JPH07206811A - Thiourea derivative, its production and use - Google Patents

Abstract

PURPOSE:To obtain a new thiourea derivative useful as a production intermediate for N-biphenylmethylthiazoline derivative which is useful as an agent for the treatment of circulatory diseases. CONSTITUTION:This thiourea derivative is a compound of formula 1 [R<1> is (substituted) lower cycloalkyl, a (substituted) phenyl or a lower alkenyl; R<2> is a halogen or cyanophenyl), e.g. N-benzoyl-N'-(2'-cyanobiphenyl-4-yl) methylthiourea. The compound can be produced by reacting an isothiocyanate derivative of formula 2 with a benzylamine compound of formula 3 in an aprotic polar solvent at 0 deg.C to room temperature. An N-biphenylmethylthiazoline of formula 4 [R<3> is H or an alkyl; Y is a (protected) carboxyl or a (protected) carboxymethyl; Z is CN or a (protected) tetrazolyl] can be produced from the thiourea derivative. For example, a compound of formula 4 wherein Z is CN can be produced by reacting a compound of formula 1 wherein R<2> is cyanophenyl with a compound of formula 5 (X1 is a halogen; Y<1> is a protected carboxyl or a protected carboxymethyl) and optionally eliminating the carboxyl- protecting group.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an intermediate for producing an N-biphenylmethylthiazoline derivative useful as a therapeutic agent for cardiovascular diseases such as hypertension, heart disease and stroke, a method for producing the intermediate and an intermediate thereof. The present invention relates to a method for producing an N-biphenylmethylthiazoline derivative used.

[0002]

BACKGROUND OF THE INVENTION Angiotensin II is an active substance of the renin-angiotensin system, has a strong vasoconstrictor action and an action of promoting synthesis and secretion of aldosterone in the adrenal cortex, and is known as a causative agent of hypertension. It is also believed that its action is mediated by specific receptors located on various target organs such as adrenal cortex, kidney, arteriole and sympathetic nerve periphery.

[0003] Angiotensin-converting enzyme inhibitors such as captopril and enalapril, angiotensin II antagonists and renin inhibitors have been known as substances exhibiting an antihypertensive effect by pharmacological inhibition of the renin-angiotensin system. Among these, angiotensin II antagonists include salaracin ([Sar ¹ , Ala ⁸ ] AGII), which is an angiotensin II-like peptide, and imidazole derivatives (JP-A-56-7103 and JP-A-56-71074). Non-peptide derivatives such as a gazette, Japanese Patent Publication No. 3-501020) and a pyrazole derivative (JP-A-3-218371) have also been found.

However, peptide derivatives have a short half-life in vivo, are not effective in oral administration, and have significant agonist activity, so that they are difficult to be applied clinically and are non-peptide. Even in the case of derivatives, no drug has been clinically used.

From this point of view, the present inventors have diligently studied in order to provide a clinically excellent drug, and conducted the following general formula (1
It was found that the N-biphenylmethylthiazolines represented by 2) have an excellent angiotensin II antagonistic action and are useful as a therapeutic agent for cardiovascular diseases such as hypertension, heart disease and stroke, and previously applied for a patent. Yes (PCT / JP93
/ 01134).

[0006]

[Chemical 20]

[In the formula, R ¹ represents a cyclo lower alkyl group which may have a substituent, a phenyl group or a lower alkenyl group which may have a substituent, and R ³ represents a hydrogen atom or a lower alkyl group. Group, Y represents an optionally protected carboxyl group or an optionally protected carboxymethyl group, and Z represents a cyano group or an optionally protected tetrazolyl group].

[0008]

As a method for producing the N-biphenylmethylthiazolines (12), PCT / J is used.
P93 / 01134 describes a method for diphenylmethylating an acid amide type thiazoline, but this method has a drawback that a side reaction occurs and the isolation operation of the target substance becomes difficult. Was not always satisfactory industrially.

Therefore, an object of the present invention is to provide an industrially advantageous method for producing a compound of the above-mentioned general formula (12) which is useful as a medicine.
An object thereof is to provide a production intermediate thereof and a method for producing the intermediate.

[0010]

Therefore, as a result of studying various production methods for solving the above-mentioned problems, the present inventors have found that if a thiourea derivative is used as an intermediate and is cyclized,
The inventors have found that N-biphenylmethylthiazolines (12) can be obtained efficiently and industrially with little side reaction, and have completed the present invention.

That is, the present invention is a compound of the general formula (1) useful as an intermediate for the production of N-biphenylmethylthiazolines (12).

[0012]

[Chemical 21]

[In the formula, R ¹ represents a cyclo lower alkyl group which may have a substituent, a phenyl group which may have a substituent or a lower alkenyl group, and R ² represents a halogen atom or cyanophenyl And a method for producing the same.

The present invention also relates to a process for producing N-biphenylmethylthiazolines (12) using this thiourea derivative (1) as a production intermediate.

In the present invention, the term "lower" used to describe each substituent in each chemical formula, when the substituent is a linear or branched group, has 1 to 7 carbon atoms, preferably 1 to 5 carbon atoms.
And a cyclic group means a group having 3 to 7 carbon atoms.

The cyclo lower alkyl group which may have a substituent includes a cyclopropyl group, a cyclobutyl group,
In addition to cyclopentyl group and cyclohexyl group, 2-fluorocyclopropyl group, 2-chlorocyclopropyl group, 2
Examples thereof include a cyclo-lower alkyl group substituted with a halogen atom such as a -fluorocyclobutyl group and a 2-chlorocyclobutyl group.

Examples of the phenyl group which may have a substituent include a phenyl group and, for example, tolyl, chlorophenyl, dichlorophenyl, trichlorophenyl, fluorophenyl, difluorophenyl, trifluorophenyl, nitrophenyl, dinitrophenyl, cyanophenyl. On the ring such as a lower alkyl group, a halogen atom,
Examples thereof include a phenyl group substituted by 1 to 3 with a nitro group or a cyano group.

Examples of the lower alkenyl group include vinyl group, allyl group, isopropenyl group and the like. Examples of the lower alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a t-butyl group,
Examples thereof include n-pentyl group.

Further, a protecting group for a carboxyl group or a carboxymethyl group means any group which is cleaved relatively easily to give a corresponding free carboxyl group. Specific examples thereof include lower alkyl groups (eg, methyl group, ethyl group, n-propyl group, t-butyl group, etc.), aralkyl groups (eg, benzyl group) or aryl groups (eg, phenyl group). Those which can be eliminated by treatment under mild conditions such as hydrolysis or catalytic reduction; or lower alkanoyloxy lower alkyl groups (eg acetoxymethyl group, pivaloyloxymethyl group etc.), lower alkoxycarbonyloxy Lower alkyl group (eg, methoxycarbonyloxymethyl group, 1-ethoxycarbonyloxyethyl group, etc.), cyclo lower alkylcarbonyloxy lower alkyl group (eg, cyclohexylcarbonyloxymethyl group, cyclopentylcarbonyloxymethyl group, etc.), lower alkoxymethyl Group ( Eg to methoxymethyl group), Rakutoniru group (such as phthalidyl group), di-lower alkylamino-lower alkyl groups (e.g., 1-dimethylaminoethyl group), (5-methyl-2-oxo-1,3
Examples thereof include those that are easily eliminated in vivo such as -dioxol-4-yl) methyl group.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, preferably a fluorine atom and a chlorine atom. In addition, examples of the protective group for the optionally protected tetrazol-5-yl group include a triphenylmethyl group, a 2-tetrahydropyranyl group,
Examples thereof include methoxymethyl group and ethoxymethyl group.

The object compound (12) of the present invention can form a pharmacologically acceptable acid addition salt and base addition salt. Examples of the acid addition salt include (a) salts with mineral acids such as hydrochloric acid and sulfuric acid, (b) salts with organic carboxylic acids such as formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid and maleic acid, (C) Methanesulfonic acid,
Examples thereof include salts with sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid, and examples of the base addition salt include (a) alkali metals such as sodium and potassium. Salt, (b) salt with alkaline earth metals such as calcium and magnesium, (c) ammonium salt,
(D) Trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-
Mention is made of salts with nitrogen-containing organic bases such as methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N, N'-dibenzylethylenediamine. be able to. The object compound (12) of the present invention can exist not only in unsolvated form but also as hydrate or solvate. Therefore, the object compound of the present invention includes all its crystal forms and hydrates or solvates. In addition, since the target compound (12) of the present invention includes one having an asymmetric carbon atom, it can exist as an optically active substance. These optically active compounds are also included in the object compound of the present invention. Furthermore, some of the object compounds (12) of the present invention have two or more asymmetric carbon atoms, and they can exist as different stereoisomers (cis type, trans type). These stereoisomers are also included in the target compound of the present invention.

The intermediate compound (1) of the present invention can be produced, for example, according to the following reaction formula.

[0023]

[Chemical formula 22]

[In the formula, R ² represents a halogen atom or a cyanophenyl group, and R ¹ is the same as above]

That is, the thiourea derivative represented by the general formula (1) is produced by reacting the isothiocyanate derivative represented by the general formula (2) with the benzylamines represented by the general formula (3).

The isothiocyanate derivative (2) used as a raw material can be easily obtained by reacting an acid halide with a thiocyanate such as sodium thiocyanate, potassium thiocyanate or ammonium thiocyanate.

The other starting material, benzylamines, is described in, for example, JP-A-3-148266, J. Med.
Chem. 35, 3714 (1992), J. Me
d. Chem. , 36, 591 (1992), Bio
organic & Medicinal Chemi
story Letters, Volume 2, 1775 (199)
As described in 2) and the like, it can be obtained by azide-forming and reducing biphenylmethyl bromide, or by phthalimidizing biphenylmethyl bromide and hydrolyzing it.

The reaction of the isothiocyanate derivative (2) with benzylamines can be carried out by using methylene chloride, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride and chlorobenzene; aromatic hydrocarbons such as benzene, toluene and acetone; ethers such as tetrahydrofuran and dioxane, or aprotic polar solvents such as acetonitrile and N, N-dimethylformamide , Stirring at 0 ° C. to room temperature.

The thiourea derivative (1) thus obtained
Can be converted to N-biphenylmethylthiazolines (12) useful as a cardiovascular disease therapeutic agent according to the following reaction formula (A) or (B).

[0030]

[Chemical formula 23]

[In the formula, R ³ represents a hydrogen atom or a lower alkyl group, X ¹ represents a halogen atom, Y ¹ represents a protected carboxyl group or a protected carboxymethyl group, and Y is protected. Optionally a carboxyl group or an optionally protected carboxymethyl group, R ¹ is the same as the above]

That is, the thiourea derivative (1-a) is reacted with α-halogenoketones (4), and the carboxyl protecting group is eliminated as desired to give N-cyanobiphenylmethylthiazolines (12-a) or its derivative. Salt is produced. Further, the obtained N-cyanobiphenylmethylthiazolines (12-a) is reacted with a metal azide compound, and the carboxyl protecting group is eliminated as desired to give N-tetrazolylbiphenylmethylthiazolines (12-b). ) Or a salt thereof is produced.

Examples of the α-halogenoketones (4) used here include 3-halogeno-2-oxopentanoic acid ester and 4-halogenoacetoacetic acid ester.

The reaction between the thiourea derivative (1-a) and the α-halogenoketones (4) is carried out by alcohols such as methanol, ethanol and isopropyl alcohol, nitriles such as acetonitrile and isobutyronitrile, acetone, methyl ethyl ketone, Methyl isobutyl ketone, ketones such as cyclohexanone, aromatic hydrocarbons such as benzene, toluene, xylene, diethyl ether, tequahydrofuran, dioxane, ethers such as diethylene glycol dimethyl ether, hexane, heptane,
Aliphatic hydrocarbons such as ligroin, petroleum ether, esters such as ethyl formate, ethyl acetate, butyl acetate, N,
Pyridine, N, N in the presence or absence of a solvent that does not adversely affect the condensation ring-closure reaction such as acid amides such as N-dimethylformamide, sulfur compounds such as dimethyl sulfoxide and sulfolane, water or a mixture thereof. -Tertiary amines such as dimethylaniline, N, N-diethylaniline, N-methylmorpholine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.0] undec-7-ene, potassium carbonate, sodium carbonate , In the presence of an inorganic base such as cesium carbonate, thallium carbonate, potassium hydroxide, sodium hydroxide, thallium hydroxide, or alkoxides of these alkali metals at a temperature of 80 to 150 ° C. for 1 to 10 hours. preferable.

Examples of the metal azide compound used in the above reaction include trimethyltin azide, triethyltin azide, tri-n-butyltin azide, trimethylsilyl azide, triethylsilyl azide and sodium azide.

The reaction between the N-cyanobiphenylmethylthiazolines (12-a) and the metal azide compound is carried out by heating under reflux in a hydrocarbon solvent such as benzene, toluene, xylene and dioxane for 1 to 80 hours. Is preferred. Since the target compound is obtained as a metal salt by this reaction, the N-tetrazolylbiphenylmethylthiazoline (1
2-c) is produced.

The elimination reaction of the carboxyl-protecting group of N-cyanobiphenylmethylthiazolines (12-a) or N-tetrazolylbiphenylmethylthiazolines (12-c) depends on the protecting group of the carboxyl group. When the protecting group is an ester residue, an ordinary hydrolysis reaction may be performed, and when the protecting group is a hydrogenolytic group such as a benzyl group, a mild catalytic reduction reaction may be performed.

[0038]

[Chemical formula 24]

[In the formula, P is a hydrogen atom or tetrazolyl group
Indicates a guardian, R¹, R³, X¹, Y¹, X ²And Y are
the same〕

That is, the thiourea derivative (1-b) was reacted with α-halogenoketones (4) to obtain N-
N-biphenylmethylthiazolines or salts thereof (12-e) are produced by reacting benzylthiazolines (5) with phenylboronic acids (6) and removing the carboxyl protecting group if desired.

The reaction between the thiourea derivative (1-b) and the α-halogenoketone (4) is carried out in the same manner as the reaction between the thiourea derivative (1-a) and the α-halogenoketone (4). . The reaction of the obtained N-benzyl thiazolines (5) with phenylboronic acids (6) is carried out using benzene, toluene, ether, tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, ethanol, methanol, propanol, dimethoxyethane. , A non-nucleophilic tertiary amine such as triethylamine or diisopropylethylamine, potassium carbonate, sodium carbonate, cesium carbonate, thallium carbonate in the presence of a nickel complex, a platinum complex, preferably a palladium complex in a suitable solvent such as water. It is preferable to carry out under basic conditions by adding an inorganic base such as potassium hydroxide, sodium hydroxide or thallium hydroxide, or an alkoxide of these alkali metals. When using an inorganic base that is insoluble in an organic solvent, it must be used as an aqueous solution.
It is preferably carried out in the presence of a phase transfer catalyst such as n-butylammonium bromide or crown ether. Examples of the palladium complex used in this reaction include tetrakis (triphenylphosphine) palladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium, and a divalent palladium phosphine complex. Examples of the divalent palladium phosphine complex include bis (triphenylphosphine) palladium chloride, bis (triphenylphosphine) palladium bromide, bis (triphenylphosphine) palladium acetate, bis (triisopropylphosphite) palladium chloride, bis (triisopropyl). Phosphite) palladium bromide, bis (triisopropylphosphite) palladium acetate, [1,2-bis (diphenylphosphino) ethane] palladium chloride, [1,2-bis (diphenylphosphino) ethane]
Palladium bromide, [1,2-bis (diphenylphosphino) ethane] palladium acetate, [1,3-bis (diphenylphosphino) propane] palladium chloride, [1,3-bis (diphenylphosphino) propane] palladium bromide , [1,3-bis (diphenylphosphino) propane] palladium acetate, [1,
4-bis (diphenylphosphino) butane] palladium chloride, [1,4-bis (diphenylphosphino) butane] palladium bromide, [1,4-bis (diphenylphosphino) butane] palladium acetate can be mentioned. In this reaction, the catalyst can be activated in the reaction mixture. For example, tris (dibenzylideneacetone) dipalladium is added to the reaction mixture containing triphenylphosphine, and the activated triphenylphosphine palladium complex is formed. The catalyst is activated by divalent palladium salts such as palladium chloride, palladium bromide, palladium acetate and triarylphosphine, generally dialkylzinc, alkylzinc halide, dialkylmagnesiumalkylmagnesium halide, trialkylaluminum, dialkylaluminum halide. Alternatively, triphenylphosphine can be reacted in the presence of a reducing agent such as sodium borohydride, hydrazine, arylboronic acid, preferably diethylzinc. This reaction is usually carried out at room temperature to 150 ° C, preferably 60 to 110 ° C, and the reaction time is usually 1 to
30 hours. Phenylboronic acids (6) used in this reaction include, for example, USP 5130439, WO93 /
10106 as described in 10
React with butyl lithium etc. to make an alkali metal salt,
It is obtained by reacting a boronic acid ester such as isopropyl borate. The elimination reaction of the protective group of the obtained N-biphenylmethylthiazolines is carried out in the same manner as in the case of the above reaction formula (A).

The obtained N-biphenylmethylthiazolines (12) or a salt thereof can be isolated by a conventional method, that is, recrystallization, extraction, chromatography and the like.

[0043]

According to the method of the present invention, N which is useful as a medicine is
-Biphenylmethyl thiazolines (12) or salts thereof can be industrially advantageously produced in high yield.

[0044]

The present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.

Example 1 0.94 ml of N-benzoyl-N '-(2'-cyanobiphenyl-4-yl) methylthiourea benzoyl isothiocyanate was added to chloroform 10
In addition to ml, (2'-cyanobiphenyl-4-yl) methylamine
A solution of 1.46 g of chloroform in 3 ml was added slowly. Stir for 30 minutes at room temperature. The solvent was distilled off. n-Hexane and ether were added to solidify, and the solid was collected by filtration. 2.70 g of the title compound was obtained. (100%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 5.01 (2H, d, J = 6Hz), 7.39-7.86 (13H, m), 9.07 (1H, brs)

Example 2 2-Benzoylimino-3- (2'-cyanobiphenyl-4-yl)
To 910 mg of methyl-5-ethylthiazoline-4-carboxylic acid ethyl ester 3-chloro-2-oxopentanoic acid ethyl ester,
N-benzoyl-N '-(2'-cyanobiphenyl-4-yl) methylthiourea (520 mg) and pyridine (0.11 ml) were added, and 90-1
Heated at 00 ° C. overnight. It was extracted with 20 ml of chloroform and washed with 20 ml of dilute hydrochloric acid. After drying over magnesium sulfate, the solvent was distilled off. Column chromatography (silica gel 60 g,
Separation with an elution solvent; chloroform) gave 100 mg of the title compound. (14%) Properties Brown oil ¹ H-NMR (δppm in CDCl ₃ ) 1.30-1.37 (6H, m), 2.99 (2H, q, J = 8Hz), 4.35 (2H, q, J = 7H
z), 6.04 (2H, s), 7.39-7.75 (11H, m), 8.33 (2H, d, J = 6Hz)

Example 3 2-Benzoylimino-3- (2'-cyanobiphenyl-4-yl)
Methyl-5-ethylthiazolin-4-carboxylic acid 100 mg of the ester obtained in Example 2 was added to 8 ml of ethanol,
It was suspended in 8 ml of water, 1.5 ml of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred for 1 hour and a half. The mixture was acidified with 6N hydrochloric acid and extracted with 50 ml of ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off. Column chromatography (silica gel 4
g, elution solvent; chloroform), ether, n-
Hexane was added, and the solidified solid was collected by filtration. 8 mg of the title compound was obtained. (9%) Properties Light yellow powder ¹ H-NMR (δppm in CDCl ₃ ) 1.35 (3H, t, J = 8Hz), 3.09 (2H, q, J = 7Hz), 6.09 (2H, s), 7.
41-7.76 (11H, m), 8.33 (2H, d, J = 7Hz)

Example 4 2-Benzoylimino-3- (2'-cyanobiphenyl-4-yl)
Methyl thiazoline-4-carboxylic acid ethyl ester N-benzoyl-N '-(2'-cyanobiphenyl-4-yl) methylthiourea 371 mg, bromopyruvic acid ethyl ester
Add 0.25 ml and pyridine 0.08 ml, and add 1 at 90-100 ℃.
Heated for half an hour. After extraction with 15 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. Add ether,
The solid was filtered off. 363 mg of the title compound was obtained. (71%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 1.35 (3H, t, J = 7Hz), 4.34 (2H, q, J = 7Hz), 6.14 (2H, s), 7.
40-7.76 (12H, m), 8.32-8.36 (2H, m)

Example 5 2-benzoylimino-3- [2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methylthiazoline-3-carboxylic acid ethyl ester 2-benzoylimino-3- (2'-cyanobiphenyl-4-yl) methylthiazoline-4-carboxylic acid ethyl ester obtained in Example 4 307 mg and trimethyltin azide 370 mg were added to toluene 15 ml, and the mixture was heated under reflux for 24 hours. After allowing to cool, the crystals were collected by filtration. It was washed with toluene and n-hexane to obtain 380 mg of trimethyltin salt. The obtained trimethyltin salt was suspended in 5 ml of ethanol, and 4m hydrochloric acid-dioxane solution 8m
l was added. The mixture was stirred at room temperature for 1.5 hours. Add 20 ml of water,
It was extracted with 40 ml of ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off. Separation was carried out by column chromatography (silica gel 20 g, elution solvent; chloroform followed by ethyl acetate). Ether was added and the solid was collected by filtration. 83
Obtained mg of the title compound. (28%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 1.37 (3H, t, J = 7Hz), 4.36 (2H, q, J = 7Hz), 6.09 (2H, s), 7.
18-7.69 (12H, m), 8.30 (2H, d, J = 8Hz)

Example 6 2-Benzoylimino-3- [2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methylthiazoline-3-carboxylic acid 70 mg of the compound obtained in Example 5 was suspended in 3 ml of ethanol, 1 ml of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 1 hour and a half. Acidify with 6N hydrochloric acid and add ethyl acetate 40
extracted with ml. After drying over sodium sulfate, the solvent was distilled off. n-Hexane was added, and the solid was collected by filtration. 38 mg of the title compound was obtained. (60%) Properties Colorless powder ¹ H-NMR (δppm in DMSO-d ₆ ) 5.97 (2H, s), 7.06 (2H, d, J = 8Hz), 7.22 (2H, d, J = 8Hz), 7.
46-7.65 (8H, m), 8.15-8.18 (2H, m)

Example 7 2-Benzoylimino-3- (2'-cyanobiphenyl-4-yl)
Methyl-5-n-propylthiazoline-4-carboxylic acid ethyl ester To 371 mg of the thiourea derivative obtained in Example 1, 3-bromo-2-
474 mg of oxohexanoic acid ethyl ester and 0.08 ml of pyridine were added, and the mixture was heated at 90 to 95 ° C for 2 hours. After extraction with 10 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. Column chromatography (silica gel 15
g, elution solvent; chloroform) to give 457 mg of the title compound as an oil. (90%) Properties Light yellow oil ¹ H-NMR (δppm in CDCl ₃ ) 1.00 (3H, t, J = 7Hz), 1.30 (3H, t, J = 7Hz), 1.66-1.77 (2H,
m), 2.93 (2H, t, J = 7Hz), 4.31 (2H, q, J = 7Hz), 6.05 (2H, s),
7.38-7.77 (11H, m), 8.30-8.34 (2H, m)

Example 8 2-Benzoylimino-3- [2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methyl-5-n-propylthiazoline-3-
Carboxylic acid ethyl ester 450 mg of the compound obtained in Example 7 and 545 mg of trimethyltin azide were added to 20 ml of toluene, and the mixture was heated under reflux for 40 hours.
The solvent was distilled off. 12 ml of dioxane was added to the residue and concentrated hydrochloric acid was added.
10 ml was added. The mixture was stirred at room temperature for 1.5 hours. 40 ml of water was added and extracted with 40 ml of ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off. Ethyl acetate was added and the solid was collected by filtration. 108 mg of the title compound was obtained. (22%) Properties colorless powder ¹ H-NMR (δppm in DMSO-d ₆ ) 0.94 (3H, t, J = 7Hz), 1.20 (3H, t, J = 7), 1.61-1.69 (2H, m),
2.92 (2H, t, J = 7Hz), 4.25 (2H, q, J = 7Hz), 5.83 (2H, s),
7.06 (2H, d, J = 8Hz), 7.15 (2H, d, J = 8Hz), 7.45-7.68 (11H,
m), 8.14-8.17 (2H, m)

Example 9 2-Benzoylimino-3- [2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methyl-5-n-propylthiazoline-3-
Carboxylic acid 95 mg of the compound obtained in Example 8 was suspended in 2 ml of ethanol, 1 ml of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. The mixture was acidified with 6N hydrochloric acid and filtered through a gradient. Ethanol was added, the solvent was distilled off, and this operation was repeated 3 times. Ether was added, gradient filtration was repeated 3 times, n-hexane was added, and the solid was collected by filtration. 30 mg of the title compound was obtained. (34%) Properties Colorless powder ¹ H-NMR (δppm in DMSO-d ₆ ) 0.94 (3H, t, J = 7Hz)), 1.61-1.70 (2H, m), 2.96 (2H, t, J = 7H)
z), 5.89 (2H, s), 7.07 (2H, d, J = 8Hz), 7.17 (2H, d, J = 8Hz),
7.38-7.63 (11H, m), 8.15 (2H, d, J = 8Hz)

Example 10 2-Benzoylimino-3- (2'-cyanobiphenyl-4-yl)
Methyl thiazoline-4-acetic acid ethyl ester To 0.41 ml of 4-chloroacetoacetic acid ethyl ester, Example 1
557 mg of the thiourea compound obtained in 1. and 0.12 ml of pyridine
Was added and heated at 80 to 90 ° C for 50 minutes. It was extracted with 40 ml of chloroform and washed with 20 ml of dilute hydrochloric acid. After drying over magnesium sulfate, the solvent was distilled off. Column chromatography (silica gel 50 g, elution solvent; ethyl acetate: n-hexane = 1: 1)
Separation in 2) gave 650 mg of the title compound. (90%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 1.28 (3H, t, J = 7Hz), 3.62 (2H, s), 4.17 (2H, q, J = 7Hz), 5.
74 (2H, s), 6.62 (1H, s), 7.35-7.77 (11H, m), 8.29-8.32 (2
H, m)

Example 11 2-Benzoylimino-3- (2'-cyanobiphenyl-4-yl)
Methylthiazoline-4-acetic acid 50 mg of the ester obtained in Example 10 was suspended in 5 ml of ethanol and 5 ml of water, 1.5 ml of 10% sodium hydroxide aqueous solution was added, and the mixture was stirred for 2.5 hours. 6
The mixture was acidified with normal hydrochloric acid and extracted with 20 ml of ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off. Ether was added and the solidified solid was collected by filtration. Obtained 10 mg of the title compound. (21%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 3.65 (2H, s), 5.74 (2H, s), 6.65 (1H, s), 7.35-7.75 (11H,
m), 8.27-8.30 (2H, s)

Example 12 2-Benzoylimino-3- [2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methylthiazoline-4-acetic acid ethyl ester trimethyltin salt The compound (500 mg) obtained in Example 11 and trimethyltin azide (236 mg) were added to toluene (5 ml), and the mixture was heated under reflux for 12 hours and a half. 100 mg of trimethyltin azide was added, and the mixture was heated under reflux for 9 hours. After allowing to cool, the crystals were collected by filtration. Washing with a small amount of ethyl acetate gave 270 mg of the title compound. (38%) Properties colorless powder

Example 13 2-Benzoylimino-3- [2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methylthiazoline-4-acetic acid ethyl ester 260 mg of the trimethyltin salt obtained in Example 12 was suspended in 5 ml of ethanol, and 5 ml of a 4N hydrochloric acid-dioxane solution was added. Stir at room temperature for 4 hours. 80 ml of ethyl acetate was added, and the mixture was washed twice with 40 ml of water. After drying with magnesium sulfate,
The solvent was distilled off. Chloroform and ether were added to solidify, and the solvent was evaporated. Ether was added and the solid was collected by filtration. Obtained 100 mg of the title compound. (50%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 1.25 (3H, t, J = 7Hz), 3.57 (2H, s), 4.08 (2H, q, J = 7Hz), 5.
67 (2H, s), 6.58 (1H, s), 7.14-7.60 (10H, m), 8.12-8.23 (3
H, m)

Example 14 2-Benzoilumino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methylthiazoline-4-acetic acid 80 mg of the ester obtained in Example 13 was added to 3 ml of ethanol.
The suspension was suspended in and 0.5 ml of a 10% aqueous sodium hydroxide solution was added.
The mixture was stirred at room temperature for 2 hours. The mixture was acidified with 6N hydrochloric acid and extracted with 20 ml of ethyl acetate. After drying over sodium sulfate, the solvent was distilled off. Ether was added and the solid was collected by filtration. 66 mg of the title compound was obtained. (89%) Properties Colorless powder ¹ H-NMR (δppm in DMSO-d ₆ ) 3.70 (2H, s), 5.59 (2H, s), 6.98-7.66 (11H, m), 8.15 (2H,
(d, J = 7Hz)

Example 15 N-Cyclopropylcarbonyl-N '-(2'-cyanobiphenyl
2.20 g of 4--4-yl) methylthiourea cyclopropylcarbonylisothiocyanate was added to 20 ml of chloroform, and 3.60 g of (2'-cyanobiphenyl-4-yl) methylamine was slowly added. The mixture was stirred at room temperature for 2 hours, and the solvent was distilled off. Separation was performed by column chromatography (silica gel 250 g, elution solvent: chloroform), ether was added, and the solid was collected by filtration. 3.27 for the title compound
g got. (57%) Properties colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 0.96-1.03 (2H, m), 1.08-1.14 (2H, m), 1.44-1.49 (1H, m),
4.93 (2H, d, J = 5Hz), 7.45-7.79 (8H, m), 8.87 (1H, brs)

Example 16 2-Cyclopropylcarbonylimino-3- (2'-cyanobiphenyl-4-yl) methylthiazoline-4-acetic acid ethyl ester To 0.41 ml of 4-chloroacetoacetic acid ethyl ester, Example 1 was added.
503 mg of thiourea compound obtained in 5 and 0.12 m of pyridine
was added and the mixture was heated at 80 to 90 ° C. for 1 hour and a half. Chloroform 2
It was extracted with 0 ml and washed with 20 ml of diluted hydrochloric acid. After drying over magnesium sulfate, the solvent was distilled off. Separation by column chromatography (silica gel 40 g, elution solvent; chloroform) gave 710 mg of the title compound. (100%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 0.84-0.87 (2H, m), 1.05-1.06 (2H, m), 1.26 (3H, t, J = 7H
z), 1.93 (1H, brs), 3.55 (2H, s), 4.15 (2H, q, J = 7Hz), 5.6
1 (2H, s), 6.53 (1H, s), 7.26-7.78 (8H, m)

Example 17 2-Cyclopropylcarbonylimino-3- (2'-cyanobiphenyl-4-yl) methylthiazoline-4-acetic acid 94 mg of the ester obtained in Example 16 was added to 3 m of ethanol.
l, suspended in 3 ml of water, 0.5 ml of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred for 1 hour and a half. The mixture was acidified with 6N hydrochloric acid and extracted with 20 ml of ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off. Ether was added and the solidified solid was collected by filtration. Obtained 25 mg of the title compound. (28%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 1.09, 0.88 (each 2H, each s), 1.95 (1H, brs), 3.60 (2H,
s), 5.70 (2H, s), 6.65 (1H, s), 7.28-7.76 (8H, m)

Example 18 2-Cyclopropylcarbonylimino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methylthiazoline-4
-Acetic acid ethyl ester trimethyltin salt 2-Cyclopropylcarbonylimino-3- (2'-cyanobiphenyl-4-yl) methylthiazoline-4-acetic acid 573 mg obtained in Example 17 and trimethyltin azide 291 mg were added to toluene 5 ml. And heated to reflux for 19 hours. 120 mg of trimethyltin azide was added, and the mixture was heated under reflux for 5 hours. After allowing to cool, the crystals were collected by filtration. Wash with a small amount of ethyl acetate, 390mg
The title compound of was obtained. (46%)

Example 19 2-Cyclopropylcarbonylimino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methylthiazoline-4
-Acetic acid ethyl ester 240 mg of trimethyltin salt obtained in Example 18 was suspended in 5 ml of ethanol, and 5 ml of 4N hydrochloric acid-dioxane solution was added. The mixture was stirred at room temperature for 2 hours. 80 ml of ethyl acetate was added, and the mixture was washed twice with 40 ml of water. After drying with magnesium sulfate,
The solvent was distilled off. It was separated by column chromatography (silica gel 8 g, elution solvent; ethyl acetate). Ether was added and the solid was collected by filtration. Obtained 100 mg of the title compound. (56
%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 0.82-8.85 (2H, m), 0.97-0.99 (2H, m), 1.20 (3H, t, J = 7H
z), 1.84-1.90 (1H, m), 3.53 (2H, s), 4.07 ((2H, q, J = 7H
z), 5.56 (2H, s), 6.48 (1H, s), 7.09-7.61 (7H, m), 8.04-
8.07 (1H, m)

Example 20 2-Cyclopropylcarbonylimino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methylthiazoline-4
-Acetic acid 80 mg of the compound obtained in Example 19 was suspended in 3 ml of ethanol, and 0.4 ml of 10% aqueous sodium hydroxide solution was added. Stir overnight at room temperature. Acidify with 6N hydrochloric acid and add ethyl acetate
Extracted with 30 ml. After drying over sodium sulfate, the solvent was distilled off. Ether was added and the solid was collected by filtration. Obtained 50 mg of the title compound. (68%) Properties Colorless powder ¹ H-NMR (δppm in DMSO-d ₆ ) 0.76-0.82 (4H, m), 1.70-1.73 (1H, m), 3.62 (2H, s), 5.39
(2H, s), 6.84 (1H, s), 7.08 (4H, s), 7.52-7.70 (4H, m)

Example 21 N- (2-chlorobenzoyl) -N '-(2'-cyanobiphenyl-4-
) Methylthiourea Potassium thiocyanate (534 mg), which was dried by heating at 110 ° C for 1 hour, was finely crushed in a mortar and mixed with acetone (5).
in addition to 0.6 ml of o-chlorobenzoyl chloride,
The mixture was heated under reflux for 50 minutes. Bring to room temperature, and then (2'-cyanobiphenyl
4-yl) methylamine (1.04 g) was added slowly. Stirred for one and a half hours at room temperature. After extraction with 50 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. Ether was added to solidify. The obtained solid was collected by filtration to give the title compound as 1.
I got 80g. (89%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 5.01 (2H, d, J = 6Hz), 7.38-7.80 (12H, m)

Example 22 2- (2-Chlorobenzoyl) imino-3- (2'-cyanobiphenyl-4-yl) methyl-5-n-propylthiazoline-4-carboxylic acid ethyl ester Obtained in Example 21. Compound 812 mg, 3-bromo-2-oxohexanoic acid ethyl ester 948 mg, and pyridine 0.1
6 ml was added, and the mixture was heated at 90 to 95 ° C. for 2 hours and a half. After extraction with 20 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. Column chromatography (silica gel 60 g,
Separation with an elution solvent; chloroform) gave 460 mg of an oil. (42%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 1.00 (3H, t, J = 8Hz), 1.39 (3H, t, J = 7Hz), 1.66-1.80 (2H,
m), 2.94 (2H, q, J = 8Hz), 4.37 (2H, q, J = 7Hz), 5.99 (2H, s),
7.29-8.06 (12H, m)

Example 23 2- (2-chlorobenzoyl) imino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-propylthiazoline-3-carboxylic acid Ethyl ester 460 mg of the compound obtained in Example 22 and 568 mg of trimethyltin azide were added to 15 ml of dioxane, and the mixture was heated under reflux for 3 days. After returning to room temperature, 10 ml of concentrated hydrochloric acid was added. The mixture was stirred at room temperature for 40 minutes and a half. 20 ml of water was added, and the mixture was extracted with 40 ml of ethyl acetate.
After drying over magnesium sulfate, the solvent was distilled off. Separation was performed by column chromatography (silica gel 45 g, elution solvent; ethyl acetate: n-hexane = 3: 2). Ether, n-
Hexane was added, and the solid was collected by filtration. 70 mg of the title compound was obtained. (15%) Properties Light yellow powder ¹ H-NMR (δppm in CDCl ₃ ) 1.00 (3H, t, J = 7Hz), 1.34 (3H, t, J = 7Hz), 1.67-1.77 (2H,
m), 2.92 (2H, t, J = 7Hz), 4.31 (2H, q, J = 7Hz), 5.91 (2H,
s), 7.12-7.57 (10H, m), 7.92 (1H, d, J = 7Hz), 8.05 (1H, d, J
= 8Hz)

Example 24 2- (2-chlorobenzoyl) imino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-propylthiazoline-3-carboxylic acid Compound 60m obtained in Example 23
g was suspended in 2 ml of ethanol, 1 ml of 10% sodium hydroxide aqueous solution was added, and the mixture was stirred overnight at room temperature. The mixture was acidified with 6N hydrochloric acid and extracted with 30 ml of ethyl acetate. It was dried over magnesium sulfate and the solvent was distilled off. Ether and n-hexane were added, and the solvent was evaporated. n-Hexane was added, and the solid was collected by filtration. Obtained 48 mg of the title compound. (83%) Properties Light yellow powder ¹ H-NMR (δppm in DMSO-d ₆ ) 0.94 (3H, t, J = 7Hz), 1.59-1.73 (2H, m), 2.98 (2H, t, J = 7H
z), 5.82 (2H, s), 7.04-7.81 (12H, m)

Example 25 2-Cyclopropylcarbonylimino-3- (2'-cyanobiphenyl-4-yl) methyl-5-n-propylthiazoline-4-carboxylic acid ethyl ester 503 mg of the compound obtained in Example 15 , 3-bromo-2-oxohexanoic acid ethyl ester 713 mg, and pyridine 0.1
2 ml was added and heated at 90-95 ° C for 2 hours. Chloroform 2
The mixture was extracted with 0 ml, dried over magnesium sulfate, and the solvent was distilled off. Separation by column chromatography (silica gel 30 g, elution solvent; chloroform) and further purification by column chromatography (silica gel 40 g, elution solvent; ethyl acetate: n-hexane = 1: 4) gave 186 mg of the title compound as an oil. It was (26%) Properties Light yellow oil ¹ H-NMR (δppm in CDCl ₃ ) 0.86-1.08 (7H, m), 1.27 (3H, t, J = 7Hz), 1.59-1.69 (3H,
m), 2.88 (2H, q, J = 8Hz), 4.23 (2H, q, J = 7Hz), 5.92 (2H, s),
7.26-7.74 (8H, m)

Example 26 2-Cyclopropylcarbonylimino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-propylthiazoline-3-carboxylic acid ethyl ester Example 25
186 mg of the compound obtained in 1. and 241 mg of trimethyltin azide were added to 15 ml of dioxane, and the mixture was heated under reflux overnight. 80 mg of trimethyltin azide was added, and the mixture was further heated and refluxed for one day. After returning to room temperature, 5 ml of concentrated hydrochloric acid was added. The mixture was stirred at room temperature for 40 minutes and a half. 20 ml of water was added, and the mixture was extracted with 40 ml of ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off. Column chromatography (silica gel 20 g, elution solvent; ethyl acetate: n
-Separated with hexane = 1: 3). Ether and n-hexane were added, and the solid was collected by filtration. Obtained 49 mg of the title compound.
(26%) Properties Light yellow amorphous ¹ H-NMR (δppm in CDCl ₃ ) 0.84-0.99 (7H, m) 1.30 (3H, t, J = 7Hz), 1.54-1.62 (2H, m),
1.86 (1H, brs), 2.80 (2H, t, J = 7Hz), 4.27 (2H, q, J = 7Hz),
5.80 (2H, s), 7.06-8.03 (8H, m)

Example 27 2-Cyclopropylcarbonylimino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-propylthiazoline-3-carboxylic acid Example 26 45 mg of the compound obtained in 1. was suspended in 0.5 ml of ethanol, 0.5 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. Acidify with 6N hydrochloric acid and add ethyl acetate
Extracted with 20 ml. It was dried over magnesium sulfate and the solvent was distilled off. Ether and n-hexane were added, and the solvent was evaporated. n-Hexane was added, and the solid was collected by filtration. 16 mg of the title compound was obtained. (37%) Properties Light yellow powder ¹ H-NMR (δppm in DMSO-d ₆ ) 0.79-0.96 (7H, m), 1.56-1.64 (2H, m), 1.73 (1H, brs), 2.
90 (2H, t, J = 7Hz), 5.69 (2H, s), 7.06 (4H, s), 7.52-7.67 (4
H, m)

Example 28 2-Cyclopropylcarbonylimino-3- (2'-cyanobiphenyl-4-yl) methyl-5-ethylthiazoline-4-carboxylic acid ethyl ester To 671 mg of the thiourea compound obtained in Example 15 was obtained. , 3-bromo-
2-Oxopentanoic acid ethyl ester (892 mg), pyridine (0.16 ml) and ethanol (2 ml) were added, and the mixture was heated at 90 to 95 ° C for 4 hours. Extract with 20 ml of chloroform and add 20 ml of saturated saline.
After washing with water and drying over magnesium sulfate, the solvent was distilled off.
Separation by column chromatography (silica gel 60 g, elution solvent; ethyl acetate: n-hexane = 1: 4) gave 168 mg of the title compound as an oil. (18%) Properties Yellow oil ¹ H-NMR (δppm in CDCl ₃ ) 0.93-1.00 (2H, m), 1.10-1.18 (2H, m), 1.25-1.32 (6H, m),
1.50-1.62 (1H, m), 2.95 (2H, q, J = 7Hz), 4.30 (2H, q, J = 7H
z), 6.01 (2H, s), 7.30-7.79 (8H, m)

Example 29 2-Cyclopropylcarbonylimino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-ethylthiazoline-4-carboxylic acid ethyl ester Example 28 160 mg of the compound obtained in 1. and 144 mg of trimethyltin azide were added to 10 ml of dioxane, and the mixture was heated under reflux overnight. 144 mg of trimethyltin azide was added, and the mixture was heated under reflux for 8 hours and a half, and 290 mg of trimethyltin azide was added, and the mixture was heated under reflux for 3 days.
After returning to room temperature, 5 ml of concentrated hydrochloric acid was added. It was stirred at room temperature for 1 hour. 40 ml of water was added, and the mixture was extracted with 60 ml of ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off. Separation was carried out by column chromatography (silica gel 20 g, elution solvent; chloroform followed by ethyl acetate). n-Hexane was added, and the solid was collected by filtration. 76 mg of the title compound was obtained. (43%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 0.86-0.88 (2H, m), 1.02-1.05 (2H, m), 1.22-1.35 (6H, m),
1.62 (1H, brs), 2.91 (2H, t, J = 8Hz), 4.30 (2H, q, J = 7Hz),
5.84 (2H, s), 7.13-7.59 (7H, m), 8.12-8.15 (1H, m)

Example 30 2-Cyclopropylcarbonylimino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-ethylthiazoline-4-carboxylic acid Obtained in Example 29. 70 mg of the obtained compound was suspended in 2 ml of ethanol, 1 ml of 10% sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 3 days.
Stir for half an hour. Acidify with 6N hydrochloric acid and wash with ethyl acetate 40
extracted with ml. It was dried over magnesium sulfate and the solvent was distilled off. n-Hexane was added, and the solid was collected by filtration. Obtained 45 mg of the title compound. (66%) Properties Colorless powder ¹ H-NMR (δppm in DMSO-d ₆ ) 0.79-0.82 (4H, m), 1.17 (3H, t, J = 7Hz), 1.69-1.75 (1H,
m), 2.93 (2H, t, J = 7Hz), 5.70 (2H, s), 7.06 (4H, m), 7.52-
7.63 (4H, m)

Example 31 2-Cyclopropylcarbonylimino-3- (2'-cyanobiphenyl-4-yl) methyl-5-n-pentylthiazoline-4-carboxylic acid ethyl ester Thiourea derivative obtained in Example 15 To 1.69 g, 2.65 g of 3-bromo-2-oxooctanoic acid ethyl ester, 0.4 ml of pyridine and 5 ml of ethanol were added, and the mixture was heated at 90 to 95 ° C for 1 hour and a half. It was extracted with 20 ml of chloroform, washed with 20 ml of saturated saline and dried over magnesium sulfate, and then the solvent was distilled off. Column chromatography (200 g of silica gel, elution solvent; ethyl acetate: n-hexane =)
Separation 1: 4) gave 372 mg of the title compound as an oil.
(15%) Properties Yellow oil ¹ H-NMR (δppm in CDCl ₃ ) 0.89 (5H, m), 1.09 (2H, brs), 1.27 (3H, t, J = 7Hz), 1.50-
1.66 (7H, m), 2.89 (2H, q, J = 7Hz), 4.27 (2H, q, J = 7Hz), 5.8
9 (2H, s), 7.28-7.77 (8H, m)

Example 32 2-Cyclopropylcarbonylimino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-pentylthiazoline-4-carboxylic acid ethyl ester The compound (370 mg) obtained in Example 31 and trimethyltin azide (304 mg) were added to dioxane (6 ml), and the mixture was heated under reflux overnight.
304 mg of trimethyltin azide was added, and the mixture was further heated and refluxed for one day. Trimethyltin azide (600 mg) was added, and the mixture was further heated and refluxed for one day. After returning to room temperature, 5 ml of concentrated hydrochloric acid was added. The mixture was stirred at room temperature for 20 minutes and a half. 20 ml of water was added, and the mixture was extracted with 40 ml of ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off. Column chromatography (silica gel 70
g, elution solvent; chloroform followed by ethyl acetate). n-Hexane was added, and the solid was collected by filtration. 161 mg of the title compound was obtained. (40%) Properties Brown oil ¹ H-NMR (δppm in CDCl ₃ ) 0.89 (5H, s), 1.06 (2H, s), 1.25-1.40 (7H, m), 1.62 (3H, b
rs), 2.88 (2H, t, J = 8Hz), 4.30 (2H, q, J = 7Hz) 5.85 (2H, s),
7.15-7.57 (7H, m), 8.18 (1H, d, J = 11Hz)

Example 33 2-Cyclopropylcarbonylimino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-pentylthiazoline-4-carboxylic acid Example 32 150 mg of the compound obtained in 1. was suspended in 2 ml of ethanol, 1.5 ml of a 10% aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. 20 ml of water was added and washed with 10 ml of chloroform. The aqueous layer was acidified with 6N hydrochloric acid and extracted with 40 ml of ethyl acetate. It was dried over magnesium sulfate and the solvent was distilled off. Chloroform and n-hexane were added, and the solvent was evaporated. n-Hexane was added, and the solid was collected by filtration. 70 mg of the title compound was obtained. (49%) Properties Brown Amorphous ¹ H-NMR (δppm in DMSO-d ₆ ) 0.79-0.86 (7H, m), 1.20-1.30 (4H, m), 1.45-1.60 (3H, m),
2.92 (2H, t, J = 7Hz), 5.70 (2H, s), 7.07 (4H, s), 7.52-7.7
0 (4H, m)

Example 34 N-methacryloyl-N ′-(2′-cyanobiphenyl-4-yl) methylthiourea Ammonium thiocyanate 41 dried by heating at 90 ° C. for 1 hour 41
9 mg was finely crushed in a mortar, added to 10 ml of acetone, 0.5 ml of methacryloyl chloride was added, and the mixture was heated under reflux for 30 minutes. After returning to room temperature, 1.04 g of (2′-cyanobiphenyl-4-yl) methylamine was slowly added. Stirred for one and a half hours at room temperature.
After extraction with 50 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. Separation by column chromatography (silica gel 50 g, elution solvent; chloroform), 785 mg
To give the title compound as an oil. (47%) Properties colorless oil ¹ H-NMR (δppm in CDCl ₃ ) 2.02 (3H, d, J = 1Hz), 4.96 (2H, d, J = 5Hz), 5.65 (1H, q, J = 1H
z), 5.92 (1H, s), 7.45-7.79 (8H, m), 8.75 (1H, brs)

Example 35 2-methacryloyluimino-3- (2'-cyanobiphenyl-4-yl) methyl-5-n-propylthiazoline-4-carboxylic acid ethyl ester To 785 mg of the thiourea compound obtained in Example 34 , 3-bromo-
2-Oxohexanoic acid ethyl ester 1.11 g, pyridine 0.19 ml, and ethanol 1 ml were added, and the mixture was heated at 90 to 95 ° C. for 2 hours and a half. Extract with 20 ml of chloroform and add 20 ml of saturated saline solution.
After washing with ml and drying over magnesium sulfate, the solvent was distilled off. Separation by column chromatography (silica gel 50 g, elution solvent; ethyl acetate: n-hexane = 1: 4) gave 379 mg of the title compound as an oil. (35%) Properties colorless oil ¹ H-NMR (δppm in CDCl ₃ ) 0.98 (3H, t, J = 7Hz), 1.29 (3H, t, J = 7Hz), 1.66-1.74 (2H,
m), 2.07 (3H, s), 2.90 (2H, t, J = 7Hz), 4.30 (2H, q, J = 7Hz),
5.56 (1H, t, J = 1Hz), 5.92 (2H, s), 6.37 (1H, q, J = 1Hz), 7.
32-7.77 (8H, m)

Example 36 2-methacryloylinomino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-propylthiazoline
-4-Carboxylic acid ethyl ester 379 mg of the compound obtained in Example 35 and 1.32 g of trimethyltin azide were added to 10 ml of dioxane, and the mixture was heated under reflux for 4 days. After returning to room temperature, 5 ml of concentrated hydrochloric acid was added. The mixture was stirred at room temperature for 30 minutes and a half. 20 ml of water was added, and the mixture was extracted with 40 ml of ethyl acetate.
After drying over magnesium sulfate, the solvent was distilled off. Separation was carried out by column chromatography (silica gel 70 g, elution solvent; ethyl acetate: n-hexane = 1: 1). n-Hexane was added, and the solid was collected by filtration. 84 mg of the title compound was obtained. (20
%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 0.99 (3H, t, J = 7Hz), 1.35 (3H, t, J = 7Hz), 1.66-1.75 (2H,
m), 2.05 (3H, s), 2.91 (2H, t, J = 7Hz), 4.32 (2H, q, J = 7Hz),
5.56 (1H, s), 5.88 (2H, s), 6.35 (1H, q, J = 1Hz), 7.18-8.2
4 (8H, m)

Example 37 2-methacryloylimino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-propylthiazoline
-4-Carboxylic acid 78 mg of the compound obtained in Example 36 was suspended in 2 ml of ethanol, 1 ml of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. 20 ml of water was added and washed with 10 ml of chloroform. The aqueous layer was acidified with 6N hydrochloric acid and extracted with 40 ml of ethyl acetate. It was dried over magnesium sulfate and the solvent was distilled off.
Chloroform and n-hexane were added, and the solvent was evaporated. n-
Hexane was added, and the solid was collected by filtration. Obtained 46 mg of the title compound. (62%) Properties Colorless powder ¹ H-NMR (δppm in DMSO-d ₆ ) 0.92 (3H, t, J = 7Hz), 1.50-1.68 (2H, m), 1.92 (3H, s), 2.9
2 (2H, t, J = 7Hz), 5.54 (1H, s), 5.76 (2H, s), 6.18 (1H, s),
7.04-7.14 (4H, m), 7.51-7.69 (4H, m)

Example 38 2-methacryloylinomino-3- (2'-cyanobiphenyl-4-yl) methyl-5-n-pentylthiazoline-4-carboxylic acid ethyl ester 270 mg of the thiourea compound obtained in Example 34 was added. , 3-bromo-
427 mg of 2-oxooctanoic acid ethyl ester, 0.06 ml of pyridine and 0.8 ml of ethanol were added, and the mixture was heated at 90 to 95 ° C. for 2 hours and a half. After extraction with 20 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. Separation by column chromatography (silica gel 60 g, elution solvent; chloroform), and further column chromatography (silica gel 15 g, elution solvent; ethyl acetate: n-hexane = 1: 4)
Separation with to give 63 mg of the title compound as an oil. (16%) Properties colorless oil ¹ H-NMR (δppm in CDCl ₃ ) 0.86-0.91 (3H, m), 1.21-1.39 (7H, m), 1.64-1.78 (2H, m),
2.06 (3H, s), 2.91 (2H, t, J = 8Hz), 4.30 (2H, q, J = 7Hz), 5.
55 (1H, s), 5.91 (2H, s), 6.36 (1H, s), 7.27-7.76 (8H, m)

Example 39 2-Cyclopropylcarbonylimino-3- (2′-cyanobiphenyl-4-yl) methyl-5-n-hexylthiazoline-4-carboxylic acid ethyl ester The thiourea compound obtained in Example 15 1.01 g, 3-bromo-
2-Oxononanoic acid ethyl ester (1.68 g), pyridine (0.24 ml) and ethanol (3 ml) were added, and the mixture was heated at 90 to 95 ° C for 2 hours and a half. It was extracted with 40 ml of chloroform, dried over magnesium sulfate, and the solvent was distilled off. Separation by column chromatography (silica gel 100 g, elution solvent; ethyl acetate: n-hexane = 1: 4) gave 195 mg of the title compound as an oil. (13%) Properties colorless oil ¹ H-NMR (δppm in CDCl ₃ ) 0.87 (5H, brs), 1.06-1.10 (2H, m), 1.23-1.39 (9H, m), 1.
60-1.67 (3H, m), 2.89 (2H, t, J = 7Hz), 4.27 (2H, q, J = 7Hz),
5.87 (2H, s), 7.26-7.77 (8H, m)

Example 40 2-Cyclopropylcarbonylimino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-hexylthiazoline-4-carboxylic acid ethyl ester Example 39
195 mg of the compound obtained in 1. and 782 mg of trimethyltin azide were added to 6 ml of dioxane, and the mixture was heated under reflux for 2 days. After returning to room temperature, 2 ml of concentrated hydrochloric acid was added. It was stirred at room temperature for 1 hour. 40m of water
l was added and extracted with 40 ml of ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off. It was separated by column chromatography (silica gel 20 g, elution solvent; ethyl acetate: n-hexane = 1: 1). 71 mg of the title compound was obtained as an oil. (33%) Properties Light yellow oil ¹ H-NMR (δppm in CDCl ₃ ) 0.85-0.95 (7H, m), 1.23-1.31 (9H, m), 1.47-1.52 (2H, m),
1.83 (1H, brs), 2.78 (2H, t, J = 7Hz), 4.25 (2H, q, J = 7Hz),
5.79 (2H, s), 7.02 (2H, d, J = 8Hz), 7.15 (2H, d, J = 8Hz), 7.
39 (1H, d, J = 7Hz), 7.48-7.56 (2H, m), 7.94 (1H, d, J = 7Hz)

Example 41 2-Cyclopropylcarbonylimino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-hexylthiazoline-4-carboxylic acid Example 40 66 mg of the compound obtained in 1. was suspended in 2 ml of ethanol, 1 ml of a 10% sodium hydroxide aqueous solution was added, and the mixture was stirred overnight at room temperature. Acidify with 6N hydrochloric acid and add 30 ml of ethyl acetate.
It was extracted with. It was dried over magnesium sulfate and the solvent was distilled off. n-Hexane was added, and the solid was collected by filtration. 40 mg of the title compound was obtained. (63%) Properties Colorless powder ¹ H-NMR (δppm in DMSO-d ₆ ) 0.83-0.86 (7H, m), 1.25 (6H, s), 1.57 (2H, brs), 1.75 (1
H, brs), 2.93 (2H, t, J = 8Hz), 5.71 (2H, s), 7.06 (4H, s),
7.52-7.70 (4H, m)

Example 42 2-Benzoylimino-3- (2'-cyanobiphenyl-4-yl)
Methyl-5-n-pentylthiazoline-4-carboxylic acid ethyl ester To 743 mg of the thiourea compound obtained in Example 1 was added 3-bromo-2-
1.06 g of oxooctanoic acid ethyl ester and 0.16 ml of pyridine were added to 2 ml of acetonitrile, and the mixture was heated at 90 to 95 ° C. for 3 hours and a half. After extraction with 20 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. Separation by column chromatography (silica gel 50 g, elution solvent; chloroform) gave 363 mg of the title compound as a colorless oil. (53%) Properties colorless oil ¹ H-NMR (δppm in CDCl ₃ ) 0.88-0.93 (3H, m), 1.30 (3H, t, J = 7Hz), 1.33-1.41 (4H,
m), 1.64-1.72 (2H, m), 2.94 (2H, t, J = 8Hz), 4.31 (2H, q, J
= 7Hz), 6.03 (2H, s), 7.38-7.76 (11, m), 8.31-8.34 (2H, m)

Example 43 2-Benzoylimino-3- [2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methyl-5-n-pentylthiazoline-4-
Carboxylic acid ethyl ester 2-benzoylimino-3- (2'-cyanobiphenyl-4-yl) methyl-5-n-pentylthiazoline-4-carboxylic acid ethyl ester 570 mg obtained in Example 42, trimethyltin azide 872 mg was added to 6 ml of dioxane, and the mixture was heated under reflux for 51 hours. 872 mg of trimethyltin azide was added, and the mixture was further heated under reflux for 22 hours. After allowing to cool, add 5 ml of concentrated hydrochloric acid, and add 2 at room temperature.
Stir for hours. 30 ml of water was added, and the mixture was extracted with 30 ml of ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off. Ether was added and the solid was collected by filtration. 288 mg of the title compound was obtained. (47%) Properties Light yellow oil ¹ H-NMR (δppm in CDCl ₃ ) 0.87-0.93 (3H, m), 1.26-1.38 (5H, m), 1.57-1.72 (4H, m),
2.94 (2H, t, J = 8Hz), 4.33 (2H, q, J = 7Hz), 5.98 (2H, s),
7.18-7.59 (10H, m), 8.19 (1H, d, J = 2Hz), 8.22-8.31 (2H, m)

Example 44 2-Benzoylimino-3- [2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methyl-5-n-pentylthiazoline-4-
Carboxylic Acid 288 mg of the compound obtained in Example 43 was suspended in 6 ml of ethanol, 3 ml of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. Acidified with 6N hydrochloric acid, ethyl acetate 30ml
It was extracted with. After drying over magnesium sulfate, the solvent was distilled off. Ether and n-hexane were added, and the solid was collected by filtration. twenty one
5 mg of the title compound was obtained. (78%) Property: Colorless powder ¹ H-NMR (δppm in DMSO-d ₆ ) 0.87 (3H, s), 1.31 (4H, s), 1.63 (2H, brs), 2.98 (2H, t, J =
7Hz), 5.89 (2H, s), 7.07 (2H, d, J = 8Hz), 7.17 (2H, d, J = 8H
z), 7.43-7.68 (6H, m), 8.15 (2H, d, J = 7Hz)

Example 45 N- (2-Fluorobenzoyl) -N '-(2'-cyanobiphenyl-4
-Yl) Methylthiourea 641 mg of potassium thiocyanate dried by heating at 110 ° C was added to 10 ml of acetone, 0.72 ml of 2-fluorobenzoyl chloride was added, and the mixture was heated under reflux for 30 minutes.
After returning to room temperature, 1.25 g of (2'-cyanobiphenyl-4-yl) methylamine was slowly added. Stir for 3 hours at room temperature. The solvent was distilled off. It was extracted with 40 ml of chloroform, dried over magnesium sulfate, and the solvent was distilled off. Separation by column chromatography (silica gel 150 g, elution solvent; chloroform) gave 728 mg of the title compound. (31%) Property Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 5.01 (2H, d, J = 6Hz), 7.19-8.08 (12H, m)

Example 46 2- (2-Fluorobenzoyl) imino-3- (2'-cyanobiphenyl-4-yl) methyl-5-n-pentylthiazoline-4-carboxylic acid ethyl ester Obtained in Example 45. Thiourea compound 389mg, 3-bromo-
Add 530 mg of 2-oxooctanoic acid ethyl ester and 0.08 ml of pyridine to 1 ml of acetonitrile, and add at 5
Heated for hours. After extraction with 20 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. Separated by column chromatography (silica gel 50 g, elution solvent; chloroform), and further column chromatography (silica gel
Separation with 50 g, eluting solvent; ethyl acetate: n-hexane = 1: 3 chloroform) gave 260 mg of the title compound as a colorless oil.
(47%) Properties colorless oil ¹ H-NMR (δppm in CDCl ₃ ) 0.88-0.93 (3H, m), 1.26-1.39 (7H, m), 1.67-1.72 (2H, m),
2.94 (2H, t, J = 8Hz), 4.31 (2H, q, J = 7Hz), 6.00 (2H, s),
7.08-7.76 (11H, m), 8.13-8.19 (1H, m)

Example 47 2- (2-Fluorobenzoyl) imino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-pentylthiazoline-4-carboxylic acid Ethyl ester 260 mg of the compound obtained in Example 46 and 774 mg of trimethyltin azide were added to 3 ml of dioxane, and the mixture was heated under reflux for 3 days. After cooling, 5 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 5 hours. 20 ml of water was added, and the mixture was extracted with 30 ml of ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off. Separation by column chromatography (silica 30 g, elution solvent; ethyl acetate: n-hexane = 1: 1) gave 146 mg of the title compound as a colorless oil. (52%) Properties colorless oil ¹ H-NMR (δppm in CDCl ₃ ) 0.91 (3H, brs), 1.33-1.38 (7H, m), 1.64-1.69 (2H, m), 2.
95 (2H, t, J = 7Hz), 4.33 (2H, q, J = 7Hz), 5.94 (2H, s), 7.09
-7.58 (10H, m), 8.09-8.22 (2H, m)

Example 48 2- (2-Fluorobenzoyl) imino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-pentylthiazoline-4-carboxylic acid The compound (140 mg) obtained in Example 47 was suspended in ethanol (2 ml), 10% aqueous sodium hydroxide solution (2 ml) was added, and the mixture was stirred at room temperature overnight. Acidified with 6N hydrochloric acid and ethyl acetate 20ml
It was extracted with. After drying over magnesium sulfate, the solvent was distilled off. n-Hexane was added, and the solid was collected by filtration. 90 mg of the title compound was obtained. (68%) Property: Colorless powder ¹ H-NMR (δppm in DMSO-d ₆ ) 0.87 (3H, s), 1.31 (4H, s), 1.63 (2H, s), 2.98 (2H, t, J = 7H
z), 5.85 (2H, s), 7.05-7.30 (6H, m), 7.51-7.66 (5H, m),
7.96-8.02 (1H, m)

Example 49 N- (2,4-Difluorobenzoyl) -N ′-(2′-cyanobiphenyl-4-yl) methylthiourea 594 mg of ammonium thiocyanate dried by heating at 90 ° C. was added to 10 ml of acetonitrile, and 2 0.74 ml of 4,4-difluorobenzoyl chloride was added, and the mixture was heated under reflux for 40 minutes. After returning to room temperature, 1.25 g of (2'-cyanobiphenyl-4-yl) methylamine
Was slowly added. Stir for 1 hour at room temperature. The solvent was distilled off. It was extracted with 40 ml of chloroform, washed with 20 ml of saturated saline and dried over magnesium sulfate, and then the solvent was distilled off. It was separated by column chromatography (silica gel 100 g, elution solvent; chloroform), solidified with n-hexane and collected by filtration. 671 mg of the title compound was obtained. (28%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 5.01 (2H, d, J = 6Hz), 6.93-7.11 (2H, m), 7.42-7.79 (8H,
m), 8.05-8.14 (1H, m)

Example 50 2- (2,4-Difluorobenzoyl) imino-3- (2'-cyanobiphenyl-4-yl) methyl-5-n-pentylthiazoline-4-carboxylic acid ethyl ester In Example 49 330 mg of the obtained thiourea compound was added to 3-bromo-
430 mg of 2-oxooctanoic acid ethyl ester and 0.06 ml of pyridine were added to 0.8 ml of ethanol, and the mixture was heated at 90 to 95 ° C for 2 hours. After extraction with 20 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. Separation by column chromatography (silica gel 30 g, elution solvent; chloroform) gave 271 mg of the title compound as a colorless oil. (58%) Properties colorless oil ¹ H-NMR (δppm in CDCl ₃ ) 0.90 (3H, brs), 1.22-1.37 (7H, m), 1.69 (2H, brs), 2.94
(2H, t, J = 8Hz), 4.31 (2H, q, J = 7Hz), 5.99 (2H, s), 6.80-6.
92 (2H, m), 7.34-7.76 (8H, m), 8.20 (1H, q, J = 7Hz)

Example 51 2- (2,4-Difluorobenzoyl) imino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-pentylthiazoline-4- Carboxylic acid ethyl ester 270 mg of the compound obtained in Example 50 and 774 mg of trimethyltin azide were added to 6 ml of dioxane and heated under reflux for 4 days. After cooling, 5 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 5 hours. 20 ml of water was added, and the mixture was extracted with 40 ml of ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off. Separation by column chromatography (silica 50 g, elution solvent; ethyl acetate: n-hexane = 1: 1) gave 99 mg of the title compound. (35
%) Property: Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 0.90 (3H, s), 1.26-1.37 (7H, m), 1.60-1.72 (2H, m), 2.94
(2H, t, J = 8Hz), 4.33 (2H, q, J = 7Hz), 5.92 (2H, s), 6.81-6.
93 (2H, m), 7.16-7.58 (7H, m), 8.10-8.18 (2H, m)

Example 52 2- (2,4-Difluorobenzoyl) imino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-pentylthiazoline-4- Carboxylic acid 90 mg of the compound obtained in Example 51 was suspended in 2 ml of ethanol, 2 ml of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. Acidified with 6N hydrochloric acid, ethyl acetate 40ml
It was extracted with. After drying over magnesium sulfate, the solvent was distilled off. n-Hexane was added, and the solid was collected by filtration. 55 mg of the title compound was obtained. (64%) Property: colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 0.86 (3H, s), 1.23-1.31 (4H, m), 1.63 (2H, brs), 2.94 (2
H, t, J = 8Hz), 4.12 (2H, q, J = 7Hz), 5.88 (2H, s), 6.75-8.15
(11H, m)

Example 53 2- (2,4-Difluorobenzoyl) imino-3- [2'-cyanobiphenyl-4-yl] methyl-5-isobutylthiazoline-4-carboxylic acid ethyl ester Obtained in Example 49. Thiourea form 310mg, 3-bromo-
382 mg of 2-oxoisoheptanoic acid ethyl ester and 0.06 ml of pyridine were added to 0.8 ml of ethanol, and the mixture was heated at 90 to 95 ° C for 4 hours and a half. 3-Bromo-2-oxoisoheptanoic acid ethyl ester (610 mg), pyridine (0.09 ml) and ethanol (0.8 ml) were added, and the mixture was heated at 90 to 95 ° C for 1 hour. In addition, 3-bromo-2-oxoisoheptanoic acid ethyl ester 3
05 mg and pyridine 0.05 ml were added, and the mixture was heated at 90 to 95 ° C for 3 hours. After extraction with 20 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. Column chromatography (silica gel 30 g, elution solvent; ethyl acetate: n-hexane)
= 1: 4) to give 236 mg of the title compound as a pale yellow oil. (56%) Properties Light yellow oil ¹ H-NMR (δppm in CDCl ₃ ) 0.98 (6H, d, J = 7Hz), 1.29 (3H, t, J = 7Hz), 1.91-2.01 (1H,
m), 2.82 (2H, d, J = 7Hz), 4.30 (2H, q, J = 7Hz), 5.98 (2H, s),
6.80-6.92 (2H, m), 7.32-7.76 (8H, m), 8.14-8.23 (1H, m)

Example 54 2- (2,4-Difluorobenzoyl) imino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-isobutylthiazoline-4-carboxylic acid Ethyl ester Example 5
236 mg of the compound obtained in 3 above, 694 mg of trimethyltin azide
Was added to 5 ml of dioxane and heated under reflux for 1 day. After cooling down,
5 ml of concentrated hydrochloric acid was added, and the mixture was stirred at room temperature for 5 hours. 20 ml of water was added, and the mixture was extracted with 40 ml of ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off. Column chromatography (silica gel 40 g, elution solvent; ethyl acetate: n-hexane = 1: 2)
Separation with gave 93 mg of the title compound. (37%) Property: Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 0.98 (6H, d, J = 7Hz), 1.35 (3H, t, J = 7Hz), 1.92-2.00 (1H,
m), 2.83 (2H, d, J = 7Hz), 4.32 (2H, q, J = 7Hz), 5.94 (2H, s),
6.84-6.93 (2H, m), 7.19-7.60 (7H, m), 8.15-8.22 (2H, m)

Example 55 2- (2,4-Difluorobenzoyl) imino-3- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-isobutylthiazoline-4-carboxylic acid 76 mg of the compound obtained in Example 54 was suspended in 2 ml of ethanol, 2 ml of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred overnight at room temperature. Acidified with 6N hydrochloric acid, ethyl acetate 40ml
It was extracted with. After drying over magnesium sulfate, the solvent was distilled off. n-Hexane was added, and the solid was collected by filtration. Obtained 69 mg of the title compound. (92%) Property: Colorless powder ¹ H-NMR (δppm in DMSO-d ₆ ) 0.93 (6H, d, J = 7Hz), 1.85-1.97 (1H, m), 2.88 (2H, d, J = 7H)
z), 5.84 (2H, s), 7.05-7.33 (6H, m), 7.51-7.69 (4H, m),
8.09 (1H, q, J = 7Hz)

Example 56 N- (trans-2-fluorocyclopropyl) carbonyl-N '
-(2'-Cyanobiphenyl-4-yl) methylthiourea 127 mg of potassium thiocyanate dried by heating at 100 ° C and 80 mg of (trans-2-fluorocyclopropyl) carbonyl chloride were added to 5 ml of acetone and heated under reflux for 10 minutes. . After returning to room temperature, 146 mg of (2′-cyanobiphenyl-4-yl) methylamine was slowly added. Stir for 30 minutes at room temperature,
It was extracted with 20 ml of chloroform. After drying over magnesium sulfate, the solvent was distilled off. Column chromatography (silica gel 20 g, elution solvent; ethyl acetate: n-hexane = 1: 1)
Separation in 5) gave 100 mg of the title compound as an oil. (43%) Properties colorless oil ¹ H-NMR (δppm in CDCl ₃ ) 1.40-1.65 (2H, m), 2.09-2.16 (1H, m), 4.68-4.94 (1H, m),
4.93 (2H, d, J = 6Hz), 7.42-7.78 (8H, m)

Example 57 2- (trans-2-fluorocyclopropyl) carbonylimino-3- (2'-cyanobiphenyl-4-yl) methyl-5-ethylthiazoline-4-carboxylic acid ethyl ester In Example 56 100 mg of the obtained thiourea derivative, 127 mg of 3-bromo-2-oxopentanoic acid ethyl ester, and 0.02 ml of pyridine,
0.2 ml of ethanol was added, and the mixture was heated at 90 to 95 ° C for 1 hour and a half. After extraction with 20 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. Column chromatography (silica gel 60 g, elution solvent; ethyl acetate: n-hexane =)
Separation 1: 5) gave 1 mg of the title compound as an oil. Properties Colorless oil ¹ H-NMR (δppm in CDCl ₃ ) 1.21-1.45 (8H, m), 2.29-2.40 (1H, m), 2.95 (2H, q, J = 8H
z), 4.30 (2H, q, J = 8Hz,), 4.76-5.07 (1H, m), 5.86 (2H, s),
7.27-8.06 (8H, m)

Example 58 2-Cyclopropylcarbonylimino-3- (2′-cyanobiphenyl-4-yl) methyl-5-n-butylthiazoline-4-carboxylic acid ethyl ester Thiourea derivative obtained in Example 15 1.00 g, 3-bromo-
2-Oxoheptanoic acid ethyl ester (2.50 g), pyridine (0.3 ml) and ethanol (3 ml) were added, and the mixture was heated at 90 to 95 ° C for 1.5 hours. Extract with 20 ml of chloroform and add 20 ml of saturated saline.
After washing with water and drying over magnesium sulfate, the solvent was distilled off.
Separation by column chromatography (silica gel 200 g, elution solvent; ethyl acetate: n-hexane = 1: 4) gave 158 mg of the title compound as an oil. (10%) Property Brown oil ¹ H-NMR (δppm in CDCl ₃ ) 1.24-1.39 (10H, m), 1.72-1.76 (2H, m), 1.82-1.89 (2H,
m), 1.98-2.03 (1H, m), 2.88-2.95 (2H, m), 4.25 (2H, q, J = 7
Hz,), 5.88 (2H, s), 7.38-7.90 (8H, m)

Example 59 2-Cyclopropylcarbonylimino-3- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-butylthiazoline-4-carboxylic acid ethyl ester The compound (158 mg) obtained in Example 58 and trimethyltin azide (332 mg) were added to dioxane (5 ml), and the mixture was heated under reflux overnight. Trimethyltin azide (390 mg) was added, and the mixture was further heated and refluxed for one day. After returning to room temperature, 2 ml of concentrated hydrochloric acid was added. Stirred for 20 minutes at room temperature. 20 ml of water was added, and the mixture was extracted with 30 ml of ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off. Separation was carried out by column chromatography (silica gel 70 g, elution solvent; chloroform → ethyl acetate). Ether was added and the solid was collected by filtration. 80 mg of the title compound was obtained. (47%) Properties colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 0.88-1.98 (7H, m), 1.27-1.38 (5H, m), 1.50-1.52 (2H, m),
1.82-1.84 (1H, m), 2.79 (2H, t, J = 7Hz), 4.27 (2H, q, J = 7H
z) 5.78 (2H, s), 7.07 (2H, d, J = 8Hz), 7.18 (2H, d, J = 8Hz),
7.52-7.57 (2H, m), 8.02 (1H, d, J = 7Hz)

Example 60 2-Cyclopropylcarbonylimino-3- [2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-butylthiazoline-4-carboxylic acid Example 59 Compound 8 obtained in
0 mg was suspended in 2 ml of ethanol, 2 ml of 10% sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature overnight. Add 20 ml of water,
It was washed with 10 ml of chloroform. The aqueous layer was acidified with 6N hydrochloric acid and extracted with 20 ml of ethyl acetate. It was dried over magnesium sulfate and the solvent was distilled off. Chloroform and n-hexane were added, and the solvent was evaporated. Ether was added and the solid was collected by filtration. Obtained 45 mg of the title compound. (59%) Properties colorless powder ¹ H-NMR (δppm in DMSO-d ₆ ) 0.78-0.92 (7H, m), 1.53-1.58 (2H, m), 1.71-1.77 (1H, m),
2.17-2.26 (2H, m), 2.92-2.96 (2H, m), 5.71 (2H, s), 7.04
(4H, s), 7.55-7.61 (2H, m), 7.67-7.70 (2H, m)

Example 61 N-benzoyl-N '-(4-bromobenzyl) thiourea Benzoyl isothiocyanate (0.67 ml) and 4-bromobenzylamine hydrochloride (1.11 g) were added to chloroform (10 ml), and triethylamine (0.77 ml) was slowly added at room temperature. It was
Stir at room temperature for 3 hours. It was washed with 10 ml of water and 10 ml of dilute hydrochloric acid, dried over magnesium sulfate, and the solvent was distilled off. Ether was added, solidified, and collected by filtration. It was washed with ether and then hekinsan in this order to obtain 1.40 g of the title compound. (80%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 4.88 (2H, d, J = 6Hz), 7.25-7.85 (9H, m)

Example 62 2-Benzoylimino-3- (4-bromobenzyl) -5-n-hexylthiazoline-4-carboxylic acid ethyl ester N-benzoyl-N '-(4- Bromobenzyl) thiourea (594 mg), 3-bromo-2-oxononanoic acid ethyl ester (950 mg) and pyridine (0.14 ml) were added to ethanol (2 ml), and the mixture was heated at 90 to 95 ° C for 3 hours. After extraction with 20 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. Column chromatography (silica gel 40 g,
Separation with an eluting solvent: chloroform) gave 503 mg of an oily substance. (56%) Properties Colorless prism crystals ¹ H-NMR (δppm in CDCl ₃ ) 0.88 (3H, t, J = 6Hz), 1.21-1.39 (9H, m), 1.62-1.70 (2H,
m), 2.92 (2H, t, J = 7Hz), 4.30 (2H, q, J = 7Hz), 5.91 (2H, s),
7.16 (2H, d, J = 7Hz), 7.40-7.50 (5H, m), 8.29 (2H, d, J = 7H
z)

Example 63 2-Benzoylimino-3- [2 '-(1-triphenylmethyl-1H-
Tetrazol-5-yl) biphenyl-4-yl] methyl-5-n-
Hexylthiazoline-4-carboxylic acid ethyl ester 238 mg of the compound obtained in Example 62, 2- (1-triphenylmethyl-1H-tetrazol-5-yl) phenylboronic acid tetrahydrofuran 1 solvate 277 mg, and tetrakis (tri) 60 mg of phenylphosphine) palladium was added to 2 ml of toluene, 0.45 ml of a 2M sodium carbonate aqueous solution was added, and the mixture was heated under reflux for 6 hours under a nitrogen stream. After extraction with 20 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. Separation by column chromatography (silica gel 20 g, elution solvent: chloroform) gave 360 mg of the title compound as a yellow oil. (95%) Properties Yellow oil ¹ H-NMR (δppm in CDCl ₃ ) 0.88 (3H, s), 1.21 (3H, t, J = 7Hz), 1.30 (6H, s), 1.62-1.6
6 (2H, m), 2.89 (2H, t, J = 8Hz), 4.20 (2H, q, J = 7Hz), 5.91 (2
H, s), 6.91 (4H, d, J = 7Hz), 7.04 (3H, s), 7.20-7.45 (18H,
m), 7.87 (1H, d, J = 9Hz), 8.29 (2H, d, J = 7Hz)

Example 64 2-Benzoylimino-3- [2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methyl-5-n-hexylthiazoline-4-
Carboxylic acid ethyl ester To 350 mg of the trityl compound obtained in Example 63, 5 ml of dioxane and 5 ml of concentrated hydrochloric acid were added, and the mixture was stirred at room temperature for 3.5 hours. Add 20 ml of water and add 20 ml of ethyl acetate.
It was extracted with. After drying over magnesium sulfate, the solvent was distilled off. Separation by column chromatography (silica gel 30 g, elution solvent; ethyl acetate: n-hexane = 1: 1 → ethyl acetate) gave 130 mg of the title compound. (52%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 0.89 (3H, t, J = 7Hz), 1.24-1.38 (9H, m), 1.63-1.72 (2H,
m), 2.95 (2H, t, J = 7Hz), 4.33 (2H, q, J = 7Hz), 5.98 (2H, s),
7.18-7.59 (10H, m), 8.20-8.31 (3H, m)

Example 65 2-Benzoylimino-3- [2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methyl-5-n-hexylthiazoline-4-
Carboxylic Acid 122 mg of the compound obtained in Example 64 was suspended in 2 ml of ethanol, 2 ml of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature overnight. Acidify with 6N hydrochloric acid and add ethyl acetate
Extracted with 20 ml. It was dried over magnesium sulfate and the solvent was distilled off. n-Hexane was added, and the solid was collected by filtration. 60 mg of the title compound was obtained. (52%) Property Colorless powder ¹ H-NMR (δppm in DMSO-d ₆ ) 0.86 (3H, s), 1.29 (6H, s), 1.62 (2H, brs), 2.98 (2H, t, J =
7Hz), 5.90 (2H, s), 7.06 (2H, d, J = 8Hz), 7.18 (2H, d, J = 7H
z), 7.48-7.65 (7H, m), 8.15 (2H, d, J = 7Hz)

Example 66 2-Benzoylimino-3- (4-bromobenzyl) -5-isobutylthiazoline-4-carboxylic acid ethyl ester N-benzoyl-N '-(4-bromobenzyl obtained in Example 61 ) To 349 mg of thiourea, 502 mg of 3-bromo-2-oxoisoheptanoic acid ethyl ester and 0.08 ml of pyridine were added to 1 ml of ethanol, and the mixture was heated at 90 to 100 ° C for 2 hours.
After extraction with 20 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. Ether was added to the residue and the solid was collected by filtration. 170 mg of the title compound was obtained. (34%) Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 0.95 (6H, d, J = 7Hz), 1.32 (3H, t, J = 7Hz), 1.91-2.03 (1H,
m), 2.80 (2H, d, J = 7Hz), 4.29 (2H, q, J = 7Hz), 5.90 (2H, s),
7.13-7.52 (7H, m), 8.28 (2H, d, J = 7Hz)

Example 67 2-Benzoylimino-3- [2 '-(1-triphenylmethyl-1H-
Tetrazol-5-yl) biphenyl-4-yl] methyl-5-isobutylthiazoline-4-carboxylic acid ethyl ester 2-benzoylimino-3- (4-bromobenzyl) -5-isobutylthiazoline obtained in Example 66 -4-carboxylic acid ethyl ester 130 mg, 2- (1-triphenylmethyl-1H-tetrazol-5-yl) phenylboronic acid tetrahydrofuran 1
The solvate (159 mg) and tetrakis (triphenylphosphine) palladium (35 mg) were added to toluene (1.2 ml), 2M aqueous sodium carbonate solution (0.3 ml) was added, and the mixture was heated under reflux for 6 hours under a nitrogen stream. After extraction with 20 ml of chloroform and drying over magnesium sulfate, the solvent was distilled off. Separation by column chromatography (silica gel 20 g, elution solvent; chloroform) gave 210 mg of the title compound as a yellow oil. (99%) Properties Yellow oil ¹ H-NMR (δppm in CDCl ₃ ) 0.95 (6H, d, J = 7Hz), 1.20 (3H, t, J = 7Hz), 1.90-2.00 (1H,
m), 2.77 (2H, d, J = 7Hz), 4.19 (2H, q, J = 7Hz), 5.90 (2H, s),
6.90-7.46 (26H, m), 8.28 (2H, d, J = 7Hz)

Example 68 2-Benzoylimino-3- [2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methyl-5-isobutylthiazoline-4-
Carboxylic acid ethyl ester To 200 mg of the trityl derivative obtained in Example 67, 6 ml of dioxane and 3 ml of concentrated hydrochloric acid were added, and the mixture was stirred overnight at room temperature. 10 ml of water
Was added and extracted with 20 ml of ethyl acetate. After drying over magnesium sulfate, the solvent was distilled off. Separation by column chromatography (silica gel 20 g, elution solvent; ethyl acetate: n-hexane = 1: 1 → ethyl acetate) gave 50 mg of the title compound. Properties Colorless powder ¹ H-NMR (δppm in CDCl ₃ ) 0.98 (6H, d, J = 7Hz), 1.35 (3H, t, J = 7Hz), 1.95-1.99 (1H,
m), 2.83 (2H, d, J = 7Hz), 4.32 (2H, q, J = 7Hz), 5.99 (2H, s),
7.19-7.57 (10H, m), 8.20-8.32 (3H, m)

Example 69 2-Benzoylimino-3- [2 '-(1H-tetrazol-5-yl)
Biphenyl-4-yl] methyl-5-isobutylthiazoline-4
-Carboxylic acid 40 mg of the compound obtained in Example 68 was suspended in 2 ml of ethanol, 2 ml of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature overnight. Acidify with 6N hydrochloric acid and add ethyl acetate 20
extracted with ml. It was dried over magnesium sulfate and the solvent was distilled off. n-Hexane was added and the solvent was distilled off. n-Hexane was added, and the solid was collected by filtration. 29 mg of the title compound was obtained. (7
6%) Properties colorless powder ¹ H-NMR (δppm in DMSO-d ₆ ) 0.93 (6H, d, J = 7Hz), 1.87-1.94 (1H, m), 2.88 (2H, d, J = 7H)
z), 5.89 (2H, s), 7.07 (2H, d, J = 8Hz), 7.17 (2H, d, J = 8Hz),
7.21-7.88 (7H, m), 8.15 (2H, d, J = 7Hz)

Claims (6)

[Claims] 1. A compound represented by the general formula (1): [In the formula, R ¹ represents a cyclo lower alkyl group which may have a substituent, a phenyl group or a lower alkenyl group which may have a substituent, and R ² represents a halogen atom or a cyanophenyl group. ] The thiourea derivative represented by these. 2. A compound represented by the general formula (2): embedded image R ¹ CON = C = S (2) [wherein R ¹ has a cyclo lower alkyl group which may have a substituent, and a substituent. An optionally substituted phenyl group or a lower alkenyl group] is added to the isothiocyanate derivative represented by the general formula (3): [Wherein R ² represents a halogen atom or a cyanophenyl group] is reacted with benzylamines represented by the general formula (1): [Wherein R ¹ and R ² are the same as defined above]. 3. A compound represented by the general formula (1-a): [Wherein R ¹ represents a cyclo lower alkyl group which may have a substituent, a phenyl group which may have a substituent or a lower alkenyl group], and a thiourea derivative represented by the general formula (4) [Chemical 6] [In the formula, R ³ represents a hydrogen atom or a lower alkyl group, and X ¹
Represents a halogen atom, and Y ¹ represents a protected carboxyl group or a protected carboxymethyl group] and is reacted with an α-halogenoketone to optionally eliminate the carboxyl protecting group. General formula (6) [In the formula, Y represents an optionally protected carboxyl group or an optionally protected carboxymethyl group, and R ¹
And R ³ is the same as the above], a process for producing an N-cyanobiphenylmethylthiazoline compound or a salt thereof. 4. A compound represented by the general formula (1-a): [Wherein R ¹ represents a cyclo lower alkyl group which may have a substituent, a phenyl group which may have a substituent or a lower alkenyl group], and a thiourea derivative represented by the general formula (4) [Chemical 9] [In the formula, R ³ represents a hydrogen atom or a lower alkyl group, and X ¹
Represents a halogen atom, and Y ¹ represents a protected carboxyl group or a protected carboxymethyl group], and the resulting α-halogenoketone is reacted to obtain a compound represented by the general formula (12-a): [Wherein Y ¹ represents a protected carboxyl group or a protected carboxymethyl group, and R ¹ and R ³ are the same as those defined above], and N-cyanobiphenylmethylthiazoline is reacted with a metal azide compound, If desired, the carboxyl protecting group may be eliminated to give a compound of the general formula (12-d): [In the formula, Y represents an optionally protected carboxyl group or an optionally protected carboxymethyl group, and R ¹
And R ³ are the same as the above], a process for producing N-tetrazolylbiphenylmethylthiazolines or a salt thereof. 5. A compound represented by the general formula (1-b): [Wherein, R ¹ represents a cyclo lower alkyl group which may have a substituent, a phenyl group or a lower alkenyl group which may have a substituent, and X ² represents a halogen atom] The thiourea derivative has the general formula (4): [In the formula, R ³ represents a hydrogen atom or a lower alkyl group, and X ¹
Represents a halogen atom, and Y ¹ represents a protected carboxyl group or a protected carboxymethyl group], and an α-halogenoketone represented by the formula (5) [Wherein R ¹ , R ³ , X ² and Y ¹ are the same as defined above] and N-benzylthiazolines are represented by the general formula (6): [In the formula, P represents a hydrogen atom or a tetrazolyl protecting group]
A phenylboronic acid represented by the formula (12-e) is characterized by reacting with a phenylboronic acid to eliminate a carboxyl protecting group if desired. [In the formula, Y represents a carboxyl group which may be protected or a carboxymethyl group which may be protected,
R ^1, R ³ and P are the preparation of N- biphenyl-methyl thiazoline compound and its salt represented by the same] to the. 6. A compound represented by the general formula (5): [In the formula, R ¹ represents a cyclo lower alkyl group which may have a substituent, a phenyl group which may have a substituent or a lower alkenyl group, and R ³ represents a hydrogen atom or a lower alkyl group. , X ² represents a halogen atom, and Y ¹ represents a protected carboxyl group or a protected carboxymethyl group], and the N-benzylthiazoline represented by the general formula (6): [In the formula, P represents a hydrogen atom or a tetrazolyl protecting group]
And reacting with phenylboronic acids represented by the formula (3) to eliminate the carboxyl protecting group, if desired. [In the formula, Y represents a carboxyl group which may be protected or a carboxymethyl group which may be protected,
R ^1, R ³ and P are the preparation of N- biphenyl-methyl thiazoline compound and its salt represented by the same] to the.