JPH07157459A - Biphenylmethyl-substituted valerylamide derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new derivative useful as a preventing or a therapeutic medicine for cardioangiopathy, nephropathy, etc. CONSTITUTION:This compound is expressed by formula I [R<1> is H, an alkyl, an alkylthioalkyl, a hydroxyalkyl, an aminoalkyl, an alkoxyalkyl or an aryloxyalkyl; A and B are each H, a halogen or an alkyl; X is COOH or formula II (R<4> is H, an alkyl or an arylakyl); (m) is 0-2], its ester or a salt thereof, e.g. N-[(2S)-2-(p-biphenylmethyl)-4-carboxy-5-phenoxyvaleryl]glycine. Furthermore, a compound expressed by formula III (Y is COOR<3> or formula II; R<2> and R<3> are each H, an alkyl, an arylalkyl, an aryl, etc.) or its salt and a compound expressed by formula IV (R<11> and R<12> are each H, an alkyl, an arylalkyl, an aryl, etc.) or its salt are new compounds. The compounds expressed by formulas I to III are obtained from a partially protected valeric acid derivative and an amino acid or an amine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a compound useful as a pharmaceutical for the prevention and / or treatment of cardiovascular disorders, renal diseases and the like.

[0002]

2. Description of the Related Art Neutral endopeptidase (EC 3.4.24.1
1, also called enkephalinase) is a metalloendopeptidase contained in many in vivo tissues such as kidney and brain. Neutral endopeptidase degrades several peptide hormones, including atrial natriuretic factor (ANF) and enkephalin (ANF: Stephenson et al., Biochem. J., 243 , 183, 1987).
Year, Enkephalin: Malfroy et al., Natur
e, 276 , 523, 1978).

A peptide consisting of 21 to 28 amino acids called ANF secreted from the heart of humans and other mammals causes diuresis, increased natriuresis, and relaxation of smooth muscle of blood vessels and other tissues (Needleman). (Needleman)
Hypertension, 7 , 469, 1985). In addition, human A
Administration of NF to humans causes diuresis, increased natriuresis,
And decreased blood pressure (Richards et al., Hypertention, 7 , 812, 1985).

From this, if the action of neutral endopeptidase is inhibited, the degradation of ANF can be suppressed and the concentration of ANF can be increased, and the physiological action of ANF can be used for the prevention of cardiovascular disorders, renal diseases and / or the like. It can be used for treatment.

Therefore, a drug that inhibits the action of neutral endopeptidase is considered to have industrial utility.

To date, many compounds are known to inhibit neutral endopeptidases. However, it was expected that these compounds would not be able to fully develop the expected effects at low doses. Therefore, it was considered necessary to develop a compound that can more strongly inhibit neutral endopeptidase.

As a result of earnest research, the present inventors have found that the compound of the general formula (I)
It was found that the compound represented by the formula (1) has a strong neutral endopeptidase inhibitory activity, and completed the present study.

[0008]

The compounds of the invention, formula (I)

[0009]

[Chemical 18]

(Wherein R ¹ is 1. hydrogen atom, 2. alkyl group, 3. alkylthioalkyl group, 4. hydroxyalkyl group, 5. aminoalkyl group, 6. alkoxyalkyl group or 7. aryloxyalkyl group X represents 1.-COOH or 2.

[0011]

[Chemical 19] R ⁴ represents 1. a hydrogen atom, 2. an alkyl group or 3. an arylalkyl group, A and B independently represent 1. a hydrogen atom, 2. a halogen atom or 3. an alkyl group, and m is Represents an integer of 0, 1 or 2. The compound represented by the formula (1), an ester thereof, or a salt thereof can be used as a pharmaceutical for the prevention and / or treatment of cardiovascular disorders, renal diseases and the like. Formula (II)

[0012]

[Chemical 20]

[Wherein Y is 1.-COOR ³ or 2.

[0014]

[Chemical 21]

R ¹ and R ⁴ are as defined above, m is an integer of 0, 1 or 2, and R ² and R ³ are independently 1. hydrogen atom, 2. alkyl group, 3 .Arylalkyl group, 4. Aryl group, 5. Group,

[0016]

[Chemical formula 22]

(R ⁵ represents a hydrogen atom, an alkyl group or an aryl group, and R ⁶ represents an alkyl group, an alkoxy group or a cycloalkyl group.) 6. Group,

[0018]

[Chemical formula 23]

7. groups,

[0020]

[Chemical formula 24]

(R ⁷ represents an alkyl group.) 8. Group,

[0022]

[Chemical 25]

(R ⁸ represents an alkyl group, and n represents an integer of 1 to 4.) 9. Group,

[0024]

[Chemical formula 26]

Or 10. groups,

[0026]

[Chemical 27]

(R ⁹ and R ¹⁰ independently represent a hydrogen atom or an alkyl group). ] A compound represented by the formula or a salt thereof can be used as a drug for preventing and / or treating cardiovascular disorders, renal diseases and the like. Expression (I
II)

[0028]

[Chemical 28]

[Wherein R ¹ is as defined above, m is 0, 1
Or an integer of 2, R ¹¹ and R ¹² are independently 1. hydrogen atom, 2. alkyl group, 3. arylalkyl group or 4. aryl group, 5. group,

[0030]

[Chemical 29]

(R ⁵ represents a hydrogen atom, an alkyl group or an aryl group, and R ⁶ represents an alkyl group, an alkoxy group or a cycloalkyloxy group.) 6. Group,

[0032]

[Chemical 30]

7. groups,

[0034]

[Chemical 31]

(R ⁷ represents an alkyl group.) 8. Group,

[0036]

[Chemical 32]

(R ⁸ represents an alkyl group, and n represents an integer of 1 to 4.) 9. Group,

[0038]

[Chemical 33]

Or 10. groups,

[0040]

[Chemical 34]

(R ⁹ and R ¹⁰ independently represent a hydrogen atom or an alkyl group)] or a salt thereof, for the prevention and / or treatment of cardiovascular disorders, renal diseases and the like. It can be used as a medicine.

N-[(2S) -2- (p-biphenylmethyl) -4-carboxy-5-phenoxyvaleryl] glycine, its monoester, its diester or their salts can be used for cardiovascular disorders and kidneys. It can be used as a drug for preventing and / or treating diseases and the like.

Furthermore, N-[(2S, 4R) -2-, which is an optically active substance,
Use of (p-biphenylmethyl) -4-carboxy-5-phenoxyvaleryl] glycine, its monoester, its diester or salts thereof as a pharmaceutical for the prevention and / or treatment of cardiovascular disorders, renal diseases, etc. it can.

In addition, N-[(2S, 4S) -2- (p-biphenylmethyl) -4-carboxy-5-phenoxyvaleryl] glycine,
The monoester, diester or salt thereof can be used as a pharmaceutical for the prevention and / or treatment of cardiovascular disorders, renal diseases and the like.

Furthermore, N-[(2S) -2- (p-biphenylmethyl) -4
-Carboxy-5-phenoxyvaleryl] -L-alanine, its monoester, its diester or salts thereof can be used as a pharmaceutical for the prevention and / or treatment of cardiovascular disorders, renal diseases and the like.

The ester compound N-[(2S) -2- (p-biphenylmethyl) -4-ethoxycarbonyl-5-phenoxyvaleryl] glycine or a salt thereof can be used as a prodrug for cardiovascular disorders. It can be used as a medicine for the prevention and / or treatment of kidney diseases and kidney diseases.

Furthermore, N-[(2S, 4R) -2-, which is an optically active substance,
If (p-biphenylmethyl) -4-ethoxycarbonyl-5-phenoxyvaleryl] glycine or a salt thereof is used as a prodrug, it can prevent and / or prevent cardiovascular disorders and kidney diseases.
Or it can be used as a therapeutic drug.

In addition, N-[(2S, 4S) -2- (p-biphenylmethyl) -4-ethoxycarbonyl-5-phenoxyvaleryl] glycine or a salt thereof can be used as a prodrug for cardiovascular disorders and It can be used as a pharmaceutical for the prevention and / or treatment of kidney diseases and the like.

Since the compounds represented by the general formulas (I), (II) and (III) have two or more asymmetric carbon atoms, diastereomers exist as isomers. The invention also includes all mixtures of diastereomers and each of the separated diastereomers. In addition, when the compound of the present invention is administered to humans or animals, it is usually preferable to administer a single diastereomer. As used herein, the phrase "consisting of a single diastereomer" is understood to mean not only the case of containing no other diastereomer but also the degree of being chemically or physiologically pure. That is, it means that other diastereomers may be contained as long as they do not affect the physical constants and physiological activities.

When a free carbosyl group or tetrazole group is present in the compound of the general formula (I), (II) or (III), it may be a pharmaceutically acceptable salt, which is a pharmaceutically acceptable salt. It shows that it is a non-toxic salt. Examples thereof include salts with alkali metals or alkaline earth metals such as sodium, potassium and calcium, and salts with amines such as diethylamine and N-methylglucamine. On the other hand, even toxic salts are useful for isolation and purification of intermediates and for production.

Substituents of the compound of the present invention will be described below. In addition, when description is not made corresponding to the substituent of a specific site, the description is an explanation of each substituent described throughout the present specification which is not limited to the specific site.

Examples of the alkyl group include those having 1 to 6 carbon atoms such as methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group and tertiary butyl group. It may be linear or branched. Preferred are a methyl group and an ethyl group.

The alkylthioalkyl group is formed by combining an alkylthio group having 1 to 4 carbon atoms such as methylthio group, ethylthio group, n-propylthio group or isopropylthio group and an alkylene group having 1 to 6 carbon atoms. Good. A methylthioethyl group is preferred.

The hydroxyalkyl group has a structure in which a hydroxyl group is substituted with an alkyl group. The substitution position of the hydroxyl group is not particularly limited, such as the terminal or middle of the alkyl group.

The aminoalkyl group has a structure in which an amino group is substituted with an alkyl group. The substitution position of the amino group is not particularly limited, such as the terminal or middle of the alkyl group.

Examples of the alkoxy group include those having 1 to 6 carbon atoms such as methoxy group, ethoxy group and propoxy group. The alkyl moiety may be linear or branched. Further, it may be a cycloalkyl group.

The alkoxyalkyl group has 1 to 6 carbon atoms.
And an alkylene group having 1 to 6 carbon atoms may be combined.

Examples of the aryl group include a phenyl group and a naphthyl group. The phenyl group may be unsubstituted, but may be a substituent selected from the group consisting of a halogen atom, a nitro group, a hydroxy group, an alkyl group having 1 to 4 carbon atoms and an alkoxy group having 1 to 4 carbon atoms. It may be substituted by 1 to 3. Or a 5-membered ring or a 6-membered ring in which an adjacent alkyl group substituted with an aryl group or an alkyl substituent and an alkoxy group (for example, an indanyl ring, a dihydrobenzofuranyl ring)
May be formed.

The arylalkyl group may be formed by combining the above aryl group and an alkylene group having 1 to 6 carbon atoms. The aryl group of the arylalkyl group is preferably a phenyl group or a substituted phenyl group. Examples thereof include a benzyl group, a substituted benzyl group and a phenethyl group.

The aryloxyalkyl group may be formed by combining the above aryl group, an oxygen atom and an alkylene group having 1 to 6 carbon atoms in this order. Examples thereof include a phenoxymethyl group, a phenoxyethyl group, and a naphthyloxyethyl group. A phenoxymethyl group is preferable.

The isomers A and B mentioned in the examples are
It is defined as a separation method for separating isomers. That is, when the compound represented by the general formula of the present invention is a dicarboxylic acid, H
The substance that first elutes when PLC (eluting solvent is acetonitrile-water) is called isomer A, and the substance that elutes later is called isomer B. When the compound represented by the general formula of the present invention is an ester, the substance that firstly elutes when a silica column is used is called isomer A, and the substance that elutes later is called isomer B.

The isomer A and the isomer B have a relationship that if one of the asymmetric carbons whose absolute coordination is not determined is the (R) isomer, the other is the (S) isomer, and the compound is analyzed by structural analysis. Can be coordinated.

Examples of the ester of the compound represented by the general formula (I) of the present invention include monoester and diester,
One to two hydrogen atoms of two carboxylic acids in the compound
Wherein one of the two carboxylic acid hydrogen atoms in the compound is, for example, an alkyl group, an arylalkyl group or an aryl group. And the diester of the compound means that the hydrogen atoms of two carboxylic acids in the compound are substituted with, for example, an alkyl group, an arylalkyl group or an aryl group.
The alkyl group, arylalkyl group or aryl group is as described above.

The monoesters of the compounds represented by the general formulas (I), (II) and (III) of the present invention, their diesters or salts thereof are used for the prevention and / or treatment of cardiovascular disorders, renal diseases and the like. The use of the drug as a prodrug is considered, and it shows an important aspect in considering the administration of the drug.

Among the esters, preferred are compounds substituted with a group that can be used as a prodrug. As this group, 1. alkyl group, 2. arylalkyl group, 3. aryl group, 4. group,

[0066]

[Chemical 35]

(R ⁵ represents a hydrogen atom, an alkyl group or an aryl group, and R ⁶ represents an alkyl group, an alkoxy group or a cycloalkyloxy group.) 5. Group,

[0068]

[Chemical 36]

6. groups,

[0070]

[Chemical 37]

(R ⁷ represents an alkyl group.) 7. Group,

[0072]

[Chemical 38]

(R ⁸ represents an alkyl group, and n represents an integer of 1 to 4.) 8. Group,

[0074]

[Chemical Formula 39]

Or 9. groups

[0076]

[Chemical 40]

(R ⁹ and R ¹⁰ independently represent a hydrogen atom or an alkyl group).

The method of synthesizing the compound represented by the general formula (I), (II) or (III) of the present invention is a method in which a partially protected valeric acid derivative and, if necessary, a partially protected amino acid or amine are used. To obtain valeryl amide.

The synthetic route is shown in Reaction Scheme 1.

[0080]

[Chemical 41]

Reaction process Compound of formula (IV) of formula 1
(R ¹³ is one defined as R ² from which a hydrogen atom has been removed, or is an ordinary carboxylic acid protecting group.) And a compound represented by the formula (V) (in the formula, R ¹ , R ⁴ and m are as defined above and X ′ is —COOR ¹⁴ or

[0082]

[Chemical 42]

Wherein R ¹⁴ is defined as R ^{3 with the} hydrogen atom removed, or is a conventional carboxylic acid protecting group. ) Can be obtained by dehydration condensation using an ordinary amide bond method. For example, the reactant is dissolved in an organic solvent (for example, methylene chloride), and a diimide-based condensing agent (for example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride or dicyclohexylcarbodiimide) is used, preferably 1-hydroxy It is carried out in the presence of benzotriazole and optionally an organic base (eg N-methylmorpholine).
The reaction generally requires 5 to 24 hours at room temperature. The product (VI) is then isolated by customary methods, for example by washing with water or filtration to remove the by-product urea and evaporating the solvent.

A compound represented by the formula (VI) (wherein R ¹ ,
R ^13, m and X 'are the same) the definitions, groups in the formula R ¹³
And R ¹⁴ (or R ⁴ ) depending on the chemical nature of them, may be represented by formula (I), (II) or (III) by selectively removing those groups or by removing all of these groups. Can be converted into a large number of compounds. For example, a compound in which only the benzyl group is deprotected by hydrogenation can be obtained from a compound in which one is a benzyl ester and the other is an alkyl ester. Further, a compound in which one is a methyl ester and the other is a benzyl ester is dissolved in an organic solvent (for example, methylene chloride), a sulfide (for example, methyl sulfide) and an aluminum halide (for example, aluminum chloride) are added, and the mixture is cooled from ice to room temperature at room temperature. By stirring for 5 minutes to 5 days, a monocarboxylic acid in which only the benzyl group is deprotected or a dicarboxylic acid in which both the methyl group and the benzyl group are deprotected can be selectively synthesized depending on the amount of the reagent and the reaction time. . In the case of dimethyl ester or monomethyl ester, dicarboxylic acid can be obtained under the same conditions. There are also methods such as hydrolysis under acidic or alkaline conditions, but the protecting group may be removed using a method suitable for the protecting group used. When X'is an N-paramethoxybenzyl substituted tetrazole group, treatment with trifluoroacetic acid gives the corresponding free tetrazole derivative.

The monocarboxylic acid represented by the formula (IV) can be produced by the method shown in the reaction step 2.

[0086]

[Chemical 43]

Methods described in the literature (Cavallini et al., J. Am. C
hem. Soc., 79 , 3514 1957), 3- (p-biphenyl) propionic acid (VII) was converted to an acid chloride using a conventional method (for example, a method using thionyl chloride), and commercially available oxazolidinone ( VIII) is directly reacted with a lithium salt derived by treatment with n-butyllithium at low temperature to give N-acyl oxazolidinone (IX).
Then, this is reacted with a strong base (for example, lithium diisopropylamide) at a low temperature to produce a lithium enolate, and a compound represented by the formula (X) (wherein Z is a leaving group, for example, Halogen atom or p-toluenesulfonyloxy, preferably iodine atom) is added to give compound (XI). This compound can be converted to the optically active benzyl ester (XII) by direct reaction with a lithium salt derived by treating n-butyllithium and benzyl alcohol at low temperature. Although oxazolidinone (VIII) having (S) -coordination is used here, the enantiomer of compound (VIII) having (R) -coordination or a related compound (for example, (4R, 5S) -4-methyl-5 -Phenyl-2-oxazolidinone) can be used instead to obtain the antipode of compound (XII) with the opposite coordination.

As a method for converting an olefin into an alcohol, there is a method utilizing hydroboration, for example. After dissolving the compound of formula (XII) in an inert solvent (eg tetrahydrofuran), adding a borane compound (eg 9-borabicyclo [3,3,1] nonane) under ice cooling or at room temperature and reacting for 1 to 8 hours. When treated with hydrogen peroxide in the presence of an alkali (eg, sodium hydroxide), an alcohol (XIII) having a mixing ratio of diastereomers depending on the borane compound used can be obtained. This compound can be treated with an oxidizing agent (for example, sodium bromate using 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl as a catalyst) to obtain a monocarboxylic acid (XIV).

From monocarboxylic acid (XIV) to diester (XV)
For the conversion of, the method may be selected according to the substituent to be introduced. For example, a method using diazomethane, a method using a condensing agent (for example, dicyclohexylcarbodiimide), a method using a base and various halides, and the like. The diester (XV) thus obtained (wherein R ¹³ is the same as defined above) is debenzylated by hydrogenation to give the compound of formula (I
V) compounds can be obtained. The compound in which X ′ of the formula (V) is an ester group is a commercially available compound, but the compound in which X ′ is a free tetrazole group should be produced according to the method described in the literature (JP-A-63-41469). (Eg, by reaction of appropriately substituted aminoacetonitrile with sodium azide). On the other hand, N-substituted tetrazole (X
X) can be produced, for example, by the method shown in reaction step 3.
Method described in literature (Sugano et al., Chem. Pharm. Bull., 39 , 109
9, 1991) tetrazoleacetic acid (XVI)
(In the formula, R ¹⁵ represents an ordinary carboxylic acid protecting group, and R ¹⁶ represents R
(Which represents hydrogen atoms excluding those defined for ⁴ ) is condensed with hydrazine in the absence of solvent or in a solvent (for example, ethanol) to form hydrazide (XVII). Then, this compound is dissolved in an aqueous hydrochloric acid solution, treated with sodium nitrite under cooling, and the resulting acyl azide (XVIII) is heated in an organic solvent (for example, toluene) to produce an isocyanate ester.
(XIX), then alkali (eg sodium hydroxide)
The desired compound represented by the formula (XX) can be obtained by reacting with and acidifying.

[0090]

[Chemical 44]

The reaction product in each reaction is purified by an ordinary purification method such as distillation using a vacuum pump, column chromatography using silica gel, recrystallization, high performance liquid chromatography, or a combination thereof. It can be performed.

[0092]

EXAMPLES The present invention will be further described below with reference to examples, but the present invention is not limited thereto.

Reference Example 2-Iodomethyl-3-phenoxy
1-propene 2-chloromethyl-3-phenoxy-1-propene 29.7 g
26.8 g of sodium iodide was added to a solution dissolved in 150 ml of methyl ethyl ketone, and the mixture was heated under reflux for 2 hours and 30 minutes. The reaction solution is concentrated, ether is added to the residue, washed with water,
It was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 45.4 g of the title compound as a brown oily substance.

¹ H-NMR (CDCl ₃ , 90 MHz) δ: 4.05 (2H, s), 4.69 (2H, s), 5.32 (1H, s), 5.48 (1H,
s), 6.8-7.0 (3H, m), 7.2-7.4 (2H, m).

Example 1 (4S) -3- [3- (p-biphenyl)
15 g of propionyl] -4- (1-methylethyl) -2-oxazolidinone 3- (p-biphenyl) propionic acid was dissolved in 100 ml of thionyl chloride and heated under reflux for 2 hours. After the solvent was distilled off, acid chloride was obtained as brown crystals, which were directly used in the next reaction. (4S) -4- (1-Methylethyl) -2-oxazolidinone (8.56 g) in tetrahydrofuran (200 ml)
And n-butyllithium (1.6M
(Solution) 48 ml was added, and after stirring for 1 hour, the above-mentioned tetrahydrofuran solution of acid chloride was added, and stirring was continued for further 2 hours, and the temperature was returned to 0 ° C. 1N aqueous potassium carbonate solution was added to the reaction solution, extracted with chloroform, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: n
-Hexane = 1: 4) and concentrate the fractions containing the desired compound under reduced pressure to give the title compound with a melting point of 103-104 ° C.
19.4 g was obtained as white crystals. [Α] _D + 53.7 (c = 1.0, chloroform).

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 0.84 (3H, d, J = 6.8 Hz), 0.91 (3H, d, J = 6.8 Hz),
2.36 (1H, m), 3.05 (2H, m), 3.2-3.4 (2H, m), 4.2
(2H, m), 4.5 (1H, m), 7.2-7.7 (9H, m).

Example 2 (4S) -3-[(2S) -2- (p-biphenylmethyl) -4-phenoxymethyl-4-pentenoyl] -4-
(1-Methylethyl) -2-oxazolidinone diisopropylamine 1.27 g in tetrahydrofuran 3
After dissolving in 0 ml and cooling to -78 ℃, n-butyl lithium
(1.6 M hexane solution) (7.6 ml) was added, and the mixture was stirred for 30 minutes. (4S) -3- [3- (p-biphenyl) propionyl] -4- (1-
A solution of 2.82 g of (methylethyl) -2-oxazolidinone in tetrahydrofuran was added dropwise and stirred for 1 hour.After adding 2.75 g of 2-chloromethyl-3-iodo-1-propene, the temperature was gradually raised from -20 ° C to -15 ° C. Stirring was continued for hours. To the reaction solution was added 10% aqueous ammonium chloride solution, extracted with chloroform, dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: n-hexane = 1: 5).
And the fraction containing the desired product was concentrated under reduced pressure to obtain 2.39 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 0.77 (3H, d, J = 6.8 Hz), 0.84 (3H, d, J = 6.8 Hz),
2.2 (1H, m), 2.40 (1H, dd, J = 4.9 and 14.4 Hz),
2.69 (1H, dd, J = 9.3 and 14.6 Hz), 2.9 (2H, m),
3.7 (1H, t, J = 8.8 Hz,), 4.0 (1H, m), 4.1 (1H, m),
4.49 (1H, d, J = 13.2 Hz), 4.55 (1H, d, J = 13.2 H
z), 4.7 (1H, m), 5.11 (1H, s), 5.20 (1H, s), 6.8-
7.0 (3H, m), 7.2-7.7 (11H, m).

Example 3 Benzyl (2S) -2- (p-biphenylmethyl) -4-phenoxymethyl-4-pentenoate benzyl alcohol 1.4 g was added to tetrahydrofuran 30 m.
10 ml of n-butyllithium (1.6M hexane solution) was added to the solution dissolved in l at -10 ° C, stirred for 20 minutes, and then (4S) -3-
[(2S) -2- (p-biphenylmethyl) -4-phenoxymethyl-4-
A tetrahydrofuran solution of 3.2 g of pentenoyl] -4- (1-methylethyl) -2-oxazolidinone was added, and the mixture was stirred at -5 ° C overnight. To the reaction solution was added a saturated aqueous solution of ammonium chloride, concentrated under reduced pressure, extracted with chloroform, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate: n -Hexane = 1:10) and the fraction containing the desired product was concentrated under reduced pressure to give the title compound as a mp 52-54.
1.99 g was obtained as pale yellow needle crystals at ℃. [Α] _D + 8.76 (c = 1.78, chloroform).

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 2.43 (1H, dd, J = 5.0 and 14.6 Hz), 2.56 (1H, dd,
J = 9.3 and 14.6 Hz), 2.87 (1H, dd, J = 5.9 and 1
3.2 Hz), 2.9-3.1 (2H, m), 4.43 (1H, d, J = 12.7 H
z), 4.48 (1H, d, J = 12.2 Hz), 4.97 (1H, d, J = 12.2
Hz), 5.03 (1H, d, J = 12.3 Hz), 5.04 (1H, s), 5.17
(1H, s), 6.8-7.6 (19H, m).

Example 4 Benzyl (2S, 4RS) -2- (p-
Biphenylmethyl) -4-methoxycarbonyl-5-phenoxyvalerate benzyl (2S) -2- (p-biphenylmethyl) -4-phenoxymethyl-4-pentenoate 2.0 g tetrahydrofuran
The solution dissolved in 10 ml was added to 9-borabicyclo [3,3,
1] Nonane (9-BBN) 12.2 ml was added, and the mixture was stirred at room temperature for 3 hours and 30 minutes. To the reaction solution were added 3N aqueous sodium hydroxide solution (3 ml) and then 20% aqueous hydrogen peroxide solution (3 ml) at the same temperature. After stirring for 20 minutes, the mixture was extracted with chloroform and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give benzyl (2S, 4RS) -2- (p-biphenylmethyl) -4-hydroxymethyl-5-phenoxyvalerate as a colorless oil 1.33 g.
Got This oily substance was directly used in the next reaction.

Benzyl (2S, 4RS) -2- (p-biphenylmethyl) -4-hydroxymethyl-5-phenoxyvalerate 1.33
g and 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl 0.01 g in acetonitrile 15 ml
15 ml of 5% aqueous sodium hydrogen carbonate solution
Then, 1.58 g of sodium bromate was added under ice cooling. The reaction solution was stirred at room temperature for 2 hours and 30 minutes, 50% aqueous 10% tartaric acid solution was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give (2RS, 4S) -4-benzyloxycarbonyl-5- (p-biphenyl) -2- (phenoxymethyl). ) 1.4 g of valeric acid was obtained as a pale yellow oil. This oily substance was used in the next reaction without purification.

A mixture of 7 ml of 40% aqueous potassium hydroxide solution and 20 ml of ether was cooled to 5 ° C., and with vigorous stirring, 1.0 g of N-methyl-N-nitrosourea was added to about 20 ° C.
After stirring for minutes, the ether layer was separated and dried over potassium hydroxide. This diazomethane ether solution (2RS, 4S)
4-Benzyloxycarbonyl-5- (p-biphenyl) -2- (phenoxymethyl) valeric acid 1.4 g ether solution 100 ml
After stirring for 30 minutes, acetic acid was added to react with the remaining diazomethane. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate: n-hexane = 1: 8).
And the fraction containing the desired product was concentrated under reduced pressure to obtain 0.73 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.8-2.1 (2H, m), 2.7-2.9 (3H, m), 3.0 (1H, m),
3.66 and 3.69 (total 3H, each s), 3.9-4.1 (2H,
m), 4.9-5.1 (2H, m), 6.6-6.8 (3H, m), 7.1-7.7
(16H, m).

Example 5 Benzyl (2S, 4RS) -2- (p-biphenylmethyl) -4 (2S, 4RS) -2- (p-biphenylmethyl) -4-methoxycarbonyl-5-phenoxyvalerate -Methoxycarbonyl-5-phenoxyvalerate (0.73 g) was dissolved in methanol (10 ml), 10% palladium-supported activated carbon catalyst (0.09 g) was added, and the mixture was stirred under a hydrogen pressure of 10 atm for 2 hours. The reaction mixture was filtered through Celite, the filtrate was concentrated, the residue was purified by silica gel column chromatography (eluting solvent: chloroform: methanol = 10: 1), and the fraction containing the target compound was concentrated under reduced pressure. 0.38 g of the title compound was obtained as a colorless oil.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.8-2.3 (2H, m), 2.8-3.2 (4H, m), 3.66 and 3.6
7 (total 3H, each s), 3.9-4.2 (2H, m), 6.7-7.0
(3H, m), 7.1-7.6 (11H, m).

Example 6 Benzyl (2S, 4RS) -2- (p-
Biphenylmethyl) -4-ethoxycarbonyl-5-phenoxyvalerate By the same method as in Example 4, benzyl (2S) -2- (p-
Biphenylmethyl) -4-phenoxymethyl-4-pentenoate 17 g to (2RS, 4S) -4-benzyloxycarbonyl-
After obtaining 19 g of 5- (p-biphenyl) -2-phenoxymethylvaleric acid, a solution prepared by dissolving this in 100 ml of methylene chloride was added to 510 mg of 4-pyrrolidinopyridine and 1.75 of ethanol.
g and 7.82 g of dicyclohexylcarbodiimide were added, and the mixture was stirred at room temperature for 3 hours. The insoluble matter in the reaction solution was filtered using a glass filter, the filtrate was extracted with ethyl acetate, washed with water, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (eluting solvent; ethyl acetate: n-xane = 1: 7), and the fraction containing the target compound was concentrated under reduced pressure to give the title compound. 7.15 g was obtained as a pale yellow oil.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.18 and 1.26 (total 3H, each t, J = 7.3 Hz), 1.8
-2.2 (2H, m), 2.7-3.1 (4H, m), 3.9-4.2 (4H, m),
4.98 and 5.00 (total 1H, each d, J = 12.2 Hz), 5.
05 and 5.06 (total 1H, each d, J = 12.2 Hz), 6.7-
6.9 (3H, m), 7.1-7.7 (16H, m).

Example 7 Benzyl (2S, 4RS) -2- (p-biphenylmethyl) -4 (2S, 4RS) -2- (p-biphenylmethyl) -4-ethoxycarbonyl-5-phenoxyvalerate 7.15 g of -ethoxycarbonyl-5-phenoxyvalerate was dissolved in 100 ml of ethanol, 0.7 g of an activated carbon catalyst supporting 5% palladium was added, and the mixture was stirred under a hydrogen pressure of 10 atm for 2 hours. The reaction mixture was filtered through Celite, the filtrate was concentrated, the residue was purified by silica gel column chromatography (elution solvent; chloroform: methanol = 10: 1), and the fraction containing the target compound was concentrated under reduced pressure. The title compound was obtained as a colorless oil to give 2.64 g.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.19 and 1.22 (total 3H, each t, J = 7.3 Hz), 1.9
-2.0 (2H, m), 2.7-3.1 (4H, m), 4.0-4.2 (4H, m),
6.7-7.0 (3H, m), 7.2-7.6 (16H, m).

Example 8 N-[(2S, 4RS) -2- (p-biphenylmethyl) -4-methoxycarbonyl-5-phenoxyvaleryl] glycine benzyl ester (2S, 4RS) -2- (p -Biphenylmethyl) -4-methoxycarbonyl-5-phenoxyvaleric acid 0.38 g methylene chloride 10 ml
Glycine benzyl ester p-toluenesulfonate 0.31 g, 1-hydroxybenzotriazole 0.125 g and N-methylmorpholine 0.3 ml
Was added. Then, under ice-cooling, 0.35 g of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride was added,
It returned to room temperature and stirred for 4 hours. The reaction solution was washed with water, 2N hydrochloric acid,
After washing with a saturated aqueous solution of sodium hydrogencarbonate in this order and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (elution solvent; ethyl acetate: n-hexane = 1: 3). After purification, the fraction containing the desired product was concentrated under reduced pressure to obtain 0.45 g of the title compound as a colorless oil.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.8-2.1 (2H, m), 2.6 (1H, m), 2.8 (1H, m), 3.0 (2
H, m), 3.70 and 3.71 (total 1H, each s), 3.8-4.2
(4H, m), 5.12 (2H, s), 5.95 and 6.07 (total 1H, eac
ht, J = 5 Hz), 6.8-7.0 (3H, m), 7.1-7.6 (16H,
m).

Example 9 N-[(2S) -2- (p-biphenylmethyl) -4-carboxy-5-phenoxyvaleryl] glycine N-[(2S, 4RS) -2- (p-biphenylmethyl) ) -4-Methoxycarbonyl-5-phenoxyvaleryl] glycine benzyl
To a solution prepared by dissolving 1.08 g of the ester in 20 ml of methylene chloride, 1.04 g of aluminum chloride and 5 ml of dimethyl sulfide were added, and the mixture was stirred at room temperature for 10 hours. 1N in the reaction solution
Hydrochloric acid was added, the mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. High-performance liquid chromatography of the residue (column: Senshupack O
DS-5251-SH 20 φ x 250 mm; solvent: 55% acetonitrile; flow rate: 4 ml / min), and concentrate the fraction with an elution time of 13 minutes under reduced pressure to give the title compound (isomer A).
0.15 g was obtained as white crystals. The title compound (isomer) was obtained by concentrating the fractions with an elution time of 15.6 minutes under reduced pressure.
B) 0.46 g was obtained as white crystals.

Isomer A: melting point 78-80 ° C, [α] _D + 22.8
(c = 1.0, methanol). ¹ H-NMR (CD ₃ OD, 400 MHz) δ: 1.9 (2H, m), 2.7-3.0 (4H, m), 3.72 (1H, dd, J =
17.6 and 8.3 Hz), 3.90 (1H, dd, J = 17.6 and 7.8 H
z), 4.0-4.2 (2H, m), 6.8-7.0 (3H, m), 7.1-7.6
(11H, m). Isomer B: melting point 84-86 ℃, [α] _D + 26.7 (c = 0.97,
Methanol). ¹ H-NMR (CD ₃ OD, 400 MHz) δ: 1.95 (2H, m), 2.8-3.0 (4H, m), 3.75 (1H, d, J = 1
7.6 Hz), 3.89 (1H, d, J = 17.6 Hz), 4.08 (2H, m), 6.
8-7.0 (3H, m), 7.1-7.6 (11H, m).

Example 10 N-[(2S) -2- (p-biphenylmethyl) -4-methoxycarbonyl-5-phenoxyvaleryl] -L-alanine benzyl ester In the same manner as in Example 8 ( 2S, 4RS) -2- (p-Biphenylmethyl) -4-methoxycarbonyl-5-phenoxyvaleric acid 1.0 g
After condensing 0.84 g of L-alanine benzyl ester p-toluenesulfonate with the product
Column chromatography (elution solvent: methylene chloride)
The target compound (isomer A) was purified from the first eluted fraction by concentrating the fraction containing the desired compound under reduced pressure.
0.22 g was obtained as a colorless candy. Further, from the fraction eluted later, 0.55 of the crude isomer B was obtained as colorless candy.
g got. Isomer A: [α] _D +17.0 (c = 1.0, methylene chloride). ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.37 (3H, d, J = 6.9 Hz), 1.8-2.1 (2H , m), 2.4-
2.6 (1H, m), 2.73 (1H, d, d, J = 13.7 and 6.3 Hz),
2.8-3.0 (1H, m), 3.00 (1H, d, d, J = 13.7 and 7.3 H
z), 3.70 (3H, s), 3.9-4.2 (2H, m), 4.54 (1H, q, J
= 7.3 Hz), 5.03 (1H, d, J = 12.2 Hz), 5.07 (1H, d,
J = 12.7 Hz), 6.08 (1H, d, J = 6.8 Hz), 6.85 (2H, d,
J = 8.8 Hz), 6.94 (1H, t, J = 7.3 Hz), 7.1-7.6 (1
1H, m).

[Example 11] N-[(2S) -2- (p-biphenyl)
Lumethyl) -4-carboxy-5-phenoxyvaleryl] -L-a
Lanine A) N-[(2S) -2- (p-biphenylmethyl) as in Example 9
-4-Methoxycarbonyl-5-phenoxyvaleryl] -L-ara
Reacted 0.22 g of nin benzyl ester (isomer A)
Liquid chromatography (column: Sensitivity
TU-PACK ODS-6251-SH 30 φ × 250 mm; solvent: 58%
Purification with cetonitrile; flow rate: 10 ml / min), elution time
The title compound was obtained by concentrating the 29.2 min fraction under reduced pressure.
0.13 g of (isomer B) was obtained as a white foam. [α]_D +13.7 (c = 0.97, methanol).¹  H-NMR (CD₃OD, 400 MHz) δ: 1.36 (2H, d, J = 7.3 Hz), 1.8-2.0 (2H, m), 2.73
(1H, d, d, J = 12.7 and 7.3 Hz), 2.6-2.9 (2H, m),
 3.04 (1H, d, d, J = 12.7and 6.3 Hz), 4.0-4.2 (2H,
 m), 4.35 (1H, q, J = 7.3Hz), 6.87 (2H, d, J = 8.3H
z), 6.90 (1H, t, J = 8.3 Hz), 7.1-7.6 (11H, m).

B) By the same method as in Example 9, N-[(2
S) -2- (p-biphenylmethyl) -4-methoxycarbonyl-5-
After reacting 0.55 g of phenoxyvaleryl] -L-alanine benzyl ester (crude isomer B), high performance liquid chromatography (column: Senshupack ODS-6251
-SH 30 φ x 250 mm; solvent: 58% acetonitrile; flow rate:
(10 ml / min) and the fractions with an elution time of 28.3 minutes were concentrated under reduced pressure to give the title compound (isomer A: B = 3: 1; isomer ratio was calculated from the integral ratio of NMR). 0.16 g was obtained as a white foam.

¹ H-NMR (CD ₃ OD, 400 MHz) δ: 1.36 (2H, d, J = 7.3 Hz), 1.8-2.0 (5 / 4H, m), 2.0-
2.2 (3 / 4H, m), 2.7-2.9 (3H, m), 2.9-3.1 (1H,
m), 3.9-4.2 (2H, m), 4.3-4.4 (1H, m), 6.84 (2H,
d, J = 8.3 Hz), 6.90 (1H, t, J = 8.1 Hz), 7.1-7.6
(11H, m).

Example 12 N-[(2S, 4RS) -2- (p-biphenylmethyl) -4-carboxy-5-phenoxyvaleryl] -L
-Methionine In the same manner as in Example 8, (2S, 4RS) -2- (p-biphenylmethyl) -4-methoxycarbonyl-5-phenoxyvaleric acid 2.0 g
And L-methionine methyl ester hydrochloride 0.96 g are condensed to give N-[(2S, 4RS) -2- (p-biphenylmethyl) -4-methoxycarbonyl-5-phenoxyvaleryl] -L as colorless oil.
-2.60 g of methionine methyl ester was obtained.

This compound was further treated by the method shown in Example 9 and then subjected to high performance liquid chromatography (column: Senshupack ODS-6251-SH 30 φ × 250 mm;
Solvent: 58% acetonitrile; flow rate: 10 ml / min) and the fractions with an elution time of 37.6 minutes were concentrated under reduced pressure to obtain 0.71 g of the title compound as a white foam.

¹ H-NMR (CD ₃ OD, 400 MHz) δ: 1.8-2.2 (4H, m), 2.01 and 2.02 (total 3H, each
s), 2.3-2.6 (2H, m), 2.7-2.9 (3H, m), 2.9-3.1
(1H, m), 4.0-4.2 (2H, m), 4.44 and 4.49 (total 1H,
each dd, J = 9.3 and 4.4 Hz), 6.8-7.0 (3H, m),
7.1-7.6 (11H, m).

Example 13 N-[(2S, 4RS) -2- (p-biphenylmethyl) -4-ethoxycarbonyl-5-phenoxyvaleryl] glycine benzyl ester By the same method as in Example 8, ( 2S, 4RS) -2- (p-Biphenylmethyl) -4-ethoxycarbonyl-5-phenoxyvaleric acid 2.64 g is condensed with glycine benzyl ester p-toluenesulfonate 2.06 g to give the title compound as a colorless oil. As a result, 3.13 g was obtained.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.20 and 1.25 (total 3H, each t, J = 7.3 Hz), 1.8
-2.0 (2H, m), 2.5-3.1 (4H, m), 3.8-4.3 (6H, m),
5.12 (2H, s), 6.8-7.0 (3H, m), 7.1-7.6 (16H, m).

Example 14 N-[(2S, 4RS) -2- (p-biphenylmethyl) -4-ethoxycarbonyl-5-phenoxyvaleryl] glycine N-[(2S, 4RS) -2- ( p-biphenylmethyl) -4-ethoxycarbonyl-5-phenoxyvaleryl] glycine benzyl
Dissolve 3.13 g of ester in 20 ml of methanol and add 5%
Add 0.3 g of activated carbon catalyst supporting palladium from
Stirred under atmospheric hydrogen pressure for 2 hours. The reaction mixture was filtered through Celite, the filtrate was concentrated, the residue was purified by silica gel column chromatography (eluting solvent: chloroform: methanol = 10: 1), and the fraction containing the target compound was concentrated under reduced pressure. The title compound as white crystals
1.69 g were obtained.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.2 (3H, m), 1.5-1.9 (2H, m), 2.5-3.0 (4H, m),
3.8-4.2 (6H, m), 6.8-7.0 (3H, m), 7.1-7.6 (11
H, m).

Example 15 Methyl (2RS, 4S) -5- (p-
Biphenyl) -4- [N- [1H-1- (p-methoxybenzyl) -5-tetrazolyl] methyl] carbamoyl-2-phenoxymethylvalerate By the method of Example 8, (2S, 4RS) -2- (p -Biphenylmethyl) -4-methoxycarbonyl-5-phenoxyvaleric acid 0.5
g and 5-aminomethyl-1H-1- (p-methoxybenzyl) tetrazole hydrochloride 0.31 g were condensed to give 0.55 g of the title compound as a colorless oil.

¹ H-NMR (CDCL ₃ , 400 MHz) δ: 1.8-2.2 (2H, m), 2.6-3.0 (4H, m), 3.65 (3H, s),
3.77 (3H, s), 4.0-4.2 (2H, m), 4.4-4.6 (2H, m),
5.4 (2H, s), 6.8-7.6 (18H, m).

Example 16 Methyl (2RS, 4S) -5- (p-
Biphenyl) -4- [N-[(5-tetrazolyl) methyl] carbamoyl] -2-phenoxymethylvalerate methyl (2RS, 4S) -5- (p-biphenyl) -4- [N- [1H-1- ( A solution of 0.53 g of p-methoxybenzyl) -5-tetrazolyl] methyl] carbamoyl-2-phenoxymethylvalerate in 6 ml of trifluoroacetic acid was stirred at 60 ° C for 2 hours, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent; chloroform: methanol = 10: 1), and the fraction containing the desired product was concentrated under reduced pressure to give the title compound as a colorless oil (0.43 g).

¹ H-NMR (CDCL ₃ , 400 MHz) δ: 1.8-2.2 (2H, m), 2.5-3.0 (4H, m), 3.70 (3H, s),
3.9-4.2 (2H, m), 4.4-4.7 (2H, m), 6.6-7.6 (14H,
m).

Example 17 (2RS, 4S) -5- (p-biphenyl) -4- [N-[(5-tetrazolyl) methyl] carbamoyl] -2-
Phenoxymethylvalerate Methyl (2RS, 4S) -5- (p-biphenyl)-(4S) -4- [N-[(5-tetrazolyl) methyl] carbamoyl] -2-phenoxymethylvalerate 0.43 g methylene chloride 5 2 ml of dimethyl sulfide and 0.6 g of aluminum chloride were added to the solution dissolved in ml, and the mixture was stirred for 12 hours at room temperature. 1N Hydrochloric acid was added to the reaction solution, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. High-performance liquid chromatography of the residue (column: Senshupack ODS
-5251-SH 20 φ x 250 mm; Solvent: 55% acetonitrile;
Flow rate: 4 ml / min), and the fractions having an elution time of 14 minutes were concentrated under reduced pressure to give the title compound as white crystals at 0.1%.
I got 1 g.

¹ H-NMR (CD ₃ OD, 400 MHz) δ: 1.7-1.9 (2H, m), 3.5-4.0 (4H, m), 3.8-4.1 (2
H, m), 4.5 (2H, m), 6.6-7.6 (14H, m).

[Example 18] 2- [1H-1- (p-methoxybenzyl) -5-tetrazolyl] acetohydrazide ethyl 2- [1H-1- (p-methoxybenzyl) -5-tetrazolyl] acetate 2.5 g ethanol 15 2.5 ml of hydrazine monohydrate was added to the solution dissolved in ml, and the mixture was stirred at room temperature for 3 days. The crystals precipitated from the reaction solution were collected by filtration and recrystallized from ethanol to obtain 1.68 g of the title compound as white flaky crystals having a melting point of 143-144 ° C.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.60 (1H, broad s), 3.73 (2H, s), 3.80 (3H, s), 3.
85 (1H, broad s), 5.60 (2H, s), 6.89 (2H, d, J = 8.8
Hz), 7.20 (2H, d, J = 8.8 Hz), 7.99 (1H, broad s).

Example 19 5-Isocyanatomethyl-1
H-1- (p-methoxybenzyl) tetrazole 2- [1H-1- (p-methoxybenzyl) -5-tetrazolyl] acetohydrazide 3.07 g suspended in 20 ml of 1N hydrochloric acid under ice-salt cooling Then, 10 ml of an aqueous solution of 0.81 g of sodium nitrite was added dropwise. After completion of dropping, the mixture was stirred for 20 minutes, a mixed solvent of toluene and ethyl acetate (mixing ratio 1: 2) was added,
Stirring was continued for another 20 minutes. The organic layer was separated, dried over anhydrous magnesium sulfate, the solvent was concentrated under reduced pressure to about 1/3, and the mixture was heated under reflux for 2 hours. The solvent of the reaction solution was evaporated under reduced pressure to give the title compound (3.2 g) as a pale-yellow oil.

¹ H-NMR (CDCl ₃ , 400 MHz) δ: 3.81 (3H, s), 4.59 (2H, s), 5.56 (2H, s), 6.91 (2H,
d, J = 8.8 Hz), 7.20 (2H, d, J = 8.8 Hz).

Example 20 5-Aminomethyl-1H-1- (p
-Methoxybenzyl) tetrazole hydrochloride 5-isocyanatomethyl-1H-1- (p-methoxybenzyl) tetrazole in 15 ml of an aqueous solution of 1.5 g of sodium hydroxide
After adding 3.2 g and 10 ml of methanol,
The mixture was stirred at 0-60 ° C for 1 hour. The reaction solution was concentrated under reduced pressure, and the concentrated solution was acidified with concentrated hydrochloric acid and stirred for 30 minutes. Then, the mixture was made alkaline with an aqueous sodium hydroxide solution, extracted with ethyl acetate, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was dissolved in ether, 10% hydrochloric acid-methanol was added, and the solvent was evaporated under reduced pressure again. Ethyl acetate was added to the residue, and the precipitated crystals were collected by filtration to give the title compound as a melting point 2
1.29 g was obtained as pale yellow prism crystals at 07-209 ° C.

¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 3.74 (3H, s), 4.48 (2H, s), 5.67 (2H, s), 6.95 (2H,
d, J = 8.3 Hz), 7.34 (2H, d, J = 8.3 Hz).

Example 21 N-[(2S) -2- (p-biphenylmethyl) -4-ethoxycarbonyl-5-phenoxyvaleryl] glycine benzyl ester In the same manner as in Example 8, (2S, 4RS ) -2- (p-Biphenylmethyl) -4-ethoxycarbonyl-5-phenoxyvaleric acid 1.72
After condensing 1.35 g of glycine benzyl ester P-toluenesulfonate with g
Column chromatography (elution solvent; methylene chloride:
Methanol = 100: 2), and the fraction containing the desired product was concentrated under reduced pressure to give 0.61 g of the title compound (isomer A) as a colorless candy from the first eluted fraction.
Furthermore, the title compound (isomer
0.53 g of B) was obtained as a colorless candy.

Isomer A: ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.21 (3H, t, J = 7.36 Hz), 1.8-2.1 (2H, m), 2.
6 (1H, m), 2.77 (1H, dd, J = 13.7 and 6.3 Hz), 2.9
-3.1 (2H, m), 3.89 (1H, dd, J = 18 and 5 Hz), 4.0
(1H, m), 4.0-4.3 (4H, m), 5.13 (2H, s), 6.13 (1
H, t, J = 5 Hz), 6.8-7.0 (3H, m), 7.1-7.6 (16H,
m).

Isomer B: ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.25 (3H, t, J = 7.3 Hz), 1.9 (1H, m), 2.2 (1H,
m), 2.6 (1H, m), 2.83 (1H, dd, J = 13.7 and 5.9 H
z), 2.9-3.1 (2H, m), 3.87 (1H, dd, J = 18.6 and
4.9 Hz), 3.9-4.2 (5H, m), 5.11 (2H, s), 5.98 (1
H, t, J = 5Hz), 6.8-7.0 (3H, m), 7.2-7.6 (16H,
m).

Example 22 N-[(2S) -2- (p-biphenylmethyl) -4-ethoxycarbonyl-5-phenoxyvaleryl] glycine A) N-[(2S) -2- (P- Biphenylmethyl) -4-ethoxycarbonyl-5-phenoxyvaleryl] glycine benzyl
0.71 g of ester (isomer A) was dissolved in 10 ml of ethyl acetate, 0.1 g of activated carbon catalyst supporting 10% palladium was added, and the mixture was stirred for 15 hours in the presence of hydrogen at atmospheric pressure. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give the title compound (isomer A) as a white foam 0.56.
g got. [α] _D +12.6 (c = 0.1, chloroform). ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.18 (3H, t, J = 7.3 Hz), 1.8-2.1 (2H, m), 2.7
(1H, m), 2.76 (1H, dd, J = 13.7 and 6.4 Hz), 2.9
-3.1 (2H, m), 3.86 (1H, dd, J = 18.5 and 4.8 Hz),
4.0-4.2 (5H, m), 6.28 (1H, t, J = 5 Hz), 6.8-
7.0 (3H, m), 7.2 -7.6 (16H, m).

B) In a similar manner N-[(2S) -2- (P-biphenylmethyl) -4-ethoxycarbonyl-5-phenoxyvaleryl] glycine benzyl ester (isomer B) 0.52 g
From this, 0.38 g of the title compound (isomer B) was obtained as white crystals having a melting point of 155-156 ° C. [Α] _D +21.1 (c = 0.1, chloroform). ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.23 (3H, t, J = 7.3 Hz), 1.8 -2.0 (1H, m), 2.1
-2.3 (1H, m) 2.6-2.7 (1H, m), 2.82 (1H, dd, J = 13.6 and 5.8
Hz), 2.9-3.1 (2H, m), 3.85 (1H, dd, J = 18.6 an
d 4.9 Hz), 3.97 (1H, dd, J = 18.6 and 5.4 Hz), 4.
0-4.2 (4H, m), 6.19 (1H, t, J = 4.9 Hz), 6.8-7.
0 (3H, m), 7.2-7.6 (16H, m).

Example 23 N-[(2S) -2- (p-biphenylmethyl) -4-methoxycarbonyl-5-phenoxyvaleryl] -β-alanine benzyl ester In the same manner as in Example 8 2S, 4RS) -2- (p-Biphenylmethyl) -4-methoxycarbonyl-5-phenoxyvaleric acid 1.0
After condensing g with β-alanine benzyl ester P-toluenesulfonate 0.84 g, the product is purified by silica gel column chromatography (elution solvent; methylene chloride: methanol = 200: 1) to contain the desired product. By concentrating the fractions under reduced pressure, 0.46 g of the title compound (isomer A) was obtained as a colorless candy from the first eluted fraction.
And 0.43 g of the title compound (isomer B) was obtained as a colorless candy from the fractions eluted later.

Isomer A: [α] _D +4.39 (c = 1.0, methylene chloride). ¹ H-NMR (CDCl ₃ , 400 MHz) δ: 1.9 (1H, m), 2.06 (1H, m), 2.3 (1H, m), 2.3-
2.5 (2H, m), 2.76 (1H, dd, J = 13.7 and 5.4 Hz),
2.8-2.9 (1H, m), 2.94 (1H, dd, J = 13.7 and 9.3 H
z), 3.3-3.4 (1H, m), 3.4-3.5 (1H, m), 3.70 (3H,
s), 4.03 (1H, dd, J = 9.3 and 5.4 Hz), 4.12 (1H,
dd, J = 9.3 and 7.8 Hz), 4.85 (1H, d, J = 12.2 H
z), 5.03 (1H, d, J = 12.7 Hz), 5.95 (1H, t, J = 6.
3 Hz), 6.86 (2H, d, J = 7.8 Hz), 6.94 (1H, t, J =
7.3 Hz), 7.1-7.6 (13H, m).

[Example 24] N-[(2S) -2- (p-biphenylmethyl) -4-carboxy-5-phenoxyvaleryl] -β-alanine A) As in Example 9, N-[( 2S) -2- (p-Biphenylmethyl) -4-methoxycarbonyl-5-phenoxyvaleryl] -β-
The crystals obtained after reacting 0.42 g of alanine benzyl ester (isomer A) were recrystallized from acetonitrile,
0.13 g of the title compound (isomer B) was obtained as white crystals. Melting point 110-112 ° C, [α] _D + 29.0 (c = 1.0, methanol). ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.6-1.9 (2H, m), 2.2-2.4 (2H, m), 2.5-2.7
(3H, m), 2.86 (1H, dd, J = 12.7 and 6.3 Hz), 3.1
-3.3 (2H, m), 4.01 (2H, d, J = 5.9 Hz), 6.88 (2H,
d, J = 8.3 Hz), 6.92 (1H, t, J = 7.3 Hz), 7.2-7.
7 (11H, m), 7.97 (1H, t, J = 5.4 Hz).

B) By the same method as in Example 9, N-
[(2S) -2- (p-biphenylmethyl) -4-methoxycarbonyl-
After reacting 0.43 g of 5-phenoxyvaleryl] -β-alanine benzyl ester (crude isomer B), high performance liquid chromatography (column: Senshupack ODS
-6251-SH 30 φ × 250 mm; Solvent: 56% Acetonilolyl; Flow rate: 10 ml / min)
0.15 g was obtained as a white foam. [α] _D + 13.3 (c = 1.0, methanol). ¹ H-NMR (DMSO-d ₆ , 400 MHz) δ: 1.66 (1H, m), 1.92 (1H, m), 2.1-2.3 (2H, m), 2.5
-2.7 (3H, m), 2.83 (1H, dd, J = 12.7 and 8.3 H
z), 3.1-3.3 (2H, m), 4.05 (1H, dd, J = 9.3 and
7.3 Hz), 4.15 (1H, dd, J = 9.3 and 4.4 Hz), 6.87
(2H, d, J = 7.8 Hz), 6.92 (1H, t, J = 7.3 Hz), 7.2
-7.7 (11H, m), 8.04 (1H, t, J = 5.4 Hz).

[Example 25] Neutral endopeptidase (E
Method for measuring inhibitory activity against C 3.4.24.11) The measurement was carried out by the method of Florentin et al.
in) et al., Anal. Biochem., 141 , 62, 1984).

SD male rats (300-350 g) were anesthetized with Nembutal (40 mg / kg, ip), and the kidneys were excised. pH
7.4) A buffer solution was added and homogenized using Polytron (manufactured by KINEMATICA).

The above buffer solution was added and adjusted so that the final volume was 10 times (V / W, 10 times the value of kidney weight, for example, if the kidney was 5 g, it was 50 ml). did. The mixed solution thus prepared was centrifuged (1000 G, 5 minutes, 4 ° C), and the supernatant thus obtained was further centrifuged (60000 G, 60 minutes,
(4 ° C) to obtain a precipitate. This precipitate is added to 50 mM Tris-HCl.
It was resuspended in (pH 7.4) buffer and used as the neutral endopeptidase enzyme source.

50 μM of synthetic substrate for neutral endopeptidase (dansyl-D-alanyl-glycyl-p-nitrophenylalanyl-glycine) and test compounds, and their inhibition to suppress the activity of angiotensin converting enzyme and aminopeptidase. Agent (captopril 0.5 μM,
Puromycin (0.5 μM) was added and preincubated at 37 ° C. for 15 minutes, then the above-mentioned neutral endopeptidase enzyme source was added, and incubated at 37 ° C. for 30 minutes.
The reaction was stopped by heating at 100 ° C for 5 minutes. After stopping the reaction, add 50 mM Tris-HCl (pH 7.4) buffer and centrifuge (500
0 G, 30 minutes, room temperature), and the supernatant is measured with a fluorometer (λex: 35
5 nm, λex: 538 nm). The effect of the sample is
It can be expressed as the concentration that inhibits hydrolysis of the substrate by 50% (IC ₅₀ ).

As a control of inhibitory activity against neutral endopeptidase, UK-69578 (Da
nilewicz et al., Biochem. Biophys. Res. Commun., 164 ,
58, 1989) was also measured in the same manner.

The measurement results of the compound of the present invention are shown in Table 1.

[0153]

[Table 1]

[0154]

The compounds of the present invention have potent neutral endopeptidase inhibitory activity. Therefore, the compound of the present invention and its salt are expected as a drug for cardiovascular disease and renal disease.

Claims (10)

[Claims] 1. Formula (I): (In the formula, R ¹ represents 1. hydrogen atom, 2. alkyl group, 3. alkylthioalkyl group, 4. hydroxyalkyl group, 5. aminoalkyl group, 6. alkoxyalkyl group or 7. aryloxyalkyl group, A and B independently represent 1. a hydrogen atom, 2. a halogen atom or 3. an alkyl group, and X is a 1. -COOH or 2. group, R ⁴ represents 1. hydrogen atom, 2. alkyl group or 3. arylalkyl group, and m represents an integer of 0, 1 or 2. ) The compound represented by these, its ester, or those salts. 2. Formula (II): [Wherein Y is 1.-COOR ³ or 2. R ¹ and R ⁴ are as defined above, m is an integer of 0, 1 or 2, R ² and R ³ are independently 1. hydrogen atom, 2. alkyl group, 3. arylalkyl Group, 4. aryl group, 5. group, (R ⁵ represents a hydrogen atom, an alkyl group or an aryl group,
R ⁶ represents an alkyl group, an alkoxy group, or a cycloalkyl group. ) 6. Group, embedded image 7. Group, embedded image (R ⁷ represents an alkyl group.) 8. Group, embedded image (R ⁸ represents an alkyl group, and n represents an integer of 1 to 4.) 9. Group, embedded image Or 10. group, (R ⁹ and R ¹⁰ independently represent a hydrogen atom or an alkyl group). ] The compound represented by these, or its salt. 3. Formula (III): [Wherein, R ¹ is as defined above, m represents an integer of 0, 1 or 2, and R ¹¹ and R ¹² are independently 1. hydrogen atom, 2. alkyl group, 3. arylalkyl group or 4. Aryl group, 5. Group, embedded image (R ⁵ represents a hydrogen atom, an alkyl group or an aryl group,
R ⁶ represents an alkyl group, an alkoxy group or a cycloalkyloxy group. ) 6. Group, embedded image 7. Group, embedded image (R ⁷ represents an alkyl group.) 8. Group, embedded image (R ⁸ represents an alkyl group, and n represents an integer of 1 to 4.) 9. Group: embedded image Or 10. groups, (R ⁹ and R ¹⁰ independently represent a hydrogen atom or an alkyl group.)] Or a salt thereof. 4. N-[(2S) -2- (p-biphenylmethyl) -4-carboxy-5-phenoxyvaleryl] glycine, a monoester thereof, a diester thereof or a salt thereof. 5. N-[(2S, 4R) -2- (p-biphenylmethyl) -4-
Carboxy-5-phenoxyvaleryl] glycine, its monoester, its diester or salts thereof. 6. N-[(2S, 4S) -2- (p-biphenylmethyl) -4-
Carboxy-5-phenoxyvaleryl] glycine, its monoester, its diester or salts thereof. 7. N-[(2S) -2- (p-biphenylmethyl) -4-carboxy-5-phenoxyvaleryl] -L-alanine, its monoester, its diester or salts thereof. 8. N-[(2S) -2- (p-biphenylmethyl) -4-ethoxycarbonyl-5-phenoxyvaleryl] glycine or a salt thereof. 9. N-[(2S, 4R) -2- (p-biphenylmethyl) -4-
Ethoxycarbonyl-5-phenoxyvaleryl] glycine or a salt thereof. 10. N-[(2S, 4S) -2- (p-biphenylmethyl)-
4-Ethoxycarbonyl-5-phenoxyvaleryl] glycine or a salt thereof.