JP3306571B2 - Endothelin converting enzyme inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an endothelin converting enzyme inhibitor comprising a 1,3-di (carboxyalkyl) urea derivative as an active ingredient.

[0002]

2. Description of the Related Art Endothelin is a peptide consisting of 21 amino acids, is secreted from vascular endothelium, and has a strong and continuous vascular smooth muscle contraction action and tracheal smooth muscle contraction action. From the study of the gene encoding endothelin, the mechanism of biosynthesis of endothelin from preproendothelin of 212 amino acids to big endothelin of 38 amino acids with little activity was presumed as the biosynthesis mechanism of endothelin. (Nature, 332, 411-4
15 (1988)). Subsequent studies have revealed the existence of an enzyme (endothelin converting enzyme) that hydrolyzes the Trp-Val bond of big endothelin to endothelin (Biochem. Biophys. Res. Commun., 171, 669).
-675 (1990), Biochem. Biophys. Res.Commun., 171,
1192-1198 (1990)).

[0003] Endothelin is widely distributed in various tissues in the body and is deeply involved in maintaining the homeostasis of the living body. At the same time, overproduction of endothelin causes cerebral blood flow such as cerebral vasospasm which causes essential hypertension, cerebral infarction and the like. Abnormalities, myocardial infarction, pulmonary hypertension, asthma such as bronchial asthma, dysfunction after organ transplantation such as liver transplantation and kidney transplantation, rejection, kidney disease and diabetes. Therefore, inhibition of endothelin-converting enzyme, which is the rate-limiting enzyme for endothelin overproduction, is considered to be useful for improving the above-mentioned various symptoms.

Compounds that inhibit endothelin converting enzyme include phosphoramidon (JP-A-4-41430), dipeptide derivatives in which the amino acid side chain is alkyl (International Publication WO92 / 13545), and phosphones into which dipeptides have been introduced. Acid amide derivatives (Japanese Unexamined Patent Publication No.
327592, JP-A-5-105698,
JP-A-5-148277), acyltryptophan derivatives (JP-A-5-39266), and aspergillomarasmins A and B (JP-A-6-192081) have been reported. However, all of the compounds disclosed therein are compounds having two or more amino acid residues, and no compounds having a urea skeleton in the molecule have been reported.

[0005] The action of the compound that inhibits endothelin converting enzyme includes cerebral vasospasm inhibitory action in a dog subarachnoid hemorrhage model (Life Sci., 49, 841-848 (1991)) and endothelin-1 in cerebrospinal fluid. Expression suppression (Bioche
m. Biophys. res. Commun., 178, 24-30 (1991)). In addition, it has been reported that an endothelin receptor antagonist suppressed acute renal failure due to tissue incompatibility after liver transplantation in rats (transplantation, 28 , 261 (199)
3)).

Endothelin-1 in the blood of patients on chronic maintenance dialysis
Although the concentration was higher than that in healthy subjects, it was observed that the concentration decreased with the development of the function of the transplanted kidney after renal transplantation, and then increased again when rejection occurred (Journal of the Japanese Urological Association, 85 , 16).
22-1628 (1993)). In addition, an increase in endothelin-like immunoreactive cells in airway epithelial cells of patients with bronchial asthma (Lance
t, 337, 697-701 (1991)) and the blood of asthmatics (Jikei
kai Med. J., 41 , 91-98 (1994)) and in alveolar lavage fluid during seizures (J. Allergy Clin. immunol., 88, 376-384).
(1991)) has been found to increase the concentration of endothelin-1.

[0007] Furthermore, compared to healthy subjects, the blood of patients with essential hypertension (Am. J. Med., 88, 614-618 (1990)) and the blood of patients with acute heart failure after myocardial infarction (Jpn. Circ. J., 57,
371-378 (1993)), blood in patients with pulmonary hypertension (Circulatio
n, 85, 504-509 (1992)) and in lung tissue (N. Engl.
J. Med., 328, 1732-1739 (1993)) and blood of patients with acute renal failure due to ureteral atresia (N. Engl. J. Med., 321, 112).
7 (1989)), in the blood of diabetic patients (Diabetelogia, 33 , 30
6-310 (1990)) has been reported to increase endothelin-1 concentrations.

On the other hand, the structural feature of the compound as an active ingredient of the present invention is that a carboxyl group is introduced into both ends of an alkylene chain of 1,3-dialkylurea, and a biphenylyl group, a naphthyl group or the like is further added to the alkylene chain. As described above, the group in which a plurality of aromatic hydrocarbons are bonded or condensed is substituted. From the viewpoint of the chemical structure, conventional techniques will be described below.

A compound in which a carboxyl group is introduced into one end of an alkylene chain of a 1,3-dialkylurea derivative has an angiotensin II antagonistic activity (Japanese Patent Application Laid-Open Nos. 6-72985 and 6-184086). ), And that a compound having a carboxyl group introduced into the terminal of both alkylene chains inhibits angiotensin converting enzyme (Japanese Patent Application Laid-Open No. 58-54551). In addition, an amino acid derivative having a urea structure inhibits the activity of enkephalinase (Japanese Patent Publication No.
No. 79339). However, there is no disclosure of the endothelin converting enzyme inhibitory activity which is the object of the present invention.

[0010]

It has been a very interesting problem to find a compound that inhibits the enzyme activity of the endothelin converting enzyme involved in this biological function.

[0011]

Means for Solving the Problems The present inventors conducted a search for compounds that inhibit endothelin converting enzyme, and as a result,
A compound in which a group in which a plurality of aromatic hydrocarbons are bonded or condensed, such as a biphenylyl group or a naphthyl group, is introduced into an alkylene chain of a 1,3-di (carboxyalkyl) urea derivative, and the compound is an endothelin converting enzyme. Was found to be inhibited. These compounds are ameliorating agents for symptoms in which endothelin is deeply involved, particularly cerebral blood flow improving agents for suppressing cerebral vasospasm causing cerebral infarction, etc., therapeutic agents for asthma such as bronchial asthma, and organs such as liver transplantation and kidney transplantation It is expected to be useful as an agent for preventing dysfunction after transplantation or an agent for suppressing rejection.

[0012]

DISCLOSURE OF THE INVENTION The present invention relates to an endothelin converting enzyme inhibitor comprising a compound represented by the following general formula [I] or a salt thereof (hereinafter, referred to as the present compound) as an active ingredient.

[0013]

Embedded image [In the formula, R ¹ represents a carboxyl group which may be converted to an ester, amide or hydroxamic acid.

R ² represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a hydroxy group, a lower alkoxy group or a phenyl lower alkoxy group, wherein the phenyl lower alkyl group and the phenyl ring of the phenyl lower alkoxy group are a halogen atom, Lower alkyl group, hydroxy group,
It may be substituted with a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group.

R ³ represents a lower alkyl group or a phenyl lower alkyl group, wherein the phenyl ring of the phenyl lower alkyl group is a halogen atom, a lower alkyl group, a hydroxy group,
It may be substituted with a lower alkoxy group or a lower alkylenedioxy group.

R ⁴ represents a carboxyl group which may be converted to an ester, amide or hydroxamic acid.

R ⁵ represents a group represented by the following general formula [II], [III] or [IV].

[0018]

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Embedded image R ⁶ represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group.

R ⁷ represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group, a lower alkylamino group, a phenyl group or a naphthyl group; The group and the naphthyl group may be substituted by a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group.

R ⁸ represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group.

R ⁹ represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group, a lower alkylamino group, a phenyl group or a naphthyl group; The group and the naphthyl group may be substituted by a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group.

R ¹⁰ represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group, a lower alkylamino group, a phenyl group or a naphthyl group; The group and the naphthyl group may be substituted by a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group.

A represents a lower alkylene group. same as below. ].

The above-mentioned groups defining the present compound are described in detail below.

Halogen is fluorine, chlorine, bromine,
Shows iodine. Lower alkyl refers to straight-chain or branched alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, hexyl, isopropyl, isobutyl, isopentyl, isohexyl, tert.-butyl, tert.-pentyl and the like. . Lower alkoxy refers to straight or branched alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, isopropoxy, tert.-butoxy and the like. Lower alkylene means methylene, ethylene, trimethylene, hexamethylene, propylene, (ethyl) methylene, (dimethyl)
Shows a linear or branched alkylene having 1 to 6 carbon atoms such as methylene, and lower alkylenedioxy is
Alkylenedioxy having a linear or branched alkylene having 1 to 6 carbon atoms between two oxygen atoms such as methylenedioxy, ethylenedioxy, propylenedioxy, (diethyl) methylenedioxy and the like. Is shown.

Esters include lower alkyl esters such as methyl ester, ethyl ester, isopropyl ester, butyl ester and hexyl ester; lower alkanoyl such as acetylaminomethyl ester, acetylaminoethyl ester, propionylaminomethyl ester and propionylaminoethyl ester. Examples thereof include those commonly used as carboxylic acid esters such as phenyl lower alkyl esters such as amino lower alkyl esters and benzyl esters, phenyl esters, methoxyphenyl esters, and indanyl esters. Lower alkanoyl refers to straight or branched alkanoyl having 2 to 6 carbon atoms such as acetyl, propionyl, butyryl, valeryl, isobutyryl, isovaleryl, pivaloyl and the like. Amides are those commonly used as amides of carboxylic acids, such as amides with ammonia, amides with lower alkylamines such as methylamine, dimethylamine and ethylamine, and amides with phenyl lower alkylamines such as benzylamine. Show. The salts in the present compound are not particularly limited as long as they are pharmaceutically acceptable salts.Examples thereof include salts with alkali metals such as sodium, potassium and calcium or alkaline earth metals, ammonium salts, and organic salts such as diethylamine and triethanolamine. Salts with amines and salts with inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid and the like can be mentioned.

The present compound has diastereoisomers and optical isomers, all of which are included in the present invention. Further, the present compounds may be in the form of a hydrate.

Preferred examples of the present compound include the following. a) In formula [I], R ¹ is a carboxyl group which may be converted to lower alkyl, lower alkanoylamino lower alkyl, phenyl lower alkyl, phenyl or indanyl ester; ammonia, lower alkylamine or phenyl lower alkylamine A carboxyl group which may be converted to an amide with; or a carboxyl group which may be converted to hydroxamic acid, wherein the phenyl lower alkyl, the phenyl and the phenyl ring of the phenyl lower alkylamine have a halogen atom,
A lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group may be substituted, and R ² is a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, A hydroxy group, a lower alkoxy group or a phenyl lower alkoxy group, wherein the phenyl ring of the phenyl lower alkyl group and the phenyl lower alkoxy group is a halogen atom,
A lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group, and R ³ represents a lower alkyl group or a phenyl lower alkyl group; The phenyl ring of the phenyl lower alkyl group is a halogen atom
A lower alkyl group, a hydroxy group, may be substituted with a lower alkoxy group or a lower alkylenedioxy group,
R ⁴ is a carboxyl group which may be converted to lower alkyl, lower alkanoylamino lower alkyl, phenyl lower alkyl, phenyl or indanyl ester;
A carboxyl group that may be converted to an amide with ammonia, lower alkylamine or phenyl lower alkylamine; or a carboxyl group that may be converted to hydroxamic acid,
The phenyl and the phenyl ring of the phenyl lower alkylamine may be substituted with a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group, A is a compound in which A represents a lower alkylene group and R ⁵ represents a group represented by the general formula [II], [III] or [IV] (hereinafter referred to as compound (a)).

B) In the general formula [I], R ¹ and R ⁴ both represent a carboxyl group, and R ² is a hydrogen atom;
A lower alkyl group, particularly an isopentyl group; a phenyl lower alkyl group, particularly a benzyl group, a phenethyl group, a phenylpropyl group, a phenylbutyl group; a hydroxy group; or a phenyl lower alkoxy group, particularly a benzyloxy group, wherein the phenyl ring of the phenyl lower alkyl group is It may be substituted by a halogen atom, especially a chlorine atom, R ³ represents a lower alkyl group, especially an isobutyl group, A represents a lower alkylene group, particularly a methylene group, and R ⁵ represents the following general formulas [II], [III]
Or a compound showing a group represented by [IV]

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Embedded image [Wherein, R ⁶ represents a hydrogen atom or a nitro group.

R ⁷ represents a hydrogen atom; a halogen atom, especially a bromine atom and a chlorine atom; a lower alkyl group, especially a methyl group; a lower alkoxy group, especially a methoxy group;

R ⁸ represents a hydrogen atom.

R ⁹ represents a hydrogen atom.

R ¹⁰ represents a hydrogen atom, a halogen atom, especially a bromine atom or a lower alkoxy group, especially a methoxy group. ].

In the general formula [I], R ¹ and R ⁴ both represent a carboxyl group, and R ² is a hydrogen atom; a lower alkyl group, especially an isopentyl group; a phenyl lower alkyl group, especially a phenethyl group, a phenylpropyl group, and a phenyl group. A butyl group; a hydroxy group; or a phenyl lower alkoxy group, particularly a benzyloxy group, wherein the phenyl ring of the phenyl lower alkyl group may be substituted with a halogen atom, particularly a chlorine atom, and R ³ represents a lower alkyl group, particularly an isobutyl group. Wherein A is a lower alkylene group, particularly a methylene group, and R ⁵ is a compound represented by the following general formula [II] or [IV].

[0035]

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Embedded image [Wherein, R ⁶ represents a hydrogen atom or a nitro group.

R ⁷ represents a hydrogen atom or a phenyl group.

R ¹⁰ represents a hydrogen atom or a halogen atom, especially a bromine atom. ].

In particular, in the above compound (a), R
⁵ the following general formula [II], compound a group represented by [III] or [IV]

Embedded image

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Embedded image Wherein R ⁶ represents a hydrogen atom or a nitro group, R ⁷ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group, R ⁸ and R ⁹ both represent a hydrogen atom, ¹⁰ represents a hydrogen atom, a halogen atom or a lower alkoxy group. ] And R ⁵ is represented by the following general formula [I
A compound showing a group represented by [I] or [IV]

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Embedded image [In the formula, R ⁶ represents a hydrogen atom or a nitro group, R ⁷ represents a hydrogen atom or a phenyl group, and R ¹⁰ represents a hydrogen atom or a halogen atom, particularly a bromine atom. A compound wherein R ³ represents a lower alkyl group, particularly an isobutyl group; R ² is a hydrogen atom; a lower alkyl group, particularly an isopentyl group; a phenyl lower alkyl group, particularly a phenethyl group, a phenylpropyl group, a phenylbutyl group; a hydroxy group; A compound in which the phenyl ring of the phenyl lower alkyl group may be substituted with a halogen atom, particularly a chlorine atom, a compound in which both R ¹ and R ⁴ represent a carboxyl group, and a compound in which R ³ is a lower alkyl group A compound wherein R ⁵ is a group represented by the following general formula [II], [III] or [IV]

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Embedded image Wherein R ⁶ represents a hydrogen atom or a nitro group, R ⁷ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group, R ⁸ and R ⁹ both represent a hydrogen atom, ¹⁰ represents a hydrogen atom, a halogen atom or a lower alkoxy group. A compound wherein R ³ represents a lower alkyl group, particularly an isobutyl group, and R ⁵ represents a group represented by the following general formula [II] or [IV]

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Embedded image [In the formula, R ⁶ represents a hydrogen atom or a nitro group, R ⁷ represents a hydrogen atom or a phenyl group, and R ¹⁰ represents a hydrogen atom or a halogen atom, particularly a bromine atom. ], R ² is a hydrogen atom, a lower alkyl group, a phenyl-lower alkyl group, a hydroxy group or a phenyl-lower alkoxy group, a phenyl ring of the phenyl-lower alkyl group may be substituted with a halogen atom, R ³ is a lower an alkyl group, R ⁵
Is a compound represented by the following general formula [II], [III] or [IV]

Embedded image

Embedded image

Embedded image [Wherein, R ⁶ represents a hydrogen atom or a nitro group, R ⁷ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group, R ⁸ and R ⁹ represent a hydrogen atom, and R ¹⁰ Represents a hydrogen atom, a halogen atom or a lower alkoxy group. And R ² represents a hydrogen atom; a lower alkyl group, especially an isopentyl group; a phenyl lower alkyl group, particularly a phenethyl group, a phenylpropyl group, a phenylbutyl group; a hydroxy group; or a phenyl lower alkoxy group, particularly a benzyloxy group. The phenyl ring of the alkyl group may be substituted with a halogen atom, particularly a chlorine atom, R ³ represents a lower alkyl group, particularly an isobutyl group, and R ⁵ represents a group represented by the following general formula [II] or [IV]. Compounds shown

Embedded image

Embedded image [In the formula, R ⁶ represents a hydrogen atom or a nitro group, R ⁷ represents a hydrogen atom or a phenyl group, and R ¹⁰ represents a hydrogen atom or a halogen atom, particularly a bromine atom. Is particularly preferred.

As an example of the compound having particularly excellent action among the present compounds, (2S) -3- (4-biphenylyl)
2- [3- (2-carboxyethyl) -3-isobutylureido] propionic acid (following formula [V]), (2S)
-3- (4-Biphenylyl) -2- [3- (2-carboxy-4-phenylbutyl) -3-isobutylureido] propionic acid (the following formula [VI]), (2S) -3-
(4-biphenylyl) -2- [3- [2-carboxy-
4- (4-chlorophenyl) butyl] -3-isobutylureido] propionic acid (formula [VII] below), (2S)
-3- (4-Biphenylyl) -2- [3- (2-carboxy-6-phenylhexyl) -3-isobutylureido] propionic acid (formula [VIII] below), (2S) -3-
(4-biphenylyl) -2- [3- (2-carboxy-
2-hydroxyethyl) -3-isobutylureido] propionic acid (following formula [IX]), (2S) -2- [3-
(2-carboxyethyl) -3-isobutylureido]
-3- (1,1 ': 2', 1 "-terphenyl-4-yl) propionic acid (following formula [X]) (2S) -2- [3- (2-carboxy-4-phenylbutyl) -3-isobutylureido] -3- (2-naphthyl) propionic acid (following formula [XI]), (2S) -2-
[3- (2-benzyloxy-2-carboxyethyl)
-3-isobutylureido] -3- (2-naphthyl) propionic acid (following formula [XII]), (2S) -3- [2-
(1-Bromo) naphthyl] -2- [3- (2-carboxyethyl) -3-isobutylureido] propionic acid (the following formula [XIII]), further salts and single diastereoisomers and optical isomers Body.

[0040]

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Embedded image This compound can be synthesized by the method described in Japanese Patent Application No. 6-270957 or Japanese Patent Application No. 6-310493.

A typical method for synthesizing the present compound is shown below.

[0042]

Embedded image In this method, first, a compound represented by the general formula [XIV] and 1,1
1'-carbonyldiimidazole is reacted in the presence of a base such as imidazole to lead to a compound of the general formula [XV], which is then reacted with a compound of the general formula [XVI] to form urea, and the compound of the formula (X) [I]). Some of the compounds represented by the general formula [XIV] were synthesized according to the method reported by Shieh et al. (J. Org. Chem., 57, 379-381 (1992)
) Or from Evans et al. (J. Am. Chem. Soc., 109 , 6881-6883 (198
It can be synthesized via the azide form using 7)).

The carboxyl group can be converted into an ester or an amide by using a commonly used method as required. Conversely, esters and amides can be hydrolyzed to carboxylic acids using commonly used methods.

The carboxyl group can be converted into an ester or an amide, and the phosphoryl group can be converted into an ester, if necessary, using a commonly used method. Conversely, these esters and amides can be hydrolyzed into carboxylic acids and phosphonic acids using commonly used methods.

The compound obtained by the above method can be converted into the above-mentioned salts by a conventional method.

The optical isomers of the compound represented by the general formula [I] are all included in the present invention as described above. When an optically active raw material is used, an optically active substance is obtained. When a racemic form is used as a raw material, a racemic product can be optically resolved using an optical resolving agent or the like.

Endothelin converting enzymes are widely distributed in various tissues in the body and are indispensable enzymes for the production of endothelin involved in various biological functions. Already, in model animals, compounds that inhibit endothelin converting enzyme inhibit cerebral vasospasm (Life Sci., 49, 841-848 (19
91)) and suppression of endothelin-1 expression in cerebrospinal fluid (Biochem. Biophys. Res. Commun., 178, 24-30 (19
91)), Endothelin receptor antagonists suppress acute renal failure due to tissue incompatibility after liver transplantation (transplantation, 28 , 261).
(1993)). In addition, blood of chronic maintenance dialysis patients and patients with rejection after renal transplantation (Journal of the Japanese Urological Association, 85 , 1622-1628 (1993)), blood of asthmatic patients (Jikeikai Med. J., 41 , 91-98 (1994)) and in alveolar lavage fluid during seizures (J. Allergy Clin. Immunol., 88,
376-384 (1991)), patients with essential hypertension (Am. J. Med., 88, 614-618 (1990)), and patients with acute heart failure after myocardial infarction (Jpn. Circ. J., 57, 371-378 (199
3)), pulmonary hypertension (Circulation, 85, 504-509 (199
2)), patients with acute renal failure due to ureteral atresia (N. Engl.J.
Med., 321, 1127 (1989)), diabetic patients (Diabetelogi
a, 33 , 306-310 (1990)) have been reported to have high endothelin-1 concentrations.

Some compounds have been reported as compounds inhibiting endothelin converting enzyme, but all of them have two or more amino acid residues, and no compounds having a urea skeleton in the molecule have been reported. .

Thus, the present inventors conducted a search for a compound that inhibits endothelin converting enzyme, and detailed data will be described in the section of the effect of the present invention. This compound was found to inhibit endothelin converting enzyme. Therefore, an agent for improving symptoms in which endothelin is deeply involved, particularly a cerebral blood flow improving agent for suppressing cerebral vasospasm causing cerebral infarction, a therapeutic agent for asthma such as bronchial asthma, and an organ transplant such as liver transplantation and kidney transplantation This compound is expected to be useful as an agent for preventing dysfunction or an agent for suppressing rejection.

The present compound is also known to be involved in cardiovascular diseases such as heart failure and hypertension, renal diseases, gastrointestinal disorders, pain, endocrine and metabolic diseases and autoimmune diseases. Studies have been made on the effect of the compound of formula (11) on Japanese Patent Application No. Hei 6-270957.
No. 6-310493).

The present compound can be administered orally or parenterally. Dosage forms include tablets, capsules,
Granules, powders, injections and the like can be mentioned, and can be formulated using widely used techniques. For example, tablets, capsules, granules, oral preparations such as powders, lactose, crystalline cellulose, bulking agents such as starch, magnesium stearate, lubricants such as talc, binders such as hydroxypropylcellulose polyvinylpyrrolidone, Carboxymethylcellulose Disintegrators such as calcium and low-substituted hydroxypropylmethylcellulose, and coating agents such as hydroxypropylmethylcellulose, macrogol, and silicone resin may be added as needed.

In the present invention, the dose of the present compound depends on symptoms,
Although it can be appropriately selected according to age, dosage form, etc., if it is an oral preparation, it is usually 0.1 to 6000 mg per day, preferably 1 to
600 mg may be administered once or in several divided doses.

The following are preparation examples of the present compound. These examples are for better understanding of the present invention.
It does not limit the scope of the invention.

[0054]

【Example】

[Production Examples] Production examples of the present compound (Compounds 1 to 27) will be described.

Reference Example 1 (2S) -3- (4-biphenylyl) -2- [3- (2
-Ethoxycarbonylethyl) -3-isobutylureido] propionic acid benzyl ester (Compound a-1)

Embedded image Under a nitrogen atmosphere, (2S) -2-amino-3- (4-biphenylyl) propionic acid benzyl ester hydrochloride (1
g), 1,1'-carbonyldiimidazole (529 m
g) and imidazole (185 mg) are added with tetrahydrofuran (14 ml) and stirred at room temperature for 20 minutes.
3- (N-isobutyl) aminopropionic acid ethyl ester hydrochloride (599 mg) is added to the reaction solution, and the mixture is heated under reflux for 1 hour. After cooling, a 10% aqueous citric acid solution is added to the reaction solution, and the mixture is extracted with diethyl ether. The organic layer is washed with water and then with saturated saline, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to give 1.42 g of the title compound (compound a-1).
(98%).

[Α] _D ²⁰ −26.8 ° (c = 1.0,
Methanol) IR (Film, cm ^-1 ) 3350, 3030, 295
9,2871,1732,1651,1519,145
5,1188

Using the same method as in Reference Example 1, the following compound is obtained.

(2S) -3- (4-biphenylyl)-
2- [3- (2-tert.-butoxycarbonylethyl)-
3-isobutylureido] propionic acid benzyl ester (compound a-2) [α] _D ²⁰ -23.9 ° (c = 0.98, methanol) IR (Film, cm ⁻¹ ) 3350, 3029, 296
1,1726,1644,1519,1487,145
5

(2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido]-
3- (4-Biphenylyl) propionic acid benzyl ester (compound a-3) [α] _D ²⁰ −29.9 ° (c = 0.29, methanol) IR (Film, cm ⁻¹ ) 3447, 3030, 295
8,1733,1651,1516,1487,138
6,1259,1173,756,698

(2S) -3- (4-biphenylyl)-
2- [3-[(2RS) -2-tert.-butoxycarbonyl-5-methylhexyl] -3-isobutylureide]
Propionic acid benzyl ester (compound a-4) [α] _D ²⁰ -19.4 ° (c = 1.1, methanol) IR (Film, cm ⁻¹ ) 3448, 3359, 295
7,2869,1723,1651,1511,115
2,1008,846,757,698

(2S) -3- (4-biphenylyl)-
2- [3-[(2RS) -2-tert.-butoxycarbonyl-3-phenylpropyl] -3-isobutylureido] propionic acid benzyl ester (compound a-5) [α] _D ²⁰ -11.6 ° ( c = 0.52, chloroform) IR (Film, cm ^-1 ) 3448, 3360, 296
1,1724,1650,1514,1455,136
8,1253,1152

(2S) -2- [3-[(2RS) -2
-Benzyloxycarbonyl-4-phenylbutyl]-
3-isobutylureido] -3- (4-biphenylyl)
Propionic acid benzyl ester (Compound a-6) [α] _D ²⁰ -20.3 ° (c = 0.049, methanol) IR (Film, cm ⁻¹ ) 3445, 3029, 295
6,1733,1653,1509,1454,138
5,1174,754,698

(2S) -3- (4-biphenylyl)-
2- [3-[(2RS) -2-tert.-butoxycarbonyl-5-phenylpentyl] -3-isobutylureido] propionic acid benzyl ester (compound a-7) [α] _D ²⁰ −29.5 ° ( c = 0.073, methanol) IR (Film, cm ^-1 ) 3366, 3028, 295
8,1722,1651,1505,1367,115
2,758,698

(2S) -3- (4-biphenylyl)-
2- [3-[(2RS) -2-tert.-butoxycarbonyl-6-phenylhexyl] -3-isobutylureido] propionic acid benzyl ester (compound a-8) [α] _D ²⁰ -20.1 ° ( c = 0.63, methanol) IR (Film, cm ^-1 ) 3363, 2933, 172
3,1652,1510,1367,1153,75
6,698

(2S) -2- [3-[(2RS) -2
-Benzyloxy-2-benzyloxycarbonylethyl] -3-isobutylureido] -3- (4-biphenylyl) propionic acid benzyl ester (compound a-9) [α] _D ²⁰ -15.2 ° (c = 1. 0, chloroform) IR (Film, cm ^-1 ) 3342, 2957, 174
2,1657,1514,1455,1251,117
2,1114,754,698

(2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido]-
3- [4- (4'-Fluoro) biphenylyl] propionic acid benzyl ester (compound a-10) [α] _D ²⁰ -27.9 ° (c = 0.48, methanol) IR (Film, cm ⁻¹ ) 3359, 3032, 295
8, 1736, 1650, 1498, 1455, 138
6,1173,1008,819,752,698

(2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido]-
3- [4- (4'-Chloro) biphenylyl] propionic acid benzyl ester (compound a-11) [α] _D ²⁰ -17.8 ° (c = 0.29, chloroform) IR (Film, cm ⁻¹ ) 3789, 3659, 296
0,1732,1651,1504,1486,121
5,1142,1006

(2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido]-
3- [4- (4'-methyl) biphenylyl] propionic acid benzyl ester (compound a-12) [α] _D ²⁰ -28.3 ° (c = 1.4, methanol) IR (Film, cm ⁻¹ ) 3447,3030,295
8,1731,1645,1501,1182,91
0,809,734,699

(2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido]-
3- [4- (3'-methoxy) biphenylyl] propionic acid benzyl ester (compound a-13) [α] _D ²⁰ -16.6 ° (c = 1.0, chloroform) IR (Film, cm ⁻¹ ) 3450, 3365, 295
9,1732,1651,1519,1455,121
5,1051

(2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido]-
3- [4- (2'-methoxy) biphenylyl] propionic acid benzyl ester (compound a-14) [α] _D ²⁰ -15.4 ° (c = 0.74, chloroform) IR (Film, cm ⁻¹ ) 3360, 3065, 295
9,1731,1649,1516,1455,117
9

(2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido]-
3- [4- (2-Nitro) biphenylyl] propionic acid benzyl ester (compound a-15) [α] _D ²⁰ -38.6 ° (c = 0.093, methanol) IR (Film, cm ⁻¹ ) 2959 , 1732, 164
4,1531,1359,1175,756,699

(2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido]-
3- (1,1 ′: 4 ′, 1 ″ -terphenyl-4-yl) propionic acid benzyl ester (compound a-16) mp 96.0-99.0 ° C. [α] _D ²⁰ −20.1 ° (C = 0.51, chloroform) IR (KBr, cm ^-1 ) 3385, 2954, 173
4,1626,1519,1366,1291

(2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido]-
3- (1,1 ': 2', 1 "-terphenyl-4-yl) propionic acid benzyl ester (compound a-17) [α] _D ²⁰ -17.8 ° (c = 0.67, methanol) IR (Film, cm ^-1 ) 3368, 3032, 295
8, 2362, 1733, 1651, 1514, 147
5,1386,746,699

(2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido]-
3- [4- (2-Naphthyl) phenyl] propionic acid benzyl ester (compound a-18) [α] _D ²⁰ -22.5 ° (c = 0.48, chloroform) IR (Film, cm ⁻¹ ) 3350 , 3032,295
8,1735,1651,1502,1173,75
1,698

(2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido]-
3- [4- (1-Naphthyl) phenyl] propionic acid benzyl ester (Compound a-19) [α] _D ²⁰ -28.3 ° (c = 0.17, methanol) IR (Film, cm ⁻¹ ) 3446 , 2957, 173
2,164,1514,1455,1386,117
3,779,697

(2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido]-
3- (2-naphthyl) propionic acid benzyl ester (compound a-20) [α] _D ²⁰ -24.1 ° (c = 1.1, methanol) IR (Film, cm ⁻¹ ) 3355, 2957, 173
5,1649,1509,1172

(2S) -2- [3-[(2RS) -2
-Tert.-butoxycarbonyl-4-phenylbutyl]-
3-isobutylureido] -3- (2-naphthyl) propionic acid benzyl ester (compound a-21) [α] _D ²⁰ -20.5 ° (c = 0.50, chloroform) IR (Film, cm ⁻¹ ) 3445,3361,295
8, 1718, 1653, 1507, 1454, 136
7,1150,747,698

(2S) -2- [3-[(2RS) -2
-Benzyloxy-2-benzyloxycarbonylethyl] -3-isobutylureido] -3- (2-naphthyl) propionic acid benzyl ester (compound a-22) [α] _D ²⁰ -21.8 ° (c = 0. 98, chloroform) IR (Film, cm ^-1 ) 3343, 3062, 295
8,1742,1651,1511,1455,117
5,1115

(2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido]-
3- [2- (1-Bromo) naphthyl] propionic acid methyl ester (Compound a-23) IR (Film, cm ^-1 ) 3366, 2955, 173
2,1644,1519,1176,1074,102
9,1002,816,750,698

(2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido]-
3- [2- (6-Methoxy) naphthyl] propionic acid benzyl ester (compound a-24) [α] _D ²⁰ -26.2 ° (c = 0.51, methanol) IR (Film, cm ⁻¹ ) 3361 , 3033,295
8,1732,1651,1607,1505,126
5,1175,853,753,698

(2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido]-
3- (1-Naphthyl) propionic acid benzyl ester (compound a-25) [α] _D ²⁰ -32.5 ° (c = 1.0, methanol) IR (Film, cm ⁻¹ ) 3368, 2958, 173
6,1650,1511,1455,1386,117
4,753,698

(2S) -3- (4-biphenylyl)-
2- [3-[(2RS) -2-tert.-butoxycarbonyl-4- (4-chloro) phenylbutyl] -3-isobutylureido] propionic acid benzyl ester (Compound a-26)

Embedded image [Α] _D ²⁰ −22.3 ° (c = 0.06, methanol) IR (Film, cm ⁻¹ ) 3360, 3029, 295
9, 1897, 1723, 1654, 1491, 136
7, 1255, 1149, 1090, 1014, 84
5,758,698

Reference Example 2 (2S) -3- (4-Biphenylyl) -2- [3- (2
-Carboxyethyl) -3-isobutylureido] propionic acid benzyl ester (compound b-1)

Embedded image (2S) -3- (4-biphenylyl) -2- [3- (2
-Tert.-butoxycarbonylethyl) -3-isobutylureido] propionic acid benzyl ester (compound a-
2,7.84 g) in 4.0 N hydrochloric acid / dioxane (35 m
1) and stirred at room temperature for 3 hours 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained oil was purified by silica gel column chromatography to give 6.12 g (8) of the title compound (Compound b-1).
7%) as an amorphous powder.

[Α] _D ²⁰ -28.0 ° (c = 0.9
8, methanol) IR (Film, cm ^-1 ) 3029, 2959, 173
1,1615,1523,1487,1451,119
0

Using the same method as in Reference Example 2, the following compound is obtained.

[0086]

From compound a-21 to (2S) -2-
[3-[(2RS) -2-carboxy-4-phenylbutyl] -3-isobutylureido] -3- (2-naphthyl) propionic acid benzyl ester (compound b-2) [α] _D ²⁰ -27.0 ° (c = 0.49, chloroform) IR (Film, cm ⁻¹ ) 3441, 2958, 173
4,1617,1522,1454,1190,75
1,699

From compound a-4, (2S) -3- (4
-Biphenylyl) -2- [3-[(2RS) -2-carboxy-5-methylhexyl] -3-isobutylureido] propionic acid benzyl ester (Compound b-3)

From compound a-5, (2S) -3- (4
-Biphenylyl) -2- [3-[(2RS) -2-carboxy-3-phenylpropyl] -3-isobutylureido] propionic acid benzyl ester (Compound b-4)

From compound a-7, (2S) -3- (4
-Biphenylyl) -2- [3-[(2RS) -2-carboxy-5-phenylpentyl] -3-isobutylureido] propionic acid benzyl ester (Compound b-5)

From compound a-8, (2S) -3- (4
-Biphenylyl) -2- [3-[(2RS) -2-carboxy-6-phenylhexyl] -3-isobutylureido] propionic acid benzyl ester (Compound b-6)

From compound a-26, (2S) -3-
(4-biphenylyl) -2- [3-[(2RS) -2-
Carboxy-4- (4-chloro) phenylbutyl] -3
-Isobutylureido] propionic acid benzyl ester (Compound b-7)

Embedded image Reference Example 3 (2S) -3- (4-biphenylyl) -2- [3- (2
-Carboxyethyl) -3-isobutylureido] propionic acid (compound 1)

Embedded image Under a nitrogen atmosphere, (2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido]-
3- (4-Biphenylyl) propionic acid benzyl ester (Compound a-3, 270 mg) in methanol (5 m
l) To the solution is added 5% palladium-on activated carbon (50 mg), and the mixture is stirred under a hydrogen atmosphere for 1 hour and 30 minutes. The palladium on activated carbon is removed by celite filtration, and the filtrate is concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography, and 90 mg (48.4) of the title compound (compound 1) was obtained.
%).

Mp 131-133 ° C. (decomposition) [α] _D ²⁰ -11.9 ° (c = 1.0, methanol) IR (KBr, cm ⁻¹ ) 3435, 2958, 172
0,1592,1526,1488,1278,124
0,764

Using the same method as in Reference Example 3, the following compound is obtained.

From compound a-6, (2S) -3- (4
-Biphenylyl) -2- [3-[(2RS) -2-carboxy-4-phenylbutyl] -3-isobutylureido] propionic acid (compound 4) [α] _D ²⁰ -43.5 ° (c = 0. 26, chloroform) IR (KBr, cm ^-1 ) 2957, 1734, 160
2,1522,1452,1203,756,697

From compound a-7 through compound b-5,
(2S) -3- (4-biphenylyl) -2- [3-
[(2RS) -2-carboxy-5-phenylpentyl] -3-isobutylureido] propionic acid (compound 6) [α] _D ²⁰ -39.7 ° (c = 1.0, chloroform) IR (KBr, cm) ^-1 ) 3435, 2959, 172
6,1603,1523,1487,1203,75
6,698

From compound a-8 to compound b-6,
(2S) -3- (4-biphenylyl) -2- [3-
[(2RS) -2-carboxy-6-phenylhexyl] -3-isobutylureido] propionic acid (compound 7) [α] _D ²⁰ -39.8 ° (c = 0.97, chloroform) IR (KBr, cm) ^-1 ) 3435, 2933, 172
8,1603,1526,1487,1201,75
7,698

From compound a-10, (2S) -2-
[3- (2-carboxyethyl) -3-isobutylureido] -3- [4- (4'-fluoro) biphenylyl]
Propionic acid (compound 10) [α] _D ²⁰ -11.5 ° (c = 0.52, methanol) IR (Film, cm ⁻¹ ) 2960, 1722, 160
4,1526,1498,1224,1159,107
6,820,757,667

From compound a-12, (2S) -2-
[3- (2-carboxyethyl) -3-isobutylureido] -3- [4- (4'-methyl) biphenylyl] propionic acid (compound 13) mp 139.5-142.0 ° C (decomposition) [α] _D ²⁰ -30.3 ° (c = 0.98, chloroform) IR (KBr, cm ⁻¹ ) 3442, 2959, 172
6, 1704, 1591, 1529, 1500, 127
4,804

From compound a-13, (2S) -2-
[3- (2-carboxyethyl) -3-isobutylureido] -3- [4- (3'-methoxy) biphenylyl]
Propionic acid (compound 14) [α] _D ²⁰ -22.8 ° (c = 1.0, chloroform) IR (KBr, cm ⁻¹ ), 2960, 1733, 160
7, 1527, 1482, 1405, 1296, 121
3

From compound a-14, (2S) -2-
[3- (2-carboxyethyl) -3-isobutylureido] -3- [4- (2'-methoxy) biphenylyl]
Propionic acid (compound 15) [α] _D ²⁰ -15.4 ° (c = 0.49, dimethyl sulfoxide) IR (KBr, cm ⁻¹ ) 2961, 1728, 159
9,1530,1488,1237,1029

From compound a-17, (2S) -2-
[3- (2-carboxyethyl) -3-isobutylureido] -3- (1,1 ': 2', 1 "-terphenyl-
4-yl) propionic acid (compound 18) [α] _D ²⁰ −3.1 ° (c = 0.51, methanol) IR (Film, cm ⁻¹ ) 3021, 960, 172
1,1615,1527,1449,1217,75
9,701

From compound a-18, (2S) -2-
[3- (2-carboxyethyl) -3-isobutylureido] -3- [4- (2-naphthyl) phenyl] propionic acid (compound 19) [α] _D ²⁰ -34.5 ° (c = 1.0 , Dimethyl sulfoxide) IR (KBr, cm ^-1 ) 2959, 1721, 160
2,1526,1410,1197,813,750

From compound a-19, (2S) -2-
[3- (2-carboxyethyl) -3-isobutylureido] -3- [4- (1-naphthyl) phenyl] propionic acid (compound 20) mp 182.0 ° C (decomposition) [α] _D ²⁰ -47. 3 ° (c = 1.0, dimethyl sulfoxide) IR (KBr, cm ⁻¹ ) 3369, 2957, 172
2,1610,1537,1231,1161,89
8,802,776,670

From compound a-20, (2S) -2-
[3- (2-carboxyethyl) -3-isobutylureido] -3- (2-naphthyl) propionic acid (compound 2
1) mp 132.8-134.0 ° C. [α] _D ²⁰ -24.5 ° (c = 0.50, methanol) IR (KBr, cm −1) 3428, 2960, 175
0,1732,1717,1614,1544,125
3,1177

From compound a-25, (2S) -2-
[3- (2-carboxyethyl) -3-isobutylureido] -3- (1-naphthyl) propionic acid (compound 2
7) mp 150.0 to 150.6 ° C. (decomposition) [α] _D ²⁰ -71.9 ° (c = 0.32, methanol) IR (KBr, cm ⁻¹ ) 3430, 1751, 171
5,1614,1543,1385,1253,117
5

Reference Example 4 (2S) -2- [3- (2-Ethoxycarbonylethyl) -3-isobutylureido] -3- (2-naphthyl) propionic acid (Compound c-1)

Embedded image Under a nitrogen atmosphere, (2S) -2- [3- (2-ethoxycarbonylethyl) -3-isobutylureido] -3-
To a solution of benzyl (2-naphthyl) propionate (compound a-23, 687 mg) in ethanol (14 ml) was added 20% palladium hydroxide on carbon (70 m
g) and stirred under a hydrogen atmosphere for 4 hours 30 minutes. The palladium hydroxide on carbon is removed by filtration through celite, and the filtrate is concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to give the title compound (Compound c-1)
Obtain 401 mg (71.1%).

Mp 92.0-95.2 ° C. (hexane-
Ethyl acetate) [α] _D ²⁰ -34.6 ° (c = 0.99, chloroform) IR (KBr, cm ⁻¹ ) 3413, 2962, 173
7, 1715, 1603, 1532, 1454, 131
8,1187,748

Using the same method as in Reference Example 4, compound a-
Compound 24 is obtained from 24.・ (2S) -2- [3
-(2-carboxyethyl) -3-isobutylureido] -3- [2- (6-methoxy) naphthyl] propionic acid (compound 26) mp 100-127 ° C [α] _D ²⁰ -7.9 ° (c = 0.99, dimethyl sulfoxide) IR (KBr, cm ^-1 ) 3351, 2960, 260
0,1727,1636,1608,1265,123
0,1031,852,809

Reference Example 5 (2S) -2- [3- (2-carboxyethyl) -3-
Isobutylureido] -3- [4- (2-nitro) biphenylyl] propionic acid (compound 16)

Embedded image (2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido] -3- [4- (2
-Nitro) biphenylyl] propionic acid benzyl ester (compound a-15, 457 mg) in ethanol (1
4.4N solution in 1N lithium hydroxide (1.44m
1) and stir for 2 hours. The reaction mixture is neutralized by adding 1N hydrochloric acid, and concentrated under reduced pressure to distill off ethanol.
A 10% aqueous citric acid solution is added to the resulting solution, and extracted with chloroform. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 230 mg (69.9%) of the title compound (compound 16) as an amorphous powder.

[Α] _D ²⁰ -20.1 ° (c = 1.0,
Methanol) IR (KBr, cm ^-1 ) 2961, 1723, 160
6,1530,1362,1201,758,701

Using the same method as in Reference Example 5, the following compound is obtained.

From compound a-16, (2S) -2-
[3- (2-carboxyethyl) -3-isobutylureido] -3- (1,1 ': 4', 1 "-terphenyl-
4-yl) propionic acid (compound 17) mp 147.8-150.2 ° C (decomposition) [α] _D ²⁰ -6.6 ° (c = 0.32, methanol) IR (KBr, cm ^-1 ) 2963 , 1724, 161
4,1523,1467,1217

From compound a-4 to compound b-3,
(2S) -3- (4-biphenylyl) -2- [3-
[(2RS) -2-carboxy-5-methylhexyl]
-3-isobutylureido] propionic acid (compound 2) [α] _D ²⁰ −46.0 ° (c = 0.97, chloroform) IR (KBr, cm ⁻¹ ) 3438, 2958, 173
1,1610,1527,1487,1198,75
7,697

From compound a-5 through compound b-4,
(2S) -3- (4-biphenylyl) -2- [3-
[(2RS) -2-carboxy-3-phenylpropyl] -3-isobutylureido] propionic acid (compound 3) [α] _D ²⁰ -32.3 ° (c = 1.0, chloroform) IR (KBr, cm ^-1 ) 3500 to 3000 (broa
d), 2960, 1727, 1602, 1524, 14
87, 1447, 1201

From compound a-11, (2S) -2-
[3- (2-Carboxyethyl) -3-isobutylureido] -3- [4- (4'-chloro) biphenylyl] propionic acid (compound 12) [α] _D ²⁰ -36.1 ° (c = 0. 34, dimethyl sulfoxide) IR (KBr, cm ^-1 ) 2961, 1717, 160
9,1532,1486,1213,1141,109
4

From compound a-21 through compound b-2, (2S) -2- [3-[(2RS) -2-carboxy-4-phenylbutyl] -3-isobutylureido]
-3- (2-Naphthyl) propionic acid (compound 22) [α] _D ²⁰ -41.4 ° (c = 1.0, chloroform) IR (KBr, cm ⁻¹ ) 3438, 2959, 173
3,1602,1525,1454,1200,74
5,700

From the compound a-23, (2S) -3-
[2- (1-Bromo) naphthyl] -2- [3- (2-carboxyethyl) -3-isobutylureido] propionic acid (compound 25) IR (KBr, cm ^-1 ) 3641, 2958, 172
4,1609,1526,1431,1152,86
2,814,768

From compound a-26 to compound (b-7), (2S) -3- (4-biphenylyl) -2- [3-
[(2RS) -2-carboxy-4- (4-chloro) phenylbutyl] -3-isobutylureido] propionic acid (compound 5) [α] _D ²⁰ -37.7 ° (c = 1.0, chloroform) IR (Film, cm ^-1 ) 3359, 3029, 295
9, 1898, 1723, 1654, 1491, 136
7, 1255, 1148, 1090, 845, 758,
698

Embedded image Reference Example 6 (2S) -2- [3-[(+)-2-benzyloxy-
2-carboxyethyl] -3-isobutylureido]-
3- (4-Biphenylyl) propionic acid (compound 9) and (2S) -2- [3-[(-)-2-benzyloxy-2-carboxyethyl] -3-isobutylureido] -3- (4- Biphenylyl) propionic acid (compound d-1)

Embedded image (2S) -2- [3-[(2RS) -2-benzyloxy-2-benzyloxycarbonylethyl] -3-isobutylureido] -3- (4-biphenylyl) propionic acid benzyl ester (compound a-9, 252 mg) of methanol (1.6 ml) -chloroform (1 ml) mixed with 1N lithium hydroxide (0.8 ml),
Stir for 3 hours. The reaction mixture is neutralized by adding a 10% aqueous citric acid solution, and concentrated under reduced pressure to distill off methanol and chloroform. A 10% aqueous solution of citric acid is added to the resulting solution and extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 69 mg (37%) of the title compound (Compound 9) and 64 mg (34%) of (Compound d-1) as amorphous powders.

(2S) -2- [3-[(+)-2-benzyloxy-2-carboxyethyl] -3-isobutylureido] -3- (4-biphenylyl) propionic acid (compound 9) [α _D ²⁰ -44.6 ° (c = 0.36, chloroform) IR (KBr, cm ⁻¹ ) 2960, 1740, 160
7,1530,1210,1114,759,698

(2S) -2- [3-[(-)-2-benzyloxy-2-carboxyethyl] -3-isobutylureido] -3- (4-biphenylyl) propionic acid (compound d-1) [Α] _D ²⁰ −69.8 ° (c = 0.36, chloroform) IR (KBr, cm ⁻¹ ) 3321, 2960, 173
2,1611,1530,1209,1112,75
8,698

Compound a- was prepared in the same manner as in Reference Example 6.
Compound 22 is obtained from 22.

(2S) -2- [3-[(-)-2-benzyloxy-2-carboxyethyl] -3-isobutylureido] -3- (2-naphthyl) propionic acid (compound 24) [α ^{_{] D 20 -56.0 ° (c =}} 1.0, ^{chloroform) IR (KBr, cm -1)} 3500~3000 (broa
d), 2958, 1736, 1601, 1528, 14
54, 1213, 1113

Reference Example 7 (2S) -2- [3-[(2RS) -2-ethoxycarbonyl-2-hydroxyethyl] -3-isobutylureido] -3-phenylpropionic acid ethyl ester (Compound e-1)

Embedded image Under a nitrogen atmosphere, tetrahydrofuran (4.4 ml) was added to L-phenylalanine ethyl ester hydrochloride (293 mg), 1,1′-carbonyldiimidazole (247 mg) and imidazole (86 mg), and the mixture was added at room temperature for 20 minutes.
Stir for minutes. Add (±) -2-hydroxy-3 to the reaction solution.
A solution of-(N-isobutyl) aminopropionic acid ethyl ester (241 mg) in tetrahydrofuran (2 ml) is added, and the mixture is heated under reflux for 30 minutes and concentrated under reduced pressure. The obtained oil is dissolved in ethyl acetate, and the solution is washed with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was purified by silica gel column chromatography to give the title compound (Compound e-1) 3
78 mg (73%) are obtained.

[Α] _D ²⁰ -15.1 ° (c = 0.4
0, methanol) IR (Film, cm ^-1 ) 3338, 2960, 173
7,1634,1524,1370,1201,75
6,702

Using the same method as in Reference Example 7, the following compound is obtained.

(2S) -2- [3-[(2RS) -2
-Benzyloxycarbonyl-2-hydroxyethyl]
-3-isobutylureido] -3- (4-biphenyl)
Propionic acid benzyl ester (compound e-2) [α] _D ²⁰ -19.0 ° (c = 1.0, methanol) IR (Film, cm ⁻¹ ) 3325, 2959, 174
2,1639,1520,1455,1261,119
0,756,698

(2S) -2- [3-[(2RS) -2
-Benzyloxycarbonyl-2-hydroxyethyl]
-3-Isobutylureido] -3- [4- (4'-fluoro) biphenylyl] propionic acid benzyl ester (compound e-3) [α] _D ²⁰ -19.2 ° (c = 0.36, methanol) IR (Film, cm ^-1 ) 3355, 3033, 295
9,2872,1742,1634,1520,149
8,1214,1111,753,698

(2S) -2- [3-[(2RS) -2
-Benzyloxycarbonyl-2-hydroxyethyl]
-3-isobutylureido] -3- (2-naphthyl) propionic acid benzyl ester (compound e-4) [α] _D ²⁰ -19.4 ° (c = 1.0, methanol) IR (Film, cm ⁻¹⁾ ) 3338,2959,173
8,1634,1520,1190

Reference Example 8 (2S) -3- (4-biphenyl) -2- [3-[(2
RS) -2-carboxy-2-hydroxyethyl] -3
-Isobutylureido] propionic acid (compound 8)

Embedded image Under a nitrogen atmosphere, (2S) -2- [3-[(2RS) -2
-Benzyloxycarbonyl-2-hydroxyethyl]
-3-isobutylureido] -3- (4-biphenyl)
Propionic acid benzyl ester (Compound e-2, 500
mg) in ethanol (16 ml) is sparged with nitrogen for 5 minutes. Add 5% palladium on carbon (50 mg) and stir overnight under a hydrogen atmosphere. The palladium carbon is removed by celite filtration, and the filtrate is concentrated under reduced pressure. The obtained oil is purified by silica gel column chromatography to obtain 252 mg (72%) of the title compound (compound 8) as an amorphous powder.

[Α] _D ²⁰ -2.7 ° (c = 0.48,
Methanol) IR (KBr, cm ^-1 ) 2960, 1737, 160
2,1531,1487,1467,1217,76
2,697

Using the same method as in Reference Example 8, the following compound is obtained.

From the compound e-3, (2S) -2- [3
-[(2RS) -2-carboxy-2-hydroxyethyl] -3-isobutylureido] -3- [4- (4'-
Fluoro) biphenylyl] propionic acid (compound 11) [α] _D ²⁰ −2.5 ° (c = 0.32, methanol) IR (KBr, cm ⁻¹ ) 2960, 1732, 160
3,1531,1498,1226,1159,111
0,1008,819,759

From compound e-4, (2S) -2- [3
-[(2RS) -2-carboxy-2-hydroxyethyl] -3-isobutylureido] -3- (2-naphthyl) propionic acid (compound 23) [α] _D ²⁰ -13.8 ° (c = 0. 45, chloroform) IR (KBr, cm ^-1 ) 2959, 1736, 160
1,1531,1439,1369,1213,746

[Formulation Example] An example of the formulation of the present compound is shown below.

1) Tablet Formulation 1 In 100 mg of the present compound 1 mg Lactose 66.4 mg Maize starch 20 mg Carboxymethylcellulose Calcium 6 mg Hydroxypropylcellulose 4 mg Magnesium stearate 0.6 mg

The tablets of the above formula are coated with 2 mg of a coating agent (eg, a normal coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin) to obtain the desired coated tablet (tablets of the following formula) The same).

Formulation 2 100 mg of the present compound 10 mg lactose 61 mg corn starch 15 mg carboxymethylcellulose calcium 5 mg hydroxypropylcellulose 5 mg magnesium stearate 1 mg talc 1 mg coating agent 2 mg

Formulation 3 In 220 mg of the present compound 100 mg Lactose 67 mg Maize starch 20 mg Carboxymethylcellulose Calcium 10 mg Hydroxypropylcellulose 10 mg Magnesium stearate 4 mg Talc 4 mg Coating agent 5 mg

2) Capsule Formulation 1 150 mg of the present compound in 150 mg Lactose 140 mg

By changing the mixing ratio of the present compound and lactose, a capsule having a component amount of the present compound of 100 mg / capsule can be prepared.

3) Granules Formulation 1 Formulation 1 In 100 mg The present compound 30 mg Mannitol 46.5 mg Polyvinylpyrrolidone K-30 7 mg Eudragit RL 15 mg Triacetin 1.5 mg

4) Injection Formulation 1 In 10 ml of the present compound 10 to 100 mg sodium chloride 90 mg sodium hydroxide qs sterile purified water qs

[0144]

【The invention's effect】

[Pharmacological test] The C-terminal specific antibody recognizing positions 15 to 21 of endothelin-1 and the Fab 'fragment of the N-terminal specific antibody of endothelin-1
A so-called sandwich enzyme immunoassay has been reported in which endothelin-1 is specifically measured by sandwiching the C-terminal side and the N-terminal side with an antibody labeled with oxidase (HRP) (J. Immunol. Methods , 118 , 245-250 (1
989)). Therefore, according to the method described in this document,
The effect of this compound on endothelin converting enzyme was examined.

(Experimental Method) The buffers used in this pharmacological test are shown in Table 1.

[0146]

[Table 1] The preparation of the enzyme preparation and the enzymatic reaction using Big Endothelin-1 as a substrate were reported by Takaoka et al. (Biochem. I
nt., 25, 697-704 (1991)).

Sprague-Dawley rats (weight 280-280)
A 300 g) lung was perfused with physiological saline under thoracotomy and then removed. This was homogenized in 5 volumes of buffer A, and then centrifuged at 4 ° C. for 10 minutes at low speed (600 × g) to obtain a supernatant. The supernatant was centrifuged at 4 ° C. for 30 minutes (105,0
The resulting pellet was suspended in buffer A to give an enzyme preparation.

Next, 350 μl of buffer B, 50 μl of the test compound solution and 5 mg of enzyme preparation (1 mg-protein / ml)
After incubating 0 μl of the mixed solution at 37 ° C. for 30 minutes, a physiological saline solution containing big endothelin-1 (0.1% bovine serum albumin (BSA)) (1 μg / m 2)
l) was added, and the mixed solution was further added at 37 ° C for 3 hours.
Incubated for 0 minutes. This at 100 ° C for 10
After boiling for 1 minute, neutralize with 1N sodium hydroxide
The supernatant was obtained by high-speed centrifugation (8,000 × g) at 5 ° C. for 5 minutes.

The amount of endothelin-1 in the supernatant was
The measurement was carried out by the following sandwich-type enzyme immunoassay using various kinds of antibodies.

[0150]

[Table 2] 100 μl of an antibody for immobilization was previously added to a well, left at 4 ° C. overnight, removed, and then buffer D was added to 200 μl.
Add μl and leave at 4 ° C. overnight to remove.
100 μl of the above supernatant was added to the well, left at 37 ° C. for 1 hour and removed, and then 100 μl of the labeled antibody was added and left at 37 ° C. for 30 minutes to remove. Then, a buffer E solution of o-phenylenediamine (4 mg /
ml) was added and left at room temperature for 20 minutes under light shielding. After adding 100 μl of 1N sulfuric acid, the wavelength 492
The absorbance was measured in nm.

The amount of endothelin-1 produced was calculated from a linear regression line prepared using the absorbance at a wavelength of 492 nm for a known amount of endothelin-1.

The degree of the inhibitory effect of the test compound on endothelin-converting enzyme was determined by the inhibition rate determined by the following formula.

[0153]

(Equation 1) A: Amount of endothelin-1 produced in the absence of test compound B: Amount of endothelin-1 produced in the presence of test compound

(Results) Tables 3 and 4 show examples of the experimental results as follows: (2S) -3- (4-biphenylyl) -2- [3-
(2-carboxyethyl) -3-isobutylureido]
Propionic acid (compound 1), (2S) -3- (4-biphenylyl) -2- [3-
[(2RS) -2-carboxy-4-phenylbutyl]
-3-isobutylureido] propionic acid (compound 4), · (2S) -3- (4-biphenylyl) -2- [3-
[(2RS) -2-carboxy-4- (4-chlorophenyl) butyl] -3-isobutylureido] propionic acid (compound 5), (2S) -3- (4-biphenylyl) -2- [3-
[(2RS) -2-carboxy-6-phenylhexyl) -3-isobutylureido] propionic acid (compound 7), (2S) -3- (4-biphenylyl) -2- [3-
[(2RS) -2-carboxy-2-hydroxyethyl) -3-isobutylureido] propionic acid (compound 8), (2S) -2- [3- (2-carboxyethyl) -3
-Isobutylureido] -3- (1,1 ': 2', 1 "
-Terphenyl-4-yl) propionic acid (compound 1
8), · (2S) -2- [3-[(2RS) -2-carboxy-4-phenylbutyl] -3-isobutylureido]-
3- (2-naphthyl) propionic acid (compound 22), (2S) -2- [3-[(2RS) -2-benzyloxy-2-carboxyethyl) -3-isobutylureido] -3- (2 -Naphthyl) propionic acid (compound 2
4) ・ (2S) -3- [2- (1-bromo) naphthyl] -2
The concentration (IC50) required for inhibiting 50% of the endothelin converting enzyme in 27 compounds such as-[3- (2-carboxyethyl) -3-isobutylureido] propionic acid (compound 25) is shown.

[0155]

[Table 3]

[Table 4] As shown in Tables 3 and 4, this compound was found to significantly inhibit endothelin converting enzyme activity.

As described above, the present compound has an excellent endothelin converting enzyme inhibitory activity, and is an agent for improving a symptom in which endothelin is deeply involved. It is expected to be useful as an agent, a therapeutic agent for asthma such as bronchial asthma, an agent for preventing dysfunction after organ transplantation such as liver transplantation and kidney transplantation, and an agent for suppressing rejection.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁷ Identification symbol FI // C07C275 / 24 C07C275 / 24 (56) References JP-A-8-231492 (JP, A) JP-A-8-208589 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/198 A61K 31/22 A61K 31/223 A61P 43/00 111 C12N 9/99 CA (STN) REGISTRY (STN)

Claims (29)

(57) [Claims] 1. An endothelin converting enzyme inhibitor comprising a compound represented by the following general formula [I] or a salt thereof as an active ingredient. Embedded image [In the formula, R ¹ represents a carboxyl group which may be converted to an ester, an amide or a hydroxamic acid. R
² represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a hydroxy group, a lower alkoxy group or a phenyl lower alkoxy group, wherein the phenyl lower alkyl group and the phenyl ring of the phenyl lower alkoxy group are a halogen atom, a lower alkyl group, It may be substituted with a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group.
R ³ represents a lower alkyl group or a phenyl lower alkyl group, and the phenyl ring of the phenyl lower alkyl group may be substituted with a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group or a lower alkylenedioxy group. R ⁴ represents a carboxyl group which may be converted to an ester, amide or hydroxamic acid. R
⁵ represents a group represented by the following general formula [II], [III] or [IV]. Embedded image Embedded image Embedded image R ⁶ represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group. R ⁷ represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group, a lower alkylamino group, a phenyl group or a naphthyl group; The naphthyl group may be substituted with a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group. R ⁸ represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group. R ⁹ represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group,
A lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group, a lower alkylamino group, a phenyl group or a naphthyl group, wherein the phenyl group and the naphthyl group are a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group; , A lower alkylenedioxy group, a nitro group,
It may be substituted with an amino group or a lower alkylamino group. R ¹⁰ represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group, a lower alkylamino group, a phenyl group or a naphthyl group; The naphthyl group may be substituted with a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group. A represents a lower alkylene group. ] 2. An endothelin converting enzyme inhibitor comprising, as an active ingredient, a compound represented by the following general formula [I] or a salt thereof. Embedded image Wherein R ¹ is a carboxyl group which may be converted to lower alkyl, lower alkanoylamino lower alkyl, phenyl lower alkyl, phenyl or indanyl ester; converted to amide with ammonia, lower alkylamine or phenyl lower alkylamine Or a carboxyl group which may be converted to hydroxamic acid, wherein the phenyl lower alkyl, the phenyl and the phenyl ring of the phenyl lower alkylamine are a halogen atom, a lower alkyl group, a hydroxy group, It may be substituted with a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group. R ² is a hydrogen atom, a lower alkyl group,
A phenyl lower alkyl group, a hydroxy group, a lower alkoxy group or a phenyl lower alkoxy group, wherein the phenyl ring of the phenyl lower alkyl group and the phenyl lower alkoxy group is a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkyl group; Rangeoxy group,
It may be substituted with a nitro group, amino group or lower alkylamino group. R ³ represents a lower alkyl group or a phenyl lower alkyl group, and the phenyl ring of the phenyl lower alkyl group may be substituted with a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group or a lower alkylenedioxy group. R ⁴ is lower alkyl,
Carboxyl group which may be converted to lower alkanoylamino lower alkyl, phenyl lower alkyl, phenyl or indanyl ester; carboxyl group which may be converted to amide with ammonia, lower alkylamine or phenyl lower alkylamine; or hydroxam A carboxyl group which may be converted to an acid, wherein the phenyl lower alkyl, the phenyl and the phenyl ring of the phenyl lower alkylamine are a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, It may be substituted with a nitro group, amino group or lower alkylamino group. R
⁵ represents a group represented by the following general formula [II], [III] or [IV]. Embedded image Embedded image Embedded image R ⁶ represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group. R ⁷ represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group, a lower alkylamino group, a phenyl group or a naphthyl group; The naphthyl group may be substituted with a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group. R ⁸ represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group. R ⁹ represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group,
A lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group, a lower alkylamino group, a phenyl group or a naphthyl group, wherein the phenyl group and the naphthyl group are a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group; , A lower alkylenedioxy group, a nitro group,
It may be substituted with an amino group or a lower alkylamino group. R ¹⁰ represents a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group, a lower alkylamino group, a phenyl group or a naphthyl group; The naphthyl group may be substituted with a halogen atom, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkylenedioxy group, a nitro group, an amino group or a lower alkylamino group. A represents a lower alkylene group. ] 3. An endothelin converting enzyme inhibitor comprising, as an active ingredient, a compound represented by the following general formula [I] or a salt thereof. Embedded image [Wherein, R ¹ represents a carboxyl group. R ² represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a hydroxy group or a phenyl lower alkoxy group, and the phenyl ring of the phenyl lower alkyl group may be substituted with a halogen atom. R ³ represents a lower alkyl group.
R ⁴ represents a carboxyl group. R ⁵ represents a group represented by the following general formula [II], [III] or [IV]. Embedded image Embedded image Embedded image R ⁶ represents a hydrogen atom or a nitro group. R ⁷ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group. R ⁸ represents a hydrogen atom.
R ⁹ represents a hydrogen atom. R ¹⁰ represents a hydrogen atom, a halogen atom or a lower alkoxy group. A represents a lower alkylene group. ] 4. R ¹ and R ⁴ both represent a carboxyl group, and R ² represents a hydrogen atom, isopentyl group, benzyl group, phenethyl group, chlorophenethyl group, phenylpropyl group, phenylbutyl group, hydroxy group or benzyloxy group. , R ³ is an isobutyl group, R ⁵ is a biphenylyl group, a fluorobiphenylyl group, a chlorobiphenylyl group, a methylbiphenylyl group, a methoxybiphenylyl group, a nitrobiphenylyl group, a terphenylyl group, a naphthylphenyl group, a naphthyl group, a bromo group An endothelin converting enzyme inhibitor comprising a compound according to claim 3 or a salt thereof as an active ingredient, wherein the inhibitor represents a naphthyl group or a methoxynaphthyl group, and A represents a methylene group. 5. An endothelin converting enzyme inhibitor comprising, as an active ingredient, a compound represented by the following general formula [I] or a salt thereof. Embedded image [Wherein, R ¹ represents a carboxyl group. R ² represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a hydroxy group or a phenyl lower alkoxy group, and the phenyl ring of the phenyl lower alkyl group may be substituted with a halogen atom. R ³ represents a lower alkyl group.
R ⁴ represents a carboxyl group. R ⁵ represents a group represented by the following general formula [II] or [IV]. Embedded image Embedded image R ⁶ represents a hydrogen atom or a nitro group. R ⁷ represents a hydrogen atom or a phenyl group. R ¹⁰ represents a hydrogen atom or a halogen atom. A represents a lower alkylene group. ] The method according to claim 6 wherein R ¹ and R ⁴ are both a carboxyl group, R ² is a hydrogen atom, an isopentyl group, a phenethyl group, chlorophenethyl group, phenylpropyl group, phenylbutyl group, a hydroxy group or a benzyloxy group, R ³ Represents an isobutyl group, R ⁵ represents a biphenylyl group, a nitrobiphenylyl group, a terphenylyl group, a naphthyl group or a bromonaphthyl group, and A represents a methylene group, and the compound according to claim 5 or a salt thereof as an active ingredient is converted into endothelin. Enzyme inhibitors. 7. An endothelin converting enzyme inhibitor comprising as an active ingredient a compound or a salt thereof according to claim 2, wherein R ⁵ represents a group represented by the following general formula [II], [III] or [IV]. Embedded image Embedded image Embedded image [Wherein, R ⁶ represents a hydrogen atom or a nitro group. R
⁷ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group. R ⁸ represents a hydrogen atom. R ⁹ represents a hydrogen atom. R ¹⁰ represents a hydrogen atom, a halogen atom or a lower alkoxy group. ] 8. R ⁵ is represented by the following general formula [II] or [IV]
An endothelin converting enzyme inhibitor comprising as an active ingredient the compound according to claim 2 or a salt thereof, which represents a group represented by the formula: Embedded image Embedded image R ⁶ represents a hydrogen atom or a nitro group. R ⁷ represents a hydrogen atom or a phenyl group. R ¹⁰ represents a hydrogen atom or a halogen atom. ] 9. The endothelin converting enzyme inhibitor comprising the compound according to claim 2 or a salt thereof as an active ingredient, wherein R ⁵ represents a biphenylyl group, a nitrobiphenylyl group, a terphenylyl group, a naphthyl group or a bromonaphthyl group. 10. An endothelin converting enzyme inhibitor comprising the compound according to claim 2, wherein R ³ represents a lower alkyl group, or a salt thereof as an active ingredient. 11. The method according to claim 2, wherein R ³ represents an isobutyl group.
An endothelin converting enzyme inhibitor comprising the compound or a salt thereof as an active ingredient. 12. R ² is a hydrogen atom, a lower alkyl group,
An endothelin converting enzyme comprising a compound or a salt thereof as an active ingredient, wherein the compound or a salt thereof is a phenyl lower alkyl group, a hydroxy group or a phenyl lower alkoxy group, wherein the phenyl ring of the phenyl lower alkyl group may be substituted with a halogen atom. Inhibitors. 13. R ² is a hydrogen atom, an isopentyl group,
An endothelin converting enzyme inhibitor comprising as an active ingredient the compound according to claim 2, which represents a phenethyl group, a chlorophenethyl group, a phenylpropyl group, a phenylbutyl group, a hydroxy group or a benzyloxy group. 14. An endothelin converting enzyme inhibitor comprising, as an active ingredient, the compound according to claim 2, wherein R ¹ and R ⁴ both represent a carboxyl group. 15. R ³ represents a lower alkyl group;
3. An endothelin converting enzyme inhibitor comprising the compound according to claim 2 or a salt thereof as an active ingredient, wherein ⁵ represents a group represented by the following general formula [II], [III] or [IV]. Embedded image Embedded image Embedded image [Wherein, R ⁶ represents a hydrogen atom or a nitro group. R
⁷ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group. R ⁸ represents a hydrogen atom. R ⁹ represents a hydrogen atom. R ¹⁰ represents a hydrogen atom, a halogen atom or a lower alkoxy group. ] 16. R ³ represents a lower alkyl group;
3. An endothelin converting enzyme inhibitor comprising the compound according to claim 2 or a salt thereof as an active ingredient, wherein ⁵ represents a group represented by the following general formula [II] or [IV]. Embedded image Embedded image [Wherein, R ⁶ represents a hydrogen atom or a nitro group. R
⁷ represents a hydrogen atom or a phenyl group. R ¹⁰ represents a hydrogen atom or a halogen atom. ] 17. The method according to claim 2, wherein R ³ represents an isobutyl group, and R ⁵ represents a biphenylyl group, a nitrobiphenylyl group, a terphenylyl group, a naphthyl group or a bromonaphthyl group.
An endothelin converting enzyme inhibitor comprising the compound or a salt thereof as an active ingredient. 18. R ² is a hydrogen atom, a lower alkyl group,
A phenyl lower alkyl group, a hydroxy group or a phenyl lower alkoxy group, wherein the phenyl ring of the phenyl lower alkyl group may be substituted with a halogen atom;
³ represents a lower alkyl group, and R ⁵ represents the following general formula [I
An endothelin converting enzyme inhibitor comprising as an active ingredient the compound according to claim 2, which represents a group represented by [I], [III] or [IV]. Embedded image Embedded image Embedded image [Wherein, R ⁶ represents a hydrogen atom or a nitro group. R
⁷ represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group or a phenyl group. R ⁸ represents a hydrogen atom. R ⁹ represents a hydrogen atom. R ¹⁰ represents a hydrogen atom, a halogen atom or a lower alkoxy group. ] (19) R ² is a hydrogen atom, a lower alkyl group,
A phenyl lower alkyl group, a hydroxy group or a phenyl lower alkoxy group, wherein the phenyl ring of the phenyl lower alkyl group may be substituted with a halogen atom;
³ represents a lower alkyl group, and R ⁵ represents the following general formula [I
An endothelin converting enzyme inhibitor comprising the compound according to claim 2 or a salt thereof, which represents a group represented by I] or [IV]. Embedded image Embedded image [Wherein, R ⁶ represents a hydrogen atom or a nitro group. R
⁷ represents a hydrogen atom or a phenyl group. R ¹⁰ represents a hydrogen atom or a halogen atom. ] 20. R ² is a hydrogen atom, an isopentyl group,
Phenethyl group, chlorophenethyl group, phenylpropyl group, phenylbutyl group, hydroxy group or benzyloxy group, R ³ is isobutyl group, R ⁴ is biphenylyl group, nitrobiphenylyl group, terphenylyl group, naphthyl group or bromonaphthyl group And the compound of claim 2 wherein A represents a methylene group or a salt thereof as an active ingredient. 21. (2S) -3- (4-biphenylyl)
An endothelin converting enzyme inhibitor comprising, as an active ingredient, -2- [3- (2-carboxyethyl) -3-isobutylureido] propionic acid or a salt thereof. 22. (2S) -3- (4-biphenylyl)
-2- [3- (2-carboxy-4-phenylbutyl)
-3-isobutylureido] an endothelin converting enzyme inhibitor comprising propionic acid or a salt thereof as an active ingredient. 23. (2S) -3- (4-biphenylyl)
An endothelin converting enzyme inhibitor comprising, as an active ingredient, 2- [3- [2-carboxy-4- (4-chlorophenyl) butyl] -3-isobutylureido] propionic acid or a salt thereof. 24. (2S) -3- (4-biphenylyl)
An endothelin converting enzyme inhibitor comprising, as an active ingredient, 2- [3- (2-carboxy-6-phenylhexyl) -3-isobutylureido] propionic acid or a salt thereof. 25. (2S) -3- (4-biphenylyl)
An endothelin converting enzyme inhibitor comprising, as an active ingredient, 2- [3- (2-carboxy-2-hydroxyethyl) -3-isobutylureido] propionic acid or a salt thereof. 26. (2S) -2- [3- (2-carboxyethyl) -3-isobutylureido] -3- (1,
1 ': 2', 1 "-terphenyl-4-yl) an endothelin converting enzyme inhibitor containing propionic acid or a salt thereof as an active ingredient. 27. (2S) -2- [3- (2-carboxy-4-phenylbutyl) -3-isobutylureido]
An endothelin converting enzyme inhibitor comprising, as an active ingredient, -3- (2-naphthyl) propionic acid or a salt thereof. 28. An endothelin comprising (2S) -2- [3- (2-benzyloxy-2-carboxyethyl) -3-isobutylureido] -3- (2-naphthyl) propionic acid or a salt thereof as an active ingredient. Converting enzyme inhibitors. 29. (2S) -3- [2- (1-bromo)
Naphthyl] -2- [3- (2-carboxyethyl) -3
-Isobutylureide] An endothelin converting enzyme inhibitor comprising propionic acid or a salt thereof as an active ingredient.