl)-4-oxo-
Butyl group, 1-phenyl- or α-naphthyl-5-
Dimethylamino-4-oxo-2-pentyl group, l-phenyl- or α-naphthyl-5-dimethylamino-
2-pentyl group, 1-phenyl- or α-naphthyl-3-dimethylamino-2-propyl group, α,p-diaminobenzyl group or α,p-diacylaminobenzyl group, such as α,p-dibenzyloxycarbonyl It is an aminobenzyl group or a pivaloylamino-p-benzyloxycarbonylaminobenzyl group.

The aryl lower alkenyl group Ra or RI:I contains, for example, 8 to 16 carbon atoms and includes, for example, the unsubstituted or substituted groups listed under the lower alkenyl group Ra or Rb and the aryl group Ra or Rb. Such aryl lower alkenyl groups, including the unsubstituted or substituted groups mentioned, are for example styryl, 3-phenylallyl, 2-(α
-naphthyl)-vinyl group or 2-(β-naphthyl)-vinyl group.

In the heterocyclic aromatic or heterocyclic aromatic-aliphatic hydrocarbon group Ra or Rb, the heterocycle is monocyclic, bicyclic or tricyclic and contains 1 to 2 nitrogen atoms and/or containing one oxygen or sulfur atom, and by one of its ring carbon atoms the group -CO-1-O-CO-, -N-C0-1:
l:N-CS-1:=N-CO-C0-1-SO,
- or ;N-302-. Such a heteroaryl group Ra or Rb is, for example, a pyrrolyl group, a furyl group, a chenyl group, an imidazolyl group, a pyrazolyl group, an oxasilyl group, a thiazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, an indolyl group, a quinolyl group, an isoquinolyl group. , quinoxalinyl group, β-carbolinyl group, or derivatives of these groups condensed with benzene, cyclobencune, cyclohexane, or cyclohebutane.

The heterocycle may be partially saturated and may include a lower alkyl group at the nitrogen atom, such as a methyl or ethyl group, a phenyl group, or a phenyl lower alkyl group.
For example, it may be substituted with benzyl groups and/or 1
At one or more carbon atoms, lower alkyl groups, such as methyl, phenyl, phenyl lower alkyl, such as benzyl, halogen, such as chlorine, hydroxy, lower alkoxy, such as methoxy, phenyl lower alkoxy, such as benzyl May be substituted with oxy or oxo groups, for example 2- or 3-pyrrolyl groups,
Phenyl-pyrrolyl group, for example 4-fL<4;! 5-phenyl-2-pyrrolyl group, 2-furyl group, 2-chenyl group, 4-imidazolyl group, 2-53- or 4-pyridyl group, 2-13- or 5-indolyl group, substituted 2
-indolyl group, e.g. 1-methyl-15-methyl-1
5-methoxy-15-benzyloxy-55-chloro-
or 4.5-dimethyl-2-indolyl group, 1-benzyl-2- or -3-indolyl group, 4.5.6
．． 7-tetrahydro-2-indolyl group, cyclohebuta(b)-5-pyrrolyl group, 2-13- or 4-quinolyl group, 4-hydroxy-2-quinolyl group, 1-13-
or 4-isoquinolyl group, 1-oxo-1,2-dihydro-3-isoquinolyl group, 2-quinoxalinyl group,
2-benzoxasilyl group, 2-benzothiazolyl group,
benz(e) indol-2-yl group or β-carbolin-3-yl group.

The heterocyclic aromatic-aliphatic hydrocarbon group Ra or Rb is
For example, unsubstituted or substituted groups listed under lower alkyl 5 Ra or Rb and heteroaryl groups Ra or R 15
including the unsubstituted or substituted groups listed below, for example 2
- or 3-pyrrolylmethyl group, 2-13- or 4-pyridylmethyl group, 2- (2-13- or 4
-pyridyl)-ethyl/C group, 4-imidazolylmethyl group, 2-(4-imidazolyl)-ethyl group, 2- or 3-indolylmethyl group, 2-(3-indolyl)-ethyl group or 2-quinolylmethyl group It is the basis.

A 5- or 6-membered saturated heterocycle Ha or Rh has at least one carbon atom, 1 to 3 nitrogen atoms and optionally one oxygen or sulfur atom as ring members, and the ring carbon atoms by one of the groups -CO-1 or -CO-
1>N -CO-1'; N -CS-, N -CO-
It is bonded to C0-1-3O2- or ;N-S O2-. The heterocycle is substituted at its carbon atom or ring nitrogen atom with a lower alkyl group, such as a methyl or ethyl group, a phenyl group or a phenyl lower alkyl group, such as a benzyl group, or at its carbon atom a hydroxy group. Alternatively, it may be substituted with an oxo group and/or fused with a benzene ring at two adjacent carbon atoms.

Such heterocycles include, for example, pyrrolidin-3-yl, hydroxypyrrolidin-2- or -3-yl,
For example, 4-hydroxypyrrolidin-2-yl group, oxopyrrolidin-2-yl group, such as 5-oxopyrrolidin-2-yl group, piperidin-2- or -3-yl group, 1-lower alkylbiperidin-2 -1-3- or -4-yl group, e.g. 1-methylpiperidine-2-1-
3- or -4-yl group, morpholin-2- or -3-yl group, thiomorpholin-2- or -3-yl group, and/or 4-lower alkylbiperazin-2- or -3-yl group groups such as the 1,4-dimethylpiperazin-2-yl group, the indolinyl group such as the 2- or 3-indolinyl group, the 1.2.3.4-tetrahydroquinolyl group such as the 1. 2. 3. 4-tetrahydroquinol-2-1-3- or -4-yl group or 1.
2°3.4-Tetrahydroisoquinolyl group, for example l.

2.3.4-Tetrahydroinquinol-1-1-3-
or -4-yl group or l-oxo-1゜2.3.4
-tetrahydroisoquinol-3-yl group. The optional N-substituted pyrrolidin-2-yl group, ie the residue of the amino acid proline, is excluded as a heterocycle Hb in the acyl group R''-Co-.

Preferred acyl groups R1 are, for example, alkanoyl groups, such as n-decanoyl groups or lower alkanoyl groups, such as formyl, acetyl, propionyl or pivaloyl groups, hydroxy lower alkanoyl groups, such as β-hydroxypropionyl groups, lower alkoxy lower alkanoyl groups. , such as lower alkoxyacetyl groups, particularly lower alkoxypropionyl groups, such as methoxyacetyl or β-methoxypropionyl groups, phenoxy lower alkanoyl groups, such as phenoxyacetyl groups, naphthoxy lower alkanoyl groups, such as α- or β-naphthoxyacetyl groups, Lower alkanoyloxy lower alkanoyl groups, such as lower alkanoyloxyacetyl or lower alkanoyloxypropionyl groups, such as acetoxyacetyl or β-acetoxypropionyl groups, halogen lower alkanoyl groups, such as α-halogenacetyl groups, such as α-chloro-1α- Bromo-1
an α-iodo- or α,α,α-trichloroacetyl group, or a halogenpropionyl group, such as a β-chloro-
or β-bromopropionyl group, carboxy lower alkanoyl group, such as carboxyacetyl group or β
-carboxypropionyl group, lower alkoxycarbonyl lower alkanoyl group, e.g. lower alkoxycarbonylacetyl S or lower alkoxycarbonylfurohionyl group, e.g. methoxycarbonylacetyl group, β-
Methoxycarbonylpropionyl group, ethoxycarbonylacetyl group or β-ethoxycarbonylpropionyl group, carbamoyl lower alkanoyl group such as carbamoylacetyl group or β-carbamoylpropionyl group, lower alkylcarbamoyl lower alkanoyl group such as methylcarbamoylacetyl group, di-lower alkylcarbamoyl group Lower alkanoyl groups, such as dimethylcarbamoylacetyl, oxo-lower alkanoyl, such as acetoacetyl or propionylacetyl, hydroxycarboxy lower alkanoyl, such as α
-Hydroxy-α-carboxyacetyl group or α-
Hydroxy-β-carboxypropionyl group, hydroxy-lower alkoxycarbonyl-lower alkanoyl group, such as α-hydroxy-α-ethoxy- or monomethoxycarbonylacetyl group or α-hydroxy-β-ethoxy- or -methoxycarbonylprobionyl group, esterified Hydroxy lower alkoxycarbonyl lower alkanoyl group, such as α-acetoxy-α-methoxy carbonylacetyl group, dihydroxy-carboxy lower alkanoyl group, such as α,β-dihydroxy-β-carboxypropionyl group, dihydroxy-lower alkoxycarbonyl lower alkanoyl group, For example α.

β-dihydroxy-β-ethoxy- or -methoxycarbonylpropionyl group, esterified dihydroxy lower alkoxycarbonyl lower alkanoyl group, e.g. α
, β-diacetoxyβ-methoxycarbonylpropionyl group, α-naphthoxy-carboxy lower alkanoyl group, e.g. 2-α-naphthoxy-4-carboxybutyryl group, α-naphthoxy-lower alkoxycarbonyl lower alkanoyl group, e.g. α-naphthoxy Ethoxycarbonylacetyl group, 2-α-naphthoxy-3-ethoxycarbonylprobionyl group or 2-α-naphthoxy-
``''4-tert4-tert-Butoxycarbonylbutyryl group cy-benzyloxycarbonyl lower alkanoyl group, e.g. 2-α-naphthoxy-3-benzyloxycarbonylpropionyl group, α-naphthoxy-carbamoyl lower alkanoyl group, e.g. 2-α -Naphthoxy-
4-.

Carbamoylbutyryl group, α-naphthoxy-cyano lower alkanoyl group, such as α-naphthoxy-cyanoacetyl group or 2-α-naphthoxy-4-cyanobutyryl group, α-naphthoxy-dilower alkylamino lower alkanoyl group, such as 2-α -naphthoxy-5-dimethylaminopentanoyl group, α-naphthoxy-oxo lower alkanoyl group, such as 2-α-naphthoxy-4-oxopentanoyl group, lower alkenoyl group, such as acryloyl group, vinylacetyl group, crotonoyl group, or - or 4-pentenoyl group, lower alkinoyl group such as propionyl group or 2- or 3-butynoyl group, cycloalkylcarbonyl group such as cyclopropyl group,
cyclobutyl-, cyclopentyl- or cyclohexylcarbonyl group, bicycloalkylcarbonyl group, e.g. evaendo- or exo-norbornyl-2-carbonyl group, bicyclo(2,2,2)oct-2-ylcarbonyl group or bicyclo(3, 3,1) Non-9-
ylcarbonyl group, tricycloalkylcarbonyl group,
For example, a 1- or 2-adamantylcarbonyl group, a cycloalkenylcarbonyl group, such as a 1-cyclohexenylcarbonyl group or a 1,4-cyclohexagenylcarbonyl group, a bicycloalkenylcarbonyl group, such as 5-norbornen-2-yl a carbonyl group or a bicyclo(2,2,2)octen-2-ylcarbonyl group, a cycloalkyl lower alkanoyl group such as a cyclopropylacetyl group, a cyclopentylacetyl group or a cyclohexylacetyl group, a cycloalkyl lower alkenoyl group such as a cyclo xylacryloyl, cycloalkenyl lower alkanoyl, such as 1-cyclohexylacetyl or 1,4-cyclohexagenylacetyl, unsubstituted or lower alkyl, such as methyl, halogen, such as chlorine, hydroxy, 1 with a lower alkoxy group, such as a methoxy group and/or a nitro group
or more substituted benzoyl groups, e.g. 4-chloro-1
4-methoxy- or 4-nitrobenzoyl radicals, and also phenyl-1α-naphthyl- or β-naphthyl-lower alkanoyl radicals (phenyl radicals are unsubstituted or lower alkyl radicals, such as methyl radicals, halogen radicals, such as chlorine, hydroxy radicals, lower One or more alkoxy groups, such as methoxy and/or nitro groups, are substituted, lower alkanoyl groups are unsubstituted or, for example, hydroxy groups, lower alkoxy groups, acyloxy groups, carboxy groups, esterified carboxy groups, carbamoyl groups, substituted carbamoyl groups , cyano groups, phosphono groups, esterified phosphono groups, benzofuranyl groups and/or oxo groups, optionally branched), such as phenylacetyl groups, α-naphthylacetyl groups, β-naphthylacetyl groups , lower alkylphenylacetyl groups, e.g. 4-methylphenylacetyl groups, lower alkoxyphenylacetyl groups, e.g. 4-
Methoxyphenylacetyl group, 3-phenylpropionyl group, 3-(I)monohydroxyphenyl)-propionyl group, diphenylacetyl group, di(4-methoxyphenyl)-acetyl group, triphenylacetyl group, substituted anilinophenyl acetyl group , for example 2-(o,o-dichloroanilino)-phenylacetyl group or 2-
(0,0-dichloro-N-benzylanilino)-phenylacetyl group, 3-α- or β-naphthylpropionyl group, 3-phenyl- or 3-α-naphthyl-2
-hydroxypropionyl group, 3-phenyl- or 3-α-naphthyl-2-lower alkoxypropionyl group, such as 3-phenyl- or 3-α-naphthyl-2
-neopentyloxypropionyl group, 3-phenyl-
or 3-α-naphthyl-2-acyloxyprohionyl 1M, 4M such as 3-phenyl-2-pivaloyloxy- or 2-acetoxy-propio=/L4.3-
α-naphthyl-2-pivaloyloxy- or 2-acetoxy-propionyl group, 3-α-naphthyl-2-acetoacetoxypropionyl group, 3-α-naphthyl-2
-ethylaminocarbonyloxyprobionyl group or 3-α-naphthyl-2-(2-amino- or 2-
benzyloxycarbonylamino-2-methylpropionyloxy)-propionyl group, 3-phenyl- or 3-α-naphthyl-2-carboxymethylpropionyl group, 3-phenyl- or 3-α-naphthyl-2-
lower alkoxycarbonylpropionyl group, e.g. 3-
α-naphthyl-2-ethoxycarbonylpropionyl group, 3-phenyl-2-benzyloxy group, 3-α-naphthyl-2-penzyloxylponylmethylpropionyl group, 3-phenyl-2-ethoxycarbonyl<413-α-naphthyl-2 -carbamoylpropionyl group, 3-phenyl- or 3-α-naphthyl-2-tert-butylcarbamoylpropionyl group, 3-phenyl-ft,, < has -α-naphthyl-2-(2-dimethylaminoethyl) - Rubamoylprobionyl group, 3-α-naphthyl-2-(carboxy- or tert-butoxycarbonyl)-methylcarbamoylpropionyl group, 3-phenyl- or 3-α-naphthyl-2-(3-hydroxy-2 -propyl)-rubamoylpropionyl group, 3-phenyl or 3-α-naphthyl-2-(2,2-dimethoxyethyl)-rubamoylpropionyl group, 3-phenyl-
or 3-α-naphthyl-2-(5-amino-5-carboxypentyl)-carbamoylpropionyl group, 3
-phenyl- or 3-α-naphthyl-2-cyanopropionyl group, 3-phenyl- or 3-α-naphthyl-2-cyanomethyl-propionyl group, 3-7enyl-2-phosphono- or phosphonomethyl-propionyl group, 3- phenyl-2-dimethoxyphosphoryl- or -dimethoxyphosphorylmethyl-propionyl group,
3-phenyl-2-jethoxyphosphoryl- or -
Jetoxyphosphorylmethyl-propionyl group, 3-phenyl-2-ethoxy- or -methoxyhydroxyphosphoryl-propionyl group, 3-phenyl-2-ethoxy- or -methoxyhydroxyphosphoryl-propionyl group
<Ha 3-α-naphthyl-2-a7tonylpropionyl group, 3-phenyl- or 3-α-naphthyl-2-
Dimethylaminomethyl-propionyl group, 2-benzyl- or 2-α-naphthylmethyl-4-cyanobutyryl group, 4-phenyl- or 4-α-naphthyl-3-
Carboxybutyryl group, 4-phenyl- or 4-α
-Naphthyl-3-butyryl group, 2-benzyl-4-(2-benzofuranyl)-4-
Oxo-butyryl group 1,2-benzyl- or 2-α
-Naphthylmethyl-4-oxopentanoyl group, 2-benzyl- or 2-α-naphthylmethyl-4,4-dimethyl-3-oxo-pentanoyl group, 2-benzyl-
or 2-α-naphthylmethyl-5-dimethylaminopentanoyl group, 2-benzyl- or 2-α-naphthylmethyl-5-dimethylamino-4-oxo-pentanoyl group, 2-benzyl- or 2-α-naphthyl Methyl-5°5-dimethyl-4-oxo-hexanoyl group, α.

p-diaminophenylacetyl group, α, p-diacylaminophenylacetyl group, such as α, p-dibenzyloxycarbonylaminophenylacetyl group or α-pivaloylami/p-benzyloxycarbonylamino-phenylacetyl group, phenyl lower Alkenoyl groups, such as β-phenylacryloyl or β-phenylvinylacetyl, naphthylcarbonyl groups, such as α- or β-naphthylcarbonyl, or! .

8-naphthalene dicarbonyl group, indenylcarbonyl group, such as 1-12- or 3-indenylcarbonyl group, indanylcarbonyl group, such as 1- or 2
- indanylcarbonyl group, phenanthrenylcarbonyl group, such as 9-phenanthrenylcarbonyl group, optionally substituted pyrrolylcarbonyl group, such as 2- or 3-pyrrolylcarbonyl group or 4- or 5-
phenylpyrrolyl-2-carbonyl group, furylcarbonyl group, e.g. 2-furylcarbonyl group, Cheni) Ltf
J Rubonil! , N such as a 2-chenylcarbonyl group, a pyridylcarbonyl group, such as a 2-53- or 4-pyridylcarbonyl group, an optionally substituted indolylcarbonyl group, such as a 2-13- or 5-indolylcarbonyl group, 1 -Methyl-15-methyl-15-methoxy-15-benzyloxy-15-chloro- or 4,5-dimethylindolyl-2-carbonyl group, l-
Benzylindolyl-2- or -3-carbonyl group, 4.5.6.7-tetrahydroindolyl-2-carbonyl group, cyclopenta(b)-pyrrolyl-5-carbonyl group, optionally substituted quinolylcarbonyl group basis,
For example, a 2-13- or 4-quinolylcarbonyl group or a 4-hydroxyquinolyl-2-carbonyl group, an optionally substituted isoquinolylcarbonyl group, such as a 1-
13- or 4-quinolylcarbonyl group or 1-
Oxo-1,2-dihydroisoquinolyl-3-carbonyl group, 2-quinoxalinylcarbonyl group, 2-penzofurarylcarbonyl group, benzo(e) indo-glue 2-
carbonyl group, β-carbonyl-3-carbonyl group,
pyrrolidinyl-3-carbonyl group, hydroxypyrrolidinylcarbonyl group, e.g. 3- or 4-hydroxypyrrolidinyl-2-carbonyl group, oxopyrrolidinylcarbonyl group, e.g. 5-oxopyrrolidinyl-2-carbonyl group, piperidinylcarbonyl group, e.g. 2-1
3- or 4-piperidinylcarbonyl group, indolinylcarbonyl group, such as 2- or 3-indolinylcarbonyl group, 1°2.3.4-tetrahydroquinolylcarbonyl group, such as 1.2,3.4- tetrahydroquinolyl-2-1-3- or -4-carbonyl group,
1°2.3.4-tetrahydroisoquinolylcarbonyl group, such as 1.2.3.4-tetrahydroisoquinolyl-ni, -3- or -4-carbonyl group or 1-oxo-1,2,3 ,4-tetrahydroisoquinolyl-3
-carbonyl groups, lower alkoxycarbonyl groups, such as methoxy-, nidoxy- or tart-lower alkoxycarbonyl groups, such as tert-butoxycarbonyl groups, 2-halogen lower alkoxycarbonyl groups, such as 2-chloro-12-bromo-12-iodo -Preferably 2゜2.2-)lichloroethoxycarbonyl group, OK-
a lower alkoxycarbonyl group, such as an arylmethoxycarbonyl group (aryl group being a phenyl group, a 1- or 2-naphthyl group, or a lower alkyl group, such as a methyl group or a tert-butyl group, a lower alkoxy group,
(for example, phenyl groups substituted with one or more methoxy, ethoxy or Lert-butoxy groups, hydroxy groups, halogens such as chlorine or bromine, and/or nitro groups), e.g. benzyloxycarbonyl groups, 4
-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl, di(4-methoxyphenyl)-methoxycarbonyl or trityloxycarbonyl, as well as oxamoyl or lower alkyloxamoyl groups, such as methyl- or an ethyloxamoyl group.

A is an α-amino acid, e.g. a natural α-amino acid with one unit as normally present in proteins, a homologue of such an amino acid, e.g. an amino acid in which the side chain of the amino acid is extended by one or two methylene groups or Homologues, substituted aromatic α, truncated and/or in which one methyl group is replaced by hydrogen
- amino acids, such as one or more substituted phenylalanine or phenylglycine (substituents include lower alkyl groups, e.g. methyl groups, halogens, e.g. fluorine, chlorine, bromine or iodine, hydroxy groups, lower alkoxy groups, e.g. methoxy groups, lower Alkanoyloxy groups, such as acetoxy groups, amino groups, lower alkylamino groups, such as methylamino groups, di-lower alkylamino groups, such as dimethylamino groups, lower alkanoylamino groups, such as acetylamino or pivaloylamino groups, lower alkoxycarbonylamino groups , such as a tert-butoxycarbonylamino group, an arylmethoxycarbonylamino group, such as a benzyloxycarbonylamino group, and/or
or a nitro group), phenylalanine or phenylglycine fused to a benzene ring, e.g.
naphthylalanine, or hydrogenated phenylalanine or phenylglycine, such as cyclohexylalanine or cyclohexylglycino, a 5- or 6-membered cyclic α-amino acid fused to a benzene ring, such as indoline-2-carboxylic acid or 1.2゜3.4-
Tetrahydroisoquinoline-3-carboxylic acid, in a form in which the side chain carboxy group is esterified or amidated, for example, a lower alkyl ester group, such as a methoxycarbonyl group or a tert-butoxycarbonyl group, or a carbamoyl group, a lower alkylcarbamoyl group, Natural or homologous α-amino acids present, for example, as methylcarbamoyl or di-lower alkylcarbamoyl groups, e.g. dimethylcarbamoyl, in the form of acylated amino groups in the side chain, e.g. lower alkanoylamino groups, e.g. or a natural or homologous α-amino acid present as a pivaloylamino group, a lower alkoxycarbonylamino group, such as a tar t-butoxycarbonylamino group, or an arylmethoxycarbonylamino group, such as a benzyloxycarbonylamino group, or a hydroxy group in the side chain. natural or homologous ατ amino acids present in etherified or esterified form, for example as lower alkoxy groups, such as methoxy groups, aryl lower alkoxy groups, such as benzyloxy groups, or lower alkanoyloxy groups, such as acetoxy groups; epimers of such amino acids, ie, divalent groups of amino acids having a non-naturally occurring D-configuration.

Such amino acids include, for example, glycine (II-Gly
-OH), alanine (H-Ala-OH), valine (It-Val-OH), norvaline (α-aminovaleric acid), leucine (tl-Leu-OH), isoleucine (H-11e-OH), norleucine (α-aminohexanoic acid, tN1e-OH), serine (H-Ser
-OH), homoserine (α-amino-T-hydroxybutyric acid), threonine (H-Thr-OH), methionine (B-Met-0[ri], cysteine (H-Cys-
OH), proline (H-Pro-011), ) trans-3- and trans-4-hydroxyproline, phenylalanine (B-Phe-OH), tyrosine (H-
Tyr-Otl), 4-) L-lualanine, 4
-Aminophenylalanine, 4-chlorophenylalanine, β-phenylserine (β-hydroxyphenylalanine), phenylglycine, α-naphthylalanine, cyclohexylalanine (H-Cha-OH), cyclohexylglycine, tryptophan (H-Trp-OH) )
, indoline-2-carboxylic acid, l.

2.3.4-Tetrahydroisoquinoline-3-carboxylic acid, aspartic acid (H-Asp-OH), asparagine (H-Asn-OR>, aminomalonic acid, aminomalonic acid monoamide, glutamic acid (H-Glu-OH)
), glutamic acid mono-tert-butyl ester, glutamine (H-Gln-OH), N'-dimethylglutamine, histidine (formerly 5-0H), arginine (H-Arg-OH), lysine ()I-Lys- OH)
, N'-Lert-butoxycarbonyl-lysine, δ-hydroxylysine, ornithine (α, δ-diaminovaleric acid), N'-pivaloyl-ornithine, α
, r-diaminobutyric acid or α.

β-diaminopropionic acid.

In order to improve the stability of the compounds of the general formula N) against enzymatic degradation, the amino acid group A can be substituted at the N-terminus by a lower alkyl group, for example a methyl group or an ethyl group.

A is alanine, valine, norvaline, leucine, norleucine, serine, etherified serine, proline, phenylalanine, β-phenylserine, α-naphthylalanine, cyclohexylalanine, indoline-2-carboxylic acid, L, 2.3゜4-Tetrahydroisoquinoline-
3-carboxylic acid, aspartic acid, esterified aspartic acid, asparagine, aminomalonic acid, aminomalonic acid monoamide, glutamic acid, esterified glutamic acid, glutamine, di-lower alkylglutamine, histidine, lysine, acylated lysine, ornithine or acylated ornithine It is preferable that it is a divalent group of N-
The terminal is substituted with a lower alkyl group, such as a methyl group. The divalent group of histidine is particularly preferred as group A.

The lower alkyl group R2 or R3 has the definition given above for the lower alkyl group Ra or Rb.

The lower alkyl group R2 is preferably a methyl group or an ethyl group, and the lower alkyl group R3 is preferably an isopropyl group, an isobutyl group or a tert-butyl group.

Hydroxy lower alkyl SR3 or R5 is preferably a hydroxymethyl group or a hydroxyethyl group, optionally etherified or esterified with the groups described below for the etherified or esterified hydroxy group R4.

Cycloalkyl group R3 or R5 is cycloalkyl group R
a or Rb has the above definition, preferably a cyclopentyl group or a cycloalkyl group.

The cycloalkyl lower alkyl groups R3 and R5 have the definitions given above for the cycloalkyl lower alkyl group, Ra or R1=, and are preferably cyclohexylmethyl groups.

A bicycloalkyl lower alkyl radical R3 or Rs contains, for example, 6 to 14, especially 7 to 12 carbon atoms and is substituted, for example by a methyl or ethyl group, such as a bicyclo (
2,2,1) hept-2-ylmethyl group.

The tricycloalkyl lower alkyl group R or Rs contains, for example, 9 to 14, especially 10 to 12 carbon atoms,
For example, it is a methyl group or an ethyl group substituted with the groups mentioned above for the tricycloalkyl group Ra or Rb, preferably a l-adamantylmethyl group.

The aryl group R3 or Rs has the definition given above for the aromatic hydrocarbon group Ha or R':' and is preferably a phenyl group.

Aryl lower alkyl 5Rs or RS has the definition given above for the aryl lower alkyl group Ra or RI:I and is preferably a benzyl group.

The etherified hydroxy group R4 is preferably etherified with an organic group which is removable under physiological conditions and which, after elimination, yields a pharmaceutically harmless decomposition product at the relevant 4 degrees.

The etherified hydroxy group R4 is, for example, an acyloxy lower alkoxy group (the acyl group is an acyl group of carbonic acid monoesterified with an optionally branched lower alkane carboxylic acid or an optionally branched lower alkyl group),
For example, a lower alkanoyloxy lower alkoxy group, such as an acetoxymethoxy group, a 1-acetoxyethoxy group,
pivaloyloxymethoxy group or 1-pivaloyloxyethoxy group, or lower alkoxycarbonyloxy lower alkoxy group, such as ethoxycarbonyloxymethoxy group, 1-ethoxycarbonyloxyethoxy group,
It is a tert-butoxycarbonyloxymethoxy group or a 1-tert-butoxycarbonyloxyethoxy group.

The etherified hydroxy group R4 is furthermore a lower alkoxy group, such as a methoxy or ethoxy group, an aryloxy group, such as a phenoxy group, or an aryl lower alkoxy group, such as a benzyloxy group.

The esterified hydroxy group R4 is, for example, an aliphatic acyloxy group, such as a lower alkanoyloxy group, such as an acetoxy group or a pivaloyloxy group, an alicyclic acyloxy group, such as a cycloalkylcarbonyloxy group, such as a cyclohexylcarbonyloxy group, or an aromatic acyloxy group. , for example a benzoyloxy group.

Lower alkyl Is Rs is 2 or more, preferably 2 to
containing 7 carbon atoms, such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t
It is an ert-butyl group or an isopentyl group. Particularly preferred are isopropyl, isobutyl and tert-butyl.

The bicycloalkyl group R5 has the definition given above for the bicycloalkyl group Ra or Rb and is preferably an α-decahydronaphthyl group.

trinochloroalkyl iR, tricycloalkyl group R
a or Rb has the above definition, preferably 1
-Adamantyl group.

The optionally substituted carbamoyl group R5 is unsubstituted or substituted with one or two lower alkyl groups or hydroxy lower alkyl groups, such as carbamoyl group, methylcarbamoyl group, ethylcarbamoyl group, n-propylcarbamoyl group, isopropyl group. Carbamoyl group, n
-butylcarbamoyl group, dimethylcarbamoyl group, 2
-hydroxyethylcarbamoyl group or di(2-hydroxyethyl)-carbamoyl group.

The optionally substituted amino group Rs is unsubstituted or substituted with one or two lower alkyl groups or aryl lower alkyl groups, lower alkanoyl groups, lower alkoxycarbonyl groups or arylmethoxycarbonyl groups, such as amino groups, methylamino group, ethylamino group, n-butylamino group, dimethylamino group, benzylamino group, acetylamino group, pivaloylamino group, methoxy-, ethoxy- or tert-butoxycarbonylamino group or benzyloxycarbonylamino group, preferably dimethyl It is an amino group.

Optionally substituted hydroxy li-Rs is an unsubstituted or etherified or esterified hydroxy % R
etherified or esterified with the groups listed above for a, such as hydroxy, methoxy, ethoxy, acetoxymethoxy, phenoxy, benzyloxy,
They are an acetoxy group, a pivaloyloxy group, or a benzoyloxy group.

An optionally substituted mercapto group R5 can be an unsubstituted or lower alkyl group, such as a methyl or ethyl group, an aryl group, such as a phenyl group, an aryl lower alkyl group, such as a benzyl group, a lower alkanoyl group, such as an acetyl group, or The carbonyl group is substituted with a benzoyl group, such as a mercapto group, a methylthio group, an ethylthio group, a phenylthio group, a benzylthio group, an acetylthio group or a benzoylthio group.

Substituted amino group R6 is, for example, one or optionally two unsubstituted or substituted, saturated or unsaturated aliphatic hydrocarbon groups having up to 18 carbon atoms, preferably up to 10 carbon atoms, or one unsubstituted or substituted aliphatic hydrocarbon group having up to 18 carbon atoms. , preferably an amino group substituted with up to 10 unsubstituted or substituted aromatic, heteroaromatic, aromatic-aliphatic or heterocyclic aromatic-aliphatic hydrocarbon groups.

Groups of α-amino acids or N-substituted, esterified or amidated derivatives thereof are excluded as substituted amino groups R@.

The unsubstituted or substituted, saturated or unsaturated aliphatic hydrocarbon group substituting the amino group R@ is, for example, an optionally substituted alkyl group having up to 10 carbon atoms, a lower alkenyl group having up to 7 carbon atoms, or It is a lower alkynyl group or a cycloalkyl lower alkyl group having 4 to 10 carbon atoms.

These groups are lower alkyl 5Ra or Rb as well as 1
one or more of the above-mentioned functional groups as well as a sulfo group, an amino group, a lower alkylamino group such as a methylamino group, an ethylamino group or an n-butylamino group, a di-lower alkylamino group such as a dimethylamino group, a lower alkanoylamino group, e.g. an acetylamino group or a pivaloylamino group, a lower alkoxycarbonylamino group, such as ter
t-butoxycarbonylamino, arylmethoxycarbonylamino, e.g. penzyloquinecarbonylamino, guanidino or substituted amino groups (amino groups contain 1 to 2 nitrogen atoms and optionally 1 oxygen or sulfur atom) is part of a 5R or 6-shell heterocycle containing
, for example, 1-pyrrolidinyl group, l-piperidinyl group, l
- may be substituted with a pyridazinyl group, a 4-morpholinyl group or a 4-thiomorpholinyl group.

Preferred substituents are hydroxy group, lower alkoxy group,
For example, a methoxy group, a lower alkanoyloxy group, such as an acetoxy group, a substituted or unsubstituted phenoxy group, such as a carbamoylphenoxy group or a carbamoyl-hydroxyphenoxy group, a carboxy group, an esterified carboxy group, such as a lower alkoxycarbonyl group, such as a methoxycarbonyl group, a tert-butoxycarbonyl group, or a physiologically degradable esterified carboxy group, such as a 1-(lower alkanoyloxy)-lower alkoxycarbonyl group, such as an acetoxymethoxycarbonyl group, a pivaloyloxymethoxycarbonyl group or a 1-propionyloxy group ethoxycarbonyl group,
1-(lower alkoxycarbonyloxy)-lower alkoxycarbonyl group, such as 1-(ethoxycarbonyloxy)-ethoxycarbonyl group, or α-amino lower alkanoyloxymethoxycarbonyl group, such as α-aminoacetoxymethoxycarbonyl group or (S) −
α-Amino-β-methylbutyryloxymethoxycarbonyl group, carbamoyl group, substituted or unsubstituted lower alkylcarbamoyl group, such as hydroxy lower alkylcarbamoyl group, such as 2-hydroxyethylcarbamoyl group or tris-(hydroxymethyl)-methylcarbamoyl group a pemoyl group, an amino group, a lower alkylamino group, such as a methylamino group, a di-lower alkylamino group, such as a dimethylamino group, a lower alkoxycarbonylamino group, such as a tert-butoxycarbonylamino group, a guanidino group, or via a nitrogen atom. a 5- or 6-membered saturated heterocyclyl group optionally substituted with an oxo group, such as a 1-piperidyl group, a 1,4-morpholinyl group or a 2-oxo-1-pyrrolidinyl group.

The aromatic or aromatic-aliphatic hydrocarbon group in the group R@ is R
It represents the same thing as listed under a or Rb, and preferably represents a phenyl group or a phenyl lower alkyl group.

These groups include aromatic groups such as lower alkyl groups, such as methyl or ethyl groups, hydroxy groups, etherified hydroxy groups, such as lower alkoxy groups, such as methoxy or tart-butoxy groups, esterified hydroxy groups, e.g. lower alkanoyloxy groups, such as acetoxy groups, or halogens, such as fluorine or chlorine, carboxy groups, esterified carboxy groups, such as lower alkoxycarbonyl groups, such as tert-butoxycarbonyl groups, carbamoyl groups, amino groups, lower alkylamino groups, For example, methylamino group, di-lower alkylamino group, such as dimethylamino group, acylated amino group,
For example, lower alkoxycarbonylamino groups, such as te
It may be substituted with rt-butoxycarbonylamino and nitro groups.

The lower alkyl group in the phenyl lower alkyl group is the group R6
It may be substituted with the same substituent as the alkyl group therein.

The heteroaromatic or heteroaromatic-aliphatic hydrocarbon radicals in radical R6 represent the same as listed under Ra and Rb, preferably pyridyl lower alkyl radicals, e.g. 2- a 13- or 4-pyridylmethyl group, an imidazolyl lower alkyl group, such as a 2-(4-imidazolyl)-ethyl group or a 2-(2-(4-imidazolylgoethylamino)-ethyl group, or an indolyl lower alkyl group, e.g. 3-indolylmethyl group or 2-(
3-indolyl)-ethyl group.

The substituted amino group R, is preferably an alkylamino group, such as methyl-, ethyl-1n-propyl-, isopropyl-1n-butyl-, isobutyl-1tert-butyl-1n-pentyl-, isopentyl-1n-hexyl-
1n-octyl- or n-decylamino group, di-lower alkylamino group such as dimethylamino group or diethylamino group, hydroxy lower alkylamino group such as 2-hydroxyethylamino group, 1-hydroxybudo-2-ylamino group, 5-hydroxypentyl group an amino group or a tri(hydroxymethyl)-methylamino group, a di(hydroxylower alkyl)-amino group, such as a di(2-hydroxyethyl)-amino group, a lower alkoxy lower alkylamino group, such as a 2-methoxyethylamino group, A lower alkanoyloxy lower alkylamino group, such as a 2-7cetoxyethylamino group, a phenoxy lower alkylamino group or a phenoxy-hydroxy-lower alkylamino group (the phenoxy group may optionally be a lower alkyl group, a lower alkoxy group, a hydroxy group, a carboxy 2-phenoxyethylamino M, 2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino group or 3-(3-carbamoylphenoxy)- 2-hydroxypropylamino, carboxyalkylamino or amino-carboxyalkylamino (the carboxy group is not present in the 1-position of the alkyl group), such as 4-carboxy-n-butylamino, 5-carboxy-n- Pentylamino group, 5-amino-5-carboxy-n-pentylamino group, 6-carboxy-n-hexylamino group, 7-carboxy-n
-hebutylamino group or 8-carboxy-n-octylamino group, further dicarboxymethylamino group, lower alkoxycarbonylalkylamino group or acylamino lower alkoxycarbonylalkylamino group (carbonyl group is not present in the 1-position of the alkyl group) ), for example 4
-tert-butoxycarbonyl-n-butylamino group, 5-tart-butoxycarbonylamino-5-methoxycarbonyl-n-pentylamino group, 7-tert
-butoxycarbonyl-n-hebutylamino group or 8-tert-butoxycarbonyl-〇-octylamino group, further di-lower alkoxycarbonyl-methylamino group, such as dimethoxycarbonyl-methylamino group,
Physiologically degradable esterified carboxyalkylamino groups (the ester function is not present in the 1-position of the alkyl group), such as the 4-t'haoyloxymethoxycarbonyl-n-butylamino group, 7-(I -ethoxycarbonyloxyethoxycarbonyl)-n-hebutylamino group or 7-pivaloyloxymethoxycarbonyl-
n-hebutylamino group, carbamoylalkylamino group or hydroxy lower alkylcarbamoylalkylamino group (carbamoyl group is not present in the 1-position of the alkyl group), such as 4-carbamoyl-n-7'thylamino group, 7-carbamoyl- n-hebutylamino group or 4-(tris[hydroxymethyl)-methyl)-carbamoyl-n-butylamino group, further dicarbamoyl-methylamino group, di(lower alkylcarbamoyl)-
Methylamino group, e.g. di(methylcarbamoyl)-
methylamino group, di(hydroxy-lower alkylcarbamoyl)-methylamino group, such as di(2-hydroxyethylcarbamoyl)-methylamino group, or bis-
(di-lower alkylcarbamoyl)-methylamino group, such as bis-(dimethylaminocarbamoyl)-methylamino group, amino lower alkylamino group, such as 2-aminoethylamino group or 3-aminopropylamino group, lower alkylamino lower alkyl Amino group, e.g. 2
-methylaminoethylamino group, di-lower alkylamino lower alkylamino group, such as 2-dimethylaminoethylamino group or 3-dimethylaminopropylamino group, lower alkoxycarbonylamino lower alkylamino group, such as 2-(tert- butoxycarbonylamino)-ethylamino group, guanidino lower alkylamino group, e.g. 2-guanidinoethylamino group, 5- or 6-membered saturated heterocyclyl lower alkylamino group bonded via a nitrogen atom, e.g. 2- (4- morpholinyl)-ethylamino i, 3-(4-morpholinyl)
-propylamino group or 3-(2-oxo-1-pyrrolidinyl)-propylamino group, lower alkenylamino group such as allylamino group or 2- or 3-butenylamino group, lower alkynylamino group such as propagylamino group, cyclo alkyl lower alkylamino group,
For example, cyclopropylmethylamino or cyclohexylmethylamino, phenylamino or phenyl lower alkylamino (phenyl is optionally a lower alkyl group, such as a methyl group, a hydroxy group, a lower alkoxy group, such as a methoxy group or a tert- butoxy groups, lower alkanoyloxy groups such as ethoxy groups, halogens such as fluorine or chlorine, carboxy groups,
Lower alkoxycarbonyl groups, such as Lert-butoxycarbonyl groups, carbamoyl groups, amino groups, lower alkylamino groups, such as methylamino groups, di-lower alkylamino groups, such as dimethylamino groups, acylamino groups,
For example, tert-butoxycarbonylamino group and/or
or substituted with one or more nitro groups), such as a phenylamino group, a 2-13- or 4-methylphenylamino group, a 4-hydroxyphenylamino group, a 4-methoxyphenylamino group, a 2.3-12. 4- or 2
, 5-dimethoxyphenylamino group, 4-chlorophenylamino group, 2-13- or 4-carboxyphenylamino group, 2-13- or 4-methoxy- or tart-butoxycarbonylphenylamino group, 2
-13- or 4-carbamoylphenylamino group,
4-aminophenylamino group, 4-tert-butoxycarbonylaminophenylamino group or 4-nitrophenylamino group, furthermore for example benzylamino group, 4-
Methylbenzylamino group, 4-methoxybenzylamino group, 2-53- or 4-carboxybenzylamino group, 2-13- or 4-tert-butoxycarbonylbenzylamino group, 2-53- or 4-carbamoylbenzylamino group , 2-phenylethylamino or 3-phynylpropylamino, pyridyl lower alkylamino, such as 2-, 3- or 4-pyridylmethylamino, 2-(2-, 3- or 4-pyridyl) )-ditylamino group or 3- (2-, 3-
or 4-pyridyl)-propylamino group, imidazolyl lower alkylamino group, such as 4-imidazolylmethylamino group, 2-(4-imidazolyl)-ethylamino group or 2-(2-(4-imidazolyl)-ethylamino) -ethylamino group, or indolyl lower alkylamino group, such as 3-indolylmethylamino group or 2-(3-indolyl)-ethylamino group.

Salts are in particular pharmaceutically acceptable salts or non-toxic salts of the compounds of general formula (I).

Such salts are formed, for example, from compounds of general formula (I) having an acidic group, such as a carboxy group, in particular from suitable alkali metal salts, such as sodium or potassium salts, or from suitable alkaline earth metal salts, for example magnesium salts or calcium salts, also zinc salts, or ammonium salts, and also organic amines, such as mono-, di- or trialkylamines optionally substituted with hydroxy groups, such as diethylamine, di(2-hydroxyethyl)-amine, Triethylamine, N.

N-dimethyl-N-(2-hydroxyethyl)-amine, tri(2-hydroxy-ethyl)-amine or N-
It is a salt formed from methyl-glucamine. Compounds of general formula (I) containing a basic group, such as an amino group, are
For example, inorganic acids such as hydrochloric acid, sulfuric acid or phosphoric acid, or organic carboxylic, sulfonic or sulfonic acids such as acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, hydroxymaleic acid, fumaric acid, malic acid, tartaric acid, citric acid. acids, benzoic acid, cinnamic acid, mandelic acid, salicylic acid, 4-aminosalicylic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, emponic acid, nicotinic acid or isonicotinic acid, as well as amino acids such as the above-mentioned α
-Amino acids, as well as methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2
- disulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid or naphthalene-2-sulfonic acid,
or form acid addition salts with other acidic organic compounds, such as ascorbic heptaic acid. Compounds of general formula (I) having an acidic group and a basic group can also form internal salts.

For isolation or purification purposes, pharmaceutically unsuitable salts can also be used.

The compounds of the present invention exhibit an enzyme inhibitory effect, in particular inhibiting the action of the natural enzyme renin. Renin enters the blood through the kidneys, where it breaks down angiotensinogen to form the decapeptide angiotensin■, which is then broken down into the octapeptide angiotensin■ in the lungs, kidneys, and other organs. be done. Angiotensin ■ increases blood pressure directly by constricting arteries and indirectly by releasing aldosterone, a sodium ion-retaining hormone, from the adrenal glands, and also increases the amount of extracellular fluid as the aldosterone is released. This increase is due to the action of angiotensin ■ itself or the heptapeptide angiotensin ■ formed as a degradation product from it.
Reduces the formation of angiotensin I. As a result, less angiotensin ■ is produced. This reduction in the concentration of the active peptide hormone is directly responsible for the hypotensive effect of renin inhibitors.

The action of renin inhibitors is proven experimentally, especially by in vitro tests, in which a reduction in the formation of angiotensin in various systems (human plasma, purified human renin with synthetic or natural renin substrates) is determined. . In particular, the following in vitro test is used: Extract of human renin from kidney (0,
5mGU (Goldbla
Synthetic renin substrate: tetradecapeptide H-^sp-Arg- Val-Tyr-Roe
-His-Pro-Phe-His-Leu-Leu-
Incubate with Val-Tyr-5er-OH23pg/ml for 1 hour at 37°C and pH 7.2. The amount of angiotensin ■ produced is measured by radioimmunoassay. The inhibitory substance according to the invention is added to the inkinivation mixture in various concentrations. 4 degrees of each inhibitor reduce the formation of angiotensin T by 50%
Compounds of the present invention, designated as C old, have approximately 10
It exhibits an inhibitory effect at the lowest concentrations of -'' to about 10-9 mol/l.

In salt-deficient animals, renin inhibitors have a hypotensive effect. Human renin is different from renin of other species. Since human renin and primate renin are significantly similar in their range of drug activity, we tested primate M (Marmocenot, Ca1lithrix ja) to test inhibitors of human renin.
In particular, the following in-vivo test is used. Conscious, normotensive female and male marmosets weighing approximately 300 g are tested. Blood pressure and heart rate are measured with a catheter in the femoral artery. The internal MM of renin is stimulated by intravenous injection of furosemide (5■/kg).

- administering the test substance by single injection or continuous infusion into the lateral tail vein 30 minutes after the injection of furosemide and evaluating its effect on blood pressure and heart rate. About 0.1 to about 1.0 ■ by intravenous injection
It is forward motion at a dose of +r to /.

The compounds of the invention can be used in the treatment of renin-related hyperaldosteronism, hypertension and heart failure.

The invention particularly provides that R1 is hydrogen or has the sub-formula Rb-C0-5
Ra-o-co-4 is (R” ') (R” )N-GO
-GO- (wherein Ra is an unsubstituted or substituted, saturated or unsaturated aliphatic, cycloaliphatic or cycloaliphatic group having 18 or less carbon atoms, preferably 10 or less, or 18 or less carbon atoms, Preferably up to 10 unsubstituted or substituted aromatic, heterocyclic aromatic, araliphatic or peterocyclic aromatic-aliphatic hydrocarbons, or unsubstituted or substituted 5- or 6-membered saturated heterocycles , Rb represents hydrogen or has the definition of Ra), but does not represent the optional N-substituted acyl group of a natural amino acid, and A is an acyl group whose N-terminus is bonded to R+ represents an optionally N-alkylated α-amino acid group whose C-terminus is bonded to a group -NR2-, R2 represents hydrogen or a lower alkyl group, R3 represents hydrogen or a lower alkyl group,
represents a hydroxy lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a bicycloalkyl lower alkyl group, a tricycloalkyl lower alkyl group, an aryl group or an aryl lower alkyl group, R4 represents a hydroxy group, and R5 represents the number of carbon atoms 2 or more lower alkyl groups,
Hydroxy lower alkyl group, cycloalkyl group, cycloalkyl lower alkyl group, bicycloalkyl group, bicycloalkyl lower alkyl group, tricycloalkyl group, tricycloalkyl lower alkyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylamino group ,
represents an aryl group or an aryl lower alkyl group, where RG represents an amino group excluding an amine group derived from an α-amino acid, and this group has one or optionally two carbon atoms of 18 or less, preferably 10 or less non-substitution or substitution of
Saturated or unsaturated aliphatic hydrocarbon group, or unsubstituted or substituted aromatic, heterocyclic aromatic, aromatic-aliphatic or heterocyclic aromatic-aliphatic carbonized group having up to 18 carbon atoms, preferably up to 10 carbon atoms General formula (I
) and a pharmaceutically acceptable salt of the core compound having a salt-forming group.

The present invention mainly provides that R1 is hydrogen, a lower alkanoyl group having 1 to 7 carbon atoms, such as a formyl group, an acetyl group,
propionyl or pivaloyl, hydroxy lower alkanoyl, such as β-hydroxypropionyl, lower alkoxy lower alkanoyl, such as lower alkoxyacetyl or lower alkoxypropionyl, such as methoxyacetyl, especially β-methoxypropionyl, phenoxy lower alkanoyl groups, such as phenoxyacetyl, naphthoxy-lower alkanoyl, such as α- or β-naphthoxyacetyl, lower alkanoyloxy-lower alkanoyl, such as lower alkanoyloxyacetyl, or lower alkanoyloxypropionyl, such as acetoxyacetyl or β- Acetoxypropionyl group, carboxy lower alkanoyl group, such as alkyl acetyl group or β
-carboxypropionyl group, lower alkoxycarbonyl lower alkanoyl group, such as lower alkoxycarbonylacetyl group or lower alkoxycarbonylpropionyl group, such as methoxycarbonylacetyl group, β-
Methoxycarbonylpropionyl, ethoxycarbonylacetyl or β-ethoxycarbonylprobionyl, carbamoyl lower alkanoyl, such as carbamoylacetyl or β-carbamoylpropionyl, lower alkylcarbamoyl lower alkanoyl, such as methylcarbamoylacetyl, di-lower alkyl Carbamoyl lower alkanoyl group, e.g. dimethylcarbamoylacetyl group, α-naphthoxy-carboxy-
Lower alkanoyl groups, such as 2-α-naphthoxy-4-
Carboxybutyryl group, α-naphthoxy-lower alkoxycarbonyl lower alkanoyl group, e.g. naphthoxy-
Ethoxycarbonylacetyl group, 2-α-naphthoxy-
3-ethoxycarbonylprobionyl group or 2-α
-naphthoxy-4-tert-butoxycarbonylbutyryl group, α-naphthoxy-benzyloxycarbonyl lower alkanoyl group, e.g. 2-α-naphthoxy-3-benzyloxycarbonylpropionyl group, α-naphthoxy-carbamoyl lower alkanoyl group, e.g. 2 −α−
naphthoxy-4-carbamoylbutyryl group, α-naphthoxycyano lower alkanoyl group, such as α-naphthoxy-cyanoacetyl group or 2-α-naphthoxy-4-
Cyanobutyryl group, α-naphthoxydilower alkylamino lower alkanobiyl group, e.g. 2-α-naphthoxy-5-dimethylaminopentanoyl group, α-naphthoxy-oxo-lower alkanoyl group, e.g. 2-α-naphthoxy-4-oxopentanoyl group , lower alkenoyl groups having 3 to 7 carbon atoms, such as acryloyl, vinylacetyl, crotonoyl or 3- or 4-pentenoyl, lower alkinoyl groups having 3 to 7 carbon atoms, such as propionyl or 2- or 3 -butynoyl group, cycloalkylcarbonyl group having 4 to 9 carbon atoms, such as cyclopropylcarbonyl group, cyclobutylcarbonyl group, cyclopentylcarbonyl group or cyclohexylcarbonyl group, bicycloalkylcarbonyl group having 6 to 11 carbon atoms, e.g. and- or exo-norbornyl-2-carbonyl group, bicyclo(
2,2,2) oct-2-ylcarbonyl group or bicyclo(3,3,1)non-9-ylcarbonyl group, tricycloalkylcarbonyl group having 9 to 11 carbon atoms,
For example, l- or 2-adamantylcarbonyl group, cycloalkenylcarbonyl group having 4 to 9 carbon atoms, such as 1-cyclohexenyl carbonyl group or 1.4-
Cyclohexagenylcarbonyl group, number of carbon atoms 6 to 1
1 bicycloalkenylcarbonyl group, such as 5-norbornen-2-ylcarbonyl or bicyclo(2,
2,2) Octen-2-ylcarbonyl group, cycloalkyl lower alkanoyl group having 5 to 11 carbon atoms, such as cyclopropylacetyl group, cyclopentylacetyl group or cyclohexylacetyl group, having 6 to 1 carbon atoms
1 cycloalkyl lower alkenoyl group, such as cyclohexyl acryloyl group, cycloalkenyl lower alkanoyl group having 5 to 11 carbon atoms, such as 1-cyclohexylacetyl group or 1,4-cyclohexagenylacetyl group, non- benzoyl groups substituted with one or more substituted or lower alkyl groups, such as methyl groups, halogens, such as chlorine, hydroxy groups, lower alkoxy groups, such as methoxy groups, and/or nitro groups, such as 4-chlorobenzoyl groups, 4- Methoxybenzoyl group or 4-nitrobenzoyl group, phenyl-1α-naphthyl- or β-naphthyl-lower alkanoyl group (phenyl group is
unsubstituted or substituted with one or more lower alkyl groups, such as methyl groups, halogens, such as chlorine, hydroxy groups, lower alkoxy groups, such as methoxy groups, and/or nitro groups; lower alkanoyl groups are unsubstituted or substituted with hydroxy groups, lower It may be substituted with an alkoxy group, an acyloxy group, a carboxy group, an esterified carboxy group, a carbamoyl group, a substituted carbamoyl group, a cyano group, a phosphono group, an esterified phosphono group, a benzofuranyl group and/or an oxo group, and optionally branched. ), such as phenylacetyl group, α-naphthylacetyl group, β-naphthylacetyl group, lower alkylphenylacetyl group, such as 4-methylphenylacetyl group, lower alkoxyphenylacetyl group, such as 4-methoxyphenylacetyl group, 3 -phenylpropionyl group, 3-(p-hydroxyphenyl)-propionyl group, diphenylacetyl group, di(4
-methoxyphenyl)-acetyl group, triphenylacetyl group, substituted anilinophenyl acetyl group, e.g. 2-
(o,o-dichloroanilino)-phenylacetyl group or 2-(0,0-dichloro-N-benzylanilino)-phenylacetyl group, 3-α- or β-naphthylpropionyl group, 3-phenyl- or 3-α-
Naphthyl-2-hydroxypropionyl group, 3-phenyl- or 3-α-naphthyl-2-lower alkoxypropionyl group, e.g. 3-phenyl- or 3-α
-naphthyl-2-neopentyloxy-propionyl group, 3-phenyl- or 3-α-naphthyl-2-cycyloxybrobionyl group, such as 3-phenyl-2-pivaloyloxy- or 2-acetoxypropionyl group; 14.3-α-naphthyl-2-pivaloyloxy- or 2-acetoxypropionyl group, 3-α-naphthoxy-2-acetoacetoxypropionyl group, 3-α-
naphthyl-2-ethylaminocarbonyloxypropionyl group or 3-α-naphthyl-2-(2-amino-
or 2-benzyloxycarbonylamino-2-
methylpropionyloxy)-propionyl group, 3-phenyl- or 3-α-naphthyl-2-carboxymethylpropionyl group, 3-phenyl- or 3-α-
Naphthyl-2-lower alkoxycarbonylpropionyl group, such as 3-naphthyl-2-ethoxycarbonylpropionyl group, 3-phenyl or 3-α-naphthyl-2-penzyloxylponylmethylpropionyl group, 3-phenyl- or 3-α-naphthyl-2-carbamoylpropionyl group, 3-phenyl- or 3
-χ-naphthyl-1-tert-butylcarbamoylpropionyl group, 3-phenyl- or 3-α-naphthyl-2-(2-dimethylaminoethyl)-carbamoylpropionyl group, 3-α-naphthyl-2-(carboxy- or tert-butoxycarbonyl)-methylcarbamoylpropionyl group, 3-phenyl- or 3-α-naphthyl-.

2-(3-hydroxy-2-propyl)-rubamoylpropionyl group, 3-phenyl- or 3-α-naphthyl-2-(5-amino-5-carboxypentyl)-
Rubamoylpropionyl group, 3-phenyl- or 3-α-naphthyl-2-anopropionyl group, 3-phenyl- or 3-α-naphthyl-2-cyanomethylpropionyl group, 3-phenyl-2- Phosphono- or phosphonomethylpropionyl group, 3-phenyl-2-
dimethoxyphosphoryl or dimethoxyphosphorylmethylpropionyl group, 3-phenyl-2-jethoxyphosphoryl or jetoxyphosphorylmethylpropionyl group, 3-phenyl-2-ethoxy- or methoxy-hydroxyphosphorylpropionyl group, 3-phenyl- or 3-α-naphthyl-2-a7tonylprobionyl group, 3-phenyl- or 3-α-naphthyl-2-dimethylaminomethylpropionyl group, 2-benzyl- or 2-α-naphthylmethyl-4-cyanobutyryl group , 4-phenyl- or 4-α-naphthyl-3-carboxybutyryl group, 4-phenyl- or 4-α-naphthyl-3-benzyloxycarbonylbutyryl group, 2-pen'; benzofuranyl)
-4-oxobutyryl group, 2-benzyl- or 2-
α-naphthylmethyl-4-oxopentanoyl group, 2-
Benzyl- or 2-α-naphthylmethyl-4゜4-
Dimethyl-3-oxopentanoyl group, 2-benzyl-
or 2-α-naphthylmethyl-5-dimethylaminobentanoyl group, 2-benzyl- or 2-α-naphthylmethyl-5-dimethylamino-4-oxopentanoyl group, 2-benzyl- or 2-α-naphthyl Methyl-5,5-dimethyl-4-oxohexanoyl group, α
, p-diaminophenyl acetyl group, α, p-diacylaminophenyl acetyl group, for example α, p-dibenzyloxy group ponylaminophenyl acetyl JL4 Young 1. <
is α-pivaloylamino-p-benzyloxycarbonylaminophenylacetyl group, phenyl lower alkenoyl group, such as β-phenylacryloyl group or β-
a phenylvinylacetyl group, a naphthylcarbonyl group, such as an α- or -β-naphthylcarbonyl group or 1. 8-naphthalene dicarbonyl group, indenylcarbonyl group, e.g. 1-12- or 3-indenylcarbonyl group, indanylcarbonyl group, e.g. 1- or 2-indanylcarbonyl group, phenanthrenylcarbonyl group, e.g. 9 - a phenanthrenylcarbonyl group, an optionally substituted pyrrolylcarbonyl group, such as a 2- or 3-pyrrolylcarbonyl group or a 4- or 5-phenylpyrrolyl-2-carbonyl group, a furylcarbonyl group, such as a 2- Furylcarbonyl, chenylcarbonyl, such as 2-thenylcarbonyl, pyridylcarbonyl, such as 2-13- or 4-pyridylcarbonyl, optionally substituted indolylcarbonyl, such as 2-53- or 5 -indolylcarbonyl group, 1-methyl-15-methyl-15-methoxy-15-benzyloxy-15-chloro or 4
．． 5-dimethylindolyl-2-carbonyl group, 1-benzylindolyl-2- or -3-carbonyl group, rubonyl group, 4,5,6.7-tetrahydroindolyl-2-carbonyl group, cyclohebuta( b) a pyrrolyl-5-carbonyl group, an optionally substituted quinolylcarbonyl group, such as a 2-53- or 4-quinolylcarbonyl group or a 4-hydroxyquinolyl-2-carbonyl group, an optionally substituted isoquino lyl carbonyl group, e.g. 1-1
3- or 4-inquinolylcarbonyl group or 1-oxo-1,2-dihydroisoquinolyl-3-carbonyl group, 2-quinoxalinylcarbonyl group, 2-benzofuranylcarbonyl group, benzo(e)indolyl group -2-carbonyl group, β-carbonyl-3-carbonyl group, pyrrolidinyl-3-carbonyl group, hydroxypyrrolidinylcarbonyl group, such as 3- or 4-hydroxypyrrolidinyl-2-carbonyl group, oxopyrrolidinylcarbonyl group groups such as 5-oxopyrrolidinyl-2-carbonyl groups, piperidinylcarbonyl groups such as piperidinyl-2-1-3- or -4-carbonyl groups, indolinylcarbonyl groups such as 2- or 3-indolinyl Carbonyl group, 1°2.3.4-tetrahydroquinolylcarbonyl group, for example 1. 2. 3. 4-tetrahydroquinolyl-2-1-3- or -4-carbonyl group, 1°2.3.4-tetrahydroisoquinolylcarbonyl group, e.g. l, 2.3.4-tetrahydroisoquinolyl-1- 1-3- or -4-carbonyl group or l-oxo-1,2,3,4-tetrahydroisoquino-4y-3-carbonyl group, aryl lower alkoxycarbonyl group, e.g. arylmethoxycarbonyl group (aryl group is phenyl group) , l- or 2-naphthyl or lower alkyl groups, such as methyl or tert-
butyl, lower alkoxy, such as methoxy, ethoxy or tert-butoxy, hydroxy, phenyl substituted with one or more halogens, such as chlorine or bromine, and/or nitro), such as benzyl. oxycarbonyl group, 4-methoxybenzyloxycarbonyl group, 4-nitrobenzyloxycarbonyl group, diphenylmethoxycarbonyl group, di(4-methoxyphenyl)-methoxycarbonyl group or trityloxycarbonyl group, further oxamoyl group or lower alkyloxamoyl a group, such as a methyl- or ethyloxamoyl group, and A represents an α-amino acid, such as a natural α-amino acid with one unit, such as is normally present in proteins, in which the amino acid side chain of such an amino acid has one or homologs which are lengthened or shortened by two methylene groups and/or in which one methyl group is replaced by hydrogen, substituted aromatic α-amino acids, such as one or more substituted phenylalanine, particularly phenylglycine ( Substituents include lower alkyl groups such as methyl groups, halogens such as fluorine, chlorine, bromine or iodine,
hydroxy group, lower alkoxy group, such as methoxy group,
Lower alkanoyloxy groups, such as acetoxy groups, amino groups, lower alkylamino groups, such as methylamino groups,
di-lower alkylamino groups, such as dimethylamino, lower alkanoylamino groups, such as acetylamino or pivaloylamino, lower alkoxycarbonylamino groups, such as ter L-butoxycarbonylamino, arylmethoxycal, bonylamino groups, such as benzyloxycarbonyl phenylalanine or phenylglycine fused with a benzene ring, such as α-naphthylalanine, or hydrogenated phenylalanine or phenylglycine, such as cyclohexylalanine or cyclohexylglycine , a 5- or 6-membered cyclic α-amino acid fused to a benzene ring, such as indoline-
2-carboxylic acid or 1.2.3.4-tetrahydroisoquinoline-3-carboxylic acid, in which the carboxy group in the side chain is esterified or amidated, such as a lower alkyl ester group, such as a methoxycarbonyl group or tert-butoxy A natural or homologous α-amino acid present as a carbonyl group, or a carbamoyl group, a lower alkylcarbamoyl group, such as a methylcarbamoyl group, or a di-lower alkylcarbamoyl group, such as a dimethylcarbamoyl group, in which the side chain amino group is acylated. natural or homologous compounds present, for example, as lower alkanoylamino groups, such as acetylamino or pivaloylamino groups, lower alkoxycarbonylamino groups, such as tert-butoxycarbonylamino groups, or arylmethoxycarbonylamino groups, such as benzyloxycarbonylamino groups. α-amino acids, or in the form in which the hydroxy group of the side chain is etherified or esterified, for example, a lower alkoxy group, such as a methoxy group,
Ori-ru lower alkoxy group, such as benzyloxy group,
or divalent radicals of natural or homologous α-amino acids present as lower alkanoyloxy groups, e.g. acetoxy groups, or epimers of such amino acids, i.e. optionally substituted at the N-atom with lower alkyl groups, e.g. methyl groups. It also represents a divalent group of a non-naturally occurring D-configured amino acid, R2 represents hydrogen or a lower alkyl group, such as a methyl group, R3 represents a lower alkyl group, such as an isopropyl group or an isobutyl group, a cycloalkyl group, e.g. Represents a cyclohexyl group, a cycloalkyl lower alkyl group, such as a cyclohexylmethyl group, a tricycloalkyl lower alkyl group, such as a 1-adantylmethyl group, a phenyl lower alkyl group, such as a benzyl group, or a phenyl group, and R4 represents a hydroxy group. , R5 is a lower alkyl group having 2 or more carbon atoms, such as isopropyl group, isobutyl group or tert-butyl group, cycloalkyl group, such as cyclopentyl group or cyclohexyl group, cycloalkyl lower alkyl group, such as cyclohexylmethyl group, bicycloalkyl group groups, α-decahydronaphthyl groups, tricycloalkyl groups, such as l-adamantyl groups, phenyl groups, phenyl lower alkyl groups, such as benzyl groups, carbamoyl groups, lower alkylcarbamoyl groups, such as methylcarbamoyl groups or di-lower alkylamino groups. , for example, dimethylamino group, and R6 is an alkylamino group having 1 to 10 carbon atoms, such as methyl-, ethyl-2n-propyl-, isopropyl-
1n-butyl-, isobutyl-1tert-butyl-1
n-pentyl, isopentyl-1n-hexyl-1n
-octyl- or n-decylamino groups, di-lower alkylamino groups such as dimethylamino or diethylamino groups, hydroxy lower alkylamino groups such as 2-hydroxyethylamino groups, 1-hydroxybudo-2-ylamino groups, 5-hydroxypentyl an amino group or a tris-(hydroxymethyl)-methylamino group, a di(hydroxy-lower alkyl)amino group, such as a di(2-hydroxyethyl)-amino group, a lower alkoxy-lower alkylamino group, such as a 2-methoxyethylamino group, A lower alkanoyloxy lower alkylamino group, such as a 2-acetoxyethylamino group, a phenoxy lower alkylamino group or a phenoxyhydroxy lower alkylamino group (the phenoxy group may optionally be a lower alkyl group, a lower alkoxy group, a hydroxy group, a carboxy group, a lower alkoxy group) 2-phenoxyethylamino 5.2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino group or 3-(3-carbamoylphenoxy)-2-hydroxyethyl an amino group, a carboxyalkylamino group or an amino-carboxyalkylamino group (the carboxy group is not present in the 1-position of the alkyl group), e.g. 4-carboxy-n-butyl-15
-carboxy-n-pentyl-16-carboxy-n-
Hexyl-57-carboxy-n-hebutyl- or 8-carboxy-n-octylamino group or 5-amino-5-carboxy-n-pentylamino group, further dicarboxymethylamino group, lower alkoxycarbonylalkylamino group or Acylamino lower alkoxycarbonylalkylamino groups (the carbonyl group is not present in the 1-position of the alkyl group), such as 4-tart-butoxycarbonyl-n-octylamino groups or 5-te
rt-butoxycarbonylamino-5-methoxycarbonyl-n-pentylamino group, further di-lower alkoxycarbonylmethylamino group, e.g. dimethoxycarbonylmethylamino group, physiologically degradable esterified carboxyalkylamino group (ester function is ), e.g. 4-pivaloyloxymethoxycarbonyl-n-butylamino group, 7-(I-
ethoxycarbonyloxyethoxycarbonyl)-n-
Hebutylamino group or 7-pivaloyloxymethoxycarbonyl n-hebutylamino group, carbamoyl-
or hydroxy lower alkylcarbamoylalkylamino S (the carbamoyl group is present at the 1-position of the alkyl group), such as 4-carbamoyl-n-butylamino group, 7-carbamoyl-n-hephthylamino group or 4-(tris-[ hydroxymethyl2methyl)-carbamoyl-n-butylamino group, further dicarbamoylmethylamino group, di(lower alkylcarbamoyl)methylamino group, such as di(methylcarbamoyl)-methylamino group, di(hydroxylower alkylcarbamoyl)methyl Amino groups, such as di(2-hydroxyethylcarbamoyl)-methylamino, also hahis(di-lower alkylcarbamoyl)methylamino, such as bis-(dimethylcarbamoyl)-methylamino, amino lower alkylamino groups, such as 2- Aminoethylamino group or 3-aminopropylamino group, lower alkylamino lower alkylamino group, such as 2-methylaminoethylamino group, di-lower alkylamino lower alkylamino group, such as 2-dimethylaminoethylamino group or 3-dimethyl Aminopropylamino group, lower alkoxycarbonylamino lower alkylamino group, e.g. 2
- (tert-butoxycarbonylamino)-ditylamino group, guanidino lower alkylamino group, e.g. 2
-guanidinoethylamino group, a 5- or 6-membered saturated heterocyclyl lower alkylamino group bonded via a nitrogen atom, such as 2-(4-morpholinyl)-dithylamino group, 3-(4-morpholinyl)-propyl Amino group or 3-(2-oxopyrrolidin-1-yl)-
propylamino group, lower alkenylamino group such as allylamino group or 2- or 3-butenylamino group, lower alkynylamino group such as propargylamino group, cycloalkyl lower alkylamino group such as cyclopropylmethylamino group or cyclohexylmethylamino group a phenylamino group or a phenyl lower alkylamino group (the phenyl group may optionally be a lower alkyl group such as a methyl group, a hydroxy group, a lower alkoxy group such as a methoxy group or a tart-butoxy group,
Lower alkanoyloxy groups, such as acetoxy groups, halogens, such as fluorine or chlorine, carboxy groups, lower alkoxycarbonyl groups, such as tart-butoxycarbonyl groups, carbamoyl groups, amino groups, lower alkylamino groups, such as methylamino groups, di-lower alkyl substituted with one or more amino groups, e.g. dimethylamino, acylamino, e.g. tert-butoxycarbonylamino and/or nitro groups), e.g. phenyl-1
2-13- or 4-methylphenyl-14-hydroxyphenyl-14-methoxyphenyl-12,3-1
2,4- or 2,5-dimethoxyphenyl-54-
Chlorophenyl-12-53- or 4-carboxyphenyl-52-53- or 4-methoxy- or tert-butoxycarbonylphenyl-12-13-
or 4-carbamoylphenyl-14-aminophenyl-14-tart-butoxycarbonylaminophenyl- or 4-nitrophenyl-amino group, further for example benzylamino group, 4-methylbenzylamino group,
4-methoxybenzylamino, 2-13- or 4-
Carboxybenzylamino group, 2-13- or 4-
tert-butoxycarbonylbenzylamino group, 2-
13- or 4-carbamoylbenzylamino group, 2
-phenylethylamino group or 3-phenylpropylamino group, pyridyl lower alkylamino group, e.g. 2
-13- or 4-pyridylmethyl-12-(2-1
3- or 4-pyridyl)-ethyl- or 3-(
2-13- or 4-pyridyl)-propylamino group, imidazolyl lower alkylamino group, e.g. 4-imy,
Dazolylmethylamino group, 2-(4-imidazolyl)-
an ethylamino group or a 2-(2-[4-imidazolyltoethylamino)-ditylamino group, or an indolyl lower alkylamino group, such as a 3-indolylmethylamino group or a 2-(3-indolyl)-ethylamino group. The present invention relates to compounds of general formula (I) represented by the formula (I) and pharmaceutically acceptable salts of these compounds having a salt-forming group.

The invention particularly provides that R1 is a lower alkanoyl group, such as a formyl group, an acetyl group, a propionyl group or a pivaloyl group, a lower alkenoyl group, such as an acryloyl group or a crotonoyl group, a lower alkinoyl group, such as a propionyl group, a cycloalkylcarbonyl group, e.g. cyclopentyl- or cyclohexylcarbonyl group,
unsubstituted or lower alkyl groups, such as methyl groups, halogens, such as chlorine, hydroxy groups, lower alkoxy groups,
For example, a benzoyl group substituted with one or more methoxy and/or nitro groups, such as a 4-chlorobenzoyl group, 4
- methoxybenzoyl or 4-nitrobenzoyl, phenyl lower alkanoyl (phenyl is an unsubstituted or lower alkyl group, such as a methyl group, a halogen, such as chlorine, a hydroxy group, a lower alkoxy group, such as a methquine group and/or a nitro group) The lower alkanoyl group may be substituted with one or more hydroxyl groups,
acyloxy, carboxy or esterified carboxy), such as phenylacetyl, lower alkylphenylacetyl, such as 4-methylphenylacetyl, lower alkoxyphenylacetyl, such as 4-methoxyphenylacetyl. , 3-phenylpropionyl group, 5-phenyl-2-(phenylmethyl)-pentanoyl group, 3-(p-hydroxyphenyl)-propionyl group, 2-hydroxy-3-phenylpropionyl group, 2-acyloxy-3-phenyl group Propionyl groups, such as 2-acetoxy-3-phenylpropionyl or 2-pivaloyloxy-3-phenylpropionyl, diphenylacetyl, di(4
-methoxyphenyl)acetyl group, triphenylacetyl group, and also substituted anilinophenyl acetyl group, e.g.
-(o,o-dichloroanilino)-phenylacetyl group or '1-(o,o-dichloro-N-benzylanilino)-phenylacetyl group, phenyl lower alkenoyl group, such as β-phenylacryloyl group or β-
phenylvinylacetyl groups, naphthylcarbonyl groups, such as 1- or 2-naphthylcarbonyl groups, naphthyl lower alkanoyl groups (lower alkanoyl groups may be substituted, for example, with hydroxy groups, acyloxy groups, carboxy groups or esterified carboxy groups), For example, 1- or 2-naphthylacetyl group, 2- or 3-α-
Naphthylpropionyl group, 2- or 3-β-naphthylpropionyl group, 2-hydroxy-3-(α- or β-naphthyl)-propionyl group, 2-acyloxy-3-(α- or β-naphthyl)-propionyl group , for example, 2-acetoxy-3-α-naphthylprobionyl M or 2-pivaloyloxy-3-α-naphthylpropionyl group, 3-carboxy-4-α-naphthylbutyryl group, 3-carboxy-2-(α-naphthyl methyl)-propionyl group, esterified carboxy-(α-
or β-naphthyl)-butyryl group, such as 3-benzyloxycarbonyl-4-α-naphthylbutyryl group,
Esterified carboxy-(α- or β-naphthylmethyl)-propionyl groups, such as 3-benzyloxycarbonyl-2-(α-naphthylmethyl)-propionyl groups, indenylcarbonyl groups, such as 1-12- or 3-indenyl nylcarbonyl group, indanylcarbonyl group, such as 1-particularly 2-indanylcarbonyl group,
phenanthrenylcarbonyl'5.4M x ha 9-phenanthrenylcarbonyl group, optionally substituted pyrrolylcarbonyl group, such as 2- or 3-pyrrolylcarbonyl group or 4- or 5-phenylpyrrolyl-
2-carbonyl group, furylcarbonyl group, e.g. 2-furylcarbonyl group, chenylcarbonyl group, e.g. 2-
chenylcarbonyl group, pyridylcarbonyl group, e.g. 2-13- or 4-pyridylcarbonyl group, optionally substituted indolylcarbonyl group, e.g. 2-1
3- or 5-indolylcarbonyl group, 1-methyl-15-methyl-15-methoxy-55-benzyloxy-25-chloro- or 4,5-dimethylindolyl-2-carbonyl 5,1-benzyl-indolyl -2
-carbonyl group, 4,5,6.7-tetrahydroindolyl-2-carbonyl group, optionally substituted quinolylcarbonyl group, such as 2-13- or 4-quinolylcarbonyl group or 4-hydroxyquinolyl- 2-carbonyl group, optionally substituted isoquinolylcarbonyl group, such as 1-13- or 4-isoquinolylcarbonyl group or l-oxo-1,2-dihydroinquinolyl-3-carbonyl group, 2-quinolylcarbonyl group, Xalinylcarbony/
14.2-Benzofuranylcarbonyl group, benzo(e)
indolyl-2-carbonyl group, β-carbolinyl-3
-carbonyl group, indolinylcarbonyl group, e.g. 2
- or 3-indolinylcarbonyl group, 1.2.3
．． 4-tetrahydroquinolylcarbonyl group, for example 1.
2,3.4-tetrahydroquinolyl-2-1-3- or -4-carbonyl group, 1,2,3.4-tetrahydroisoquinolylcarbonyl group, e.g. 1.2,3°4-
Tetrahydroisoquinolyl-1-1-3- or -4
-carbonyl group or 1-oxo-1゜2.3.4-tetrahydroisoquinolyl-3-carbonyl group, or arylmethoxycarbonyl group having one or two aryl groups (aryl group is optionally a lower alkyl group) , for example a methyl or tert-butyl group, a lower alkoxy group such as a methoxy group, a hydroxy group, a phenyl group substituted with 1.2 or 3 halogens, such as chlorine and/or nitro groups), such as benzyloxy The general formula ( The present invention relates to compounds of I) and pharmaceutically acceptable salts of these compounds having a salt-forming group.

The present invention also provides alanine, valine, norvaline, leucine, norleucine, serine, proline, phenylalanine, β-phenylserine, α-
Naphthylalanine, cyclohexylalanine, indoline-2-carboxylic acid, 1.2.3.4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid, asparagine, aminomalonic acid, aminomalonic acid monoamide,
It represents a divalent group of glutamic acid, glutamine, di-lower alkylglutamine, histidine, lysine or ornithine, and the side chain carboxy group of aspartic acid or glutamic acid is a lower alkanol, such as methanol or te.
esterified with r t-butanol (the hydroxy group of serine may be etherified with a lower alkyl group, such as a methyl group or a benzyl group, the amino group of the side chain of lysine or ornithine can be a lower alkanoyl group, It may be acylated, for example with a pivaloyl group, a lower alkoxycarbonyl group, such as a Lert-butoxycarbonyl group, or an arylmethoxycarbonyl group, such as a benzyloxycarbonyl group, and/or the α-nitrogen atom of the amino acid may be acylated with a lower alkyl group, such as a methyl The present invention relates to compounds of general formula (I) optionally substituted with groups and pharmaceutically acceptable salts of these compounds having salt-forming groups.

R2 represents hydrogen or a lower alkyl group, such as a methyl group, and R3 represents a lower alkyl group, such as an isopropyl group or an isobutyl group, a cycloalkyl lower alkyl group, such as a cyclohexylmethyl group, or a tricycloalkyl lower alkoxy group, such as 1-adamantyl represents a methyl group, R4 represents a hydroxy group, and R% represents a lower alkyl group having 2 or more carbon atoms, such as an isopropyl group or a te
General formula representing an rt-butyl group, a cycloalkyl group, such as a cyclopentyl group or a cyclohexyl group, a cycloalkyl lower alkyl group, such as a cyclohexylmethyl L 1-adamantyl group, a benzyl group, a carbamoyl group or a lower alkylcarbamoyl group, such as a methylcarbamoyl group Particular preference is likewise given to the compounds of (I) and the pharmaceutically acceptable salts of these compounds having salt-forming groups.

R6 is an amino group, an alkylamino group, such as methyl,
Ethyl-1n-propyl-, isopropyl-1n-butyl-, isobutyl-1tert-butyl-, n-pentyl-, isopentyl-1n-hexyl-1n-octyl- or n-decylamino groups, di-lower alkylamino groups, e.g. dimethylamino group, hydroxy lower alkylamino group, e.g. 2-hydroxyethylamino group, 1
-hydroxybudo-2-ylamino group or tris(
hydroxymethyl)-methylamino group, carboxyalkylamino group (the carboxy group is not present in the 1-position of the alkyl group), e.g. 4-carboxy-n-7”thyl-1
5-carboxy-n-pentyl, 6-carboxy-n
-Hexyl-17-carboxy-n-hebutyl- or 8-carboxy-n-octylamino group, further dicarboxymethylamino group, lower alkoxycarbonylalkylamino group (carbonyl group is not present in the 1-position of the alkyl group) , for example 4-tert-butoxycarbonyl-
n-butyl-1? -tert-butoxycarbonyl-n
-hebutyl- or F3-tert-butoxycarbonyl-n-octylamino groups, also di-lower alkoxycarbonylmethylamino groups, e.g. dimethoxycarbonylmethylamino groups, physiologically degradable esterified carboxyalkylamino groups (ester functional groups). is not present in the 1-position of the alkyl group), for example, 4-pivaloyloxymethoxycarbonyl-n-butylamino group, 7-(I-
ethoxycarbonyloxyethoxycarbonyl)-n-
Hebutylamino group or 7-pivaloyloxymethoxycarbonyl-n-hebutylamino group, carbamoyl-
or a hydroxy lower alkylcarbamoylalkylamino group (the carbamoyl group is not present in the 1-position of the alkyl group), such as a 4-carbamoyl-n-butylamino group, a 7-carbamoyl-n-hebutylamino group, or a 4-carbamoyl-n-butylamino group.
-(tris-[hydroxymethyl]-methyl)-carbamoyl-n-butylamino group, also dicarbamoylmethylamino group, di(lower alkylcarbamoyl)-methylamino group, such as di(methylcarbamoyl)-methylamino group, dicarbamoylmethylamino group, (Hydroxy-lower alkylcarbamoyl)-methylamino group, e.g. everdi(2-hydroxyethylcarbamoyl)-methylamino group, or bis-(di-lower alkylcarbamoyl)-methylamino group, e.g. bis-(dimethylcarbamoyl)-methylamino group , amino lower alkylamino groups, such as 2-aminoethylamino or 3-aminopropylamino groups, lower alkylamino lower alkylamino groups, such as 2-methylaminoethylamino groups, di-lower alkylamino lower alkylamino groups, such as 2 -dimethylaminoethylamino group, lower alkokynecarbonylamino lower alkylamino group, e.g. 2-(tert-butoxycarbonylamino)-ethylamino group, guanidino lower alkylamino group, e.g. 2-guanidinoethylamino group, cycloalkyl lower alkyl Amino groups, such as cyclopropylmethylamino groups, benzylamino groups, pyridyl lower alkylamino groups, such as 2-13- or 4-pyridylmethylamino groups, 2-(2-13- or 4-pyridyl)-
ethylamino group or 3-(2-13- or 4-
pyridyl)-propylamino group, imidazolyl lower alkylamino group, such as 4-imidazolylmethylamino group or 2-(4-imidazolyl)-ethylamino group,
or an indolyl lower alkylamino group, such as a 3-indolylmethylamino group or 2-(3-indolyl)
Preference is likewise given to compounds of monocatalytic formula (I) representing an -ethylamino group and pharmaceutically acceptable salts of these compounds representing a salt-forming group.

R1 is a lower alkanoyl group, such as a formyl group, an acetyl group, a propionyl group or a pivaloyl group, 2-(
o,'-dichloroanilino)-phenylacetyl group, 2
- (o,o-dichloro-N-benzylanilino)-phenylacetyl group, optionally substituted pyrrolylcarbonyl group, such as optionally 2- or 3-pyrrolylcarbonyl group or 4- or 5-phenylpyrroli -2-carbonyl group, furylcarbonyl group, e.g. 2-
Furylcarbonyl group, chenylcarbonyl group, e.g. 2
-chenylcarbonyl group, pyridylcarbonyl group, e.g. 2-13- or 4-pyridylcarbonyl group, optionally substituted indolylcarbonyl group, e.g. 2-
13- or 5-indolylcarbonyl group, 1-methyl-15-methyl-15-methoxy-15-benzyloxy-15-chloro- or 4,5-dimethylindolyl-2-carbonyl group, 4,5,6 .7-tetrahydroindolyl-2-carbonyl group, optionally substituted quinolylcarbonyl group, such as 2-13- or 4
-quinolylcarbonyl group or 4-hydroxyquinolyl-
2-carbonyl group, optionally substituted isoquinolylcarbonyl group, such as 1-53- or 4-isoquinolylcarbonyl group or 1-oxo-1,2-dihydroisoquinolyl-3-carbonyl group, 2- quinoxalinylcarbonyl group, 2-benzofuranylcarbonyl group, benzo(e)indolyl-2-carbonyl group, β-carbolinyl-3-carbonyl group, indolinylcarbonyl group, such as 2- or 3-indolinylcarbonyl group ,l
2,3. ．． 4-tetrahydroquinolinylcarbonyl group, for example 1,2,3°4-tetrahydroquinolyl-2-
1-3- or -4-carbonyl group, 1.2, 3.4
-tetrahydroisoquinolylcarbonyl group, e.g. 1,
2゜3.4-tetrahydroisoquinolyl-1-5-3-
or -4-carbonyl group or 1-oxo-1,2,
3,4-tetrahydroisoquinolyl-3-carbonyl group, where A is an amino acid, norleucine, phenylalanine,
cyclohexylalanine, glutamic acid, glutamine,
Ns-dimethyl-glutamine, ornithine or Ns-Vivaloy! Represents a divalent group of rheonithine, R2 represents hydrogen, R3 represents an isobutyl group, cyclohexylmethyl group, or 1-adamantylmethyl group, R4 represents a hydroxy group, and Rs represents an isopropyl group, a cyclohexyl group, or a cyclohexylmethyl group. or a methylcarbamoyl group, R6 is a lower alkylamino group, such as methyl-, ethyl-1n-pro, isopropyl-1n-butyl or isopentylamino group, di-lower alkylamino group, such as dimethylamino group, hydroxy Lower alkylamino groups, such as 2-hydroxyethylamino or 1-hydroxybudo-2-ylamino groups, carboxyalkylamino groups (the carboxy group is not present in the 1-position of the alkyl group), such as 4-carboxy-n-butyl Amino group, 7-carboxy-n-hebutylamino group or 8
-carboxy-n-octylamino group, lower alkoxycarbonylalkylamino group (the carbonyl group is not present in the 1-position of the alkyl group), such as 4-jerk-butoxycarbonyl-n-butylamino group or 7-ter
t-butoxycarbonyl-n-hexylamino group, amino lower alkylamino group, such as 2-ethylaminoethylamino group, guanidino lower alkylamino group, such as 2-guanidinoethylamino group, benzylamino group or pyridyl lower alkylamino group, Also preferred are compounds of general formula (I) representing, for example, a 2-pyridylmethylamino group and pharmaceutically acceptable salts of these compounds having a salt-forming group.

The invention particularly provides that R+ is a lower alkanoyl group having 1 to 7 carbon atoms, such as a formyl group, an acetyl group, a propionyl group or a pivaloyl group, a phenoxy lower alkanoyl group, such as a phenoxy acetyl group, a naphthoxy lower alkanoyl group, such as a - or β-naphthoxyacetyl group, α-naphthoxycarboxy lower alkanoyl group, e.g. 2-a-naphthoxy-4-carboxybutyryl group, α-naphthoxy lower alkoxycarbonyl-lower alkanoyl group, e.g. α-naphthoxyethoxycarbonyl group. Acetyl group, 2-α-naphthoxy-3-ethoxycarbonylpropionyl group or 2-α-naphthoxy-4
-tert-butoxycarbonylbutyryl group, α-naphthoxy-benzyloxycarbonyl lower alkanoyl group, e.g. 2-α-naphthoxy-3-benzyloxycarbonylpropionyl group, α-naphthoxycarbamoyl lower alkanoyl group, e.g. 2-α-naphthoxy -4-carbamoylbutyryl group, α-naphthoxycyano-lower alkanoyl group, such as α-naphthoxycyanoacetyl group or 2-α-naphthoquine-4-cyanobutyryl group, α-naphthoxy-dilower alkylamino-lower alkanoyl group, For example, 2-α-naphthoxy-5-dimethylaminopentanoyl, α-naphthoxy-oxo-lower alkanoyl, such as 2-α-naphthoxy-4-oxo-pentanoyl, phenyl-1α-naphthyl or β-naphthyl. Lower alkanoyl group (lower alkanoyl group is unsubstituted or, for example, hydroxy group, lower alkoxy group, acyloxy group, carboxy group, esterified carboxy group, carbamoyl group, substituted carbamoyl group, cyan group, phosphono group, esterified phosphono group, benzofuranyl group) and/or oxo groups, optionally branched), such as phenylacetyl, α-naphthylacetyl, β-naphthylacetyl, 3-phenylpropionyl, 3-α- or β-naphthylpropionyl group, 3-phenyl- or 3-α-naphthyl-2
-hydroxypropionyl group, 3-phenyl- or 3-α-naphthyl-2-lower alkoxyprobionyl group, e.g. 3-phenyl- or 3-α-naphthyl-2
-neopentyloxypropionyl group, 3-phenyl-
or a 3-α-naphthyl-2-acyloxyprobitonyl group, such as 3-phenyl-2-pivaloyloxy or 2-acetoxypropyl group
Naphthyl-2-pivaloyloxy- or 2-acetoxy-propionyl group, 3-α-naphthyl-2-acetoacetoxypropionyl group, 3-α-naphthyl-2-dithylaminocarbonyloxypropionyl group or 3
-α-naphthyl-2-(2-amino- or 2-benzyloxycarbonylamino-2-methylpropionyloxy)-propionyl group, 3-phenyl- or 3
-α-naphthyl-2-carboxymethylpropionyl group, 3-phenyl- or 3-α-naphthyl-2-lower alkoxycarbonylpropionyl group, e.g. 3-α-
naphthyl-2-ethoxycarbonylprobionyl group, 3
-Phenyl- or 3-α-naphthyl-2-benzyloxycarbonylmethylpropionyl group, 3-phenyl- or 3-α-naphthyl-2-carbamoylpropionyl group, 3-phenyl- or 3-α-naphthyl −
"l-tert-butylcarbamoylpropionyl group, 3-phenyl-lower L<ha 3-α-naphthyl-2-
(2-dimethylaminoethyl)-carbamoylpropionyl group, 3-α-naphthyl-2-(carboxy- or ter t-butoxycarbonyl)-methylcarbamoylpropionyl group, 3-phenyl- or 3-α-
Naphthyl-2-(2,2-dimethoxyethyl)-rubamoylprobionyl group, 3-phenyl- or 3-α
-naphthyl-2-(5-amino-5-carboxypentyl)-rubamoylpropionyl group, 3-phenyl- or 3-α-naphthyl-2-cyanopropionyl group,
3-phenyl- or 3-α-naphthyl-2-cyanomethylpropionyl group, 3-phenyl-2-phosphono-
or monophosphonomethylpropionyl group, 3-phenyl-2-dimethoxyphosphoryl- or -dimethoxyphosphorylmethyl-propionyl group, 3-phenyl-2
-jethoxyphosphoryl- or -jethoxyphosphorylmethyl-propionyl group, 3-phenyl-2-ethoxy- or monomethoxyhydroxyphosphoryl-propionyl group, 3-phenyl- or 3-α-naphthyl-2-a7tonyl group Propionyl group, 3-phenyl-
or 3-α-naphthyl-2-dimethylaminemethylpropionyl group, 2-benzyl- or 2-α-naphthylmethyl-4-cyanobutyryl group, 4-phenyl- or 4-α-naphthyl-3-carboxy-butyryl group, 4-phenyl- or 4-α-naphthyl-3-penzyloxy group, 2-benzyl-
4-(2-Benzofuranyl)-4-oxo-butyryl group, 2-benzyl- or 2-ct-naphthylmethyl-
4-oxo-pentanoyl group, 2-benzyl- or 2-α-naphthylmethyl-4,4-dimethyl-3-oxo-pentanoyl group, 2-benzyl- or 2-α-
Naphthylmethyl-5-dimethylamino-pentanoyl group, 2-hensyl- or 4:! 2-α-naphthylmethyl-5-dimethylamino-4-oxo-pentanoyl group, 2-benzyl- or 2-α-naphthylmethyl-
5,5-dimethyl-4-oxo-hexanoyl group, α,
a p-diaminophenylacetyl group, an α,p-diacylaminophenylacetyl group, such as an α,p-dihenzyloxylponylaminophenylacetyl group or an α-pivaloylamino-p-benzyloxycarbonylaminophenylacetyl group, furthermore 2 - (0,O-dichloroanilino)-phenylacetyl group, 'l-(o,
o-dichloro-N-benzylanilino)-phenylacetyl group, naphthylcarbonyl group, e.g. α- or β
- naphthylcarbonyl group or 1,8-naphthalene dicarbonyl group, pyrrolylcarbonyl group, e.g. 2- or 3-pyrrolylcarbonyl group, cyclohebuta(b) pyrrolyl-5-carbonyl group, indolylcarbonyl group, e.g. 2 -13- or 5-indolylcarbonyl group, 1
-benzylindolyl-3-carbonyl group, 4,5.6
．． 7-tetrahydroindolyl-2-carbonyl group, quinolylcarbonyl group, such as 2-13- or 4-quinolylcarbonyl group, or oxamoyl group, where A is an amino acid, leucine, norleucine, phenylalanine, N-methylphenylalanine , β-phenylserine, cyclohexylalanine, glutamine, histidine or N-methyl-histidine, R2 represents hydrogen, R3 represents an isobutyl group or cyclohexylmethyl group, and R4 represents a hydroxy group. , R5 represents an isopropyl group, a cyclohexylmethyl group, an α-decahydronaphthyl group, or a dimethylamino group, and R6 represents a lower alkylamino group having 1 to 7 carbon atoms, such as methyl-, ethyl-1n-pro, and isopropyl. -, n-butyl-, isobutyl-5n-pentyl or isopentylamino groups, di-lower alkylamino groups such as dimethylamino groups, hydroxy lower alkylamino groups such as 2
-Hydroxyethylamino group, 1-hydroxybudo2
-ylamino group or 5-hydroxypentylamino group, 2-phenoxyethylamino group, 2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamino group, carboxyalkylamino group or amino-carboxyalkylamino group (carboxy group is , not present in the 1-position of the alkyl group), such as 4-carboxy-n-butylamino group, 5-amino-5-carboxy-n-pentylamino group, 7-carboxy-n-hebutylamino group or 8-carboxy -n-octylamino group, lower alkoxycarbonylalkylamino group or acylamino lower alkoxycarbonylalkylamino group (C carbonyl group is not present in the 1-position of the alkyl group), for example 4-j
erL-butoxycarbonyl-n-butylamino group, 5
-terk-butoxycarbonylamino-5-methoxycarbonyl-〇-pentylamino group or 7-ter
L-butoxycarbonyl-〇-hebutylamino i, 4-
Tris-(hydroxymethyl)-methylcarbamoyl-
n-butylamino group, amino lower alkylamino group, such as 2-aminoethylamino group, di-lower alkylamino lower alkylamino group, 2-dimethylaminoethylamino group or 3-dimethylaminopropylamino group, lower alkoxycarbonylamino group alkylamino group,
For example, 2-tert-butoxycarbonylaminoethylamino group, morpholino lower alkylamino group, e.g.
- a morpholinoethylamino group, a cycloalkyl lower alkylamino group, such as a cyclopropylmethylamino group or a cyclohexylmethylamino group, a benzylamino group, a pyridyl lower alkylamino group, such as a 2-pyridylmethylamino group, or an imidazolyl lower alkylamino group, For example, compounds of the general formula CI> representing a 2-(4-imidazolyl)-ethylamino group or a 2-(2-(4-imidazolyl)-ethylamine)-ethylamino group and the pharmacology of these compounds containing a salt-forming group. regarding legally acceptable salts.

The present invention particularly provides that R1 is a phenoxy lower alkanoyl group, such as a phenoxy acetyl group, a naphthoxy lower alkanoyl group, such as an α- or β-naphthylacetyl group, a phenyl lower alkanoyl group (the lower alkanoyl group is unsubstituted or, for example, an acyloxy group), For example, a lower alkanoyloxy group, a carboxy group, an esterified carboxy group, such as a lower alkoxycarbonyl group, a carbamoyl group, a substituted carbamoyl group, such as a lower alkylcarbamoyl group, a cyano group, an esterified phosphono group, such as a di-lower alkoxyphosphoryl group, or a lower optionally branched), e.g. 3-phenylpropionyl, 2-acetoxy-3-phenylpropionyl, 2-pivaloyloxy-3-phenyl Propionyl group, 2-ethoxy- or -methoxycarbonyl-3-phynylpropionyl group, 5.2-tert-butylcarbamoyl-3-phenylpropionyl group, 2-
benzyl-3-cyanopropionyl group, 2-dimethoxyphosphoryl-3-phenylpropionyl group, 2-benzyl-5,5-dimethyl-4-oxo-hexanoyl group,
2-benzyl-4゜4-dimethyl-3-oxo-pentanoyl group or 4-(2-benzofuranyl)-2-benzyl-4-oxo-butyryl group, naphthyl lower alkali/a) L4<lower alkanoyl group is unsubstituted or may be substituted, for example, with acyloxy groups, such as lower alkanoyloxy groups, carboxy groups, esterified carboxy groups, such as lower alkoxycarbonyl groups, unsubstituted carbamoyl groups, substituted carbamoyl groups, cyano groups or lower alkyl groups and oxo groups. , optionally branched), e.g. 3-α- or β-naphthylpropionyl groups, 2-
Acetoxy-3-α-naphthylpropionyl group, 2-bivaloyloxy-3-α-naphthylpropionyl group, 2
-Ethoxy- or methoxycarbonyl-3-α-naphthylpropionyl group, 2-carbamoyl-3-α-naphthylpropionyl group, 2-ert-7'thylcarbamoyl-propionyl group, 2-carboxymethylcarbamoyl-
3-tx-naphthylpropionyl group, 3-cyano-2-
α-naphthylmethylpropionyl group, 5,5-dimethyl-2-α-naphthylmethyl-4-oxo-hexanoyl group or 4,4-dimethyl-2-α-naphthylmethyl-3-oxopentanoyl group, indolyl-2 - Represents a carbonyl group or cyclohebuta (b) pyrrolyl-5-carbonyl group, A represents a divalent group of the amino acid L-histidine, R2 represents hydrogen, and R3 represents an isobutyl group or a cyclohexylmethyl group. , R4 represents a hydroxy group, R5 represents an isopropyl group or a cyclohexylmethyl group, and R@ represents a lower alkylamino group, such as methyl-, ethyl-, n-propyl-, isopropyl-, n
-butyl-, isobutyl-, n-pentyl or isopentylamino groups or amino-carboxy lower alkylamino groups (no substituent is present in the 1-position of the lower alkyl group), such as 5-amino-5-carboxy-pentylamino groups and the carbon atom having groups R3 and R4 is S-
Compounds of general formula (I) having the configuration and pharmaceutically acceptable salts of these compounds.

The present invention particularly provides a phenyl group in which R+ is a lower alkanoyl group substituted with a lower alkanoyloxy group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, a di-lower alkoxyphosphoryl group, or a lower alkyl group and an oxo group, particularly α-naphthyl. Lower alkanoyl group (
lower alkyl groups have 1 to 7 carbon atoms), for example 2(S)-pivaloyloxy-3-phenylpropionyl, 2(R)- and 2(S)-dimethoxyphosphoryl-3-phenylbrobitonyl. , 2(R)- and 2(S)-benzyl-5,5-dimethyl-4-oxo-pentanoyl groups, 2fR)- and 2(S)-
tert-butylcarbamoyl-3-α-naphthylpropionyl group or 2 (R)- and 2 (S)-ethoxycarbonyl-3-α-naphthyl-propionyl group, furthermore indolyl-2-carbonyl group or cyclohepta (b)
represents a pyrrolyl-5-carbonyl group, A represents a divalent group of L-histidine which is an amino acid, R2 represents hydrogen,
R3 represents a cyclohexylmethyl group, R4 represents a hydroxy group, R5 represents an isopropyl group, and R6 represents a lower alkylamino group having 1 to 7 carbon atoms, such as methyl-
, ethyl-1n-propyl-, isopropyl-1n-butyl-, isobutyl-1n-pentyl or isopentylamino group, and the carbon atoms having the groups R3, Ra and R1 have an S-configuration of the general formula ([) The present invention relates to compounds and pharmaceutically acceptable salts of these compounds.

The present invention particularly relates to the compounds listed in the Examples and their pharmaceutically acceptable salts, particularly where R1 is 2(S).

- represents a pivaloyloxy-3-phenylpropionyl group, A represents a divalent group of the amino acid L-histidine, R2 represents hydrogen, R3 represents a cyclohexylmethyl group, R4 represents a hydroxy group, and R, represents an isopropyl group, R@ represents an n-butylamino group, the group R3,
Compounds of general formula (I) in which the carbon atom having R and Rs has an S-configuration and pharmaceutically acceptable salts thereof, R1
represents 2 (R,5)-12(R)- or 2 (S)-dimethoxyphosphoryl-3-phenylpropionyl group, A represents a divalent group of the amino acid L-histidine, and R2 represents hydrogen. , R3 represents a cyclohexylmethyl group, R4 represents a hydroxy group, R5 represents an isopropyl group, R6 represents an n-butylamino group, the group R,
, a compound of general formula (I) in which the carbon atoms with R4 and R3 have an S-configuration, and pharmaceutically acceptable salts thereof, R
1 represents 2 (R,5)-52(R)- or 2(S)-benzyl-5,5-dimethyl-4-oxo-hexanoyl group, and A represents the divalent group of L-histidine, which is an amino acid. , R2 represents hydrogen, R3 represents a cyclohexylmethyl group, R4 represents a hydroxy group, R5 represents an isopropyl group, R@ represents an n-butylamino group, and the group R
, R, and Rs having an S-configuration, and pharmaceutically acceptable salts thereof;
R1 is 2 (R,S)-benzyl-4,4-dimethyl-
represents a 3-oxo-pentanoyl group, A represents a divalent group of the amino acid L-histidine, R2 represents hydrogen,
R3 represents a cyclohexylmethyl group, R4 represents a hydroxy group, Rs represents an isopropyl group, and R6 represents n-
Compounds of general formula (I) representing a butylamino group and in which the carbon atoms forming the groups R3, R4 and R5 have an S-configuration and pharmaceutically acceptable salts thereof, wherein R2 is 2 (R,S)-ethyl : represents a 1-cyclocarbonyl-3-alpha-phthylbrobionyl group, A represents a divalent group of the amino acid L-histidine, R2 represents hydrogen, R3 represents a cyclohexylmethyl group, Compounds of general formula (I) in which R4 represents a hydroxy group, Rs represents an isopropyl group, R@ represents an n-butylamino group, and the carbon atoms of 6Rs, R4, and R5 have an S-configuration, and their A pharmaceutically acceptable salt, R7 represents a cyclohebuta(b)pyrrolyl-5-carbonyl group, A represents a divalent group of the amino acid L-histidine, R2 represents hydrogen, and R3 represents cyclohexylmethyl. group, R4 represents a hydroxy group, R5
represents an isopropyl group, R6 represents an n-butylamino group, and a compound of general formula (I) in which the carbon atoms having IR3, R4 and Rs have an S-configuration and a pharmaceutically acceptable salt thereof, Rt is 2(S)-pivaloyloxy-3-phenylpropionyl group, A is an amino acid, and
Represents a divalent group of histidine, R2 represents hydrogen, R3 represents an isobutyl group, R4 represents a hydroxy group, R5
represents a cyclohexylmethyl group, R@ represents an n-butylamino group, and the carbon atoms having groups R3 and R4 are S-
The present invention relates to compounds of general formula (I) having the configuration and pharmaceutically acceptable salts thereof.

Compounds of formula (I) and salts of such compounds having at least 1 salt-forming group can be obtained in a manner known per se, for example: a) compounds of the general formula having a terminal carboxy group; A fragment of a compound of (I) or a reactive acid derivative thereof having a free amino group is supplemented to form a compound of general formula (I) or a reactive derivative thereof having an active amino group (reactive component The free functional groups present in the b.
) In order to produce a compound of general formula (I) in which R4 represents a hydroxy group, general formula (■): c) compounds of general formula (I) in which R4 represents a hydroxy group; To prepare an aldehyde compound of the general formula (DI): where the substituents have the above definitions and the free functional group is optionally present in a protected form, excluding the aldehyde group participating in the reaction. is the general formula (■); [In the formula, the substituents have the above definitions, and M represents a metal group]
or d) General formula (■); [wherein X represents a nucleofugal leaving group, and the remaining substituents have the above definitions] and the free functional group is optionally present in a protected form], the substituent X in the compound with a nucleophilic substituent R4
tJ:, replacing R4 with a drug, or e) General formula (■): Yoshi3(VE) [wherein the substituents have the above definitions, the functional groups present are optionally or f) R4 is T! In order to produce a compound of the general formula <1) representing a free hydroxyl group, the general formula (■): [wherein the substituents have the above definitions and the functional groups present are optionally present in a protected form] ) is reduced with a regioselective reducing agent to form the corresponding alcohol, optionally g) removing the protecting groups present in the resulting compound, and/or optionally as described in methods a) to f) or the general formula (
After carrying out any other process for preparing the compounds of I), the obtained compounds of general formula (I) with salt-forming groups are converted into their salts, or the obtained salts are converted into the free compounds or other salts. and/or optionally separating the isomer mixture obtained and/or reversing the configuration of the chiral carbon atoms in the compound of general formula (I) obtained and/or Compounds of formula (I) can be converted into compounds of general formula (I) according to the invention.
) can be obtained by changing to other compounds.

Uninvented compounds include compounds (by-products) other than the compound of general formula (I) obtained by any of the above-mentioned methods, and compounds of formula (I) and salts thereof produced by methods other than the above-mentioned methods. It also relates to

Method a) (Notification to Amidobo) Two compounds of the general formula (I) having a terminal carboxy group that can be condensed with a supplementary fragment to form an amide bond.
Fragments of compounds of I) may have, for example, the formula R1-OH,
O-reactive acid derivatives, which are compounds of R+-A-OH or, active esters or reactive anhydrides derived from these compounds, as well as reactive cyclic amides, can be formed in situ.

Active esters are in particular esters which are unsaturated at the bonding carbon atom of the group to be esterified, for example of the vinyl ester type, for example vinyl esters (obtained, for example, by transesterification of the corresponding ester with vinyl acetate:
Activated vinyl ester method), carbamoyl vinyl ester C example, t I, t: Obtained by treating the corresponding acid with an isoxazolium reagent: 1,2-oxacillium- or Woodward method]
, or 1-lower alkoxy vinyl esters (obtained for example by treating the corresponding acids with lower alkoxyacetylenes: ethoxyacetylene method), or esters of the amidino type, such as N,N'-disubstituted amidino esters (for example the corresponding N,N"-disubstituted carbodiimide, e.g. the corresponding acid with a condensing agent, e.g. The presence of N,N'-dicyclohexylcarbodiimide allows suitable substituted phenols such as 4-nitrophenol, 4-methylsulfonylphenol, 2.4.5-trichlorophenol, 2.3.4,5.6-penta Cyanomethyl esters (obtained by treatment with chlorophenol or 4-phenyldiazophenol: activated aryl ester method), cyanomethyl esters (e.g. obtained by treatment of the corresponding acid with chloroacetonitrile in the presence of base) , thioester,
In particular, optionally, e.g. phenylthioesters monosubstituted with a nitro group, e.g. obtained by treating the corresponding acid with a thiophenol optionally substituted, e.g. (activated thiol ester method) or in particular amino esters or amide esters (e.g. the corresponding acids can be prepared using the N-
Hydroxyamino- or N-hydroxyamide compounds, such as N-hydroxysuccinimide, N-hydroxypiperidine, N-hydroxyphthalimide, N-
Obtained by treatment with hydroxy-5-norbornene-2,3-dicarboxylic imide, 1-hydroxybenzotriazole or 3-hydroxy-3,4-dihydro-1,2,3-benzotriazin-4-one: active N-hydroxy ester method).

Anhydrides of acids are symmetrical anhydrides or preferably mixed anhydrides of acids, such as anhydrides with inorganic acids, such as acid halides, especially acid chlorides (for example, the corresponding acids with thionyl chloride, phosphorus pentachloride or oxalyl chloride). obtained by processing: acid loride method), azide (for example, from the corresponding acid ester via the corresponding hydrazide, which is obtained by treating this with nitrous acid, the near acid method), carbonic acid half esters, such as lower alkyl carbonates. Anhydrides with half esters (e.g., the corresponding acid with chloroformic acid lower alkyl ester or 1-lower alkoxycarbonyl-2-lower alkoxy-1,2-
dihydroquinolines, such as those obtained by treatment with 1-lower alkoxydicarbonyl-2-ethoxy-1゜2-dihydroquinolines (mixed 0-alkyl carbonic anhydride method), or dihalogenated anhydrides, especially with dichlorinated phosphoric acids. (e.g. the nioxychloride method obtained by treating the corresponding acid with phosphorous oxychloride), anhydrides with other phosphoric acid derivatives (e.g. those obtained using phenyl-N-phenylphosphoric acid amide chloride) ) or anhydrides with phosphorous acid derivatives, or anhydrides with organic acids, e.g. obtained by treatment with phenylacetic acid, pivalic acid or trifluoroacetic acid chloride (mixed carboxylic anhydride method) or anhydrides with residual sulfonic acids (e.g. salts of the corresponding acids, e.g. alkali metal salts). Suitable organic sulfonic acid halides, such as lower alkanes or aryls, such as methane or p
-) obtained by treatment with luenesulfonic acid chloride: mixed sulfonic anhydride method) and control anhydride (
For example, they are obtained by condensing the corresponding acids in the presence of carbodiimide or 1-diethylaminopropyne (symmetrical anhydride method).

Suitable cyclic amides are in particular amides with aromatic 5-membered diazacyclenes, such as imidazoles, such as amides with imidazole (for example by converting the corresponding acid into N,N'-
obtained by treatment with carbonyldiimidazole (imidazole method), or pyrazole, e.g. 3.
5-dimethylpyrazole (obtained for example by treatment with acetylacetone via acid hydrazide:
pyrazolid method).

Depending on the definition, the amino groups participating in the reaction in the fragments which, when supplemented, give rise to the compounds of the general formula (I), are in particular primary or secondary amines, with which the carboxy groups react. If present in the natural form, it is preferred to be present in the free form, but e.g. Derivatives of such supplementary fragments with amino groups, which may themselves form m1l monomers by reaction with pyrophosphites, are also, for example, carbamate halides or isocyanates, in which case the amino acids involved in the reaction are the group is substituted with a halogencarbonyl group, e.g. a chlorocarbonyl group,
Alternatively, it is transformed into an isocyanate group, and in the latter case, only the compound of general formula (I) in which the nitrogen atom of the amide group formed by the reaction has a hydrogen atom can be obtained.

If the supplementary fragment having an amino group is a lower alkyl group or
If the urea compound is an amine substituted with one or two lower alkyl groups, the corresponding urea compound is also a reactive derivative. , -C The corresponding compound of formula (I) is obtained.

If the supplementary fragment is dimethylamine, dimethylformamide is also a reactive derivative.

Functional groups in the starting materials whose reaction is to be avoided, in particular carboxy, amino, hydroxy and mercapto groups, can be treated with suitable SN retention agents commonly used in the synthesis of peptide compounds and cephalosporins and penicillins. ! groups (commonly used protecting groups), which may already be present in the previous step and which protect the relevant functional groups from undesired side reactions, such as acylation, etherification, esterification, etc. should be protected from chemical reactions, oxidation, solvolysis, etc. However, compounds of general formula (I) with protected functional groups, in which protecting groups may be present in the final product, have higher metabolic stability than corresponding compounds with free functional groups. Sometimes.

The protection of functional groups by such protecting groups, the protecting groups themselves, and their decomposition reactions are described, for example, in McCormie (J, F, H,
McOmie), 6Brotective Groups
In Organic Chemistry (Protecti)
ve Groups in Organic
Chemjstry) ” [Blenheim Press (P
lenum Press), London and New York, 1973], Green (Th.

W. Greene), “Protective Groups in Organic Synthesis (Protec
tiveGroups in Organic Syr
+thesis) ' (Wiley
), New York, 1981], “The Peptides” Volume 83 (Gross (
E., Gross) and Maienhofer (J.

Meienhofer), Academic Breath (A
cadeIIlicPress), London and New York, 1981], and “Methoden d'Organisoschen Hemie”
erorganischenchemie)
, Houben-Weyl, 4th edition, 15/1=1 (Georg Thieme Verlag,
published in 1974].

Carboxy groups are protected, for example, as ester groups that can be selectively removed under mild conditions.

A protected carboxy group in esterified form is in particular branched in the 1-position of the lower alkyl group or substituted in the 1- or 2-position of the lower alkyl group with a suitable substituent. is esterified with a lower alkyl group.

A protected carboxyl group which is esterified with a lower alkyl group branched in the 1-position of the lower alkyl group is, for example, one or two tert-lower alkoxycarbonyl groups, such as a tert-butoxycarbonyl group. an arylmethoxycarbonyl group having an aryl group (the aryl group is unsubstituted or a lower alkyl group, e.g. t
er - a phenyl group substituted one, two or three times with a lower alkyl group, such as a tert-butoxy group, a lower alkoxy group, e.g. ), for example, a benzyloxycarbonyl group, a benzyloxycarbonyl group substituted with the above-mentioned substituents, such as a 4-nitrobenzyloxycarbonyl group or 4-methoxybenzyloxycarbonyl group, a diphenylmethoxycarbonyl group, or a benzyloxycarbonyl group substituted with the above-mentioned substituents. and diphenylmethoxycarbonyl group, such as di(4-methoxyphenyl)-methoxycarbonyl group.

esterified with a lower alkyl group substituted with a suitable substituent at the 1- or 2-position of the lower alkyl group,
Protected carboxyl groups are, for example, 1-lower alkoxy-lower alkoxycarbonyl groups, such as methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxymethoxycarbonyl groups, 1-lower alkylthio lower alkoxycarbonyl groups, such as 1-methylthio Methoxycarbonyl group or 1-ethylthioethoxycarbonyl group, aroylmethoxycarbonyl group, such as phenacyloxycarbonyl group, 2-halogen lower alkoxycarbonyl group, such as 2.2.2-trichloroethoxycarbonyl group, 2-bromoethoxycarbonyl group or 2-iodoethoxycarbonyl group, and 2-trilower alkylsilyl lower alkoxycarbonyl group, such as 2-trimethylsilylethoxycarbonyl group.

Carboxyl groups can also be protected as organic silyloxycarbonyl groups. An organic silyloxycarbonyl group is, for example, a tri-lower alkylsilyloxycarbonyl group, such as a trimethylsilyloxycarbonyl group.

The silicon atom of the silyloxycarbonyl group may be substituted with two lower alkyl groups, such as a methyl group and a carboxyl group or ami2 group of the second molecule of formula (I).

Compounds having such protecting groups can be produced using, for example, dimethylchlorosilane as a silylating agent.

The protected carboxyl group is preferably a tart-lower alkoxycarbonyl group, such as a tart-butoxycarbonyl group, a benzyloxycarbonyl group, a 4-nitrobenzyloxycarbonyl group or a diphenylmethoxycarbonyl group.

Amino groups can be protected, for example in the form of acylamino, arylmethylamino, etherified mercaptoamino or silylamino groups or as an azido group.

In the corresponding acylamino groups, the acyl group is, for example, an acyl group of an organic carboxylic acid having up to 18 carbon atoms, in particular a lower alkanecarboxylic acid optionally substituted with, for example, a halogen or an aryl group, or optionally, for example, a halogen, a lower alkyl group. Alternatively, it is an acyl group of benzoic acid or carbonic acid half ester substituted with a nitro group. Acyl groups of this type include, for example, lower alkanoyl groups, such as formyl, acetyl, propionyl or pivaloyl groups,
Halogen lower alkanoyl groups, such as 2-halogenacetyl groups, especially 2-chloro-12-bromo, 2-iodo-12,2,2-trifluoro or 2,2,2-trichloroacetyl groups, benzoyl groups, optionally e.g. A benzoyl group substituted with a halogen, lower alkoxy or nitro group, such as a benzoyl group, 4-chlorobenzoyl group, 4-methoxybenzoyl group or 4-nitrobenzoyl group, or branched at the 1-position of the lower alkyl group or a lower alkoxycarbonyl group substituted in the 1- or 2-position with a suitable substituent, such as a tert-lower alkoxycarbonyl group, such as a tert-butoxycarbonyl group, having one or two aryl groups. -rumethoxycarbonyl group (aryl group may optionally include, for example, a lower alkyl group, such as a tert-lower alkyl group,
tart-butyl, lower alkoxy, such as methoxy, hydroxy, phenyl substituted with one or more halogens, such as chlorine, and/or nitro), such as benzyloxycarbonyl, 4-nitrobenzyl oxycarbonyl group, diphenylmethoxycarbonyl group or di(4-methoxyphenyl)-methoxycarbonyl group, aroylmethoxycarbonyl group, e.g. phenacyloxycarbonyl group, 2-halogen lower alkoxycarbonyl group, e.g. 2.2.2-) Lichloroethoxy carbonyl group, 2-bromoethoxycarbonyl group or 2-iodoethoxycarbonyl group, 2-trilower alkylsilyl lower alkoxycarbonyl group, e.g.
A trimethylsilylethoxycarbonyl group, or a triarylsilyl lower alkoxycarbonyl group, such as a 2-triphenylsilylethoxycarbonyl group.

Arylmethylamino is, for example, mono-, di- or especially triphenylmethylamino, such as benzylamino, diphenylmethylamino or tritylamino.

The etherified mercapto group in the etherified mercapto amino group is particularly a substituted arylthio group, such as a 4-
It is a nitrophenylthio group.

A silylamino group is, for example, a tri-lower alkylsilylamino group, such as a trimethylsilylamino group. The silicon atom of the silylamino group may be protected by just two lower alkyl groups, such as a methyl group, and an amino group or a carboxy group of the second molecule of general formula (I). For example, the compound can be produced using dimethylchlorosilane as a silylating agent.

Preferred amino-protecting ffE groups are the acyl groups of carbonic acid half-esters, especially the terk-butoxycarbonyl group, optionally substituted benzyloxycarbonyl groups, such as the 4-
Nitrobenzyloxycarbonyl group, diphenylmethoxycarbonyl group, 2-halogen lower alkoxycarbonyl group, such as 2.2.2-trichloroethoxycarbonyl group, tritylamino group and formyl group.

The hydroxy group is protected, for example, by an acyl group, for example a lower alkanoyl group substituted with a halogen, e.g. chlorine, a 2,2-dichloroacetyl group, or an acyl group of a carbonic acid half-ester as mentioned in particular for protected amino groups. Good and preferred hydroxy protecting groups are, for example, 2.2.2
-) dichloroethoxycarbonyl group, 4-nitrobenzyloxycarbonyl group, diphenylmethoxycarbonyl group or trityl group. The hydroxy group can furthermore be a tri-lower alkylsilyl group, such as a trimethylsilyl group or a dimethyl-n-butylsilyl group, or an easily removable alkyl group, such as a tert-lower alkyl group, such as a t-
art-butyl, 2-oxa- or 2-thiaaliphatic or cycloaliphatic hydrocarbon groups, such as 1-lower alkoxy-lower alkyl or i-lower alkylthio-lower alkyl, such as methoxymethyl, 1-methoxyethyl , l-ethoxyethyl group, methylthiomethyl group, 1-methylthioethyl group or 1-ethylthioethyl group, or 5-7
2-oxa- or 2-thiacycloalkyl radicals having 2 ring atoms, such as 2-tetrahydrofuryl radicals or 2-oxa- or 2-thiacycloalkyl radicals having 2
- a tetrahydropyranyl group or the corresponding thia M derivative,
and 1-phenyl lower alkyl groups, such as benzyl groups,
They may be protected with diphenylmethyl or trityl groups, and the phenyl groups may be substituted, for example, with halogens, such as chlorine, lower alkoxy groups, such as methoxy groups, and/or nitro groups.

Two adjacent hydroxy groups can also be protected, for example with preferably substituted methylene groups, such as lower alkylidenes, such as isopropylidene groups, cycloalkylidenes, such as cyclohexylidene groups, or benzylidene groups.

For example, the mercapto group in cysteine can be protected, in particular by S-alkylation with an optionally substituted alkyl group, thioacetal formation, S-acylation or formation of an asymmetric disulfide group. Preferred mercapto protecting groups are, for example, a benzyl group in which the phenyl group is optionally substituted, for example by a methoxy group or a nitro group, such as a 4-methoxybenzyl group, a diphenylmethyl group, in which the phenyl group is optionally substituted by, for example, a methoxy group, such as a 4-methoxybenzyl group, e.g. .4'-dimethoxydiphenylmethyl group, triphenylmethyl group, trimethylsilyl group, benzylthiomethyl group, tetrahydropyranyl group, acylaminomethyl group, benzoyl group, benzyloxycarbonyl group or lower alkylaminocarbonyl group, such as ethylaminocarbonyl It is the basis.

The condensation to produce the amide bond can be carried out in a manner known per se, for example as described in
Organifthien Hemy (Houben-Weyl)
,Methoden der organische
nChewie)'', 4th edition, Volume 15/■ [Georg
Georg Thieme V
The Peptides
” [E, Gross and J, Meienhofer, l @ and 2 @, Academic Press.
ress), London and New York, 1979/
Published in 1980], or Bodansky (M., Boda
Principles of Peptide Synthesis (Principles of Peptide Synthesis)
ide 5ynthesis) @, Springer-Verlag,
Berlin, 1984].

The condensation can be carried out in the presence of customary condensing agents.

Customary condensing agents are, for example, carbodiimides, such as diethyl-, dipropyl-1N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide or especially dicyclohexylcarbodiimide, and also suitable carbonyl compounds, such as carbonyldiimidazole, 1.2-oxacillium compound, VA 2-ethyl-5-phenyl-1゜2-oxacillium-31-sulfonate and 2
-tert-butyl-5-methylisoxazolium perchlorate, or a suitable acylamino compound, e.g. 2-
Ethoxy-1-ethoxycarbonyl-1°2-dihydroquinoline and also active phosphates such as diphenylphosphoryl azide, diethylphosphoryl cyanide or phenyl-N-phenylphosphoramide chloridate.

If necessary, organic bases are added, for example tri-lower alkylamines with bulky groups, such as ethyldiisopropylamine, or heterocyclic bases, such as evapyridine, 4-dimethylaminopyridine or preferably N-methylmorpholine.

The condensation of an acid anhydride with an amine can be carried out, for example, using an inorganic carbonate, such as an alkali metal carbonate or bicarbonate, such as sodium carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate (usually in combination with a sulphate). It can be done with presence.

The condensation is carried out in an inert polar, aprotic, preferably anhydrous solvent or solvent mixture, for example with a carboxylic acid amide,
For example in formamide or dimethino Gamide, halogenated hydrocarbons such as methylene chloride, carbon tetrachloride or chlorobenzene, ketones such as acetone, cyclic ethers such as tetrahydrofuran, esters such as acetic acid ethyl ester, or nitrites such as acetonitrile or mixtures thereof. at a temperature range of, for example, from about -40°C to about +100°C, preferably from about -10°C to about +50°C, optionally under an inert gas atmosphere, e.g. nitrogen atmosphere, with optionally lowering or increasing the temperature. do.

Reactive acid derivatives can also be formed in situ. For example, a mixture of a fragment with a free carboxy group and a supplementary fragment with an amino group can be prepared by adding a suitable disubstituted carbodiimide,
For example, N by reaction in the presence of dicyclohexylcarbodiimide.

N-disubstituted amidino esters can also be formed in situ. Furthermore, a mixture of the corresponding acid and amino-starting materials is combined with a disubstituted carbodiimide, such as dicyclohexylcarbodiimide, and an N-hydroxylamine or N-hydroxyamide, such as N-hydroxybenzotriazole, N-hydroxysuccinimide or N-hydroxybenzotriazole, N-hydroxysuccinimide or N-hydroxylamine.
-Hydroxy-5-norbornene-2,3-dicarboxylic acid imide, optionally with a suitable base, e.g.
By reacting in the presence of dimethylaminopyridine, N-methylmorpholine or ethyldiisopropylamine, amino- or amidoesters of such acids can be formed in the presence of the amino moiety to be acylated.

Process b) In the starting materials of the general formula (n), the functional groups, with the exception of the keto group to be reduced, are optionally protected with protecting groups as described in process a).

-a The reduction of keto i in the compound of formula (II) can be carried out selectively under the reaction conditions of the process to remove the remote keto group or
Suitable are reducing agents that reduce faster than the amide groups present in the compounds of ).

In particular, suitable borohydrides, such as alkali metal borohydrides, especially borohydrides), lithium borohydride or sodium borohydride cyanide, or suitable aluminum hydrides, such as lower alkali metals with bulky groups. Alkoxyaluminum hydride, e.g. lithium-
Tris-jert-butoxyaluminum hydride is mentioned.

The reduction is carried out using hydrogen in the presence of a suitable heavy metal catalyst, such as Raney nickel, platinum catalyst or palladium catalyst, or Meerwein-Bondlhuberley (Me
It can also be carried out by the Erwein-Ponndorf-Verley method using aluminum alkoxides, preferably aluminum 2-propoxide or monoethoxide.

The reduction is carried out in an inert solvent using a stoichiometric amount or a suitable excess of reducing agent at temperatures between 0°C and the boiling point of the solvent, preferably 12°C.
Preferably carried out at a temperature of 0° C. to +100° C., optionally under a protective gas, such as nitrogen or argon.
An excess of reducing agent is necessary, especially if the reducing agent also reacts with protons of the solvent, such as a protic solvent.

Suitable solvents when using sodium borohydride are polar protic solvents, such as methanol, ethanol or isopropanol, and when using other reducing agents, polar aprotic solvents as mentioned in process a), such as e.g. Tetrahydrofuran is suitable.

Method c) (organometallic compound i/addition) knee i formula (III
In the starting materials of ), with the exception of the aldehyde groups, the functional groups are optionally protected with the protecting groups mentioned in process a). Similarly, the functional groups present in the compound of -1 formula (IV) are also protected.

In the compound of general formula (■), the metal group -M is, for example, -Li or -MgHal, for example -MgCI, -M
gBr or one? It is IgJ.

The reaction of the compound of general formula (I [ or in a mixture thereof, in particular after initiation of the reaction, optionally with cooling, e.g. below about −30° C., or with heating, e.g. to the boiling point of the reaction mixture, optionally in an inert gas atmosphere, e.g. nitrogen atmosphere. , a preferred implementation of this process is the reaction of an aldehyde of general formula (m) with an excess of a lithium compound of formula (IV) -a.

Hydrolysis of the adduct results in a solvent that produces H+- ions;
e.g. water (ice-water mixture) or dilute aqueous acid solutions, e.g. dilute K
M, such as a dilute aqueous sulfuric acid solution, or a dilute organic acid, such as a dilute aqueous acetic acid solution.

The reaction of compounds of the general formula (I[I) is prepared in situ, e.g. obtained from the corresponding halide, e.g. chloride, by reaction with a metallating agent, e.g. magnesium, lithium or tert-butyllithium. General formula (I
It can also be carried out using the compound of V).

Method d) (I) In the starting materials of general formula (V), functional groups are optionally protected with the protecting groups mentioned in method a).

In the compounds of general formula (V), the nucleofugal leaving group acid or hydriodic acid, and also sulfuric acid, halogenosulfuric acid, such as fluorosulfuric acid, or strong organic sulfonic acids, optionally substituted with, for example, halogen, such as fluorine, lower alkanesulfonic acids or aromatic sulfonic acids, such as optionally lower alkyl groups. , for example with benzenesulfonic acids substituted with methyl groups, halogens such as bromine and/or nitro groups, such as methanesulfonic acid, trifluoromethanesulfonic acid or p-toluenesulfonic acid, or with hydroxy groups esterified with hydronitridic acid. be.

Reagents introducing substituents R4 in nucleophilic form can be used, depending on the definition of R4, to convert the hydroxyl group into a base, such as sodium hydroxide or potassium hydroxide (Ra"OH), an alcohol, such as methanol or ethanol (R4 −
etherified hydroxy group) or a salt of a carboxylic acid, such as acetic acid m (R4=esterified hydroxy group).

It is preferable to select reaction conditions such that the reaction proceeds primarily as a bimolecular nucleophilic substitution (3M2). For example, X
A compound of general formula (V) in which represents a leaving group with high electron cloud localization properties, such as iodine, is mixed with a silver salt of a carboxylic acid in a polar aprotic solvent such as acetone, acetonitrile, nitromethane, dimethyl sulfoxide or dimethyl formamide. , for example with silver acetate. The reaction with the hydroxy-containing base is preferably carried out in water, optionally with the addition of an organic solvent, such as ethanol, tetrahydrofuran or acetone, as solubilizing agent, and the reaction with the alcohol is carried out in an excess of this alcohol, optionally with said polar Preferably, the substitution reaction is carried out in the presence of an aprotic solvent, optionally at reduced or increased temperatures, e.g. from about -40°C to about +100°C, preferably about -10°C.
It is carried out in the temperature range from about +50 DEG C., optionally under an inert gas atmosphere, for example nitrogen.

Method e) (Conversion of cyano to amide) General formula (Vl)
In the starting materials, the functional groups may optionally contain the functional groups listed in a)! ! protected by

The conversion of compounds of general formula (Vl) to compounds of general formula (Summer) can be carried out by Ritter-reaction or via carboxylic acid ester imide salts.

In the Ritter reaction, the nitrile is treated with a strong acid, e.g.
in the presence of ~90% sulfuric acid, or polyphosphoric acid, hydrogen fluoride, formic acid, boron trifluoride or other Lewis acids (excluding aluminum chloride), often without solvent, or for example in glacial acetic acid. , with a compound capable of forming carbenilam ions in an acidic medium, such as an olefin, such as propylene, or an alcohol, such as benzyl alcohol.

In a modification of the Ritter reaction, a nitrile of general formula (■) is reacted with an olefin and 1 m (n) of aqueous nitric acid, and the organomercury compound is then reduced with sodium borohydride to obtain the N-substitution of general formula (I). make into a compound.

The addition reaction of an alcohol to a nitrile of the general formula (■) catalyzed by an acid, preferably hydrochloric acid, gives a carboxylic acid ester imide, which is thermally rearranged at a temperature of about 80° C. or higher to form the general formula ( The amide of I) is obtained.

In the starting materials of the general formula (■), the Kankuma group is optionally protected by the protecting groups listed in method a).

Under the reaction conditions of this process, the epoxy groups are reduced selectively or earlier than the amide groups present, so that sufficient and as much as possible of the reaction product is newly placed in the corresponding position of general formula (I). Reducing agents can be used that open the epoxide to have hydroxy groups formed. Examples of such selective reducing agents are lithium borohydride or sodium cyanoborohydride/boron trifluoride etherate. Using the last-mentioned reagents, e.g. 1 mol of a compound of general formula (■) in tetrahydrofuran and an excess, e.g. 1.4 to 3 mol of sodium cyanoborohydride, at elevated temperature, e.g. Boron trifluoride etherate BF3 .O(C
It can be carried out by adding a solution of 2Ha)2 such that the pH of the reaction solution is kept near the end point of the indicator bromcresol green also added. The reduction with lithium borohydride is preferably carried out in an ether such as tetrahydrofuran, 1,2-dimethoxyethane or diethylene glycol dimethyl ether at room temperature to reflux temperature.

191 by 1: RIs As In the obtained compound of general formula (I) in which R2, R3, R4, Rs and R6 represent the above,
Carboxamide groups can be substituted, carboxyl groups present in free or reactive form can be esterified, or esterified carboxyl groups can be converted into carboxamide groups.

Substitution of carboxamide groups or other amino groups is carried out, for example, by alkylation.

Suitable reagents for alkylating carboxamide groups in compounds of general formula (I) are, for example, diazo compounds, such as diazomethane. The diazomethane is decomposed in an inert solvent and the free methylenes formed are reacted with the carboxamide groups in the compound of general formula (I). The decomposition of diazomethane is preferably carried out using a catalyst, for example using a finely divided noble metal, such as copper, or a noble metal salt, such as copper chloride (
I) or in the presence of sulfuric acid lii(II).

Alkylating agents may furthermore be the alkylating agents listed in DE 2,331,133, for example alkyl halides, sulfonic acid esters, Meyerwein salts or 1-substituted-3-aryl triads. zene, which can be reacted with a compound of general formula (I) having a carboxamide group under the reaction conditions described in the publication.

To esterify the carboxy group in the compound of Ikkuroni (I), the free acid is used, or the free acid is converted into a reactive derivative listed in method a) and reacted with an alcohol, or the free acid Remarkably, reactive salts, such as cesium salts, can be reacted with reactive derivatives of alcohols; for example, cesium salts of carboxylic acids can be reacted with halogenides of alcohols.

Esterification of the carboxyl group is carried out under the same reaction conditions using the alkylating agents mentioned for the substitution of the carboxamide group, e.g. diazomethane, alkyl halides, sulfonic acid esters, Meyerwein salts or 1-substituted-3-aryltriazenes. This can be done using, etc.

The conversion of an esterified carboxy group in a compound of general formula (I) into a free carboxy group can be carried out by the method described for a) removal of the carboxy protecting group or optionally by the method described in "Organikum" 115th edition (VE
B Deutscher Verlag der Wis
Alkaline hydrolysis can be used according to the reaction conditions listed in J. Senschaften, East Berlin, 1976).

In the compounds of general formula (I), the esterified carboxy group can be converted into an optionally substituted carboxamide group by amitrilysis using ammonia or -class or secondary amines. Amythrisis is published in ``Organikum'', 15th edition (VEBD Deutscher Verlag der East Berlin).
Wissenschaften Publishing) under the reaction conditions listed for such reactions.

In the resulting compounds of general formula (I) in which the substituents represent those mentioned above, at least one free hydroxy group is present and other functional groups are optionally present in protected form,
Free hydroxy groups, such as hydroxy groups R4, can be etherified or esterified.

Etherification of this hydroxy group is carried out using the alkylating agents described above under the same reaction conditions, e.g. diazomethane, alkyl halides, sulfonic acid esters, Meyerwein salts, 1-substituted-3-aryltriazenes, etc. be able to.

Esterification of free hydroxy groups can be carried out using conventional acylating agents and conventional reaction conditions as described in "Organicum", for example with acetic anhydride.

The above alkylation reaction, etherification, esterification, etc.
Instead of working on the final product, it can be carried out correspondingly on the starting materials.

In the resulting compounds of general formula (I) in which one or more functional groups are protected, these groups, such as carboxy groups, amino groups, hydroxy groups and/or mercapto groups, can be solvated in a manner known per se. It can be liberated stepwise or simultaneously by decomposition, alcoholysis or acidolysis, or reduction, especially hydrogenolysis, or chemical reduction.

Removal of protecting groups is described in the literature listed in the "Protecting Groups" section above.

For example, a protected carboxy group, e.g. tert-
a lower alkoxycarbonyl group, a lower alkoxycarbonyl group substituted at the 2-position with an organic silyl group, or a lower alkoxycarbonyl group substituted at the 1-position with a lower alkoxy group or a lower alkylthio group, or in some cases a more substituted diphenylmethoxycarbonyl group; , optionally with the addition of a nucleophilic compound such as phenol or anisole, e.g. a suitable acid,
For example, it can be converted into a free carboxy group by treatment with formic acid or trifluoroacetic acid. Optionally substituted benzyloxycarbonyl groups can be liberated, for example, by hydrogenolysis, ie treatment with hydrogen in the presence of a metal hydrogenation catalyst, for example a palladium catalyst. Furthermore, a suitably substituted benzyloxycarbonyl group, for example a 4-nitrobenzyloxycarbonyl group, can be reduced, for example an alkali metal dithionite, for example sodium dithionite or a reducing metal, for example zinc or a reducing metal salt, for example Chromium(II) salts, such as chromium(I[) chloride, are usually used, and hydrogen releasing agents (which together with the metal can form nascent hydrogen) are used, such as acids, in particular suitable carboxylic acids, e.g. lower alkanecarboxylic acids substituted with hydroxy groups, such as acetic acid, formic acid, glycolic acid, diphenylglycolic acid,
In the presence of lactic acid, mandelic acid, 4-chloromandelic acid, tartaric acid, or alcohols or thiols, they can be converted into free carboxy groups by treatment, preferably with the addition of water. 2-halogen lower alkoxycarbonyl & (optionally after converting the 2-bromo lower alkoxycarbonyl group to the corresponding 2-iodo lower alkoxycarbonyl group) or aroyl by treatment as described above with a reducing metal or metal salt. A methoxycarbonyl group can be converted to a free carboxy group. Similarly, an acoylmethoxycarbonyl group can be cleaved by treatment with a nucleophilic, preferably salt-forming, reagent such as sodium thiophenolate or sodium iodide. A 2-tri-lower alkylsilyl lower alkoxycarbonyl group is combined with a fluoride ion-forming salt of hydrofluoric acid, such as an alkali metal fluoride, such as sodium fluoride or fluoride, optionally in the presence of a macrocyclic polyether (“crown ether”). or an aprotic polar solvent such as dimethyl sulfoxide or N.

Free carboxylic acids can be isolated by treatment with a fluoride of an organic quaternary base, such as a tetra-lower alkylammonium fluoride or a tri-lower alkylaryl ammonium fluoride, such as tetraethylammonium fluoride or tetrabutylammonium fluoride, in the presence of N-dimethylacetamide. It can be changed to the base. The carboxy group esterified with an organosilyl group, such as a tri-lower alkylsilyl group, such as a trimethylsilyl group, is liberated in the conventional manner by solvolysis, for example by treatment with water, alcohol or acid, or with a fluoride as mentioned above. be able to. Esterified carboxy groups can also be cleaved with enzymes, for example esterified arginine or lysine, such as lysine methyl ester, with trypsin.

The protected amino group is liberated in a manner known per se, depending on the nature of the protecting group, preferably by solvolysis or reduction. 2-halogen lower alkoxycarbonylamino group (optionally after changing the 2-bromo lower alkoxycarbonylamino group to 2-iodo lower alkoxycarbonylamino group), aroylmethoxycarbonyl 7mino group or 4-nitrobenzyloxycarbonylamino group can be decomposed, for example, by treatment with a suitable reducing agent, such as zinc, in the presence of a suitable carboxylic acid, such as aqueous acetic acid. an aroylmethoxycarbonylamino group with a nucleophilic, preferably salt-forming reagent,
It can also be decomposed, for example by treatment with sodium thiophenolate, and the 4-nitrobenzyloxycarbonylamino group can be decomposed by treatment with an alkali metal dithionite, such as sodium dithionite. The optionally substituted diphenylmethoxycarbonylamino group, ter -lower alkoxycarbonylamino group or 2-trilower alkylsilyl lower alkoxycarbonylamino group is liberated by treatment with a suitable acid, such as formic acid or trifluoroacetic acid. , an optionally substituted benzyloxycarbonylamino group is liberated, for example by hydrogenolysis, i.e. by treatment with hydrogen in the presence of a suitable hydrogenation catalyst, such as a palladium catalyst, and an optionally substituted triarylmethylamino group or The formylamino group is liberated by treatment with an acid, such as a mineral acid, such as hydrochloric acid, or an organic acid, such as formic acid, acetic acid or trifluoroacetic acid, optionally in the presence of water, and the amine group is protected with an organosilyl group. can also be liberated, for example by hydrolysis or alcoholysis. When an amino group protected with a 2-halogenacetyl group, e.g. a 2-chloroacetyl group, is treated with thiourea in the presence of a base or with a thiolate salt of thiourea, e.g. The product can subsequently be liberated by solvolysis, for example alcoholysis or hydrolysis. 2
- treating the amino group protected with a tri-lower alkylsilyl lower alkoxycarbonyl group with a fluoride ion-forming salt of hydrofluoric acid as described in connection with the liberation of the correspondingly protected carboxy group; can be converted into a free amino group by Similarly, a silyl group, such as a trimethylsilyl group, bonded directly to a heteroatom, such as nitrogen, can be eliminated by fluoride ions.

The protected amino group in the form of an azide group is reduced, for example by catalytic hydrogenation with hydrogen in the presence of a hydrogenation catalyst such as platinum oxide, palladium or Raney nickel, or treated with zinc in the presence of an acid such as acetic acid. can be converted into a free amino group by Catalytic hydrogenation is carried out at about 20-25° C. in an inert melt, e.g. a halogenated hydrocarbon, e.g. methylene chloride or water or a mixture of water and an organic solvent, e.g. alcohol or dioxane, or under cooling or heating. It is preferable to do so.

The hydroxy or mercapto group protected with a suitable acyl group, organosilyl group or optionally substituted l-phenyl lower alkyl group is liberated in the same manner as the correspondingly protected amino group. 2. The hydroxy group or mercapto group protected by the 2-dichloroacetyl group is released, for example by basic hydrolysis, and the tart-lower alkyl group or the 2-oxa- or 2-thia-aliphatic or alicyclic hydrocarbon A hydroxy group or a mercapto group protected with a group such as i! It is liberated by treatment with acids or strong carboxylic acids such as trifluoroacetic acid. A group in which the two hydroxy groups are preferably protected together with a substituted methylene group, such as a lower alkylidene group, such as an isopropylidene group, a cycloalkylidene group, such as a cyclohexylidene group or a benzylidene group, in particular a mineral acid Alternatively, it can be liberated by acidic solvolysis in the presence of a strong organic acid.

Salts of compounds of general formula (I) having a salt-forming group can be produced by methods known per se. A salt of a compound of general formula (I) having an acidic group can be used, for example, as a metal compound, such as an alkali metal salt of a suitable organic carboxylic acid, such as the sodium salt of 2-ethylhexanoic acid, or an organic alkali metal salt or an alkaline earth salt. Metal salts of the general formula (I Acid addition salts of compounds of formula (I) which are obtained in conventional manner, for example by treatment with an acid or a suitable anion exchange reagent, include, for example, internal salts of compounds of general formula (I) containing free carboxy groups and free amino groups can be formed, for example, by neutralizing a salt, such as an acid addition salt, to its isoelectric point, for example with a weak base, or by treating it with an ion exchanger.

Salts can be converted into free compounds in a conventional manner.

Thus, metal salts and ammonium salts can be converted into the free compounds, for example, by treatment with a suitable acid, and acid addition salts, for example, by treatment with a suitable basic reagent.

Stereoisomeric mixtures, in particular diastereoisomeric mixtures, can be separated into the individual isomers by methods known per se, such as fractional crystallization, chromatography and the like.

Racemates can be resolved in a manner known per se, for example by converting the optical antipodes into diastereoisomers and then reacting them with optically active acids or bases.

-a The arrangement can be reversed at the individual chirality center in the compound of formula (I), e.g. at the C-atom of CH-R4, e.g. by changing the hydroxy group into a leaving group X and introducing the substituent R4. After reacting with a reagent, the configuration at the carbon atom of CH--Ra can be reversed by bimolecular nucleophilic substitution according to method d).

The invention further provides that starting from the compound obtained as an intermediate product in any step, carrying out the missing steps or discontinuing the operation at any step, or manipulating the compound obtained by the process of the invention. Regarding actual yEB-like products produced under conditions and further processed in situ.

Pharmaceutical formulations: The pharmaceutically usable compounds of the present invention can be prepared, for example, by containing an effective amount of the active ingredient in a significant amount of an inorganic or organic solid or liquid, together with a pharmaceutically acceptable excipient or in a mixture. It can be used in the manufacture of pharmaceutical formulations containing.

Pharmaceutical formulations according to the invention are formulations for administration to warm-blooded animals (humans and animals) either enterally, e.g. intranasally, rectally or orally, or parenterally, e.g. intramuscularly or intravenously, using an effective amount of The dosage of the active ingredient, either alone or together with significant amounts of pharmaceutically acceptable excipients, depends on the species of warm-blooded animal, body weight, age and individual condition, the disease to be treated and the method of administration. depends on.

The dosage to be administered to a warm-blooded animal, such as a human, weighing about 70 + r is about 3 and about 3 g, preferably about 10 mg to about 1 g, for example about 300 g, per person per day, and For example, it is divided into equal amounts, preferably 1 to 3 doses.

Children are usually given half the adult dose.

The novel pharmaceutical preparations contain about 1 to 95% of the active ingredient, preferably about 20% to 90%. The pharmaceutical preparations according to the invention can be, for example, in the form of unit dosage preparations, e.g. , tablets or capsules.

The pharmaceutical preparations according to the invention are produced by methods known per se, such as conventional dissolving, lyophilizing, mixing, granulating or dragee methods.

Preference is given to using solutions, also suspensions and especially isotonic aqueous solutions or suspensions of the active ingredient, for example in lyophilized preparations containing the active ingredient alone or together with excipients such as mannitol. solutions or suspensions can be prepared before use. The pharmaceutical preparations may be sterile and/or may contain auxiliary agents, such as preservatives, stabilizing agents, wetting agents and/or emulsifying agents, solubilizing agents, osmotic salts and/or buffering agents. It can be produced by methods known per se, for example by conventional dissolution or freeze-drying methods. Said solutions or suspensions may also contain viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Suspensions in oil contain as oil component the vegetable oils, synthetic oils or semi-synthetic oils commonly used for injections, the oil preferably having 8 to 22 carbon atoms, in particular 12 to 22 carbon atoms, as acid component. long-chain fatty acids such as lauric acid, tridecylic acid, myristic acid, pentadecylic acid, valmitic acid, margaric acid,
Mention may be made of liquid fatty acid esters containing stearic acid, arachidic acid, behenic acid or the corresponding unsaturated acids, such as oleic acid, elaidic acid, erucic acid, brassic acid or linoleic acid. The alcohol content of this fatty acid ester is up to 6
carbon atoms, monovalent or polyhydric, for example monohydric, dihydric or trihydric alcohols, such as methanol, ethanol, propatool, butanol or pentanol or isomers thereof, especially glycols or glycerin. Therefore, fatty acid esters include, for example, ethyl oleate, isopropyl myristate, isopropyl valmitate, 1 Labrafil M 27
35" (polyoxyethylene glycerol trioleate manufactured by Gatte-fosse in Paris), 'Myglyol 812" [West Germany, diisothene/Ruhr, Hemisoj-'Werke (Chem)
Ische 'Derke) 8-12 carbon atoms
saturated fatty acid triglycerides), especially vegetable oils,
Mention may be made, for example, of cottonseed oil, mandel oil, olive oil, castor oil, sesame oil, soybean oil and especially peanut oil.

The manufacture of injections is carried out in a conventional manner under sterile conditions, and the filling of ampoules or vials and the closure of the containers are likewise carried out in a conventional manner.

Pharmaceutical preparations for oral administration are prepared by mixing the active ingredient with a solid excipient, optionally granulating the resulting mixture, and processing the mixture or granules into tablets or dragee cores, if necessary after addition of suitable auxiliaries. obtained by doing. In this case, the tablets or dragees can be embedded in plastic carriers which release or diffuse the active ingredient in a metered amount.

Suitable excipients are, in particular, fillers, such as) lactose, sucrose, mannitol or sorbitol, cellulosic substances and/or Hf1. Calcium, such as HeR tricalcium or fA dicalcium oxide, and also a binder,
Starch pastes, e.g. using corn starch, wheat starch, rice starch or potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone, and/or optionally disintegrants, e.g. The above-mentioned starches are furthermore carboxymethyl starch, reticulated polyvinylpyrrolidone, agar, alginic acid or its salts, such as sodium alginate. Auxiliaries are in particular flow regulators and lubricants, such as silicic acid, talc,
Stearic acid or a salt thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol. The dragee core is provided with a suitable, optionally gastric juice-resistant coating, with
In particular, concentrated sugar solutions optionally containing gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions in suitable organic solvents or solvent mixtures, or suitable for producing gastric juice-resistant coatings. Dyestuffs or pigments can be added to the tablets or dragee coatings using cellulose preparations such as ethylcellulose phthalate or hydroxypropylmethylcellulose phthalate, for example to identify or indicate different doses of the active ingredient.

■ Main milled beans: New starting materials and/or intermediates and methods for their production are also subject to the present invention. It is preferred to use starting materials and to select reaction conditions such that the compounds listed as preferred are reached.

The starting materials for carrying out process a) can be prepared in a manner known per se, for example by condensation analogously to process a) from the relevant amino acids.

For example, a compound of the general formula (澹): [wherein R3, R5 and R6 have the definitions given below in the general formula (I)] is a compound of the general formula (IX): ZI H
A compound of N-CH-C-H(IX)3 [in the formula, R3 represents the above-mentioned one, and ZI represents an amino-protecting group] is a sulfur-ylide compound.

[In the formula, R3 and ZI represent the above-mentioned] epoxide, and optionally after separating isomers, the obtained compound of general formula (X) is aerobically separated. A compound of the general formula () obtained by reacting with a reagent for introducing a group Ra-(
C=O)-Rh (XII) [In the formula, the groups Ra and Rb are each independently hydrogen, a lower alkyl group,
or aryl-lower alkyl group, or Ra and Rb together optionally bridged and have from 4 to 1 carbon atoms.
Representing the alkylidene group of 2] or a reactive derivative of this lanocarbonyl compound in the presence of an acidic reagent, the obtained general formula (XI[I): [substituent represents the above] The compound has the general formula %Formula %: [wherein R5 has the definition given below in the general formula N], Z2
represents a kalboxyl protecting group, and Y+ represents a cation, such as an alkali metal ion, such as a sodium ion or preferably a lithium ion], resulting in general formula (XV): The carboxy-protecting group Z2 in the compound (Z2 has the above definition) is eliminated, and/or the resulting isomer mixture is separated into individual isomers, and the resulting compound having a free carboxy group (Z2 -H) with amine Rε-H, and the ring in the compound of the general formula (XVI) obtained is opened with an appropriate solvolysis reagent. It can be produced by ringing and optionally removing the protecting group Z+.

This method is carried out analogously to the method described in European Patent Application No. 143,746.

All reaction sequences for preparing intermediate products of general formula (VIII) can be carried out in situ or after isolation of the preproducts obtained by individual or all steps.

Compounds of the general formula (II) can be prepared, for example, by the general formula (X■): [wherein the substituents are as defined above, and the free functional groups, except for the optionally modified carboxy group, are optionally in a protected form. or a suitable functional derivative thereof, wherein R3 and R6 are as defined above, and M is a metal group, e.g. -Li, -MgHal, e.g. -MgC1,
It is obtained by reacting with an organometallic compound of general formula (Vl) representing -MgBr or -MgJ and solvolyzing the formed addition product.

Suitable functional derivatives of carboxylic acids of general formula (XVI[) are, for example, the corresponding lithium salts of carboxylic acids, carboxylic acid halides such as carboxylic acid chlorides, anhydrides,
For example, symmetrical carboxylic anhydrides or mixed carboxylic anhydrides with sterically hindered carboxylic acids, such as pivalic acid, or thioesters, such as 2-pyridylthioesters.

The reaction of the carboxylic acid of general formula (X■) or a suitable functional derivative thereof with a compound of general formula (IV) is carried out in a customary manner, for example under the reaction conditions described in method C), but optionally with cooling. , for example at a temperature of about -50°C to about 0°C.
A preferred embodiment of this method is 1. General formula (X■)
The 2-pyridylthioester of carboxylic acid of general formula (I
V) is reacted with the bromomagnesium compound.

The compound of general formula (III) can be prepared by a method known per se.
For example, a carboxy group in a compound of the general formula (X) in which the substituents represent those mentioned above and the free functional group is optionally present in protected form can be converted in a manner known per se, for example to the corresponding methyl- or It can also be prepared by reduction to the aldehyde function via ethyl ester, imidazolide or N-methoxy-N-methylamide.

The compound of general formula (IV) is, for example, general formula (XVf)
can be prepared by reacting the known halides of or which can be prepared in a manner known per se, such as the chloride, with a metallating agent such as magnesium, lithium or tert-butyllithium.

The compound of general formula (V) can be prepared by combining, for example, an aldehyde of general formula (III) with an organometallic compound of general formula (IV) and method C).
The hydroxy compound of the general formula (I) formed by reacting the hydroxy compound of the general formula (I), optionally after separation of the isomers, with a strong organic or inorganic acid according to the definition of It is produced by esterification as described above.

-IG A nitrile of formula (VI) is, for example, a nitrile of general formula (XI
) : [In the formula, WltA group represents the above-mentioned compound] can be produced by reacting the compound with a salt of hydrocyanic acid.

A suitable salt of hydrocyanic acid should be sufficiently soluble in the inert solvent of choice to carry out the reaction. Such salts are, for example, ammonium cyanide, alkali metal or alkaline earth metal cyanides, such as sodium or potassium cyanide, or transition metal cyanides, such as copper cyanide. The latter are particularly suitable in that they are less basic than alkali metal cyanides.

Depending on the type of cyanide and solvent used, an equilibrium is established between the isomeric nitrile and isonitrile forms.For example, with a metal cyanide in which the metal cation has an atomic weight lower than that of copper. If the reaction is carried out, it is preferred to form the nitrile form.

Suitable inert solvents are, in particular, polar aprotic solvents, such as carboxylic acid amides, such as dimethylformamide or dimethylacetamide, nitriles, such as acetonitrile or propionitrile, or di-lower alkyl sulfoxides, such as dimethyl sulfoxide.

The reaction may be carried out at room temperature, at reduced or increased temperatures, e.g. from about -40°C to about +100°C, preferably from about 10°C to about +
It is carried out in a temperature range of 50° C., if necessary, in an inert gas atmosphere, such as nitrogen.

-C Epoxide of formula (■) is, for example, a compound of general formula (IX) general formula (XX): C [wherein RC represents an optionally substituted hydrocarbon group,
R5 represents the above-mentioned compound and Z2 represents a carboxy protecting group], and the resulting compound of the general formula (XXI) is converted into an epoxide using a peroxo group-containing oxidizing agent. It is produced by eliminating the retained NaZ+ and Z2 in the compound and replacing them with groups R1-A- and R6 in an arbitrary reaction step sequence.

Rc is preferably a phenyl group, general formula (IX)
The reaction of the compound with the phosphoranylidene compound of the general formula (XX) is carried out under the reaction conditions known for the Wittig reaction, for example as described in "Organicum", the reaction of the compound of the general formula (XXI) of the olefin is optionally reacted in situ with an oxidizing agent such as peracetic acid or m-chloroperbenzoic acid. Protecting groups Z1 and Z
The elimination of 2 and the introduction of the group R1-A- or Re have already been described in process a).

The following examples are intended to illustrate the invention:
This invention is not intended to limit the scope of the invention.

Temperatures are given in degrees Celsius, Rf values were measured with the following cutting system on thin silica gel plates: 2N1 Chloroform/methanol 9:IN2 Chloroform/methanol 19:IN3 Acetate/n-
Hexane 1:IN4 Acetate/n-hexane 1:4N5 Acetate/n-hexane
1:9N6 methylene chloride/ether 4:
IN7 Methylene chloride/ether 1:1N8
Methylene chloride/methanol 9:IN9 ゛Methylene chloride/methanol 6:lNl0 Methylene chloride/methanol 20:lNi1 Methylene chloride/methanol 1o:lNl2 Methylene chloride/methanol 5:lN13 Acetate ester/n
-Hexane 4:lN14 Acetate/n-hexane 2:lN13 Acetate/n-hexane l:2N16 Methylene chloride/methanol/water 300:10:l N17 Acetate/n-hexane 1:6N1
8 Acetate/methanol 1:IN l
9 Acetate/methanol 4:lN2O Methylene chloride/methanol 3:lN21 Methylene chloride/methanol 4:IN 22 Methylene chloride/methanol/water 40:10:I B1 Chloroform/methanol/lyx ammonia 40:10:1
Below white B2 Chloroform/methanol/concentrated ammonia
350:50:IB3
Methylene chloride/methanol/concentrated ammonia
1000:50:IB4 Methylene chloride/methanol/concentrated ammonia
350:50:IB5 Methylene monide/methanol/concentrated ammonia
140:10:IB6 Methylene chloride/methanol/concentrated ammonia 10
5:50:IB7 Methylene chloride/methanol/concentrated ammonia 90:I
Q:IB8 Methylene chloride/methanol/concentrated ammonia 80:10:I
B9 Methylene chloride/methanol/concentrated ammonia
65:10:IBIO
Methylene chloride/methanol/concentrated ammonia
50:10:1B11 Methylene chloride/methanol/concentrated ammonia
40=10:1B12 methylene chloride/methanol/concentrated ammonia
40: 25: lB1
3 Methylene chloride/methanol/concentrated ammonia
30:10:lB14
Methylene chloride/methanol/concentrated ammonia
25:10:lB15
Methylene chloride/methanol/concentrated ammonia
20:5:lB16
Methylene chloride/methanol/concentrated ammonia
10:10:1B17 Acetate/Pyridine/Glacial acetic acid/Water 62:21:6:1
1 B18 n-butanol/pyridine/glacial acetic acid/water 38
:24:8:30 B19 Pyridine/n-butanol/n-amyl alcohol/methyl ethyl ketone/glacial acetic acid/formic acid/water 25:20:15:10:3:3:25B20 n-
Butanol/pyridine/formic acid/water 42:24:4:20 B21 n-butanol/pyridine/glacial acetic acid/water 42
: 24 : 4 ; 30 B22 n-butanol/pyridine/formic acid/water 44
: 24 : 2 : 20 B23 Methylene chloride/methanol/concentrated ammonia
700:50:lB2
4 Methylene chloride/methanol/a ammonia
60:10:l
B25 Methylene chloride/methanol/concentrated ammonia
370:30:lB2
6 Methylene chloride/methanol/concentrated ammonia
300:10:lB27
Methylene chloride/methanol/concentrated ammonia
70:10:IB2B
Methylene chloride/methanol/concentrated ammonia
800:50:1B29 Methylene chloride/methanol/1 ammonia
, 500:50:1B50 methylene chloride/methanol/1 ammonia
750:50:1B31 Methylene chloride/methanol/concentrated ammonia
200:10:1B52 Methylene chloride/methanol/concentrated ammonia
5:3:1B53 Methylene chloride/methanol/concentrated ammonia
100:10: ISl Acetate/Pyridine/Glacial acetic acid/Water 62:21:6:11 B2 Acetate/Methanol/Glacial acetic acid/Water 67:
10:12:23 B3 Chloroform/methanol/water/glacial acetic acid 300
:108:20:2 B4 Chloroform/methanol/water/glacial acetic acid 150
:54:10:I B5 Chloroform/methanol/water/glacial acetic acid 140
:80:20:I B6 Chloroform/methanol/water/glacial acetic acid 180
:20:2:IS7 Chloroform/methanol/water/glacial acetic acid 110
:94:26:1 B8 Chloroform/methanol/water/glacial acetic acid 80
: 20 : 3 : 3 B9 Chloroform/methanol/water/glacial acetic acid 70:
30:3:3 510 Methylene chloride/methanol/water/glacial acetic acid 75
0:270:50:5 SlI n-butanol/glacial acetic acid/water 67:10
: 23 312 Methylene chloride/methanol/water/glacial acetic acid 16
0:30:3:9 S13 Acetate/n-hexane/glacial acetic acid 40:
60:1 For example, the symbol “Rf (Nl)” represents the R-f value in the system N
1. The mutual quantity ratio of solvents is indicated by volume ratio.

The same symbols are used to indicate flow agent systems in flash chromatography and medium pressure chromatography.

Abbreviations for amino acids and amino acid derivatives are as follows: 1(-Ala-OHL-alanine) 1-Arg-OHL-arginine H-Cha-OHL-cyclohexylalanine 1l-G
ln-OHL-glutamic acid)
1-Glu (OR+oO)1 The carboxylic acid function on the side is esterified with the group R and monoglutamic acid H-Guy-0)1 Glycine If-His-OHL-Histidine) 1-11e-0) I L -isoleucine H-L
eu-OHL-leucine H-Lys-OHL-lysine II-Lys (R+oOH side chain amino functional group is group R
L-lysine H-Nle-0) I L-norleucine substituted with (
S) -α-amino acid hexanoic acid H-Orn-OHL-ornithine, (S)-α.

δ-valeric acid rI-Orn (R)-OH side chain amino functional group is iR
Ornithine H-Phe-OHL-phenylalanine H(N-methyl-Phe)-OHN-methyl-L-phenylalanine H-Val-0) I instead of L-valine-OH! JHt: C-terminal (carboxylic acid) amide-0)l instead of -OMe: C-terminal (carboxylic acid)
-NHMe:C-terminus (carboxylic acid amide symbol -Leu -Val- instead of methyl ester -OH)
5゜53) - Represents a divalent group of -5-amino-2-isopropyl-4-hydroxy-7-methyloctanoic acid and has the following formula: ) is obtained from the fragment of -Leu -Val- by NH and O
m'll- by cross-linking H with an isopropylidene group, resulting in the following formula: The fragment designated by the symbol -Cha-Val- is (2S, 4S
.

5S)-5-amino-6-cyclohexyl-2-isopropyl-4-hydroxyhexanoic acid and has the following formula: The fragment designated by the symbol -Cha-Val- is -Cha-V
From the fragment of al-, =i is obtained by bridging the NH and OH by the isopropylidene group.

Symbol -Gly (Rs) -Gly (Rs)-
The fragment shown with °(
2-Rs-4(S) with R)- or (S)-configuration
-Hydroxy-5-amino-5-Rs pentanoic acid 2
It represents a valence group and has the following formula.

The fragment indicated by the symbol -Gly (R3) "Gly (Rs)-" is -Gay (R3) -Gly (Rs
)- by bridging the NH and OH through isopropylidene groups.

Other symbols: Ac = acetyl BOC = tert-butoxycarbonyl DCCI = dicyclohexylcarbodiimide DC)l = dicyclohexyl urea DMF = dimethylformamide DMSO = dimethyl sulfoxide HOBt = 1-hydroxybenzotriazole b, p,
= boiling point m, ρ, = melting point T) IF-tetrahydrofuran Z = benzyloxycarbonyl (Example) N-(quinolyl-2-carbonyl)-L-phenylalanine 54■, H-Leu -Val-NHMe 41
trxr and HOBt 26 N (Fluka pu
rum, containing 11-13% water] to 0MF2.511
1 to 0°C. After adding DCCI45■,
Stir for 15 hours under water cooling and then for 2 days at room temperature. The crystalline DCH is passed through a suction port and the filtrate is concentrated under high vacuum. The residue is stirred for 30 minutes at 60° C. in a mixture of methanol/water/glacial acetic acid (94:3:3) and then concentrated. The residue was separated by Franchet chromatography (6035 g of silica gel, 40-63 μm, eluent system N10),
The fractions containing the product are concentrated by evaporation. After drying in high vacuum, the title compound is obtained as a pale yellowish powder. Rf (N10)-0,33, Rf (N
13) -0,08 Starting material H-Leu-Val-NHM
e can be produced by the following reaction formula.

The following margin (S, S, S-isomer: z-Leu -Val-OH
)/< (z-Leu -Vat-NHMc) a) Sodium hydride dispersion (55% in oil) 8,75
The oil is separated by stirring three times in 85 l of petroleum ether (boiling point 40 DEG -60 DEG C.) in a dry sulfonated flask under argon and then decanting the solvent each time. After drying in a high vacuum a gray powder is obtained. Dimethyl sulfoxide xonium iodine is added to this powder, the temperature rising to about 40°C. The gray suspension was stirred at room temperature for 1 h and then treated with DMS at 10 °C for 50 min.
Ol 8 0o+1 (7) (S) -2 -<n'
; oxycarbonylamino-4-methylpentanal (XXn) CIJ-made: Helvetica Chimica Acta
Add 43.4 g of the solution. The yellow suspension is stirred at 10°C for 15 minutes and then at room temperature for 1.5 hours. Pour the yellowish turbid liquid onto 500 g of ice.

The aqueous solution is extracted with ether, the organic phase is washed with water, dried over sodium sulfate and then concentrated by evaporation. The oily residue is separated by flash chromatography on 2-electrode silica gel (40-63 μm) using a mixture of methylene chloride/n-hexane/ethyl acetate (5:10:3).

The fractions containing the product are combined and concentrated by evaporation,
Dry in high vacuum. The epoxide CXXm) (diastereomeric mixture, approximately 3:1) is obtained as a pale yellowish oil. Rf (Bl) -0,57; Rr (N4)
-0,16b) 33.8 g of compound (XXDI) are taken up in 255 ml of a7tonitrile and the resulting solution is cooled to 0°C. After adding 19.24 g of sodium iodide, 16.27 g of trimethylchlorosilane was added in 30 minutes at 0°C.
Add ml. The mixture is stirred for 40 minutes at 0-3 DEG C. and then poured onto ice-cold water 250a+1, the aqueous mixture is extracted with ether and the organic phase is washed with 10% aqueous sodium thiosulfate solution and saturated aqueous sodium chloride solution. After drying over sodium sulfate and concentration by evaporation, the desired alcohol CXXN) and the corresponding trimethylsilyl ether (
An oily mixture of both diastereomeric mixtures is obtained. Free alcohol is separated by flash chromatography (silica gel 602ksr, 40-63μ
After concentrating the combined fractions containing m, flow agent N4) and product by evaporation, alcohol (X X IV)
is obtained as an oil. The fractions containing trimethylsilyl ether were combined and, after concentration by evaporation, the residue was taken up in THF and 2.67 g of tetraphytylammonium fluoride in water was dissolved. Add solution g and stir the mixture thus obtained at room temperature for 3 days.The solution is then shaken between water and ether. The organic phase is washed with water, dried over sodium sulphate and concentrated by evaporation. After drying in a high vacuum, a diastereomeric mixture of compound (XXrV) is obtained as an oil.One total amount of the diastereomeric mixture (XXIV) is separated into two parts by medium pressure chromatography for further purification. [Lichroprep (trademark) Si601.
4 kg, 25-40 un, eluent: acetic acid ethyl ester/n-hexane (I: 8), about 220 ml of the crude material and mixed fractions by crystallization from petroleum ether (boiling point 40-60 °C) By partially enriching the more polar component (at 104 DEG -106 DEG C.), two diastereomers are formed in a ratio of about 3:1. The less polar oily component is the desired compound (XXIV), Rf (N4) -0,16;
Rf(B1) Snow 0.54 C) 66.6 g of the compound (XXrV) and 1.62 g of p-toluenesulfonic acid monohydrate are heated under reflux for 3 hours in 1500 l of 2,2-dimethoxypropane. After cooling to room temperature, the mixture is shaken between 1000+1 ether and 500 ml of saturated aqueous sodium bicarbonate solution.

The organic phase is washed with water, dried over sodium sulphate and concentrated by evaporation.

The semi-crystalline crude product was purified by flash chromatography (
By concentrating the combined product-containing fractions by evaporation, the compound (XXV) is obtained as pale yellowish crystals. Rf (N4)-0,48, Rf
(N5) -0,26d) Diisopropylamine 10.
82 ml of n-butyllithium in hexane is dissolved in 100 ml of anhydrous tetrahydrofuran under argon and cooled to 0°C.Then the mixture is heated to 0-5°C for 20 min. Add W solution dropwise and stir for 15 minutes. Next, -
Isovaleric acid methyl ester at 70°C to -75°C 10.1
ml is added dropwise and the mixture is stirred at -75° C. for 1.5 hours. 190 ml of hexamethylphosphoric acid triamide are added dropwise with stirring at -SO<0>C to -75<0>C.

Does it occur? The A suspension was stirred for 10 minutes and finally heated to -70℃~
A solution of 30.0 g of compound (XXV) in 50 ml of tetrahydrofuran is added dropwise in 5 min at -75°C. The reaction mixture is stirred at room temperature for 2.5 h and finally added with 450 ml of saturated aqueous ammonium chloride solution on ice. The aqueous phase is extracted with ether, the organic phase is washed with water and dried over sodium sulfate. After concentration by evaporation, a diastereomeric mixture of compound (XXV'l) is obtained as a yellow oil.

Rf (N5)=0.20; Rf (N4)=
0.40 (value for the less polar component) e) To 10.7 g of potassium tert-butoxide are added 1.07+ ml of water at approx. 5° C. in 80 ml of ether. The white suspension is stirred for 10 minutes in a water bath and then 10.0 g of compound (XXVI) (diastereomeric mixture) in 80 ml of ether are added, the temperature being kept below 10° C. The reaction mixture is stirred at room temperature. Stir for 18 hours and finally pour onto 1600 ml of saturated ammonium chloride aqueous solution.
The aqueous phase is extracted with ether, the organic phase is washed with saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated by evaporation. Oily ff1B! The products are separated by medium pressure chromatography.
rep) (trademark) 5160740g, 25-40
crm, eluent: acetic acid ethyl ester/n-hexane 1
: 5) Z-Leu "Val-0) which is the less polar component of the compound 'jM(XX■) having the desired configuration (S-configuration) on the carbon atom bonded to the isopropyl group
1 is obtained as a yellow oil.

RfC methylene chloride/methanol/water 500:10
: 1) =0.1 3, Rf (N6)
=0.58r)Z-Leu'SVal-NH
Me: Z-Leu “Val-OH500■, D
MF 10ml, HOBt245■ and DCCl33
The mixture consisting of 0Qr is left at 0°C for 24 hours. Add excess methylamine to this mixture and stir at 0° C. for 2 hours and at room temperature for 2 hours. The crystalline DCH is removed, concentrated and dried in high vacuum. The title compound is obtained from the residue by flash chromatography (elution subsystem N3) as a colorless oil. Rf (methylene chloride/ether 2:1)-0,45 g) Z-Leu'Val-NHMe: Z-L
eu” Val-NHMe 352 volumes were mixed with palladium on activated carbon (
Hydrogenate the reaction mixture to saturation at normal pressure and room temperature in the presence of 70% PdlO%) and 70% water at room temperature.
Stir with 5ml. After evaporating the solvent, the title compound is obtained as a colorless oil. Rf (B4)-0
, 08; Rf (S4)-0,27 (hereinafter referred to as phenylalanine)N(quinolyl-2-carbonyl)-L-ferL-3-3: A solution of 0.50 g of phenylalanine in iN caustic soda 3s+1 4.5+*l of IN caustic soda and 1l of methylene chloride at the same time for 10 minutes at 0°C.
Quinolyl-2-carboxylic acid chloride [quinaldic acid chloride, melting point 91-94°C, humming (D, L
, l1aau+1ck) l Dickinson (W,
P.

Dickinson), J, Che+++, S
oc, 1929% 214) 0.
Add 78 g dropwise. The mixture is stirred for 30 minutes at room temperature, then 7.5 ml of IN hydrochloric acid are added and extracted with acetic ester. Dry the extract over sodium sulfate and concentrate. The title compound crystallizes as a pale rose-colored powder with a melting point of 160-162°C from a mixture of methylene chloride and hexane.

Rr(Bll) Zero 0.25 In the same manner as in Example 1, N-(quinolyl-2-carbonyl)
-L-phenylalanine (Example 1h) 96■, DMF 5m
H-Leu''-Val-7-tert-butoxycarbonyl-n-hebutylamide 128 in l, HOBt
Flash chromatography (6035 g of silica gel, 4
0-63 μm, the title compound is obtained after generation by the dissolution system N3). Rf(NIO) 0.31 The starting material was Nidoxycarbonyl-hebutylamide 213, which was prepared as follows, which was hydrogenated in the same manner as in Example 1g in the presence of palladium-coated activated carbon (I0%>40). It can be obtained by: Rf(B2)
．． Example 1 using 13 Val-0) 1 162 w and 10.3 g of 8-aminooctanoic acid-jet-butyl ester.
Similarly, HOBt61■, 4-methylmorpholine 5
obtained by adding 3 μl and DCC1107■. Rf (N4) = 0.20c) 8-Amino-octane-tert-butyl ester Example 1 g of 8-benzyloxycarbonylaminooctane u-tert-butyl ester 1.5 g in 15 ml methanol
In the same manner as above, activated carbon with palladium (I0%) 0.1
Obtained as a colorless oil by hydrogenation with the addition of 0 g.

Rf (B3)-0,08 d) 8-benzyloxycarbonylaminooctane -
tert-Butyl ester: 2 g of 8-benzyloxycarbonylaminooctanoic acid in 12 m+1 of dioxane are reacted with 7.5 g of isobutylene in the presence of 1.2+ wl of sulfuric acid in an autoclave and left at room temperature for 48 h. .8 N ammonia aqueous solution 40n+
Add 1 to 0. Extract the reaction mixture with ether. The organic phase is washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and concentrated in vacuo. The title compound is obtained as a clear yellow oil. Rf (N8) =
0.44 or less margin e) 8-benzyloxycarbonylaminoocta7fi
:To 7 g of 9-amino-octanoic acid add 25a+1 of 2N sodium hydroxide solution.Then add benzyl chloroformate (50% in toluene) and 12.5 ml of 4N sodium hydroxide solution over 30 minutes simultaneously at about 0-5°C. Add. 150 o+1 ether and 60 ml water are added to the reaction mixture in which a voluminous white precipitate is observed. The aqueous phase is extracted with ether, ice is added and the pH is gradually brought to 2 with dilute aqueous HCI solution while stirring. The resulting suspension is extracted twice with acetic acid ester. The organic phases are combined, washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The title compound is obtained, melting point 63-64°C. Rf (Nl)-0,53N-(quinolyl-
2-carbonyl) -Phe-LeuLVal -7-
tart-butoxycarbonyl-n-hebutyramide (
Example 2) 124 ml and 2.5 ml of trifluoroacetic acid are stirred at room temperature for 10 minutes. The solution was concentrated and the residue was subjected to flash chromatography (6035 g of silica gel, 40~
63 μm, purified by eluent system B11). The fractions containing the product are concentrated by evaporation. After drying at 40° C. in high vacuum, the title compound is obtained as an amorphous powder. Rf(Bll)=0.30 indole-2
-Carboxylic acid 56■, H-Nle-Leu 1Val
-n-butyramide 140■ and 1IOBt54 [(
Fluka purum (containing 11-13% water) is cooled to 0° C. in 4 ml DMF. After adding DCCI95■, the mixture was stirred for 24 hours under water cooling and then for 2 days at room temperature. The crystalline DCH is passed through a suction port and the filtrate is concentrated in a high vacuum. The residue was dissolved in methanol/water/glacial acetic acid (94:3
: Stir in mixture 4a+1 consisting of 3) at 60° C. for 30 minutes and then concentrate. The residue is separated by flash chromatography (100 g of silica gel 60, 4
0-63 μm.

Eluent system N10), the fractions containing the product are concentrated by evaporation. The title compound is obtained from the residue as a white powder by crystallization from acetonitrile. Melting point 243-244°C, Rf(N14)-0,17 The starting material is prepared as follows: a) H
-Nle-Leu j-Val -n-butyramide:
Z-Nle-Leu 1Val -n-butyramide 1
The reaction mixture is hydrogenated in 10 ml of a 9:1 mixture of methanol/water in the presence of palladium-on-activated carbon (10% Pd) 3011 IIr at normal pressure and room temperature until saturation. After evaporation of the solvent, the residue is dried in high vacuum to obtain the title compound as a colorless oil. Rf
(B4) Density 0.41 “b) Z-Nl
e-Leu 1Val -n-butyramide: Z-Nle-Off 138 N as starting material, 6 ml DMF
H-Lau LVal-n-buty) Lt7mid 1
Purification by flash chromatography (100 g of silica gel 60, 40-63. crm, flow agent N3) analogously to Example 1 using 50 g, ) 10Bt80 and DCCI 140 gives the title compound. Rf (N3) =0.15c)
H-Leu-'Val-n-butyramide: Z-L
595 μg of eu”Vat-n-butyramide is hydrogenated to saturation in 40 ml of a 9:1 mixture of methanol/water in the presence of 100+ ng of palladium-on-activated carbon (PdlO%) at normal pressure and room temperature. , stir with 40 ml of water at room temperature. After evaporating the solvent,
The title compound is obtained as a pale yellowish oil. Rf (
Bl 1)-0,57; Rf (N4)-0,42 d) Z-Leu”Val-n-butyramide:
Z-Leu “Val-OH (Example 1e) 122.mg,
DMF 2mL HO8t60■ and DCCI 80■
The mixture was left at 0°C for 3 days. Add 120 ml of n-butylamine to the mixture with stirring, and add 2 ml of n-butylamine under water cooling.
Stir for 24 hours at room temperature. The crystalline DCH is aspirated and concentrated in high vacuum. Flash chromatography (6030 g of silica gel) from the residue.

40-63 μm, eluent N4) gives the title compound as a pale yellowish oil. Rf (N3) wing 0.5
2 The following was prepared analogously to Example 4: a) N-(indolyl-2-carbonyl) -Nle-Leu iV
Flash chromatography using at-NHMs, eluent NIO iRf (B4) -0,61:Rf
(N8)-0,46 b) N-(indolyl-2-carbonyl) -Nl
e-Leu LVal-isopropylamide, eluent N
Flash chromatography using 14; Rf(N
14) -0,11: Melting point 241-243°C c) N-(indolyl-2-carbonyl) -Nle-Leu ”-
Flash chromatography using Val-n-propylamide, eluent N14; Rf(N14)-0,1
4: Melting point 220-224°C d) N-(indolyl-2-
Carbonyl) -Nle-Lau LVal-2-hydroxyethylamide, flash chromatography using eluent NIO; Rf (84)-0,55: Melting point below 241-242°C Margin e) N-(indolyl-2-carbonyl) -Nle-
Leu'=Val-benzylamide, flash chromatography with eluent N3; Rf(NIO)=
0.35: Melting point 231-234°C f) N-(indolyl-2-carbonyl) -Nle-
Leu “Val-2-pyridylmethylamide; Rf(
BS) -0,23; Rf (B7) -0,4
6g) N-(indolyl-2-carbonyl) -Nle
-Leu LVal-1-hydroxy-2(S)-butylamit':Rf (B23)-0,243h)N-(
indolyl-2-carbonyl) -Nle-Leu'
-Val-ethylamide, flash chromatography using eluent N14; Rf(N14)=0.08:
Melting point 236-238°C 1) N-(indolyl-2-carbonyl) -Nle-
Leu "Val-2-(tert-butoxycarbonylamino)-ethylamide, flash chromatography using eluent NIO: Rf (NIO)-0°20: melting point 225-226°C below margin 1: N-(indolyl-2- carbonyl)-N-(indolyl-2-carbonyl)-Nle-Leu''-V
al-2-(tert-butoxycarbonylamino)-
Dithylamide (Example 5i) 30■ and trifluoroacetic acid 3
ml was stirred for 20 min at room temperature.The reaction solution was concentrated and the residue was purified by flash chromatography (silica gel 6035).
g, 40-63 μm sT separating agent system B8). The product-containing fractions are concentrated by evaporation.

From the residue, the title compound is obtained as a white lyophilizate by lyophilization in 5 to 1 liters of tert-butanol.

Rf(B11)-0,47 2-indolecarboxylic acid 25■, H-Phe-Leu
iVal-2-<3-carbamoyl-4-hydroxyphenoxy)-ethylamide 71■, HOBt23■ and DCCr4 (I■ are reacted as in Example 1, chromatography on system B7 gives the title compound a yellowish color. Obtained as a powder. Rf (Bl) = 0.2
7, Rf(B9)-0,46 starting material is
Produced as follows: Z-Phe-Leu”
Val-2-(3-carbamoyl-4-hydroxyphenoxy)-ethylamide 236 ml is obtained by hydrogenation analogously to Example 1g in the presence of 40 vg of active R with palladium (I0%). Rf (Nil)-
0,23Z-L-phenylalanine 113w, H-La
u -'Val-2-(3-Carbamoyl-4-hydroxyphenoxy)-ethyl Obtained analogously to Example 1, starting from JL/7 Mid 140111r and 58 ml of HOBt and after addition of 99 ml of DCCI. The product is converted into a system Nil
#il is prepared by flash chromatography at .

Rf (Nl 1) -0,39 c ) H-Leu 1Val-2-(3-carbamoyl-4-Leu included Val-2-(3-carbamoyl-4
-Hydroxyphenoxy)-ethylamide is obtained by hydrogenation in analogy to Example 1g in the presence of 40 g of activated carbon with palladium (I0%). System Bl
Purification by flash chromatography at R.
f (Bl 1) = 0.401Rf (Bl) Earthquake 0.1
5 Leu “2SVal-OH (Example 1e) 147■, 2-
(3-Carbamoyl-4-hydroxyphenoxy)-ethylamine (J, Mad, Chew, 27183
Obtained analogously to Example 1, starting from 107 g (page 1 (I984)) and 61 ■ of HOBt and adding 97 ■ of DCCI. The product is purified by flash chromatography on Nil system. Rf (Nl 1)-0,
38; Rf (b7) −0,46 or less margin flu: N-(indolyl-2-carbonyl)-indole-2-carboxylic acid 29■, H-His-Leu”
-Val -n-butyramide 75■ and HOBt27
N (Fluka purum, containing 11-13% water) is cooled to 0<0>C in DMFZml. DCCI4
After adding 8 stomachs, it was kept under water cooling for 24 hours, then at room temperature for 2 hours.
Stir for a day. The crystalline DCH is passed through a suction port and the filtrate is concentrated in a high vacuum. The residue was dissolved in methanol/water/glacial acetic acid (94%
: 3 : 6 at 60°C in 2al of a mixture consisting of 3)
Stir for 0 min, then concentrate. The residue is separated by flash chromatography (silica gel 60 100
g, 40-63 μm.

Eluent system B23) The product-containing fraction is concentrated by evaporation. The title compound is obtained from the residue by lyophilization in 6 ml of tert-butanol as a white lyophilized product. Rf (B4)-0,40 The starting material is a secondary lower margin produced as follows a) H-His-Leu "Val -n-butyramide: Z-His-Lau 1Val -n-butyramide 98 Akebono a 9:1 mixture of methanol/water 10a+
The reaction mixture is hydrogenated in the presence of 20 V of palladium-coated activated carbon (Pd 10%) at normal pressure and room temperature in No. 1 to saturation. After evaporation of the solvent, the residue was dried in high vacuum to give the title compound as a pale yellowish oil.
Rf (B 11) -0,39b) Z-His
-Leu '-Val -n-butyramide: Z-His-01172at as starting material, H-Leu 'Val -n-butyramide 72■ in DMF3al, H
Purification by flash chromatography (100 g of silica gel 60, 40-63 pm, eluent B23) analogously to Example 1 using OB L38■ and DCCI 68■ gives the title compound. Rf
(84)-0,46 ■Work: The following was produced in the same manner as in Example 8.

a) N-(indolyl-2-carbonyl) -Hls-
Leu 1Val-NH? Ie, flash chromatography using eluent B8, Rf (54) = 0.
60: Rf (B4) = 0.27 b) N-(indolyl-2-carbonyl) -Hls-
Flash chromatography using Leu 1 Val-benzylamide, eluent B23; Rr (B4
) = 0.36 c) N-(indolyl-2-carbonyl) -Hls-
Leu 1Val-isoamylamide, flash chromatography using eluent B23, Rf(B4)-
0,48 d) N-(indolyl-2-carbonyl) -Hls-
Flash chromatography using Leu”-Val-cyclopropylmethylamide, eluent B23; R
f (B4)-0,39 N-benzyl-indole-2-carboxylic acid 29■, H
-His-Leu”-Val-NHMe40 mir
, HOBt18■ and DCCI28■ as DMFl,
Stir in 5*1 at room temperature for 1.5 days. After evaporating the solvent in high vacuum, the residue was dissolved in methanol/water/glacial acetic acid (9
4:3:3) mixture 4011 at 60° C. for 1 hour. After evaporation to dryness, medium pressure chromatography (Lobar™ pre-prepared column, size B, particle size 40-60 μm, Merck NILQ4Q1,
Eluent B8) gives the product as a colorless amorphous powder. The Rf (B24)-0,4 starting material is prepared in the following manner: a) N-benzyl-indole-
2-Carvone can be prepared from the corresponding ethyl ester [for the production, see Synthesis,
738] by treatment with 2 ml of IN NaOH in 2 ml of THF for 2 days at room temperature.

After adding 2 ml of NHCl, evaporate to dryness, shaken between ether and water, dry the organic phase and separate the crude product obtained after evaporation by medium pressure chromatography (Lobar column, Merck 11h
10401, eluent acetate/n-hexane 1:
19), Rf (N4)-0,03; I H-NMR
(TMS, DMSO-d@) = L lppm (L
H), 7.7 (d, LH), 7.54
(d, IH), 7.34-7.0 (8H)
, 5.9 (s, 2H)b) H-)1is-L
eu! -Vat-NHMe is Z4is-LeuA1
7al-NHMe410 try on activated carbon with palladium (I0%) 50I! in 20++1 of a (95:5) mixture of methanol and water! Obtained by hydrogenation at room temperature for 4 hours with absorption of CO2 at normal pressure in the presence of 1 g. ' After removing the medium and concentrating and drying by evaporation,
When lyophilized from tert-butanol, the product is obtained as an amorphous powder, Rr (B24)
-0,09c) Z-His-Leu i-Vat-
NHMe: Z-His-OH326N, )1-Le
u”Val-NHMe250 ag and) lOBt1
72 [274 g of DCCI in 7 ml of DMF at water bath temperature.
Add.

This is stirred at 0° C. overnight and then at room temperature for 24 hours. After evaporation of the solvent, the residue was dissolved in methanol/water/glacial acetic acid (9
Stir in 5 ml of a mixture of 4:3:3) at 60°C for 1 hour. The solvent mixture is evaporated in vacuo and the product is obtained as an amorphous powder by medium pressure chromatography (Lobar™ finished column, size B, Merck k10401, eluent B7). R
f (B8) dust 0.35! IL: The following compounds were prepared analogously to Example 10: a) N-(2-(N-bendi)Lt-o,o''-dichloroanilinogophenylacetyl) -Hls-Leu
-G'-Val-NHMe, Rf (N8)
= 0.35b) N-(quinolyl-2-carbonyl)
-Hls-Leu''-Val-NHMe, iFlashk O?Thornfy using release agent B4; Rf
(B4)=0.31c) N-oxamoyl-former 5-Le
Flash chromatography using u-'Val-NHMe, eluent B4: RE (B4)-0,27 2 (R,S") -(α-naphthylmethyl)-succinic acid 1-benzyl ester as starting material 40. Flash chromatography (100 g of silica gel 60, 40-63 μm, elution system B25) as in Example 10 using H-His-Leu-'Val-NHMe44 gives the title compound as a white solid. .Rf (B4) -0,30;Rf (S1
2) = 0.40 The starting materials are prepared as follows: toluene 5
α-naphthylmethyl-succinic anhydride in 1 (for the preparation, J. Chew, Soc, 1956.35
A solution of 480.5 mm and 216.3 mm of benzyl alcohol is boiled for 6 z hours and then concentrated by evaporation. The residue was dissolved in 10 ml of diisopropyl ether, 362 ml of dicyclohexylamine was added, and the whole was stirred overnight. The resulting white crystals of dicyclohexylammonium salt are separated into three portions and recrystallized from diisopropyl ether.

Melting point 120 DEG -122 DEG C., the mother liquor is used for the preparation of the isomeric 4-benzyl ester (Example 13a).

The recrystallized dicyclohexylammonium salt was dissolved in THFl.
0 ml, acidified with 0.5 Ill IN HCI, filtered, concentrated by evaporation, then dissolved in 20+++1 toluene, filtered, concentrated again by evaporation. Crystallization of the residue from cyclohexanone yields the title compound as white needles.

Melting point 122-124°C; Rf (513)-0,30
As starting materials, 2 (R,S)-(α-naphthylmethyl)-succinic acid-4-benzyl ester 36 and H-
His-Lau'-Val-NHMe3B,5
Flash chromatography in system B25 analogously to Example 10 using 1 gives the title compound as a white solid. Rf (B4)-0,40;
The Rf(S 12) -0,51 starting material is prepared as follows: the mother liquor of the dicyclohexylammonium salt of Example 12a is evaporated.
4, dissolved in THFlOml, IN HCl
Acidify with 1.5 ml, sip, and concentrate by evaporation. The residue is dissolved in ether, washed with INI (CI) and brine, dried over Na2SO4 and concentrated by evaporation to give the title compound as a colorless oil.

R(313)-0,30 indole-2-carboxylic acid 3
9■, H-Leu-Leu-'Val-NHMe 7
DM 8 N, [1OBt37N and DCCI5!3g
Stir in 5 ml of Fl at room temperature for 2 days.

After evaporation of the solvent in high vacuum, medium pressure chromatography (Lobar™ column,
Size B1 Merck 10401, eluent B26) gives the product as an amorphous powder. Rf (B24)
-0,53 The starting material is produced as follows =a))
I-Leu-Leu “Val-NHMe is Z-Le
15 ffg of u-Leu iVal-NHMel was evaporated with CO2 at normal pressure in 10 ml of a mixture of methanol and water (95:5) in the presence of 40 μ of activated carbon with palladium (I0%).
It is obtained by hydrogenation at room temperature for 5 hours while absorbing. After removing the catalyst and concentrating to dryness by evaporation,
The product is obtained as an amorphous powder. Rf (Bll
)-0,8 b) Z-Leu-Leu j-Val-NHMe
: Z-Leu-OH (dicyclohexylammonium salt) 151 N, H-Leu -'Val-NH
To 75 qr Me and 52 g HOBt are added 82 ■ DCCr in 3 ml DMF at water bath temperature. This is stirred for 8 hours in a water bath and then for 10 hours at room temperature. After evaporation of the solvent in a high vacuum, the product is obtained as an amorphous powder by medium pressure chromatography (Lobar column, Merck 10401, eluent B8).

Rf (B27)-0,38 Example 15: The following compound was prepared similarly to Example 14: a) N-(indolyl-2-carbonyl) -Cha-
Leu iVal-NHMex Rf (B 24)
-0,56b)N-(indolyl-2-carbonyl)
-Gln-Leu 'LVal-NHMeSRf
(B 9 ) -0,23c)N-(N-(indolyl-2-carbonyl)-L-threo-β-phenylseryl) Leu "Va1-NHMe, Rf (B
8) =0.47H-)1is-Cha-'Va
l-NHMe 98.6 n, indole-2-carboxylic acid 37.7 rrgSHOBt 35.8 mg, DC
A mixture consisting of Cl 63,9■ and DMF 5.2+*I is stirred at room temperature for 50 hours. Crystalline DCH is divided by day,
Oral speech is concentrated by evaporation. The crude product was purified by flash chromatography (110 g of silica gel 60, 40-6
3 μm, purified by flow agent B4). Concentration of the combined product-containing fractions by evaporation gives the title compound.

Rf (b4) = 0.22 The starting material is prepared as follows: a) H
-His-Cha -'Val-NHMe: Z-H
130 g of is-Cha"Val-NHMe are hydrogenated in a 9:1 mixture of methanol/water 5+*1 in the presence of 20 μm of palladium on activated carbon (10% Pd) at normal pressure and room temperature until saturation.

The reaction mixture is passed through the mouth and stirred with 5 ml of water at room temperature. After evaporating the solvent, the title compound is obtained as a colorless oil. Rf (Bl 1) =0.38b
) Z-His-Cha LVal-NHMe: H
-Cha -1&-Val-Nl1Me150.8w,
DMF 6+aL HOBt81. L K, Z-)1
The mixture consisting of is-0) 1153.3■ and DCC1144,2■ is stirred at room temperature for 48 hours. Separate the DCH, concentrate and dry in high vacuum. The residue was subjected to flash chromatography (silica gel 60145 g,
The title compound is obtained by concentrating the combined product anastomoses by evaporation of the fractions separated by 40-63 μm, eluent B23). Rf (B4)
-0,35;Rf (S4)-0,65 H-Cha"Vat-NHMe is prepared analogously to the reaction scheme shown in Example 1: SAT!2 (S)-Benzyloxycarbonylamino- 3-cyclohexylpropion M (Manufacturing: Helvety force, °
Helvetica Chimica
Acta) 57.2131 (I974)) 243g
The reaction mixture, previously taken up in 600 ml of toluene and 900 ml of ethanol, is cooled to 0° C. and 88.3 g of thionyl chloride are added dropwise within 30 minutes. Cooling is stopped and removed and the reaction mixture is stirred for 18 hours.

Pass the reaction mixture and concentrate. The residue was subjected to flash chromatography (silica gel 60 2 kg, 40
~63 um, separated by eluent N5). The product-containing fractions are combined, concentrated by evaporation and dried in a high vacuum. The title compound is obtained as a pale yellowish oil. Rf (N5) −0,2, Rf (Nl 5) −
0,522(S)-benzyloxycarbonylamino-
3-Cyclohexylpropionic acid ethyl ester 116
, 1 g in 2.21 g of toluene and cooled to -65°C. 836 ml of diisobutylaluminum hydride are added dropwise within 30 minutes at -65°C and the mixture is stirred for a further 30 minutes. Then 84.2 ml of methanol is added at -65°C.
Add dropwise within 0 minutes and then without cooling 825 ml of aqueous potassium sodium tartrate solution. The reaction mixture is poured onto 31 parts of aqueous potassium sodium tartrate solution/ice and extracted with 5 parts of ether. ether phase with water 21
and then immediately poured into a solution consisting of 1106 g of semicarbazide hydrochloric acid and 156.5 g of sodium acetate in 620 ml of water and 620 ml of ethanol.

The reaction mixture is stirred for a further 1 hour at room temperature, then separated in a separatory funnel and the aqueous phase is extracted twice with 1.51 g of ether each time. The organic phase is dried over magnesium sulphate and concentrated by evaporation. The crude product is purified by flash chromatography (silica gel 60'2ksr, 40-63 μm 1 eluent N3).

The semicarbazone of the title compound is obtained by concentrating the combined product-containing fractions by evaporation.

Rf (N8)-0,51, this semicarbazone 13
0 g was dissolved in THFIl, 28·2 ml of 37% formaldehyde solution and then 0.5 N HCl at 10°C.
Add 143 g 1 liter of water.The reaction mixture was stirred at room temperature for 2 hours, filtered, and 0.51 g of water added. , NaHCO3
Wash with 0.51- and water 0.51-. The aqueous phase is extracted with 600 IIll of ether. The ether phase is dried over magnesium sulfate and concentrated by evaporation. 100 ml of toluene is added to the residue and the mixture is condensed by evaporation to give the title compound. This will be processed further immediately.

18.9 g of a sodium hydride dispersion (55% in oil) were dissolved in petroleum ether (
The oil is removed by stirring three times in 50 ml (boiling point 40 DEG -60 DEG C.) and decanting the solvent each time. After drying in a high vacuum a gray powder is obtained. Put this in 500 ml of THF and add 55.6 ml of trimethylsulfoxonium iosite.
When g is added, the temperature rises to about 40°C. The gray suspension was boiled for 1 hour with a reflux condenser, then heated at -70°C for 5 hours.
A solution of 108.6 g of 2 (S)-benzyloxycarbonylamino-3-cyclohexylpropanal in 250 ml of THF is added within 0 minutes. The yellow suspension is stirred at 0° C. for 2 hours. The yellowish, cloudy solution is poured onto 500 g of ice, the aqueous solution is extracted with 2.5 g of ether, the organic phase is washed with water and sulfuric acid). After drying over IJum, it is concentrated by evaporation. Flash chromatography (
Silica gel 602.5mm, 40-63μm, eluent N4
) to separate. The product-containing fractions are combined, concentrated by evaporation and dried in a high vacuum. The title compound (diastereomeric mixture, approximately 4:1) is obtained as a pale yellowish oil.7 Rr (N16) = 0.71
, Rf (N4) -0,16(I(S)-benzyloxycarbonylamino-2-cyclohexylethyl)-oxirane 42.3 g was dissolved in acetonitrile 200
(1) and cool the resulting solution to 0°C. After addition of 20.9 g of sodium iodide, 17.7 ml of trimethylchlorosilane are added in 30 minutes at 0°C. The mixture is stirred for 40 minutes at 0-3 DEG C. and then poured onto 700 ml of ice-cold water, the aqueous mixture is extracted with ether and the organic phase is washed with 750 ml of 5% aqueous sodium thiosulfate solution and 750+ ml of saturated aqueous sodium chloride solution. After drying over sodium sulfate and concentration by evaporation, an oily mixture of the title compound is obtained, which is directly worked up further.

49.3 g of the compound of example 16f) and 1.07 g of p-)luenesulfonic acid monohydrate are stirred in 140 ml of 2,2-dimethoxypropane and 450 m+1 methylene chloride at room temperature for 3 hours. Add 1 part of methylene chloride to the mixture! and 500 μl of saturated aqueous sodium bicarbonate solution.

The organic phase is washed with water, dried over sodium sulfate and concentrated by evaporation. The crude product is purified by Franch chromatography (3 kg of silica gel 60,
40-63 pm.

Eluent N17), the combined product-containing fractions are concentrated by evaporation to give the title compound as a pale yellowish oil. Rf (N4) = 0.55; Rf (N17
) 10.46 Diisopropylamine 14.3 1 is dissolved in 200 ml of anhydrous tetrahydrofuran under argon and cooled to 0° C. Then, at 0-5° C., this mixture is dissolved in n-butyllithium in hexane. 65.8g+ of 1.6M solution of
Add 1 dropwise over 20 minutes and stir for 20 minutes. Next, -7
Isovaleric acid methyl ester 13.3m at 0℃~-75℃
1 is added dropwise and the mixture is stirred at -75° C. for 1.5 hours.

Hexamethylphosphoric acid triamide 320a+1 is added dropwise with stirring at -60°C to -75°C. The resulting suspension is stirred for 10 minutes and finally a solution of 43.4 g of the compound of Example 16) in 110 ml of tetrahydrofuran at -70°C to -75°C is added dropwise over 5 minutes.The reaction mixture is stirred at room temperature for 2 hours. Stir for .5 hours and finally pour onto a mixture of 11 ml of saturated aqueous ammonium chloride solution and 500 g of water, extract the aqueous phase with 21 ml of acetic ester, wash the organic phase with water and dry over sodium sulfate. After concentration by evaporation, a diastereomeric mixture of the title compound is obtained as a yellow oil. Rf (N
4) -0,36; Rf (N5) = 0.21 (value for the less polar component).

To 16.5 g of potassium tert-butoxide in 250 ml of ether are added at about 5 DEG C. 1.77 a+1 of water.

The white suspension is stirred for a further 10 minutes in a water bath, then 35.8 g of the compound of example 16h) (diastereomeric mixture) in 250 nl of ether are added and the reaction mixture is stirred, keeping the temperature below 10 °C. Stir for 18 hours at room temperature and finally pour onto 500 ml of saturated aqueous ammonium chloride solution, extract the aqueous phase with acetic acid ester and saturated the organic phase) IJ
The solution is washed with an aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to 14 m.

The oily crude product is separated by flash chromatography (2.5 kg of silica gel 60, 40-63.crm; eluent N4). Z-ChaQgVal, the less polar component of the title compound, where the carbon atom attached to the isopropyl group is in the desired configuration IE (S-configuration)
-011 is obtained as a yellow oil. Rf (N16)
=0.20; Rf (N5n -0,35j
) Z-Cha “Val-NHMe: Z-Cha
“Val-OH311,9■, DMF6.4s+l,
HOBtl 38.2+n+r and DCC1186,
The mixture consisting of 1N is left at o'c for 24 hours. Add excess methylamine to the mixture and stir at 0° C. for 2 hours and at room temperature for 2 hours. The crystalline DCH is separated daily, concentrated and dried in a high vacuum.

The residue was subjected to flash chromatography (eluent system N3
) gives the title compound as a colorless oil.
Rf (N3) -0,45k) H-Cha
”Val-NHMe: Z-Cha 'aVal-N
HMe 243■ in a 9:1 mixture of methanol/water IC
Activated carbon with palladium (Pd10%) 5ON in 1+1
The reaction mixture is hydrogenated to saturation at normal pressure and room temperature in the presence of water, and the solution is stirred with water at room temperature. After evaporating the solvent, the title compound is obtained as a colorless oil. Rf (B4) −0,111Rf(N
4) = 0.31 21.4 ■ (R,S)-acetoxy-3-α-naphthylpropionic acid in 1.5 ml of anhydrous DMF, H-old 5
-Leu 1Val -n-butyramide 35 and H
To a solution of OBt l 2.7 rN at 0 °C, add 22.2 qr DCCI while stirring. Bring the reaction mixture to 0.
The solution was stirred for 12 hours at ℃ and then for 48 hours at room temperature.
It is kept at 60° C. for 60 minutes in 2 il of a mixture consisting of glacial acetic acid (94:3:3). The solution is then concentrated by evaporation on a rotary evaporator, briefly dried in a high vacuum and the residue thus obtained is chromatographed on silica gel using solvent system 82B to give the title compound as white crystals. Rf(I34) richness 0.415 The starting material is prepared as follows: a>2
(R,S)-acetoxy-3-α-naphthylfurohionic acid: 2-hydroxy-3-α-naphthylfurohionic acid 0
．． A mixture of 21 g and 0.2 ml of acetyl chloride is stirred at room temperature for 40 minutes and then concentrated by evaporation at below 50° C. in a rotary evaporator.

The remaining title compound is dried in high vacuum at 40'C over potassium carbonate for 16 hours. Rf(N18)=0.
6 3 b) 2-Hydroxy-3-α-naphthylpropio”: A solution of 1.4 g of 2-bromo-3-α-naphthylpropion a and 1.4 g of calcium carbonate in 14 μl of water was added with a reflux device. Boil for 10 hours, cool, adjust to pH 2 with 2N hydrochloric acid, and extract with acetic ester. The organic phase is dried over sodium sulphate and concentrated by evaporation. The residue gives the crystalline title compound by chromatography on silica gel with the eluent N21. Rf
(N18)=0.5 c) 2-bromo-3-α-methylpropionacetone 1
To a solution of 10 g of α-naphthylamine in 0 (I+1) was added 39.2 lIl of 95HBr with stirring at room temperature and then 17.4 ml of 4N aqueous sodium nitrite solution at 0-5°C.
Then, quickly add 70 ml of acrylic d and add 0.4 g of copper(I) bromide.

The reaction mixture was adjusted to pH 3 at 60°C with approximately 30 g of sodium acetate.
The mixture was further stirred at 70° C. for 90 minutes, and then concentrated by evaporation in a rotary oven. The residue is dissolved in acetic ester and extracted four times with sodium bicarbonate solution.The bicarbonate extract is made acidic with hydrochloric acid and extracted with acetic ester. The organic phase was washed with water and brine, dried over sodium sulfate,
Concentrate by evaporation. The residue was dissolved in toluene/acetate (
9:1) on silica gel to give the title compound as brownish crystals. Rf
(Nl 9) -0,25 or less attempted example 18: N-(4-(2-benzofuranyl)-24-
(2-Benzofuranyl)-2(R,S)-benzyl-4
-Oxobutyric acid 50■, H-His-Leu 1Val-
n-butylamide 50mg, HOBt25ff and DC
The title compound is obtained analogously to Example 17 from CI22■. This is purified by flash chromatography using solvent system B7. Rf(B7)=0.30 The starting material is 2-carponylmenyl)-benzylmalonic acid diethyl ester 2 prepared as follows.
．． Dissolve 0g in 10+ml of ethanol and add 10ml of water and 7.4ml of 2N caustic soda in sequence at room temperature. After stirring at room temperature for 16 hours, the mixture was acidified to pH 3 with INMCI.
Extract with methylene chloride. ! ! When compressed, the melting point is 154℃
The crude diacid crystallizes.

This is decarboxylated in a round bottom flask at a temperature of 170°C.

After cooling the melt, crystallization from acetate/hexane yields the title compound in pure form, melting point 170-171°C. Rf(N12)-0,63 5.0 g of benzylmalonic acid diethyl ester are added to a suspension of 870 μl of sodium hydride in 25 ml of DMF at room temperature. After 20 minutes, add bromomethyl-2-benzofuranyl ketone (Liebigs
Ann, Chew, 312.332 (I900)
(manufactured by) 4.78g.

After stirring for 2 hours at room temperature, pour onto ice and IN IIcI and extract with methylene chloride. The crude product was purified by flash chromatography on 260 g of silica gel using methylene chloride as eluent.
The title compound is obtained as an oil. Rr (CH2
CI2) = 0.23 Example 19: N-(4-cyano-2
(R,S)-α-naphthylmethylbutyryl) -Hls
-Leu 1Val-n -butylamide 4-cyano-2(R,S) -re-naphthylmethyl acid M21. (]+r,H-)1is-Leu LVal-
The title compound is obtained analogously to Example 17 from 35.0 ■ of n-butylamide, 117 ■ of HOBt and 22.2 ■ of DCCI. This is purified by flash chromatography using solvent system B3. Rf (B4)-
0,46 (slower diastereomer).

The starting material is prepared as follows: a) 4-cyano-2(R,S)-α-naphthylme9 2D M F
2-cyanoethylmalonic acid diethyl ester in a suspension of 0.48 g of sodium hydride in 25 ml.
The reaction mixture is stirred for 2 hours at 80° C. and then 1.77 g of α-cyanomethylnaphthalene in 5 ml of DMF are added at room temperature. The mixture was further heated at 50°C for 16
Stir for an hour and concentrate by evaporation. The residue is dissolved in acetic acid ester, washed with 0.1N hydrochloric acid and water, dried over sodium sulfate and concentrated by evaporation, leaving 2-cyanoethyl-α-naphthylmethylmalonic acid diethyl ester.

7.2 g of this intermediate product was mixed with 036 ml of DMS and 360 ml of water.
The reaction mixture was stirred at 180 °C for 3 h in μl and 1.73 g of lithium chloride by evaporation in a high vacuum.
I4 condensation, the residue is dissolved in acetate, washed with water and brine, dried over sodium sulfate and concentrated by evaporation to give 4-cyano-2(RlS)-α-naphthylmethylbutyric acid ethyl ester. .

For hydrolysis, 0.45 g of this ester was heated at 35° C. in 7 ml methanol and 1.8 n+1 IN caustic soda.
Stir for 16 hours. The reaction mixture was then concentrated by evaporation and the residue was dissolved in water and washed with ethyl acetate, 2N
Acidify with sulfuric acid and extract with ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulfate,
Concentration by evaporation gives the title compound as a yellow oil.

2 (R,S)-cyanomethyl-α-naphthylpropionic acid 19.9 N,H-His-Leu”-Val-
Analogously to Example 17, the title compound is obtained in the form of a diastereomeric mixture from 35.0 .mu. of n-butylamide, 12.7 .mu. of HOBt and 22.2 .mu. of DCCI. This is separated by flash chromatography using solvent system B28. Rf (B4)-0,46 (faster diastereomer): Rf (B4)-0,46 (slower diastereomer).

The starting material is 20MF50 produced as follows.
To a stirred suspension of 44 g of sodium hydride dispersion in a+1 is added 3.0 g of α-naphthylmethylmalonic acid diethyl ester. The reaction mixture is stirred at 50 °C for 1 h and then evaporated in a high vacuum. The residue was dissolved in ethyl acetate and diluted with 0. Wash with IN hydrochloric acid and water,
Dry over sodium sulfate, concentrate by evaporation and chromatography on silica gel with toluene to obtain M.
When prepared, cyanmethyl-(α-naphthylmethyl)-malonic acid diethyl ester Kasyl.

This malonic ester is hydrolyzed and decarboxylated analogously to Example 19a) and the resulting 2 (R,S)-cyanomethyl-3-α-naphthylpropionic acid ethyl ester is chromatographed using the solvent system N4. Purified sodium hydroxide in methanol? Hydrolysis with 87 & gives the title compound in the form of a yellowish oil.

N-benzyloxycarbonyl-p-benzyloxycarbonylamino-phenylalanine 58q, H-former 5-Leu 1Val-n-butylamide 50■, HO
The title compound is prepared analogously to Example 17 from Bt20nv and DCCI 32N and purified by flash chromatography using solvent system B31.6. Rr
(B8) = 0.51 The starting material is prepared as follows: a) N-benzyloxycarbonyl--benzie: p-amino-phenylalanine [Bache AG] , 31.01 g of Bubendorf in the form of its sodium salt are taken up in 6 l of water. Then, while cooling in a water bath, 3.35 ml of benzyl chloroformate (50% in toluene) and 2 N
Add 5 ml of NaOH at the same time and stir the whole thing for 20 minutes. The white suspension is adjusted to p)11 with 2N HCI, extracted with ethyl acetate, the organic phase is dried over sodium sulfate and evaporated to:Iri'N.

The residue is purified by flash chromatography using the solvent system Bll. The eluent is acidified with 2N) ICI, extracted with ethyl acetate, the extract is dried and concentrated by evaporation to give the title compound in the form of white crystals. Rf
(Bl 1) -0,22butylamide N-pivaloyl-p-benzyloxycarbonylamino-phenylalanine 52■, H-His-Leu
'-Val-n-butyramide 50■, HOBt20g
The title compound is prepared analogously to Example 17 from and DCCI 32■ and purified by flash chromatography using solvent system B31.

Rf (B8)-0,41 The starting material is prepared as follows: 2.22 g of N-pivaloyl p-amino-phenylalanine.
into 4 ml of 2N NaOH and 5 ml of water. While cooling in a water bath, chloroformic acid benzyl ester 1.3 m
1 and 4 N NaOH 2,1 + sl simultaneously. The M suspension is then stirred for 30 min and adjusted to pH 1 with concentrated HCI. Extracted with ethyl acetate, washed with water, dried,
Evaporation of the solvent in vacuo produces beige crystals. IH-NMR (DMSO-ds, TMS): 1
．． Oppm (s, 9H); 2.9-3.0 (d
d, 2H); 4.4 (m, LH)
;5.15 (s, 2H) ;5.72 (
s, 2H) Near, 1(d, L H):
7.3-7.5 (m, 5H); 1
4.6 (s, IH).

b) N-pivaloyl-amino-phenylalanine: 2.73 g of N-pivaloyl-p-nitro-phenylalanine in methanol 5 (Iwl) 270 μg of activated carbon with palladium (Pd 10%) at total atmospheric pressure and room temperature. Hydrogenate for 20 minutes in the presence of hydrogen. Remove the catalyst and concentrate to dryness by evaporation to give the title compound in the form of a pink-red powder. I H-NMR (DMSo-d@, TMS
): 1.0 5ppm (s, 9
H); 2.8-2.95 (m, 2H): 4.
2-4.5 (m.

IH): 6.45 (d, 2H); 6.9 (d, 2H
25 (d, IH) 2.0 g of p-nitro-phenylalanine (Bachem AG, Bubendorf) was dissolved in 5 ml of 2 N NaOH and THF2+il and diluted with toluene 1 at 10-15°C.
．． 1.2 ml pivaloyl chloride and 4NNa in 3a+1
2.4 ml of OH are added simultaneously.The whole is then stirred for 1 hour at room temperature and then adjusted to pH 1 with concentrated hydrochloric acid.

The aqueous phase is extracted with ethyl acetate, the organic phase is dried and concentrated by evaporation, yielding the title compound in the form of a yellowish powder. Rf (N20) , -0,23±Y'' Example 17
The following compounds were prepared in the same manner as: a) N-(2(R)- and 2(s)-hydroxy-3-
α-naphthylpropionyl) -Hls-Leu ”-
Diastereomer separation by flash chromatography using Val-n-butyramide, solvent system B30; Rf (B4) = 0.43 (slower diastereomer) and Rf (B4) - 0,49 (faster diastereomers).

b) N-(3-α-naphthylpropionyl)-His-
Flash chromatography using Leu 1Val-n-butyramide, eluent 82B; Rf(B4)-
0,41゜c) N-(quinolyl-2-carbonyl) -Hls-L
eu'-Val-n-butyramide, pre-produced on Lobar™ using eluent B31! i
Medium pressure chromatography using the prepared column, Rf (B8
)-0,64 d)N-(β-naphthylcarbonyl)-)lis-L
eu”-Val-n-butyramide, flash chromatography using eluent B31, Rf (B8)
-0,60 e)N-(I-naphthoxyacetyl)-)1is-L
flash chromatography using euiVal-n-butyramide, eluent B23; Rf (B4)-
0,49 f”) N-(2(R,S)-benzyl-5,5-dimethyl-4-oxohexanoyl) -1(is-Lau
'-Val-n-butyramide: Rf (B7)-
The 0.33° starting material was described in Example 25a.

2 (R,S)-acetoxy-3-α-naphthylpropionic acid 30 rNISH-His-Cha “Val-
n-butylamide 54■, HOBt 17.8■ and D
The title compound is prepared analogously to Example 17 from CCI 31■ and purified by flash chromatography using solvent system 828. The Rf (B4) -0,5 starting material is prepared as follows: a) H-
His-Cha jL-Val-n-butyramide is
Similarly to Example 16a, Z-His-Cha”-Val
- 1.6 g of n-butylamide was added to palladium-coated activated carbon (
It is obtained by hydrogenation in the presence of I0%) 200 μm. Rf (B4) = 0.05: Rf (B
4) Snow 0.16 b) Z-old 5-Cha LVal-n-butyramide was prepared as in Example 16b with 1.75 g of Z-His-OH.
, H-Cha”-Val-n-butyramide 1.9
The title compound is prepared from 7 g of HOBt, 930 mg of HOBt and 62 g of DCCll and purified by flash chromatography using solvent system B4. Melting point 208~2
10℃, Rf (B4) 0.49; Rf (34)
-0,62c) H-Cha 1Val-n-butyramide was prepared in the same manner as in Example 16 to prepare Z-Cha "Va"
Obtained by hydrogenating 4.2 g of l-n-butylamide in the presence of 500 μg of palladium-coated activated carbon (I0%). Rf (B4) = 0.25 d) Z-Cha MVal-n-butyramide is
Similarly to Example 16j, Z-Cha “Val-Of4
4.01 g, n-butylamine 2.68 g,
Obtained from 80 g of HOBtl and 41 g of DCC12 and purified by flash chromatography using the solvent system N4.

Rf (N3) -0,61 2(R,5)-12(R)- and 2(S)-benzyl-
5,5-dimethyl-4-oxohexanoic acid 40 each
ffv. Rf (B5)-Q, 24 ; Rr (
B7) =0.35 <both diastereomers) The starting materials are prepared in the following manner: Examples 18a and 1
Analogously to 8b, the title compound is obtained from 5.0 g of benzylmalonic acid diethyl ester, 870 g of sodium hydroxide and 3.58 g of bromomethyl-tert-butyl ketone in DMF. Melting point 94-95℃, Rf
(Nl 1) -0,56 Racemic compound 9 from example 25a
1400*, 2(S)-amino-3-phenylpropanol (L-7 enylalaninol) 370■, HOBt
272■ and DCCI 500■ are reacted as in Example 1.

The diastereomers are separated by flash chromatography using the solvent system N3. Rf(N3)-0,2
3 (faster diastereomer) and Rt (N3)
-0,17 (slower diastereomer) -#u/
2N HCI (D1:1a compound and 8Q℃
The phenylalaninol group is again removed by boiling at .

α-Naphthylmethylmalonic acid monoethyl ester 42■
, H-His-Cha J&-Val-n-butyramide 60μ, HOBt26g and DCCI40q Example 2
The title compound is prepared analogously to 4 and purified by flash chromatography using solvent system B5.

R((BS)-0,22iRf (B7)-0,36 The starting material is prepared in the following way: a) α-naphthylmethylmalonate monoethyl varnish base: 50 ml of a 1:1 mixture of water and ethanol α dissolved in
-naphthylmethylmalonic acid diethyl ester CJ,
8m, Chew, Soc, 6 2
, 2335 (I940)) to 5.0g
Add 6.5 ml of NaOHl. After 30 minutes at room temperature,
Hydrolysis is complete. 16.5 ml of 1N HCl are added to the reaction mixture and extracted with methylene chloride. The extract is concentrated by evaporation and the residue is purified by Franche chromatography using the solvent system Nil. Rf (Nl
1) = 0.35; Rf (N7) = 0.25 Ecyclohebuta (b) pyrrole-5-carboxylic acid 37,
! The title compound was prepared analogously to Example 24 from -His-Cha J&-Val-n-butyramide 60■, HOBt32■ and DCCI 48■, in solvent system B7.
Purify by Fransch chromatography using Rf (B7) 0.35 The starting material is secondary lower margin a) cyclohebuta[b]pyrrole-5-carvone-monocyclohebuta[b]pyrrole-5-carvone produced by the following method. 260 Qr of acid nitrile are boiled under reflux for 24 hours in 16 l of a 1:1 mixture of ethanol and ION sodium hydroxide solution. The whole is then acidified with concentrated hydrochloric acid, extracted with methylene chloride, and the extract is evaporated. Rf (Bl
l)-0,18; Rf(N12)-0,55 cyclohebuta(b)pyrrole (Helv, Chill
.

Acta67.1647 (manufactured by I984) 8
00■ in 1.1 ml of oxalyl chloride in 40 sl of DMF
Add it little by little to the solution at 0°C. The whole was then stirred for 30 minutes at room temperature, and then 60 mL of saturated sodium acetate solution was added.
1 and adjust the pH to 9 with concentrated ammonia. The resulting cyclohepta(b)pyrrole-5-carbaldehyde is extracted with methylene chloride and produced by flash chromatography using the solvent system N6. Rf (N6
)-0,4 aldehyde 300g in methanol 20m
The vigorously stirred reaction mixture at room temperature with 640 μl of hydroxyamine and 1.5 g of sodium acetate in +1 was poured onto water to form cyclohebuta(b)pyrrole-5.
- Extract the carbaldoxime with methylene chloride. Rf
(N6) -0,35N,N'-Carbonyldiimidazole 371 .mu. are added to 340 .mu. of the above oxime in 20+1 methylene chloride at room temperature. After 1 hour, the reaction mixture was applied directly to 65 g of silica gel under slight pressure.
The title compound is eluted using solvent system B6. Rf(B
S)-0,70 2(R,S)-(2-dimethylaminoethylcarbamoyl)-3-α-naphthylpropionic acid 49 nv, )
l-His-Cha 1Val-n-butyramide 60
(2) The title compound was prepared analogously to Example 24 from HOBL26+ng and DCCI 40Ilv, and solvent system B
Purify by flash chromatography using 9. Rf (B9)-0,27; Rf (B7)
Snow 0.13 The starting material is prepared in the following way: α-naphthylmethylmalonic acid monoethyl ester (Example 26a)1. OO
g, 2-dimethylaminoethylamine 0.80 g,
2(R,S)-(2-dimethylaminoethylcarbamoyl)-3-α-naphthylpropionate ethyl esteno C is prepared in the same manner as in Example 1 from HOBto, 67 g and DCC11, 14 g. Rf (BS)-
Q,33; The ethyl ester of Rf (B7)-0,4 is hydrolyzed analogously to Example 26a using sodium hydroxide solution in aqueous ethanol. The title compound crystallizes from water at 4°C in the form of pale colorless crystals with a melting point of 102°C.

Rf (Bl 1) -0,08 Example 29: N-(2(R,S)-(2-hydroxy 2
(R,S)-(2-hydroxy-1(S)methylethylcarbamoyl)-3-α-naphthylpropionic acid 47■
, H-His-Cha J&Val-n-butyramide 60■, HOBt26■ and DCCI 40■ Example 2
・Prepare the title compound in the same manner as in 4, and use solvent system B7
Purify by flash chromatography using Rf (Bl)'-0,21; Rf (BS) depth 0.
31 The starting material is near”o[?,d produced by the following method.
- and the ridges are α-naphthylmethylmalonic acid monoethyl ester (Example 26a)2. OOg, 2 (S)-amino-1
- Same S as in Example 28a from Propertool 0.69 g, HOBtl 46 g and DCCI 2.27 g,
Manufactured. Rf (Bll)-0,18; Rf
(SIO)-0,52 2(R,S)-(2,2-dimethoxyethylcarbamoyl)-3-α-naphthylpropionic acid 51■, H-Hi
s-Cha 1Val-n-butyramide 60■, HO
The title compound is prepared analogously to Example 24 from Bt26N and DCCI 40qr and purified by flash chromatography using solvent system B7! , Rf (
Bl)-0,35; Rf (BS)-0,20 The starting material is prepared in the following manner: α-naphthylmethylmalonic acid monoethyl ester (Example 26a)1.
00g1 Aminoacetaldehyde dimethyl acetal 0
．． 48■L HOBtO, 73g and DCCll, 14
Example 28a is prepared from Example 28a. Rf
(Bl 1) -0,28; Rf (S10) -0
,65 Amide 2 (R,S) (tert-butoxycarbonylmethylcarbamoyl)-3-α-naphthylpropionic acid 92 ■, H-His-Cha LVal-n-butylamide 100 ■, HOBt 43 ■ and DCCI 67 ■ Example 24 The title compound was prepared in a manner analogous to the above and subjected to flash quamography using solvent system B5, Rf (BS) = 0.21; Rf
(Bl) 0.34 The starting material is produced by the following method: The main material is α-
Naphthylmethylmalonic acid monoethyl ester (Example 26a
)1. OOg, glycine ter L-butyl ester dibenzenesulfimide salt 1.73ml, HOBtO,7
Prepared analogously to Example 28a from 3 g and DCCll, 14 g and purified by flash chromatography using the solvent system N12. Rf(N12) =0.3
8N-(2(R,S)-(tert-butoxycarbonylmethylcarbamoyl)-3-α-naphthylpropionyl)-His-Cha LVal-n-butylamide (90 μl) was dissolved in 0.5 wl of trifluoroacetic acid, and the solution was dissolved at room temperature. Leave for 1 hour. The whole is then concentrated to dryness by evaporation and the product is purified by flash chromatography using the solvent system BII.

Rf (Bl 1) −0,34; Rf (BS) −
0,215,5-dimethyl-2(R,S)-(α-naphthylmethyl)-4-oxohexanoic acid 46fffSH-
) 1is-Cha 1Val-n, -butyramide 60
The title compound was prepared analogously to Example 24 from HOBt26IIv, HOBt26IIv and DCCI40rrw, and solvent system B
Purify by flash chromatography using 5.

Rr (B5) curvature 0.21; Rf (B7) −0,
37 Starting material is prepared in the following manner: α-naphthylmethyl acid diethyl ester D, Aa+ in DMF analogously to Examples 18a and 18b.

Chew, Soc, 62.2335 (I940
)) 730 g of sodium hydride and 2.9 g of bromomethyl-tert-butyl ketone give the title compound after subsequent hydrolysis and decarboxylation. Melting point 9
3-93.5℃, Rf (Nl 1) -0,50
ヱα-Naphthoxymalonic acid monoethyl ester 29, 6
ay, H-His-Cha-'Val-n-butyramide 50.0■, HOBt 16.5 mg and DCC
The title compound is prepared analogously to Example 24 from I28.8 and purified by flash chromatography using solvent system B3. Rf (B4)-0,54 starting material is prepared by the following method: a) α-naphthoxymalone monoethyl ethyl α-naphthoxymalonic acid diethyl ester (2.0 g) is dissolved in 5 ml of absolute ethanol and stirred. A solution of 0.41 g of potassium hydroxide in 5 ml of absolute ethanol is added while the reaction mixture is stirred at room temperature for 16 hours and then concentrated to dryness by evaporation. The residue is dissolved in water, washed with ether, acidified with 5N hydrochloric acid and extracted with ethyl acetate. From these ethyl acetate extracts, the title compound is obtained in the form of a pale brown oil by washing with brine, drying over sodium sulfate and concentration by evaporation.

Ruamide 4-cyano-2(R,S)-α-naphthoxybutyric acid27.
The title compound was prepared analogously to Example 24 from 6 vt, H-His-Cha j-Val-n-butylamide 50.0 yxr, HOBtl 6.5 g and DCCI 28.8 mg, and subjected to flash chromatography using solvent system B28. Purify by graphy. Rf (B4)-
The 0,52 starting material is prepared in the following way: a) 4
-Cyano-2(R,5)-1-naphthoxy solidity: 50%
0.11 ml of potassium hydroxide aqueous solution was stirred at 0°C and then added to a mixture of 5.0 g of α-naphthoxymalonic acid diethyl ester and 1.09 all of acrylonitrile.The reaction mixture was stirred at room temperature for 5 days, and then ethyl acetate Dissolve in. The ethyl acetate solution was washed with 2N sodium bicarbonate solution, 2N hydrochloric acid and brine, dried over sodium sulfate and concentrated by evaporation to give (2-cyanoethyl).
-α-naphthoxymalonic acid diethyl ester is obtained.

7.84 g of this malonic acid ester was heated to 0MS at 180°C.
O39, 2 forehead straight, water 398μ! and lithium chloride 1, 8
The reaction mixture, stirred for 3 hours in 7 g, is concentrated by evaporation in a high vacuum, the residue is dissolved in ethyl acetate and extracted with water. The aqueous extract is adjusted to pH 2 with 2N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate extract is washed with water and brine, dried over sodium sulfate and concentrated by evaporation to give the title compound in the form of a light brown oil.

4-tert-butoxycarbonyl-2(R,S)-
α-Naphthoxybutyric acid 35.7 W, H-His-Cha
'-Val-n-butyramide 50.0 W, HOB
The title compound is prepared analogously to Example 24 from t 16.51w and DCCI 28.8■ and purified by flash chromatography using solvent system 82B. R
f(B4)Full 0.33 The starting material is prepared in the following way: 50 ml DMF
A solution of 25 g of 1-naphthol was gradually added to a solution of 7.6 g of sodium hydride dispersion in 300 ml of DMF. Stir the suspended fA solution for 30 minutes, then add DMF50a+
The reaction mixture containing 41.5 g of diethyl bromomalonate in 1 is stirred for a further 16 hours at room temperature and concentrated by evaporation in a high vacuum. The residue is dissolved in ethyl acetate, washed with 2N hydroxide solution, water and brine, dried over sodium sulfate and concentrated by evaporation. Distill the residue at 145-170°C/2.6 Pa,
α-Naphthoxymalonic acid diethyl ester is obtained in the form of an orange oil.

This malonic ester in 5 m+1 acetonitrile3.
0g and acrylic fitert-butyl ester 1.4
1,8-diazabicyclo(5,4,0) in 5ml solution
Add 71.49 ml of Undek-7-2 and stir the whole at room temperature for 24 hours. Add 25 ml of water to the reaction mixture;
Approximately 12 ml of 2N hydrochloric acid '1' pH2 nitiiiff
Extract with ether. The ethereal phase was washed with brine and water, dried over sodium sulfate and concentrated by evaporation to give (2-tert-butoxycarbonylethyl)-
α-Naphthoxymalonic acid diethyl ester is obtained in the form of a light brown oil.

The ester is hydrolyzed and decarboxylated as in Example 35a using lithium chloride and water in DMSO at 180°C. Purification of the crude acid by chromatography using solvent system B4 gives the title compound in the form of a white foam.

2 (R,S)-ethylaminocarbonyloxy-3-
α-Naphthylpropion f11.15.5■, H-Hi
s-Cha'-VaJ-n-butyramide 25.0
The title compound was prepared from #, BOB t8.3■ and DCC114,4■ in the same manner as in Example 24, and the solvent system 828
Purify by flash chromatography using . Rf (B29)-0,25 The starting material is produced by the following method: DMF2F1
2-hydroxy-3-α-naphthylpropionic acid (
Example L7b) 54μ of ethyl isocyanate in a solution of 50μ
The reaction mixture is stirred for 3 hours at 100 °C and then in a rotary evaporator at high temperature! Concentrate by evaporation to the bottom.

The residue was dissolved in ethyl acetate, washed with 0.1 N hydrochloric acid, water and brine, dried over t=a sodium, concentrated by evaporation and purified by chromatography on silica gel using the solvent system Bll. do. Yellow oil, Rf
(Bl 1) -0,272(R,S)-(2-benzyloxycarbonylamino-2-methylpropionyloxy)-3-α-naphthylpropionic acid 47.0■
,) l-His-Cha 1-Val-n-butyramide 50.0 N,) lOBt16,5 IIv and DC
The title compound is prepared analogously to Example 24 from 28.2 mg of CI and purified by flash chromatography using solvent system B30. Rf (B29) term 0.
38 The starting material is produced in the following way: DMF 10w
To a stirred suspension of 0.14 g of sodium hydride (55% in mineral oil) in 'fL is added 10.77 g of α-penzyloxycarbonylamino 7alt in 5 ml of DMF at room temperature.
7) solution and 2-bromo- in DMFssl for 30 min i.
The reaction mixture containing 1 g of 3-α-naphthylpropionic acid ethyl ester is stirred at room temperature for 16 hours and then concentrated by evaporation in a high vacuum. The residue is dissolved in ethyl acetate, washed with water and brine, dried over sodium sulphate and concentrated by evaporation. Chromatography of the residue on silica gel with toluene/ethyl acetate (95:5) gives the ethyl ester of the title compound.

Due to hydrolysis, Lr0jl ) 12020.8 mg
Conoester 230 ■ THF/water (9:1) 5 liters
The reaction mixture is stirred at 0°C for 20 hours and extracted three times with ethyl acetate.

The ethyl acetate phase is washed with water and brine, dried over sodium sulphate and concentrated by evaporation. Solvent the residue with a solvent system Bll
Chromatography on silica gel gives the title compound in the form of a yellow oil. Rf (Bit
)-0,34Butyramide 3-phenyl-2(S)-pivaloyloxypropionic acid 30■,)l-1(is-Cha"Val-n-butyramide 5ON, HOBtl 8gg and DCC
The title compound was prepared analogously to Example 24 from I 29■, using methylene chloride/methanol/conc.
Purify by medium pressure chromatography using 0:IQ:1. Rf (B8) 0.45 The starting material is prepared by the following method: a) 3-phenyl-2(S)-pivaloyloxy 3-phenyl-2(S)-pivaloyloxypropionic acid 3.01 g of benzyl ester are hydrogenated in 35 ml of methanol in the presence of 300 ml of palladized activated carbon (I0%) at room temperature and normal pressure for 30 minutes. The catalyst is separated and the liquid is concentrated by evaporation in vacuo. The title compound was obtained in the form of a clear colorless oil, Rf (N21) -0,74
, IH-NMR (DMSO-d@): 12.
5 (I H); 7.25 (s, 5H); 5.1
(dxd, IH); 3.15 (m, 2H): 1.
lppm (s, 9H).

0.24 ml pivalic acid chloride in 2 ml methylene chloride
3-phenyl-2(S)- in 5 ml of methylene chloride
A solution of 250 w of hydroxypropionic acid benzyl ester (L-β-phenyllactic acid benzyl ester) and 0.408 ml of triethylamine is poured into a solution cooled to 0°C. The mixture is stirred at room temperature for 30 hours, then poured onto ice, the organic phase is washed with IN hydrochloric acid and water and dried over sodium sulfate. The solvent is evaporated in vacuo and the residue is purified by medium pressure chromatography (Lobar™ pre-(lift preparative column, Merck, size B, eluent, petroleum ether/ether 11:1).

The title compound is obtained in the form of a colorless oil. Rf (N4
)-0,5220% cesium carbonate aqueous solution (pH 7) 23
ml of Shiichi β in 65 ml of methanol and 6.5 ml of water.
- Add a solution of 4.0 g of phenyl lactic acid (3-phenyl-2(S)-hydroxypropionic acid) at room temperature. The solvent is evaporated and the residue is dried in high vacuum at room temperature for 24 hours. Take the dried cesium salt in anhydrous DMF371 and
℃, and add 3.15 ml of benzyl bromide to it. The resulting white suspension was stirred at room temperature for 24 hours, then the filtrate was concentrated by evaporation in a high vacuum, the residue was taken up in ether, washed with water and saturated aqueous sodium bicarbonate solution and concentrated over sodium sulfate. Dry with. After evaporating the solvent in vacuo, the title compound is obtained in the form of a yellowish oil. Rf (N4)-0,2,t H-NMR''(
DMSO-d@) Near, 3 Cs, 5H); 7.2(s
, 5H); 5.6 (d, IH); 5.15 (s.

2H): 4.4 (m, LH); 3. Oppm (m
, 2H) eヱ2 (R,S)-dimethoxyphosphoryl-3-phelpropionic acid 31■, H-[1is-Cha LVal
-n-butylamide 50■, HOBt18■ and DCC
The title compound was obtained analogously to Example 24 from 129■ in the form of a diastereomeric mixture and was purified by medium pressure flash chromatography (Lobar™ preparative column, eluent methylene chloride/methanol/concentrated ammonia). 120:10:1). Rt
(B8)-o,46 (faster diastereomer): Rf (B8)-0,41 (slower diastereomer), diastereomers can be separated by chromatography.

The starting material is prepared by the following method: 2-dimethoxyphosphoryl-3-phenylpropionic acid methyl ester (α-benzylphosphonoacetic acid trimethyl ester) 6
．． 66 gjti-MaOH (20 liters), 8111 of water and 12.14a+1 of 2 N KOB were added at room temperature, and the whole was stirred for 90 minutes. Then, the reaction mixture was
Neutralize with 12.14 ml of N ICI, concentrate in one shot to 20+1, extract with ethyl acetate, dry and recondense with tIA by evaporation. IH-NMR (DMSO
-d@): 2.8-3.2ppm (m,
2H); 3.6 (s, 3H): 3.75 (s
, 3H) Near, 2(s, 5H) b) α-Benzylphosphono trimethyl varnish - Earthworks 2.4 g of NaH (50% in oil) in dimethoxyethane 25
01 and cooled in a water bath, dimethoxyethane 4
Add 0 Log of phosphonoacetic acid trimethyl ester in 1 steel. The whole is stirred at room temperature for 90 minutes and then 6.52 ml of benzyl bromide in 40 ml of dimethoxyethane are added. After stirring at room temperature for 4.5 h, the reaction mixture was dissolved in NaHz
Pour onto 100 ml of a 2N aqueous solution of PO4, extract with ether, dry the organic phase and concentrate by evaporation. The crude product was purified by medium pressure chromatography [Lich
oprep ) Si60 1000 g - eluent: ethyl acetate/n-hexane 2:l and pure ethyl acetate]. 'H-NMR (DM
SO-da): 2.9-3.4ppm (m, 2
H); 3.60 Cs, 3H); 3.61 (s, 3
H): 3.85 (s, 3H); 7.22 (s, 5H
) monophosphonatopropionyl)-formerly 5-Cha”Val
-N-(2(R,S)-dimethoxyphosphoryl-3-phenylpropionyl)-His- in -n-butyramide chloroform 1 garden 1
Cha-'Val-n-butyramide (Example 40) 43■
45 μl of trimethylbromosilane are added at room temperature and the whole is left to stand for 30 hours. The reaction mixture is concentrated by evaporation, L ml of IN hydrochloric acid is added, the whole is stirred for 1 hour at room temperature and concentrated again by evaporation. The residue was flash chromatographed (eluent: methylene chloride/methanol/conc. ammonia, first 10:5:1 and then 5:3:
1).

Methyl ester ammonium salt: Rf (B32)-
0,38 (faster diastereomer); Rf(B
32) -0,33 (slower diastereomer);
Diammonium salt: Rf (B32)-0,32 (faster diastereomer); Rf (B32)=0.
26 (slower diastereomer): N − (
2(R,S)-Henry)Lt-3-';ethoxyphosphorylpropionyl)-)1is-Cha-''-V
al-n-butylamide 2 (R,S)-benzyl-3-jethoxyphosphorylpropionic acid 93■, H-His-Cba “Val-
n-butylamide 130w, HOBt47■ and D
The title compound is prepared analogously to Example 24 from CC175■ and purified by flash chromatography using solvent system B5. Rf (B8)-0,37 (faster diastereomer); Rf (B8)-0,32 (
later diastereomer).

The starting material is prepared in the following manner: 745 μl of 2-benzyl-3-jethoxyphosphorylpropionic acid ethyl ester are placed in 5 ml of ethanol and 4 ml of water;
13ml of N KOH was added and the whole was stirred at room temperature for 4 hours, then neutralized with 2NllC11,13a+1,
Concentrate by evaporation. The residue is purified by flash chromatography using the solvent system NIO. Rf
(Na)=0.46,'H-NMR(DMSO-do
): 1.2p9糟 (I+6H) ;1.7
(m, IH) ;2.05 (m, IH)
;2.7-3.0 (m, 3H) ;3.95
(9,4H); 7.1 5-7.35 (m,
5H) 1% sodium ethoxide solution 4 ra l
1.0 g of sα-benzylacrylic acid ethyl ester and 0.6 phosphorous acid diethyl ester in 5*1 ethanol
Add 8 ml to 30 ml of ethanol at room temperature. The mixture was stirred at room temperature for 24 hours and then dissolved in NaH2 in 1 ml of water.
Po4200■ is added and the whole is condensed by evaporation.

The mixture is partitioned between water and water, the organic phase is dried,
Concentrate by evaporation and purify by flash chromatography using methylene chloride/ether 7:1.

IH-NMR (DMSO-de): 1. O5ppm
(t, 3H); 1.18 (t.

6H): 1.8-2.2 (m, 2H): 2.9
(m, 3H): 3.95 (m, 6) (); 7.
2 (m,5H)C) α-Benzyl acrylic ethyl ester: Potassium hydroxide in 50 ml of ethanol 4.
0 g was added to 20 g of benzylmalonic acid diethyl ester in 40 sl of ethanol at room temperature, the whole was stirred at room temperature overnight, concentrated by evaporation, 7.1 ml of water was added and the whole was acidified with 6.3 ml of concentrated hydrochloric acid in a water bath. Make it. The product is partitioned between water and ether, the organic phase is dried and the ether is evaporated. Pyridine 12.9+*l, piperidine 0
．． 61 g and 1.78 g of paraformaldehyde are added to the residue. The mixture was heated in an oil bath (I 30 °C) for 90 minutes, cooled, 220 ml of water was added and the whole was dissolved in n-hexane 7
Extract 3 times with 5ml.

The combined organic phase was water, INtlCl, water, and saturated NaEIC.
Wash with Oi solution and saline. Distillation gives the title compound. IH-NMR(DMSO-ds)=
1.2pp■ (t, 3H); 3.6 (4,28);
4.1 (9,2H); 5.6 (m, IH); 6.
15 (m, IH); 7.25 (m, 5H) 3-benzyloxycarbonyl-2(R,S)-α-naphthoxypropionic acid 135 ■, Fl-His-Cha-'Va
l-n-butyramide 181■, HOBt60■ and D
The title compound is prepared analogously to Example 24 from CC1105■ and purified by flash chromatography using solvent system B23.

The Rf (B23)-0,34 starting material is prepared in the following way: 0.35 g of sodium hydride (55% in oil) is dissolved in α-
1.04 g of naphthoxysuccinic acid was added at 0°C, the whole was stirred at room temperature for 4 hours, and then 1.08 g of benzyl bromide
The reaction mixture is concentrated by evaporation, dried in a high vacuum, taken up in IN hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over 'P;H magnesium and concentrated by evaporation. The residue was dissolved in ethyl acetate) Ll/n-hexane/methanol 20:1
Purification by flash chromatography using 0:1 gives the title compound in the form of a beige oil. Rf (S13)-0,48b) α-naphthoxysuccine: 20.2 g of sodium hydride (55% in oil) in DMF7
α-naphthol 2 in 00 l and THF 200 sl
Add it little by little to 3g at 0°C while stirring. After 15 minutes at 10°C, bromosuccinic acid 29.
The reaction mixture was stirred at room temperature for 2 hours and at 100 °C for 15 hours, and the 1THF
The reaction mixture is then concentrated in a high vacuum and partitioned between IN hydrochloric acid and ethyl acetate. The organic phase is dried, concentrated by evaporation and purified by flash chromatography using the solvent system BIO. Ethyl acetate/
With n-hexane! : The title compound is crystallized from a mixture of the two as a beige powder (melting point 161-162
°C). Rf(S10)-0,17 aiva(-n-butylamide 4-carbamoyl-2(R,S)-α-naphthoxybutyric acid 14.8w, H-His-Cha'-Val-n-butylamide 25.ON, HOBt 8.3 rrw
; r and DCC114,42 analogously to Example 24, the title compound is obtained in the form of a diastereomeric mixture and separated by flash chromatography using solvent system B29. Rf(B4)-0.35 (faster diastereomer) and Rf(B4)-0,25 (slower diastereomer) The starting materials are prepared in the following manner: a) 4-carbamoyl 3 g of α-naphthoxymalonic acid diethyl ester (Example 36a) and 0.7 acrylamide in 2(R,S)-α-naphthoxybutyric acid settonitrile 51
1.49 ml of 1,8-diazabicyclo(5,4,0)undec-7-nin are added to 1 g of solution and the whole is stirred at room temperature for 24 hours. Add 25 liters of water to the reaction mixture,
Adjust the pH to 2 with 2N hydrochloric acid and extract with ether. The ether phase is washed with water and brine, dried over sodium sulfate and concentrated by evaporation, leaving (2-carbamoylethyl)-α-naphthoxymalonic acid diethyl ester.

The ester is hydrolyzed and decarboxylated in DMSO with lithium chloride and water at 180° C. as in Example 35a.

The crude acid is purified by chromatography using the solvent system Bll to obtain the pure title compound.

Example 45: The following compounds were prepared analogously to Example 24: a) N-
(2(R)- and 2(S)-cyanomethyl-3-α-naphthylpropionyl) -)Iis-Cha-'Val
-n-Butyramide: m by eluent B2 eluent -2B rush chromatography; Rf(B4)-0,4
3 (faster diastereomer) and Rf (B4)-
0,38 (slower diastereomer) b) N-(indolyl-2-carbonyl) -1(is
-Cha”-Val-n-butyramide: Eluent B2
Franch chromatography using Rf(B4
) −0,43; Rf (B 4) −0,59c)
N-phenoxyacetyl-formerly 5-Cha 1Val-n
-Butyramide: flash chromatography using eluent B23; Rf (B4)-0,48; Rf
(B4)-0,62 d)N-(β-naphthylcarbonyl)-Hls-Ch
aLVal-n-butyramide: flash chromatography using eluent B23; Rf (B4)-0
,44;RE (B4) -0,67e)N-(α-
naphthoxyacetyl) -Hls-ChaLVal-n
-Butyramide: flash chromatography using eluent B23; Rr (B4) = 0.52 f)N-(3-benzyloxycarbonyl-2(R,S
)-α-naphthylmethylpropionyl)-l(is-C
b3
Franch chromatography using Rf (B23
)=0.21;Rf, (B6)-0,23g)N-(
2(R,S)-benzyl-4-oxopentanoyl)
-His-Cha 1Val-n-butyramide: Rf
(B7)-0,43 h)N-(2(R,S)-benzyl-4,4-dimethyl-3-oxopentanoyl)-His-ChaLVal
-n-butyramide: Rf (B7)-0,35i)
N-(5-dimethylamino-2(R)- and 2(S)
-α-naphthylmethylpentanoyl)-His-Cha
”-Val-n-butyramide: Rf(Bll)-0
, 63 (faster diastereomer) and Rf (B 1
1) -0,18 (slower diastereomer) j)
N-(2(R,S)-benzyl-5,5-dimethyl-
4-oxohexanoyl) -Hls-Cha LVa
l-n-butyramide: Rf (B7)-0,30k
) N -(2(R,S) -tert-butylcarbamoyl-3-α-naphthylpropionyl) -His-
Cha LVal-n-butyramide; Rr (BS
)=0.20 ;Rf (B7) −0,30N−(
3-Benzyloxycarbonyl-2(R9S)-α-naphthylmethylpropionyl) -Hls-Cha'-
60 ag of Val-n-butyramide (Example 45f) was dissolved in 6 ml of methanol, and activated carbon with palladium (Pd1
Hydrogenate until saturation is reached in the presence of 0%) 100μ. The residue was dissolved on 30 g of silica gel in methylene chloride/methanol/water (first 110:10=1, then 50:10:1).
) and separated by chromatography. Rf
(510)-0,66 and Rr (N22)-0,
37 (faster diastereomer): Rf (SIO
) = 0.48 and Rr (N22) - 0,17 (slower cyastereomer) DCCI 41■ in DMF2+sl in a water bath.
ha LVal-n-butyramide (Example 24c) 50+
agN'-(quinolyl-2-carbonyl)-te methyl-L-histidine 55■ and HOBt26■. The whole is stirred in a water bath for 6 hours and at room temperature for 3 days. After evaporating the solvent in high vacuum, the residue was dissolved in methanol/water/
6 in a mixture of glacial acetic acid (94:3:3) 5111
Heat at 0° C. for 60 minutes and concentrate again by evaporation. The residue is purified by medium pressure chromatography on a Lobar™ preconditioned column (size B) using solvent system B26 and isolated by lyophilization from tert-butanol. Rf (B8)-0,
36 The starting material was prepared by dissolving 321 ml of 2N'-(quinolyl-2-carbonyl)-N' methyl-L-histidine methyl ester produced by the following method in 3 ml of THF.
1.42 ml of N NaOH are added at room temperature. After 1.5 hours, the reaction mixture is neutralized with 1.42 ml of IN hydrochloric acid and concentrated to dryness by evaporation.

Rf (B8)-0,02 N'-methyl-L-histidine methyl ester dihydrochloride 400Qr, quinoline-2-carboxylic acid 298gv,
HOBtZ 63■, ethyldiisopropyl'amine 0
．． 531o+1 and DCCI418■ in DMF2 at room temperature.
ml for 5 days and then reduced to 4 by evaporation. The residue was stirred for 1 h at 60 °C in a mixture of methanol/water/glacial acetic acid (94:3:3) and again evaporated to tR.
Lobar (trademark) (JM)
Purify by medium pressure chromatography using solvent system B31 on an i preparative column (size B).

Rf (B8)-0,63 C) N'-Methyl-L-histidine methyl ester dihydrochloride: 2 g of Nd--methyl-L-histidine hydrochloride [Baches AG, Pubendorf] Dissolve in 30 liters of methanol,
After cooling in a water bath, 121.2 ml of 5OC is added.

The whole is stirred at room temperature overnight and then concentrated to dryness by evaporation. IH-NMR (DMSO-d,.

TMS): 2.65pp* (s, 3H
); 3.45 (dd, 2H); 3.7 (s,
3H); 4.4 (m, IH); 7.55 (s,
H);9.1 (s, IH)N-methyl-N'-(3-phenyl-2(S)-pivaloyloxypropionyl)-L-histidine 68■, H-Cha
"Val-n-butyramide 50■, HOBt26■
The title compound is prepared analogously to Example 47 from and DCCI 41■ and purified by medium pressure chromatography on a Roper™ preparative column using solvent system B26. The Rf (B8)-0,29 starting material is prepared in the following way: Histidine: Analogously to Example 47a, the corresponding methyl ester is hydrolyzed with sodium hydroxide solution. Rf(B8)10.
01 All white b) N'-methyl-N'-(3-phenyl-2N'-
Methyl-L-histidine methyl ester dihydrochloride and 3
The title compound is prepared analogously to Example 47b from -phenyl-2(S)-pivaloyloxypropionic acid (Example 39a) by flash chromatography using the eluent NlO followed by medium pressure chromatography [ Lichroprep (trademark) ・5i60
．． 25-4077m-Eluent B33].

Rf (B8)-0,59: N'-(indolyl-2-carbonyl)-N'-methyl-L-histidine 53■, former 5-Cha -LVal-
n-butylamide 50■, HOBt26w and DCCI
The title compound was prepared from Example 41■ in the same manner as in Example 47,
Medium pressure chromatography (Lichro
prep) (trademark) 5i60.25-40μm
, eluent B33] and lyophilized from tert-butanol. Rf (88) = 0.57 Starting material N' - (indolyl-2-carbonyl) + Ntl-
-Methyl-L-histidine is prepared analogously to Example 47a.

naphthalene-1,8-dicarbonyl-L-phenylene/L/
Alanine (Egypt, J, Chew, 2 Sat.
127 (I981)) 110g, H-Cha LVal
-n-butylamide (Example 24c) 80■, HOBt49
The title compound is prepared analogously to Example 1 from 1 and DCCI81qr and purified by flash chromatography using the solvent system N6. Rf (N7)-0,4
1: Rf (N6) Proverb 0.17 Indole 5-2-carboxylic acid in 6sl DMF 39■
, H-Phe-Cha j-Val-n-butyramide 114 ■, 1 (OBL 37 ■ and DCCI 66 ■) is stirred at room temperature for 24 hours. The crystallized DCH is split into portions and the portion is concentrated by evaporation. Crude The product was purified by flash chromatography (100 g of silica gel 60).
, 40-63 pm, purifying agent N6)
The combined product-containing fractions are evaporated to 4FM to give the title compound. Rf (B3)-0,
46; Rf (B9)-0,89 Starting material is prepared by the following method: a) H-P
he-Cha”-Val-n-butyramide: Z-P
hi-Cha'J! al-n-butylamide 144g
is hydrogenated in 5 ml of a 9-1 mixture of methanol and water in the presence of 20 μl of palladium-coated activated carbon (Pd 10%) at normal pressure until saturation is reached at room temperature. and stir at room temperature. After evaporating the solvent, the title compound is obtained in the form of a colorless oil. Rf
(B2)-0,62:Rf(39)''0.85
Margin below b) Z-Phe-Ch
a”-Val-n-butyramide: 150tt Z-Phe-OH in 6 ml DMF, H-Cha LVal-
n-butyramide 164■, HOBt76N and DCC
The mixture of 1134 .mu. is stirred at room temperature for 48 hours. DCH
The mouth is cut open, the mouth is compressed, and the mouth is dried in a high vacuum.

The residue was subjected to flash chromatography (silica gel 60
185g, 40-63#m.

The combined product-containing fractions, separated by eluent N6), are concentrated by evaporation to give the title compound, Rf(B4)-0,80:Rf(N?)-0,
37 Indole-2-carboxylic acid 40 v in 6 ml DMF
tSH-Nle-Cha”-Val-n-butyramide 110v, ll0Bt 38 N and DCCI 68
The title compound is prepared analogously to Example 51 from 111r and purified by flash chromatography using solvent system N7. Rf (B2)-0,38; Rf
(B9) Snow 0.89 The starting material is produced by the following method: a) H-N
le-Cha 1Val-n-butyramide Example 51
Similarly to a, Z-Nle-Cha -'Val-n
-butyramide 144+ng with methanol and water 9:
Activated carbon with palladium (PdlO%
) is obtained by hydrogenation in the presence of 20■.

Rf (B2)-0,57.

Rf (S9) = 0.69 b) Z-Nle-Cha”-Val-n-butyramide was prepared from Z-Nle-Cha”-Val-n-butyramide in DMF6+al as in Example 51b.
-Nle-OH133■, H-Cha 1Val-n-
Butyramide 163■, HOBt76mg and DCCI
Produced from 134mg. Rf (B2) 寞0.
80: Rf (N7)-〇, 31 Top: 15 ■ indole-2-carboxylic acid in 2 ml DMF,
H-His-Cha ji-Val-3-dimethylaminopropylamide 43■,) IOBt14Qr and DC
The title compound is prepared analogously to Example 17 from C125■ and purified by flash chromatography using the solvent system Bll. Rf (Bl)-0,32; Rf
(S9) -0,12 starting material is prepared by the following method: a) H-His-Cha “Val-3
-Dimethylaminopropylamide was prepared in the same manner as in Example 16a by mixing 2-old s-ChaJg-Val-3-dimethylaminopropylamide 57 with methanol and water in a 9:1 solution.
Activated carbon with palladium (PdlO%
) is obtained by hydrogenation in the presence of 15■.

Rf(Bl) = 0.085b) Z-His-Cha LVal-3-dimethylaminopropylamide was treated with DM as in Example 16b.
Z-His-OH136qr, tl-C in F6ml
obtained from ha LI/al-3-dimethylaminopropylamide 167"1g5HOBt72 and DCC1128. Rf(Bl)-0,32; Rf(S
9) -0,14c) H-Cha 1Val-3
-Dimethylaminopropylamide: Z-Cha included Va
0 reaction in which 247 μl of l-3-dimethylaminopropylamide is hydrogenated in 10 ml of a 9=1 mixture of methanol and water in the presence of 40 μl of palladium-coated activated carbon (PdlO%) at normal pressure and room temperature until saturation is reached. kiss the mixture,
Stir the oral mixture with water foil at room temperature. After evaporating the solvent, the title compound is obtained in the form of a colorless oil. Rf(B
1)=0.13 d) Z-Cha included Val-3-dimethylaminopropyl acetate: Z-Cha included Val-OR (Example 16i) 3
A mixture of 57q, 8.5 ml of DM F, HOBt 153 and DCC 1206v is left at 0° C. for 24 hours. Dimethyl-3-aminopropylamine 33 to the mixture
7 ml is added and the whole is stirred at 0° C. for 2 hours and at room temperature for 39 hours. The crystallized DCH is poured, concentrated and dried in a high vacuum. Flash chromatography of the residue (eluent B4) gives the title compound in the form of a colorless oil. Rr(B4)=0.32 i Rr
(N l 2) -0,24 Indole-2-carboxylic acid 26 in 4 ml of DMF, H-His-Cha
-”Val-2-morpholinoethylamide 83■, 1l
The title compound is prepared analogously to Example 17 from OBt25■ and DCCI 43■ and purified by flash chromatography using solvent system B4. Rf (B
2) -0,19; Rf(S9) Snow 0.41 The starting material is produced by the following method: a) H-H
is-Cha” Val-2-morpholinoethylamine and Z-His-Cha j-
Val-2-morpholinoethylamide 104 ml is obtained by hydrogenation in 10 ml of a 9=1 mixture of methanol and water in the presence of 40 ml of palladium on activated carbon (PdlO %). Rf (Bl)-0,43, Rf
(S9)-0,13t>) Z-His-Cha” Val-2-morpholinoethylamine was treated with DMF8a as in Example 16b.
(7) Z-tlis-OH 17410 g in +l, II-
Cha” Val-2-morpholinoethylamide 230
■, obtained from HOBt92qr and DCC1163■. Rf (82)-0,28; Rt (s9)
=0.39 c ) H-Cha ”-Val-2-morpholinoethylamide was prepared as Z-Cha ”-Val as in Example 53c.
-2-morpholinoethylamide 340cm mixed with methanol and water at 9:1'! Produced by hydrogenation in yJ10+1 in the presence of 50 μm of palladium on activated carbon (Pd 10%). Rf (Bl) =0.48
; Rf (N9), = 0.21 d )
a<JVal-OH267tag, 4-(2-aminoethyl)-morpholine 98■, HOBL115nv and DCC1155■. R((Nl)-0,
68; Rf (N6)-0,10 mido: indole-2-carboxylic acid 31 n in 3 ml DMF
v, H-His-Cha-'Val-(5-jer
t-Butoxycarbonylamino-5-methoxycarbonylpentyl)-amide 124■, HOBt29N and D
The title compound is prepared analogously to Example 17 from CCI52■ and purified by flash chromatography using solvent system B23. Rf (B4)=0.42;R
f (N9)-0,71 starting material is Z-H
is-ChaJ&-Val-(5-tart-butoxycarbonylamino-5-methoxycarbonylpentyl)
- Amide 143 sv on palladium-coated activated carbon (Pd 10%) 25 ml in 1° ml of a 9:1 mixture of methanol and water
Obtained by hydrogenation in the presence of nv.

Rf (B4)-0,10: Rf (all) 0.
6-low amide was added to DMFI1m as in Example 16b.
Z-His-OH197tt in l, H-Cha”V
al-(5-tert-butoxycarbonylamino-
5-methoxycarbonylpentyl)-amide 349 r
q, HOBt104■ and DCC1183■.

Rr(B4) 0.59 amide was prepared in the same manner as in Example 53c with Z-Cha included Val-
Prepared by hydrogenation of (5-tert-butoxycarbonylamino-5-methoxycarbonylpentyl)-amide 469 µ in the presence of 100 µ of palladium on activated carbon (Pd 10%) in 7 ml of a 9:1 mixture of methanol and water. be done. Rf (B4) = 0.16 Amide was prepared as Z, Cha "Val-OH446nv, N'-t in DMF14+wl as in Example 53d.
ert-butoxycarbonyl-lysine methyl ester 320■, 110BL 153 N and DCCI 2
Manufactured from 78IIv, Rf (N3) = 0
．． 48; Rr (NI 0)-0,63 N-(indolyl-2-carbonyl) -Hls-Ch
a "Va'l-(5-tert-butoxycarbonylamino-5-methoxycarbonylpentyl)-amide 1
02N, 0. 1.9 ml of IN NaOH and 1 water
The reaction mixture was stirred in 5 ml of methanol for 16 hours at room temperature. Neutralize with 1.9 ml of IN MCI, concentrate by evaporation and extract with ethyl acetate. The extract was concentrated by evaporation and added with 1.5 ml of trifluoroic acid H.
Add and leave the whole thing at room temperature for 20 minutes. The trifluoroacetic acid is evaporated and the crude product is purified by flash chromatography (160 g of silica gel, 40-63 um, eluent S4). Take the remaining solution in lNllCl,
Complete concentration by evaporation and lyophilization from tert-butanol gives the title compound as a pale beige powder. Rf (B32) = 0.76, Example 57: N
-(α-Naphthoxyacetyl) -11is-α-naphthoxyacetic acid 59 mg, H-His-Cha 1Va
l-2-hydroxyethylamide 146■, HOBt4
The title compound is prepared analogously to Example 53 from 5 ol and DCCI78 and purified by flash chromatography using solvent system B4. Rf(B4)=0.30 23-phenyl-2(S)-pivaloyloxypropionic acid (Example 39a) 40 mg, It-His-
Leu -LGly-(R- and S-cyclohexylmethyl) -n-butylamide 70■, HOBt25nv
The title compound was prepared analogously to Example 17 from DCC139 and DCC139 and purified by Loba using solvent system B31.
r ) (trademark) (pre-purified by medium pressure chromatography on an MS11 column and isolated by lyophilization from tert-butanol. Rf (B8)
=0.64 (diastereomer A) and Rf(B8)=
0.55 (Diastereomer B) The starting material is prepared in the following way: "-Gly-(
Rf(B8)-0,17(diastereo?-A) and Rf(B8)= obtained by hydrogenating R- and S-cyclohexylmethyl)-n-butyramide analogously to Example 16a. 0.11 (Diastereomer B) b) Z-former 5-Leu”Gl-(R- and S-cyclohexylmethyl)-n-butyramide is Z-Flis
-OH and H-Leu LGly-(R- and S-cyclohexylmethyl)-n-butyramide are obtained analogously to Example 16b and purified by flash chromatography using the eluent NIO. Rf(B8
)-0,33 (diastereomer A) and Rf (B8
)-0,43(diastereomer B) 1鵠-whitec) II-Leu''-Gly-(R- and S-cyclohexyl (R- and s-cyclohexylmethyl)-n
obtained by hydrogenating -butyramide analogously to Example 16. Rf (BIO)-0,64(
Diastereomer A) and Rf (BIO) = 0.6
1 (diastereomer B) (R- and S-cyclohexylmethyl) -01 (and n-butylamine obtained analogously to Example 16j and separated by flash chromatography using eluent N4. Rf ( N3)-0,65 (diastereomer A) and Rf(N3)=0°59 (diastereomer B) nyl-2,2-dimethyl-4(S)-isobutyl-1,
3-oxazolidin-5(S)-yl]-2(R,S)
-cyclohexylmethylpropionic acid) is prepared by hydrolysis of the corresponding methyl ester analogously to Example 16i.

Rr (N4)-0,05 (diastereomeric mixture)±earth was prepared analogously to Example 1d from compound (X Purify by medium pressure chromatography on a Roper pre-il column using 19:1. Rf (N5)-0, 14 and 0.
17 g) 3-cyclohexylpropion nutilnis±soil:
20g of cyclohexylprobionic acid in methanol
Leave overnight at room temperature in 200 wl of N HCl. The solvent was evaporated and the residue was taken up in ether and saturated NaHCO3.
Wash with solution and saline and dry.

121-b Upon distillation, the title compound is obtained.

Example 59: N (3-phenyl-2(S)-bivalolamide: 3-phenyl-2(S)-pivaloyloxypropionic acid (Example 39 a) 29 mg, ■-former 5-Leu"
-G! Y-(R- and S-α-decahydronaphthyl)-
The title compound was prepared analogously to Example 17 from 55 mm of 〇-butyramide, 18 mm of HCIBt and 28 mm of DCCI and purified using Lobar using solvent system B31.
) (Trademark) Purify by medium pressure chromatography on a pre-prepared column. Rf (B8)”0.53
(diastereomer A) and Rf(B8)-0,45(
Diastereomer B) The starting material is prepared in the following way:
ly-(R- and S-α-decahydronaphthyl)-n-
Obtained by hydrogenating butyramide analogously to Example L6a. Rf (B8)-0 (both diastereomers) b) Z-His-Leu”-Gl-(R-bi5
-or-decahydronaphthyl)-n-butyramide is
Z-His-OH and H-Leu-'Gly-(R-
and 5-ct-decahydronaphthyl)-n-butylamide in analogy to Example 16b, which was purified using eluent B3.
Purify by medium pressure chromatography using 1.

R [(B 8) = 0.59 (diastereomer A
) and Rf (B8)-0,48 (diastereomer B) c) tl-Leu -'Gly-(R- and 5-
ex-decahydronaphthyl)-n-butyramide is Z
-Leu-containing cty-(R- and S-α-decahydronaphthyl)-n-butyramide was obtained by hydrogenation analogously to Example 16, which was neutralized using eluent N8 and then pure methanol. Purify by pressure chromatography. Rf (B8)-0 (both diastereomers) d) Lu incl.
R- and S-α-decahydronaphthyl)-OH and n-
It is obtained analogously to Example 16j from butylamine and separated by flash chromatography using eluent N4. Rf (N3) = 0.68 (diastereomer A) and Rf (N3)-0,61 (diastereomer B) Bonyl-2,2-dimethyl-4(S)-isobutyl-1
,3-oxazolidin-5(S)-yl]-2(R,S
)-α-decahydronaphthylpropionic acid) was prepared by hydrolysis of the corresponding methyl ester analogously to Example 1-6i and chromatographed under medium pressure using n-hexane/ethyl acetate 19:1. Purify by graphy.

Rf (N4) = 0.13 and 0.18 stellates were prepared analogously to Example 1d from compound (XXV) and α-decahydronaphthyl acetic acid methyl ester using n-hexane/ethyl acetate 19:1. Purify by medium pressure chromatography.

g) α-decahydronaphthyl-methyl ester is α-
Prepared analogously to Example 58g by esterifying decahydronaphthyl acetic acid.

IH-NMR (DMSO-d, , TMS): 3.
58ppm (s, 3H) and others h) α-decahydronaphthyl: 25g of α-naphthyl acetic acid to 1 part of water
20+++1 and IN sodium hydroxide solution 134+w
Platinum/rhodium catalyst (PtO2/H2
O-Rh2O3-54: 46) Hydrogenate in the presence of 1.3 g at room temperature and normal pressure for 31 hours.

The catalyst is placed on the side, acidified with concentrated hydrochloric acid (p) 11, and extracted with ether. Drying the ethereal extract and concentrating it by evaporation gives the title compound.

l engineering: N-(3-phenyl-2(S)-bihalo-to-shoj)
YOζtJiDan Osan'dDouble pressure and pregnancy lossBnie and S
-dimethylamino)-n-butyramide 3-phenyl-
2(S)-Pihyroyloxypropionic acid (Example 39
a) 20w, It-His-Leu -'cly-
, (R- and S-dimethylamino)-n-butyramide 27, 110Bt12 and DCCI 20 to prepare the title compound analogously to Example 17 using Lobar™ using solvent system B5. Purified by medium pressure chromatography on a pre-prepared column and te
The starting materials were separated by lyophilization from r t-butanol, Rf (B8) = 0.36 (diastereomer A) and Rf (B8) = 0.30 (diastereomer B). Produced by: a) H-)
1is-Leu "Gly-(R- and S-dimethylamino)-n-butyramide is Z-His-Leu"
'Gly-(R- and S-dimethylamino)-n-butyramide is obtained by hydrogenation analogously to Example 16a. Rf (B8) -0,01 (both diastereomers) b) Z-His-Leu''-Gl -(R-biS-
dimethylamino)-n-butyramide is Z-)is
-Oll and H-Leu -'Gly-(, R- and S
-dimethylamino) -n-butyramide to Example 16b
and purified by medium pressure chromatography using eluent B33. Rf (B8
) = 0.36 (diastereomer A) and Rr (B
8) = 0.15 (diastereomer B) c) H-Leu iGl -(R- and S-dimethylamino)-n-butyramide is
-(R,S-dimethylamino)-n-butyramide is obtained analogously to Example 16 by hydrogenation and separation by medium pressure chromatography using eluent B33. Rf (B8)-0,28 (diastereomer A) and Rf (B8)-0,19 (diastereomer B) d) Z-Leu "Gly-(R,S-dimethylamino)-n-butyramide is , Z-Leu “Gly-(
R,S-dimethylamino)-○H and n-butylamine as in Example 16j and purified by flash chromatography using the eluent methylene chloride/methanol/conc. ammonia 500:10=1.

Rf (B31) = 0.91 and 0.95e) Z
-Leu uGly-(R,S-dimethylamino)-0
11(3-(3-benzyloxycarbonyl-2゜2-
dimethyl-4(S)-isobutyl-1,3-oxazolidin-5(S)-yl)-2(R,S)-dimethylaminopropionic acid) was prepared using the corresponding ethyl ester in Example 16.
It is prepared by hydrolysis analogously to i and purified by medium pressure chromatography using eluent N8.

Rr (N 3) -0,21 and 0.10 compounds (
XXV) and dimethylaminoacetic acid ethyl ester in analogy to Example 1d, ? t/7 by medium pressure chromatography using a releasing agent N3. Rr
(N3)=0.52 and 0.35!・、!゛、'iE
! L'11 Example 61: N-(indolyl-2-carbonyl)-indole-2-carvone 5122111v, HOBt20
■ and 23 μl of ethyldiisopropylamine in DMF2
Cool to 0°C in +gl* H41s-Leu −'
After addition of Val-4-[tris-(tert-butyldimethylsilyloxymethyl)-methylcarbamoyl]-butylamide 116111r and DCCI 3411t, the whole is stirred for 24 hours while cooling with ice and then for 2 days at room temperature. The crystalline DCH is passed through the suction port and the plate is concentrated in a high vacuum. The residue is purified by flash chromatography using solvent system B23. tert-
Freeze-drying in 20 ml of butanol gives the title compound in the form of a pale yellow lyophilizate, ? L, Rf
(B4) -0,49 starting material is prepared in the following way: a) H-old 5-Lcu -G-Val-4-
()Lis-(tert-butyldimethylsyloxymethyl)-methylcarhamoylcubyramide was prepared from the corresponding N-hensyloxycarbonyl compound in Example 4 a.
It can be obtained by hydrogenation in the same manner as . Rf
(B4)=0. Z-11is-01158rrg, I in 4 ml DMF
f-Leu 1Val-4-[Tris-(ter t-
butyldimethylsilyloxymethyl)-methylcarbamoylbutylamide (European Patent Application Publication No. 14374)
Manufactured according to Publication No. 6) 155■, ethyldiisopropylamide 735μff, ll0BL31 ITg and DC
The title compound is prepared analogously to Example 61 from 54 mg of CI and purified by flash chromatography using eluent B23. Rf (B4) Tength 0.42
N(indolyl-2-carbonyl)-11is-Le
u J-Val-4()lis-(ter t-butyltmethylsilyloxymethyl)-methylcarbamoyl]-
Butyramide 36nw and 2:1 mixture of acetic acid/water 2m
1 is stirred at room temperature for 2 hours and then concentrated by evaporation.

The residue is purified by flash chromatography using the solvent system Bll to give the title compound in the form of a white powder. Rf (Bl 1) = 0.27 N-benzylindole-3-carboxylic acid 30■, H-
His-Leu 1Val-2-picolylamide 45■
The title compound is prepared analogously to Example 4 from 1108t19 and DCCI 30 and purified by flash chromatography using eluent B7.

Rf (B7) −0,31; Rf (B9) −
The 0,43 starting material is produced in the following way: a)
H-His-Leu J&-Val-2-picolylamide is prepared by adding 2゜His-Leu''-Val-2-picolylamide 430cm to palladium-coated activated carbon (I0%) 5
Obtained analogously to Example 1g by hydrogenation in the presence of 0ffv. Rf (Bl 1) = 0.18;
Rf (B7) = 0.12 b ) Z-11is-Leu 1Val-2-picolylamide is Z-tlis-OH225IIv, H-
Leu J-Val-2-picolylamide 350■,,
The title compound is prepared analogously to Example 1 from 110Bt 130 and DCCI 218 and purified by flash chromatography using eluent B7.

Rf (B7) = 0.30; Rf (B 1 1)
-0,63 c) II-Leu 1Val-2-picolylamide is Z-Leu”Val-2-picolylamide 1.69
Example 1g is obtained analogously to Example 1g by hydrogenating g in the presence of 170 μm of palladium-coated activated carbon (I0%).

Rf (B7) = 0.25 d) Z-Leu "Val-2-picolylamide is Z-Lcu'-; Val-OH1,50g, 2-
Aminomethylpyridine 0.76ml, HO [lt 68
0ff! and DCCll, prepared analogously to Example 1 from 070 g, and purified by flash chromatography using eluent N7. Rf (N7)
=0.32 Example 64 The following compounds were prepared analogously to Example 8: a) N-(
indolyl-2-carbonyl) -Hls-Leu”
-Val-n-pentylamide; flash chromatography using eluent B4; Rf (B4)=0.
42 b) N-(indolyl-2-carbonyl) -11is
-Leu “Val-cyclohexylmethylamide; flash chromatography using eluent B23; R
f (B4)-0,34 c) N-(indolyl-2-carbonyl) -tlis
-Leu LVal-5-Hydroxypentylamide, D; flash chromatography with drench agent B4; Rf (B4)-0,18 d) N-(α-naphthoxyacetyl) -Hls-Le
Excision B of uiVal-2-hydroxyethylamide;
Flash chromatography using Rf(B4
)=O°27, lower margin Example 65 The following compounds were prepared in analogy to Example 4: a) N-(
oNinaphthoxyacetyl) -Phe-Leu-'V
al-n-butyramide; furanotsuyu chromatography using 1-drug NIO; Rf(NIO)-0,15 b) N-methyl-N(α-naph I xyacetyl)-P
he-Leu”-Val-n-butyramide; flash chromatography with solvent N7; Rr(N
7) = 0.26 Example 66 The following compound can be prepared by one of the above examples: N-(2-(2-amino-2-methylpropionyloxy)-3-α-naphthylpropionyl]- H1s-Ch
a LVal-n-butyramide; N-(2-acetoacetoxy-3-α-naphthylpropionyl) -Hls
-Cha 1Val-n-butyramide; N-(2-cyano-3-α-naphthylpropionyl)-
Old 5-Cha-'Val-n-butyramide; N-(
2-acetyl-3-α-naphthylpropionyl) -H
ls-Cha 1VaLn-butyramide; N-(2-
acetonyl-3-α-naphthylpropionyl) -Hl
s-Chaiνal-n-butyramide-N-(5-
dimethylamino-2-α-naphthoxypentanoyl)
-Hls-Cha'-Val-n-butyramide; N-(4-carboxy-2-α-naphthoxybutyryl)
-Hls-Cha "Val-n-butyramide; N
-(2-α-naphthoxy-4-oxopentanoyl)
-Hls-Cha”-Val-n-butyramide; N
-(cyano-α-naphthoxyacetyl)-former 5-Cha
"-Val-n-butyramide; N-(3-phenyl-2-pivaloyloxypropionyl) -Hls-C
ha 1Gly (dimethylamino)-n-butylamide↓ N-(2-benzyl-5,5-dimethyl-4-oxohexanoyl) -Its-Cha 1Gly (dimethylamino)-n-butylamide; N-(3-phenyl -2-pivaloyloxypropionyl) -11is-Cha -LVal-2-(4-imidazolyl)-ethylamide; N-(2-benzyl-5,5-dimethyl-4-oxohexanoyl) -Hls-Cha - 'Val-2-(
4-imidazolyl)-ethylamide; N-(3-phenyl-2-pivaloyloxypropionyl)-11is-Cha”-Val-2-(2-(
4-imidazolyl)-ethylaminoco-ethylamide;
N-(2-benzyl-5,5-dimethyl-4-oxohexanoyl) -Hls-Cha -'-Val-2-
(2-(It-imidazolyl)-ethylaminoco-ethylamide: N-(2-benzyl-5,5-dimethyl-4-oxohexanoyl) -Hls-Cha'-Val-4-carboxybutyramide; N-(2 -(2-dimethylaminoethylcarbamoyl)
-3-phenylpropionyl) -11is-Chai
Val-4-carboxybutyramide; N-(2-dimethoxyphosphoryl-3-phenylpropionyl)-former 5
-Cha 1Val-4-carboxybutyramide; N-(2-(5-amino-5-carboxypentylcarbamoyl)-3-phenylpropionyl)-His-C
ha "Val-n-butyramide; N-(2-dimethylaminomethyl-3-α-naphthylpropionyl) -
Hls-Cha 1Vat-4-carboxybutyramide; N-(2-benzyl-5-dimethylamino-4-oxopentanoyl) -Hls-Cha 1Val-methylamide; N-(2-acetoxy-4-phenylbutyryl) -Old 5
-Cha-'Val-n-butyramide; N-(2-
cyanmethyl-4-phenylbutyryl)-His-Ch
a 1Val-n-butyramide; N-(2-ethylaminocarbonyloxy-4-phenylbutyryl) -H
is-Cha -'Val-n-butylamide; N-(3-α-naphthyl-2-neopentyloxypropionyl) -Hls-Cha J-Val-n-butylamide; N-(2-hensyl-5,5- N-(,t,4-dimethyl-3-oxo-2-(2-phenylethyl)-pentanoyl) -Hls -Chai
Val-n-butyramide; N-(2-dimethoxyphosphoryl-4-phenylbutyryl) -His-Cha J-Val-n-butyramide; N-(2-jethoxyphosphorylmethyl-4-phenylbutyryl) -11is -Cha -'Val-n
-Butylamide; N-(5,5-dimethyl-4-oxo-2-(2-phenylethyl)-hexanoyl)-former 5-ChaLVal
-n-butyramide; N (2-tert-butylcarbamoyl-4-phenylbutyryl) -Hls-Cha 1Vat-n-butyramide; N (2-tert-butylcarbamoyl-3-phenylpropionyl) -Hls-Cha 1Val- n
-butyramide; N (2-tert-butylcarbamoyl-3-α-
naphthylpropionyl) -tlis-Cha”-V
at-methylamide; N-(2-hensyl-5,5-dimethyl-4-oxohexanoyl)-Hls-Cha”-Val-methylamide; N-(2-benzyl-5,5-dimethyl-4-oxohexanoyl) N-(2-benzyl-4,4-dimethyl-3-oxopentanoyl) -Hls-Leu -'Gly-(cyclohexylmethyl) -n-butylamide; N (2-tert-butylcarbamoyl-3-phenylpropionyl) -Hls-Leu''-Gly-
(Cyclohexylmethyl)-n-butylamide;
-oxohexanoyl)-formerly 5-Cha”-Val-
While heating a sterile aqueous solution of n-butylamide under aseptic conditions, mix with a sterile gelatin solution containing phenol as a preservative such that 1.0 ml of the solution has the following composition: N (2(R, S)-benzyl-5,5-dimethyl-
4-oxohexanoyl)-His-Cha”Val
-n-butyramide 3 ■Gelatin
150.0 ■ Phenol
4.711Ig in distilled water
Mixture under sterile conditions until 1-0w1
．． Introduce into a 0 ml vial.

Example 68: Sterile dry product for injection with N-(2(R,S)-benzyl-5,5-dimethyl-4
-oxohexanoyl) -Hls-Cha J'-V
5 ml of al-n-butyramide is dissolved in 1 ++ 1 aqueous solution containing 20+ ng of mannitol, the solution is sterile sifted, emptied under sterile conditions into 2 ml ampoules, frozen and lyophilized. Before use, the lyophilizate is dissolved in distilled water la+1 or physiological saline 1+++1, and the solution is administered intramuscularly or intravenously. This formulation can also be introduced into two-chamber injection ampoules.

Example 69: l bile gueyu Finely ground (<5.(lrm)N-(2(R).

S)-benzyl-5,5-dimethyl-4-oxohexanoyl) -Hls-Cha-'Vat-n-butyramide 500at
) 812”3.5ml and benzyl alcohol 0.
08 g. This suspension is placed in a container with an 11-volume valve. “Freon
) 12'' 5.0 g from the pulp into the container under pressure. By shaking, 'Freon 1
is dissolved in a mixture of myglyol and benzyl alcohol.

This spray container contains approximately 100 individual doses that can be administered individually.

Example 70: IC5o of renin inhibition (direct IC5o (I represents the concentration that reduces the formation of angiotensin I from angiotensinogen (renin substrate) by 50% in the presence of human-renin.

ICs with the side numbers below.

The following margin shows the title compound (μMof/7ri4
0.07 5 a 0.65b
O,6 5c O,3 5d O,3 5e O,4 5f O,4 5g 0.3 5h O,3 5i 4 60.8 "8 0.05 9a O,2 9b O,2 9c O,2 9d 0.1 10 0.411a
2 11b 0.311 C2 120,4 130,01 15a 2 15 b 3 15 C2 160,002 170,003 1B 0.00519
0.0420
0.00221 0.1
22 0, 0723 a
0.12 3 b
0.22' 3 c
O-0923d 0.6 23 e 0.0223f
O,009240,002 250,006 260,OO2 270,01 280,01 290,001 300,00B 31 0.02 32 0.00433
0, OO3340,02 350,02 360,09 370,005 3B O,012390,OO
7 400,007 420,004 430,02 440,1 45a O,OO345b
O, O(I345c
O,01345d
O,01345e O,01
45f O, 0845g
0.0545 h
0.0245i 0.0
345j O, 00245k
O,002460,1 480,1 490,5 500,013 510,4 52 0,0953
0.2 54 0.1 55 0, OO2570,2 580,005 620,03

Claims (1)

[Claims] 1. General formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R_3 is hydrogen or an acyl group other than an acyl group substituted with N in the case of a natural amino acid. , A represents an optionally N-alkylated α-amino acid group whose N-terminus is bonded to R_1 and whose C-terminus is bonded to the group -NR_2-, and R_2 is hydrogen or a lower alkyl group. represents,
R_3 is hydrogen, a lower alkyl group, optionally an etherified or esterified hydroxy lower alkyl group,
represents a cycloalkyl group, a cycloalkyl lower alkyl group, a bicycloalkyl lower alkyl group, a tricycloalkyl lower alkyl group, an aryl group or an aryl lower alkyl group, R_4 represents a hydroxy group or an etherified or esterified hydroxy group, R_5 is a lower alkyl group having 2 or more carbon atoms, optionally an etherified or esterified hydroxy lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a bicycloalkyl group, a bicycloalkyl lower alkyl group, a tricycloalkyl group , represents a tricycloalkyl lower alkyl group, an aryl group, an aryl lower alkyl group, an optionally substituted carbamoyl group, an optionally substituted amino group, an optionally substituted hydroxy group or an optionally substituted mercapto group, R_6 represents a substituted amino acid excluding the amino group derived from α-amino acid]
and salts of the compounds having a salt-forming group. 2, R_1 is hydrogen or partial formula R^bO-, R^a-O-CO- or (R^b) (R^b)N-CO
-CO- (wherein R^a is an unsubstituted or substituted, saturated or unsaturated aliphatic, cycloaliphatic or alicyclic-aliphatic group having 18 or less carbon atoms, preferably 10 or less, or 18 carbon atoms or less, preferably up to 10 unsubstituted or substituted aromatic, heterocyclic aromatic or araliphatic or heterocyclic aromatic-aliphatic hydrocarbons, or unsubstituted or substituted 5- or 6-membered saturated hetero Represents a ring, R^b
represents hydrogen or represents an acyl group with the definition R^a), but does not represent an optionally N-substituted acyl group of a natural amino acid, A is N-terminally linked to R_1, C
- terminal is bonded to the group -NR_2-, optionally N
- represents an alkylated α-amino acid group, R_2 represents hydrogen or a lower alkyl group, R_3 represents hydrogen, a lower alkyl group, a hydroxy lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a bicycloalkyl lower alkyl group , represents a tricycloalkyl lower alkyl group, an aryl group, or an aryl lower alkyl group, R_4 represents a hydroxy group, and R_5 represents a lower alkyl group having 2 or more carbon atoms, a hydroxy lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group group, bicycloalkyl group, bicycloalkyl lower alkyl group, tricycloalkyl group, tricycloalkyl lower alkyl group, carbamoyl group, lower alkylcarbamoyl group, di-lower alkylamino group, aryl group or aryl lower alkyl group, and R_6 represents Represents an amino group other than an amino group derived from an α-amino acid, and this group may contain one or optionally two
unsubstituted or substituted, saturated or unsaturated aliphatic hydrocarbon group having up to 18 carbon atoms, preferably up to 10 carbon atoms,
or substituted with an unsubstituted or substituted aromatic, heteroaromatic, aromatic-aliphatic or heterocyclic aromatic-aliphatic hydrocarbon group having up to 18 carbon atoms, preferably up to 10 carbon atoms. General formula (I) described in range 1
and a pharmaceutically acceptable salt of the compound having a salt-forming group. 3, R_1 is hydrogen, a lower alkanoyl group having 1 to 7 carbon atoms, a hydroxy lower alkanoyl group, a lower alkoxy lower alkanoyl group, a phenoxy lower alkanoyl group,
Naphthoxy lower alkanoyl group, lower alkanoyloxy lower alkanoyl group, carboxy lower alkanoyl group, lower alkoxycarbonyl lower alkanoyl group, carbamoyl lower alkanoyl group, lower alkylcarbamoyl lower alkanoyl group, di-lower alkylcarbamoyl lower alkanoyl group, α-naphthoxy-carboxy lower Alkanoyl group, α-naphthoxy-lower alkoxycarbonyl lower alkanoyl group, α-naphthoxy-benzyloxycarbonyl lower alkanoyl group, α-naphthoxy-
Carbamoyl lower alkanoyl group, α-naphthoxycyano lower alkanoyl group, α-naphthoxy-dilower alkylamino lower alkanoyl group, α-naphthoxy-oxo-lower alkanoyl group, lower alkenoyl group having 3 to 7 carbon atoms, 3 to 7 carbon atoms 7 lower alkinoyl group, a cycloalkylcarbonyl group having 4 to 9 carbon atoms, a bicycloalkylcarbonyl group having 6 to 11 carbon atoms, a tricycloalkylcarbonyl group having 9 to 11 carbon atoms, a cycloalkylcarbonyl group having 4 to 9 carbon atoms, Monocycloalkenylcarbonyl group, bicycloalkenylcarbonyl group having 6 to 11 carbon atoms,
Cycloalkyl lower alkanoyl group having 5 to 11 carbon atoms, cycloalkyl lower alkanoyl group having 6 to 11 carbon atoms, cycloalkenyl lower alkanoyl group having 5 to 11 carbon atoms, unsubstituted or lower alkyl group, halogen, hydroxy group , benzoyl group substituted with one or more lower alkoxy groups and/or nitro groups, phenyl-, α
-naphthyl- or β-naphthyl-lower alkanoyl group (phenyl group is unsubstituted or substituted with one or more lower alkyl groups, halogen, hydroxy group, lower alkoxy group and/or nitro group, lower alkanoyl group is unsubstituted or groups, lower alkoxy groups, acyloxy groups, carboxy groups, esterified carboxy groups, carbamoyl groups, substituted carbamoyl groups, cyano groups, phosphono groups, esterified phosphono groups, benzofuranyl groups and/or oxo groups; ), a substituted anilinophenylacetyl group, a phenyl lower alkenoyl group, a naphthylcarbonyl group, an indenylcarbonyl group, an indanylcarbonyl group, a phenanthrenylcarbonyl group, an optionally substituted pyrrolylcarbonyl group,
Furylcarbonyl group, thienylcarbonyl group, pyridylcarbonyl group, optionally substituted indolylcarbonyl group, 4,5,6,7-tetrahydroindolyl-2
- carbonyl group, cyclohepta[b]pyrrolyl-5-carbonyl group, optionally substituted quinolylcarbonyl group, optionally substituted isoquinolylcarbonyl group,
2-quinoxalinylcarbonyl group, 2-benzofuranylcarbonyl group, benzo[e]indolyl-2-carbonyl group, β-carbolinyl-3-carbonyl group, pyrrolidinyl-3-carbonyl group, hydroxypyrrolidinylcarbonyl group , oxopyrrolidinylcarbonyl group, piperidinylcarbonyl group, indolinylcarbonyl group, 1,
2,3,4-tetrahydroquinolylcarbonyl group, 1,
2,3,4-tetrahydroisoquinolylcarbonyl group,
represents an aryl lower alkoxycarbonyl group, an oxamole group or a lower alkyl oxamole group, A is a natural α-amino acid having the L-configuration as normally present in proteins, and the amino acid side chain of such amino acid is 1 extended or shortened by one or two methylene groups,
and/or homologs in which one methyl group is substituted with hydrogen, one or more substituted phenylalanine or phenylglycine (substituents include lower alkyl group, halogen, hydroxy group, lower alkoxy group, lower alkanoyloxy group, phenylalanine or phenylglycine fused with a benzene ring) , hydrogenated phenylalanine or phenylglycine, 5- or 6-membered cyclic α-amino acids condensed with a benzene ring, side chain carboxy groups esterified or amidated, side chain amino groups acylated. divalent radicals of natural or homologous α-amino acids in which the hydroxyl groups of the side chains are present in etherified or esterified form, or epimers of such amino acids, i.e. with a non-naturally occurring D configuration; , represents a divalent group of an amino acid optionally substituted at the N-atom, R_2 represents hydrogen or a lower alkyl group, R_3 represents a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a tricycloalkyl lower alkyl group, group, phenyl lower alkyl group or phenyl group, R_4 represents a hydroxy group, R_5 is a lower alkyl group having 2 to 7 carbon atoms, a cycloalkyl group, a cycloalkyl lower alkyl group, a bicycloalkyl group, a tricycloalkyl group , phenyl group, phenyl lower alkyl group, carbamoyl group,
Represents a lower alkylcarbamoyl group or a di-lower alkylamino group, R_6 is an alkylamino group having 1 to 10 carbon atoms, a di-lower alkylamino group, a hydroxy lower alkylamino group, a di-(hydroxy lower alkyl) amino group, a lower alkoxy Lower alkylamino group, lower alkanoyloxy lower alkylamino group, phenoxy lower alkylamino group or phenoxyhydroxy lower alkylamino group (phenoxy group may optionally be lower alkyl group, lower alkoxy group, hydroxy group, carboxy group, lower alkoxycarbonyl group or (substituted with carbamoyl group)
, carboxyalkylamino group or amino-carboxyalkylamino group (carboxy group is one of the alkyl groups)
position), and further dicarboxymethylamino group,
lower alkoxycarbonylalkylamino groups or acylamino lower alkoxycarbonylalkylamino groups (the carbonyl group is not present in the 1-position of the alkyl group), further di-lower alkoxycarbonylmethylamino groups, physiologically degradable esterified carboxyalkylamino groups ( ester functionality is not present in the 1-position of the alkyl group)
, carbamoyl- or hydroxy-lower alkylcarbamoylalkylamino group (the carbamoyl group is not present in the 1-position of the alkyl group), further dicarbamoylmethylamino group, di-(lower alkylcarbamoyl)-methylamino group, di-(hydroxy-lower alkyl group) carbamoyl)
-methylamino group or bis-(di-lower alkylcarbamoyl)-methylamino group, amino lower alkylamino group, lower alkylamino lower alkylamino group, di-lower alkylamino lower alkylamino group, lower alkoxycarbonylamino lower alkylamino group, guanidino lower alkylamino group, 5- or 6-membered saturated heterocyclyl-lower alkylamino group bonded via a nitrogen atom, lower alkenylamino group, lower alkynylamino group, cycloalkyl lower alkylamino group, phenylamino group, Phenyl lower alkylamino group (Phenyl group may optionally include lower alkyl group, hydroxy group, lower alkoxy group, lower alkanoyloxy group, halogen, carboxy group, lower alkoxycarbonyl group, carbamoyl group, amino group, lower alkylamino group, di-lower (substituted with one or more alkylamino groups, acylamino groups and/or nitro groups), pyridyl lower alkylamino groups, imidazolyl lower alkylamino groups, or indolyl lower alkylamino groups according to claim 1. Compounds of formula (I) and pharmaceutically acceptable salts of these compounds having salt-forming groups. 4, R_1 is a lower alkanoyl group, a lower alkenoyl group, a lower alkinoyl group, a cycloalkylcarbonyl group,
Unsubstituted or lower alkyl group, halogen, hydroxy group, lower alkoxy group and/or benzoyl group substituted with one or more nitro group, phenyl lower alkanoyl group (
Phenyl group is unsubstituted or lower alkyl group, halogen, hydroxy group, lower alkoxy group and/or nitro group.
lower alkanoyl group may be unsubstituted or substituted with hydroxy group, acyloxy group, carboxy group or esterified carboxy group), substituted anilinophenyl acetyl group, phenyl lower alkenoyl group, naphthylcarbonyl group. group, naphthyl lower alkanoyl group (lower alkanoyl group may be substituted with hydroxy group, acyloxy group, carboxy group or esterified carboxyl group), indenylcarbonyl group, indanylcarbonyl group, phenanthrenylcarbonyl group, case pyrrolylcarbonyl group, furylcarbonyl group, thienylcarbonyl group, pyridylcarbonyl group, optionally substituted indolylcarbonyl group, 4
, 5,6,7-tetrahydroindolyl-2-carbonyl group, optionally substituted quinolylcarbonyl group, optionally substituted isoquinolylcarbonyl group, 2-quinoxalinylcarbonyl group, 2-benzofuran Nylcarbonyl group, benzo[e]indolyl-2-carbonyl group,
β-Carbolinyl-3-carbonyl group, indolinylcarbonyl group, 1,2,3,4-tetrahydroquinolylcarbonyl group, 1,2,3,4-tetrahydroisoquinolylcarbonyl group, 1 or 2 aryl an arylmethoxycarbonyl group (wherein the aryl group is a phenyl group optionally substituted with 1, 2 or 3 by lower alkyl, lower alkoxy, hydroxy, halogen and/or nitro groups), an oxamole group or Represents a lower alkyloxamole group, and A is an amino acid: alanine, valine, norvaline, leucine, norleucine, serine, proline, phenylalanine, β-phenylserine, α-naphthylalanine,
Cyclohexylalanine, indoline-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid, asparagine, aminomalonic acid, aminomalonic acid monoamide, glutamic acid, glutamine, di-lower alkylglutamine, histidine , represents a divalent group of lysine or ornithine, the carboxy group of the side chain of aspartic acid or glutamic acid may be esterified with a lower alkanol, and the hydroxy group of serine is etherified with a lower alkyl group or a benzyl group. Often, the amino group of the side chain of lysine or ornithine may be acylated with a lower alkanoyl group, lower alkoxycarbonyl group or arylmethoxycarbonyl group and/or the α-nitrogen atom of the amino acid may be substituted with a lower alkyl group. Often, R_2 represents hydrogen or a lower alkyl group, R_3 represents a lower alkyl group, cycloalkyl lower alkyl group, or tricycloalkyl lower alkyl group, R_4 represents a hydroxy group, and R_5 represents a lower alkyl group having 2 to 7 carbon atoms. represents an alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a 1-adamantyl group, a benzyl group, a carbamoyl group, or a lower alkylcarbamoyl group, and R_6 is an amino group, an alkylamino group, a di-lower alkylamino group, or a hydroxy lower alkylamino group. group, carboxyalkylamino group (carboxy group is not present in the 1-position of the alkyl group), further dicarboxymethylamino group, lower alkoxycarbonylalkylamino group (carbonyl group is not present in the 1-position of the alkyl group), further di-lower an alkoxycarbonylmethylamino group, a physiologically degradable esterified carboxyalkylamino group (the ester function is not present in the 1-position of the alkyl group), a carbamoyl- or hydroxylower alkylcarbamoyl-alkylamino group (a carbamoyl group is an alkyl group) ), and further dicarbamoylmethylamino group, di-(lower alkylcarbamoyl)-methylamino group, di-(hydroxy-lower alkylcarbamoyl)-methylamino group or bis-(di-lower alkylcarbamoyl)
- methylamino group, amino lower alkylamino group, lower alkylamino lower alkylamino group, di-lower alkylamino lower alkylamino group, lower alkoxycarbonylamino lower alkylamino group, guanidino lower alkylamino group, cycloalkyl lower alkylamino group, Pharmacology of compounds of the general formula (I) according to claim 1 representing a benzylamino group, a pyridyl lower alkylamino group, an imidazolyl lower alkylamino group or an indolyl lower alkylamino group, and of these compounds having a salt-forming group acceptable salt. 5, R_1 is a lower alkanoyl group, 2-(o,o-dichloroanilino)-phenylacetyl group, 2-(o,o-
dichloro-N-benzylanilino)-phenylacetyl group, optionally substituted pyrrolylcarbonyl group, furylcarbonyl group, thienylcarbonyl group, pyridylcarbonyl group, optionally substituted indolylcarbonyl group, 4,5,6 , 7-tetrahydroindolyl-2-carbonyl group, optionally substituted quinolylcarbonyl group, optionally substituted isoquinolylcarbonyl group,
2-quinoxalinylcarbonyl group, 2-benzofuranylcarbonyl group, benzo[e]indolyl-2-carbonyl group, β-carbolinyl-3-carbonyl group, indolinylcarbonyl group, 1,2,3,4- Norleucine, phenylalanine, which represents a tetrahydroquinolinylcarbonyl group or a 1,2,3,4-tetrahydroisoquinolylcarbonyl group, and A is an amino acid;
cyclohexylalanine, glutamic acid, glutamine,
N^8-dimethyl-glutamine, ornithine or N^8
- represents a divalent group of pivaloyl-ornithine, R_2 represents hydrogen, R_3 represents an isobutyl group, cyclohexylmethyl group, or 1-adamantylmethyl group, R_4 represents a hydroxy group, R_5 represents an isopropyl group, a cyclohexyl group, Represents a cyclohexylmethyl group or a methylcarbamoyl group, and R_2 is a lower alkylamino group, di-lower alkylamino group, hydroxy lower alkylamino group, carboxyalkylamino group (carboxy group does not exist at the 1-position of the alkyl group), lower alkoxycarbonyl The general group according to claim 1, which represents an alkylamino group (the carbonyl group is not present at the 1-position of the alkyl group), an amino lower alkylamino group, a guanidino lower alkylamino group, a benzylamino group, or a pyridyl lower alkylamino group. Formula ( I
) and pharmaceutically acceptable salts of these compounds having a salt-forming group. 6, R_1 is a lower alkanoyl group having 1 to 7 carbon atoms,
Phenoxy lower alkanoyl group, naphthoxy lower alkanoyl group, α-naphthoxycarboxy lower alkanoyl group, α-naphthoxy lower alkoxycarbonyl-lower alkanoyl group, α-naphthoxy-benzyloxycarbonyl lower alkanoyl group, α-naphthoxycarbamoyl lower alkanoyl group, α-naphthoxy-cyano-lower alkanoyl group, α-naphthoxy-di-lower alkylamino-
Lower alkanoyl group, α-naphthoxy-oxo-lower alkanoyl group, phenyl-, α-naphthyl- or β
-Naphthyl-lower alkanoyl group (lower alkanoyl group is unsubstituted or hydroxy group, lower alkoxy group, acyloxy group, carboxy group, esterified carboxy group, carbamoyl group, substituted carbamoyl group, cyano group, phosphono group, esterified phosphono group, Benzofuranyl group and/or
or oxo group, optionally branched), 2-(o,o-dichloroanilino)-phenylacetyl group, 2-(o,o-dichloro-N-benzylanilino)- Phenylacetyl group, naphthylcarbonyl group, pyrrolylcarbonyl group, cyclohepta[b]pyrrolyl-5-carbonyl group, indolylcarbonyl group, 1-
benzylindolyl-3-carbonyl group, 4,5,6,
Leucine, norleucine, phenylalanine, N-methylphenylalanine, β-phenylserine, which represents a 7-tetrahydroindolyl-2-carbonyl group, quinolylcarbonyl group or oxamole group, and A is an amino acid;
Represents a divalent group of cyclohexylalanine, glutamine, histidine, or N-methylhistidine, R_2 represents hydrogen, R_3 represents an isobutyl group or cyclohexylmethyl group, R_4 represents a hydroxy group, and R_5 represents an isopropyl group or a cyclohexylmethyl group. , α-decahydronaphthyl group or dimethylamino group, R_6 is a lower alkylamino group having 1 to 7 carbon atoms, di-lower alkylamino group, hydroxy lower alkylamino group, 2-phenoxyethylamino group, 2-( 3-carbamoyl-4-hydroxyphenoxy)-ethylamino group, carboxyalkylamino group or amino-carboxyalkylamino group (carboxy group is not present in the 1-position of the alkyl group), lower alkoxycarbonylalkylamino group or acylamino lower alkoxycarbonyl group alkylamino group (carbonyl group is not present at the 1-position of the alkyl group), 4-tris-(hydroxymethyl)-methylcarbamoyl-n-butylamino group, amino lower alkylamino group, di-lower alkylamino lower alkylamino group, The general formula according to claim 1 representing a lower alkoxycarbonylamino lower alkylamino group, a morpholino lower alkylamino group, a cycloalkyl lower alkylamino group, a benzylamino group, a pyridyl lower alkylamino group, or an imidazolyl lower alkylamino group (
Compounds of I) and pharmaceutically acceptable salts of these compounds having a salt-forming group. 7, R_1 is phenoxy lower alkanoyl group, naphthoxy lower alkanoyl group, phenyl lower alkanoyl group (
The lower alkanoyl group is an unsubstituted or acyloxy group, a carboxy group, an esterified carboxy group, a carbamoyl group,
substituted carbamoyl group, cyano group, esterified phosphono group or lower alkyl group and oxo group or benzofuranyl group and oxo group, optionally branched), naphthyl lower alkanoyl group (lower alkanoyl group is unsubstituted) or may be substituted with an acyloxy group, a carboxy group, an esterified carboxy group, an unsubstituted carbamoyl group, a substituted carbamoyl group, a cyano group or a lower alkyl group and an oxo group, optionally branched),
Indolyl-2-carbonyl group or cyclohepta [b]
represents a pyrrolyl-5-carbonyl group, A represents a divalent group of the amino acid L-histidine, R_2 represents hydrogen, R_3 represents an isobutyl group or a cyclohexylmethyl group, R_4 represents a hydroxy group, and R_5 represents a represents an isopropyl group or a cyclohexylmethyl group, R_6 represents a lower alkylamino group or an amino-carboxy lower alkylamino group (the substituent is not present at the 1-position of the lower alkyl group), and the carbon atom bearing the groups R_3 and R_4 is S
- General formula according to claim 1 having the configuration (
Compounds of I) and pharmaceutically acceptable salts of these compounds. 8. Phenyl- in which R_1 is a lower alkanoyl group substituted with a lower alkanoyloxy group, a lower alkoxycarbonyl group, a lower alkylcarbamoyl group, a di-lower alkoxyphosphoryl group, or a lower alkyl group and an oxo group
or α-naphthyl lower alkanoyl group (lower alkyl group has 1 to 7 carbon atoms), indolyl-2
-carbonyl group or cyclohepta[b]pyrrolyl-5-
represents a carbonyl group, A represents a divalent group of the amino acid L-histidine, R_2 represents hydrogen, R_3 represents a cyclohexylmethyl group, R_4 represents a hydroxy group, R_5 represents an isopropyl group, and R_6 represents a Represents a lower alkylamino group having 1 to 7 carbon atoms, and the group R_3, R
Compounds of general formula (I) according to claim 1, in which the carbon atoms bearing _4 and R_5 have an S-configuration, and pharmaceutically acceptable salts of these compounds. 9, R_1 represents a 2(S)-pivaloyloxy-3-phenylpropionyl group, A represents a divalent group of the amino acid L-histidine, R_2 represents hydrogen, R_3 represents a cyclohexylmethyl group, and R_4 represents a cyclohexylmethyl group. represents a hydroxy group, R_5 represents an isopropyl group, and R_6 represents an n-
Claim 1 represents a butylamino group and the carbon atoms bearing the groups R_3, R_4 and R_5 have an S-configuration.
Compounds of general formula (I) and pharmaceutically acceptable salts thereof as described in 1. 10, R_1 is 2(R,S)-, 2(R)- or 2(S
)-dimethoxyphosphoryl-3-phenylpropionyl group, A represents a divalent group of the amino acid L-histidine, R_2 represents hydrogen, R_3 represents a cyclohexylmethyl group, R_4 represents a hydroxy group, R_5
represents an isopropyl group, R_6 represents an n-butylamino group, and the carbon atoms having the groups R_3, R_4 and R_5 have an S-configuration; Pharmaceutically acceptable salts. 11, R_1 is 2(R,S)-, 2(R)- or 2(S
)-benzyl-5,5-dimethyl-4-oxohexanoyl group, and 2 of L-histidine in which A is an amino acid
represents a valent group, R_2 represents hydrogen, R_3 represents a cyclohexylmethyl group, R_4 represents a hydroxy group, R
A compound of the general formula (I) according to claim 1, in which _5 represents an isopropyl group, R_6 represents an n-butylamino group, and the carbon atoms having the groups R_3, R_4 and R_5 have an S-configuration; and A pharmaceutically acceptable salt thereof. 12, R_1 represents a 2(R,S)-benzyl-4,4-dimethyl-3-oxopentanoyl group, A represents a divalent group of the amino acid L-histidine, R_2 represents hydrogen, R_3 represents a cyclohexylmethyl group, R_4
represents a hydroxy group, R_5 represents an isopropyl group, R_6 represents an n-butylamino group, groups R_3, R_
Compounds of general formula (I) and pharmaceutically acceptable salts thereof according to claim 1, in which the carbon atoms bearing 4 and R_5 have an S-configuration. 13, R_1 is 2(R,S)-ethoxycarbonyl-3
-α-naphthylpropionyl group, A represents the divalent group of the amino acid L-histidine, R_2 represents hydrogen, R_3 represents a cyclohexylmethyl group, R_4 represents a hydroxy group, and R_5 represents an isopropyl group. represents,
R_6 represents an n-butylamino group, and groups R_3, R_4
Compounds of general formula (I) and pharmaceutically acceptable salts thereof according to claim 1, in which the carbon atom having R_5 and R_5 has an S-configuration. 14, R_1 represents a cyclohepta[b]pyrrolyl-5-carbonyl group, A represents a divalent group of the amino acid L-histidine, R_2 represents hydrogen, R_3 represents a cyclohexylmethyl group, and R_4 represents a hydroxy group. represents,
A compound of general formula (I) according to claim 1, wherein R_5 represents an isopropyl group, R_6 represents a <n-butylamino group, and the carbon atoms having the groups R_3, R_4 and R_5 have an S-configuration. and pharmaceutically acceptable salts thereof. 15, R_1 represents a 2(S)-pivaloyloxy-3-phenylpropionyl group, A represents a divalent group of the amino acid L-histidine, R_2 represents hydrogen, R_3
represents an isobutyl group, R_4 represents a hydroxy group,
R_5 represents a cyclohexylmethyl group, and R_6 represents n-
Compounds of general formula (I) and pharmaceutically acceptable salts thereof according to claim 1, in which the carbon atoms representing a butylamino group and having the groups R_3 and R_4 have an S-configuration. 16. A pharmaceutical composition comprising a compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt of these compounds having a salt-forming group together with a pharmaceutical excipient. 17. Compounds of general formula (I) according to claim 1 or pharmaceutically acceptable salts of these compounds for use in therapeutic treatment of the human or animal body. 18. Use of the compound of general formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof for inhibiting the action of the enzyme renin. 19. Compounds of general formula (I) according to claim 1 or pharmaceutically acceptable salts of these compounds for the manufacture of therapeutic agents for hyperaldosteronism, hypertension and heart failure related to renin. use. 20. In order to produce a compound of the general formula (I) in which the substituent has the definition listed in claim 1, a) a fragment of the compound of the general formula (I) having a terminal carboxy group or a fragment thereof; A reactive acid derivative having a free amino group and replenishing to form a compound of general formula (I) or a reactive derivative thereof having an active amino group (the free functional groups present in the reaction components are not present in the reaction) (optionally present in protected form, excluding the group involved) to form an amide bond, or b) to produce a compound of general formula (I) in which R_4 represents a hydroxy group, the general formula (II): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) [In the formulas, the substituents have the above definitions, and free functional groups are optionally protected in the form other than the keto groups involved in the reaction. ] in the compound of the general formula (I) is reduced to a hydroxy group by reacting with a suitable reducing agent, or c) to prepare a compound of the general formula (I) in which R_4 represents a hydroxy group, the keto group in the compound of the general formula ( III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) [In the formula, the substituents have the above definitions, and free functional groups exist in optionally protected form, except for the aldehyde group involved in the reaction. [In the formula, the substituents have the above definitions, and M represents a metal group]
or d) General formula (V): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) [In the formula, group, the remaining substituents have the above definitions, and the free functional group is optionally present in protected form] is replaced by a nucleophilic substituent R_
or e) General formula (VI): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VI) [In the formula, the substituents have the above definitions and the functional groups present the cyano group in the compound where the group is optionally present in protected form] into an N-substituted carboxamide group -(C=O)R_6, or f) a compound of the general formula (I) in which R_4 represents a free hydroxy group. ), the general formula (VII): ▲Mathematical formulas, chemical formulas, tables, etc.▼(VII) [In the formula, the substituents have the above definitions, and the functional groups present are epoxide present in the form] with a regioselective reducing agent to form the corresponding alcohol, optionally g) removing the protecting groups present in the resulting compound, and/or optionally Methods a) to f) or general formula (
After carrying out any other process for preparing the compounds of I), the resulting compounds of general formula (I) with salt-forming groups are converted into their salts, or the salts obtained are converted into free compounds or other salts. and/or optionally separating the isomer mixture obtained and/or reversing the configuration of the chiral carbon atoms in the compound of general formula (I) obtained and/or A process for producing novel 5-amino-4-hydroxyvaleryl derivatives, characterized in that the compound of formula (I) is changed to another compound of general formula (I) according to the invention. 21. Compounds and salts thereof obtained by one of the methods described in claim 20. 22. General formula (VIII): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (VIII) [In the formula, R_3, R_5 and R_6 are the first claims.
and salts thereof. 23. In order to produce a compound of general formula (VIII) according to claim 22, in which the substituent has the definition according to claim 1, general formula (IX): ▲ mathematical formula, chemical formula, table etc.▼(IX) [In the formula, R_3 has the above definition and Z_1 represents an amino protecting group] is converted to the general formula (IX) using a sulfur ylide compound.
X): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(X) After changing to the epoxide of [in the formula, R_3 and Z_1 represent the above] and optionally separating isomers, the obtained general formula (X ) is reacted with a reagent that introduces a nucleofusive leaving group and X represents a nucleofugal leaving group] is represented by the general formula (XII): Ra-(
C=O)-R_b (XII) [wherein the groups Ra and Rb each independently represent hydrogen, a lower alkyl group, an aryl group or an aryl lower alkyl group, or Ra and Rb together optionally represent a bridged carbon group; representing an alkylidene group having 4 to 12 atoms or reactive derivatives of these carbonyl compounds in the presence of an acidic reagent, and the resulting general formula (XIII
): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XIII) [The substituents are as above]
V): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XIV) [In the formula, R_5 has the definition listed under the general formula (I), Z_2 represents a carboxy protecting group, and Y^+ is a cation , for example, representing an alkali metal ion, such as a sodium ion or preferably a lithium ion], and the resulting general formula (XV): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(XV) [Formula the intermediate substituent has the above definition], and/or the resulting isomer mixture is separated into individual isomers, and the resulting compound has a free carboxy group. (Z_2=H) to amine R_6
General formula (XVI) obtained by amidation with -H: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (XVI) [In the formula, the substituents have the above definitions] The ring in the compound is solvated with an appropriate solvent. Ring-opening with a decomposition reagent and optionally protecting group Z
A method for producing a compound of general formula (VIII), which comprises eliminating _1.