JPH0920764A - New thiazolinecarboxylic acid derivative or its salt and pharmaceutical containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having strong angiotensin II antagonistic action, smooth muscle contraction suppressing action and hypotensive action and useful as an agent for the treatment of circulatory diseases such as hypertension, cardiopathy and cerebral apoplexy. SOLUTION: The objective compound is expressed by formula I R<1> is H or COR<2> [R<2> is a (substituted) (cyclo)lower alkyl or a (substituted) phenyl]; R<3> is H, a lower alkyl or a halogen; X is OR<4> (R<4> is H or a carboxyl-protecting group) or N(R<5> )R<6> (R<5> and R<6> are each H or a lower alkyl); R<7> is H, a lower alkyl, an aralkyl or an acyl} or its salt, e.g. 3-[2'-(N-t-butylsulfamoyl)biphenyl-4- yl]methyl-2-cyclopropylcarbonyliminothiazoline-4-carboxylic acid ethyl ester. The compound of formula I can be produced by reacting a compound of formula II (R<7> a is a lower alkyl, etc.; L is a halogen, etc.) with a compound of formula III (R<4a> is a protective group), hydrolyzing with an acid, acylating the product and arbitrarily subjecting the product to deprotection, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel thiazolinecarboxylic acid derivative having a strong angiotensin II antagonistic action and a hypotensive action, or a salt thereof, and a medicament containing the same.

[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 effects are mediated by specific receptors on various target organs, such as the adrenal cortex, kidney, arterioles, and peripheral sympathetic nerves.

[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 salalacin ([Sar1, Ala8] AGII), which is an angiotensin II-like peptide, as well as imidazole derivatives (JP-A-56-7103 and JP-A-56-71074, Non-peptide derivatives such as Japanese Patent Laid-Open No. 3-501020) and pyrazole derivatives (Japanese Patent Laid-Open No. 3-218371) have also been found.

[0004]

However, since peptide derivatives have a short half-life in vivo, are not effective in oral administration, and have significant agonist activity, they are not clinically applicable. It is difficult, and even in non-peptide derivatives, few drugs are actually clinically used.

Therefore, an object of the present invention is to provide a non-peptide compound having an angiotensin II antagonistic activity, which is useful as a drug such as a therapeutic agent for hypertension.

[0006]

Under these circumstances, the present inventors have conducted diligent research in order to provide a clinically excellent drug, and as a result, a novel thiazoline carvone represented by the following general formula (1) was obtained. The acid derivative has an excellent angiotensin II antagonism, and is found to be useful as a medicine, particularly as a therapeutic agent for cardiovascular diseases such as hypertension, heart disease and stroke,
The present invention has been completed.

That is, the present invention has the following general formula (1):

[0008]

Embedded image

[In the formula, R ¹ is a hydrogen atom or a group —COR ²
(Wherein R ² represents a lower alkyl group which may have a substituent, a cyclo lower alkyl group which may have a substituent or a phenyl group which may have a substituent). , R ³ represents a hydrogen atom, a lower alkyl group or a halogen atom, X represents a group —OR ⁴ (wherein R ⁴ represents a hydrogen atom or a carboxyl protecting group) or a group —N (R ⁵ ) R ⁶ (herein). And R ⁵ and R ⁶ may be the same or different and each represents a hydrogen atom or a lower alkyl group), and R ⁷ represents a hydrogen atom, a lower alkyl group, an aralkyl group or an acyl group]. A carboxylic acid derivative or a salt thereof is provided.

The present invention also provides a medicament containing a thiazolinecarboxylic acid derivative represented by the general formula (1) or a salt thereof as an active ingredient.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The thiazolinecarboxylic acid derivative of the present invention is represented by the above general formula (1), and in the description of the substituents in the formula, the lower alkyl group means a straight chain or a branched chain. An alkyl group having 1 to 7 carbon atoms is shown, and specifically, for example, a methyl group, an ethyl group, an n-propyl group,
i-propyl group, n-butyl group, sec-butyl group, t
Examples thereof include an ert-butyl group, a linear or branched pentyl group, a hexyl group, and a heptyl group. Of these, carbon number 1-5
Are preferred. Further, "lower" in lower alkoxy, lower alkanoyl and the like means those having 1 to 7 carbon atoms, and among them, those having 1 to 5 carbon atoms are preferable.

In the present invention, the cyclo lower alkyl group means a group having 3 to 7 carbon atoms, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.

Among the substituents represented by R ² in the general formula (1), the lower alkyl group which may have a substituent includes, in addition to the above lower alkyl group, chloromethyl, bromomethyl and dichloromethyl. , Lower fluoroalkyl groups such as trifluoromethyl, chloroethyl, tetrafluoroethyl; lower hydroxy alkyl groups such as hydroxymethyl, dihydroxymethyl, hydroxyethyl, hydroxypropyl; lower alkoxy such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, etc. Lower alkyl group; cyano lower alkyl groups such as cyanomethyl, cyanoethyl, cyanopropyl, etc. are exemplified.

Further, among the groups represented by R ² , the cyclo-lower alkyl group which may have a substituent is substituted with a carboxy group such as a carboxycyclopentyl group or a carboxycyclohexyl group in addition to the above groups. And carboxycarbonyloxymethyl group, tert-butoxycarbonyloxyethyl group, cyclohexylcarbonyloxymethyl group,
(5-methyl-2-oxo-1,3-dioxole-4
-Yl) may be protected with a protecting group such as a methyl group which is easily eliminated in vivo.

Among the groups represented by R ² , the phenyl group which may have a substituent includes, in addition to the phenyl group, a lower alkyl group, a halogen atom, a cyano group, a nitro group and a halo lower alkyl group in the ring. , Halo lower alkoxy group, carboxyl group, carboxyl group having a protecting group that can be easily eliminated in vivo, lower alkoxycarbonyl group, lower alkoxy group, hydroxyl group, lower alkylthio group, mercapto group, amino group, lower alkanoyl group, etc. Is 1-3
Those substituted with an individual include, specifically, tolyl, chlorophenyl, dichlorophenyl, trichlorophenyl,
Fluorophenyl, difluorophenyl, trifluorophenyl, bromophenyl, iodophenyl, nitrophenyl, dinitrophenyl, cyanophenyl, carboxyphenyl (wherein the carboxyl group is methoxycarbonyloxymethyl group, tert-butoxycarbonyloxyethyl group, cyclohexylcarbonyloxy) Methyl group, (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group and the like, including those protected by a protecting group that is easily eliminated in vivo), methoxycarbonylphenyl, Dimethoxycarbonylphenyl, 2-carboxy-6-nitrophenyl, 2-ethoxycarbonyl-
Examples include 6-nitrophenyl, hydroxyphenyl, methoxyphenyl, trifluoromethoxyphenyl, mercaptophenyl, methylthiophenyl, aminophenyl, acetylphenyl and the like.

Among the groups represented by R ³ , examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, with a chlorine atom being particularly preferred. R ³
Among the groups represented by, examples of the lower alkyl group include those mentioned above, and among them, the n-butyl group is particularly preferable.

[0017] Among the groups represented by X, R ⁴ being -OR ⁴
Among the groups represented by, the carboxyl protecting group is not particularly limited as long as it is easily cleaved to generate a free carboxyl group. As such a protecting group, for example, a lower alkyl group, a benzyl group, an aralkyl group such as a phenylethyl group, an aryl group such as a phenyl group, a naphthyl group, or the like mentioned above may be treated under mild conditions such as hydrolysis or catalytic reduction. Those which are eliminated by; lower alkanoyloxy lower alkyl groups such as acetoxymethyl group, pivaloyloxymethyl group, lower alkoxycarbonyloxy lower alkyl groups such as methoxycarbonyloxymethyl group, 1-ethoxycarbonyloxyethyl group, cyclohexylcarbonyl Cyclolower alkylcarbonyloxy lower alkyl groups such as oxymethyl group and cyclopentylcarbonyloxymethyl group, lower alkoxymethyl groups such as methoxymethyl group, lactonyl groups such as phthalidinyl group, and dilower alkyl groups such as 1-dimethylaminoethyl group. Roh lower alkyl group, and the like which easily eliminated in vivo, such as (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl group.

Among the groups represented by R ⁵ and R ⁶ in the group —N (R ⁵ ) R ⁶ , the lower alkyl group includes those mentioned above.

Examples of the lower alkyl group represented by R ⁷ include those mentioned above, and examples of the acyl group include alkanoyl such as formyl, acetyl, propionyl, butyryl, valeryl, isovaleryl, pivaloyl and hexanoyl. Groups; for example, cyclolower alkanoyl groups such as cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl; for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, n-butoxycarbonyl,
lower alkoxycarbonyl groups such as tert-butoxycarbonyl; aralkyloxycarbonyl groups such as benzyloxycarbonyl, phenethyloxycarbonyl; aroyl groups such as benzoyl, toluoyl, chlorobenzoyl, fluorobenzoyl, bromobenzoyl, iodobenzoyl, naphthoyl; Examples thereof include an aroyl group in which a hydrogen atom on the aromatic ring of the aroyl group is substituted with 1 to 3 lower alkoxycarbonyl groups such as methoxycarbonyl group and ethoxycarbonyl group, or a carboxyl group.

Examples of the aralkyl group represented by R ⁷ include phenyl lower alkyl groups such as benzyl group and phenethyl group; diphenyl lower alkyl groups such as diphenylmethyl group; trityl group and the like.

The salt of the thiazolinecarboxylic acid derivative of the present invention includes a pharmaceutically acceptable acid addition salt or base addition salt.

Examples of the acid addition salt include (a) salts with mineral acids such as hydrochloric acid and sulfuric acid, and (b) organic carboxylic acids such as formic acid, citric acid, trichloroacetic acid, trifluoroacetic acid, fumaric acid and maleic acid. Salt of (c) methanesulfonic acid,
Examples thereof include salts with sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid, mesitylenesulfonic acid and naphthalenesulfonic acid. Examples of the base addition salt include (a) salts with alkali metals such as sodium and potassium, (b) salts with alkaline earth metals such as calcium and magnesium, (c) ammonium salts,
(D) trimethylamine, triethylamine, tributylamine, pyridine, N, N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, diethylamine, cyclohexylamine, procaine, dibenzylamine,
N-benzyl-β-phenethylamine, 1-ephenamine, N,
Mention may be made of salts with nitrogen-containing organic bases such as N'-dibenzylethylenediamine.

The compound (1) of the present invention can exist not only in unsolvated form but also as hydrate or solvate. Accordingly, the compounds of this invention include all crystalline forms and hydrates or solvates thereof.

In addition, the compound (1) of the present invention includes a compound having an asymmetric carbon atom, and thus can exist as an optically active substance. These optically active substances are also included in the compound of the present invention. Furthermore, some of the compound (1) 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 compounds of the present invention.

The compound represented by the general formula (1) of the present invention can be produced by various methods, and a preferable example thereof is a method represented by the following [Reaction scheme 1].

[0026]

Embedded image

[Wherein R ^4a represents a carboxyl protecting group, R ^7a represents a lower alkyl group or an aralkyl group, and R
^7b represents an acyl group, L represents a halogen atom or a sulfonyloxy group, and R ¹ , R ³ , R ⁷ and X have the same meanings as described above. ]

That is, the compound (1-a) is produced by condensing the biphenylmethyl derivative represented by the general formula (A) and the thiazolecarboxylic acid derivative represented by the general formula (B) in the presence of a base. You can Also,
If this compound (1-a) is acid-hydrolyzed, the compound (1-
b) is obtained, compound (1-b) is acylated to give compound (1-c), and deprotection and amidation give compound (1-d).

Examples of the halogen atom represented by L of the compound (A) include chlorine atom, bromine atom and iodine atom, and examples of the sulfonyloxy group include methanesulfonyloxy, ethanesulfonyloxy and trifluoromethanesulfonyloxy. And alkylsulfonyloxy groups such as benzenesulfonyloxy and arylsulfonyloxy groups such as p-toluenesulfonyloxy.

Examples of the base used in the reaction between the compound (A) and the compound (B) include sodium hydride, lithium hydride, potassium carbonate, sodium carbonate, sodium alcoholate, tert-butoxy potassium, sodium hydroxide and water. Examples thereof include potassium oxide, triethylamine, diisopropylethylamine and the like. Any solvent may be used as long as it does not influence the reaction, for example, N, N-dimethylformamide, aprotic polar solvent such as dimethylsulfoxide; diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme. And the like; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride and the like; alcohols such as methanol, ethanol, propanol and the like.

In the reaction between the compound (A) and the compound (B), a phase transfer catalyst may be added as a reaction accelerator. Such phase transfer catalysts include tetramethylammonium chloride, tetraoctylammonium chloride, quaternary ammonium salts such as tetrabutylammonium bromide, N-neopentyl-4- (N ', N'-dimethylamino) -pyridinium. Chloride, N- (2-ethyl-hexyl) -4- (N ', N'-dimethylamino) pyridinium salts such as pyridinium chloride, or tetrabutylphosphonium bromide, quaternary phosphonium salts such as tetraphenylphosphonium bromide Can be mentioned.

The reaction temperature is usually -30 to 150 ° C, preferably 1
The reaction time is usually 10 minutes to 24 hours, preferably 1 to 10 hours.

As a particularly preferred example of this reaction, 0 in an aprotic polar solvent such as N, N-dimethylformamide is used.
Examples include a method of reacting at ℃ ~ room temperature.

The acid hydrolysis reaction of the compound (1-a) is carried out in the presence of a mineral acid such as hydrochloric acid, sulfuric acid or hydrobromic acid; or an organic acid such as trifluoroacetic acid or p-toluenesulfonic acid; Alcohols such as methanol, ethanol, propanol, etc., ethers such as tetrahydrofuran, dioxane, etc., ketones such as acetone, methyl ethyl ketone, etc., acetic acid etc. solvent or a mixed solvent thereof or in the absence of solvent. Be seen. This reaction is usually carried out at room temperature to 180 ° C., preferably room temperature to 140 ° C.,
The reaction time is usually 1 to 72 hours.

The acylation reaction of the compound (1-b) can be carried out by any reaction which is commonly used for acylation of amino groups. For example, an acyl halide or acid anhydride corresponding to a desired acyl group and a compound can be used. (1-b) is halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, chlorobenzene; aromatic hydrocarbons such as benzene and toluene; ethers such as tetrahydrofuran and dioxane; or acetonitrile, N, N-dimethyl Presence of a base such as pyridine, picoline, N, N-dimethylaniline, N-methylmorpholine, dimethylamine, triethylamine, sodium carbonate, potassium carbonate, sodium hydride in an aprotic polar solvent such as formamide at 0 ° C to room temperature Or using pyridine, lutidine, etc. as the solvent itself. -70～1 in the absence of a base
The reaction can be carried out at 00 ° C, or by reacting an acid such as formic acid or acetic acid or an acid anhydride thereof at room temperature to 150 ° C.

Deprotection of the compound (1-c) is carried out with water such as ethanol, methanol, tetrahydrofuran and N, N-dimethylformamide in an alkaline aqueous solution such as an aqueous solution of sodium hydroxide, an aqueous solution of potassium hydroxide and an aqueous solution of sodium carbonate. It can be carried out by using a miscible solution or by reacting compound (1-c) at room temperature to 100 ° C. without using a solvent.

Amidation of the obtained deprotected product is carried out by deprotection and primary amines such as ammonia, methylamine, ethylamine and benzylamine; secondary amines such as dimethylamine and diethylamine; cyclic amines such as pyrrolidine and piperidine. , Or a salt thereof, ethers such as diethyl ether, tetrahydrofuran, dioxane; dichloromethane,
Halogenated hydrocarbons such as chloroform; dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N '-(3 in aprotic solvents such as N, N-dimethylformamide, acetonitrile and isobutyronitrile
-Dimethylaminopropyl) carbodiimide, N-ethyl-5-isoxazolium-3'-sulfonate, 2-ethyl-7-oxybenzisoxazolium trifluoroboron salt, benzotriazol-1-yl-tris (dimethylamino) ) Phosphonium hexafluorophosphide salt, 1-ethoxycarbonyl-2-ethoxy-1,2-
Condensing agents such as dihydroquinoline, carbonyldiimidazole, diethylphosphoric acid cyanide, diphenylphosphoric acid azide, and N-hydroxysuccinimide, N-hydroxybenzotriazole, 3-hydroxy-4-oxo-3,4
-The reaction can be performed at 0 ° C to room temperature for 1 to 5 hours in the presence of an additive such as dihydro-1,2,3-benzotriazine. When an amine salt is used, it may be used in the presence of a tertiary amine such as pyridine, N, N-dimethylaniline, N, N-dimethylmorpholine, triethylamine or diisopropylethylamine, or an inorganic base such as potassium carbonate, cesium carbonate or thallium carbonate. To do.

The compound (1-a) can also be synthesized by the method shown in the following [Scheme 2] or [Scheme 3].

[0039]

Embedded image

[In the formula, Y ¹ represents a halogen atom, and R ¹ ,
R ³ , R ^4a and R ^7a have the same meanings as described above. ]

That is, the compound (1-a) or a salt thereof can be obtained by reacting the thiourea derivative (C) with the α-halogenoketones (D).

The reaction between the thiourea derivative (C) and the α-halogenoketones (D) is carried out by reacting alcohols such as methanol, ethanol and isopropyl alcohol; nitriles such as acetonitrile and isobutyronitrile; acetone, methyl ethyl ketone and methyl isobutyl. Ketones, ketones such as cyclohexane; aromatic hydrocarbons such as benzene, toluene, xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, diethylene glycol dimethyl ether; aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether Ethyl formate,
Esters such as ethyl acetate and butyl acetate; Amides such as N, N-dimethylformamide; Sulfur compounds such as dimethyl sulfoxide and sulfolane; In the presence of a solvent such as water or a mixture thereof that does not adversely affect the condensation ring closure reaction. Or in the absence of solvent, pyridine, N, N-dimethylethylaniline, N, N-
Dimethylmorpholine, triethylamine, diisopropylethylamine, 1,8-diazabicyclo [5.4.
0] tertiary amines such as undec-7-ene, potassium carbonate, sodium hydroxide, cesium carbonate, thallium carbonate,
1 to 1 at a temperature of 80 to 150 ° C. in the presence of an inorganic base such as potassium hydroxide, sodium hydroxide or thallium hydroxide, or an alkoxide of these alkali metals.
It is preferably carried out for 0 hours.

[0043]

Embedded image

[In the formula, X ² represents a halogen atom or a trifluoromethanesulfonyl group, and R ¹ , R ³ , R ^4a and R ^7a
And Y ¹ have the same meaning as described above. ]

That is, the thiourea derivative (E) is reacted with α-halogenoketones (D), and the obtained N-benzylthiazolines (F) is reacted with phenylboronic acids (G). 1-a) or a salt thereof is obtained.

The reaction between the thiourea derivative (E) and the α-halogenoketone (D) is carried out in the same manner as the reaction between the thiourea derivative (C) and (D) shown in the reaction formula 2.
The reaction between the obtained N-benzylthiazolines (F) and phenylboronic acids (G) is carried out using benzene, toluene, ether, tetrahydrofuran, dioxane, acetonitrile, N, N-dimethylformamide, ethanol, methanol, propanol, dimethoxyethane. , Non-polar tertiary amines such as triethylamine and diisopropylethylamine, potassium carbonate, sodium carbonate, cesium carbonate, thallium carbonate and hydroxide 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, sodium hydroxide or thallium hydroxide, or an alkoxide of these alkali metals. When an inorganic base insoluble in an organic solvent is used, it needs to be used as an aqueous solution, and it is preferable to carry out in the presence of a phase transfer catalyst such as tetra-n-butylammonimyl bromide or crown ether. The palladium complex used in this reaction includes tetrakis (triphenylphosphine) palladium, bis (dibenzylideneacetone) palladium, tris (dibenzylideneacetone) dipalladium,
Alternatively, a divalent palladium phosphine complex may be used.

Examples of the divalent palladium phosphine complex include bis (triphenylphosphine) valadium chloride, bis (triphenylphosphine) palladium bromide, bis (triphenylphosphine) palladium acetate, bis (triisopropylphosphite) palladium chloride, Bis (triisopropylphosphite) 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.

In this reaction, the catalyst can be activated in the reaction mixture. For example, tris (dibenzylideneacetone) dipalladium may be added to the reaction mixture containing triphenylphosphine, and the activated triphenylphosphine palladium complex produced may be used. The activation of the catalyst is carried out by divalent palladium salts such as palladium chloride, palladium bromide, palladium acetate and triarylphosphine, generally dialkylzinc, alkylzinc halide, dialkylmagnesiumalkylmagnesium halide, trialkylaluminum, dialkylaluminum. It can also be carried out by reacting triphenylphosphine in the presence of a reducing agent such as halide, 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.

The phenylboronic acids (G) used in this reaction are, for example, USP 5130439, WO93 / 1.
As described in 0106, it can be obtained by reacting phenyltetrazole with n-butyllithium or the like to give an alkali metal salt, and reacting boronic acid ester such as isopropyl borate.

The biphenylmethyl derivative (A) in the reaction formula 1 can be produced according to a conventionally known method (JP-A-4-327586, JP-A-5-155867,
JP-A-5-294947), and the thiourea derivatives (C) and (E) in Reaction Schemes 2 and 3 are disclosed in Japanese Patent Application No. 6-36.
It can be obtained from the corresponding isothiocyanate derivative and benzylamines according to the method described in No. 96.

Thiazolinecarboxylic acid derivative of the present invention (1)
Is a pharmaceutically acceptable carrier for injection, parenteral administration such as rectal administration, or oral administration in solid or liquid form when used as a medicine represented by therapeutic agents for cardiovascular diseases such as antihypertensive agents. Can be formulated as a composition with.

The form of the composition according to the present invention for injection includes pharmaceutically acceptable sterile water, non-aqueous solution, suspension or emulsion. Examples of suitable non-aqueous carriers, diluents, solvents or vehicles are propylene glycol,
Examples thereof include polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Such compositions may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. These compositions may be prepared, for example, by filtration through a bacterial retention filter,
Alternatively, it can be sterilized immediately before use by incorporating the sterilant in the form of a sterile solid composition which can be dissolved in sterile water or some other sterile injectable medium.

Examples of solid preparations for oral administration include capsules, tablets, pills, powders and granules. In preparing the solid preparation, the compound of the present invention is generally mixed with at least one inert diluent such as sucrose, lactose, starch and the like. The formulation may also include additional substances in addition to the inert diluent in conventional formulation, such as lubricants (eg magnesium stearate). In the case of capsules, tablets and pills, a buffer may also be included. Tablets and pills can additionally be provided with an enteric coating.

Liquid formulations for oral administration include inert diluents commonly used by those skilled in the art, for example, pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. containing water. Is mentioned. In addition to such inert diluents, the composition can also contain auxiliary agents such as wetting agents, emulsifying agents, suspending agents, sweetening agents, seasoning agents, flavoring agents and the like. In the case of a preparation for rectal administration, it is preferable to contain excipients such as cocoa butter and a suppository wax in addition to the compound of the present invention.

The dose of the compound (1) of the present invention depends on the properties of the compound to be administered, the route of administration, the desired treatment period and other factors, but it is generally about 0.1 to 1 per day.
00 mg / kg, especially about 0.5-50 mg / kg is preferred. If desired, the daily dose can be divided and administered in 2 to 4 times.

[0057]

The thiazolinecarboxylic acid derivative of the present invention
(1) and a salt thereof are novel compounds, have a strong angiotensin II antagonistic action, a smooth muscle contraction inhibitory action and a blood pressure lowering action, and are useful as a medicine typified by the treatment and prevention of hypertension.

[0058]

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

Example 1 (1) 3- [2 '-(N-tert-butylsulfamoyl) biphenyl-4-yl] methyl-2-cyclopropylcarbonyliminothiazoline-4-carboxylic acid ethyl ester [Compound 1 ]
Synthesis of 2-Cyclopropylcarbonylaminothiazole-4-carboxylic acid ethyl ester (305 mg) was added to a suspension of N, N-dimethylformamide (4 ml) and sodium hydride (55 mg) at room temperature. 4'after confirming that hydrogen generation has ended
A solution of -bromomethyl-N-tert-butyl-2-biphenylylsulfonamide (485 mg) in N, N-dimethylformamide (4 ml) was added and the mixture was stirred at the same temperature. Ethyl acetate (50 ml) was added, and the mixture was washed 3 times with water (20 ml). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off. The residue was subjected to column chromatography (silica gel / chloroform),
3- [2 '-(N-tert-butylsulfamoyl) biphenyl-4-
Il] methyl-2-cyclopropylcarbonyliminothiazoline-4-carboxylic acid ethyl ester [Compound 1] and 2-
[N- (tert-butylsulfamoylbiphenyl-4-yl) methyl-N-cyclopropylcarbonyl] aminothiazole-4
-A single spot of a mixture of carboxylic acid ethyl esters was obtained. This mixture was mixed with ethanol (6 ml), sodium (30 m
It was added to the solution of g) and stirred at room temperature for 1 hour. After the ethanol was distilled off, the residue was acidified with 2N-hydrochloric acid and extracted with ethyl acetate. After drying the organic layer over anhydrous magnesium sulfate,
Distilled off. The residue was subjected to column chromatography (silica gel / chloroform) to obtain 71 mg of the title compound.

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.87-0.97 (2H, m), 0.93 (9H, s), 1.04-1.11
(2H, m), 1.36 (3H, t, J = 7Hz), 1.85-1.92 (1H, m), 3.43 (1H,
s), 4.32 (2H, q, J = 7Hz), 5.93 (2H, s), 7.26-7.28 (2H, m), 7.3
6 (2H, d, J = 8Hz), 7.44 (2H, d, J = 8Hz), 7.43-7.58 (1H, m), 7.5
9 (1H, s), 8.16 (1H, d, J = 8Hz)

In the same manner, the following compounds 2 to 10 were synthesized. (2) 3- [2 '-(N-tert-butylsulfamoyl) biphenyl-4-yl] methyl-2-cyclopropylcarbonylimino-5-methylthiazoline-4-carboxylic acid ethyl ester
[Compound 2]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.78-0.80 (2H, m), 0.87 (9H, s), 0.91-1.01
(2H, m), 1.28 (3H, t, J = 7Hz), 1.78-1.83 (1H, m), 2.41 (3H,
s), 3.38 (1H, s), 4.24 (2H, q, J = 7Hz), 5.78 (2H, s), 7.19-7.2
2 (3H, m), 7.37-7.48 (2H, m), 7.38 (2H, d, J = 8Hz), 8.07 (1H,
d, J = 8Hz)

(3) 3- [2 '-(N-tert-butylsulfamoyl) biphenyl-4-yl] methyl-2-cyclopropylcarbonylimino-5-ethylthiazoline-4-carboxylic acid ethyl ester [Compound 3]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.85-0.89 (2H, m), 0.97 (9H, s), 1.06-1.11
(2H, m), 1.29 (3H, t, J = 7Hz), 1.37 (3H, t, J = 7Hz), 1.87-1.91
(1H, m), 2.92 (2H, q, J = 7Hz), 3.45 (1H, s), 4.33 (2H, q, J = 7H
z), 5.82 (2H, s), 7.26-7.29 (2H, m), 7.40-7.58 (3H, m), 7.47
(2H, d, J = 7Hz), 8.16 (1H, d, J = 7Hz)

(4) 3- [2 '-(N-tert-butylsulfamoyl) biphenyl-4-yl] methyl-2-cyclopropylcarbonylimino-5-isopropylthiazoline-4-carboxylic acid ethyl ester [Compound 4]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.96-0.98 (2H, m), 0.96 (9H, s), 1.21-1.25
(2H, m), 1.35-1.40 (9H, m), 1.97-2.02 (1H, m), 3.50 (1H, s),
4.01-4.07 (1H, m), 4.36 (2H, q, J = 7Hz), 5.73 (2H, s), 7.26-
7.31 (2H, m), 7.39-7.43 (2H, m), 7.50-7.66 (3H, m), 8.06 (1
(H, d, J = 7Hz)

(5) 3- [2 '-(N-tert-butylsulfamoyl) biphenyl-4-yl] methyl-2-cyclopropylcarbonylimino-5-hexylthiazoline-4-carboxylic acid ethyl ester [Compound 5]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.86-0.95 (5H, m), 0.97 (9H, s), 1.06-1.09
(2H, m), 1.36 (3H, t, J = 7Hz), 1.27-1.39 (6H, m), 1.60-1.64
(2H, m), 1.85-1.93 (1H, m), 2.87 (2H, t, J = 7Hz), 3.45 (1H,
s), 4.37 (2H, q, J = 7Hz), 5.82 (2H, s), 7.25-7.29 (3H, m), 7.4
4-7.55 (2H, m), 7.45 (2H, d, J = 8Hz), 8.16 (1H, d, J = 8Hz)

(6) 3- [2 '-(N-tert-butylsulfamoyl) biphenyl-4-yl] methyl-5-chloro-2-cyclopropylcarbonyliminothiazoline-4-carboxylic acid ethyl ester [Compound 6]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.91-0.95 (2H, m), 0.95 (9H, s), 1.09-1.11
(2H, m), 1.37 (3H, t, J = 7Hz), 1.88-1.94 (1H, m), 3.44 (1H,
s), 4.36 (2H, q, J = 7Hz), 5.81 (2H, s), 7.26-7.30 (2H, m), 7.4
5-7.56 (5H, m), 8.16 (1H, d, J = 7Hz)

(7) 3- [2 '-(N-tert-butylsulfamoyl) biphenyl-4-yl] methyl-2-propionyliminothiazoline-4-carboxylic acid ethyl ester [Compound 7]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.93 (9H, s), 1.22 (3H, t, J = 7Hz), 1.36 (3
H, t, J = 7Hz), 2.60 (2H, q, J = 7Hz), 3.43 (1H, s), 4.32 (2H, q, J
= 7Hz), 5.98 (2H, s), 7.26-7.30 (1H, m), 7.36-7.55 (6H, m),
7.62 (1H, s), 8.16 (1H, d, J = 8Hz)

(8) 3- [2 '-(N-tert-butylsulfamoyl) biphenyl-4-yl] methyl-2-butyryliminothiazoline-4-carboxylic acid ethyl ester [Compound 8]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.93 (9H, s), 0.97 (3H, t, J = 7Hz), 1.36 (3
H, t, J = 7Hz), 1.71-1.79 (2H, m), 2.54 (2H, t, J = 7Hz), 3.43 (1
H, s), 4.32 (2H, q, J = 7Hz), 5.95 (2H, s), 7.26-7.30 (2H, m),
7.36-7.55 (5H, m), 7.60 (1H, s), 8.15 (1H, d, J = 7Hz)

(9) 3- [2 '-(N-tert-butylsulfamoyl) biphenyl-4-yl] methyl-2-cyclobutylcarbonyliminothiazoline-4-carboxylic acid ethyl ester [Compound 9]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.93 (9H, s), 1,36 (3H, t, J = 7Hz), 1.81-
2.02 (2H, m), 2.06-2.39 (4H, m), 3.33-3.42 (1H, m), 3.42 (1
H, s), 4.30 (2H, q, J = 7Hz), 5.95 (2H, s), 7.26-7.30 (1H, m),
7.39-7.55 (6H, m), 7.60 (1H, s), 8.15 (1H, d, J = 7Hz)

(10) 3- [2 '-(N-tert-butylsulfamoyl) biphenyl-4-yl] methyl-2-cyclohexylcarbonyliminothiazoline-4-carboxylic acid ethyl ester [Compound 10]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.93 (9H, s), 1.23-1.38 (3H, m), 1.36 (3
H, t, J = 7Hz), 1.46-1.75 (5H, m), 1.97-2.02 (2H, m), 2.43-2.
48 (1H, m), 3.43 (1H, s), 4.32 (2H, q, J = 7Hz), 5.96 (2H, s), 7.
26-7.29 (2H, m), 7.30-7.58 (5H, m), 7.59 (1H, s), 8.17 (1H, d
d, J = 1Hz, 7Hz)

Reference Example 1 Synthesis of N- (2-chlorobenzoyl) -N '-(4-iodobenzyl) thiourea 4-iodobenzylamine hydrochloride (14.3 g) was added to chloroform (150 ml) and triethylamine (5 ml). Added to the solution. 2-Chlorobenzoyl isothiocyanate (11.5
A solution of g) in chloroform (50 ml) was added dropwise. After stirring at room temperature for 1 hour, the mixture was washed with water, the organic layer was dried over anhydrous magnesium sulfate, and evaporated. Add isopropyl ether to the residue,
11.4 g of the title compound was obtained as yellow crystals.

Properties: colorless crystals ¹ H-NMR (CDCl ₃ ); 4.87 (2H, d, J = 7Hz), 7.18 (2H, d, J = 8Hz),
7.39-7.44 (1H, m), 7.48-7.50 (2H, m), 7.69-7.76 (3H, m), 9.
19 (1H, s)

Reference Example 2 2- (2-chlorobenzoyl) imino-3- (4-iodobenzyl)
Synthesis of thiazoline-4-carboxylic acid ethyl ester N- (2-chlorobenzoyl) -N '-(4-iodobenzyl) thiourea (1.44 g) and 3-bromopyruvic acid ethyl ester (2.06
g) was added to a mixture of ethanol (4 ml) and pyridine (0.4 ml). The mixture was stirred with heating under reflux for 1 hour. After distilling off the solvent, ethyl acetate was added to the residue and washed with water. The organic layer was dried over anhydrous magnesium sulfate and then evaporated. The residue was subjected to column chromatography (silica gel / chloroform) to obtain 672 mg of the title compound.

Properties: colorless crystals ¹ H-NMR (CDCl ₃ ); 1.34 (3H, t, J = 7Hz), 4.31 (2H, q, J = 7Hz),
5.94 (2H, s), 7.08 (2H, d, J = 8Hz), 7.26-7.42 (3H, m), 7.62 (2
H, d, J = 8Hz), 7.68 (1H, s), 7.97 (1H, d, J = 8Hz)

Example 2 (1) 3- [2 '-(N-tert-butylsulfamoyl) biphenyl-4-yl] methyl-2- (2-chlorobenzoyl) iminothiazoline-4-carboxylic acid ethyl ester Synthesis of [Compound 11] 2- (2-chlorobenzoyl) imino-3- (4-iodobenzyl)
Thiazoline-4-carboxylic acid ethyl ester (300 mg) and 2- (N
-tert-Butylsulfamoyl) phenylboronic acid (293mg)
Toluene (7 ml), 2M aqueous sodium carbonate solution (4 ml) and tetrakis (triphenylphosphine) palladium (6
6 mg) was added, and the mixture was heated under reflux for 2 hours under a nitrogen atmosphere. The mixture was returned to room temperature, washed with water, the organic layer was dried over anhydrous magnesium sulfate, and evaporated. The residue was subjected to column chromatography (silica gel / chloroform) to give 188 mg of the title compound.
Obtained.

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.89 (9H, s), 1.38 (3H, t, J = 7Hz), 3.42 (1
H, s), 4.34 (2H, q, J = 7Hz), 6.07 (2H, s), 7.14-7.55 (10H, m),
7.73 (1H, s), 8.02-8.07 (1H, m), 8.12-8.16 (1H, m)

Reference Example 3 4 '-(N'-cyclopropylcarbonylthioureido) methyl
Synthesis of -N-tert-butyl-2-biphenylylsulfonamide 4'-Aminomethyl-N-tert-butylbiphenylsulfonamide (2.0 g) was added in chloroform (15 ml). Cyclopropylcarbonyl isothiocyanate (1.0
A solution of g) in chloroform (5 ml) was added dropwise at room temperature. After the dropping was completed, the mixture was stirred for another hour at the same temperature. After washing with a saturated aqueous sodium hydrogen carbonate solution, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was subjected to column chromatography (silica gel / chloroform),
2.7 g of the title compound was obtained.

Properties: colorless crystals ¹ H-NMR (CDCl ₃ ); 0.99-1.01 (2H, m), 1.01 (9H, s), 1.08-1.
10 (2H, m), 1.50-1.56 (1H, m), 3.68 (1H, s), 4.79 (2H, d, J = 7H
z), 7.26-7.30 (1H, m), 7.41 (2H, d, J = 7Hz), 7.46-7.59 (4H,
m), 8.17 (1H, d, J = 7Hz), 9.08 (1H, s)

Example 3 (1) Ethyl 5-butyl-3- [2 '-(N-tert-butylsulfamoyl) biphenyl-4-yl] methyl-2-cyclopropylcarbonyliminothiazoline-4-carboxylate ester
Synthesis of [Compound 12] With 3-bromo-2-oxoheptanoic acid ethyl ester (780 mg)
4 '-(N'-cyclopropylcarbonylthioureido) methyl
-N-tert-butyl-2-biphenylylsulfonamide (670m
g) was added to a solution of ethanol (1.5 ml) and 7 drops of pyridine, and the mixture was heated under reflux for 1 hour. After returning to room temperature, the solvent was distilled off. Ethyl acetate was added to the residue and washed with water (10 ml) three times. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off.
The residue was subjected to column chromatography (silica gel / chloroform) to obtain 287 mg of the title compound.

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.84-0.89 (5H, m), 0.89 (9H, s), 1.04-1.
07 (2H, m), 1.26-1.38 (2H, m), 1.36 (3H, t, J = 7Hz), 1.57-1.6
5 (2H, m), 1.86-1.92 (1H, m), 2.89 (2H, t, J = 7Hz), 3.44 (1H,
s), 4.33 (2H, q, J = 7Hz), 5.82 (2H, s), 7.26-7.28 (4H, m), 7.4
6 (2H, d, J = 8Hz), 7.46-7.54 (1H, m), 8.16 (1H, d, J = 7Hz) In the same manner, Compound 13 was synthesized.

(2) 5-Isobutyl-3- [2 '-(N-tert-butylsulfamoyl) biphenyl-4-yl] methyl-2-cyclopropylcarbonyliminothiazoline-4-carboxylic acid ethyl ester [Compound 13]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.86-1.04 (8H, m), 0.98 (9H, s), 1.04-1.
08 (2H, m), 1.34 (3H, t, J = 7Hz), 1.89-2.00 (2H, m), 2.75 (2H,
d, J = 7Hz), 3.45 (1H, s), 4.30 (2H, q, J = 7Hz), 5.82 (2H, s), 7.
24-7.29 (2H, m), 7.45 (2H, d, J = 8Hz), 7.44-7.55 (3H, m), 8.1
6 (1H, d, J = 8Hz)

Example 4 (1) Synthesis of 2-cyclopropylcarbonylimino-3- (2'-sulfamoylbiphenyl-4-yl) methylthiazoline-4-carboxylic acid ethyl ester [Compound 14] 3- [2 '-(N-tert-butylsulfamoyl) biphenyl-4-
Il] methyl-2-cyclopropylcarbonyliminothiazoline-4-carboxylic acid ethyl ester (71 mg) was added in trifluoroacetic acid (4 ml). Further, 2 drops of anisole were added and the mixture was stirred at room temperature for 3 days. After trifluoroacetic acid was distilled off, ethyl acetate (10 ml) was added and the mixture was washed with water. The organic layer was dried over anhydrous magnesium sulfate and then evaporated. The residue was subjected to column chromatography (silica gel / chloroform) to obtain 56 mg of the title compound.

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.88-0.93 (2H, m), 1.09-1.12 (2H, m), 1.
35 (3H, t, J = 7Hz), 4.12 (2H, s), 4.22 (2H, q, J = 7Hz), 5.93 (2
H, s), 7.30-7.45 (5H, m), 7.50-7.59 (2H, m), 7.59 (1H, s), 8.
16 (1H, d, J = 7Hz) In the same manner, compounds 15 to 26 were synthesized.

(2) 2-cyclopropylcarbonylimino
-5-Methyl-3- (2'-sulfamoylbiphenyl-4-yl) methylthiazoline-4-carboxylic acid ethyl ester [Compound 1
5]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.86-0.89 (2H, m), 1.06-1.08 (2H, m), 1.
33 (3H, t, J = 7Hz), 1.84-1.92 (1H, m), 2.49 (3H, s), 4.12 (2H,
s), 4.29 (2H, q, J = 7Hz), 5.85 (2H, s), 7.23-7.33 (3H, m), 7.4
2 (2H, d, J = 8Hz), 7.48-7.59 (2H, m), 8.16 (1H, d, J = 7Hz)

(3) 2-cyclopropylcarbonylimino
-5-Ethyl-3- (2'-sulfamoylbiphenyl-4-yl) methylthiazoline-4-carboxylic acid ethyl ester [Compound 1
6]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.87-0.91 (2H, m), 1.07-1.12 (2H, m), 1.
28 (3H, t, J = 7Hz), 1.39 (3H, t, J = 7Hz), 1.89-1.93 (1H, m), 2.
94 (2H, q, J = 7Hz), 4.12 (2H, s), 4.33 (2H, q, J = 7Hz), 5.86 (2
H, s), 7.24-7.34 (4H, m), 7.41-7.63 (3H, m), 8.17 (1H, d, J = 7
Hz)

(4) 2-cyclopropylcarbonylimino
-5-Isopropyl-3- (2'-sulfamoylbiphenyl-4-
Iyl) methylthiazoline-4-carboxylic acid ethyl ester
[Compound 17]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.86-0.89 (2H, m), 1.05-1.08 (2H, m), 1.
23-1.37 (3H, m), 1.29 (6H, d, J = 7Hz), 1.87-1.92 (1H, m), 3.6
3-3.79 (1H, s), 4.11 (2H, s), 4.28 (2H, q, J = 7Hz), 5.79 (2H,
s), 7.24-7.33 (3H, m), 7.43 (2H, d, J = 7Hz), 7.47-7.59 (2H,
m), 8.16 (1H, d, J = 7Hz)

(5) 5-Butyl-2-cyclopropylcarbonylimino-3- (2'-sulfamoylbiphenyl-4-yl)
Methylthiazoline-4-carboxylic acid ethyl ester [Compound 18]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.85-0.94 (2H, m), 0.92 (3H, t, J = 7Hz),
1.03-1.08 (2H, m), 1.29-1.38 (2H, m), 1.32 (3H, t, J = 7Hz),
1.60-1.63 (2H, m), 1.88-1.92 (1H, m), 2.88 (2H, t, J = 7Hz),
4.14 (2H, s), 4.24 (2H, q, J = 7Hz), 5.82 (2H, s), 7.24-7.29 (3
H, m), 7.42 (2H, d, J = 8Hz), 7.47-7.59 (2H, m), 8.15 (1H, d, J =
8Hz)

(6) 5-Isobutyl-2-cyclopropylcarbonylimino-3- (2'-sulfamoylbiphenyl-4-yl) methylthiazoline-4-carboxylic acid ethyl ester [Compound 19]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.84-0.87 (2H, m), 0.98 (6H, d, J = 7Hz),
1.01-1.04 (2H, m), 1.31 (3H, t, J = 7Hz), 1.87-1.89 (2H, m),
2.73 (2H, d, J = 7Hz), 4.09 (2H, s), 4.28 (2H, q, J = 7Hz), 5.84
(2H, s), 7.24-7.28 (2H, m), 7.42-7.54 (5H, m), 8.14 (1H, d, J
= 8Hz)

(7) 2-Cyclopropylcarbonylimino
-5-hexyl-3- (2'-sulfamoylbiphenyl-4-yl)
Methylthiazoline-4-carboxylic acid ethyl ester [Compound 20]

Properties: colorless powder ¹ H-NMR (CDCl ₃ ); 0.84-0.90 (5H, m), 1.04-1.09 (2H, m), 1.
19-1.36 (9H, m), 1.58-1.70 (2H, m), 1.85-1.91 (1H, m), 2.88
(2H, t, J = 7Hz), 4.14 (2H, s), 4.27 (2H, q, J = 7Hz), 5.82 (2H,
s), 7.24-7.33 (3H, m), 7.41-7.59 (4H, m), 8.16 (1H, d, J = 8H
z)

(8) 5-chloro-2-cyclopropylcarbonylimino-3- (2'-sulfamoylbiphenyl-4-yl)
Methylthiazoline-4-carboxylic acid ethyl ester [Compound 21]

¹ H-NMR (CDCl ₃ ); 0.91-0.94 (2H, m), 1.08-
1.11 (2H, m), 1.34 (3H, t, J = 7Hz), 1.89-2.04 (1H, m), 4.16 (2
H, s), 4.27 (2H, q, J = 7Hz), 5.81 (2H, s), 7.26-7.32 (2H, m),
7.44 (2H, d, J = 8Hz), 7.51-7.60 (3H, m), 8.16 (1H, d, J = 8Hz)

(9) 2-Propionylimino-3- (2'-sulfamoylbiphenyl-4-yl) methylthiazoline-4-carboxylic acid ethyl ester [Compound 22]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 1.21 (3H, t, J = 7Hz), 1.35 (3H, t, J = 7Hz),
2.60 (2H, q, J = 7Hz), 4.14 (2H, s), 4.32 (2H, q, J = 7Hz), 5.94
(2H, s), 7.30-7.34 (1H, m), 7.40 (4H, d, J = 8Hz), 7.44-7.59
(2H, m), 7.60 (1H, s), 8.15 (1H, d, J = 7Hz)

(10) 2-Butyrylimino-3- (2'-sulfamoylbiphenyl-4-yl) methylthiazoline-4-carboxylic acid ethyl ester [Compound 23]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.96 (3H, t, J = 7Hz), 1.35 (3H, t, J = 7Hz),
1.70-1.79 (2H, m), 2.55 (2H, t, J = 7Hz), 4.13 (2H, s), 4.31 (2
H, q, J = 7Hz), 5.94 (2H, s), 7.26-7.32 (2H, m), 7.40-7.52 (3
H, m), 7.55-7.60 (2H, m), 7.60 (1H, s), 8.15 (1H, d, J = 7Hz)

(11) 2-Cyclobutylcarbonylimino
-3- (2'-sulfamoylbiphenyl-4-yl) methylthiazoline-4-carboxylic acid ethyl ester [Compound 24]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 1.38 (3H, t, J = 7Hz), 1.83-2.04 (2H, m),
2.24-2.41 (4H, m), 3.48-3.52 (1H, m), 4.12 (2H, s), 4.25 (2
H, q, J = 7Hz), 5.94 (2H, s), 7.25-7.28 (1H, m), 7.32-7.58 (6
H, m), 7.59 (1H, s), 8.14 (1H, d, J = 8Hz)

(12) 2-Cyclohexylcarbonylimino-3- (2'-sulfamoylbiphenyl-4-yl) methylthiazoline-4-carboxylic acid ethyl ester [Compound 25]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 1.24-1.38 (3H, m), 1.37 (3H, t, J = 7Hz),
1.46-1.82 (5H, m), 1.93-2.02 (2H, m), 2.44-2.52 (1H, m), 4.
10 (2H, s), 4.31 (2H, q, J = 7Hz), 5.95 (2H, s), 7.28-7.36 (1H,
m), 7.39-7.47 (4H, m), 7.50-7.59 (2H, m), 7.59 (1H, s), 8.14
(1H, d, J = 7Hz)

(13) 2- (2-chlorobenzoyl) imino-3
-(2'-Sulfamoylbiphenyl-4-yl) methylthiazoline-4-carboxylic acid ethyl ester [Compound 26]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 1.36 (3H, t, J = 7Hz), 4.09 (2H, s), 4.36 (2
H, q, J = 7Hz), 5.95 (2H, s), 7.26-7.35 (4H, m), 7.37-7.54 (6
H, m), 7.71 (1H, s), 8.00 (1H, d, J = 7Hz), 8.13 (1H, d, J = 7Hz)

Example 5 (1) 2-Cyclopropylcarbonylimino-3- [2 '-(N-
Synthesis of Ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid ethyl ester [Compound 27] 2-Cyclopropylcarbonylimino-3- (2'-sulfamoylbiphenyl-4-yl) methyl Thiazoline-4-carboxylic acid ethyl ester (56 mg) was dissolved in pyridine (2 ml), ethyl chlorocarbonate (0.2 ml) was added, and the mixture was reacted at room temperature for 1 hr.
The reaction was stopped by adding saturated aqueous sodium hydrogen carbonate solution, ethyl acetate (20 ml) was added, and the mixture was washed with water, 1N hydrochloric acid and water, dried over anhydrous magnesium sulfate, and evaporated. The obtained residue is subjected to column chromatography (silica gel /
Chloroform) to obtain 48 mg of the title compound.

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.90-0.94 (2H, m), 1.08-1.13 (2H, m), 1.
10 (3H, t, J = 7Hz), 1.35 (3H, t, J = 7Hz), 1.93-2.00 (1H, m), 4.
03 (2H, q, J = 7Hz), 4.31 (2H, q, J = 7Hz), 5.97 (2H, s), 7.26-7.
42 (4H, m), 7.53-7.61 (3H, m), 7.61 (1H, s), 8.26 (1H, d, J = 7H
z) Compounds 28 to 41 were synthesized in the same manner.

(2) 2-cyclopropylcarbonylimino
-3-[(2'-N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methyl-5-methylthiazoline-4-carboxylic acid ethyl ester [Compound 28]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.87-0.92 (2H, m), 1.06-1.13 (5H, m), 1.
24-1.37 (3H, m), 1.89-1.93 (1H, m), 2.48 (3H, s), 4.03 (2H,
q, J = 8Hz), 4.30 (2H, q, J = 8Hz), 5.84 (2H, s), 7.17-7.20 (1H,
m), 7.23-7.35 (4H, m), 7.51-7.68 (2H, m), 8.26 (1H, d, J = 8H
z)

(3) 2-cyclopropylcarbonylimino
-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methyl] -5-ethyl-thiazoline-4-carboxylic acid ethyl ester [Compound 29]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.97-1.05 (2H, m), 1.04 (3H, t, J = 7Hz),
1.08-1.10 (2H, m), 1.12 (3H, t, J = 7Hz), 1.33 (3H, t, J = 7Hz),
1.88-1.91 (1H, m), 2.88 (2H, q, J = 7Hz), 4.01 (2H, q, J = 7Hz),
4.26 (2H, q, J = 7Hz), 5.91 (2H, s), 7.17 (2H, d, J = 7Hz), 7.24-
7.33 (3H, m), 7.51-7.62 (2H, m), 8.24 (1H, d, J = 8Hz)

(4) 2-Cyclopropylcarbonylimino
-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methyl-5-isopropylthiazoline-4-
Carboxylic acid ethyl ester [Compound 30]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.88-0.89 (2H, m), 1.07-1.19 (2H, m), 1.
10 (3H, t, J = 7Hz), 1.21-1.36 (3H, m), 1.29 (6H, d, J = 7Hz), 1.
89-1.92 (1H, m), 3.56-3.66 (1H, m), 4.03 (2H, q, J = 7Hz), 4.2
7 (2H, q, J = 7Hz), 5.79 (2H, s), 7.15 (2H, d, J = 8Hz), 7.26-7.3
3 (2H, m), 7.55-7.64 (3H, m), 8.27 (1H, d, J = 8Hz)

(5) 5-Butyl-2-cyclopropylcarbonylimino-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid ethyl ester [Compound 31 ]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.85-0.94 (2H, m), 0.92 (3H, t, J = 7Hz),
1.08-1.18 (2H, m), 1.10 (3H, t, J = 7Hz), 1.31-1.38 (2H, m),
1.34 (3H, t, J = 7Hz), 1.59-1.62 (2H, m), 1.89-1.91 (1H, m),
2.86 (2H, t, J = 7Hz), 4.03 (2H, q, J = 7Hz), 4.28 (2H, q, J = 7H
z), 5.85 (2H, s), 7.18 (2H, d, J = 8Hz), 7.25-7.32 (3H, m), 7.5
3-7.64 (2H, m), 8.26 (1H, d, J = 7Hz)

(6) 5-Isobutyl-2-cyclopropylcarbonylimino-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid ethyl ester [Compound 32 ]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.89-0.97 (2H, m), 0.95 (6H, d, J = 7Hz),
1.06-1.13 (2H, m), 1.20 (3H, t, J = 7Hz), 1.34 (3H, t, J = 7Hz),
1.86-1.96 (2H, m), 2.73 (2H, d, J = 7Hz), 4.03 (2H, q, J = 7Hz),
4.27 (2H, q, J = 7Hz), 5.80 (2H, s), 7.14-7.18 (2H, m), 7.26-
7.32 (3H, m), 7.54-7.66 (2H, m), 8.23-8.26 (1H, m)

(7) 2-Cyclopropylcarbonylimino
-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methyl-5-hexylthiazoline-4-carboxylic acid ethyl ester [Compound 33]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.86-0.90 (5H, m), 1.05-1.13 (5H, m), 1.
28-1.41 (9H, m), 1.58-1.64 (2H, m), 1.87-1.93 (1H, m), 2.85
(2H, t, J = 7Hz), 4.05 (2H, q, J = 7Hz), 4.27 (2H, q, J = 7Hz), 5.8
1 (2H, s), 7.18 (2H, d, J = 8Hz), 7.25-7.33 (3H, m), 7.55-7.64
(2H, m), 8.27 (1H, d, J = 8Hz)

(8) 5-Chloro-2-cyclopropylcarbonylimino-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid ethyl ester [Compound 34 ]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.89-0.93 (2H, m), 1.06-1.14 (2H, m), 1.
10 (3H, t, J = 7Hz), 1.35 (3H, t, J = 7Hz), 1.87-1.93 (1H, m), 4.
04 (2H, q, J = 7Hz), 4.27 (2H, q, J = 7Hz), 5.83 (2H, s), 7.18 (2
H, d, J = 8Hz), 7.24-7.36 (3H, m), 7.53-7.65 (2H, m), 8.26 (1
(H, d, J = 8Hz)

(9) 3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methyl-2-propionyliminothiazoline-4-carboxylic acid ethyl ester [Compound 35]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 1.11 (3H, t, J = 7Hz), 1.22 (3H, t, J = 7Hz),
1.35 (3H, t, J = 7Hz), 2.61 (2H, q, J = 7Hz), 4.03 (2H, q, J = 7H
z), 4.31 (2H, q, J = 7Hz), 5.95 (2H, s), 7.26-7.34 (5H, m), 7.4
1-7.63 (2H, m), 7.60 (1H, s), 8.26 (1H, d, J = 8Hz)

(10) 2-Butyrylimino-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid ethyl ester [Compound 36]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.98 (3H, t, J = 7Hz), 1.11 (3H, t, J = 7Hz),
1.37 (3H, t, J = 7Hz), 1.71-1.80 (2H, m), 2.56 (2H, t, J = 7Hz),
4.04 (2H, q, J = 7Hz), 4.33 (2H, q, J = 7Hz), 5.97 (2H, s), 7.26-
7.36 (4H, m), 7.40-7.43 (1H, m), 7.55-7.64 (2H, m), 7.58 (1
H, s), 8.27 (1H, d, J = 7Hz)

(11) 2-cyclobutylcarbonylimino
-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid [Compound 37]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 1.08 (3H, t, J = 7Hz), 1.34 (3H, t, J = 7Hz),
1.91-2.02 (2H, m), 2.28-2.37 (4H, m), 3.51-3.54 (1H, m), 4.
03 (2H, q, J = 7Hz), 4.25 (2H, q, J = 7Hz), 5.96 (2H, s), 7.26-7.
41 (5H, m), 7.52-7.66 (2H, m), 7.65 (1H, s), 8.24 (1H, d, J = 8H
z)

(12) 2-Cyclohexylcarbonylimino-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid ethyl ester [Compound 38]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 1.11 (3H, t, J = 7Hz), 1.22-1.40 (7H, m),
1.44-1.80 (4H, m), 1.96-2.07 (2H, m), 2.52-2.58 (1H, m), 4.
04 (2H, q, J = 7Hz), 4.33 (2H, q, J = 7Hz), 6.02 (2H, s), 7.26-7.
39 (5H, m), 7.54-7.66 (3H, m), 8.27 (1H, d, J = 7Hz)

(13) 2- (2-chlorobenzoyl) imino-3
-[2 '-(N-Ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid ethyl ester [Compound 39]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 1.06 (3H, t, J = 7Hz), 1.34 (3H, t, J = 7Hz),
4.02 (2H, q, J = 7Hz), 4.35 (2H, q, J = 7Hz), 6.08 (2H, s), 7.26-
7.34 (4H, m), 7.35-7.54 (6H, m), 7.72 (1H, s), 8.02 (1H, d, J =
8Hz), 8.23 (1H, d, J = 8Hz)

(14) 3- [2 '-(N-benzoylsulfamoyl) biphenyl-4-yl] methyl-5-butyl-2-cyclopropylcarbonyliminothiazoline-4-carboxylic acid ethyl ester [Compound 40]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.87-0.94 (2H, m), 0.92 (3H, t, J = 7Hz),
1.07-1.15 (2H, m), 1.22-1.41 (2H, m), 1.32 (3H, t, J = 7Hz),
1.58-1.66 (2H, m), 1.86-1.91 (1H, m), 2.89 (2H, q, J = 7Hz),
4.29 (2H, q, J = 7Hz), 5.74 (2H, s), 7.03 (2H, d, J = 8Hz), 7.20
(2H, d, J = 8Hz), 7.21-7.26 (1H, m), 7.33-7.38 (2H, m), 7.46-
7.53 (3H, m), 7.54-7.65 (2H, m), 8.41 (1H, d, J = 7Hz)

(15) 5-Butyl-3- [2 '-(N-cyclohexylcarbonylsulfamoyl) biphenyl-4-yl]
Methyl-2-cyclopropylcarbonyliminothiazoline-
4-Carboxylic acid ethyl ester [Compound 41]

Properties: Oily substance ¹ H-NMR (CDCl ₃ ); 0.87-0.93 (2H, m), 0.91 (3H, t, J = 7Hz),
1.09-1.13 (5H, m), 1.23-1.44 (8H, m), 1.55-1.65 (5H, m), 1.
90-1.97 (3H, m), 2.89-2.92 (2H, m), 4.26 (2H, q, J = 7Hz), 5.8
3 (2H, s), 7.14 (2H, d, J = 7Hz), 7.23-7.30 (3H, m), 7.55-7.63
(2H, m), 8.28 (1H, d, J = 8Hz)

Example 6 (1) 2-Cyclopropylcarbonylimino-3- [2 '-(N-
Synthesis of [Ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid [Compound 42] 2-Cyclopropylcarbonylimino-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4 -Yl] methylthiazoline-4-carboxylic acid ethyl ester (478 mg) in tetrahydrofuran (4 ml), 2N-sodium hydroxide (2 ml)
To the above solution and stirred at room temperature for 1 hour. After the solvent was distilled off, diethyl ether was added to the residue. The aqueous layer was acidified with 2N-hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and then evaporated. The obtained residue was dispersed in diisopropyl ether, collected by filtration and dried to give the title compound (27 mg).

Properties: colorless powder ¹ H-NMR (CDCl ₃ ); 0.89-0.96 (2H, m), 1.04-1.06 (5H, m), 1.
90-1.96 (1H, m), 4.04 (2H, q, J = 7Hz), 5.92 (2H, s), 7.24-7.3
8 (4H, m), 7.47-7.68 (4H, m), 8.23 (1H, d, J = 7Hz) In the same manner, compounds 43 to 56 were synthesized.

(2) 2-cyclopropylcarbonylimino
-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methyl-5-methylthiazoline-4-carboxylic acid [Compound 43]

Properties: colorless powder ¹ H-NMR (CDCl ₃ ); 0.89-0.92 (2H, m), 1.02-1.10 (2H, m), 1.
05 (3H, t, J = 7Hz), 1.91-1.95 (1H, m), 2.48 (3H, s), 4.07 (2H,
q, J = 7Hz), 5.85 (2H, s), 7.18 (2H, d, J = 7Hz), 7.25-7.28 (2H,
m), 7.34-7.36 (1H, m), 7.55-7.58 (1H, m), 7.62-7.69 (1H,
m), 8.24 (1H, d, J = 7Hz)

(3) 2-cyclopropylcarbonylimino
-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methyl-5-ethylthiazoline-4-carboxylic acid [Compound 44]

Properties: colorless powder ¹ H-NMR (CDCl ₃ ) 1H-nmr (CDCl ₃ ); 0.95-1.04 (5H, m), 1.12-1.
18 (2H, m), 1.22-1.28 (3H, m), 2.13-2.20 (1H, m), 2.88-2.96
(2H, m), 3.98-4.05 (2H, m), 5.99 (2H, s), 7.21-7.49 (4H, m),
7.52-7.70 (3H, m), 8.23 (1H, d, J = 8Hz)

(4) 2-Cyclopropylcarbonylimino
-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methyl-5-isopropylthiazoline-4-
Carboxylic acid [Compound 45]

Properties: colorless powder ¹ H-NMR (CDCl ₃ ); 0.81-0.88 (2H, m), 0.87 (6H, d, J = 7Hz),
0.98-1.10 (2H, m), 1.14-1.27 (3H, m), 1.89-1.94 (1H, m), 3.
47-3.56 (1H, m), 3.95 (2H, q, J = 7Hz), 5.77 (2H, s), 7.14-7.1
8 (2H, m), 7.26-7.38 (2H, m), 7.44-7.64 (3H, m), 8.20 (1H, d,
(J = 6Hz)

(5) 5-Butyl-2-cyclopropylcarbonylimino-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid [Compound 46]

Properties: colorless powder ¹ H-NMR (CDCl ₃ ); 0.81-0.90 (5H, m), 0.93-1.04 (2H, m), 1.
12-1.26 (3H, m), 1.33-1.38 (2H, m), 1.63-1.76 (2H, m), 2.23
-2.31 (1H, m), 2.87-3.01 (2H, m), 4.02-4.05 (2H, m), 6.06 (2
H, s), 7.22-7.40 (5H, m), 7.54-7.64 (2H, m), 8.23 (1H, d, J = 6
Hz)

(6) 5-Isobutyl-2-cyclopropylcarbonylimino-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid [Compound 47]

Properties: Amorphous ¹ H-NMR (CDCl ₃ ); 0.92-0.98 (8H, m), 1.06-1.13 (5H, m), 1.
93-2.04 (2H, m), 2.75-2.77 (2H, m), 4.01-4.09 (2H, m), 5.96
(2H, s), 7.18-7.20 (2H, m), 7.26-7.38 (3H, m), 7.56-7.67 (2
H, m), 8.27 (1H, d, J = 8Hz)

(7) 2-Cyclopropylcarbonylimino
-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methyl-5-hexylthiazoline-4-carboxylic acid [Compound 48]

Properties: colorless powder ¹ H-NMR (CDCl ₃ ); 0.86-0.94 (5H, m), 1.03-1.10 (2H, m), 1.
10-1.20 (3H, m), 1.24-1.38 (6H, m), 1.61-1.69 (2H, m), 1.93
-1.98 (1H, m), 2.84-3.02 (2H, m), 4.02-4.06 (2H, m), 5.87 (2
H, s), 7.04-7.23 (1H, m), 7.22-7.34 (2H, m), 7.35-7.42 (1H,
m), 7.53-7.70 (3H, m), 8.25-8.30 (1H, m)

(8) 5-Chloro-2-cyclopropylcarbonylimino-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid [Compound 49]

Properties: colorless powder ¹ H-NMR (CDCl ₃ ); 0.92-0.96 (2H, m), 1.05 (3H, t, J = 7Hz),
1.09-1.15 (2H, m), 1.91-2.18 (1H, m), 4.04 (2H, q, J = 7Hz),
5.81 (2H, s), 7.20 (2H, d, J = 8Hz), 7.26-7.49 (3H, m), 7.57-
7.68 (2H, m), 8.25 (1H, d, J = 8Hz)

(9) 3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methyl-2-propionyliminothiazoline-4-carboxylic acid [Compound 50]

Properties: colorless powder ¹ H-NMR (CDCl ₃ ); 1.08 (3H, t, J = 7Hz), 1.23 (3H, t, J = 7Hz),
2.62 (2H, q, J = 7Hz), 4.03 (2H, q, J = 7Hz), 5.95 (2H, s), 7.22-
7.40 (5H, m), 7.51-7.67 (2H, m), 7.74 (1H, s), 8.24 (1H, d, J =
(7Hz)

(10) 2-butyrylimino-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid [Compound 51]

Properties: colorless powder ¹ H-NMR (CDCl ₃ ); 0.95 (3H, t, J = 7Hz), 1.04 (3H, t, J = 7Hz),
1.68-1.76 (2H, m), 2.53 (2H, t, J = 7Hz), 3.97 (2H, q, J = 7Hz),
5.92 (2H, s), 7.20-7.30 (5H, m), 7.52-7.68 (2H, m), 7.57 (1
H, s), 8.20 (1H, d, J = 8Hz)

(11) 2-Cyclobutylcarbonylimino
-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid [Compound 52]

Properties: colorless powder ¹ H-NMR (CDCl ₃ ); 1.07 (3H, t, J = 7Hz), 1.87-2.01 (2H, m),
2.27-2.36 (4H, m), 3.48-3.59 (1H, m), 4.02 (2H, q, J = 7Hz),
6.04 (2H, s), 7.26-7.29 (5H, m), 7.53-7.63 (2H, m), 7.79 (1
H, s), 8.23 (1H, d, J = 7Hz)

(12) 2-Cyclohexylcarbonylimino-3- [2 '-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid [Compound 53]

Properties: colorless powder ¹ H-NMR (CDCl ₃ ); 1.05-1.17 (5H, m), 1.24-1.57 (4H, m), 1.
63-1.82 (2H, m), 1.93-2.04 (2H, m), 2.43-2.55 (1H, m), 3.98
-4.04 (2H, m), 5.94 (2H, s), 7.21-7.39 (5H, m), 7.48-7.70 (3
H, m), 8.21-8.27 (1H, m)

(13) 2- (2-chlorobenzoyl) imino-3
-[2 '-(N-Ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid [Compound 54]

Properties: Light brown powder ¹ H-NMR (CDCl ₃ ); 1.05 (3H, t, J = 7Hz), 4.03 (2H, q, J = 7Hz),
6.01 (2H, s), 7.26-7.50 (7H, m), 7.51-7.66 (3H, m), 7.70 (1
H, s), 8.04 (1H, d, J = 7Hz), 8.23 (1H, d, J = 7Hz)

(14) 3- [2 '-(N-benzoylsulfamoyl) biphenyl-4-yl] methyl-5-butyl-2-cyclopropylcarbonyliminothiazoline-4-carboxylic acid [Compound 55]

Properties: colorless powder ¹ H-NMR (CDCl ₃ ); 0.87-0.92 (2H, m), 0.89 (3H, t, J = 7Hz),
1.10-1.15 (2H, m), 1.31-1.37 (2H, m), 1.60-1.66 (2H, m), 1.
92-1.96 (1H, m), 2.89 (2H, q, J = 7Hz), 5.79 (2H, s), 7.06 (2H,
d, J = 8Hz), 7.17 (2H, d, J = 8Hz), 7.26-7.36 (3H, m), 7.50-7.5
5 (3H, m), 7.60-7.63 (2H, m), 8.39 (1H, d, J = 8Hz)

(15) 5-Butyl-3- [2 '-(N-cyclohexylcarbonylsulfamoyl) biphenyl-4-yl]
Methyl-2-cyclopropylcarbonyliminothiazoline-
4-carboxylic acid [compound 56]

Properties: colorless powder ¹ H-NMR (CDCl ₃ ); 0.88-0.94 (2H, m), 0.91 (3H, t, J = 7Hz),
1.10-1.13 (5H, m), 1.25-1.43 (5H, m), 1.55-1.63 (5H, m), 1.
93-1.97 (3H, m), 2.88-2.93 (2H, m), 5.85 (2H, s), 7.17 (2H,
d, J = 7Hz), 7.26-7.34 (3H, m), 7.57-7.65 (2H, m), 8.29 (1H,
(d, J = 7Hz)

Example 7 5-Butyl-2-cyclopropylcarbonylimino-3- [2 ′-(N
-Ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxamide

5-Butyl-2-cyclopropylcarbonylimino-3- [2 ′-(N-ethoxycarbonylsulfamoyl) biphenyl-4-yl] methylthiazoline-4-carboxylic acid (0.1
g), ammonium chloride (18 mg), N-methyl-N '-(3'-dimethylaminopropyl) carbodiimide hydrochloride (33 mg, 0.17 m
mol), N-hydroxybenzotriazole monohydrate (23m
g, 0.17 mmol) and triethylamine (0.05 ml) were added to tetrahydrofuran (2 ml), and the mixture was stirred at 0 ° C. for 1 hour and at room temperature overnight. The reaction solution was concentrated, acidified with 2N hydrochloric acid, and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and concentrated, and the residue was subjected to silica gel column chromatography (chloroform: methanol = 50: 1) to give the title compound.
72 mg (71%) was obtained.

Properties: colorless powder ¹ H-NMR (CDCl ₃ ); 0.81-0.95 (5H, m), 0.95-1.11 (5H, m), 1.
25-1.37 (2H, m), 1.47-1.60 (2H, m), 1.80-1.90 (1H, m), 2.64
(2H, t, J = 7Hz), 4.00 (2H, q, J = 7Hz), 5.68 (2H, s), 5.76 (1H,
s), 6.58 (1H, s), 7.30-7.40 (5H, m), 7.53-7.70 (2H, m), 8.31
(1H, d, J = 7Hz)

Test Example 1 Method for examining angiotensin II contraction inhibitory action of the compound of the present invention in isolated guinea pig ileal longitudinal muscle: Weight 350-450 g
Male Hartley guinea pigs were exsanguinated to death and the ileum was removed. From this ileum, a longitudinal muscle sample (length: 2c
m) to prepare Tyrode's solution (composition (mM): NaCl 137, KCl 2.
7, CaCl ₂ 1.88, MgCl ₂ 1.1, NaH ₂ PO ₄ 0.4, NaHCO ₃ 11.8, Glu
It was suspended in a 20 ml Magnus tank containing cose 5.6). The Tyrode solution was kept warm at 37 ° C and aerated with 95% O ₂ -5% CO ₂ . The contraction was recorded on a computer (PC-9801, NEC) via an isometric transducer (TB-611T, Nihon Kohden).

The strips were loaded with an initial tension of 0.5 g and equilibrated with the nutrient solution for about 1 hour with washing every 15 minutes. 80m after this
The following test was conducted after confirming that contraction by MKCl administration was repeated twice and the contraction was stable. Initially, the specimen was administered 10 nM angiotensin II and the maximum contraction recorded. Then, the test compound was administered and reacted for 20 minutes, then 10 nM angiotensin II was administered again and the maximum contraction was measured. Then, the contraction inhibition rate (%) was obtained by comparing the maximum contraction of angiotensin II before and after the administration of the test compound. This test was repeated with increasing concentrations of test compound,
The% shrinkage inhibition concentration (IC ₅₀ ) was calculated. The results are shown in Table 1.

[0182]

[Table 1]

As shown in Table 1, the compounds of the present invention showed a strong inhibitory effect on muscle contraction by angiotensin II.

Test Example 2 Inhibitory effect of the compounds of the present invention on the pressor response to angiotensin II Method: Male Crj: CD (SD) rats weighing 300-350 g were used. The femoral artery and vein were cannulated under anesthesia with pentobarbital Na the day before the experiment. On the day of the experiment,
The arterial cannula was connected to a blood pressure transducer and the mean blood pressure was recorded on a polygraph. Before administration of the test compound, pressor response due to intravenous administration of angiotensin II (100 ng / kg), which serves as a control, was determined. The drug was intravenously administered, and thereafter, angiotensin II was intravenously administered at each measurement point, and the pressor response was similarly determined, and the inhibition rate (%) was determined by comparing the reactions before and after the drug administration. The experiment was conducted under the conditions of free feeding and free drinking. The results are shown in Table 2.

[0185]

[Table 2]

The compounds of the present invention showed an excellent hypotensive action as shown in Table 2.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Koichi Tamura 1624 Shimodate, Koda-cho, Takada-gun, Hiroshima Prefecture Yukunaga Pharmaceutical Co., Ltd. (72) Inventor, Satoshi Inoue 1624 Shimodateri, Koda-cho, Takada-gun, Hiroshima Prefecture Yunai Pharmaceutical Co., Ltd.

Claims (3)

[Claims] [Claim 1] The following general formula (1) [In the formula, R ¹ represents a hydrogen atom or a group —COR ² (wherein R ^1
2 represents a lower alkyl group which may have a substituent, a cyclo lower alkyl group which may have a substituent or a phenyl group which may have a substituent), and R ³ represents hydrogen. An atom, a lower alkyl group or a halogen atom, X represents a group —OR ⁴ (wherein R ⁴ represents a hydrogen atom or a carboxyl protecting group) or group —N (R ⁵ ) R ⁶ (wherein R ⁵ and R ⁶ may be the same or different and each represents a hydrogen atom or a lower alkyl group), and R ⁷ represents a hydrogen atom, a lower alkyl group, an aralkyl group or an acyl group] or a thiazolinecarboxylic acid derivative thereof salt. 2. A medicine comprising the thiazolinecarboxylic acid derivative according to claim 1 or a salt thereof as an active ingredient. 3. The medicine according to claim 2, which is a hypotensive agent.