JPH0912455A - Endothelin converting enzyme inhibitor - Google Patents

Abstract

(57) [Summary] (Modified) [Structure] [R ¹ is ester, amide, carboxyl group, R ² is hydrogen atom, lower alkyl group, phenyl lower alkyl group, hydroxy group, lower alkoxy group, phenyl lower alkoxy group, R ³ is lower alkyl group, phenyl lower alkyl group, R ⁴ is an ester, amide or carboxyl group, R ⁵ is a group represented by the general formula II, III or IV, A represents a lower alkylene group. ] The endothelin converting enzyme inhibitor which consists of a compound and its salt. [Effect] It has an excellent endothelin converting enzyme inhibitory activity and is an agent for improving endothelin-related symptoms, particularly an agent for improving cerebral blood flow that suppresses cerebral vasospasm causing cerebral infarction, a therapeutic agent for asthma such as bronchial asthma, and liver transplantation. It is expected to be useful as an agent for preventing dysfunction and an inhibitory agent for rejection after organ transplant such as kidney transplant and kidney transplant.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an endothelin converting enzyme inhibitor containing a 1,3-di (carboxyalkyl) urea derivative as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Endothelin is a peptide consisting of 21 residues of amino acid, which is secreted from vascular endothelium and has a strong and persistent vascular smooth muscle contracting action and tracheal smooth muscle contracting action. From the study of endothelin-encoding genes, the mechanism of endothelin biosynthesis was presumed to be a mechanism of biosynthesis of endothelin from amino acid 212 residue preproendothelin through almost inactive amino acid 38 residue big 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 convert it into endothelin (Biochem. Biophys. Res. Commun., 171, 669).
-675 (1990), Biochem. Biophys. Res. Commun., 171,
1192-1198 (1990)).

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

Examples of 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 a dipeptide is introduced. Acid amide derivative (JP-A-4-
327592, JP-A-5-105698,
JP-A-5-148277), an acyltryptophan derivative (JP-A-5-39266), and aspergillomarasmin 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 compound having a urea skeleton in the molecule has been reported.

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

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

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

On the other hand, the structural characteristics of the compound which is the active ingredient of the present invention are that a carboxyl group is introduced into both ends of the alkylene chain of 1,3-dialkylurea, and further a biphenylyl group or a naphthyl group is introduced into the alkylene chain. As described above, the group in the state where a plurality of aromatic hydrocarbons are bonded or condensed is substituted, but the conventional technique will be described below from the viewpoint of the chemical structure.

A compound in which a carboxyl group is introduced at the end of one alkylene chain of a 1,3-dialkylurea derivative has angiotensin II antagonistic activity (JP-A-6-72985 and JP-A-6-184086). ), And a compound in which a carboxyl group is introduced into the terminals of both alkylene chains suppresses angiotensin converting enzyme (JP-A-58-55451). In addition, the amino acid derivative having a urea structure inhibits the activity of enkephalinase (Patent Publication 3
-79339 report) has been reported. However, nothing is disclosed about the endothelin converting enzyme inhibitory effect which is the object of the present invention.

[0010]

It was a very interesting subject 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 As a result of searching for compounds that inhibit endothelin converting enzyme, the present inventors found that
A compound in which a group in which a plurality of aromatic hydrocarbons are bound 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 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 that suppress cerebral vasospasm causing cerebral infarction, therapeutic agents for asthma such as bronchial asthma, and organs such as liver transplant and kidney transplant. It is expected to be useful as an agent for preventing dysfunction after transplantation and an agent for suppressing rejection.

[0012]

DISCLOSURE OF THE INVENTION The present invention relates to an endothelin converting enzyme inhibitor containing 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, 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, and a phenyl ring of the phenyl lower alkyl group and the phenyl lower alkoxy group is 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, and 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 into 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 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. The group and 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 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 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. same as below. ].

The above groups defining this compound are described in detail below.

Halogen atom means fluorine, chlorine, bromine,
Shows iodine. The lower alkyl refers to a 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. . The lower alkoxy refers to a linear or branched alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexyloxy, isopropoxy, tert.-butoxy. Lower alkylene is methylene, ethylene, trimethylene, hexamethylene, propylene, (ethyl) methylene, (dimethyl)
A linear or branched alkylene having 1 to 6 carbon atoms such as methylene is shown, and lower alkylenedioxy is
Alkylenedioxy having straight or branched alkylene having 1 to 6 carbon atoms between two oxygen atoms such as methylenedioxy, ethylenedioxy, propylenedioxy, (diethyl) methylenedioxy Indicates.

The ester is a lower alkyl ester such as methyl ester, ethyl ester, isopropyl ester, butyl ester or hexyl ester, lower alkanoyl such as acetylaminomethyl ester, acetylaminoethyl ester, propionylaminomethyl ester or propionylaminoethyl ester. The commonly used carboxylic acid esters such as phenyl lower alkyl ester such as amino lower alkyl ester and benzyl ester, phenyl ester, methoxyphenyl ester and indanyl ester are shown. The lower alkanoyl refers to a straight or branched alkanoyl having 2 to 6 carbon atoms such as acetyl, propionyl, butyryl, valeryl, isobutyryl, isovaleryl, pivaloyl and the like. Amides include 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 salt in the present compound is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include salts with alkali metals or alkaline earth metals such as sodium, potassium and calcium, ammonium salts, organic salts such as diethylamine and triethanolamine. Examples thereof include salts with amines and salts with inorganic acids such as hydrochloric acid, nitric acid and sulfuric acid.

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

Among the present compounds, preferred examples include the following. a) a carboxyl group in which R ¹ is lower alkyl, lower alkanoylamino lower alkyl, phenyl lower alkyl, phenyl or indanyl ester in the general formula [I]; ammonia, lower alkylamine or phenyl lower alkylamine And a carboxyl group which may be converted to an amide; or a carboxyl group which may be converted to a hydroxamic acid, wherein the phenyl lower alkyl, the phenyl and the phenyl ring of the phenyl lower alkylamine are halogen atoms,
It may be substituted with 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 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 is shown, and the phenyl ring of the phenyl lower alkyl group and the phenyl lower alkoxy group is a halogen atom,
It may be substituted with 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,
It may be substituted with a lower alkyl group, a hydroxy group, a lower alkoxy group or a lower alkylenedioxy group,
A carboxyl group in which R ⁴ is lower alkyl, lower alkanoylamino lower alkyl, phenyl lower alkyl, phenyl or an indanyl ester;
A carboxyl group which may be converted to an amide with ammonia, a lower alkylamine or a phenyl lower alkylamine; or a carboxyl group which may be converted to a hydroxamic acid, wherein the phenyl lower alkyl is
The phenyl ring of the phenyl and 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 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, especially a benzyl group, a phenethyl group, a phenylpropyl group, a phenylbutyl group; a hydroxy group; or a phenyl lower alkoxy group, especially a benzyloxy group, wherein the phenyl ring of the phenyl lower alkyl group is It may be substituted with a halogen atom, especially a chlorine atom, R ³ represents a lower alkyl group, especially an isobutyl group, A represents a lower alkylene group, especially a methylene group, and R ⁵ represents a compound represented by the following general formulas [II] and [III]
Or a compound having a group represented by [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; a halogen atom, especially a bromine atom, a chlorine atom; a lower alkyl group, especially a methyl group; a lower alkoxy group, especially a methoxy 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, 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, 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, especially a chlorine atom, and R ³ is a lower alkyl group, especially an isobutyl group. A compound in which A represents a lower alkylene group, especially a methylene group, and R ⁵ represents a group represented by the following general formula [II] or [IV] is preferable.

[0035]

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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.

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

Embedded image

Embedded image

Embedded image [In the formula, 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, and R ¹⁰ represents a hydrogen atom, a halogen atom or a lower alkoxy group. ], 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].

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. ], R ² represents a hydrogen atom, a lower alkyl group, a phenyl lower alkyl group, a hydroxy group or a phenyl lower alkoxy group, the phenyl ring of the phenyl lower alkyl group may be substituted with a halogen atom, and R ³ is a lower group. An alkyl group, R ⁵
Is a compound represented by the following general formula [II], [III] or [IV]

Embedded image

Embedded image

Embedded image [In the formula, 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. R ² represents a hydrogen atom; a lower alkyl group, especially an isopentyl group; a phenyl lower alkyl group, especially a phenethyl group, a phenylpropyl group, a phenylbutyl group; a hydroxy group; or a phenyl lower alkoxy group, especially a benzyloxy group, The phenyl ring of the alkyl group may be substituted with a halogen atom, especially a chlorine atom, R ³ represents a lower alkyl group, especially an isobutyl group, and R ⁵ represents a group represented by the following general formula [II] or [IV]. Compound shown

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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. ] Is particularly preferable.

As an example of a compound having a particularly excellent action among the present compounds, (2S) -3- (4-biphenylyl)
-2- [3- (2-carboxyethyl) -3-isobutylureido] propionic acid (the 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 (the following formula [VII]), (2S)
-3- (4-biphenylyl) -2- [3- (2-carboxy-6-phenylhexyl) -3-isobutylureido] propionic acid (the following formula [VIII]), (2S) -3-
(4-biphenylyl) -2- [3- (2-carboxy-
2-Hydroxyethyl) -3-isobutylureido] propionic acid (the following formula [IX]), (2S) -2- [3-
(2-Carboxyethyl) -3-isobutylureido]
-3- (1,1 ': 2', 1 "-terphenyl-4-yl) propionic acid (the following formula [X]) (2S) -2- [3- (2-carboxy-4-phenylbutyl) -3-isobutylureido] -3- (2-naphthyl) propionic acid (the following formula [XI]), (2S) -2-
[3- (2-benzyloxy-2-carboxyethyl)
-3-isobutylureido] -3- (2-naphthyl) propionic acid (the following formula [XII]), (2S) -3- [2-
(1-Bromo) naphthyl] -2- [3- (2-carboxyethyl) -3-isobutylureido] propionic acid (formula [XIII] below), and salts thereof as well as a single diastereoisomer, optical isomerism The body.

[0040]

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

A representative synthetic method of this compound is shown below.

[0042]

Embedded image This method starts with a compound represented by the general formula [XIV]
1'-Carbonyldiimidazole is reacted in the presence of a base such as imidazole to give a compound of the general formula [XV], which is then reacted with a compound of the general formula [XVI] to form a urea, [I]) is obtained. A part of the compound represented by the general formula [XIV] is obtained by the method reported by Shieh et al. (J. Org. Chem., 57, 379-381 (1992).
), Or from the method reported by Evans et al. (J. Am. Chem. Soc., 109 , 6881-6883 (198).
7)) can be used to synthesize via the azide form.

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

If necessary, a carboxyl group can be converted into an ester or amide and a phosphoryl group can be converted into an ester by 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.

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

The endothelin converting enzyme is an enzyme which is widely distributed in each tissue in the body and is essential for the production of endothelin which is involved in various biological functions. Already, in animal models, compounds that inhibit endothelin converting enzyme suppress 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)), and that endothelin receptor antagonists suppress acute renal failure due to tissue incompatibility after liver transplantation (transplantation, 28 , 261).
(1993)) has been confirmed. In the blood of chronic maintenance dialysis patients and patients with rejection after renal transplantation (Japanese Journal of Urology, 85 , 1622-1628 (1993)), in asthma patients (Jikeikai Med. J., 41 , 91-98 (1994)) and in alveolar lavage fluid at the time of attack (J. Allergy Clin. Immunol., 88,
376-384 (1991)), further, 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)), patients with pulmonary hypertension (Circulation, 85, 504-509 (199
2)), Acute renal failure due to ureteral atresia (N. Engl. J.
Med., 321, 1127 (1989)), Diabetics (Diabetelogi
a, 33 , 306-310 (1990)) has been reported to have high endothelin-1 concentration in blood.

Several compounds have been reported as compounds that inhibit endothelin converting enzyme, but all are compounds having two or more amino acid residues, and no compound having a urea skeleton in the molecule has been reported. .

Therefore, the present inventors searched for a compound that inhibits endothelin converting enzyme, and detailed data will be described in the section of the effect of the invention. As a result of examination by a sandwich type enzyme immunoassay, It was confirmed that this compound inhibits endothelin converting enzyme. From this fact, an agent for improving the condition deeply involved in endothelin, particularly an agent for improving cerebral blood flow that suppresses cerebral vasospasm that causes cerebral infarction, a therapeutic agent for asthma such as bronchial asthma, and an organ transplant such as liver transplant and kidney transplant. It is expected that the present compound will be useful as a subsequent dysfunction preventive agent or a rejection inhibitor.

The compound is endopeptidase 24., which is known to be involved in cardiovascular diseases such as heart failure and hypertension, renal diseases, gastrointestinal disorders, pain, endocrine / metabolic diseases and autoimmune diseases. 11 has been studied (Japanese Patent Application No. 6-270957).
No. 6-310493).

The 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 agents such as powders, lactose, crystalline cellulose, fillers such as starch, magnesium stearate, lubricants such as talc, binders such as hydroxypropylcellulose polyvinylpyrrolidone, If necessary, a disintegrating agent such as carboxymethylcellulose calcium and low-substituted hydroxypropylmethylcellulose, a coating agent such as hydroxypropylmethylcellulose, macrogol, and a silicone resin may be added.

The dose of the compound of the present invention depends on the symptoms,
It may be appropriately selected depending on the age, dosage form, etc., but 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.

Formulation examples of the present compound are shown below, but these examples are for better understanding of the present invention.
It does not limit the scope of the invention.

[0054]

【Example】

[Production Example] Production examples of the present compound (Compounds 1-27) will be given.

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 (529m
Tetrahydrofuran (14 ml) is added to g) and imidazole (185 mg), and the mixture is 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 allowing to cool, 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 oily substance is purified by silica gel column chromatography to obtain 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

By using the same method as in Reference Example 1, the following compounds are obtained.

(2S) -3- (4-biphenylyl)-
2- [3- (2-tert.-butoxycarbonylethyl)-
3-isobutyl ureido] 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-isobutylureido]
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-benzyloxycarbonylamino ethyl] -3-isobutyl ureido] -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) biphenyl] 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
2,1644,1514,1455,1386,117
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-benzyloxycarbonylamino ethyl] -3-isobutyl ureido] -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-
4.0 N hydrochloric acid / dioxane (35 m
1) is added and the mixture is stirred at room temperature for 3 hours and 30 minutes. The reaction solution was concentrated under reduced pressure, and the resulting 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 compounds are obtained.

[0086]

Compound (a-21) to (2S) -2-
[3 - [(2RS) -2- carboxy-4-phenylbutyl] -3-isobutyl ureido] -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

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

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

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

Compound (a-8) to (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 (2S) -2- [3- (2-benzyloxycarbonylethyl) -3-isobutylureido] -under a nitrogen atmosphere.
3- (4-Biphenylyl) propionic acid benzyl ester (Compound a-3, 270 mg) in methanol (5 m
l) To the solution, 5% palladium-on activated carbon (50 mg) is added and stirred under a hydrogen atmosphere for 1 hour 30 minutes. The palladium-on activated carbon is removed by Celite filtration, and the filtrate is concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography to obtain 90 mg (48.4) of the title compound (Compound 1).
%).

Mp 131 to 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

By using the same method as in Reference Example 3, the following compounds are obtained.

Compound (a-6) to (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 to 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, dimethylsulfoxide) 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, 2960, 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-isobutyl ureido] -3- [4- (1-naphthyl) phenyl] propionic acid (Compound 20) mp 182.0 ° C. (decomposition) [alpha] _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 (2S) -2- [3- (2-Ethoxycarbonylethyl) -3-isobutylureido] -3- under a nitrogen atmosphere.
To a solution of (2-naphthyl) propionic acid benzyl ester (Compound a-23, 687 mg) in ethanol (14 ml) was added 20% palladium hydroxide on carbon (70 m).
g) is added, and the mixture is stirred under a hydrogen atmosphere for 4 hours and 30 minutes. Palladium hydroxide on carbon is removed by Celite filtration, and the filtrate is concentrated under reduced pressure. The obtained oily substance is purified by silica gel column chromatography to give the title compound (Compound c-1).
401 mg (71.1%) are obtained.

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

Compound a-was prepared in the same manner as in Reference Example 4.
Compound 24 is obtained from 24.・ (2S) -2- [3
- (2-carboxyethyl) -3-isobutyl ureido] -3- [2- (6-methoxy) naphthyl] propionic acid (Compound 26) mp 100~127 ℃ [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
4.4 ml) solution, 1N lithium hydroxide (1.44 m
l) is added and stirred for 2 hours. The reaction solution is neutralized by adding 1N hydrochloric acid, and then concentrated under reduced pressure to remove ethanol.
A 10% aqueous citric acid solution is added to the resulting solution, and the mixture is extracted with chloroform. The organic layer is washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting oily substance 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

By using the same method as in Reference Example 5, the following compounds are 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 to 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-isobutyl ureido] 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 to compound b-4,
(2S) -3- (4-biphenylyl) -2- [3-
[(2RS)-2-carboxy-3-phenylpropyl] -3-isobutyl ureido] propionic acid (Compound ^{_{3) [α] D 20 -32.3}} ° (c = 1.0, chloroform) IR (KBr, cm ^-1 ) 3500-3000 (broa
d), 2960, 1727, 1602, 1524, 14
87,1447,1201

Compound (a-11) to (2S) -2-
[3- (2-carboxyethyl) -3-isobutyl ureido] -3- [4- (4'-chloro) biphenylyl] propionate (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

Compound (a-21) to compound (b-2) to (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 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

Compound (a) -26 to compound (b-7) to (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, To a mixed solution of 252 mg) of methanol (1.6 ml) -chloroform (1 ml), 1N lithium hydroxide (0.8 ml) was added,
Stir for 3 hours. A 10% aqueous citric acid solution is added to the reaction solution to make it neutral, and then concentrated under reduced pressure to remove methanol and chloroform. To the resulting solution is added 10% aqueous citric acid solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting oily matter 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.
22 gives compound 24.

(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 to 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 allowed to stand at room temperature for 20 minutes.
Stir for minutes. In the reaction solution, (±) -2-hydroxy-3
A solution of-(N-isobutyl) aminopropionic acid ethyl ester (241 mg) in tetrahydrofuran (2 ml) is added, the mixture is heated under reflux for 30 minutes, and the reaction mixture is concentrated under reduced pressure. The obtained oily substance is dissolved in ethyl acetate, this solution is washed with water and then with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oily substance 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

By the same method as in Reference Example 7, the following compounds are 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-isobutyl ureido] -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-isobutyl ureido] -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
Nitrogen is bubbled through a solution of (mg) in ethanol (16 ml) for 5 minutes. Add 5% palladium on carbon (50 mg) and stir overnight under a hydrogen atmosphere. Palladium carbon is removed by Celite filtration, and the filtrate is concentrated under reduced pressure. The obtained oily substance 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

By the same method as in Reference Example 8, the following compounds are obtained.

From 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-isobutyl ureido] -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 This compound 1 mg Lactose 66.4 mg Corn starch 20 mg Carboxymethylcellulose calcium 6 mg Hydroxypropylcellulose 4 mg Magnesium stearate 0.6 mg

A tablet having the above-mentioned formulation is coated with 2 mg of a coating agent (eg, ordinary coating agent such as hydroxypropylmethylcellulose, macrogol, silicone resin) to obtain a target coated tablet (tablet having the following formulation The same).

Formulation 2 In 100 mg The present compound 10 mg Lactose 61 mg Corn starch 15 mg Carboxymethyl cellulose calcium 5 mg Hydroxypropyl cellulose 5 mg Magnesium stearate 1 mg Talc 1 mg Coating agent 2 mg

Formulation 3 In 220 mg The present compound 100 mg Lactose 67 mg Corn 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 In 150 mg This compound 10 mg Lactose 140 mg

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

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

4) Injectable Formulation 1 In 10 ml This compound 10-100 mg Sodium chloride 90 mg Sodium hydroxide Appropriate amount Sterile purified water Appropriate amount

[0144]

【The invention's effect】

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

(Experimental method) Table 1 shows the buffer solutions used in this pharmacological test.

[0146]

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

Sprague-Dawley rats (weight 280-280)
The lungs (300 g) were perfused with physiological saline under thoracotomy and then excised. This was homogenized in a 5-fold amount of buffer A and then centrifuged at 4 ° C. for 10 minutes at low speed (600 × g) to obtain a supernatant. The supernatant was ultracentrifuged at 4 ° C for 30 minutes (105,0
The enzyme preparation was obtained by suspending the pellet obtained by (00 × g) in buffer solution A.

Next, 350 μl of buffer solution B, 50 μl of test compound solution and enzyme preparation (1 mg-protein / ml) 5
After incubating 0 μl of the mixed solution at 37 ° C. for 30 minutes, a physiological saline solution containing 1% bovine serum albumin (BSA) of big endothelin-1 (1 μg / m 2
l) 50 μl was added, and the mixed solution was further added at 37 ° C.
Incubated for 0 minutes. 10 at 100 ℃
After boiling for 1 minute, neutralize with 1N sodium hydroxide, 4
The supernatant was obtained by high-speed centrifugation (8,000 xg) at 5 ° C for 5 minutes.

The amount of endothelin-1 in the supernatant was determined as 2 in Table 2.
It measured by the following sandwich type enzyme immunoassay using the antibody of the kind.

[0150]

[Table 2] In advance, 100 μl of the antibody for immobilization was added to the well, left overnight at 4 ° C., and 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-mentioned supernatant was added to this well, left at 37 ° C. for 1 hour and then removed, then 100 μl of labeled antibody was added, and further left at 37 ° C. for 30 minutes to remove. Then, a buffer E solution of o-phenylenediamine (4 mg /
(100 ml) was added, and the mixture was allowed to stand at room temperature for 20 minutes in the dark. After adding 100 μl of 1N sulfuric acid, the wavelength is 492.
Absorbance was measured at nm.

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

As the degree of inhibitory action of the test compound on endothelin converting enzyme, the inhibition rate obtained from the following formula was used.

[0153]

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

(Results) Tables 3 and 4 show an example of the experimental results: (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 50% inhibition of 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 the endothelin converting enzyme activity.

From the above, the present compound has an excellent endothelin converting enzyme inhibitory activity, and is an agent for improving the condition in which endothelin is deeply involved, particularly improving cerebral blood flow suppressing cerebral vasospasm causing cerebral infarction and the like. It is expected to be useful as an agent, a therapeutic agent for asthma such as bronchial asthma, and a dysfunction preventive agent or rejection inhibitor after organ transplantation such as liver transplantation and kidney transplantation.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location // C07C 275/24 9451-4H C07C 275/24

Claims (38)

[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 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 lower alkyl group and the phenyl ring of the phenyl lower alkoxy group are halogen atom, lower alkyl group, hydroxy group, lower alkoxy group, lower alkylenedioxy group, nitro It may be substituted with a 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 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, and the phenyl group and the The naphthyl group is 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 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, and the phenyl group and the 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 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, and the phenyl group and the The naphthyl group is 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, an amino group or a lower alkylamino group. A represents a lower alkylene group. ] 2. An endothelin converting enzyme inhibitor containing a compound represented by the following general formula [I] or a salt thereof as an active ingredient. Embedded image [Wherein R ¹ is a lower alkyl, a lower alkanoylamino lower alkyl, a phenyl lower alkyl, a phenyl group which may be converted to a phenyl or indanyl ester; a amide with ammonia, a lower alkylamine or a 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 have 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 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, and the phenyl lower alkyl group and the phenyl ring of the phenyl lower alkoxy group have a halogen atom or 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 is lower alkyl,
Lower alkanoylamino lower alkyl, phenyl lower alkyl, carboxyl group which may be converted to phenyl or indanyl ester; carboxyl group which may be converted to amide with ammonia, lower alkylamine or phenyl lower alkylamine; or hydroxam Represents a carboxyl group which may be converted to an acid, and 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, It may be substituted with a nitro group, an amino group or a lower alkylamino group. R
⁵ represents a group represented by the following general formula [II], [III] or [IV]. [Chemical 6] 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, and the phenyl group and the The naphthyl group is 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 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, and the phenyl group and the 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 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, and the phenyl group and the The naphthyl group is 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, an amino group or a lower alkylamino group. A represents a lower alkylene group. ] 3. An endothelin converting enzyme inhibitor containing 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. 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
Indicates a carboxyl group. R ⁵ is the following general formula [II],
A group represented by [III] or [IV] is shown. 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 are both carboxyl groups, and R ² is 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,
The compound or a salt thereof according to claim 3, which represents a methylbiphenylyl group, a methoxybiphenylyl group, a nitrobiphenylyl group, a terphenylyl group, a naphthylphenyl group, a naphthyl group, a bromonaphthyl group or a methoxynaphthyl group, and A represents a methylene group. An endothelin-converting enzyme inhibitor containing as an active ingredient. 5. An endothelin converting enzyme inhibitor containing 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. 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
Indicates 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. ] 6. R ¹ and R ⁴ are both a carboxyl group, R ² is a hydrogen atom, an isopentyl group, a phenethyl group,
A chlorophenethyl group, a phenylpropyl group, a phenylbutyl group, a hydroxy group or a benzyloxy group is replaced with R ³
Is an isobutyl group, R ⁵ is a biphenylyl group, a nitrobiphenylyl group, a terphenylyl group, a naphthyl group or a bromonaphthyl group, and A is a methylene group, and the endothelin conversion using the compound or a salt thereof as an active ingredient. Enzyme inhibitors. 7. An endothelin converting enzyme inhibitor comprising the compound according to claim 2 or a salt thereof as an active ingredient, wherein R ⁵ represents a group represented by the following general formula [II], [III] or [IV]. Embedded image Embedded image Embedded image [In the formula, 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. An endothelin converting enzyme inhibitor comprising the compound according to claim 2 or a salt thereof as an active ingredient, wherein 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. ] 9. An 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. A compound according to claim 2, wherein R ³ represents a lower alkyl group.
An endothelin converting enzyme inhibitor containing the described compound or a salt thereof as an active ingredient. 11. An endothelin converting enzyme inhibitor containing the compound according to claim 2 or a salt thereof, wherein R ³ represents an isobutyl group, as an active ingredient. 12. 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. An endothelin converting enzyme inhibitor comprising the compound according to 2 or a salt thereof as an active ingredient. 13. The compound according to claim 2 or a salt thereof as an active ingredient, wherein R ² represents a hydrogen atom, an isopentyl group, a phenethyl group, a chlorophenethyl group, a phenylpropyl group, a phenylbutyl group, a hydroxy group or a benzyloxy group. Endothelin-converting enzyme inhibitor. 14. An endothelin converting enzyme inhibitor containing the compound according to claim 2 or a salt thereof as an active ingredient, wherein both R ¹ and R ⁴ represent a carboxyl group. 15. R ³ is a lower alkyl group, R ⁵ is represented by the following general formula [II], [III] or compound or active ingredient a salt thereof according to claim 2, wherein a group represented by the [IV] And an endothelin converting enzyme inhibitor. Embedded image Embedded image Embedded image [In the formula, 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. An endothelin conversion using the compound according to claim 2 or a salt thereof as an active ingredient, wherein R ³ represents a lower alkyl group and R ⁵ represents a group represented by the following general formula [II] or [IV]. Enzyme inhibitors. 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. R ¹⁰ represents a hydrogen atom or a halogen atom. ] 17. R ³ is an isobutyl group, R ⁵ is a biphenylyl group, a nitrobiphenylyl group, a terphenylyl group,
An endothelin converting enzyme inhibitor comprising the compound according to claim 2 or a salt thereof having a naphthyl group or a bromonaphthyl group as an active ingredient. 18. 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. ³
Represents a lower alkyl group, and R ⁵ represents the following general formula [II],
An endothelin converting enzyme inhibitor comprising the compound according to claim 2 or a salt thereof, which represents a group represented by [III] or [IV], as an active ingredient. Embedded image Embedded image Embedded image [In the formula, 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 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. ³
Is a lower alkyl group, and R ⁵ is a group represented by the following general formula [II] or [IV], wherein the endothelin converting enzyme inhibitor comprises the compound or a salt thereof as an active ingredient. 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. R ¹⁰ represents a hydrogen atom or a halogen atom. ] 20. R ² is a hydrogen atom, isopentyl group, phenethyl group, chlorophenethyl group, phenylpropyl group, phenylbutyl group, hydroxy group or benzyloxy group, R ³ is an isobutyl group, R ⁴ is a biphenylyl group, An endothelin-converting enzyme inhibitor containing the compound or a salt thereof according to claim 2, which represents a nitrobiphenylyl group, a terphenylyl group, a naphthyl group or a bromonaphthyl group, and A represents a methylene group. 21. (2S) -3- (4-biphenylyl)
An endothelin converting enzyme inhibitor containing -2- [3- (2-carboxyethyl) -3-isobutylureido] propionic acid or a salt thereof as an active ingredient. 22. (2S) -3- (4-biphenylyl)
-2- [3- (2-carboxy-4-phenylbutyl)
-3-Isobutylureido] propionic acid or salts thereof as an active ingredient, an endothelin converting enzyme inhibitor. 23. (2S) -3- (4-biphenylyl)
An endothelin converting enzyme inhibitor containing 2- [3- [2-carboxy-4- (4-chlorophenyl) butyl] -3-isobutylureido] propionic acid or a salt thereof as an active ingredient. 24. (2S) -3- (4-biphenylyl)
An endothelin-converting enzyme inhibitor containing 2- [3- (2-carboxy-6-phenylhexyl) -3-isobutylureido] propionic acid or a salt thereof as an active ingredient. 25. (2S) -3- (4-Biphenylyl)
An endothelin converting enzyme inhibitor containing -2- [3- (2-carboxy-2-hydroxyethyl) -3-isobutylureido] propionic acid or a salt thereof as an active ingredient. 26. (2S) -2- [3- (2-Carboxyethyl) -3-isobutylureido] -3- (1,
An endothelin converting enzyme inhibitor containing 1 ': 2', 1 "-terphenyl-4-yl) 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 containing 3- (2-naphthyl) propionic acid or a salt thereof as an active ingredient. 28. An endothelin containing (2S) -2- [3- (2-benzyloxy-2-carboxyethyl) -3-isobutylureido] -3- (2-naphthyl) propionic acid or a salt thereof as an active ingredient. Converting enzyme inhibitor. 29. (2S) -3- [2- (1-bromo)
Naphthyl] -2- [3- (2-carboxyethyl) -3
-Isobutylureido] propionic acid or a salt thereof as an active ingredient, an endothelin converting enzyme inhibitor. 30. A cerebral blood flow improving agent comprising the compound according to claim 1 or claim 29 or a salt thereof as an active ingredient. 31. A cerebral vasospasm inhibitor comprising the compound according to any one of claims 1 to 29 or a salt thereof as an active ingredient. 32. A therapeutic agent for cerebral infarction, which comprises the compound according to any one of claims 1 to 29 or a salt thereof as an active ingredient. 33. An asthma therapeutic agent comprising the compound according to any one of claims 1 to 29 or a salt thereof as an active ingredient. 34. A therapeutic agent for bronchial asthma, which comprises the compound according to any one of claims 1 to 29 or a salt thereof as an active ingredient. 35. An agent for preventing dysfunction after organ transplantation, which comprises the compound according to any one of claims 1 to 29 or a salt thereof as an active ingredient. 36. An agent for preventing dysfunction after liver transplantation, which comprises the compound according to any one of claims 1 to 29 or a salt thereof as an active ingredient. 37. An agent for suppressing rejection after organ transplantation, which comprises the compound according to any one of claims 1 to 29 or a salt thereof as an active ingredient. 38. A rejection inhibitor after renal transplantation, which comprises the compound according to any one of claims 1 to 29 or a salt thereof as an active ingredient.