JPH07126288A - Cyclic hexapeptide and its production and use - Google Patents

Abstract

PURPOSE:To obtain the peptide useful as a therapeutic agent for hypertension or pulmonary hypertension, showing antagonism on an endothelin receptor, especially on an endothelin B receptor, by subjecting a specific straight-chain pentapeptide to ring closure condensation. CONSTITUTION:This peptide of formula I {A is D-neutral-alpha-amino acid residue; X is alpha-amino acid residue; Y is amino acid residue [with the proviso that an alpha-amino acid sequence of formula II (R<10> is H or 1-8C alkyl; R<11> is 1-8C alkyl)]; B is neutral-alpha-amino acid residue; C is L-alpha-amino acid residue; D is aromatic group-containing D-alpha-amino acid residue} is obtained by condensing a raw material containing a reactive carboxyl group corresponding to one of two fragments prepared by dividing the peptide of formula I at an arbitrary position with a raw material containing a reactive amino group corresponding to the other fragment to form a straight-chain pentapeptide and further subjecting the resulting substance to ring-closure condensation.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a cyclic hexapeptide having a novel structure or a salt thereof, a method for producing the same, and an endothelin receptor antagonist containing the cyclic hexapeptide or a pharmacologically acceptable salt thereof. provide.

[0002]

BACKGROUND OF THE INVENTION Endothelin (ET) is a vasoconstrictive peptide consisting of 21 amino acids, which was isolated from the culture supernatant of porcine aortic endothelial cells by Yanagisawa et al. (Yanagisawa et al., Nature, 33
2, 411-412). Then, from the study of the gene encoding endothelin, it was revealed that there are three types of peptides with similar structures in endothelin, and endothelin-1 (ET-1) and endothelin-
2 (ET-2) and endothelin-3 (ET-3).

On the other hand, regarding the endothelin receptor, ET
ET-1, ET-2 and ET-1, ET-2, E showing higher affinity for ET-1, ET-2 than -3
Two types of endothelin B receptors are known that show the same affinity for any of T-3. It has been conventionally considered that the endothelin A receptor is present in vascular smooth muscle and causes contraction of smooth muscle, and the endothelin B receptor is present in vascular endothelial cells and causes relaxation of smooth muscle. It has been clarified that it is also involved in contraction of vascular smooth muscle (Biochemical and Biophysical Research Communications (Bioc
hem. Biophys. Res. Commun.), Vol.175 (2), 556-561
(1991), Journal of Cardiovasc. Pharmacol., Vol.2
0 (Suppl.12), S11-S14 (1992)). As a result, it has been desired to develop not only ETA receptor antagonists but also ETB receptor antagonists as endothelin receptor antagonists.

Since the discovery of endothelin, the search for a compound having an endothelin receptor antagonistic activity has been vigorously carried out for the purpose of developing a therapeutic agent for diseases caused by endothelin. For example, as a cyclic peptide having an endothelin receptor antagonistic action, there is disclosed in
261198 and EP0528312A2 (Japanese Patent Application No. 4-216019) have been reported. Among them, the compound disclosed in JP-A-4-261198 has an affinity for the endothelin A receptor,
It is known that the affinity for the endothelin B receptor is extremely weak. Therefore, JP-A-4-261198
The compound disclosed in (1) can suppress the contraction of vascular smooth muscle mediated by the endothelin A receptor, but has a drawback that it cannot sufficiently suppress the contraction of vascular smooth muscle mediated by the endothelin B receptor. There is. On the other hand, EP0528312A2 (Japanese Patent Application No. 4-2160).
The compound disclosed in 19) is known to be an excellent endothelin receptor antagonist having an affinity not only for the endothelin A receptor but also for the endothelin B receptor. However, in order to efficiently suppress the contraction of vascular smooth muscle mediated by endothelin B receptor, endothelin B having a better affinity for endothelin B receptor.
Development of receptor antagonists is desired.

Further, Japanese Patent Laid-Open No. 3-2197 discloses a cyclic peptide or a salt thereof having a tachykinin agonistic (agonist) and / or tachykinin antagonistic effect. These peptides have endothelin receptor antagonistic action. There is no description that it has, and it is not suggested.

[0006]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a novel compound having a stronger antagonistic action on endothelin receptors, especially endothelin B receptors.

[0007]

[Means for Solving the Problems] In view of the above-mentioned problems, the present inventors have conducted diligent research in order to find a novel compound having a stronger antagonistic action on endothelin receptors (in particular, endothelin B receptors). As a result of stacking, the formula: cyclo [-A-X-Y-B-C-D-] (I) [In the formula, A represents a D-neutral-α-amino acid residue and X represents α-.
Represents an amino acid residue, Y represents an α-amino acid residue (provided that the formula —NR ¹⁰ —CHR ¹¹ —CO— (R ¹⁰ represents a hydrogen atom or a C _1-8 alkyl group, and R ¹¹ represents C _{1- 8} represents an alkyl group)), B represents a neutral-α-amino acid residue, C represents an L-α-amino acid residue, and D represents an aromatic ring group. The D-α-amino acid residues possessed are shown. ] It succeeded in newly synthesizing the novel cyclic hexapeptide represented by these, or its salt, Furthermore, Formula cyclo [-AX-Ya-BCDD-] (Ia) [In formula, A is D-neutral-α-amino acid residue, X is α-
Represents an amino acid residue, Ya represents an α-amino acid residue,
B represents a neutral-α-amino acid residue, C represents an L-α-amino acid residue, and D represents a D-α-amino acid residue having an aromatic ring group. Unexpectedly, the cyclic hexapeptide represented by the following formula or a salt thereof is an endothelin receptor, especially endothelin B.
Found to have a strong antagonistic effect on the receptor,
As a result of further research, the present invention has been completed.

That is, specifically, the present invention has the formula: cyclo [-A-X-Y-B-C-D-] (I) [wherein each symbol has the same meaning as described above]. ] The cyclic hexapeptide represented by these, or its salt, its manufacturing method, and a formula cyclo [-AX-Ya-BCDD-] (Ia) [In formula, each symbol has the same meaning as the above. ] The present invention relates to an endothelin receptor antagonist, preferably an endothelin B receptor antagonist, containing a cyclic hexapeptide represented by the following formula or a pharmacologically acceptable salt thereof.

The cyclic hexapeptide (I) of the present invention is E
P0528312A2 publication (Japanese Patent Application No. 4-216019)
Formula -NR The compounds disclosed have different partial structure A, also part of the cyclic peptide that has already been disclosed in JP-A-3-2197 Publication ¹⁰ -CHR ¹¹ -CO
-(R ¹⁰ represents a hydrogen atom or a C _1-8 alkyl group, R
¹¹ represents a C _1-8 alkyl group), and α-amino acid residues are excluded.

In the above formula, A represents a D-neutral-α-amino acid residue. Examples of the D-neutral-α-amino acid residue include, for example, —NR ¹ —CHR ² —CO— (R ¹ represents a hydrogen atom or a C _1-6 alkyl group, and R ² represents a C _1-6 alkyl group. , C _3-7 cycloalkyl group, C _3-7 cycloalkyl-C _1-3 alkyl group, C _1-6 alkylthio-C
_1-3 alkyl group, C _3-7 cycloalkylthio-C _1-3 alkyl group, C _1-5 alkoxy-C _1-3 alkyl group, C _3-7 cycloalkoxy-C _1-3 alkyl group, substituted _Optionally substituted C _6-14 aryl group, _optionally substituted C _6-14 aryl-C _1-3 alkyl group, _optionally substituted N,
A 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of O and S, or 1 to 3 hetero groups selected from the group consisting of optionally substituted N, O and S Represents a 4- to 7-membered heterocyclic group containing an atom, -C _1-3 alkyl group, wherein R ¹ and R ² are bonded together to form-(CH ₂ ) L-
(L represents an integer of 2 to 4) may be formed. ) D-neutral-α-amino acid residue and the like are used.

The C _1-6 alkyl group represented by R ¹ includes
For example, methyl group, ethyl group, n-propyl group, iso
-Propyl group, n-butyl group, iso-butyl group, (1
-Methyl) propyl group, tert-butyl group, n-pentyl group, (2-methyl) butyl group, (3-methyl) butyl group, neopentyl group, n-hexyl group, (2,2-dimethyl) butyl group, A (3,3-dimethyl) butyl group or the like is used, and a C _1-3 alkyl group such as a methyl group, an ethyl group, an n-propyl group or an iso-propyl group is particularly preferable. R ¹ is particularly preferably a hydrogen atom.

The C _1-6 alkyl group represented by R ² is
For example, methyl group, ethyl group, n-propyl group, iso
-Propyl group, n-butyl group, iso-butyl group, (1
-Methyl) propyl group, tert-butyl group, n-pentyl group, (2-methyl) butyl group, (3-methyl) butyl group, neopentyl group, n-hexyl group, (2,2-dimethyl) butyl group, A (3,3-dimethyl) butyl group or the like is used, and particularly n-butyl group, iso-butyl group,
(1-methyl) propyl group, tert-butyl group, n-
Pentyl group, (2-methyl) butyl group, (3-methyl)
C such as butyl group, neopentyl group and n-hexyl group
_4-6 alkyl groups are preferred.

As the C _3-7 cycloalkyl group represented by R ² , for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group are used, and particularly a cyclopentyl group, a cyclohexyl group,
C _5-7 cycloalkyl groups such as cycloheptyl groups are preferred.

C _3-7 cycloalkyl-C represented by R ²
Examples of the _1-3 alkyl group include a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclobutylethyl group,
A cyclobutylpropyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a cyclopentylpropyl group, a cyclohexylmethyl group, a cyclohexylethyl group, a cyclohexylpropyl group, a cycloheptylmethyl group, a cycloheptylethyl group, etc. are used, and a cyclopropylmethyl group, cyclo butylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, C _3-7 cycloalkyl such as cycloheptylmethyl group - such as a methyl group is preferred.

C _1-6 alkylthio-C _1-3 represented by R ²
Examples of the alkyl group include, for example, methylthiomethyl group, methylthioethyl group, methylthiopropyl group, ethylthiomethyl group, ethylthioethyl group, n-propylthiopropyl group, iso-propylthiomethyl group, n-butylthiomethyl group, tert. -Butylthiomethyl group, n-butylthioethyl group, tert-butylthiopropyl group,
(1,1-dimethyl) propylthiomethyl group and the like are used, and particularly, iso-propylthiomethyl group, n-butylthiomethyl group, tert-butylthiomethyl group,
C such as (1,1-dimethyl) propylthiomethyl group
_{A 4-7} alkylthio-methyl group and the like are preferable.

C _3-7 cycloalkylthio-represented by R ²
Examples of the C _1-3 alkyl group include a cyclopropylthiomethyl group, a cyclopropylthioethyl group, a cyclopropylthiopropyl group, a cyclobutylthiomethyl group, a cyclobutylthioethyl group, a cyclobutylthiopropyl group,
A cyclopentylthiomethyl group, a cyclopentylthioethyl group, a cyclohexylthiomethyl group, a cycloheptylthiomethyl group and the like are used, and particularly C such as cyclobutylthiomethyl group, cyclopentylthiomethyl group, cyclohexylthiomethyl group and cycloheptylthiomethyl group. _4-7
A cycloalkylthio-methyl group and the like are preferable.

Examples of the C _1-5 alkoxy-C _1-3 alkyl group represented by R ² include methoxymethyl group, methoxyethyl group, methoxypropyl group, ethoxymethyl group,
Ethoxyethyl group, n-propoxymethyl group, n-propoxyethyl group, iso-propoxymethyl group, iso
-Propoxyethyl group, n-butoxymethyl group, n-butoxyethyl group, tert-butoxymethyl group, ter
t-butoxyethyl group, n-pentyloxymethyl group,
An n-pentyloxyethyl group, a (1,1-dimethyl) propoxymethyl group, a (1,1-dimethyl) propoxyethyl group and the like are used, and particularly a methoxymethyl group, an ethoxymethyl group, an n-propoxymethyl group, iso. -Propoxymethyl group, n-butoxymethyl group, tert-butoxymethyl group, n-pentyloxymethyl group, (1,
A C _1-5 alkoxy-methyl group such as a 1-dimethyl) propoxymethyl group is preferable, and among them, an iso-propoxymethyl group, a tert-butoxymethyl group, (1,1-
A dimethyl) propoxymethyl group and the like are preferable.

C _3-7 cycloalkoxy-C represented by R ²
Examples of the _1-3 alkyl group include a cyclopropoxymethyl group, a cyclopropoxyethyl group, a cyclobutoxymethyl group, a cyclobutoxyethyl group, a cyclopentyloxymethyl group, a cyclopentyloxyethyl group, a cyclohexyloxymethyl group and a cycloheptyloxymethyl group. Is used, especially a cyclopropoxymethyl group, a cyclobutoxymethyl group, a cyclopentyloxymethyl group,
Cyclohexyloxymethyl group, C _3-7 cycloalkoxy such as cycloheptyl oxymethyl group - a methyl group.

As the C _6-14 aryl group represented by R ² , a phenyl group, an α-naphthyl group, a β-naphthyl group and the like are used, and among them, a phenyl group is preferable. These groups include halogen atoms (eg, fluoro, chloro, bromine, iodo, etc.), hydroxy groups, C _1-3 alkyl groups (eg, methyl group, ethyl group, etc.), nitro groups, carboxyl groups, C _1-5. It has about 1 to 3 substituents selected from an acyl group (eg, formyl group, acetyl group, propionyl group), C _1-5 alkoxy group (eg, methoxy group, ethoxy group, propoxy group, etc.). May be.

The C _6-14 aryl-C _1-3 alkyl group represented by R ² includes benzyl group, phenylethyl group and α-
A naphthylmethyl group, an α-naphthylethyl group, a β-naphthylmethyl group, a β-naphthylethyl group and the like are used, and among them, a C _6-14 aryl group such as a benzyl group, an α-naphthylmethyl group and a β-naphthylmethyl group. A methyl group is preferred. The C _6-14 aryl group of these groups includes a halogen atom (eg, fluoro, chloro, bromine, iodo, etc.), a hydroxy group, a C _1-3 alkyl group (eg, methyl group, ethyl group, etc.), a nitro group, Carboxyl group,
C _1-5 acyl group (eg, formyl group, acetyl group,
It may have about 1 to 3 substituents selected from a propionyl group), a C _1-5 alkoxy group (eg, a methoxy group, an ethoxy group, a propoxy group, etc.) and the like.

The 4- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from the group consisting of N, O and S represented by R ² is, for example, 2-thienyl group or 3-thienyl group. , Furyl group, 4-imidazolyl group, 2-pyridyl group, 3-indolyl group, 3-benzofuryl group and the like are used. These groups include halogen atoms (eg, fluoro, chloro, bromine, iodo, etc.), hydroxy groups, C _1-3 alkyl groups (eg, methyl group, ethyl group, etc.), nitro groups, carboxyl groups, C _1-5. It has about 1 to 3 substituents selected from an acyl group (eg, formyl group, acetyl group, propionyl group), C _1-5 alkoxy group (eg, methoxy group, ethoxy group, propoxy group, etc.). May be.

The 4- to 7-membered heterocycle-C _1-3 alkyl group containing 1 to 3 heteroatoms selected from the group consisting of N, O and S represented by R ² is 2-thienylmethyl. Group, 3-thienylmethyl group, furylmethyl group, 4-
An imidazolylmethyl group, a 2-pyridylmethyl group, a 3-indolylmethyl group, a 3-benzofurylmethyl group and the like are used. The heterocyclic group of these groups is a halogen atom (eg, fluoro, chloro, bromine, iodo, etc.), a hydroxy group, a C _1-3 alkyl group (eg, a methyl group,
Ethyl group, etc.), nitro group, carboxyl group, C _1-5 acyl group (eg formyl group, acetyl group, propionyl group), C _1-5 alkoxy group (eg methoxy group, ethoxy group, propoxy group etc.), etc. It may have about 1 to 3 substituents selected from

R ² is preferably a C _1-6 alkyl group or the like. Among them, a C _4-6 alkyl group (for example, n-butyl group, iso-butyl group, (1-methyl) propyl group, t
ert-butyl group, n-pentyl group, (2-methyl) butyl group, (3-methyl) butyl group, neopentyl group, n
-Hexyl group) and the like are preferable. In particular, as R ² , an iso-butyl group, a tert-butyl group, a neopentyl group and the like are preferable. R ¹ and R ² are bound together-
(CH ₂₎ L- (L is an integer of 2 to 4) may be formed. That is, R ¹ and R ² may be bonded together to form a 4- to 6-membered ring with the adjacent N atom and C atom. The 4- to 6-membered ring may be substituted with a hydroxy group or the like. As L, 3 is particularly preferable. Thus, R ¹ and R ² are bound together to form an adjacent N atom and C
When a 4- to 6-membered ring is formed with an atom, -NR ^1-
CHR ² —CO— represents proline, 4-hydroxyproline, azetidine-2-carboxylic acid, pipecolic acid (piperidine-2-carboxylic acid) residue and the like.

Among the above, a combination in which R ¹ is a hydrogen atom and R ² is a C _1-6 alkyl group (particularly a C _4-6 alkyl group) is preferable.

Specifically, as A, for example, D-
Alanine, D-valine, D-norvaline, D-leucine,
D-isoleucine, D-alloisoleucine, D-norleucine, D-tertiary leucine, D-gammamethylleucine, D-phenylglycine, D-phenylalanine, D
-3- (1-naphthyl) alanine, D-3- (2-naphthyl) alanine, D-proline, D-4-hydroxyproline, D-azetidine-2-carboxylic acid, D-pipecolic acid
(Piperidine-2-carboxylic acid), D-3- (2-thienyl)
Alanine, D-2- (2-thienyl) glycine, D-2-
(3-thienyl) glycine, D-1-aminocyclopropane-1-carboxylic acid, D-1-aminocyclobutane-1-carboxylic acid, D-1-aminocyclopentane-1-carboxylic acid,
D-1-aminocyclohexane-1-carboxylic acid, D-1-aminocycloheptane-1-carboxylic acid, D-2-cyclopentylglycine, D-2-cyclohexylglycine residue and the like are used. Especially, D-leucine, D-alloisoleucine, D-tert-leucine, D-gammamethylleucine, D-phenylglycine, D-3- (2-thienyl)
Alanine, D-2- (2-thienyl) glycine, D-2-
More preferred are (3-thienyl) glycine and D-2- (2-cyclopentyl) glycine residues. These neutrals-
The α-imino group of the α-amino acid may be substituted with, for example, a C _1-6 alkyl group (eg, methyl, ethyl, n-propyl, tert-butyl etc.) and the like. Examples of such α-amino acids include DN-methylleucine, DN-methylalloisoleucine, DN-methyltert-leucine, DN-methylgamma-methylleucine, DN-methylphenyl. A glycine residue or the like is used. As R ¹ , a D-leucine residue and the like are particularly preferable.

In the above formula, X represents an α-amino acid residue. Examples of the α-amino acid residue include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, 2-aminomalonic acid, 2-aminoadipic acid, glycine, histidine, isoleucine, leucine, lysine, ornithine, and 2 , 4-Diaminobutyric acid, methionine, phenylalanine, proline, 4-hydroxyproline, thioproline, azetidine-2-carboxylic acid, pipecolic acid (piperidine-2-carboxylic acid), indoline-2-carboxylic acid, tetrahydroisoquinoline-3-carboxylic acid Acid, serine, threonine, tryptophan, 5-methyltryptophan, tyrosine, valine, alloisoleucine, norvaline, norleucine,
Tertiary leucine, gamma methyl leucine, phenylglycine, 2-aminobutyric acid, cysteic acid, homocysteic acid, 3- (1-naphthyl) alanine, 3- (2-naphthyl) alanine, 2- (2-thienyl) glycine, Two
-(3-thienyl) glycine, 3- (3-benzothienyl) alanine, 3- (4-biphenyl) alanine, pentamethylphenylalanine, 1-aminocyclopropane-
1-carboxylic acid, 1-aminocyclobutane-1-carboxylic acid, 1-aminocyclopentane-1-carboxylic acid, 1-aminocyclohexane-1-carboxylic acid, 1-aminocycloheptane-1-carboxylic acid and the like are used . These α-
If the amino acid has a functional group (for example, hydroxyl group, thiol group, amino group, imino group, carboxyl group, etc.),
These functional groups may be substituted.

Examples of the substituted hydroxyl group include C _1-6 fatty acid ester (for example, formic acid ester, acetic acid ester, propionic acid ester, etc.), C _4-9 alicyclic carboxylic acid ester (for example, cyclopentane carboxylic acid ester,
Cyclohexanecarboxylic acid ester, etc.), C _7-15 arylcarboxylic acid ester (eg, benzoic acid ester, 4-methylbenzoic acid ester, etc.), C _8-16 aralkylcarboxylic acid ester (eg, phenylacetic acid ester, 2-phenylpropione) Acid ester, 3-phenylpropionic acid ester, diphenylacetic acid ester, etc.), aromatic heterocycle-alkylcarboxylic acid ester (eg, indol-2-yl acetic acid ester, indole
Ester such as (3-ylacetic acid ester), C _1-6
Alkyl ether (eg, methyl ether, ethyl ether, n-propyl ether, tertiary butyl ether, etc.), C _3-8 cycloalkyl ether (eg, cyclopentyl ether, cyclohexyl ether, etc.), C _6-12 aryl ether (eg, phenyl) Ether, 4-methylphenyl ether, etc.), C
An ether form such as _7-15 aralkyl ether (eg, benzyl ether, phenethyl ether, diphenylmethyl ether) is used.

Examples of the α-amino acid substituted with a hydroxyl group include O-acetylserine, O-acetylthreonine, 4-acetoxyproline, O-benzoylserine,
O-benzoylthreonine, 4-benzoyloxyproline, O-phenylacetylserine, O-phenylacetylthreonine, 4-phenylacetoxyproline, O-ethylserine, O-ethylthreonine, 4-ethoxyproline, O-cyclohexylserine, O- Cyclohexyl threonine, 4-cyclohexyloxyproline, O-phenylserine, O-phenylthreonine, 4-phenoxyproline, O-benzylserine, O-benzylthreonine, 4
-Benzyloxyproline, O-diphenylmethylserine, O-diphenylmethylthreonine, 4-diphenylmethoxyproline and the like are used.

Examples of the substituted thiol group include C _1-6 fatty acid thiol ester (eg, formic acid thiol ester, acetic acid thiol ester, propionic acid thiol ester, etc.), C _4-9 alicyclic carboxylic acid thiol ester (eg, cyclopentane). Carboxylic acid thiol ester, cyclohexanecarboxylic acid thiol ester, etc.), C _7-15 arylcarboxylic acid thiol ester (eg, benzoic acid thiol ester, 4-methylbenzoic acid thiol ester, etc.), C _8-16 aralkylcarboxylic acid thiol ester ( For example, thiol ester such as phenylacetic acid thiol ester, 2-phenylpropionic acid thiol ester, 3-phenylpropionic acid thiol ester, diphenylacetic acid thiol ester, etc., C _1-6 alkyl thioether (For example, methyl thioether, ethyl thioether, n-propyl thioether, tertiary butyl thioether, etc.),
C _3-8 cycloalkyl thioether (eg cyclopentyl thioether, cyclohexyl thioether etc.), C _6-12 aryl thioether (eg phenyl thioether, 4-methylphenyl thioether etc.), C _7-15 aralkyl thioether (eg benzyl thioether, Phenethyl thioether, diphenylmethyl thioether, etc.) and the like are used.

Examples of the α-amino acid substituted with a thiol group include S-acetyl cysteine, S-benzoyl cysteine, S-phenylacetyl cysteine, S-ethyl cysteine, S-cyclohexyl cysteine, S-phenyl cysteine, S- Benzyl cysteine or the like is used.

The substituted amino group (or imino group) is C _1-6 alkylamino (or imino) (eg,
N-methylamino (or imino), N-ethylamino (or imino), N-tert-butylamino (or imino) and the like), C _3-8 cycloalkylamino (or imino) (for example, N-cyclopentylamino ( Or imino), N-cyclohexylamino (or imino), etc.),
C _6-12 arylamino (or imino) (eg N-
Phenylamino (or imino), N- {4-methylphenyl} amino (or imino), etc., C _7-15 aralkylamino (or imino) (eg, N-benzylamino (or imino), N-phenethylamino ( Or imino), N
-{2-chlorobenzyl} amino (or imino), N- {3-
Chlorobenzyl} amino (or imino), N- {4-chlorobenzyl} amino (or imino), N- {2-methylbenzyl} amino (or imino), N- {3-methylbenzyl} amino (or imino) , N- {4-methylbenzyl} amino
(Or imino), N- {2-methoxybenzyl} amino (or imino), N- {3-methoxybenzyl} amino (or imino), N- {4-methoxybenzyl} amino (or imino), etc.), aromatic Group heterocycles-C _1-6 alkylamino (or imino) (eg 2-furylmethylamino (or imino), 3-furylmethylamino (or imino), 2-thienylmethylamino (or imino), 3-thienyl) Methylamino (or imino), indol-2-ylmethylamino (or imino), indol-3-ylmethylamino
(Or imino)), etc., a substituted amino form (or imino form), C _1-6 aliphatic acylamide (or imide) (eg, formamide (or imide), acetamide (or imide), propionamide (or imide), etc.) ,
C _4-9 alicyclic acylamide (or imide) (for example,
Cyclopentanecarbonylamide (or imide), cyclohexanecarbonylamide or imide), etc., C
_{7-15 arylacyl} amides (eg benzamide
(Or imide), 4-methylbenzamide (or imide), etc., C _8-16 aralkylacylamide (eg, phenylacetamide (or imide), 2-phenylpropionamide (or imide), 3-phenylpropionamide (or Imide), diphenylacetamide
(Or imide), 1-naphthylacetamide (or imide), 2-naphthylacetamide (or imide), etc.),
Aromatic heterocycle-carbonyl amide (or imide) (eg, indol-2-ylcarbonylamide (or imide), indol-3-ylcarbonylamide (or imide), etc.), aromatic heterocycle-alkylcarbonylamide
(Or imide) (eg, indol-2-ylacetamide (or imide), indol-3-ylacetamide (or imide), etc.), sulfonylamide (or imide) (eg, benzenesulfonylamide (or imide), paratoluene) Substituted amides such as sulfonylamide (or imide), 4-methoxy-2,3,6-trimethylbenzenesulfonylamide (or imide), etc.
(Or imide form) or the like is used.

Α-substituted with an amino (or imino) group
Examples of amino acids include N-methylglycine (sarcosine), N-ethylglycine, N-methylleucine, N-
Ethylleucine, N-methylphenylalanine, N-ethylphenylalanine, N (α) -methyltryptophan,
N (α) -ethyltryptophan, N-cyclopentylglycine, N-cyclohexylglycine, N-phenylglycine, N-phenylleucine, N-benzylglycine, N-
Benzylleucine, N (π) -benzylhistidine, N
(τ) -Benzylhistidine, N (π) -phenacylhistidine, N (π) -benzyloxymethylhistidine, N ^g -benzenesulfonylarginine, N ^g -paratoluenesulfonylarginine, N ^g- (4-methoxy-2) , 3,6-Trimethylbenzenesulfonyl) arginine, N (ε) -benzenesulfonyllysine, N (ε) -paratoluenesulfonyllysine, N (ε)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl) Lysine, N ⁱⁿ -methyltryptophan, N
ⁱⁿ -ethyltryptophan, N ⁱⁿ -formyltryptophan, N ⁱⁿ -acetyltryptophan, N (ε) -benzyllysine, N (ε)-(2-furylmethyl) lysine, N (ε)-(2-
Thienylmethyl) lysine, N (ε)-(indol-3-ylmethyl) lysine, N (ε) -phenylacetyllysine, N
(ε)-({2-furyl} acetyl) lysine, N (ε)-({2-thienyl} acetyl) lysine, N (ε)-({indol-3-yl}
Acetyl) lysine, N (ε) -benzoyl lysine, N (ε)-
(3-phenylpropionyl) lysine, N (δ) -benzylornithine, N (δ)-(2-furylmethyl) ornithine, N
(δ)-(2-thienylmethyl) ornithine, N (δ)-(indol-3-ylmethyl) ornithine, N (δ) -benzoylornithine, N (δ) -phenylacetylornithine, N
(δ)-(3-Phenylpropionyl) ornithine, N (δ)-
({2-Methylphenyl} acetyl) ornithine, N (δ)-
({3-Methylphenyl} acetyl) ornithine, N (δ)-
({4-Methylphenyl} acetyl) ornithine, N (δ)-
({2-chlorophenyl} acetyl) ornithine, N (δ)-
({3-Chlorophenyl} acetyl) ornithine, N (δ)-
({4-Chlorophenyl} acetyl) ornithine, N (δ)-
({2-Methoxyphenyl} acetyl) ornithine, N (δ)-
({3-Methoxyphenyl} acetyl) ornithine, N (δ)-
({4-Methoxyphenyl} acetyl) ornithine, N (δ)-
(4-biphenylacetyl) ornithine, N (γ) -benzyl
-2,4-diaminobutyric acid, N (γ)-(2-furylmethyl) -2,
4-diaminobutyric acid, N (γ)-(2-thienylmethyl) -2,4-
Diaminobutyric acid, N (γ)-(indol-3-ylmethyl)-
2,4-diaminobutyric acid, N (γ) -benzoyl-2,4-diaminobutyric acid, N (γ) -phenylacetyl-2,4-diaminobutyric acid, N (γ)-(3-phenylpropionyl) -2, 4-diaminobutyric acid, N (γ)-(2-furylacetyl) -2,4-diaminobutyric acid, N (γ)-(2-thienylacetyl) -2,4-diaminobutyric acid, N (γ)-({ Indole-3-yl} acetyl) -2,4-
Diaminobutyric acid or the like is used.

Examples of the substituted carboxyl group include amide (—CONH ₂ ), N—C _1-6 alkylamide (eg, N—
Methyl amide, N-ethyl amide, N- {n-propyl} amide, N-tertiary butyl amide, etc.), N-C _3-8
Cycloalkylamide (eg, N-cyclopentylamide, N-cyclohexylamide, etc.), N—C _6-12 arylamide (eg, N-phenylamide, N- {4-
Methylphenyl} amide, etc.), N—C _7-15 aralkylamide (eg, N-benzylamide, N-phenethylamide, N- {1,2-diphenylethyl} amide, N- {aromatic heterocycle-C _{1 -6} alkyl} amide (eg, N- [2-
{Indol-2-yl} ethyl] amide, N- [2- {indol-3-yl} ethyl] amide, etc.), piperidine amide, piperazine amide, N ⁴ -C _1-6 alkyl piperazine amide (eg, N ⁴ - methylpiperazine amide, N ⁴ -
Ethyl piperazine amide etc.), N ⁴ -C _3-8 cycloalkyl piperazine amide (eg N ⁴ -cyclopentyl piperazine amide, N ⁴ -cyclohexyl piperazine amide etc.), N ⁴ -C _6-12 aryl piperazine amide (eg N ⁴ - phenylpiperazine amide, N ⁴ - such as {4-methylphenyl} piperazine amide), N ⁴ -C _7-15 aralkyl piperazine amides (e.g., N ⁴ - benzylpiperazine amide, N ⁴ - phenethyl piperazine amide, N ⁴ -
{1,2-diphenylethyl} piperazine amide, N ⁴ - {aromatic heterocycle -C _1-6 alkyl} piperazine amides (e.g., N ⁴ - [2- {indol-2-yl} ethyl] piperazine amide, N ⁴ - [2- {indol-3-yl} ethyl] piperazine amides such), N ⁴ -C _1-6 aliphatic acyl piperazine amides (e.g., N ⁴ - acetyl piperazine amide, N
⁴ -propionyl piperazine amide, etc., N ⁴ -C _4-9 alicyclic acyl piperazine amide (eg, N ⁴ -cyclopentane carbonyl piperazine amide, N ⁴ -cyclohexane carbonyl piperazine amide, etc.), N ⁴ -C _7-15 aryl acyl piperazine amide (e.g., N ⁴ - benzoyl piperazine amide, N ⁴ - {4- methylbenzoyl} piperazine amides such), N ⁴ -C _8-16 aralkyl acyl piperazine amides (e.g., N ⁴ - phenylacetyl piperazine amide, N ⁴ - {2-phenylpropionic} piperazine amide, N ⁴ - {3- phenylpropionyl} piperazine amide, N ⁴ - diphenylacetyl piperazine amide, N ⁴ -
{1-naphthyl acetyl} piperazine amide, N ⁴ - such as {2- naphthylacetyl} piperazine amide), N ⁴ - {aromatic heterocyclic - carbonyl} piperazine amides (e.g., N ⁴ -
{Indol-2-ylcarbonyl} piperazine amide, N
⁴ - like {indol-3-yl carbonyl} piperazine amide), N ⁴ - {aromatic heterocycle - alkyl carbonyl} piperazine amides (e.g., N ⁴ - {indol-2-ylacetyl} piperazine amide, N ⁴ - {indol -3-yl acetyl} piperazine amide etc.), C _1-6 alkyl ester (eg methyl ester, ester ester, n-propyl ester etc.), C _3-8 cycloalkyl ester (eg cyclopentyl ester,
Cyclohexyl ester, etc., C _7-15 aralkyl ester (eg, benzyl ester, phenethyl ester, 1-phenylethyl ester, diphenylmethyl ester, etc.) and the like are used. Among the amides mentioned above, amides with α-amino acids and oligopeptides (for example, dipeptides, tripeptides,
Amides with tetrapeptides, etc.) are also included.

Examples of the α- amino acid in which a carboxyl group is substituted, for example, N ⁴ - methyl aspartate, N ⁴ - phenyl asparagine, N ⁴ - benzyl aspartate, N ⁴ -
Phenethyl asparagine, N ⁴ - (2- {indol-3-yl} ethyl) asparagine, N ⁵ - methyl glutamine, N ⁵ -
Phenylglutamine, N ⁵ -benzyl glutamine, N ⁵ -phenethyl glutamine, N ^5- (2- {indol-3-yl} ethyl) glutamine, aspartic acid β-methyl ester, aspartic acid β-cyclopropyl ester, aspartic acid β -Benzyl ester, aspartic acid β-
Phenethyl ester, aspartic acid β-N ⁴ - phenylpiperazine amide, aspartic acid β-N ⁴ - (2- methylphenyl) piperazine amide, aspartic acid β-N ⁴ -
(3-methylphenyl) piperazine amide, aspartic acid β-N ⁴ - (4- methylphenyl) piperazine amide, aspartic acid β-N ⁴ - (2- methoxyphenyl) piperazine amide, aspartic acid β-N ⁴ - (3 - methoxyphenyl) piperazine amide, aspartic acid β-N ⁴ - (4- methoxyphenyl) piperazine amide, aspartic acid beta
-N ⁴ - (2-chlorophenyl) piperazine amide, aspartic acid β-N ⁴ - (3- chlorophenyl) piperazine amide, aspartic acid β-N ⁴ - (4- chlorophenyl) piperazine amide, aspartic acid β-N ⁴ - ( 4-nitrophenyl) piperazine amide, aspartic acid β-N ⁴ - (4-
(Fluorophenyl) piperazine amide, aspartic acid
β-N ⁴ - (3- trifluoromethylphenyl) piperazine amide, aspartic acid β-N ⁴ - (2,3- dimethylphenyl) piperazine amide, aspartic acid β-N ⁴ - (2- pyridyl) piperazine amide, asparagine acid β-N ⁴ - (2-
Pyrimidyl) piperazine amide, glutamic acid γ-methyl ester, glutamic acid γ-cyclopropyl ester, glutamic acid γ-benzyl ester, glutamic acid γ-phenethyl ester and the like are used.

As X, for example, Asp
(R ³ ) (R ³ is the formula

[0036]

[Chemical 12]

(X ¹ and X ² are a hydrogen atom and C, respectively.
_1-6 alkyl group, C _1-6 alkoxy group, halogen atom or nitro group, wherein X ¹ and X ² are bonded together to form a neighboring C
You may form a ring with an atom. ) Represents a group represented by. And an α-amino acid residue represented by Here, R ¹ is bonded to the carbonyl group of the β-carboxyl group of the aspartic acid residue.

Examples of the C _1-6 alkyl group represented by X ¹ and X ² include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, an iso-butyl group and a tert-group. A butyl group, an n-pentyl group, an n-hexyl group and the like are used, and particularly a methyl group, an ethyl group, an n- group.
A C _1-3 alkyl group such as a propyl group or an iso-propyl group is preferable, and methyl is particularly preferable. Examples of the C _1-6 alkoxy group represented by X ¹ and X ² include methoxy group, ethoxy group, n-propoxy group, n-butoxy group, n-pentyloxy group, n-hexyloxy group and the like. , Especially methoxy group, ethoxy group, n-
A C _1-3 alkoxy group such as a propoxy group is preferable, and a methoxy group and an ethoxy group are particularly preferable.

Examples of the halogen atom represented by X ¹ and X ² include fluoro, chloro, bromo, iodo and the like, with chloro being particularly preferred. As a combination of X ¹ and X ² , it is preferable that X ² is a hydrogen atom.

R ¹ in the case where X ¹ and X ² are bonded together to form a ring with the adjacent C atom is represented by the formula:

[0041]

[Chemical 13]

The groups represented by and the like are used. The ring Q is a 4- to 7-membered ring which may contain 1 to 3 hetero atoms such as O, N and S (saturated carbocycle, aromatic carbocycle, saturated heterocycle, aromatic heterocycle, etc.). Are used.

That is, as R ¹ , specifically,

[0044]

[Chemical 14]

(X ¹¹ and X ²¹ are a hydrogen atom and C, respectively.
_1-6 alkyl group, C _1-6 alkoxy group, halogen atom or nitro group. Group represented by), formula

[0046]

[Chemical 15]

(M and n are integers of 1 to 3, X is O, S or NH, and p is 0 or 1)

[0048]

[Chemical 16]

A group represented by the formula (q is an integer of 1 to 3)

[0050]

[Chemical 17]

(X ³ and X ⁴ are each a hydrogen atom, C _1-6
It represents an alkyl group, a C _1-6 alkoxy group, a halogen atom or a nitro group. ) And the like are used.

The C _1-6 alkyl group represented by X ¹¹ , X ²¹ , X ³ and X ⁴ is, for example, a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group, Iso-butyl group, tert-butyl group, n-pentyl group, n-hexyl group and the like are used, and particularly, C _1-3 alkyl group such as methyl group, ethyl group, n-propyl group and iso-propyl group is used. Preferred is methyl, especially preferred. Examples of the C _1-6 alkoxy group represented by X ¹¹ , X ²¹ , X ³ and X ⁴ are methoxy group, ethoxy group, n-propoxy group, n-butoxy group, n-pentyloxy group, n- A hexyloxy group or the like is used, and a C _1-3 alkoxy group such as a methoxy group, an ethoxy group, and an n-propoxy group is particularly preferable, and a methoxy group and an ethoxy group are particularly preferable. X ¹¹ , X ²¹ , X ^{3 above}
As the halogen atom represented by and X ⁴ , for example, fluoro, chloro, bromo, iodo and the like are used, and chloro is particularly preferable. The combination of X ¹¹ and X ²¹ is preferably a hydrogen atom of X ²¹ , and the combination of X ³ and X ⁴ is preferably a hydrogen atom of X ⁴ .

It is preferable that m is 1 or 2 and n is 1 or 2, and it is particularly preferable that the sum of m and n is 2 or 3.

Specific examples of R ³ described above include, for example,

[0055]

[Chemical 18]

Etc. are used.

Among the above, R ³ is a formula

[0058]

[Chemical 19]

(X ¹¹ is a hydrogen atom, C _1-6 alkyl group, C
_{1-6 represents an} alkoxy group, a halogen atom or a nitro group. ) Groups represented by, for example

[0060]

[Chemical 20]

And the like are preferred.

As the α-amino acid residue represented by X,
Any of D-form, L-form, and DL-form may be used, but L-form is more preferable.

In the above formula, Y represents an α-amino acid residue, but is represented by the formula —NR ¹⁰ —CHR ¹¹ —CO— (R ¹⁰ represents a hydrogen atom or a C _1-8 alkyl group, and R ¹¹
_{Represents a} C _1-8 alkyl group) and does not include an α-amino acid residue. That is, Y is a compound represented by the formula —NR ¹⁰ —CHR ¹¹ —CO from the α-amino acid residue represented by X above.
Those in which the α-amino acid residue represented by — (R ¹⁰ and R ¹¹ have the same meanings as described above) are excluded are used. Specifically, for example, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, cysteic acid, homocysteic acid, β- (5-tetrazonyl) alanine, 2-amino-4- (5-tetrazolyl).
Butyric acid 2-aminomalonic acid, 2-aminoadipic acid, histidine, lysine, ornithine, 2,4-diaminobutyric acid, methionine, phenylalanine, proline, 4-hydroxyproline, thioproline, azetidine-2-carboxylic acid,
Pipecolic acid (piperidine-2-carboxylic acid), indoline
-2-carboxylic acid, tetrahydroisoquinoline-3-carboxylic acid, serine, threonine, tryptophan, 5-methyltryptophan, tyrosine, phenylglycine, cysteic acid, homocysteic acid, 3- (1-naphthyl) alanine, 3- (2 -Naphthyl) alanine, 2- (2-thienyl) glycine, 2- (3-thienyl) glycine, 3-
(3-Benzothienyl) alanine, 3- (4-biphenyl) alanine, pentamethylphenylalanine, 1-aminocyclopropane-1-carboxylic acid, 1-aminocyclobutane-1-carboxylic acid, 1-aminocyclopentane-1-
Carboxylic acid, 1-aminocyclohexane-1-carboxylic acid, 1-aminocycloheptane-1-carboxylic acid, O-acetylserine, O-acetylthreonine, 4-acetoxyproline, O-benzoylserine, O-benzoylthreonine, 4 -Benzoyloxyproline, O-phenylacetylserine, O-phenylacetylthreonine, 4-phenylacetoxyproline, O-ethylserine, O-ethylthreonine, 4-ethoxyproline, O-cyclohexylserine, O-cyclohexylthreonine, 4-cyclohexyl Oxyproline, O-phenylserine, O-phenylthreonine, 4-phenoxyproline, O-benzylserine, O-benzylthreonine, 4-benzyloxyproline, O-diphenylmethylserine, O-diphenylmethylthreonine, 4-diphenylmethoxy Proline, N- methyl-phenylalanine, N- ethyl-phenylalanine, N
(α) -methyltryptophan, N (α) -ethyltryptophan, N-cyclopentylglycine, N-cyclohexylglycine, N-phenylglycine, N-phenylleucine, N-benzylglycine, N-benzylleucine, N
(π) -Benzylhistidine, N (τ) -benzylhistidine, N (π) -phenacylhistidine, N (π) -benzyloxymethylhistidine, N ^g -benzenesulfonylarginine, N ^g -paratoluenesulfonylarginine, N ^g-
(4-Methoxy-2,3,6-trimethylbenzenesulfonyl) arginine, N (ε) -benzenesulfonyllysine, N
(epsilon) - p-toluenesulfonyl lysine, N (ε) - (4- methoxy-2,3,6) lysine, N ⁱⁿ - methyl tryptophan, N ⁱⁿ - ethyl tryptophan, N ⁱⁿ - formyl tryptophan, N ⁱⁿ -acetyltryptophan, N (ε) -benzyl lysine, N (ε)-(2-
Furylmethyl) lysine, N (ε)-(2-thienylmethyl) lysine, N (ε)-(indol-3-ylmethyl) lysine, N
(ε) -Phenylacetyllysine, N (ε)-({2-furyl} acetyl) lysine, N (ε)-({2-thienyl} acetyl) lysine, N (ε)-({Indol-3-yl } Acetyl) lysine,
N (ε) -benzoyl lysine, N (ε)-(3-phenylpropionyl) lysine, N (δ) -benzylornithine, N (δ)-
(2-Furylmethyl) ornithine, N (δ)-(2-thienylmethyl) ornithine, N (δ)-(indol-3-ylmethyl)
Ornithine, N (δ) -benzoylornithine, N (δ) -phenylacetylornithine, N (δ)-(3-phenylpropionyl) ornithine, N (δ)-({2-methylphenyl} acetyl) ornithine, N ( δ)-({3-methylphenyl} acetyl) ornithine, N (δ)-({4-methylphenyl} acetyl) ornithine, N (δ)-({2-chlorophenyl} acetyl) ornithine, N (δ)- ({3-Chlorophenyl} acetyl) ornithine, N (δ)-({4-chlorophenyl} acetyl) ornithine, N (δ)-({2-methoxyphenyl} acetyl) ornithine, N (δ)-({3- Methoxyphenyl} acetyl) ornithine, N (δ)-({4-methoxyphenyl} acetyl) ornithine, N (δ)-(4-biphenylacetyl) ornithine, N (γ) -benzyl-2,4-diaminobutyric acid, N (γ)
-(2-furylmethyl) -2,4-diaminobutyric acid, N (γ)-(2-
Thienylmethyl) -2,4-diaminobutyric acid, N (γ)-(indol-3-ylmethyl) -2,4-diaminobutyric acid, N (γ) -benzoyl-2,4-diaminobutyric acid, N (γ)- Phenylacetyl-2,4-diaminobutyric acid, N (γ)-(3-phenylpropionyl) -2,4-diaminobutyric acid, N (γ)-(2-furylacetyl) -2,4-diaminobutyric acid, N ( γ)-(2-thienylacetyl) -2,4-diaminobutyric acid, N (γ)-({indol-3-yl} acetyl) -2,4-diaminobutyric acid, N ⁴ -methylasparagine, N ⁴ -phenyl asparagine, N ⁴ - benzyl aspartate, N ⁴ - phenethyl asparagine, N ⁴ - (2- {indol-3-yl} ethyl) asparagine, N ⁵ - methyl glutamine, N ⁵ - phenyl glutamine, N ⁵ - benzyl glutamine, N ⁵ -phenethylglutamine, N ^5- (2- {indol-3-yl} ethyl) glutamine, aspartic acid β -
Methyl ester, aspartic acid β-cyclopropyl ester, aspartic acid β-benzyl ester, aspartic acid β-phenethyl ester, aspartic acid β-
N ⁴ -phenylpiperazine amide, aspartic acid β-N
⁴ - (2-methylphenyl) piperazine amide, aspartic acid beta-N ⁴ - (3- methylphenyl) piperazine amide,
Aspartic acid β-N ⁴ - (4- methylphenyl) piperazine amide, aspartic acid β-N ⁴ - (2- methoxyphenyl) piperazine amide, aspartic acid β-N ⁴ - (3- methoxyphenyl) piperazine amide, aspartic acid β
-N ⁴ - (4-methoxyphenyl) piperazine amide, aspartic acid β-N ⁴ - (2- chlorophenyl) piperazine amide, aspartic acid β-N ⁴ - (3- chlorophenyl) piperazine amide, aspartic acid β-N ⁴ - (4-chlorophenyl) piperazine amide, aspartic acid β-N ⁴ - (4-
Nitrophenyl) piperazine amide, aspartic acid β
-N ⁴ - (4-fluorophenyl) piperazine amide, aspartic acid β-N ⁴ - (3- trifluoromethylphenyl) piperazine amide, aspartic acid β-N ⁴ - (2,3- dimethylphenyl) piperazine amide, asparagine Acid β-
N ⁴ - (2-pyridyl) piperazine amide, aspartic acid β-N ⁴ - (2- pyrimidyl) piperazine amide, glutamic acid γ- methyl ester, glutamic acid γ- cyclopropyl ester, glutamic acid γ- benzyl ester and glutamic acid γ- phenethyl ester A residue or the like is used.

Among them, an acidic-α-amino acid residue is preferable as Y, and for example, glutamic acid, aspartic acid, cysteic acid, homocysteic acid, β- (5-tetrazolyl) alanine and 2-amino-4- (5- A tetrazolyl) butyric acid residue or the like is used, and an aspartic acid residue is particularly preferable.

As the α-amino acid residue represented by Y,
Any of D-form, L-form, and DL-form may be used, but L-form is more preferable.

In the above formula, as the α-amino acid residue represented by Ya, those similar to the α-amino acid residue represented by X are used, and among them, α-amino acid represented by Y
The same as the amino acid residue is preferable.

In the above formula, B represents a neutral-α-amino acid residue. Examples of the neutral-α-amino acid residue include, for example, the formula —NR ⁴ —CHR ⁵ —CO— (R ⁴ represents a hydrogen atom or a C _1-6 alkyl group, R ⁵ represents a C _1-6 alkyl group, C _3-7 cycloalkyl group, C _3-7 cycloalkyl-C _1-3 alkyl group, C _1-6 alkylthio-C
_1-3 alkyl group, C _3-7 cycloalkylthio-C _1-3 alkyl group, C _1-5 alkoxy-C _1-3 alkyl group, C _3-7 cycloalkoxy-C _1-3 alkyl group, substituted _Optionally substituted C _6-14 aryl group, _optionally substituted C _6-14 aryl-C _1-3 alkyl group, _optionally substituted N,
A 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of O and S, or 1 to 3 hetero groups selected from the group consisting of optionally substituted N, O and S A 4- to 7-membered heterocyclic ring containing an atom, -C _1-3 alkyl group, wherein R ⁴ and R ⁵ are bonded together to form-(CH ₂ ) r
-(R represents an integer of 2 to 4) may be formed. ) Neutral-α-amino acid residues and the like are used.

The C _1-6 alkyl group represented by R ⁴ includes
For example, methyl group, ethyl group, n-propyl group, iso
-Propyl group, n-butyl group, iso-butyl group, (1
-Methyl) propyl group, tert-butyl group, n-pentyl group, (2-methyl) butyl group, (3-methyl) butyl group, neopentyl group, n-hexyl group, (2,2-dimethyl) butyl group, A (3,3-dimethyl) butyl group or the like is used, and a C _1-3 alkyl group such as a methyl group, an ethyl group, an n-propyl group or an iso-propyl group is particularly preferable. R ⁴ is particularly preferably a hydrogen atom.

The C _1-6 alkyl group represented by R ⁵ includes
For example, methyl group, ethyl group, n-propyl group, iso
-Propyl group, n-butyl group, iso-butyl group, (1
-Methyl) propyl group, tert-butyl group, n-pentyl group, (2-methyl) butyl group, (3-methyl) butyl group, neopentyl group, n-hexyl group, (2,2-dimethyl) butyl group, A (3,3-dimethyl) butyl group or the like is used, and particularly n-butyl group, iso-butyl group,
(1-methyl) propyl group, tert-butyl group, n-
Pentyl group, (2-methyl) butyl group, (3-methyl)
C such as butyl group, neopentyl group and n-hexyl group
_4-6 alkyl groups are preferred.

As the C _3-7 cycloalkyl group represented by R ⁵ , for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group are used, and particularly a cyclopentyl group, a cyclohexyl group,
C _5-7 cycloalkyl groups such as cycloheptyl groups are preferred.

C _3-7 cycloalkyl-C represented by R ⁵
Examples of the _1-3 alkyl group include a cyclopropylmethyl group, a cyclobutylmethyl group, a cyclobutylethyl group,
A cyclobutylpropyl group, a cyclopentylmethyl group, a cyclopentylethyl group, a cyclopentylpropyl group, a cyclohexylmethyl group, a cyclohexylethyl group, a cyclohexylpropyl group, a cycloheptylmethyl group, a cycloheptylethyl group, etc. are used, and a cyclopropylmethyl group, cyclo butylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, C _3-7 cycloalkyl such as cycloheptylmethyl group - such as a methyl group is preferred.

C _1-6 alkylthio-C _1-3 represented by R ⁵
Examples of the alkyl group include, for example, methylthiomethyl group, methylthioethyl group, methylthiopropyl group, ethylthiomethyl group, ethylthioethyl group, n-propylthiopropyl group, iso-propylthiomethyl group, n-butylthiomethyl group, tert. -Butylthiomethyl group, n-butylthioethyl group, tert-butylthiopropyl group,
(1,1-dimethyl) propylthiomethyl group and the like are used, and particularly, iso-propylthiomethyl group, n-butylthiomethyl group, tert-butylthiomethyl group,
C such as (1,1-dimethyl) propylthiomethyl group
_{A 4-7} alkylthio-methyl group and the like are preferable.

C _3-7 cycloalkylthio-represented by R ⁵
Examples of the C _1-3 alkyl group include a cyclopropylthiomethyl group, a cyclopropylthioethyl group, a cyclopropylthiopropyl group, a cyclobutylthiomethyl group, a cyclobutylthioethyl group, a cyclobutylthiopropyl group,
A cyclopentylthiomethyl group, a cyclopentylthioethyl group, a cyclohexylthiomethyl group, a cycloheptylthiomethyl group and the like are used, and particularly C such as cyclobutylthiomethyl group, cyclopentylthiomethyl group, cyclohexylthiomethyl group and cycloheptylthiomethyl group. _4-7
A cycloalkylthio-methyl group and the like are preferable.

The C _1-5 alkoxy-C _1-3 alkyl group represented by R ⁵ includes, for example, methoxymethyl group, methoxyethyl group, methoxypropyl group, ethoxymethyl group,
Ethoxyethyl group, n-propoxymethyl group, n-propoxyethyl group, iso-propoxymethyl group, iso
-Propoxyethyl group, n-butoxymethyl group, n-butoxyethyl group, tert-butoxymethyl group, ter
t-butoxyethyl group, n-pentyloxymethyl group,
An n-pentyloxyethyl group, a (1,1-dimethyl) propoxymethyl group, a (1,1-dimethyl) propoxyethyl group and the like are used, and particularly a methoxymethyl group, an ethoxymethyl group, an n-propoxymethyl group, iso. -Propoxymethyl group, n-butoxymethyl group, tert-butoxymethyl group, n-pentyloxymethyl group, (1,
A C _1-5 alkoxy-methyl group such as a 1-dimethyl) propoxymethyl group is preferable, and among them, an iso-propoxymethyl group, a tert-butoxymethyl group, (1,1-
A dimethyl) propoxymethyl group and the like are preferable.

C _3-7 cycloalkoxy-C represented by R ⁵
Examples of the _1-3 alkyl group include a cyclopropoxymethyl group, a cyclopropoxyethyl group, a cyclobutoxymethyl group, a cyclobutoxyethyl group, a cyclopentyloxymethyl group, a cyclopentyloxyethyl group, a cyclohexyloxymethyl group and a cycloheptyloxymethyl group. Is used, especially a cyclopropoxymethyl group, a cyclobutoxymethyl group, a cyclopentyloxymethyl group,
Cyclohexyloxymethyl group, C _3-7 cycloalkoxy such as cycloheptyl oxymethyl group - a methyl group.

As the C _6-14 aryl group represented by R ⁵ , phenyl group, α-naphthyl group, β-naphthyl group and the like are used, and among them, phenyl group is preferable. These groups include halogen atoms (eg, fluoro, chloro, bromine, iodo, etc.), hydroxy groups, C _1-3 alkyl groups (eg, methyl group, ethyl group, etc.), nitro groups, carboxyl groups, C _1-5. It has about 1 to 3 substituents selected from an acyl group (eg, formyl group, acetyl group, propionyl group), C _1-5 alkoxy group (eg, methoxy group, ethoxy group, propoxy group, etc.). May be.

The C _6-14 aryl-C _1-3 alkyl group represented by R ⁵ is benzyl group, phenylethyl group, α-
A naphthylmethyl group, an α-naphthylethyl group, a β-naphthylmethyl group, a β-naphthylethyl group and the like are used, and among them, a C _6-14 aryl group such as a benzyl group, an α-naphthylmethyl group and a β-naphthylmethyl group. A methyl group is preferred. The C _6-14 aryl group of these groups includes a halogen atom (eg, fluoro, chloro, bromine, iodo, etc.), a hydroxy group, a C _1-3 alkyl group (eg, methyl group, ethyl group, etc.), a nitro group, Carboxyl group,
C _1-5 acyl group (eg, formyl group, acetyl group,
It may have about 1 to 3 substituents selected from a propionyl group), a C _1-5 alkoxy group (eg, a methoxy group, an ethoxy group, a propoxy group, etc.) and the like.

Examples of the 4- to 7-membered heterocyclic group containing 1 to 3 hetero atoms selected from the group consisting of N, O and S represented by R ⁵ include, for example, 2-thienyl group and 3-thienyl group. , Furyl group, 4-imidazolyl group, 2-pyridyl group, 3-indolyl group, 3-benzofuryl group and the like are used. These groups include halogen atoms (eg, fluoro, chloro, bromine, iodo, etc.), hydroxy groups, C _1-3 alkyl groups (eg, methyl group, ethyl group, etc.), nitro groups, carboxyl groups, C _1-5. It has about 1 to 3 substituents selected from an acyl group (eg, formyl group, acetyl group, propionyl group), C _1-5 alkoxy group (eg, methoxy group, ethoxy group, propoxy group, etc.). May be.

A 4- to 7-membered heterocycle-C _1-3 alkyl group containing 1 to 3 heteroatoms selected from the group consisting of N, O and S represented by R ⁵ (in particular, N, O and S As the 4- to 7-membered heterocycle-methyl group containing 1 to 3 heteroatoms selected from the group consisting of S, 2-thienylmethyl group, 3-thienylmethyl group, furylmethyl group, 4
-Imidazolylmethyl group, 2-pyridylmethyl group, 3-
Indolylmethyl group, 3-benzofurylmethyl group and the like are used. The heterocyclic group of these groups includes a halogen atom (eg, fluoro, chloro, bromine, iodo, etc.), a hydroxy group, a C _1-3 alkyl group (eg, methyl group, ethyl group, etc.), a nitro group, a carboxyl group,
C _1-5 acyl group (eg, formyl group, acetyl group,
It may have about 1 to 3 substituents selected from a propionyl group), a C _1-5 alkoxy group (eg, a methoxy group, an ethoxy group, a propoxy group, etc.) and the like.

R ⁵ is, for example, a C _1-6 alkyl group,
4 to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of N, O and S, 1 to 3 selected from the group consisting of optionally substituted N, O and S And a _4- to 7-membered heterocycle containing a heteroatom of -C _1-3 alkyl group and the like are preferable, and among them, a C _4-6 alkyl group (for example, n-butyl group, iso-butyl group, (1-methyl) propyl) Group, tert-butyl group, n-pentyl group, (2-methyl) butyl group, (3-methyl) butyl group, neopentyl group, n-hexyl group, etc.), N, O,
A 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of S (for example, 2-thienyl group, 3-thienyl group, furyl group, 4-imidazolyl group,
2-pyridyl group, 3-indolyl group, 3-benzofuryl group, etc.) are preferable. Particularly, R ⁵ is preferably a 2-thienyl group or a neopentyl group.

R ⁴ and R ⁵ are bonded together to form-(CH ₂ ) r--
(R represents an integer of 2 to 4) may be formed. That is, R ⁴ and R ⁵ may combine together to form a 4- or 6-membered ring with the adjacent N and C atoms. The 4- to 6-membered ring may be substituted with 1 to 2 hydroxy groups or the like. As r, 3 is particularly preferable. Thus, —NR ⁴ —CH when R ⁴ and R ⁵ are bonded together to form a 4- or 6-membered ring with the adjacent N atom and C atom
As R ⁵ —CO—, proline, 4-hydroxyproline, azetidine-2-carboxylic acid, pipecolic acid (piperidine-2-carboxylic acid) residue and the like are preferable.

Among the above, R ⁴ is a hydrogen atom, and R ⁵ is selected from the group consisting of C _1-6 alkyl group (especially C _4-6 alkyl group etc.) or N, O, S. To 4 to 7 membered heterocyclic group containing 3 to 3 heteroatoms (for example, 2-thienyl group, 3-thienyl group, furyl group, 4-imidazolyl group, 2-pyridyl group, 3-indolyl group, 3-benzofuryl group Groups, preferably 2-thienyl groups, etc.) are preferred.

Specific examples of B include alanine, valine, norvaline, leucine, isoleucine, alloisoleucine, norleucine, tertiary leucine, gammamethylleucine, phenylglycine, phenylalanine, 3- (1-naphthyl) alanine, 3- (2
-Naphthyl) alanine, cysteine, serine, threonine, proline, 4-hydroxyproline, azetidine-
2-carboxylic acid, pipecolic acid (piperidine-2-carboxylic acid), 2- (2-thienyl) alanine, 2- (2-thienyl) glycine, 2- (3-thienyl) glycine, 2
-Cyclopentylglycine, 2-cyclohexylglycine residue and the like are used. In particular, leucine, alloisoleucine, tertiary leucine, gamma methylleucine, phenylglycine, 2- (2-thienyl) alanine, 2- (2-thienyl) glycine, 2- (3-thienyl) glycine, 2-cyclopentylglycine residue A group and the like are more preferable. The α-imino groups of these neutral-α-amino acids are, for example, C _1-6 alkyl groups (eg methyl,
Ethyl, n-propyl, tert-butyl, etc.) and the like. Examples of such α-amino acids include N-methylleucine, N-methylalloyisoleucine, N-methyltert-leucine, N-methylgammamethylleucine, and N-methylphenylglycine residues. Particularly preferred as B is gamma-methylleucine, 2- (2-thienyl) glycine residue and the like.

The neutral-α-amino acid residue represented by B may be any of D-form, L-form and DL-form, and among them, the D-form is preferred.

In the above formula, C represents an L-α-amino acid residue. Examples of the L-α-amino acid residue include glycine, L-alanine, L-valine, L-norvaline, L-leucine, L-isoleucine, L-tertiary leucine, L-norleucine, L-methionine and L-. 2-aminobutyric acid, L-serine, L-threonine, L-phenylalanine, L-aspartic acid, L-glutamic acid, L-asparagine, L-glutamine, L-lysine, L-tryptophan, L-arginine, L-tyrosine, Commonly known L-α-amino acid residues such as L-proline residue are used. Among them, glycine, L-alanine, L-valine, L-norvaline, L-leucine, L-isoleucine,
L-tertiary leucine, L-norleucine, L-methionine, L-2-aminobutyric acid, L-serine, L-threonine, L-aspartic acid, L-glutamic acid, L-asparagine, L-glutamine, L-lysine, L-arginine residue and the like are preferable. In particular, L-valine, L-norvaline,
L-leucine, L-isoleucine, L-tert-leucine, L-norleucine, L-2-aminobutyric acid residue and the like are preferable. The α-imino group of these L-α-amino acids is
For example, it may be substituted with a C _1-6 alkyl group (eg, methyl group, ethyl group, n-propyl group, tertiary butyl group, etc.). As such L-α-amino acid, for example, L-N-methylleucine, L-N-methylnorleucine, L-N (α) -methyltryptophan residue and the like are used. As C, an L-leucine residue and the like are particularly preferable.

In the above formula, D represents a D-α-amino acid residue having an aromatic ring group. D-α- having the aromatic ring group
As the amino acid residue, for example, a D-α-amino acid having an aromatic ring group in its side chain is used. Specific examples thereof include D-tryptophan, D-5-methyltryptophan, D-phenylalanine, D-tyrosine and D-.
3- (1-naphthyl) alanine, D-3- (2-naphthyl)
Alanine, D-3- (3-benzothienyl) alanine, D-3- (4-biphenyl) alanine, D-pentamethylphenylalanine and the like are used, among which D-tryptophan and D-5-methyltryptophan are preferable. . Particularly, D-tryptophan is more preferable. D- having these aromatic rings
The α-imino group of α-amino acid is, for example, a C _1-6 alkyl group (eg, methyl group, ethyl group, n-propyl group,
Tert-butyl group, etc.), and the imino group of the indole ring of D-tryptophan is, for example, C _1-6 alkyl (eg, methyl, ethyl, n-propyl, tert-butyl), C _3-8 cycloalkyl (eg cyclopentyl, cyclohexyl etc.), C _6-12 aryl (eg phenyl, 4-
Methylphenyl, etc.), C _7-15 aralkyl (eg,
Benzyl, phenethyl, etc.) hydrocarbon groups and C _1-6
Aliphatic acyl (eg formyl, acetyl, propionyl etc.), C _4-9 alicyclic acyl (eg cyclopentanecarbonyl, cyclohexanecarbonyl etc.), C _{7-15 arylacyl} (eg benzoyl,
4-methylbenzoyl etc.), C _8-16 aralkylacyl (eg phenylacetyl, 2-phenylpropionyl, 3-phenylpropionyl, diphenylacetyl etc.), C _1-6 alkoxycarbonyl (eg methoxycarbonyl, ethoxycarbonyl etc.) It may be substituted with an acyl group such as. Examples of such α-amino acids include D-N (α) -methyltryptophan, D-N-methylphenylalanine, D-N-methyltyrosine, D-N ⁱⁿ -methyltryptophan and D-N ⁱⁿ -ethyltryptophan. , D-N ⁱⁿ -formyl tryptophan, D
-N ⁱⁿ - acetyl tryptophan, D-N ⁱⁿ - such as methoxycarbonyl tryptophan is used. Above all, D-
N ⁱⁿ -methyltryptophan, D -N ⁱⁿ -formyl tryptophan, D -N ⁱⁿ -acetyltryptophan, D -N ^in-
Methoxycarbonyltryptophan and the like are more preferable.

Further, as D, -D-Trp (N ⁱⁿ
-R ⁶⁾ - (R ⁶ is a hydrogen atom, C _1-6 alkyl groups, C
_3-7 cycloalkyl group, -COR ⁷ (R ⁷ represents a hydrogen atom or a C _1-6 alkyl group), -COOR ⁸ (R ⁸ represents a hydrogen atom or a C _1-6 alkyl group) or -CONH
R ⁹ (R ⁹ represents a hydrogen atom or a C _1-6 alkyl group) is shown. And a D-α-amino acid residue represented by Here, R ⁶ is bonded to the N atom of the indole group of the tryptophan residue.

The C _1-6 alkyl group represented by R ⁶ includes
For example, methyl group, ethyl group, n-propyl group, iso
-Propyl group, n-butyl group, iso-butyl group, (1
-Methyl) propyl group, tert-butyl group, n-pentyl group, (2-methyl) butyl group, (3-methyl) butyl group, neopentyl group, n-hexyl group, (2,2-dimethyl) butyl group, A (3,3-dimethyl) butyl group or the like is used, and a C _1-3 alkyl group such as a methyl group, an ethyl group, an n-propyl group or an iso-propyl group is particularly preferable.

As the C _3-7 cycloalkyl group represented by R ⁶ , for example, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group are used, and particularly a cyclopentyl group, a cyclohexyl group and a cycloheptyl group are used. C _5-7 cycloalkyl groups such as

Examples of the C _1-6 alkyl group represented by R ⁷ , R ⁸ and R ⁹ include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group, an n-butyl group and an iso-group.
Butyl group, (1-methyl) propyl group, tert-butyl group, n-pentyl group, (2-methyl) butyl group, (3
-Methyl) butyl group, neopentyl group, n-hexyl group, (2,2-dimethyl) butyl group, (3,3-dimethyl) butyl group and the like are used, and particularly, methyl group, ethyl group, n-propyl group, C _1-3 such as iso-propyl group
Alkyl groups are preferred.

As the C _6-15 aryl group represented by R ⁷ , R ⁸ and R ⁹ , for example, a phenyl group, α-naphthyl group, β-naphthyl group and the like are used, and a phenyl group is particularly preferable.

Examples of the C _6-15 aryl-C _1-3 alkyl group represented by R ⁷ , R ⁸ and R ⁹ include benzyl group, phenylethyl group, phenylpropyl group, α-naphthylmethyl group and α- Naphthylethyl group, α-naphthylpropyl group, β-naphthylmethyl group, β-naphthylethyl group, β-naphthylpropyl group and the like are used, and particularly C such as benzyl group, α-naphthylmethyl group and β-naphthylmethyl group is used. _{A 6-15} arylmethyl group is preferred.

Specific examples of --COR ⁷ include formyl group, acetyl group, propionyl group, butyryl group, isobutyryl group, isovaleryl group, pivaloyl group,
An n-pentylcarbonyl group, a benzoyl group, a phenylacetyl group, etc. are used, and as -COOR ⁸ , for example, a methoxycarbonyl group, an ethoxycarbonyl group, a phenoxycarbonyl group, a benzyloxycarbonyl group, etc. are used, and as -CONHR ⁹ , For example, carbamoyl group, methylaminocarbonyl group, ethylaminocarbonyl group, n-propylaminocarbonyl group, is
An o-propylaminocarbonyl group, an n-butylaminocarbonyl group, an iso-butylaminocarbonyl group, a phenylaminocarbonyl group, a benzylaminocarbonyl group and the like are used.

R ⁶ is particularly a hydrogen atom, —COR ⁷¹
(R ⁷¹ represents a hydrogen atom or a C _1-6 alkyl group) and the like are preferable. Specifically, a hydrogen atom, a formyl group, an acetyl group and the like are preferable.

Among the cyclic hexapeptides represented by the formula (I) of the present invention or salts thereof, particularly preferable are, for example, the formula cyclo [-NH-CHR ² -CO-L-Asp (R ³ ) -Y ¹ -NH-CHR ⁵ -CO-C ¹ -D-Trp (N ⁱⁿ -R ⁶ )] (II) (In the formula, R ² is a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a C _{3- 7} cycloalkyl-C _1-3 alkyl group, C _1-6 alkylthio-C _1-3 alkyl group, C _3-7 cycloalkylthio-C _1-3 alkyl group, C _1-5 alkoxy-C _1-3 alkyl group , C _3-7 cycloalkoxy-C _1-3 alkyl group, optionally substituted C _6-14 aryl group, optionally substituted C _6-14 aryl-C _1-3 alkyl group, substituted Optionally 1 to 3 selected from the group consisting of N, O and S
4 to 7 membered heterocyclic group containing 4 heteroatoms or 4 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of optionally substituted N, O and S-C _{1-3 represents} an alkyl group, R ³ is a formula

[0096]

[Chemical 21]

(X ¹¹ and X ²¹ are a hydrogen atom and C, respectively.
_1-6 alkyl group, C _1-6 alkoxy group, halogen atom or nitro group. Group represented by), formula

[0098]

[Chemical formula 22]

(M and n are integers of 1 to 3, X is O, S or NH, and p is 0 or 1)

[0100]

[Chemical formula 23]

A group or formula represented by (q represents an integer of 1 to 3)

[0102]

[Chemical formula 24]

(X ³ and X ⁴ are a hydrogen atom and C, respectively.
_1-6 alkyl group, C _1-6 alkoxy group, halogen atom or nitro group. ), Y ¹ is L-glutamic acid, L-aspartic acid, L-cysteic acid, L
-Homocysteic acid, L-β- (5-tetrazonyl) alanine or L-2-amino-4- (5-tetrazolyl)
A butyric acid residue, R ⁵ is a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a C _3-7 cycloalkyl-C _1-3 alkyl group,
C _1-6 alkylthio-C _1-3 alkyl group, C _3-7 cycloalkylthio-C _1-3 alkyl group, C _1-5 alkoxy-C
_1-3 alkyl group, C _3-7 cycloalkoxy-C _1-3 alkyl group, C _1-6 alkylthio group, C _3-7 cycloalkylthio group, C _1-5 alkoxy group, C _3-7 cycloalkoxy group, 1 selected from the group consisting of an _optionally substituted C _6-14 aryl group, an _optionally substituted C _6-14 aryl-C _1-3 alkyl group, and an _optionally substituted N, O, S 4 to 7 membered heterocyclic group containing 1 to 3 heteroatoms or 4 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of optionally substituted N, O and S Represents a -C _1-3 alkyl group, C ¹ is glycine, L-alanine, L-valine, L-norvaline, L-leucine, L-isoleucine, L-tert-isoleucine, L-norleucine, L-methionine, L -2-aminobutyric acid, L-serine, L-threonine, L-phenyl Alanine, L-aspartic acid, L-glutamic acid, L-asparagine, L-glutamine, L-lysine, L-tryptophan, L-arginine, L-tyrosine, L-proline, L-N-methylleucine, L-N- Methyl norleucine or L-N (α)-
Represents a methyltryptophan residue, R ⁶ is a hydrogen atom, C
_1-6 alkyl group, C _3-7 cycloalkyl group, -COR
⁷ (R ⁷ represents a hydrogen atom, a C _1-6 alkyl group, a C _6-15 aryl group, a C _6-15 aryl- _{l- 3} alkyl group), -CO
OR ⁸ (R ⁸ is a C _1-6 alkyl group, a C _6-15 aryl group, C
_6-15 aryl- _3- alkyl group) or -CON
HR ⁹ (R ⁹ represents a hydrogen atom, a C _1-6 alkyl group, a C _6-15 aryl group, a C _6-15 aryl-C _1-3 alkyl group). ] The cyclic hexapeptide represented by these, or its salt, etc. Among them, the formula cyclo [-NH-CHR ² -CO-L-Asp (R ³¹ ) -L-Asp-NH-CHR ⁵ -CO-L-Leu-D-Trp (N ⁱⁿ -R ⁶¹ )] (III (In the formula, R ² is a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a C _3-7 cycloalkyl-C _1-3 alkyl group, a C _1-6 alkylthio-C _1-3 alkyl group, C _3-7 cycloalkylthio-C _1-3 alkyl group, C _1-5 alkoxy-C _1-3 alkyl group, C _3-7 cycloalkoxy-C _1-3 alkyl group, optionally substituted C _{6- 14} aryl groups, optionally substituted C _6-14 aryl-C _1-3 alkyl groups, _optionally substituted 1 to 3 selected from the group consisting of N, O and S
4 to 7 membered heterocyclic group containing 4 heteroatoms or 4 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of optionally substituted N, O and S-C _{1-3 represents} an alkyl group, R ³¹ is a formula

[0104]

[Chemical 25]

(X ¹¹ and X ²¹ are a hydrogen atom and C, respectively.
_1-6 alkyl group, C _1-6 alkoxy group, halogen atom or nitro group. ) And R ⁵ is C
_1-6 alkyl group, C _3-7 cycloalkyl group, C _3-7 cycloalkyl-C _1-3 alkyl group, C _1-6 alkylthio-C
_1-3 alkyl group, C _3-7 cycloalkylthio-C _1-3 alkyl group, C _1-5 alkoxy-C _1-3 alkyl group, C _3-7 cycloalkoxy-C _1-3 alkyl group, substituted _Optionally substituted C _6-14 aryl group, _optionally substituted C _6-14 aryl-C _1-3 alkyl group, _optionally substituted N,
A 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of O and S, or 1 to 3 hetero groups selected from the group consisting of optionally substituted N, O and S A 4- to 7-membered heterocyclic group containing an atom, —C _1-3 alkyl group, R ⁶¹ is a hydrogen atom or —COR ⁷¹ (R ⁷¹
_{Represents a} hydrogen atom or a C _1-6 alkyl group). ]
The cyclic hexapeptide represented by or a salt thereof is preferable. Particularly, in the above cyclic hexapeptide (III), R ² is a C _1-6 alkyl group, R ⁵ is a C _1-6 alkyl group, or 1 to 3 groups selected from the group consisting of N, O and S. Cyclic hexapeptides which are 4- to 7-membered heterocyclic groups containing heteroatoms are particularly preferred.

Specific examples of the cyclic hexapeptide (I) of the present invention include cyclo [-D-Leu-L-Asp (Php) -L-Asp-D-Thg (2) -L-Leu-D-. Trp
-] And so on.

The salts (or pharmacologically acceptable salts) of the cyclic hexapeptide (I) of the present invention include, for example, metal salts (eg sodium salt, potassium salt, calcium salt, magnesium salt, etc.), bases. Alternatively, salts with basic compounds (for example, ammonium salt, arginine salt, etc.), inorganic acid addition salts (for example, hydrochloride, sulfate, phosphate, etc.), organic acid salts (for example, acetate salt, propionate salt, Citrate, tartrate, malate, oxalate, etc.) are used.

In the above, when the amino acids and peptides are indicated by abbreviations, IUPAC-IUB Commissi
It is based on the abbreviations based on on Biochemical Nomenclature or abbreviations commonly used in this field, and examples are given below.

Gly: Glycine Sar: Sarcosine (N-methylglycine) Ala: Alanine Val: Valine Nva: Norvaline Ile: Isoleucine aIle: Alloisoleucine Nle: Norleucine Leu: Leucine N-MeLeu: N-Methylleucine tLeu: Tertiary leucine γMeLeu: Gamma-methylleucine Met: Methionine Arg: Arginine Arg (Tos): Ng-paratoluenesulfonyl arginine (g is superscript) Lys: Lysine Lys (Mtr): N (ε)-(4-methoxy-2,3,
6-trimethylbenzenesulfonyl) lysine Orn: ornithine Orn (COPh): N (δ) -benzoylornithine Orn (COCH ₂ Ph): N (δ) -phenylacetyl ornithine Orn (COCH ₂ CH ₂ Ph): N (δ) -(3-Phenylpropionyl) ornithine Orn (COCH ₂ -Ind): N (δ)-({indol-3-yl} acetyl) ornithine His: Histidine His (Bom): N (π) -benzyloxymethylhistidine His (Bzl): N (τ) -benzyl histidine Asp: Aspartic acid Asn (CH ₂ Ph): N ⁴ -benzyl asparagine Asn (CH ₂ CH ₂ Ph): N ⁴ -phenethyl asparagine Asn (CH ₂ CH ₂ -Ind) : N ⁴ - (2- {indol-3-yl} ethyl) asparagine _{Asn (Me · CH 2 CH 2} Ph): N 4 - methyl -N ⁴ - phenethyl asparagine _{Asn (CH 2 CHMePh): N} 4 - ({ 2-phenyl} propyl)
Asparagine Asp (B1): Aspartic acid β-4-phenylpiperazine amide Asp (B2): Aspartic acid β-4-phenylpiperidine amide Asp (B3): Aspartic acid β-indoline amide Asp (B4): Aspartic acid β-1 -Aminoindanamide Asp (B5): Aspartic acid β-1-aminotetrahydronaphthalenamide Asp (B6): Aspartic acid β-4-Acetylpiperazine amide Asp (B7): Aspartic acid β-4- (2-
Methoxyphenyl) piperazine amide Glu: Glutamic acid _{Gln (CH 2 Ph): N} 5 - benzyl Glutamine _{Gln (CH 2 CH 2 Ph)} : N 5 - phenethyl glutamine _{Gln (CH 2 CH 2 -Ind)} : N 5 - (2- {Indol-3-yl} ethyl) glutamine Glu (B3): glutamic acid γ-indoline
Amide Glu (B4): Glutamic acid γ-1-aminoindan Amide Glu (B5): Glutamic acid γ-1-aminotetrahydronaphthalene amide Cys: Cysteine Cta: Cysteinic acid Ser: Serine Ser (Bzl): O-benzylserine Thr: Threonine Thr (Bzl): O-benzyl threonine Pro: proline Tpr: thioproline Hyp: 4-hydroxyproline Hyp (Bzl): 4-benzyloxyproline Azc: azetidine-2-carboxylic acid Pip: pipecolic acid (piperidine-2-
Carboxylic acid) Phe: Phenylalanine N-MePhe: N-methylphenylalanine Tyr: Tyrosine Trp: Tryptophan mTrp: 5-Methyltryptophan N-MeTrp: N (α) -methyltryptophan Trp (Me): Nin-methyltryptophan Trp (For) : Nin-formyltryptophan Trp (Ac): Nin-acetyltryptophan Phg: Phenylglycine Nal (1): 3- (1-naphthyl) alanine Nal (2): 3- (2-naphthyl) alanine Thi: 3- (2 -Thienyl) alanine Thg (2): 2- (2-thienyl) glycine Thg (3): 2- (3-thienyl) glycine Acpr: 1-aminocyclopropane-1-
Carboxylic Acid Acbu: 1-Aminocyclobutane-1-Carboxylic Acid Acpe: 1-Aminocyclopentane-1-
Carboxylic acid Achx: 1-aminocyclohexane-1-
Carboxylic acid Achp: 1-aminocycloheptane-1-
Carboxylic acid Tic: tetrahydroisoquinoline-2-
Carboxylic acid Cpg: Cyclopentylglycine The protecting groups and reagents commonly used in the present specification are indicated by the following abbreviations.

AcOEt: ethyl acetate Boc: tertiary butoxycarbonyl Bzl: benzyl BrZ: 2-bromobenzyloxycarbonyl ClZ: 2-chlorobenzyloxycarbonyl Tos: paratoluenesulfonyl For: formyl OBzl: benzyl ester OPac: phenacyl ester ONB : HONB ester TFA: trifluoroacetic acid TEA: triethylamine DIEA: diisopropylethylamine IBCF: isobutylchloroformate DMF: N, N-dimethylformamide DCC: N, N'-dicyclohexylcarbodiimide DCU: N, N'-dicyclohexylurea HONB: N -Hydroxy-5-norbornene-2,3-dicarboximide HOBt: 1-hydroxybenzotriazole DCM: dichloromethane THF: tetrahydrofuran

[0111]

[Chemical formula 26]

The cyclic hexapeptide represented by formula (I) of the present invention or a salt thereof can be produced by a conventional means for peptide synthesis. That is, either the liquid phase synthesis method or the solid phase synthesis method may be used, but the liquid phase synthesis method may be preferable in some cases. The means for synthesizing such peptides may be according to any known method, eg, M. Bodansky and MA Ondet.
ti, Peptide Synthesis, Interscience, New York, 1966; FM Finn
And K. Hofmann, The Proteins
s), Volume 2, H. Nenrath, edited by RL Hill, Academic Press, Inc., New York, 1976; Nobuo Izumiya et al., "Basics and Experiments of Peptide Synthesis," Maruzen Co., Ltd. 1985;
Haruaki Yajima, Shunpei Sakakibara et al., Laboratory of Biochemistry 1, edited by The Biochemical Society of Japan, Tokyo Chemistry Doujin 1977; Shun Kimura, et al.
JM Stewart and JD Young, Solid Phase Peptide Synth.
esis), Pierce Chemical Company, Illinois, 1984 and the like, for example, azide method, chloride method, acid anhydride method, mixed acid anhydride method, DCC method, active ester method, method using Woodward reagent K, The carbonyldiimidazole method, the redox method, the DCC / HONB method, the method using a BOP reagent and the like can be mentioned. For example, the formula cyclo [A-X-Ya-B-C-D-] (Ia) [In the formula, each of A, X, Ya, B, C and D has the same meaning as described above. ] The raw material having a reactive carboxyl group corresponding to one of the two kinds of fragments divided into two at any position of the cyclic hexapeptide represented by The cyclic hexapeptide represented by formula (I) or a salt thereof is produced by condensing by a conventional synthetic method to produce a linear pentapeptide, and then subjecting the product to ring closure condensation by a known condensation method. be able to. Furthermore, when the resulting condensate has a protecting group, it can be produced by removing the protecting group by a conventional method. Particularly in the solid phase synthesis method, an amino acid having a functional group that should not be involved in the reaction and an insoluble carrier such as Pam resin are bound through the carboxyl group of the amino acid, and the amino protecting group is removed. Condensing an amino acid with a protected functional group that should not be involved in It can be produced by removing the group and simultaneously breaking the bond with the insoluble carrier.

The first raw material and the other second raw material are
Usually, it is an amino acid and / or peptide fragment, and these are combined to form the intended cyclic hexapeptide represented by the formula (I) or a salt thereof. These are usually linear or branched.
The “reactive carboxyl group” means the carboxyl group itself or an activated carboxyl group. The "reactive amino group" means the amino group itself or an activated amino group. Usually, one of the two functional groups that act on the condensation is activated. Carboxyl groups and amino groups that do not participate in the condensation reaction are protected before entering the condensation reaction.

Protection of a functional group which should not be involved in the reaction of the starting material, protection of the protective group, elimination of the protective group, activation of the functional group involved in the reaction and the like can also be appropriately selected from known ones or means.

Examples of the protective group for the amino group of the raw material include benzyloxycarbonyl, tert-butyloxycarbonyl, tert-amyloxycarbonyl,
Isobornyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-chlorobenzyloxycarbonyl, adamantyloxycarbonyl, trifluoroacetyl, phthaloyl, formyl, 2-nitrophenylsulfenyl, diphenylphosphinothioyl, 9-fluorenyl Examples include methyloxycarbonyl. Examples of the protecting group for the carboxyl group include alkyl esters (for example, methyl, ethyl, propyl, butyl, tert-butyl, cyclopentyl, cyclohexyl,
Ester groups such as cycloheptyl, cyclooctyl, 2-adamantyl, etc.), benzyl ester, 4-nitrobenzyl ester, 4-methoxybenzyl ester, 4-chlorobenzyl ester, benzhydryl ester, phenacyl ester, benzyloxycarbonyl hydrazide, tersha Ributyloxycarbonyl hydrazide, trityl hydrazide and the like.

Examples of the thiol-protecting group for cysteine include 4-methoxybenzyl, 4-methylbenzyl, benzyl, tert-butyl, adamantyl, trityl,
Acetamidomethyl, carbomethoxysulfenyl, 3
Examples include -nitro-2-pyridinesulfenyl and trimethylacetamidomethyl.

The hydroxyl group of serine can be protected by, for example, esterification or etherification. Suitable groups for this esterification include, for example, lower alkanoyl groups such as acetyl group, aroyl groups such as benzoyl group,
Examples thereof include groups derived from carbonic acid such as a benzyloxycarbonyl group and an ethyloxycarbonyl group. Further, as a group suitable for etherification, for example, a benzyl group,
Examples thereof include a tetrahydropyranyl group and a tertiary butyl group. However, the hydroxyl group of serine does not necessarily need to be protected.

Examples of the protective group for the phenolic hydroxyl group of tyrosine include, but are not limited to, benzyl, 2,6-dichlorobenzyl, 2-nitrobenzyl, 2-bromobenzyloxycarbonyl and tert-butyl. No need. Methionine may be protected in the form of sulfoxide.

Examples of the protecting group for imidazole of histidine include paratoluenesulfonyl, 4-methoxy-2,3,6-
Trimethylbenzenesulfonyl, 2,4-dinitrophenyl, benzyloxymethyl, tert-butoxymethyl, tert-butoxycarbonyl, trityl, 9-
Examples thereof include fluorenylmethyloxycarbonyl, but they do not necessarily need to be protected.

The protecting group for the indole of tryptophan includes formyl, 2,4,6-trimethylbenzenesulfonyl, 2,4,6-trimethoxybenzenesulfonyl and 4-
Methoxy-2,3,6-trimethylbenzenesulfonyl,
Examples thereof include 2,2,2-trichloroethyloxycarbonyl and diphenylphosphinothioyl oil, but they are not necessarily protected.

The activated carboxyl group of the raw material includes, for example, corresponding acid anhydrides, azides, active esters [alcohols (eg, pentachlorophenol, 2,4,5-trichlorophenol, 2,4-dinitro, etc. Ester with phenol, cyanomethyl alcohol, para-nitrophenol, N-hydroxy-5-norbornene-2,3-dicarboximide, N-hydroxysuccinide, N-hydroxyphthalimide, N-hydroxybenztriazole) can give. The activated amino group of the raw material includes, for example, the corresponding phosphoric acid amide.

The condensation reaction can be carried out in the presence of a solvent. The solvent can be appropriately selected from those known to be usable in the peptide condensation reaction. For example, anhydrous or hydrous dimethylformamide, dimethylsulfoxide, pyridine, chloroform, dioxane, dichloromethane, tetrahydrofuran, acetonitrile, ethyl acetate, N-methylpyrrolidone, or an appropriate mixture thereof can be used. The reaction temperature is appropriately selected from the range known to be applicable to peptide bond-forming reactions, and is usually appropriately selected from the range of about -20 ° C to 30 ° C.

The intramolecular cyclization reaction can be performed at any position of the peptide by a known method. For example, first, the terminal α-carboxyl protecting group of the C-terminal amino acid of the protected peptide is eliminated by a known method, and then this is activated by a known method, and then the terminal α-amino acid residue of the N-terminal amino acid is known. It is also possible to eliminate the compound by the above method and to cyclize it in the molecule. Alternatively, after simultaneously removing the terminal α-carboxyl protecting group of the C-terminal amino acid and the terminal α-amino protecting group of the N-terminal amino acid of the protected peptide,
You may cyclize in a molecule by a well-known condensation reaction. Also,
In some cases, it may be preferable to carry out the intramolecular cyclization reaction under high dilution.

As a method for removing the protecting group, for example, Pd
Catalytic reduction in a hydrogen stream in the presence of a catalyst such as black or Pd-carbon, and acid treatment with anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, or a mixture thereof. In addition, reduction with sodium in liquid ammonia can also be mentioned. The elimination reaction by the above acid treatment is generally -20 ° C to 40 ° C.
However, in the acid treatment, addition of a cation scavenger such as anisole, phenol, thioanisole, metacresol, paracresol, dimethyl sulfide, 1,4-butanedithiol, and 1,2-ethanedithiol is performed. It is valid. Also, the 2,4-dinitrophenyl group used as the imidazole protecting group of histidine is removed by thiophenol treatment, and the formyl group used as the indole protecting group of tryptophan is the above 1,2-ethanedithiol, 1,4-butane group. In addition to deprotection by acid treatment in the presence of dithiol or the like, it is also removed by alkali treatment with dilute sodium hydroxide or dilute ammonia.

After the reaction, the cyclic hexapeptide (I) thus produced is collected by means of peptide separation and purification such as extraction, distribution, reprecipitation, recrystallization, column chromatography, high performance liquid chromatography and the like. To be done.

The cyclic hexapeptide (I) of the present invention is a metal salt (eg sodium salt, potassium salt, calcium salt, magnesium salt etc.), a salt with a base or a basic compound (eg ammonium salt, arginine) by a method known per se. Salt, etc.), an acid addition salt, especially a pharmacologically acceptable acid addition salt, such as an inorganic acid (eg hydrochloric acid, sulfuric acid, phosphoric acid) or an organic acid.
(For example, acetic acid, propionic acid, citric acid, tartaric acid,
Examples include salts such as malic acid, oxalic acid, and methanesulfonic acid.

The thus-obtained cyclic hexapeptide (I) of the present invention or a salt thereof contains endothelin receptors (ie, both endothelin A and endothelin B receptors), especially endothelin B receptors. Shows an excellent antagonism against That is, the cyclic hexapeptide (I) of the present invention or a salt thereof exhibits an antagonistic action on both endothelin A receptor and endothelin B receptor, but especially compared with conventional endothelin receptor antagonists. It shows a stronger antagonistic effect on the body. Furthermore, those that show almost no antagonism to the endothelin A receptor but only antagonize the endothelin B receptor are included. Specifically, the cyclic hexapeptide (I) of the present invention or a salt thereof is disclosed in EP0528312A2 (Japanese Patent Application No. 4-216).
019) has a stronger antagonistic effect on the endothelin B receptor (eg, I
C ₅₀ value is low) or EP0528312A2
Compared with the peptide disclosed in the publication (Japanese Patent Application No. 4-216019), the endothelin B receptor antagonism against the endothelin A receptor antagonism is stronger (for example, endothelin B receptor IC ₅₀ value / endothelin A receptor). I
It has a low C ₅₀ value). For example, the IC ₅₀ value for the endothelin B receptor is similar, but the IC ₅₀ value for the endothelin A receptor is high. Therefore, the cyclic hexapeptide (I) or a salt thereof of the present invention can more efficiently suppress endothelin B receptor-mediated contraction of vascular smooth muscle than conventional endothelin receptor antagonists. Furthermore, although the cyclic hexapeptide (I) of the present invention or a salt thereof is inferior to the endothelin B receptor antagonism, it also exhibits the endothelin A receptor antagonism, and therefore, singly via the endothelin A receptor and endothelin B receptor. EP0528312A2, which can suppress the contraction of each vascular smooth muscle, but has an excellent antagonistic effect on the endothelin A receptor
When used in combination with the peptide disclosed in the publication (Japanese Patent Application No. 4-216019), the contraction of the vascular smooth muscles mediated by the endothelin A receptor and the endothelin B receptor can be more effectively suppressed. Therefore, the cyclic hexapeptide (I) or a salt thereof of the present invention is useful as an endothelin receptor antagonist against warm-blooded animals (eg, rat, mouse, rabbit, chicken, pig, sheep, cow, monkey, human). is there. The cyclic hexapeptide (I) or a salt thereof of the present invention is a safe and low toxic peptide.

Furthermore, since the cyclic hexapeptide (I) of the present invention or a salt thereof has an excellent endothelin antagonism as described above, hypertension, pulmonary hypertension and angina caused by endothelin are caused. , Cardiomyopathy,
Myocardial infarction, Raynaud's disease, Burger's disease, cerebral infarction, cerebral vasospasm, asthma, acute renal failure, cyclosporine, decreased renal function due to cisplatin, arteriosclerosis, diabetic neuropathy, diabetic retinopathy, hemorrhagic shock, endotoxin shock , Organs that occur during surgery or transplantation of organs (for example,
It can be used as a therapeutic agent for diseases such as hypofunction of liver) and high-lipid plasma.

When using the cyclic hexapeptide (I) of the present invention or a salt thereof as an endothelin receptor antagonist,
When administered parenterally, it is usually administered in the form of a solution (eg, injection). The injections include intravenous injections, subcutaneous injections, intradermal injections, intramuscular injections, drip injections and the like. Such an injection is prepared by a method known per se, that is, by dissolving, suspending or emulsifying a compound having an endothelin receptor antagonistic action in a sterile aqueous or oily liquid. Examples of the aqueous solution for injection include physiological saline, isotonic solution containing glucose and other adjuvants (eg, D-sorbitol, D-mannitol, sodium chloride, etc.), and a suitable solubilizing agent such as alcohol. (Eg ethanol), polyalcohol (eg propylene glycol, polyethylene glycol), nonionic surfactant (eg polysorbate 80, HCO-50) and the like may be used in combination. Examples of the oily liquid include sesame oil and soybean oil, which may be used in combination with solubilizing agents such as benzyl benzoate and benzyl alcohol. Also, buffers (eg, phosphate buffer,
Combined with sodium acetate buffer, soothing agent (eg, benzalkonium chloride, procaine hydrochloride, etc.), stabilizer (eg, human serum albumin, polyethylene glycol, etc.), preservative (eg, benzyl alcohol, phenol, etc.) You may. The adjusted injection solution is usually filled in a suitable ampoule. Although the single dose varies depending on the administration subject, target organ, symptom, administration method, etc., for example, in the form of an injection, it is usually about 0.01 mg to 100 mg, preferably 0.01 to 50 per kg body weight.
It is convenient to administer about mg, more preferably about 0.01 to 20 mg by intravenous injection.

For oral administration, powders, tablets,
It is administered in the form of oral preparations such as granules and capsules.
When producing the oral preparation, a pharmaceutically acceptable carrier can be added. Examples of the carrier include excipients (eg lactose, starch etc.), lubricants (eg magnesium stearate, talc etc.), binders (hydroxypropylcellulose, hydroxypropylmethylcellulose, macrogold etc.), disintegrants ( For example,
Starch, carboxymethyl cellulose calcium, etc.) are used. If necessary, additives such as preservatives (eg, benzyl alcohol, chlorobutanol, methyl paraoxybenzoate, propyl paraoxybenzoate, etc.), antioxidants, colorants, sweeteners, etc. can be used. The single dose is usually about 5 mg to 1 g, preferably about 10 to 100 mg per kg body weight.

It can also be administered as a sustained-release preparation disclosed in Japanese Patent Application No. 5-153393. That is, it can be administered as a sustained-release preparation containing the cyclic hexapeptide (I) of the present invention or a salt thereof and a biodegradable polymer (such as a fatty acid polyester or a copolymer of glycolic acid and lactose). .

[0132]

The present invention will be described in more detail below with reference to examples, but these examples do not limit the scope of the present invention.

Example 1 cyclo [-D-Leu-Asp (B1) -Asp-D
-Thg (2) -Leu-D-Trp-] (1) Production of Boc-D-Thg (2) -Leu-OBzl 17.8 g (50 mmole) of Boc-Thg (2) -OH.CHA was added to acetic acid. The mixture was suspended in a mixed solvent of ethyl (250 mL) and water (250 mL) and vigorously stirred, and 50 mL of a 1N H ₂ SO ₄ aqueous solution was added thereto to completely dissolve it. The ethyl acetate layer was separated, dried over Na ₂ SO ₄ , and the solvent was evaporated under reduced pressure. 90 mL of DMF was added to the residue to give a solution [1].

On the other hand, Tos H-Leu-OBzl 39.4 g (100
mmole) with ethyl acetate (250 mL) -4% NaHCO 3.
₃ Aqueous solution (250 mL) was added to the mixed solvent, and the mixture was vigorously stirred and completely dissolved. The ethyl acetate layer was separated, dried over Na ₂ SO ₄ , and the solvent was evaporated under reduced pressure. DMF90 on the residue
mL was added to make a solution [2].

The solutions [1] and [2] were combined, and HOBt1
3.5 g (100 mmole) was added and dissolved. To this, under ice cooling, 20.6 g of DCC (100 mmole)
30 mL of the DMF solution of was added dropwise over 10 minutes, and the mixture was stirred for 1 hour as it was, and then stirred at 4 ° C. overnight. The insoluble material was filtered off, and the solvent was distilled off. Ethyl acetate and water were added to the residue, 50 mL of 1N H ₂ SO ₄ aqueous solution was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was separated, washed with saturated brine, 4% NaHCO ₃ aqueous solution and saturated brine, dried over Na ₂ SO ₄ , and the solvent was evaporated. The residue was purified by column chromatography using silica gel (6 cmφ, 30 cm, hexane: ethyl acetate = 10: 1 ... 3: 1).
The residue was crystallized from petroleum ether to give colorless crystals.

Yield 14.9 g (yield 87.2%) mp 71.0-72.5 ° C. Rf ₁ 0.80 Rf ₂
0.88 [α] _D ²⁵ -46.3 ° (c = 1.02, DMF) Elemental analysis Calculated as C ₂₄ H ₃₂ N ₂ O ₅ S: C, 62.59; H, 7.00; N, 6.08 Experimental value : C, 62.35; H, 7.00; N, 6.10 (2) Production of Boc-D-Thg (2) -Leu-OPac 16.1 g of Boc-D-Thg (2) -Leu-OBzl synthesized in (1).
(32.6 mmole) was dissolved in 500 mL of methanol, 5 g of activated carbon was added, and the mixture was stirred. Filter the activated carbon,
Palladium black (1 g) was added to the filtrate, and the mixture was stirred at room temperature and normal pressure under a hydrogen stream for 5 hours. The catalyst was filtered off, and the solvent was concentrated under reduced pressure to about 100 mL. To this, Cs ₂ CO ₃ 5.70g
50 mL of an aqueous solution of (17.5 mmol) was added dropwise over 10 minutes, the mixture was stirred for 30 minutes, and then the solvent was distilled off. 100 mL of DMF was added to the residue, and the solvent was distilled off under reduced pressure. This operation was repeated twice. DMF100 on the residue
50 mL of DMF solution containing 7.18 g (35.0 mmol) of phenacyl bromide under ice cooling.
mL was added dropwise over 10 minutes, the temperature was returned to room temperature, and the mixture was stirred overnight. The solvent was distilled off, ethyl acetate and water were added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was separated, washed with a 10% citric acid aqueous solution, a saturated saline solution, a 4% NaHCO ₃ aqueous solution and a saturated saline solution, dried over Na ₂ SO ₄ , and then the solvent was distilled off. Crystallization from ether-petroleum ether gave colorless crystals.

Yield 14.9 g (yield 87.2%) mp 119.0-120.0 ° C. Rf ₁ 0.79 Rf
₂ 0.91 [α] _D ²⁵ −50.2 ° (c = 1.05, DMF) Elemental analysis Calculated as C ₂₅ H ₃₂ N ₂ O ₆ S: C, 61.46; H, 6.60; N, 5.73 experiment Value: C, 61.43; H, 6.63; N, 5.85 (3) Preparation of Boc-Asp (OBzl) -D-Thg (2) -Leu-OPac Boc-D-Thg (2)-synthesized in (2) Leu-OPac 14.7g
(30.0 mmole) was dissolved in 30 mL of dioxane, 10 N-HCl / dioxane (50 mL) was added under ice cooling, and the mixture was stirred for 15 minutes. The solvent was distilled off under reduced pressure, ether was added, and the deposited precipitate was collected by filtration and dried. This is D
It was dissolved in 160 mL of MF and ice-cooled, and 5.30 mL (30.36 mmol) of diisopropylethylamine was added. Boc-Asp (OBzl) -ONB (Boc-Asp (OBzl) -OH
9.68 g (30.0 mmole), HONB 5.9
1 g (33.0 mmole), DCC 6.81 g (3
(Prepared from 3.0 mmole) was added and stirred overnight.
The resulting insoluble matter was filtered off and concentrated, and the residue was dissolved in ethyl acetate. This was dissolved in 10% aqueous citric acid solution, saturated saline solution,
It was washed with a 4% NaHCO ₃ aqueous solution and saturated saline, dried over Na ₂ SO ₄ , and then the solvent was distilled off. Ether-petroleum ether was added to the residue to obtain a precipitate.

Yield 20.31 g (Yield 97.6%) mp 67.0-68.5 ° C. Rf ₁ 0.61 Rf ₂
0.83 [α] _D ²⁵ −52.0 ° (c = 1.03, DMF) Elemental analysis Calculated as C ₃₆ H ₄₃ N ₃ O ₉ S: C, 62.32; H, 6.25; N, 6.06 Experimental value: C, 62.34; H, 6.36; N, 6.20 (4) Production of Boc-Asp (B1) -OBzl 1-phenylpiperazine (manufactured by Aldrich) 24.3 g
(150 mmol) was dissolved in 150 mL of DMF,
Under ice cooling Boc-Asp (ONB) -OBzl (Boc-Asp-OBzl 50.9 g
(158 mmole), HONB 29.6 g (165
mmole), 34.0 g of DCC (165 mmole)
100 mL of the DMF solution prepared in (e) was added dropwise, the temperature was returned to room temperature, and the mixture was stirred overnight. The solvent was distilled off under reduced pressure, the residue was dissolved in 200 mL of ethyl acetate, 11.3 mL of N, N-dimethyl-1,3-propanediamine was added, and the mixture was stirred for 5 minutes. This was washed with a 10% aqueous solution of citric acid, a saturated saline solution, a 4% aqueous solution of NaHCO ₃ and a saturated saline solution, dried over Na ₂ SO ₄ , and then the solvent was distilled off. Crystallized from ether-petroleum ether,
Colorless crystals were obtained.

Yield 65.0 g (Yield 92.6%) mp 75-76 ° C. Rf ₁ 0.63 Rf ₂ 0.81 [α] _D ^25-2.1 ° (c = 1.24, DMF) Element Analysis Calculated as C ₂₆ H ₃₃ N ₃ O ₅ : C, 66.79; H, 7.11; N, 8.99 Experimental value: C, 66.85; H, 7.39; N, 8.98 (5) Boc-Asp (B1) -OH 65.0 g (139) of Boc-Asp (B1) -OBzl synthesized in Production (4)
(m mole) was dissolved in 1 L of methanol, 1 g of palladium black was added, and the mixture was stirred for 2 hours under a hydrogen stream at room temperature and atmospheric pressure. The catalyst was filtered off, the solvent was evaporated under reduced pressure, and the residue was crystallized from ethyl acetate-petroleum ether to give colorless crystals.

Yield 49.2 g (Yield 93.8%) mp 147-148 ° C. Rf ₁ 0.15 Rf ₂ 0.6
3 [α] _D ²⁵ + 21.4 ° (c = 1.88, DMF) Elemental analysis Calculated as C ₁₉ H ₂₇ N ₃ O ₅ : C, 60.46; H, 7.21; N, 11.13 Experimental value: C , 60.40; H, 7.08; N, 10.98 (6) Preparation of Boc-Asp (B1) -Asp (OBzl) -D-Thg (2) -Leu-OPac Boc-Asp (OBzl) synthesized in (3) ) -D-Thg (2) -Leu-OPac1
8.0 g (25.9 mmole) of dioxane 10 mL
Dissolved in 10 N HCl / dioxane 50 mL under ice cooling
Was added and stirred for 15 minutes. The solvent was distilled off under reduced pressure, and
Tellurium was added to the precipitate, and the precipitate was collected by filtration and dried. This was dissolved in 80 mL of DMF and cooled with ice, and 4.74 mL (27.2 mmol) of diisopropylethylamine was added. Boc-Asp (B1) -OH 10.8 synthesized in (5)
g (28.5 mmole) and HONB 5.37 g (3
0.0m mole), 6.18g (30.0m) of DCC
Boc-Asp (B1) -ONB prepared by using Mole) was added and stirred overnight. The resulting insoluble matter was filtered off and concentrated, the residue was dissolved in ethyl acetate, 2.15 mL (17.1 mmole) of N, N-dimethyl-1,3-propanediamine was added, and the mixture was stirred for 5 minutes. This was washed with 10% citric acid aqueous solution, saturated saline, 4% NaHCO ₃ aqueous solution, saturated saline, and washed with Na ₂ S.
After drying with O ₄ , the solvent was distilled off. Ether-Oil-
Crystallization from tell gave colorless crystals.

Yield 22.4 g (yield 90.6%) mp 85-87 ° C. Rf ₁ 0.36 Rf ₂ 0.65 [α] _D ²⁵ -39.6 ° (c = 0.97, DMF) Element Analysis Calculated as C ₅₀ H ₆₀ N ₆ O ₁₁ S: C, 63.01; H, 6.35; N, 8.82; S, 3.36 Experimental value: C, 63.00; H, 6.36; N, 8.76; S, 3.10 (7) Boc-D-Leu-Asp (B1) -Asp (OBzl) -D-Thg (2) -Leu-OPa
Production of c Boc-Asp (Php) -Asp (OBzl) -D-Thg (2) -Le synthesized in (6)
u-OPac 1.00g (1.05m mole) under ice cooling 1
20 mL of 0N HCl / dioxane was added and stirred for 15 minutes. The solvent was distilled off under reduced pressure, ether was added, and the deposited precipitate was collected by filtration and dried. This was dissolved in DMF (10 mL) and cooled with ice, and diisopropylethylamine (0.30) was added.
mL (1.72 mmol) was added. Boc-DL
eu-ONB (Boc-D-Leu-OH ・ H2O288mg (1.16m m
ole), and HONB228 mg (1.27 mmol)
e) and 262 mg (1.27 mmole) of DCC) were added and the mixture was stirred overnight. The resulting insoluble matter was filtered off and concentrated, and the residue was dissolved in ethyl acetate and washed with 10% citric acid aqueous solution, saturated saline, 4% NaHCO ₃ aqueous solution and saturated saline, and dried over Na ₂ SO ₄ . After that, the solvent was distilled off. The residue was precipitated with ether to give a white powder. .

Yield 0.89 g (yield 79.5%) mp 100-101 ° C. Rf ₁ 0.38 Rf ₂ 0.6
8 [α] _D ²⁵ -33.5 ° (c = 0.96, DMF) Elemental analysis Calculated as C ₅₆ H ₇₁ N ₇ O ₁₂ S: C, 63.08; H, 6.71; N, 9.20; S, 3.01 Experimental value: C, 62.19; H, 6.98; N, 9.31; S, 2.84 (8) Boc-D-Trp-D-Leu-Asp (B1) -Asp (OBzl) -D-Thg (2) -L
Production of eu-OPac Boc-D-Leu-Asp (B1) -Asp (OBzl) -D-Thg synthesized in (7)
(2) -Leu-OPac (750 mg, 0.704 mmole) was added with 10 N HCl / dioxane (5 mL) under ice cooling to give 15
Stir for minutes. The solvent was distilled off under reduced pressure, ether was added, and the deposited precipitate was collected by filtration and dried. DMF10 this
It was dissolved in mL and ice-cooled, and 0.20 mL (1.15 mmol) of diisopropylethylamine was added. Boc-D-Trp-ONB (Boc-D-Trp-OH 236 mg (0.77
mmole), 153 mg of HONB (0.85m mo)
le) and DCC176 mg (prepared from 0.85 mmole)) were added and stirred overnight. The resulting insoluble matter was filtered off and then concentrated, the residue was dissolved in ethyl acetate, and N, N-dimethyl was added.
-1,3-Propanediamine 0.04mL (0.319mm
ole) was added and the mixture was stirred for 5 minutes, washed with 10% citric acid aqueous solution, saturated saline, 4% NaHCO ₃ aqueous solution and saturated saline, dried over Na ₂ SO ₄ , and then the solvent was distilled off. The precipitate was collected from the ether as a precipitate.

Yield 0.80 g (yield 90.6%) mp 180-181 ° C. Rf ₁ 0.31 Rf ₂ 0.6
4 [α] _D ²⁵ −29.1 ° (c = 1.01, DMF) Elemental analysis Calculated as C ₆₇ H ₈₁ N ₈ O ₁₄ S: C, 64.15; H, 6.51; N, 8.93; S, 2.56 Experimental value: C, 64.20; H, 6.55; N, 8.95; S, 2.60 (9) Boc-D-Trp-D-Leu-Asp (B1) -Asp (OBzl) -D-Thg (2) -L
Production of eu-OH Boc-D-Trp-D-Leu-Asp (B1) -Asp (OBzl)-synthesized in (8)
D-Thg (2) -Leu-OPac 627mg (0.50m mole)
Was dissolved in 20 mL of 90% acetic acid aqueous solution, and Zn powder 1.6 was added.
4 g (25 mmole) was added and stirred for 1 hour. Z
n powder was filtered off, the filtrate was concentrated, the residue was dissolved in dichloromethane, washed with diluted sulfuric acid and saturated brine, dried over Na ₂ SO ₄ , and then the solvent was distilled off. Ether was added to the residue to obtain a precipitate.

Yield 0.52 g (Yield 91.5%) mp 170-171 ° C. Rf ₁ 0.10 Rf ₂ 0.6
2 [α] _D ²⁵ −24.8 ° (c = 0.93, DMF) Elemental analysis Calculated as C ₅₉ H ₇₅ N ₈ O ₁₃ S: C, 62.36; H, 6.65; N, 9.86; S, 2.82 Experimental value: C, 62.52; H, 6.55; N, 9.99; S, 2.74 (10) cyclo [-D-Leu-Asp (B1) -Asp-D-Thg (2) -Leu-D-Tr
Production of p-] Boc-D-Trp-D-Leu-Asp (B1) -Asp (OBzl)-synthesized in (9)
D-Thg (2) -Leu-OH (440 mg, 0.40 mmol) was dissolved in DMF (5 mL), and HONB (144 mg) was cooled with ice.
(0.80m mole), DCC165mg (0.8
0 mmole) was added and the mixture was stirred at 4 ° C. overnight. The formed insoluble matter was filtered off, the solvent was evaporated under reduced pressure, and 10N HCl / dioxane (5 ml) was added to the residue under ice cooling, followed by stirring for 15 minutes. The reaction mixture was concentrated, ether was added to the residue, and the precipitate was collected by filtration and dried. This was dissolved in 10 mL of DMF and 0.70 mL of diisopropylethylamine (4 m
(mole) -containing DMF (70 ml), and the mixture was stirred at room temperature for 3 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate, and this was washed with 10% citric acid aqueous solution, saturated saline, 4% NaHCO ₃ aqueous solution, saturated saline, and Na ₂ S
After drying with O ₄ , the solvent was distilled off and the precipitate was collected by filtration from ether-petroleum ether. 20 of the obtained precipitate
Dissolve 0 mg in DMF 20 mL and add palladium black 0.1 g
Was added, and the mixture was stirred under a hydrogen stream at room temperature and atmospheric pressure for 6 hours. The catalyst was filtered off, the solvent was distilled off under reduced pressure, water was added to the residue and freeze-dried to obtain 170 mg (97.0%) of a white powder.
42.5 mg of this was analyzed by reverse phase liquid chromatography.
(Column: YMC D-ODS-5 (2 cm x 25
cm), eluent: 0.1% TFA-containing acetonitrile aqueous solution (45% -55% acetonitrile linear concentration gradient / 3)
0 min)).

Yield 13.8 mg LSIMS (M + H) + = 926 Theoretical value = 926 [Reference Example 1] The following peptide was produced according to Example 96 of Japanese Patent Application No. 4-216019.

Cyclo (-D-Asp-L-Asp (B1) -L-Asp-D-Thg (2)-
L-Leu-D-Trp-) [Test Example 1] Measurement of endothelin receptor-binding activity (1) Method for measuring ET _A receptor-binding activity _A membrane fraction prepared from pig ventricular muscle was assayed using an assay buffer. It was diluted to 12 μg / mL, and 100 μL of this was dispensed to the assay tube and used for the assay. This membrane fraction suspension was added to endothelin-1 ([ ¹²⁵ I] ET-1) (Amersham) labeled with 100 pmole of radioactive iodine.
2 μL, and 3 μL of test compound solutions of various concentrations
Was added and the mixture was kept at 25 ° C. for 1 hour. To this, ice-cooled assay buffer was added to dilute, and then glass filter-GF was added.
/ F (manufactured by Whatman). The membrane fraction containing the endothelin A (ET _A ) receptor and [ ¹²⁵ I] ET-1 bound to this receptor are collected on the filter. Therefore, by measuring the radioactivity retained on this filter, [ ¹²⁵ I] ET bound to the ET _A receptor was detected.
-1 amount was quantified. A large excess of ET-1 as a test compound
The amount of [ ¹²⁵ I] ET-1 binding when using is defined as the non-specific binding amount. At this time, the specific binding amount (SPB) of [ ¹²⁵ I] ET-1 is a value obtained by subtracting the nonspecific binding amount from the measured binding amount, and the specific binding amount when the concentration of the test compound is 0. When the amount is 100 and the concentration C (volume molar concentration) of the test compound is the percentage of the specific binding amount, the value is defined as% SPB at the concentration C. The value thus obtained was input to the "Pseudo-Hill equation" shown below to test for the amount of specific binding of [ ¹²⁵ I] ET-1 of 50%. The compound concentration (IC ₅₀ value) was calculated.

Log [% SPB / (100-% SP
B)] = n [logC- log (IC 50)] n: push - Hill coefficient de (2) ET _B receptor binding activity The membrane fraction prepared from the measuring method bovine brain using the assay buffer 1
It was diluted to 50 μg / mL, and 100 μL of this was dispensed to the assay tube and used for the assay. To this membrane fraction suspension, 2 μL of endothelin-1 ([ ¹²⁵ I] ET-1) (manufactured by Amersham) labeled with 100 pM radioactive iodine,
Further, 3 μL of test compound solutions having various concentrations were added, and the mixture was incubated at 25 ° C. for 1 hour. To this, ice-cooled assay buffer was added to dilute, and then glass filter-GF / F was added.
(Manufactured by Whatman). The membrane fraction containing the endothelin B (ET _B ) receptor and [ ¹²⁵ I] ET-1 bound to this receptor are collected on the filter. Therefore, the filter - by measuring the radioactivity retained above bound to ET _B receptors ^[125 I] ET-1
The amount was quantified. The amount of [ ¹²⁵ I] ET-1 binding when a large excess of ET-1 was used as the test compound is defined as the nonspecific binding amount. At this time, the specific binding amount of [ ¹²⁵ I] ET-1 (S
PB) is a value obtained by subtracting the nonspecific binding amount from the measured binding amount, and the specific binding amount when the concentration of the test compound is 0 is 100, and the concentration C (volume molar concentration) of the test compound is The value obtained by converting the specific binding amount at that time into a percentage is defined as% SPB at the concentration C. By inputting the value thus obtained into the "Pseudo-Hill equation" shown below,
The concentration of the test compound (IC ₅₀ value) required to bring the specific binding amount of [ ¹²⁵ I] ET-1 to 50% was calculated.

Log [% SPB / (100-% SP
B)] = n [logC- log (IC 50)] n: push - Hill coefficient de (3) using the peptide of Example 1 and Reference Example 1, E
The results of calculating IC ₅₀ values for T _A receptor and ET _B receptor are shown below.

[0149]

[Table 1]

ET _B / ET _A is the ET _A -IC ₅₀ value (M)
The ratio of ET _B -IC ₅₀ value (M) to

From the above results, the peptide of the present invention
The _A receptors and ET _B receptors, superior have antagonism and ET _B for ET _A receptor antagonism than peptides disclosed in Japanese Patent Application No. 4-216019
It can be seen that the receptor antagonism is strong.

[0152]

INDUSTRIAL APPLICABILITY The cyclic hexapeptide (I) or a salt thereof of the present invention is an endothelin receptor, especially endothelin B.
It exhibits excellent antagonism of receptors, so hypertension, pulmonary hypertension, angina, cardiomyopathy, myocardial infarction, Raynaud's disease, Burger's disease, cerebral infarction, cerebral vasospasm, asthma, acute renal failure, cyclosporine , Renal function decline due to cisplatin,
It is useful as a therapeutic agent for diseases such as arteriosclerosis, diabetic neuropathy, diabetic retinopathy, hemorrhagic shock, endotoxin shock, functional deterioration of organs that occur during surgery or transplantation of organs, and high-lipid plasma.

Claims (28)

[Claims] 1. A formula cyclo [-A-X-Y-B-C-D-] (I) [wherein A represents a D-neutral-α-amino acid residue, and X represents α-.
Represents an amino acid residue, Y represents an α-amino acid residue (provided that the formula —NR ¹⁰ —CHR ¹¹ —CO— (R ¹⁰ represents a hydrogen atom or a C _1-8 alkyl group, and R ¹¹ represents C _{1- 8} represents an alkyl group)), B represents a neutral-α-amino acid residue, C represents an L-α-amino acid residue, and D represents an aromatic ring group. The D-α-amino acid residues possessed are shown. ] The cyclic hexapeptide represented by these, or its salt. 2. A is --NR ¹ --CHR ² --CO-- (R ¹ is a hydrogen atom or a C _1-6 alkyl group, R ² is a C _1-6 alkyl group, a C _3-7 cycloalkyl group, C _3-7 cycloalkyl-C _1-3 alkyl group, C _1-6 alkylthio-C
_1-3 alkyl group, C _3-7 cycloalkylthio-C _1-3 alkyl group, C _1-6 alkoxy-C _1-3 alkyl group, C _3-7 cycloalkoxy-C _1-3 alkyl group, substituted _Optionally substituted C _6-14 aryl group, _optionally substituted C _6-14 aryl-C _1-3 alkyl group, _optionally substituted N,
A 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of O and S, or 1 to 3 hetero groups selected from the group consisting of optionally substituted N, O and S Represents a 4- to 7-membered heterocyclic group containing an atom, -C _1-3 alkyl group, wherein R ¹ and R ² are bonded together to form-(CH ₂ ) L-
(L represents an integer of 2 to 4) may be formed. 3. The cyclic hexapeptide or a salt thereof according to claim 1, which is a D-neutral-α-amino acid residue represented by 3. The cyclic hexapeptide or a salt thereof according to claim ² , wherein R ¹ is a hydrogen atom and R ² is a C _1-6 alkyl group. 4. A is D-alanine, D-valine, D-norvaline, D-leucine, D-isoleucine, D-alloisoleucine, D-norleucine, D-tertiary leucine,
D-gamma methyl leucine, D-phenylglycine, D-
Phenylalanine, D-3- (1-naphthyl) alanine, D-3- (2-naphthyl) alanine, D-cysteine, D-serine, D-threonine, D-proline, D-4-
Hydroxyproline, D-azetidine-2-carboxylic acid, D-pipecolic acid (piperidine-2-carboxylic acid), D-2- (2-thienyl) alanine, D-2- (2
-Thienyl) glycine, D-2- (3-thienyl) glycine, D-2-cyclopentylglycine, D-2-cyclohexylglycine, DN-methylleucine, DN-methylalloisoleucine, DN-methyl Tertiary leucine, D-N-methyl gamma methyl leucine and D-
The cyclic hexapeptide according to claim 1, which is selected from the group consisting of N-methylphenylglycine residues, or a salt thereof. 5. X is alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, cysteic acid, homocysteic acid, β- (5-
Tetrazolyl) alanine, 2-amino-4- (5-tetrazolyl) butyric acid 2-aminomalonic acid, 2-aminoadipic acid, glycine, histidine, isoleucine, leucine,
Lysine, ornithine, 2,4-diaminobutyric acid, methionine, phenylalanine, proline, 4-hydroxyproline, thioproline, azetidine-2-carboxylic acid, pipecolic acid (piperidin-2-carboxylic acid), indoline-2-
Carboxylic acid, tetrahydroisoquinoline-3-carboxylic acid, serine, threonine, tryptophan, 5-methyltryptophan, tyrosine, valine, alloisoleucine, norvaline, norleucine, tertiary leucine, gamma methylleucine, phenylglycine, 2-aminobutyric acid, cysteine Acid, homocysteic acid, 3- (1
-Naphthyl) alanine, 3- (2-naphthyl) alanine,
2- (2-thienyl) glycine, 2- (3-thienyl) glycine, 3- (3-benzothienyl) alanine, 3-
(4-biphenyl) alanine, pentamethylphenylalanine, 1-aminocyclopropane-1-carboxylic acid, 1-
Aminocyclobutane-1-carboxylic acid, 1-aminocyclopentane-1-carboxylic acid, 1-aminocyclohexane-1
-Carboxylic acid, 1-aminocycloheptane-1-carboxylic acid, O-acetylserine, O-acetylthreonine, 4-
Acetoxyproline, O-benzoylserine, O-benzoylthreonine, 4-benzoyloxyproline, O-phenylacetylserine, O-phenylacetylthreonine, 4-phenylacetoxyproline, O-ethylserine, O-ethylthreonine, 4-ethoxyproline , O-cyclohexylserine, O-cyclohexylthreonine, 4-cyclohexyloxyproline, O-phenylserine, O-phenylthreonine, 4-phenoxyproline, O-benzylserine, O-benzylthreonine, 4-benzyloxyproline, O- Diphenylmethylserine, O-diphenylmethylthreonine, 4-diphenylmethoxyproline, N-
Methylglycine (sarcosine), N-ethylglycine, N-
Methylleucine, N-ethylleucine, N-methylphenylalanine, N-ethylphenylalanine, N (α) -methyltryptophan, N (α) -ethyltryptophan, N-
Cyclopentylglycine, N-cyclohexylglycine, N-phenylglycine, N-phenylleucine, N-
Benzylglycine, N-benzylleucine, N (π) -benzylhistidine, N (τ) -benzylhistidine, N (π)-
Phenacylhistidine, N (π) -benzyloxymethylhistidine, N ^g -benzenesulfonylarginine, N ^g-
Paratoluenesulfonyl arginine, N ^g- (4-methoxy
-2,3,6-trimethylbenzenesulfonyl) arginine, N (ε) -benzenesulfonyllysine, N (ε) -paratoluenesulfonyllysine, N (ε)-(4-methoxy-2,3,
6-trimethylbenzenesulfonyl) lysine, N ⁱⁿ -methyltryptophan, N ⁱⁿ -ethyltryptophan, N ^in-
Formyltryptophan, N ⁱⁿ -acetyltryptophan, N (ε) -benzyl lysine, N (ε)-(2-furylmethyl) lysine, N (ε)-(2-thienylmethyl) lysine, N
(ε)-(Indol-3-ylmethyl) lysine, N (ε) -phenylacetyllysine, N (ε)-({2-furyl} acetyl) lysine, N (ε)-({2-thienyl} acetyl) Lysine, N (ε)
-({Indol-3-yl} acetyl) lysine, N (ε) -benzoyllysine, N (ε)-(3-phenylpropionyl) lysine, N (δ) -benzylornithine, N (δ)-(2- Furylmethyl) ornithine, N (δ)-(2-thienylmethyl) ornithine, N (δ)-(indol-3-ylmethyl) ornithine, N (δ) -benzoylornithine, N (δ) -phenylacetylornithine, N (δ)-(3-phenylpropionyl)
Ornithine, N (δ)-({2-methylphenyl} acetyl) ornithine, N (δ)-({3-methylphenyl} acetyl) ornithine, N (δ)-({4-methylphenyl} acetyl) ornithine, N (δ)-({2-chlorophenyl} acetyl) ornithine, N (δ)-({3-chlorophenyl} acetyl) ornithine, N (δ)-({4-chlorophenyl} acetyl) ornithine, N (δ)- ({2-methoxyphenyl} acetyl) ornithine, N (δ)-({3-methoxyphenyl} acetyl) ornithine, N (δ)-({4-methoxyphenyl} acetyl) ornithine, N (δ)-(4 -Biphenylacetyl) ornithine, N
(γ) -Benzyl-2,4-diaminobutyric acid, N (γ)-(2-furylmethyl) -2,4-diaminobutyric acid, N (γ)-(2-thienylmethyl) -2,4-diaminobutyric acid , N (γ)-(Indole-3-
Ilmethyl) -2,4-diaminobutyric acid, N (γ) -benzoyl-
2,4-diaminobutyric acid, N (γ) -phenylacetyl-2,4-
Diaminobutyric acid, N (γ)-(3-phenylpropionyl) -2,
4-diaminobutyric acid, N (γ)-(2-furylacetyl) -2,4-
Diaminobutyric acid, N (γ)-(2-thienylacetyl) -2,4-
Diaminobutyric acid, N (γ)-({indol-3-yl} acetyl) -2,4-diaminobutyric acid, N ⁴ -methylasparagine, N
⁴ -phenyl asparagine, N ⁴ -benzyl asparagine,
N ⁴ - phenethyl asparagine, N ⁴ - (2- {indol -3
- yl} ethyl) asparagine, N ⁵ - methyl glutamine,
N ⁵ - phenyl glutamine, N ⁵ - benzyl glutamine, N
⁵ -phenethylglutamine, N ^5- (2- {indol-3-yl} ethyl) glutamine, aspartic acid β-methyl ester, aspartic acid β-cyclopropyl ester, aspartic acid β-benzyl ester, aspartic acid
β- phenethyl ester, aspartic acid β-N ⁴ - phenylpiperazine amide, aspartic acid β-N ⁴ - (2- methylphenyl) piperazine amide, aspartic acid β-
N ⁴ - (3- methylphenyl) piperazine amide, aspartic acid β-N ⁴ - (4- methylphenyl) piperazine amide, aspartic acid β-N ⁴ - (2- methoxyphenyl) piperazine amide, aspartic acid beta-N ⁴ - (3-methoxyphenyl) piperazine amide, aspartic acid beta-N ⁴ -
(4-methoxyphenyl) piperazine amide, aspartic acid β-N ⁴ - (2- chlorophenyl) piperazine amide,
Aspartic acid β-N ⁴ - (3- chlorophenyl) piperazine amide, aspartic acid β-N ⁴ - (4- chlorophenyl) piperazine amide, aspartic acid β-N ⁴ - (4- nitrophenyl) piperazine amide, aspartic acid β-
N ⁴ - (4-fluorophenyl) piperazine amide, aspartic acid β-N ⁴ - (3- trifluoromethylphenyl) piperazine amide, aspartic acid β-N ⁴ - (2,3- dimethylphenyl) piperazine amide, aspartic acid β-
N ⁴ - (2-pyridyl) piperazine amide, aspartic acid
β-N ⁴ - (2- pyrimidyl) piperazine amide, glutamic acid γ- methyl ester, glutamic acid γ- cyclopropyl ester claim are those selected from the group consisting of glutamic acid γ- benzyl ester and glutamic acid γ- phenethyl ester residue 1. The cyclic hexapeptide according to 1 or a salt thereof. 6. X is Asp (R ³ ), wherein R ³ is of the formula: (X ¹ and X ² each represent a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen atom or a nitro group, and X ¹ and X ² are bonded together to form a ring with an adjacent C atom. May be formed). The cyclic hexapeptide or salt thereof according to claim 1, which is an α-amino acid residue represented by 7. R ³ is of the formula: (X ¹¹ and X ²¹ each represent a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen atom or a nitro group), a compound represented by the formula: (M and n represent an integer of 1 to 3, X represents O, S or NH, and p represents 0 or 1), and a group represented by the formula: (Q represents an integer of 1 to 3) or a group represented by the formula: The cyclic hexapeptide according to claim 3, wherein X ³ and X ⁴ each represent a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen atom or a nitro group. Its salt. 8. R ³ is of the formula: The cyclic hexapeptide or a salt thereof according to claim 1, which is a group represented by (X ¹¹ represents a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen atom or a nitro group). 9. Y is arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, cysteic acid, homocysteic acid, β- (5-tetrazolyl) alanine, 2-amino-4- (5-tetrazolyl).
Butyric acid 2-aminomalonic acid, 2-aminoadipic acid, histidine, lysine, ornithine, 2,4-diaminobutyric acid, methionine, phenylalanine, proline, 4-hydroxyproline, thioproline, azetidine-2-carboxylic acid,
Pipecolic acid (piperidine-2-carboxylic acid), indoline
-2-carboxylic acid, tetrahydroisoquinoline-3-carboxylic acid, serine, threonine, tryptophan, 5-methyltryptophan, tyrosine, phenylglycine, cysteic acid, homocysteic acid, 3- (1-naphthyl) alanine, 3- (2 -Naphthyl) alanine, 2- (2-thienyl) glycine, 2- (3-thienyl) glycine, 3-
(3-Benzothienyl) alanine, 3- (4-biphenyl) alanine, pentamethylphenylalanine, 1-aminocyclopropane-1-carboxylic acid, 1-aminocyclobutane-1-carboxylic acid, 1-aminocyclopentane-1-
Carboxylic acid, 1-aminocyclohexane-1-carboxylic acid, 1-aminocycloheptane-1-carboxylic acid, O-acetylserine, O-acetylthreonine, 4-acetoxyproline, O-benzoylserine, O-benzoylthreonine, 4 -Benzoyloxyproline, O-phenylacetylserine, O-phenylacetylthreonine, 4-phenylacetoxyproline, O-ethylserine, O-ethylthreonine, 4-ethoxyproline, O-cyclohexylserine, O-cyclohexylthreonine, 4-cyclohexyl Oxyproline, O-phenylserine, O-phenylthreonine, 4-phenoxyproline, O-benzylserine, O-benzylthreonine, 4-benzyloxyproline, O-diphenylmethylserine, O-diphenylmethylthreonine, 4-diphenylmethoxy Proline, N- methyl-phenylalanine, N- ethyl-phenylalanine, N
(α) -methyltryptophan, N (α) -ethyltryptophan, N-cyclopentylglycine, N-cyclohexylglycine, N-phenylglycine, N-phenylleucine, N-benzylglycine, N-benzylleucine, N
(π) -Benzylhistidine, N (τ) -benzylhistidine, N (π) -phenacylhistidine, N (π) -benzyloxymethylhistidine, N ^g -benzenesulfonylarginine, N ^g -paratoluenesulfonylarginine, N ^g-
(4-Methoxy-2,3,6-trimethylbenzenesulfonyl) arginine, N (ε) -benzenesulfonyllysine, N
(epsilon) - p-toluenesulfonyl lysine, N (ε) - (4- methoxy-2,3,6) lysine, N ⁱⁿ - methyl tryptophan, N ⁱⁿ - ethyl tryptophan, N ⁱⁿ - formyl tryptophan, N ⁱⁿ -acetyltryptophan, N (ε) -benzyl lysine, N (ε)-(2-
Furylmethyl) lysine, N (ε)-(2-thienylmethyl) lysine, N (ε)-(indol-3-ylmethyl) lysine, N
(ε) -Phenylacetyllysine, N (ε)-({2-furyl} acetyl) lysine, N (ε)-({2-thienyl} acetyl) lysine, N (ε)-({Indol-3-yl } Acetyl) lysine,
N (ε) -benzoyl lysine, N (ε)-(3-phenylpropionyl) lysine, N (δ) -benzylornithine, N (δ)-
(2-Furylmethyl) ornithine, N (δ)-(2-thienylmethyl) ornithine, N (δ)-(indol-3-ylmethyl)
Ornithine, N (δ) -benzoylornithine, N (δ) -phenylacetylornithine, N (δ)-(3-phenylpropionyl) ornithine, N (δ)-({2-methylphenyl} acetyl) ornithine, N ( δ)-({3-methylphenyl} acetyl) ornithine, N (δ)-({4-methylphenyl} acetyl) ornithine, N (δ)-({2-chlorophenyl} acetyl) ornithine, N (δ)- ({3-Chlorophenyl} acetyl) ornithine, N (δ)-({4-chlorophenyl} acetyl) ornithine, N (δ)-({2-methoxyphenyl} acetyl) ornithine, N (δ)-({3- Methoxyphenyl} acetyl) ornithine, N (δ)-({4-methoxyphenyl} acetyl) ornithine, N (δ)-(4-biphenylacetyl) ornithine, N (γ) -benzyl-2,4-diaminobutyric acid, N (γ)
-(2-furylmethyl) -2,4-diaminobutyric acid, N (γ)-(2-
Thienylmethyl) -2,4-diaminobutyric acid, N (γ)-(indol-3-ylmethyl) -2,4-diaminobutyric acid, N (γ) -benzoyl-2,4-diaminobutyric acid, N (γ)- Phenylacetyl-2,4-diaminobutyric acid, N (γ)-(3-phenylpropionyl) -2,4-diaminobutyric acid, N (γ)-(2-furylacetyl) -2,4-diaminobutyric acid, N ( γ)-(2-thienylacetyl) -2,4-diaminobutyric acid, N (γ)-({indol-3-yl} acetyl) -2,4-diaminobutyric acid, N ⁴ -methylasparagine, N ⁴ -phenyl asparagine, N ⁴ - benzyl aspartate, N ⁴ - phenethyl asparagine, N ⁴ - (2- {indol-3-yl} ethyl) asparagine, N ⁵ - methyl glutamine, N ⁵ - phenyl glutamine, N ⁵ - benzyl glutamine, N ⁵ -phenethylglutamine, N ^5- (2- {indol-3-yl} ethyl) glutamine, aspartic acid β -
Methyl ester, aspartic acid β-cyclopropyl ester, aspartic acid β-benzyl ester, aspartic acid β-phenethyl ester, aspartic acid β-
N ⁴ -phenylpiperazine amide, aspartic acid β-N
⁴ - (2-methylphenyl) piperazine amide, aspartic acid beta-N ⁴ - (3- methylphenyl) piperazine amide,
Aspartic acid β-N ⁴ - (4- methylphenyl) piperazine amide, aspartic acid β-N ⁴ - (2- methoxyphenyl) piperazine amide, aspartic acid β-N ⁴ - (3- methoxyphenyl) piperazine amide, aspartic acid β
-N ⁴ - (4-methoxyphenyl) piperazine amide, aspartic acid β-N ⁴ - (2- chlorophenyl) piperazine amide, aspartic acid β-N ⁴ - (3- chlorophenyl) piperazine amide, aspartic acid β-N ⁴ - (4-chlorophenyl) piperazine amide, aspartic acid β-N ⁴ - (4-
Nitrophenyl) piperazine amide, aspartic acid β
-N ⁴ - (4-fluorophenyl) piperazine amide, aspartic acid β-N ⁴ - (3- trifluoromethylphenyl) piperazine amide, aspartic acid β-N ⁴ - (2,3- dimethylphenyl) piperazine amide, asparagine Acid β-
N ⁴ - (2-pyridyl) piperazine amide, aspartic acid
β-N ⁴ - (2- pyrimidyl) piperazine amide, glutamic acid γ- methyl ester, glutamic acid γ- cyclopropyl ester, according to claim 1, wherein those selected from the group consisting of glutamic acid γ- benzyl ester and glutamic acid γ- phenethyl ester A cyclic hexapeptide or a salt thereof. 10. The cyclic hexapeptide according to claim 1, wherein Y is an acidic-α-amino acid residue, or a salt thereof. 11. An acidic-α-amino acid residue consisting of glutamic acid, aspartic acid, cysteic acid, homocysteic acid, β- (5-tetrazolyl) alanine and 2-amino-4- (5-tetrazolyl) butyric acid residue. The cyclic hexapeptide or a salt thereof according to claim 10, which is selected from the group. 12. Y is an aspartic acid residue.
The described cyclic hexapeptide or a salt thereof. 13. B is --NR ⁴ --CHR ⁵ --CO-- (R ⁴ is a hydrogen atom or a C _1-6 alkyl group, R ⁵ is a C _1-6 alkyl group, a C _3-7 cycloalkyl group, C _3-7 cycloalkyl-C _1-3 alkyl group, C _1-6 alkylthio-C _1-3 alkyl group, C _3-7 cycloalkylthio-C _1-3 alkyl group,
C _1-6 alkoxy-C _1-3 alkyl group, C _3-7 cycloalkoxy-C _1-3 alkyl group, optionally substituted C
_6-14 aryl group, _optionally substituted C _6-14 aryl-C _1-3 alkyl group, _optionally substituted N, O, S
A 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of or optionally containing 1 to 3 heteroatoms selected from the group consisting of N, O, S A 4- to 7-membered heterocycle-C _1-3 alkyl group, wherein R ⁴ and R ⁵ are bonded together to form-(CH 2) r- (r
Represents an integer of 2 to 4). The cyclic hexapeptide or a salt thereof according to claim 1, which is a residual group of neutral α-amino acid represented by 14. R ⁴ is a hydrogen atom, R ⁵ is a C _1-6 alkyl group, an _optionally substituted C _6-14 aryl group, an _optionally substituted C _6-14 aryl group-C _{1 -3} alkyl group, a 4- to 7-membered heterocyclic group containing 1 to 3 heteroatoms selected from the group consisting of optionally substituted N, O, S and optionally substituted N, O, 4 to 7 containing 1 to 3 heteroatoms selected from the group consisting of S
14. A cyclic hexapeptide or a salt thereof according to claim 13, which is selected from the group consisting of member heterocycle-C _1-3 alkyl groups. 15. B is alanine, valine, norvaline, leucine, isoleucine, alloisoleucine, norleucine, tertiary leucine, gamma methylleucine, phenylglycine, phenylalanine, 3- (1-naphthyl) alanine, 3- (2-naphthyl). ) Alanine, cysteine, serine, threonine, proline, 4-hydroxyproline, azetidine-2-carboxylic acid, pipecolic acid (piperidine-2-carboxylic acid), 2- (2-thienyl) alanine, 2- (2-thienyl) Glycine, 2-
From (3-thienyl) glycine, 2-cyclopentylglycine, 2-cyclohexylglycine, N-methylleucine, N-methylalloisoleucine, N-methyltertiaryleucine, N-methylgammamethylleucine and N-methylphenylglycine residues The cyclic hexapeptide or a salt thereof according to claim 1, which is selected from the group consisting of: 16. B is D-gamma-methylleucine or D-
The cyclic hexapeptide according to claim 1, which is a 2-thienylglycine residue, or a salt thereof. 17. C is L-glycine, L-alanine, L-valine, L-norvaline, L-leucine, L-isoleucine, L-tert-isoleucine, L-norleucine,
L-methionine, L-2-aminobutyric acid, L-serine, L-threonine, L-phenylalanine, L-aspartic acid,
L-glutamic acid, L-asparagine, L-glutamine,
L-lysine, L-tryptophan, L-arginine, L-tyrosine, L-proline, L-N-methylleucine, L-N
A cyclic hexapeptide or a salt thereof according to claim 1, which is selected from the group consisting of -methylnorleucine and L-N (α) -methyltryptophan residues. 18. The cyclic hexapeptide according to claim 1, wherein C is an L-leucine residue, or a salt thereof. 19. D is D-tryptophan, D-5-methyltryptophan, D-phenylalanine, D-tyrosine,
D-3- (1-naphthyl) alanine, D-3- (2-naphthyl) alanine, D-3- (3-benzothienyl) alanine, D-3- (4-biphenyl) alanine, D-pentamethylphenylalanine , D-N (α) - methyl tryptophan, D-N-methyl-phenylalanine, D-N-methyl-tyrosine, D-N ⁱⁿ - methyl tryptophan, D-N ⁱⁿ - ethyl tryptophan, D-N ⁱⁿ - formyl tryptophan, D
-N ⁱⁿ - acetyl tryptophan and D-N ⁱⁿ - cyclic hexapeptide or a salt of claims 1, wherein those selected from the group consisting of methoxycarbonyl tryptophan residues. 20. D is D-Trp (N ⁱⁿ -R ⁶ ) (R ⁶ is a hydrogen atom, a C _1-6 alkyl group, a C _3-7 cycloalkyl group,-
COR ⁷ (R ⁷ represents a hydrogen atom, a C _1-6 alkyl group, a C _6-15 aryl group, a C _6-15 aryl-C _1-3 alkyl group), —COOR ⁸ (R ⁸ represents C _1-6 Alkyl group, C _6-15 aryl group, C _6-15 aryl-C _1-3 alkyl group)
Or a D-α-amino acid residue represented by —CONHR ⁹ (R ⁹ represents a hydrogen atom, a C _1-6 alkyl group, a C _6-15 aryl group, a C _6-15 aryl-C _1-3 alkyl group) A cyclic hexapeptide or a salt thereof according to claim 1, which is a group. 21. R ⁶ is a hydrogen atom or —COR ⁷ (R ⁷ is a hydrogen atom, a C _1-6 alkyl group, a C _6-15 aryl group, C
_6-15 aryl-C _1-3 alkyl group), The cyclic hexapeptide according to claim 20, or a salt thereof. 22. The formula cyclo [-NH-CHR ² -CO-L-Asp (R ³ ) -Y ¹ -NH-CHR ⁵ -CO-C ¹ -D-Trp (N ⁱⁿ -R ⁶ )] (II (In the formula, R ² is a C _1-6 alkyl group, a C _3-7 cycloalkyl group, a C _3-7 cycloalkyl-C _1-3 alkyl group, a C _1-6 alkylthio-C _1-3 alkyl group, C _3-7 cycloalkylthio-C _1-3 alkyl group, C _1-5 alkoxy-C _1-3 alkyl group, C _3-7 cycloalkoxy-C _1-3 alkyl group, optionally substituted C _{6- 14} aryl groups, optionally substituted C _6-14 aryl-C _1-3 alkyl groups, _optionally substituted 1 to 3 selected from the group consisting of N, O and S
4 to 7 membered heterocyclic group containing 4 heteroatoms or 4 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of optionally substituted N, O and S-C _{1-3 represents} an alkyl group, and R ³ has the formula: (X ¹¹ and X ²¹ each represent a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen atom or a nitro group), a group represented by the formula: (M and n each represent an integer of 1 to 3, X represents O, S or NH, and p represents 0 or 1), a group represented by the formula: (Q represents an integer of 1 to 3) or a group represented by the formula: (X ³ and X ⁴ each represent a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen atom or a nitro group), and Y ¹ represents L-glutamic acid, L -Aspartic acid, L-cysteic acid, L-homocysteic acid, L-β- (5-tetrazolyl) alanine or L-2-amino-4- (5-tetrazolyl) butyric acid residue, R ⁵ is C _{1 -6} alkyl group, C _3-7 cycloalkyl group, C _3-7 cycloalkyl-C _1-3 alkyl group, C _1-6
Alkylthio-C _1-3 alkyl group, C _3-7 cycloalkylthio-C _1-3 alkyl group, C _1-6 alkoxy-C _1-3 alkyl group, C _3-7 cycloalkoxy-C _1-3 alkyl group, 1 selected from the group consisting of an _optionally substituted C _6-14 aryl group, an _optionally substituted C _6-14 aryl-C _1-3 alkyl group, and an _optionally substituted N, O, S A 4 to 7 membered heterocyclic group containing 1 to 3 heteroatoms or a 4 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of optionally substituted N, O and S Represents a -C _1-3 alkyl group, wherein C ¹ is L-glycine, L-alanine, L-valine, L-norvaline, L-leucine, L-
Isoleucine, L-tertiary isoleucine, L-norleucine, L-methionine, L-2-aminobutyric acid, L-serine, L-threonine, L-phenylalanine, L-aspartic acid, L-glutamic acid, L-asparagine, L-
Glutamine, L-lysine, L-tryptophan, L-arginine, L-tyrosine, L-proline, L-N-methylleucine, L-N-methylnorleucine or L-N (α)
Represents a methyltryptophan residue, R ⁶ is a hydrogen atom,
C _1-6 alkyl group, C _3-7 cycloalkyl group, -COR ⁷
(R ⁷ represents a hydrogen atom, a C _1-6 alkyl group, a C _6-15 aryl group, a C _6-15 aryl-C _1-3 alkyl group), —C
OOR ⁸ (R ⁸ is a C _1-6 alkyl group, a C _6-15 aryl group,
C _6-15 aryl-C _1-3 alkyl group) or -C
ONHR ⁹ (R ⁹ is a hydrogen atom, C _1-6 alkyl group, C _6-15
Aryl group and C _6-15 aryl-C _1-3 alkyl group). ] The cyclic hexapeptide of Claim 1 represented by these, or its salt. 23. The formula cyclo [-NH-CHR ² -CO-L-Asp (R ³¹ ) -L-Asp-NH-CHR ⁵ -CO-L-Leu-D-Trp (N ⁱⁿ -R ⁶¹ )]. (III) (wherein, R ² is C _1-6 alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkyl -C _1-3 alkyl group, C _1-6 alkylthio -C _1-3 alkyl Group, C _3-7 cycloalkylthio-C _1-3 alkyl group, C _1-5 alkoxy-C _1-3 alkyl group, C _3-7 cycloalkoxy-C _1-3 alkyl group, optionally substituted C 1 to 3 selected from the group consisting of a _6-14 aryl group, an _optionally substituted C _6-14 aryl-C _1-3 alkyl group, and an _optionally substituted N, O, S
4 to 7 membered heterocyclic group containing 4 heteroatoms or 4 to 7 membered heterocyclic ring containing 1 to 3 heteroatoms selected from the group consisting of optionally substituted N, O and S-C _{1-3 represents} an alkyl group, and R ³¹ has the formula: (X ¹¹ and X ²¹ each represent a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a halogen atom or a nitro group), and R ⁵ represents a C _1-6 alkyl group. Group, C _3-7 cycloalkyl group, C _3-7 cycloalkyl-C
_1-3 alkyl group, C _1-6 alkylthio-C _1-3 alkyl group, C _3-7 cycloalkylthio-C _1-3 alkyl group, C
_1-5 alkoxy-C _1-3 alkyl group, C _3-7 cycloalkoxy-C _1-3 alkyl group, C _1-6 alkylthio group, C _3-7
Cycloalkylthio group, C _1-5 alkoxy group, C _3-7 cycloalkoxy group, optionally substituted C _6-14 aryl group, optionally substituted C _6-14 aryl-C _1-3 alkyl group , 4 to 7 containing 1 to 3 heteroatoms selected from the group consisting of optionally substituted N, O, S
Membered heterocyclic group or a 4- to 7-membered heterocyclic-C _1-3 alkyl group containing 1 to 3 heteroatoms selected from the group consisting of optionally substituted N, O and S, and R ⁶¹
Is a hydrogen atom or -COR ⁷ (R ⁷ is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkyl group, a C _6-15 aryl group, C
_6-15 aryl-C _1-3 alkyl group is shown). ] The cyclic hexapeptide of Claim 1 represented by these, or its salt. 24. A 4- to 7-membered _{product, wherein} R ² is a C _1-6 alkyl group, R ⁵ is a C _1-6 alkyl group, or 1 to 3 heteroatoms selected from the group consisting of N, O and S. 24. The cyclic hexapeptide or a salt thereof according to claim 23, which is a heterocyclic group of 25. The cyclic hexapeptide represented by formula (I) is cyclo [-D-Leu-L-Asp (Php) -L-Asp-D-Thg (2) -L-Leu-DT.
The cyclic hexapeptide or salt thereof according to claim 1, which is rp-]. 26. The formula cyclo [-A-X-Y-B-C-D-] (I) [wherein A, X, Y, B, C and D have the same meanings as defined in claim 1. Show. ] The cyclic hexapeptide represented by [2] is condensed with two kinds of fragments bisected at an arbitrary position to produce a linear pentapeptide, which is then subjected to ring-closure condensation. A method for producing a cyclic hexapeptide or a salt thereof. 27. An active ingredient represented by the formula: cyclo [-AX-Ya-BC-D-] (Ia) [wherein A represents a D-neutral-α-amino acid residue, and X represents α. -
Represents an amino acid residue, Ya represents an α-amino acid residue,
B represents a neutral-α-amino acid residue, C represents an L-α-amino acid residue, and D represents a D-α-amino acid residue having an aromatic ring group. ] The cyclic | annular hexapeptide represented by these or its pharmacologically acceptable salt is contained, The endothelin receptor antagonist characterized by the above-mentioned. 28. The antagonist according to claim 27, which is an endothelin B receptor antagonist.