KR910003345B1 - Process for the preparation of bicyclic sulphonamide pharmaceuticals - Google Patents

Abstract

No content.

Description

Method for preparing bicyclo cyclic sulfonamide derivative

The present invention relates to a method for producing a sulfonamide derivative represented by formula (I) or a salt thereof, which is used as an antithrombotic agent, an antivascular vessel, and a bronchial constrictor in the field of pharmaceuticals.

는, 단일결합 또는 이중결합 ; 을 각각 나타낸다.][Wherein R ₁ is hydrogen, lower alkyl or salt forming group; R ₂ is alkyl, substituted or unsubstituted aryl, aralkyl or heteroaromatic hydrocarbon group; R ₃ is hydrogen or methyl; R ₄ is hydrogen or fluorine; X is alkylene or alkenylene which may contain phenylene; Y is methylene or dimethylmethylene;

Is a single bond or a double bond; Respectively.]

More specifically, it relates to preparation methods I and II.

Recipe Ⅰ

는 단일결합 또는 이중결합 ; 을 각각 나타낸다]로 표시되는 화합물과[Wherein, R ₁ is lower alkyl; R ₃ is hydrogen or methyl; R ₁ is hydrogen or fluorine; X is alkylene or alkenylene which may contain phenylene; Y is methylene or dimethylmethylene;

Is a single bond or a double bond; Each of which is represented by

Hal-SO ₂ -R ₂

[Wherein R ₂ is alkyl, substituted or unsubstituted aryl, aralkyl or heteroaromatic hydrocarbon group; Hal is halogen; Are represented respectively], and if necessary, a deprotection reaction and / or a salt formation reaction are carried out.

는 상기과 같은 뜻이다]로 표시되는 술폰아미드 유도체 또는 그의 염의 제조법 및 제조법 Ⅱ[Wherein R ₁ is the same as R ₁ ′ or represents a hydrogen or salt forming group and R ₁ , R ₃ , R ₄ , X, Y and

Means the same as the above] Preparation and preparation method of sulfonamide derivative or salt thereof

는 상기와 같은 뜻이다]로 표시되는 화합물과 식Wherein R ₂ , R ₃ , R ₄ , Y and

Means the same as above]

Wherein Ar represents an aromatic hydrocarbon group, A represents alkylene or phenylene, and Hal and R ₁ ′ have the same meaning as described above, and if necessary, a reduction, deprotection reaction and / or salt formation. General formula characterized in that to react

은 상기와 같은 뜻이다]로 표시되는 술폰아미드 유도체 또는 그의 염의 제조법에 관한 것이다.[Wherein, R ₁ , R ₂ , R ₃ , R ₄ , X, Y and

Is the same meaning as described above] relates to a method for producing a sulfonamide derivative or a salt thereof.

Atherosclerosis, which is the main cause of myocardial infarction or cerebral infarction, begins with the accumulation of mucoid substrates in the arterial lining, proliferation of fibroblasts, followed by degeneration, lipid, cholesterol deposition, and destruction of endometrial tissue. It is a common symptom to progress to the formation of atherosclerosis and gradually bring about a high degree of Korean thickening. Atherosclerosis has long been caused by the formation of thrombus and fibrin deposition in the arterial wall, but recently it was pro- duced by thromboxane A2 (TXA2) or vane by Samuelsson. The discovery of stacyclin (PGI2) has made the interaction of platelets and blood vessel walls clear. Platelets have an important relationship in the development and progression of atherosclerosis, and it has been recognized that administration of antithrombotic drugs, in particular drugs having a platelet aggregation inhibitory effect, is effective for the treatment of atherosclerosis related diseases.

It is known that certain types of prostaglandins have a strong platelet aggregation inhibitory effect in addition to heparin, coumarin compounds, and the like, which are conventional antithrombotic drugs. In view of this fact, prostaglandin derivatives are attracting attention as antithrombogenic agents. Cyclooxygenase, for example, develops flexible bodies of agonists for receptors such as prostaglandin E ₁ and prostagrindin I _2, and that thromboxane A ₂ has strong platelet aggregation and vasoconstrictive action. Thromboxane A ₂ synthesis inhibitors such as inhibitors, thromboxane synthetase inhibitors, thromboxane A ₂ receptors, antagonists and the like have also been developed. The thromboxane A ₂ receptor, antagonist, 13-APA (Venton DL et al., Day, Orb, Medical, J.Med, Chem Vol. 22, p. 824 (1979)), PTA ₂ (Lefer Lefer AM), etc., Poro Sidings, Orb, The, National, Academy, Orb, Science, Orb, Yu, S, A. (Proc, Nat, Acad.Sic. USA) (1979)], BM-13177 [Referers, Drax, Orbs, Today, Vol. 21, p. 283 (1985)], SQ-29548 [Ogletree et al. , Pharmacologic, End, Experimental, Therafutics, Vol. 34, No. 435, page 1985).

Thromboxane A ₂ activates cyclooxygenase when thrombin acts on platelets, and it is an enzyme in various cells including platelets and blood vessel walls from arachidonic acid via prostaglandin G ₂ and H ₂ . Generated by It has several powerful physiological or pathological actions. In particular, strong platelet aggregation and smooth muscle contraction of the bronchus, coronary artery, and pulmonary artery are thought to be mediating the development and progression of circulatory respiratory diseases such as angina pectoris, myocardial infarction, cerebral infarction, and bronchial asthma. Moreover, the potent action concentration is said to be 10 ^{-10 -10 -11} M. Therefore, the development of antagonists or inhibitors of thromboxane A ₂ has been attracting attention as antithrombotic agents, antivascular vasoconstrictors and anti-bronchoconstrictors. Inhibitors also have problems such as prostaglandins which have various important roles other than thromboxane A ₂ , and the inability to control the bad action of thromboxane-like accumulation of substrates. Development of tannists is desired.

The present inventors have completed the present invention by successfully producing a bicyclocyclic sulfonamide derivative represented by the general formula (I), which has a potent action as a thromboxane A ₂ receptor antagonist and is a chemically and biochemically stable compound. .

Definitions of various phrases used in the present specification are as follows.

Examples of "lower alkyl" include C ₁ -C ₅ linear or branched alkyl such as methyl, ethyl, n-propyl, isopropyl, butyl, tert-butyl, pentyl and the like.

Examples of "alkyl" include C ₁ -C ₁₀ linear or branched alkyl such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, heptyl, octyl and nonyl Or decyl.

Examples of the "aryl" include substituted or unsubstituted phenyl or naphthyl or polycyclic aromatic hydrocarbon groups.

"Aralkyl" means that the alkyl is substituted at any position by the aryl, and examples thereof include benzyl or phenethyl.

The "heteroaromatic" hydrocarbon group means a 5- or 6-membered ring containing nitrogen, oxygen and / or sulfur, and examples thereof include furyl, thienyl, oxozoyl, pyridyl, pyrimidyl or benzoimizoyl. Substituents for aryl, aralkyl, heterocycle include lower alkyl (such as methyl or ethyl), lower alkoxy (such as methoxy), nitro, hydroxy, carboxy, cyano, amino, lower alkylamino (such as methyl amino), Dialkyl alkylamino (for example, dimethylamino), alkanoyl amino (for example, acetoamino), halogen (for example, fluorine, chlorine, bromine, or oxo) which may differ from lower alkyl may be mentioned. Means of such alkanoyl is C ₁ ~C _3-formyl, acetyl or propionyl. One or more substituents may be substituted at all possible positions.

There can be a means such as an alkylene of the "alkylene" means C ₁ -C _7, and, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or heptamethylene.

"Alkenylene" means a group having one or more double bonds in the alkylene, such as vinylene, 1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene, 3- Butenylene, 1,2-butadienylene, 1,3-butadienylene, 1-pentenylene, 2-pentenylene, 3-pentenylene, 4-pentenylene, 1,2-pentadienylene, 1,3 -Pentadienylene, 1,4-pentadienylene, 2,3-pentadienylene, 2,4-pentadienylene, 1-hexenylene, 2-hexenylene, 3-hexenylene, 4-hexe Senylene, 5-hexanylene, 1,2-hexadienylene, 1,3-hexadienylene, 1,4-hexadienylene, 1,5-hexadienylene, 2,3-hexadienylene, 2 , 4-hexadienylene, 2,5-hexadienylene, 3,4-hexadienylene, 3,5-hexadienylene, 4,5-hexadienylene, 1-heptenylene, 2-heptenylene, 3 -Heptenylene, 4-heptenylene, 5-heptenylene, 6-heptenylene, 1,2-heptadienylene, 1,3-heptadienylene, 1,4-heptadienylene, 1,5-heptadienylene , 1,6-heptadienylene, 2,3-hepta Dienylene, 2,4-heptadienylene, 2,5-heptadienylene, 2,6-heptadienylene, 3,4-heptadienylene, 3,5-heptadienylene, 3,6-heptadienylene , 4,5-heptadienylene, 4,6-heptadienylene, 5,6-heptadienylene, and the like.

Alkylene or alkenylene which may contain phenylene means that the alkylene or alkenylene contains phenylene at any position, and means, for example, vinylene-m-phenylene.

Halogen means chlorine, bromine, iodine or fluorine. Salts of the general formula (I) include alkali metal salts such as lithium salts, sodium salts or potassium salts, alkaline earth metal salts such as calcium salts, ammonium salts, organic bases such as triethylamine, N-methylmorpholine, and disiflo. Hexylamine, pyridine or trimethylamine or amino acid salts such as glycine, valine or alanine.

The present invention can be carried out as follows, for example.

[Production Method I]

This production method is a method for obtaining compound sulfonamide derivative I of the present invention by reacting compound II with a substituted sulfonic acid halide in the presence of a base. The compound II can be used in the next step even with an ammonium salt, but may be formed into glass and an amine by treating with a suitable basic substance such as sodium carbonate, sodium bicarbonate or the like as necessary.

Reactions with sulfonamide derivatives are substituted sulfonic acid halides such as methanesulfonyl chloride, ethanesulfonyl chloride, propanesulfonyl chloride, butanesulfonyl chloride, pentanesulfonyl chloride, hexanesulfonyl chloride, heptanesulfonyl chloride, chloride Octanesulfonyl, benzenesulfonyl chloride, methoxybenzenesulfonyl chloride, nitrobenzenesulfonyl chloride, hydroxybenzenesulfonyl chloride, O-toluenesulfonyl chloride, m-toluenesulfonyl chloride, p-toluenesulfonyl chloride, Ethylbenzenesulfonyl chloride, pentylbenzenesulfonyl chloride, carboxybenzenesulfonyl chloride, aminobenzenesulfonyl chloride, acetylaminobenzenesulfonyl chloride, dimethylaminobenzenesulfonyl chloride, fluorobenzenesulfonyl chloride, chlorobenzenesulfonyl chloride Pyridine, triethylamine and the like using a sulfonic acid derivative having a desired substituent, such as phenylmethanesulfonyl chloride, phenylethanesulfonyl chloride, nattalenesulfonyl chloride or pyridinesulfonyl chloride. As a substance, it can be achieved in a few minutes at room temperature in a solvent such as chloroform of chlorinated hydrocarbon, dichloromethane, ether of ethyl ether, tetrahydrofuran, or aromatic benzene. By this reaction, carboxylic ester I-a in the compound of the present invention can be obtained. Moreover, carboxylic acid ester I-a can be hydrolyzed according to the conventional method of hydrolysis of ester, and can be changed into the free carboxylic acid I-b in the compound of this invention. For hydrolysis, hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide or barium hydroxide is used as the catalyst. As the solvent, methanol-water, ethanol-water, acetone-water, acetonitrile-water or the like may be used. If necessary, carboxylic acid I-b is a salt such as sodium methoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, dicyclohexylaman, methylmorpholine, pyridine, triethylamine, or glycine, valine, alanine, etc. It can be changed to carboxylic acid salt I-c in the compound of this invention represented by General formula (I) by processing according to a normal method using amino acid of.

[Production Method II]

This production process is a process for obtaining compound I of the present invention by reacting aldehyde III with illi. The reaction between the aldehyde body and the lide (reaction to generate a double bond) may be performed according to the conventional method of the Witig reaction. It synthesize | combines from the trivalent phosphine used for reaction, and the halide of the alkanoic acid or alkenic acid which may contain the phenylene which has a carboxyl group in a ω position. The halogenated alkanoic acid or halogenated alkanoic acid of C ₄ -C ₆ used in this process is, for example, 3-bromopropanoic acid, 4-bromobutanoic acid, 4-bromo-2-butenoic acid, 4-bromo-3 Butene acid, 5-bromopentanoic acid, 5-bromo-2-pentenoic acid, 5-bromo-3-pentanoic acid, 5-bromo-4-pentanoic acid, 6-bromohexanoic acid, 6- Bromo-2-hexanoic acid, 6-bromo-3-hexanoic acid, 6-bromo-4-hexanoic acid, 6-bromo-4-hexanoic acid, 6-bromo-5-hexanoic acid, or 4 -Bromomethylbenzoic acid, etc. are mentioned. Examples of the base include sodium hydride, dimsil sodium, dimsil potassium, n-butyllithium, tert-butoxy potassium or lithium diisopropylamide. The reaction is completed under cooling or at room temperature for several hours using, for example, ether-based ethyl ether, tetrahydrofuran or n-hexane, toluene, dimethyl sulfoxide and the like as a solvent. By this reaction, free carboxylic acid I-b in the compound of the present invention can be obtained. In this reaction, only Z-form or a mixture of Z- and E-forms is produced under the reaction conditions. If necessary, carboxylic acid I-b may be esterified.

The esterification is a method of reacting a carboxylic acid with an alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol or pentanol as necessary with a catalyst of dry hydrogen chloride and concentrated sulfuric acid, the carboxylic acid as a halide and the alcohol and metal The method of reacting with a base of magnesium, dimethylaniline, pyridine, sodium hydroxide, the method by diazomethane, or the method by dimethyl sulfate and diazabicyclononene or diazabicyclo undecene may be performed according to the conventional method.

By this esterification reaction, the carboxylic acid ester I-a in the compound of this invention can be obtained.

The reduction reaction may be carried out under hydrogen at atmospheric pressure or medium pressure, using a metal platinum, palladium-carbon, nickel catalyst, or the like as a catalyst. As a solvent, ether, terahydrofuran, dioxane, methanol, ethanol, etc. may be used. The reaction is completed for several hours at room temperature. By this reaction, the compound of this invention which the side chain of 2 position is saturated is obtained.

Moreover, the free carboxylic acid I-b can also be changed to carboxylate I-c in the compound of this invention by processing according to the method of the manufacturing method I.

The compound represented by general formula (I) can be obtained by the series of reactions shown below.

In the formula, all compounds are racemates and are represented only as one active agent for convenience. In the formula, the dashed lines indicate α-coordination or β-coordination or mixtures thereof.

[Step 1]

This step is a step of introducing an yl group in the presence of a catalyst to the active methylene of Compound 1. As the allylating agent, allyl halide such as allyl chloride, allyl bromide, allyl iodide, and the like are used in the present process.As a catalyst, a relatively strong base such as sodium amide, potassium t-butoxide, sodium hydride and lithium diisopropylamide is used. Do it. As the solvent, ethers such as tetrahydrofuran, ether, glyme and diglyme are preferable. The reaction is achieved in a few minutes to several hours between # 78 ° C and 25 ° C.

Second Process

This step is a step wherein the ketone at the 3-position of compound 2 is oxime. The oxime may be performed in the presence of a base using hydroxyamine hydrochloride, hydroxyamide sodium disulfate, or the like. Potassium hydroxide, sodium carbonate, sodium acetate and the like are used as the base material, and methanol, ethanol and the like are used as the solvent. The reaction is achieved by several hours from tens of minutes at room temperature.

[Third process]

This step is a step of reducing oxime 3 to amine 4 and attaching a protecting group to the amine without refining. Reduction is also achieved by zinc and hydrochloric acid, stannous chloride and hydrochloric acid or lithium aluminum hydride. As a solvent used for the reduction reaction, ether, tetrahydrofuran, diglyme, ethanol or methanol may be used. This reaction is achieved in several hours at room temperature or under reflux. As a protecting group of an amine, what is normally used as a protecting group, for example, benzyloxycarbonyl, tert-butoxycarbonyl, triphenylmethyl, etc. may be used. In this reaction, bases, such as a pyridine, 4-dimethyl aminopyridine, and triethylamine, may be added as needed. What is necessary is just to use dichloromethane, chloroform, etc. as a solvent, and reaction is achieved in tens of minutes to hours under room temperature.

[4th process]

This process is a process of oxidizing the double bond of the allyl group of the compound 5 to an epoxide. As the oxidizing agent, a combination of sorghum peroxide and a transition element metal catalyst, peric acid, peracetic acid, perbenzoic acid, monoperphthalic acid, monopermaleic acid, pertrifluoroacetic acid, metachloroperbenzoic acid or paranitroperbenzoic acid, or peracid ester is used. good. Examples of the solvent used may include ethers such as ether and tetrahydrofuran, alcohols such as methanol and ethanol, and chlorinated hydrocarbon solvents such as dichloromethane and chloroform. The reaction is achieved in a few minutes to several hours at room temperature from 0 ° C.

[5th process]

This step is a step of converting epoxide 6 to aldehyde 7 having less carbon number by oxidative cleavage of the glycol produced by hydration. As an oxidizing agent which also serves as a hydration catalyst, periodic acid or ortho and iodic acid may be used. As a solvent to be used, it is preferable to mix with water, for example, ether, tetrahydrofuran, dioxane, methanol, or ethanol. The reaction is completed in tens of minutes to a few hours at room temperature. By performing the 4th and 5th processes simultaneously, 7 can also be obtained at once by ozone decomposition of 5th.

[Sixth Step]

This process is a process of reacting aldehyde 7 with illi to produce a double bond and esterifying to protect the carboxylic acid without purification. The reaction for generating the double bond may be carried out according to the conventional method of the wittig reaction. Ilide used in the reaction is synthesized from triphenylphosphine in the presence of a base and halogenated alkyl having alkyl to be condensed, such as 5-bropentanoic acid or 3-bropropanoic acid and the like. Examples of the base include sodium dimsil, dimsil potassium, sodium hydride, n-butyllithium potassium, tert-butoxide or lithium diisopropylamide. The reaction is completed at room temperature for several hours using, for example, ether, tetrahydrofuran, n-nucleic acid or dimethyl sulfoxide as a solvent. The esterification may be carried out by a diazomethane method or diazabicyclononene (DBN) or diazabicyclo undecene (DBU) and dimethyl sulfuric acid according to a conventional method.

[7th process]

This step is a step of reducing the double bond of the side chain of Compound 8 to a single bond, reducing the protecting group of the amino group, and introducing the amine 9 of the intercalate. Hydrogenation may be performed by using a metal platinum, palladium-carbon, nickel catalyst, or the like as a catalyst under a normal or medium pressure hydrogen environment. As a solvent, ether, tetrahydrofuran, dioxane, methanol, ethanol, etc. may be used.

The reaction is complete in room temperature to several hours.

[Step 8]

This step is a step of producing a double bond by reacting lide with aldehyde 7. Ilide produced by reacting a hydroxyl group of 3-halogenopropanol with, for example, tetrahydropyranyl or the like with triphenylphosphine in the presence of a base is used. Examples of the halogen include chloro, bromine and the like, and examples of the base include sodium hydride, n-butyllithium, dimsil sodium or dimsil potassium. The reaction is completed using ether, tetrahydrofuran, n-hexane or dimethyl sulfoxide and the like as a solvent, at room temperature to several hours.

[Ninth process]

This step is a step of removing the protecting group of hydroxy of compound 10 by acid hydrolysis and then oxidizing the alcohol with aldehyde. As an acid catalyst used for acid hydrolysis, hydrochloric acid, sulfuric acid, p-toluenesulfonic acid, etc. are preferable. As a solvent, tetrahydrofuran, methanol, ethanol, acetone, acetonitrile may be used singly or in a mixed state. The reaction is complete in minutes or hours at room temperature or under heating. In the reaction for aldehyde oxidation of alcohol, a combination of a suitable activator and dimethyl sulfoxide may be used as the oxidizing agent. As the activator, for example, thionyl chloride, sulfuryl phosgene chloride or oxalyl chloride may be used. If necessary, bases such as triethylamine and diethylmethylamine may be added.

[10th process]

This step is a reaction in which an aldehyde is reacted with aldehyde 11 to generate a double bond. What is necessary is just to carry out reaction according to 8th process using the yilide or anion which arises from 2-bromine acetate methyl ester, a triphenyl phosphine, or a trialkyl phosphono acetate.

[Step 11]

This step is a step of reducing the double bond of the side chain of Compound 10 to a single bond. This step may be performed in accordance with the seventh step. In some cases, the amino protecting group may fall off at the same time by the reduction reaction, so that the amino protecting group such as benzyloxycarbonyl chloride is reacted in the presence of a base such as pyridine, 4-dimethylaminopyridine, triethylamine and the like to be reprotected. What is necessary is just to use dichloromethane, chloroform, etc. as a solvent, and reaction is achieved by tens of minutes-several hours under room temperature.

[12th process]

This step is a step of removing the hydroxy protecting group of compound 13 by acid hydrolysis, followed by aldehyde oxidation of alcohol. What is necessary is just to react according to a ninth process.

[13th process]

This step is a reaction in which aldehydes are reacted with aldehyde 14 to generate double bonds. The reaction may be carried out in accordance with the tenth step.

[14th process]

In this step, a monosubstituted acetylene metal derivative is added to aldehyde 7, and then esterified to protect the carboxylic acid. As the adduct, a dilithium compound of 4-phosphane pentanate is used. Liquid ammonia, ether, tetrahydrofuran, glycol ether or dimethylformamide is used as the solvent. The reaction for esterifying the carboxylic acid may be carried out in accordance with a conventional method using diazomethane.

[15th process]

This step is a step wherein allene 17 is obtained by acetylating the hydroxyl group of compound 16 and then transposing a triple bond. Acetylation is carried out in a solvent such as ether, tetrahydrofuran, benzene or pyridine using an acylating agent such as acetic anhydride and acetyl chloride. If necessary, bases such as pyridine, triethylamine and 4-dimethylaminopyridine are added. The rearrangement reaction is achieved by reacting with dimethyl copper lithium as an attack reagent and then hydrolyzing with hydrochloric acid, hydrobromic acid or the like. You may add lithium aluminum hydride etc. as needed.

[Step 16]

This step is a step wherein aldehyde 7 is reacted with phenyl produced in the presence of a base by triphenylphosphine and halogenmethyl ether to obtain enol ether 18. Halogen means chloro or bromine. What is necessary is just to react this process according to an 8th process.

[17th process]

This step is a step of acid hydrolyzing enol ether 18 to produce aldehyde 19. Perchloric acid or sulfuric acid is used as the acid catalyst. Water or dioxane or the like is used as the solvent. The reaction is achieved by refluxing from several tens of minutes to several hours.

[The 18th process]

This step is a reaction for reacting lide with aldehyde 19 to generate a double bond. What is necessary is just to react 4-methyl- butyric-acid methyl ester, 4-chloro-butanoic acid methyl ester, etc. according to the 8th process using the yield produced by triphenylphosphine.

[19th process]

This step removes the amino protecting groups of the compounds 8, 12, 15, 17 and 20 obtained in the sixth, tenth, thirteenth, fifteenth and eighteenth steps to the amine IIa as an intermediate of the compound of the present invention. It is a process of introduction. In this reaction, for example, trifluoroacetic acid and anisol can be heated for several hours according to a conventional method, and treated with a suitable basic substance such as sodium carbonate, sodium hydrogen carbonate or the like to obtain free amine IIa. It can also be used in the next step even in the IIIa 'human body of trifluoroacetic acid.

[Step 20]

This step is a step of reacting the substituted sulphonic acid halide in the presence of a base with free amine 9 and IIa or salt IIa 'to form sulfonamide derivative Ia.

This step may be performed according to the production method I of the present invention. By this process, the sulfonamide derivative carboxylic ester Ia-a which is the objective compound of this invention, free carboxylic acid Ia-b, and carboxylate Ia-c can be obtained.

[Step I-2]

Starting compound IIIa (2S ^* -t) reacts compound 4 (see Process I-1) with a substituted sulfonic acid halogen compound, followed by epoxidation and oxidation (see steps 4 and 5 of step I-1). It can be manufactured by attaching).

[Step 1]

In this process, aldehyde IIIa (2S ^* -t) is converted to aldehyde enolsilyl ether by a silylating agent in the presence of a base. As a base substance, what is normally used, such as a Heunhibase, diazabicyclo undecene, is used. As the silylating agent, trimethylsilyl chloride, dimethyl-tert-butylsilyl chloride, trimethylsilyl plaart, bis (trimethylsilyl) acetamide, etc. may be used according to a conventional method. As the solvent, dichloromethane based on chlorinated hydrocarbon, diethyl ether based on ether, tetrahydrofuran, diglyme, or dimethyl sulfoxide may be used. The reaction is almost completely achieved in one day at room temperature.

Second Process

-플루오로알데히드로 변환하는 공정이다. 친전자적 불소화제로써는 크세논디플루오라이드 외에 퍼클로릴플루오리드, 트리플로오로메틸하이포플루오라이트, 불소기체, 아세틸하이포플루오라이트, N-플루오로피롤리돈, N-플루오로-N-알킬-P-톨루엔술폰아미드, 세슘플루오로술페이트 등이 사용되어도 좋다. 반응 용매로써 염소화탄화수소계 용매(주로 디클로로메탄) 또는 아세토니트릴, 초산에틸 등이 사용된다. 반응은 빙냉 혹은 -78°~0℃에서 행하여지며, 1~수시간만에 달성된다.This step is a step, aldehyde Id Ⅲa (2S ^* -t) of enol silyl ether Ⅲa2 '(2S ^* -t) is reacted with a fluorinating agent derived from the parent electronic

It is a process of converting -fluoroaldehyde. As electrophilic fluorinating agents, in addition to xenon difluoride, perchloryl fluoride, trifluoromethylhypofluorite, fluorine gas, acetyl hypophosphite, N-fluoropyrrolidone, N-fluoro-N-alkyl-P Toluene sulfonamide, cesium fluorosulfate, or the like may be used. As the reaction solvent, a chlorinated hydrocarbon solvent (mainly dichloromethane), acetonitrile, ethyl acetate, or the like is used. The reaction is carried out at ice cooling or at -78 ° to 0 ° C., and is achieved in 1 to several hours.

[Third process]

This step is a step of reacting fluorine-containing aldehyde IIIa2 (2S ^* -t) with various unsubstituted and fluorine-substituted illides to obtain compound Ia2 (2S ^* -t) of the present invention, which may be carried out according to the production method II of the present invention. The reaction between the aldehyde and the ilide may be carried out in accordance with the conventional method of the Wittig reaction. This reaction yields a novel bicyclosulfonamide compound having a fluorine-containing α-side chain. This reaction produces only Z or a mixture of Z and E. In addition, the fluorine-containing illide is synthesized from a halogen compound of fluorine-containing alkanoic acid or alkenic acid having a carboxyl group on ω-.

Sulfonamide derivative carboxylic ester Ia2-a (2S ^* -t) which is a target compound of this invention by this process. Free carboxylic acid IIa2-b (2S ^* -t) and carboxylate IIa2-c (2S ^* -t) can be obtained.

[Step I-3]

[Step 1]

This step is a step of esterifying acid anhydride 1 to compound 2 by esterification by dialcohol decomposition. The esterification reaction can be achieved by refluxing the acid anhydride for several minutes to several hours in alcohol or phenol such as methanol, ethanol, propanol, isopropanol, butanol, or tert-butanol.

Second Process

This step is a step of azating the tertiary carboxyl group of compound 2, transposing it to isocyanate and reacting with alcohol to lead to urethane 3. This process can be achieved by the kurutus potential. That is, the acid chloride or carboxyl group obtained by treating the carboxyl group with thionyl chloride, phosphoryl chloride or phosphorus pentachloride is reacted with ethyl chloroformate, isobutoxycarbonyl chloride and acetone in the presence of a base catalyst such as triethylamine or 4-dimethylaminopyridine. The azide compound is obtained by reacting sodium azide with an acid anhydride obtained by reacting in a solvent such as dimethylformamide, dimethyl sulfoxide, ethyl acetate or tetrahydrofuran under cooling for several minutes to several hours. Isocyanate is obtained by refluxing an azide compound in benzene, toluene, diphenyl ether for several tens of minutes to several hours. It is preferable that the first amine is easily obtained from the urethane obtained such as isobutanol, tert-butanol, diisopropylmethanol, cyclopentanol, cyclohexanol, benzyl alcohol, diphenylmethanol or triphenylmethanol as the alcohol to react with the isocyanate. . This reaction can be achieved by refluxing for several hours in a solvent such as benzene, dichloromethane, chloroform or ethyl acetate in the presence of a base such as triethylamine, 4-dimethylaminopyridine, 4-pyrrolidinopyridine and the like as necessary.

[Third process]

This step is a step of isomerizing compound 3 to compound 4. This process is completed by heating for several days in solvents, such as toluene, xylene, dimethyl sulfoxide, and dimethylformamide. If necessary, a catalytic amount of basic substances such as diazabicyclononene, diazabicyclo undecene, pyrrolidine-acetic acid, piperidine-acetic acid, triethylamine and the like may be added.

[4th process]

In this step, the ester of the compound 4 is reduced to aldehyde, and again, the aldehyde is reacted with the aldehyde to obtain enol ether 5. The reduction reaction was carried out using a reducing agent such as sodium bis (2-methoxyethoxy) aluminum hydride, diisobutylaluminum hydride, lithium hydride trimethoxyaluminum or sodium tri-tert-butoxyaluminum, ether ether, Complete in tens of minutes to several hours at room temperature or cooling in a solvent such as tetrahydrofuran, aromatic benzene or toluene. In this reaction, cyclic amines such as pyrrolidine, piperidine, morpholine, N-methylpiperidine, and N-ethylpiperidine may be added as necessary to control the reducing power. The reaction for obtaining enoether 5 by reacting lide with aldehyde may be carried out according to the conventional method of witig reaction. Ilide is produced from triphenylphosphine and chloromethyl ether or bromomethyl ether in the presence of a base such as sodium hydride, n-butyllithium, potassium-tert-butoxide, lithium diisopropylamine, dimsil sodium, dimsil potassium It is good to use. The reaction is completed in a few hours under cooling or at room temperature using, for example, ether-based ethyl ether, tetrahydrofuran or n-hexane, toluene, dimethyl sulfoxide and the like as a solvent.

[5th process]

This process is an acid hydrolysis of enol ether 5 to produce aldehyde 6. Formic acid, acetic acid, hydrochloric acid, sulfuric acid, perchloric acid, etc. may be used as the acid catalyst. As the solvent, alcohol-based methanol, ethanol, ether-based ethyl ether, tetrahydrofuran or acetonitrile and the like are used. The reaction can be achieved in tens of minutes to several hours at room temperature to warming.

[Sixth Step]

This step is a step in which aldehyde 6 is reacted with an lide to remove the amino protecting group again, thereby obtaining starting material IIb of the preparation method of the present invention. The reaction between the aldehyde body and the illi (reaction to generate a double bond) may be performed in accordance with the conventional method of the Witig reaction. Ilide used for the reaction is synthesized in the presence of a base in triphenylphosphine and a halide of alkanoic acid or alkenic acid having a carboxyl group at the ω position. The halogenated alkanoic acid or halogenated alkanoic acid of C ₄ -C ₆ used in this process is, for example, 3-bromopropanoic acid, 4-bromobutanoic acid, 4-bromo-2-butenoic acid, 4-bromo-3 -Butene acid, 5-bromopentanoic acid, 5-bromo-2-pentenoic acid, 5-bromo-3-pentenoic acid, 5-bromo-4-pentenoic acid, 6-bromohexanoic acid, 6-bro Mother-2-hexanoic acid, 6-bromo-2-hexanoic acid, 6-bromo-3-hexenoic acid, 6-bromo-4-hexanoic acid, 6-bromo-5-hexanoic acid, and the like. Examples of the base include sodium hydride, dimsil sodium, dimsil potassium, n-butyllithium, tert-butoxy potassium or lithium diisopropylamide. The reaction is completed in a few hours under cooling or at room temperature using, for example, ether-based ethyl ether, tetrahydrofuran or n-hexane, toluene, dimethyl sulfoxide and the like. According to the reaction conditions, this reaction produces only Z-form or a mixture of Z- and E-forms. It is then esterified to protect the carboxylic acid in subsequent reactions. The esterification is a method in which a carboxylic acid and an alcohol such as methanol, ethanol, n-propanol, isopropanol, butanol or pentanol are reacted with a catalyst of dry hydrogen chloride or concentrated sulfuric acid if necessary, and the carboxylic acid is used as a halide. The method of reacting with a base such as metal magnesium, dimethylaniline, pyridine, sodium hydroxide, a method of diazomethane, or a method of dimethyl sulfate and diazabicyclononene or diazabicyclo undecene may be performed according to a conventional method.

The reaction for removing the amino protecting group is carried out using a hydrolysis reaction using an acid such as hydrochloric acid or sulfuric acid or a base such as sodium hydroxide, potassium hydroxide or barium hydroxide, an acid decomposition reaction or a hydrogenolysis reaction using trifluoroacetic acid according to a conventional method. Do it.

[7th process]

This step is a step wherein the compound of the present invention is obtained by reacting starting material IIb of the compound of the present invention according to Preparation I. Carboxylic acid ester Ib-a (2S ^* -t) of 2S ^* -trans-sulfamide derivative Ib (2S ^* -t) in the compound of this invention by this process, Free carboxylic acid Ib-b (2S ^*) -t) and carboxylate Ib-c (2S ^* -t) can be obtained.

In the formula, R ₁ , R ₁ ′, R ₂ and X have the same meanings as above. R ₅ represents hydrogen, linear or branched alkyl such as methyl, ethyl, n-propyl, isopropyl, butyl or tert-butyl or benzyl. R ₆ represents substituted or unsubstituted alkyl such as diisopropylmethyl, isobutyl, tert-butyl, cyclopentyl, benzyl, diphenylmethyl or triphenylmethyl and the like. Prot means the amino protecting group normally used, and represents benzyloxycarbonyl, tert-butoxycarbonyl, triphenylmethane, etc. THP represents tetrahydro-2-pyranyl of a hydroxy protecting group.

Although an Example and a physical constant are shown below and the aspect of this invention will be clear, the scope of the present invention is not limited to this.

In the following examples, each compound is represented as one enantiomer in each step. The optically active substance has an absolute configuration represented by the structural formula. In the structural formula, the dashed line represents the congestion of the epimer or the α-batch or β-batch.

EXAMPLE

Example 1

Synthesis of 2 (S ^* )-2-exo-2-allyl-bicyclo [2,2,1] heptan-3-one

It synthesize | combines as follows by the method of Tetraheadon, the Letters (Tetr. Lett.) 21, 1897 (1980). 94.0 ml (0.15 M) of n-butyllithium (1.6 M n-hexane solution) was added dropwise at 30 ° C. in a solution of 21.0 ml (0.15 M) of diisopropylamine (hereinafter referred to as THF) (50 ml) in diisopropylamine. And it stirred for 15 minutes at 20 degreeC. Separately, 16.5 g (0.15 M) of THF solution of Nor, Campa-1 (manufactured by Aldrich) (100 mL) was prepared, and the lithium diisopropylamide (LDA) solution mentioned above was added at ­78 占 폚. Subsequently, 14.3 ml (0.15 M x 1.1) allyl bromide is added and stirred at # 78 ° C, and the reaction mixture is gradually warmed to 20 ° C over 1.5 hours. The reaction solution is concentrated under reduced pressure, ether is added when it is about 100 ml, and at the same time, 300 ml of 2N hydrochloric acid is added thereto for separation. The organic layer is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was distilled under reduced pressure and the residue having a boiling point of 88-98 ° C./15 mm Hg was collected to give 17.0 g (yield 75.6%) of the title compound 2. Colorless oily substance (liquid, boiling point 92 占 폚 / 10 mmHg).

Example 2

S ^* -2-exo-2-allyl-3 (E) hydroxyimino-bicyclo [2,2,1] heptane and 2 (S ^* )-2-exo-2-allyl-3 (Z) hydroxy Synthesis of Mino-bicyclo [2,2,1] heptane

6.00 g (40 mM) of 2 (S ^* )-2-exo-2-allyl-bicyclo [2,2,1] heptan-2-one 2, 5.56 g (80 mM) of hydroxylamine hydrochloride. 4.49 g (80 mM) of powdered potassium hydroxide are mixed in methanol at 0 ° C and stirred at 25 ° C for 30 minutes. The reaction mixture was partitioned between ether and 0.1N hydrochloric acid, the organic layer was washed with water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel (hereinafter referred to as SiO ₂ ). -C; 3 (E) oxime body 3a is obtained from an initial elution section by n-hexane-ethyl acetate (it is abbreviated as AcOEt (it is abbreviated hereafter as 95: 5).) A colorless oily 3.76g (56.91%) yield.

¹ HNMR (CDCl ₃ ) δppm: 1.03 ~ 1.09 (m, 7H), 1.90 ~ 2.60 (m, 4H), 3.50 (br.s., 1H), 4.86 ~ 5.25 (m, 2H), 5.60 ~ 6.18 (m , 1H)

IR (CHCl ₃ ) ν _max : 3590, 3285, 3140, 3080, 1680, 1640cm ^-1

Elemental Analysis: (C ₁₀ H ₁₅ NO)

Calculated (%): C; 72.67, H; 9.17, N; 8.48

Found (%): C; 72.38, H; 9.14, N; 8.49

2.02 g (yield 30.64%) of 3 (Z) oxime 3b is obtained in the rear eluting part. Colorless oil.

¹ HNMR (CDCl ₃ ) δppm: 1.15 ~ 2.00 (m, 7H), 2.15 ~ 3.15 (m, 5H), 4.90 ~ 5.22 (m, 2H), 5.60 ~ 6.12 (m, 1H)

IR (CHCl ₃ ) ν _max : 3590, 3280, 3140, 3085, 1678, 1641cm ^-1

Elemental Analysis: (C ₁₀ H ₁₅ NO)

Calculated (%): C; 72.67, H; 9.17, N; 8.48

Found (%): C; 72.45, H; 9.26, N; 8.21

Example 3

2 (S ^* )-2-exo-3-endo-2-allyl-3 benzyloxycarbonylamino-bisylchloro [2,2,1] heptane

2 (S ^* )-2-exo-2-allyl-3 (E) hydroxyiminobicyclo [2,2,1] heptane 3a, 6.26 g (37.9 mM) was dissolved in 60 ml of dry THF and lithium hydride 1.44 g (37.9 mM) of aluminum was added and refluxed for 1.5 hours. The reaction mixture is decomposed by adding water in the usual manner, followed by extraction with AcOEt, and then with dilute hydrochloric acid. The aqueous layer thus obtained is washed with AcOEt, made alkaline with an aqueous solution of 0.1N sodium hydroxide (hereinafter referred to as NaOH), and extracted with AcOEt. After drying with sodium sulfate (hereinafter referred to as Na ₂ SO ₄ ), the solvent is distilled off under reduced pressure. The obtained amine 4 (4.4 g) (29.1 mM) was immediately dissolved in 30 ml of dichloromethane (hereinafter referred to as CH ₂ Cl ₂ ) without purification, and 2.87 ml (29.1 mM x 1.2) of pyridine at 0 ° C, 5.0 ml (29.1 mM x 1.2) of benzyloxycarbonyl chloride is added and stirred at the same temperature for 30 minutes. It is partitioned between CH ₂ Cl ₂ and 0.2N hydrochloric acid, and the organic layer is dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to SiO ₂ column chromatography [Lova C from Merck Co .; n-hexane-AcOEt (9: 1)] to obtain 4.27 g (yield 39.5%) of the title compound 5a. Colorless columnar crystal, melting point 60-61 degreeC.

IR (CHCl ₃ ) ν _max : 3430, 1715, 1505cm ^-1

¹ HNMR (CDCl ₃ ) δppm: 0.74 ~ 1.89 (m, 7H), 1.90 ~ 2.30 (m, 3H), 2.43 (br.s., 1H), 3.53 (t, d, J = 4.7Hz, 1H), 4.80 (br.s., 1H), 4.91 (m, 1H), 5.09 (s, 2H), 5.50 ~ 6.00 (m, 1H), 7.36 (s, 5H)

Elemental Analysis: (C ₁₈ H ₂₃ NO ₂ )

Calculated (%): C; 75.74, H; 8.14, N; 4.91

Found (%): C; 75.84, H; 8.10, N; 4.95

Amines by lithium aluminum hydride reduction in the same manner from 2 (S ^* )-2-exo-2-allyl-3 (Z) hydroxyiminobicyclo [2,2,1] heptane 3b 3.37 g (20.4 mM) 4 2.2 g are obtained and 2.13 g (yield 40.0%) of the title compound 5 are obtained. As for 4,5 obtained from this Z-body, the spectrum of 4,5 and IR.NMR correspond from said correspondent (E) body.

Example 4

2 (S ^* )-2-exo-3-endo-2- (2,3-epoxypropyl) -3-benzyloxycarbonylaminobicyclo [2,2,1] heptane

6.8 g (23.8 mM) of 2 (S ^* )-2-exo-3-endo-2-allyl-3-benzyloxycarbonylaminobicyclo [2,2,1] heptane 5a was added to 150 ml of CH ₂ Cl ₂ . It melt | dissolves, 10.3 g (23.8 mM * 2) of m-chloro perbenzoic acid is added at 0 degreeC, and it stirred at 20 degreeC for 3 hours. The resulting crystals are filtered off, and the filtrate is washed with 10% aqueous sodium thiosulfate solution, 5% aqueous sodium bicarbonate solution and then water. After drying over sodium sulfate, the mixture is concentrated under reduced pressure. The residue was subjected to SiO ₂ column chromatography [manufactured by Merck, Rova C; n-hexane-AcOEt (4: 1)] to obtain 7.17 g (yield 100%) of the title compound 6a. Colorless oily.

IR (CHCl ₃ ) ν _max : 3455, 1717, 1505, 1479, 1456cm ^-1

¹ HNMR (CDCl ₃ ) δppm: 1.00 ~ 1.85 (m, 9H), 2.05 (br.s., 1H), 2.40 (br.s., 1H), 2.43 (m, 1H), 2.70 (m, 1H) , 2.89 (m, 1H), 3.55 (m, 1H), 4.90 (m, 1H), 5.06 (s, 2H), 7.32 (s, 5H)

Elemental _{analysis: (C 18 H 23 NO 3} · 0.1H 2 O)

Calculated (%): C; 71.29, H; 7.72, N; 4.62

Found (%): C; 71.27, H; 7.47, N; 4.57

Example 5

5 (Z) -7- [2 (S ^* )-2-exo-3-endo-3-benzyloxycarbonylaminobicyclo [2,2,1] hepto-2-yl] -5-heptenate methyl ester

4.52 g (15 mM) of epoxide 6a is dissolved in 500 ml of dioxane, an aqueous solution of 6.84 g (30 mM) of iodine 2H ₂ O (15 ml) is added at 25 ° C, and the mixture is stirred for 4 hours at the same temperature. AcOEt is added to the reaction solution and washed with water. After drying over Na ₂ SO ₄ and concentrated under reduced pressure to obtain 3.97 g of aldehyde 7a.

2.88 g (13.8 mM x 6 x 0.9) of sodium hydride (in 60.0% mineral oil) is added to 100 ml of dimethyl sulfoxide (hereinafter referred to as DMSO) at 25 ° C until no hydrogen gas is generated (1.5 ° C). Time) and 17.8 g (13.8 mM × 3 × 0.97) of 5-carboxybutyltriphenylphosphonium bromide synthesized from triphenylphosphine and 5-bromopentanoic acid were added at 18 ° C., and 40 ml of DMSO was further added. And stirred at 20 ° C. for 20 minutes.

3.97 g (13.8 mM) DMSO (60 ml) solution of the aldehyde 7a obtained first is added at 18-20 degreeC, and it stirred at 25 degreeC for 4 hours. The reaction solution is left overnight and then diluted with AcOEt and washed with 0.1N hydrochloric acid. Wash with water and then dry with Na ₂ SO ₄ . Concentrated under reduced pressure, the residue was dissolved in 50 ml of AcOEt, and methyl esterified by a conventional method by adding an ether solution of distilled diazomethane. The reaction solution was concentrated under reduced pressure, and the residue was then subjected to SiO ₂ column chromatography [Merck, Rova-C; developed with n-hexane AcOEt (9: 1) to afford 2.80 g (48.4% yield; from epoxide) of the title compound 8. Colorless oily.

IR (CHCl ₃ ) ν _max : 3450, 1721, 1602, 1501, 1453, 1437cm ^-1

¹ HNMR (CDCl ₃ ) δppm: 1.00 ~ 1.85 (m, 9H), 1.85 ~ 2.30 (m, 5H), 2.30 (t, J = 7Hz, 2H), 2.40 (br.s., 1H), 3.50 (t , d, J = 4, 7Hz, 1H), 3.63 (s, 3H), 4.93 (d, J = 7Hz, 1H), 5.09 (s, 2H), 5.36 (m, 2H), 7.34 (s, 5H)

Elemental Analysis: (C ₂₃ H ₃₁ NO ₄ )

Calculated (%): C; 71.65, H; 8.12, N; 3.63

Found (%): C; 71.60, H; 7.95, N; 3.71

Example 6

5 (Z) -7- [2 (S ^* )-2-exo-3-endo-3-aminobicyclo [2,2,1] hepto-2-yl] -5-heptenic acid methyl ester

A mixture of 771 mg (2 mM) of compound 8, 10 ml of trifluoroacetic acid and 2 ml of anisol is warmed at 45 ° C. for 3 hours. The reaction solution is concentrated under reduced pressure, and the residue is added with benzene and concentrated. This operation is repeated three times, petroleum ether is added to the obtained residue, and the resulting residue is washed well, and then concentrated under reduced pressure to obtain 500 mg of light brown oily trifluoroacetate 9 (yield 99.6%). This can be used for the next reaction even in the state of a salt.

NMR (CDCl ₃ ) δ ppm: 1.10 to 2.50 (m, 15H), 2.32 (t, J = 7 Hz, 2H), 3.08 (m, 1H), 3.68 (s, 3H), 5.40 (m, 2H), 7.60 ( br, 2H), 8.85 (br, 1H)

IR (CHCl ₃ ) ν _max : 3100br, 2560br, 1779, 1725, 1675, 1522, 1436cm ^-1

This salt 9 is decomposed into water and ether, the aqueous layer is separated, washed with ether, alkaline with aqueous sodium carbonate solution and extracted with AcOEt. The AcOEt solution was washed with water, dried over Na ₂ SO ₄ , concentrated under reduced pressure, and 330 mg (yield 65.7%) of amine 10 was obtained.

IR (CHCl ₃ ) ν _max : 3400br, 1728, 1600, 1583cm ^-1

¹ HNMR (CDCl ₃ ) δppm: 1.00 ~ 2.35 (m, 17H), 2.30 (t, J = 7Hz, 2H), 2.73 (m, 1H), 3.64 (s, 3H), 5.40 (m, 2H)

Example 7

5 (Z) -7- [2-exo-3-endo-3-phenylsulfonamidebicyclo [2,2,1] hepto-2-yl] -5-heptenic acid methyl ester and 5 (Z) -7 -[2-exo-3-endo-3-hexylsulfonamidebicyclo [2,2,1] hepto-2-yl] -5-heptenic acid methyl ester

140 mg (0.557 mM) of amine 10 were dissolved in 3 ml of CH ₂ Cl ₂ , and 155 μl (0.557 mM × 2) of triethylamine and 107 μl (0.557 mM × 1.5) of benzenesulfonyl chloride were added at 0 ° C., and 23 ° C. Stir for 15 minutes. The reaction solution is diluted with AcOEt, washed with 0.1N hydrochloric acid, washed with water, 5% aqueous sodium hydrogen carbonate solution, and then dried with Na ₂ SO ₄ . Concentrated under reduced pressure and the residue was purified by SiO ₂ column chromatography [Merck, Rova-A; developed with n-hexane-AcOEt (9: 1)], 188 mg (yield 86.2%) of benzenesulfonamide 11 was obtained. Colorless oil.

IR (CHCl ₃ ) ν _max : 3375, 1725, 1158, 1090cm ^-1

¹ HNMR (CDCl ₃ ) δppm: 0.80 ~ 2.10 (m, 15H), 2.17 (br.s., 1H), 2.26 (t, J = 7Hz, 2H), 3.02 (m, 1H), 3.67 (s, 3H ), 5.20 (m, 2H), 7.40-7.85 (m, 3H), 7.83-8.03 (m, 2H)

Elemental Analysis: (C ₂₁ H ₂₉ NO ₄ S)

Calculated (%): C; 64.41, H; 7.48, N; 3.58, S; 8.19

Found (%): C; 64.51, H; 7.48, N; 3.61, S; 7.87

Hexylsulfonamide 13 was obtained using the n-hexylsulfonyl chloride instead of benzenesulfonyl chloride (yield 42.3%) in a pale yellow oily phase.

¹ HNMR (CDCl ₃ ) δ ppm: 0.89 (t, J = 7 Hz, 3H), 1.00-2.25 (m, 22H), 2.30 (t, J = 7 Hz, 2H), 2.35 (br.s., 1H), 2.85 ~ 3.06 (m, 2H), 3.22 (t, d, J = 4,7 Hz, 1H), 3.65 (s, 3H), 4.73 (d, J = 7 Hz, 1H), 5.39 (m, 2H)

IR (CHCl ₃ ) ν _max : 3400, 3295, 1730, 1458, 1437, 1409cm ^-1

Elemental Analysis: (C ₂₁ H ₃₇ NO ₄ S)

Calculated (%): C; 63.11, H; 9.35, N; 3.51, S; 8.02

Found (%): C; 62.98, H; 9.29, N; 3.56, S; 7.72

Example 8

5 (Z) -7- [2-exo-3-endo-3-phenylsulfonamidebicyclo [2,2,1] hepto-2-yl] -5-heptenic acid

1500 mg (0.383 mM) of ester 11 are dissolved in 2.0 ml of methanol, 0.77 ml (0.383 mM × 2) of 1N-sodium hydroxide is added at 23 ° C., and left overnight at the same temperature. Decompose in ether and water, acidify the aqueous layer with hydrochloric acid and extract with AcOEt. After washing with water, the mixture was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The obtained crude crystal is recrystallized from ether and n-hexane to give 126 mg (87.5%) of carboxylic acid 12. Colorless columnar crystals.mp. 85 to 86 ° C.

IRν _max : 3380, 3550 ~ 2500, 1710, 1160, 1090cm ^-1

¹ HNMR (CDCl ₃ ) δppm: 0.85 ~ 2.30 (m, 15H), 2.31 (t, J = 7Hz, 2H), 3.00 (t, d, J = 4.7Hz, 1H), 5.20 (m, 2H), 5.69 (d, J = 7 Hz, 1H), 7.43-7.70 (m, 3H), 7.83-8.10 (m, 2H), 9.52 (br.s., 1H)

Elemental Analysis: (C ₂₀ H ₂₇ NO ₄ S)

Calculated (%): C; 63.62, H; 7.22, N; 3.71, S; 8.49

Found (%): C; 63.67, H; 7.15, N; 3.71, S; 8.36

Sodium salt 12a of compound 12

Elemental analysis: (C ₂₀ H ₂₆ NO ₄ SNa · 1 / 4H ₂ O)

Calculated (%): C; 59.46, H; 6.61, N; 3.47, S; 7.94, N; 5.69

Found (%): C; 59.26, H; 6.60, N; 3.59, S; 7.95, N; 5.63

NMR (D ₂ O ext TMS) δ ppm: 1.40 to 2.65 (m, 17H), 3.36 (m, 1H), 5.53 (m, 2H), 8.00 to 8.39 (m, 5H)

IR (KBr) ν _max : 3390br, 3270, 1560, 1445, 1408cm ^-1

In the same manner, the following ester 13 is hydrolyzed to obtain carboxylic acid 14.

Yield 97.8%, colorless oily.

IR (CHCl ₃ ) ν _max : 3380, 3500 ~ 2450, 1710, 1142cm ^-1

¹ HNMR (CDCl ₃ ) δppm: 0.88 (t, J = 7Hz, 3H), 1.00 ~ 2.25 (m, 22H), 2.33 (br.s., 1H), 2.34 (t, J = 7Hz, 2H), 2.85 ~ 3.10 (m, 2H), 3.20 (t, d, J = 4.7 Hz, 1H), 4.85 (d, J = 7 Hz, 1H), 5.39 (m, 2H), 8.30 (br.s., 1H)

Example 9

5 (Z) -7- [2-exo-3-endo-3-methanesulfonamidebicyclo [2,2,1] hepto-2-yl] -5-heptenic acid methyl ester

148 μl (3 × 0.35 mM) of triethylamine, followed by 41 μl (1.5 × 0.35 mM) of methanesulfonyl chloride in a nitrogen stream in 129 mg (0.35 mM) of CH ₂ Cl ₂ in a nitrogen stream. In addition, it stirred at room temperature for 30 minutes. The reaction solution is mixed with AcOEt-0.2N hydrochloric acid and separated. The AcOEt layer is washed with 5% sodium bicarbonate and with water. After drying over magnesium sulfate, the mixture is concentrated under reduced pressure. The similar residue was subjected to column chromatography with 8 g of SiO ₂ (containing 10% water), eluted with benzene-AcOEt (9: 1), and the solvent was distilled off to remove 85 mg of the title compound. Is obtained as an oily residue. Yield 73.7%.

Elemental analysis: (C ₁₆ H ₂₇ NO ₄ S · 0.05C ₆ H ₆ )

Calculated (%): C; 58.72, H; 8.25, N; 4.20, S; 9.62

Found (%): C; 58.71, H; 8.13, N; 4.27, S; 9.18

IR (CHCl ₃ ) ν _max : 3400, 3302, 1730.5cm ^-1

¹ HNMR (CDCl ₃ ) δppm: 1.00 ~ 2.13 (m, 15H), 2.32 (t, J = 7Hz, 2H), 2.95 (s, 3H), 3.23 (m, 1H), 3.67 (s, 3H), 4.99 (d, J = 7 Hz, 1H), 5.41 (m, 2H)

Example 10

5 (Z) -7- [2-exo-3-endo-3-methoxybenzenesulfonamidebicyclo [2,2,1] hepto-2-yl] -5-heptenic acid methyl ester

148 µl (3 x 0.35 mM) of triethylamine, followed by ice cooling in a nitrogen stream of 129 mg (0.35 mM) of CH ₂ Cl _{2 in a} raw material 9, and then 108 mg (1.5 mg of p-methoxybenzenesulfonyl chloride). X 0.35 mM) is added and stirred at room temperature for 1 hour. The reaction solution is mixed with AcOEt-0.2N hydrochloric acid and separated. The AcOEt layer is washed with 5% sodium bicarbonate and with water. After drying over magnesium sulfate, the mixture is concentrated under reduced pressure. Obtain an oily residue. Column chromatography is performed with 8 g of SiO ₂ (containing 10% of water), the portions eluted with benzene-AcOEt (9: 1) are collected and the solvent is distilled off to obtain 104 mg of oily target product 16. Yield 70.5%.

Elemental Analysis (C ₂₂ H ₃₁ NO ₅ S · 0.15C ₆ H ₆ )

Calculated (%): C; 63.48, H; 7.42, N; 3.23, S; 7.40

Found (%): C; 63.24, H; 7.33, N; 3.28, S; 6.99

IR (CHCl ₃ ) ν _max : 3385, 3282, 1730, 1599, 1580, 1499cm ^-1

¹ NMR (CDCl ₃ ) δppm: 0.87 ~ 2.15 (m, 15H), 2.25 (t, J = 7Hz, 2H), 2.95 (m, 1H), 3.65 (s, 3H), 3.85 (s, 3H), 5.20 (m, 3H), 6.94 (A ₂ B ₂ q, Apart J = 9 Hz, 2H), 7.81 (A ₂ B ₂ q, Bpart J = 9 Hz, 2H)

Example 11

5 (Z) -7- [2-exo-3-endo-3-p-nitrobenzenesulfonamidebicyclo [2,2,1] hepto-2-yl] -5-heptenic acid methyl ester

235 μl (3 × 0.56mM) of triethylamine under ice-cooling in a 3 mL solution of CH ₂ Cl ₂ (205 × 0.56 mM) CH ₂ Cl ₂ , followed by 186 mg (1.5 × 0.56 mM) of p-nitrobenzenesulfonyl chloride ) Is added and stirred at room temperature for 30 minutes. The reaction solution is mixed with AcOET-0.2N hydrochloric acid and separated. The AcOEt layer was washed with 5% sodium bicarbonate and water in order, dried over magnesium sulfate and concentrated under reduced pressure to obtain an oily residue. Collected by column chromatography on 10 g SiO ₂ (10% function) and eluting with benzene-AcOEt (20: 1), distilling off the solvent and obtaining 130 mg of the title compound 17 as an oily residue. Yield 53%.

Elemental analysis: (C ₂₁ H ₂₈ N ₂ O ₆ S · 0.2C ₆ H ₆₎

Calculated (%): C; 58.96, H; 6.51, N; 6.20, S; 7.09

Found (%): C; 58.91, H; 6.51, N; 6.14, S; 6.53

IR (CHCl ₃ ) ν _max : 3400, 3295, 1731, 1610, 1534cm ^-1

¹ NMR (CDCl ₃ ) δppm: 1.02 ~ 2.17 (m, 15H), 2.28 (t, J = 7Hz, 2H), 3.06 (m, 1H), 3.69 (s, 3H), 5.23 (m, 2H), 5.72 (d, J = 6 Hz, 1H), 8.12 (A ₂ B ₂ q, Apart J = 9 Hz, 2H), 8.37 (A ₂ B ₂ q, Bpart J = 9 Hz, 2H)

Example 12

5 (Z) -7- [2-exo-3-endo-3-methanesulfonamidebicyclo [2,2,1] hepto-2-yl] -5-heptenic acid

431 µl (2 x 0.22 mM) of 1N-sodium hydroxide was added to 1.2 ml of methanol of 71 mg (0.22 mM) of raw material 15, followed by stirring at 23 ° C for 4 hours. The reaction mixture is decomposed by mixing with AcOEt-0.2N hydrochloric acid. The AcOEt layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain 65 mg of oily carboxylic acid.

Yield 93.6%

NMR (CDCl ₃ ) δppm: 1.02 ~ 2.37 (m, 15H), 2.35 (t, J = 7Hz, 2H), 2.95 (s, 3H), 3.22 (m, 1H), 5.20 (d, J = 6Hz, 1H ), 5.40 (m, 2H)

To carboxyl 18 ml of 65 mg (0.206 mM) of 1 ml of methanol, 806 µl (0.9 x 0.206 mM) of 0.23 N sodium methoxide was added. After 5 minutes, the mixture was concentrated under reduced pressure, and the residue was dissolved in 1.5 ml of water and freeze-dried to obtain 69 mg of the title compound 18 as a white powder.

Yield 99%.

Elemental analysis: (C ₁₅ H ₂₄ NO ₄ SNa · 0.25H ₂ O)

Calculated (%): C; 52.69, H; 7.22, N; 4.10, S; 9.38, Na; 6.72

Found (%): C; 52.74, H; 7.17, N; 3.91, S; 9.34, Na; 6.92

IR (KBr) ν _max : 3400br, 3245, 1636sh, 1560, 1450,1404cm ^-1

NMR (d-MeOH) δ ppm: 1.08 to 2.35 (m, 17H), 2.92 (s, 3H), 3.18 (m, 1H), 3.43 (m, 2H)

Example 13

5 (Z) -7- [2-exo-3-endo-3-methoxybenzenesulfonamidebicyclo [2,2,1] hepto-2-yl] -5-heptenic acid

398 µl (2 x 0.2 mM) of 1N-NaOH was added to 1.2 ml of methanol in 84 mg (0.2 mM) of raw material 16, and stirred at 23 ° C for 7 hours. The reaction mixture is decomposed by mixing with AcOEt-0.2N hydrochloric acid. The AcOEt layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give 81 mg of an oily residue (carboxylic acid).

Yield 99%

NMR (CDCl ₃ ) δppm: 0.95 ~ 2.12 (m, 15H), 2.30 (t, J = 7Hz, 2H), 2.97 (m, 1H), 3.84 (s, 3H), 5.25 (m, 3H), 6.94 ( A ₂ B ₂ q, Apart J = 9 Hz, 2H), 7.78 (A ₂ B ₂ q, Bpart J = 9 Hz, 2H), 9.19 (brs, 1H)

To 82 mL of methanol of 81 mg of carboxylic acid was added 782 μL (0.9 × 0.2 mM) of 0.23 N sodium methoxide. After 5 minutes, the mixture was concentrated under reduced pressure, and the residue was dissolved in 1.5 ml of water and freeze-dried to obtain 81 mg of the titled compound 19 as a white powder.

Yield 94%

Elemental analysis: (C ₂₁ H ₂₈ NO ₅ SNa · 0.25H ₂ O)

Calculated (%): C; 58.12, H; 6.62, N; 3.23, S; 7.39, Na; 5.30

Found (%): C; 58.14, H; 6.61, N; 3.31, S; 7.20, Na; 5.39

IR (KBr) ν _max : 3400br, 3280, 1640sh, 1598, 1576, 1560br, 1500, 1458, 1439, 1450cm ^-1

NMR (d-MeOH) δ ppm: 0.87-2.13 (m, 15H), 2.12 (t, J = 7 Hz, 2H), 2.89 (m, 1H), 3.87 (s, 3H), 5.21 (m, 2H), 7.07 (A ₂ B ₂ q, Apart J = 9Hz, 2H), 7.81 (A ₂ B ₂ q, Bpart J = 9Hz, 2H)

Example 14

5 (Z) -7- [2-exo-3-endo-3-p-nitrobenzenesulfonamidebicyclo [2,2,2] hepto-2-yl] -5-heptenic acid

536 µl (2 x 0.268 mM) of 1N potassium hydroxide was added to 1 ml of a methanol solution of 117 mg (0.268 mM) of raw material 17, followed by stirring at 23 ° C for 24 hours. The reaction solution is mixed with AcOEt-0.2N hydrochloric acid and separated. The AcOEt layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give 109 mg of an oily residue (carboxylic acid).

Yield 96.2%

NMR (CDCl ₃ ) δppm: 1.0 ~ 2.13 (m, 15H), 2.32 (t, J = 7Hz, 2H), 3.06 (m, 1H), 5.22 (m, 2H), 5.69 (d, J = 7Hz, 1H ), 8.08 (A ₂ B ₂ q, Apart J = 9 Hz, 2H), 8.35 (A ₂ B ₂ q, Bpart J = 9 Hz, 2H), 9.89 (brs, 1H)

1 ml (0.9 x 0.26 mM) of 0.23 N-sodium methoxide is added to a 1.5 ml solution of 109 mg of carboxylic acid. After 5 minutes, the mixture was concentrated under reduced pressure, and the residue was dissolved in 1.5 ml of water and freeze-dried to obtain 107 mg of the title compound 20 as a white powder.

Yield 92.6%

Elemental Analysis: (C ₂₀ H ₂₅ N ₂ O ₆ SNa)

Calculated (%): C; 54.04, H; 5.67, N; 6.30, S; 7.21, Na; 5.17

Found (%): C; 54.08, H; 5.98, N; 6.16, S; 7.03, Na; 4.54

IR (KBr) ν _max : 3385br, 1650sh, 1605, 1560, 1529, 1400cm ^-1

NMR (d-MeOH) δppm: 1.05 ~ 1.92 (m, 15H), 2.11 (t, J = 7Hz, 2H), 3.00 (m, 1H), 5.15 (m, 2H), 8.08 (A ₂ B ₂ q Apart J = 9Hz, 2H), 8.40 (A ₂ B ₂ q, Bpart J = 9Hz, 2H)

[Examples 15 to 29]

The following compounds were prepared according to the above method.

TABLE 1a

TABLE 1b

TABLE 1c

TABLE 1d

Elemental analysis: C ₂₁ H ₂₈ NO ₄ SCl0.1C ₆ H ₆

Calculated (%): C; 59.80, H; 6.65, N; 3.23, S; 7.39, Cl; 8.17

Found (%): C; 59.70, H; 6.60, N; 3.24, S; 7.02, Cl; 8.33

IRν _max (CHCl ₃ ) cm ^-1 : 3400, 3290, 1733, 1590, 1578, 1164, 1098, 1089

¹ H-NMRδ ppm (CDCl ₃ ): 0.95 to 2.18 (m, 15H), 2.29 (t, J = 7 Hz, 2H), 3.00 (m, 1H), 3.69 (s, 3H), 5.02 (d, J = 7 Hz , 1H), 5.28 (m, 2H), 7.49 (A ₂ B ₂ q Apart J = 10 Hz, 2H), 7.84 (A ₂ B ₂ q, Bpart J = 10 Hz, 2H)

Elemental analysis: C ₂₀ H ₂₆ NO ₄ SClNa · 0.5H ₂ O

Calculated (%): C; 54.23, H; 5.92, N; 3.16, S; 7.24, Cl; 8.01, Na; 5.19

Found (%): C; 54.45, H; 6.04, N; 3.25, S; 6.90, Cl; 7.89, Na; 5.13

IRν _max (KBr) cm ^-1 : 3410br, 1640, 1560, 1160, 1196, 1086.

¹ H-NMRδ ppm (d-methanol): 1.10-2.22 (m, 17H), 2.94 (m, 1H), 5.20 (m, 2H), 7.57 (A ₂ B ₂ q Apart J = 10 Hz, 2H), 7.86 ( A ₂ B ₂ q, Bpart J = 10Hz, 2H)

Elemental analysis: C ₂₂ H ₃₁ NO ₄ S · 0.12C ₆ H ₆

Calculated (%): C; 65.76, H; 7.71, N; 3.38, S; 7.73

Found (%): C; 65.59, H; 7.68, N; 2.86, S; 7.41

IRν _max (CHCl ₃ ) cm ^-1 : 3390, 1730, 1150, 1126

¹ H-NMRδ ppm (CDCl ₃ ): 0.81-2.10 (m, 15H), 2.30 (t, J = 7 Hz, 2H), 3.18 (m, 1H), 3.63 (s, 3H), 4.20 (s, 2H), 4.84 (d, J = 7 Hz, 1H), 5.40 (m, 2H), 7.39 (s, 5H)

¹ H-NMRδ ppm (CDCl ₃ ): 0.89 to 2.41 (m, 17H), 3.17 (m, 1H), 4.20 (s, 2H), 5.04 (d, J = 7 Hz, 1H), 5.39 (m, 2H), 7.39 (s, 5 H), 10.18 (brs, 1 H)

Elemental analysis: C ₂₁ H ₂₈ NO ₄ SNa · 0.4H ₂ O

Calculated (%): C; 59.95, H; 6.90, N; 3.33, S; 7.62, Na; 5.46

Found (%): C; 60.18, H; 6.89, N; 3.29, S; 7.51, Na; 5.31

IRν _max (KBr) cm ^-1 : 3405, 3280, 1561, 1430sh, 1411, 1316, 1150, 1125

¹ H-NMRδ ppm (CDCl ₃ ): 0.95 to 2.30 (m, 17H), 3.09 (m, 1H), 4.20 (s, 2H), 5.37 (m, 2H), 7.32 (s, 5H)

Elemental Analysis: C ₂₃ H ₃₃ NO ₄ S

Calculated (%): C; 65.84, H; 7.93, N; 3.34, S; 7.64

Found (%): C; 65.90, H; 7.84, N; 3.38, S; 7.38

IRν _max (CHCl ₃ ) cm ^-1 : 3390, 3295, 1730, 1604, 1498, 1144, 1072, 1054

¹ H-NMRδ ppm (CDCl ₃ ): 1.02 to 2.09 (m, 15H), 2.29 (t, J = 7 Hz, 2H), 3.20 (m, 5H), 3.65 (s, 3H), 4.94 (d, J = 7 Hz , 1H), 5.37 (m, 2H), 7.24 (m, 5H)

Elemental analysis: C ₂₂ H ₃₀ NO ₄ SNa · 0.3H ₂ O

Calculated (%): C; 61.03, H; 7.12, N; 3.24, S; 7.41, Na; 5.31

Found (%): C; 60.97, H; 7.06, N; 3.37, S; 7.46, Na; 5.62

IRν _max (KBr) cm ^-1 : 3425, 3295, 1562, 1455, 1499.5, 1407, 1312, 1146, 1080, 1059

NMRδ ppm (d-methanol): 1.15 to 2.32 (m, 17H), 3.19 (m, 5H), 5.38 (m, 2H), 7.25 (s, 5H)

Elemental analysis: C ₂₆ H ₃₁ NO ₄ S · 0.1H ₂ O

Calculated (%): C; 67.72, H; 7.09, N; 3.16, S; 7.23

Found (%): C; 67.64, H; 6.88, N; 3.04, S; 6.93

IRν _max (CHCl ₃ ) cm ⁻¹ : 3395, 1732, 1156, 1132, 1076.

¹ H-NMRδ ppm (CDCl ₃ ): 1.05 to 2.23 (m, 17H), 3.05 (m, 1H), 3.65 (s, 2H), 5.10 (m, 2H), 5.64 (d, J = 7 Hz, 1H), 7.60 (m, 2H), 7.97 (m, 4H), 8.50 (s, 1H)

Elemental analysis: C ₂₄ H ₂₈ NO ₄ SNa · 0.4H ₂ O

Calculated (%): C; 63.11, H; 6.36, N; 3.07, S; 7.02, Na; 5.03

Found (%): C; 63.18, H; 6.27, N; 3.20, S; 6.83, Na; 4.96

IRν _max (KBr) cm ^-1 : 3360, 3285, 1562, 1407, 1316, 1153, 1130, 1075

¹ H-NMRδ ppm (d-methanol): 1.03 to 2.20 (m, 17H), 2.97 (m, 1H), 5.02 (m, 2H), 7.64 (m, 2H), 8.00 (m, 4H), 8.43 (s , 1H)

Elemental analysis: C ₂₀ H ₂₈ N ₂ O ₄ S · 1 / 10C ₆ H ₆

Calculated (%): C; 61.97, H; 7.17, N; 6.97, S; 7.97

Found (%): C; 61.71, H; 7.30, N; 6.80, S; 7.76

IRν _max (CHCl ₃ ) cm ⁻¹ : 3390, 3290, 1730, 1577, 1168, 1107.

¹ H-NMRδ ppm (CDCl ₃ ): 1.02 to 2.26 (m, 15H), 2.27 (t, J = 7.0 Hz, 2H), 3.03 (m, 3H), 5.22 (m, 2H), 5.87 (d, J = 7.0 Hz, 1H), 7.44 (m, 1H), 8.17 (m, 1H), 8.78 (m, 1H), 9.09 (m, 1H)

¹ H-NMRδ ppm (CDCl ₃ ): 1.02 to 2.22 (m, 15H), 2.33 (t, J = 1 Hz, 2H), 3.05 (m, 1H), 5.23 (m, 2H), 5.94 (d, J = 7 Hz , 1H), 7.51 (d, d, J = 5Hz, 8Hz, 1H), 8.25 (m, 1H), 8.85 (m, 1H), 9.17 (brs, 1H), 9.73 (brs, 1H)

Elemental analysis: C ₁₉ H ₂₆ N ₂ O ₄ SNa · 0.03H ₂ O

Calculated (%): C; 56.90, H; 6.30, N; 6.99, S; 8.00

Found (%): C; 57.07, H; 6.38, N; 7.07, S; 8.15

IRν _max (KBr) cm ^-1 : 3420, 3260, 3080, 1698, 1570, 1413, 1320, 1166, 1106

¹ H-NMRδ ppm (d-methanol): 1.12-2.16 (m, 15H), 2.14 (t, J = 7 Hz, 2H), 2.97 (m, ppm 1H), 5.14 (m, 2H), 7.10 (d, d , J = 5 Hz, 8 Hz, 1H), 8.25 (m, 1H), 8.76 (m, 1H), 8.99 (brs, 1H)

[Examples 30-31]

Example 30

Preparation of Compound 2

To 74 ml of dry dimethyl sulfoxide was added 2.43 g (60%, 60.9 mM) of sodium hydrogen in a nitrogen stream, and the temperature was raised to 75 ° C. After stirring for 50 minutes at the same temperature, it was cooled to 10 ° C, and (2-carboxyethyl) -triphenylphosphonium bromide 13.63 (32.8 mM) was added thereto. After stirring for 15 minutes, a 14 ml solution of 3.24 g (11.28 mM) of dry dimethyl sulfoxide of raw material aldehyde 7a was added, and stirred at room temperature for 1.5 hours. The reaction solution was added to diluted hydrochloric acid-ethyl acetate and separated. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure to obtain an oily residue. Column chromatography (SiO ₂ ) is carried out, and the part eluted from ethyl acetate is collected and methyl esterified with diazomethane. Purification by column chromatography (SiO ₂ ), and the part eluted with n-hexane-ethyl acetate (4: 1) are collected to obtain 2.47 g of an oily target product. 61.3%

IRνmax (CHCl ₃ ) cm ^-1 : 3445, 1720

NMRδ ppm (CDCl ₃ ): 0.90 to 2.40 (m, 1H), 3.05 (m, 2H), 3.47 (m, 1H), 3.63 (S, 3H), 4.88 (m, 1H), 5.06 (s, 2H), 5.54 (m, 2H), 7.33 (s, 5H)

Example 31

① Preparation of compound I a3-aa (2S ^* -t)

5 ml of anisole and 20 ml of trifluoroacetic acid solution of 1.27 g (3.55 mM) of raw material 2 was heated and stirred at 45 ° C. for 4 hours. The reaction solution is concentrated under reduced pressure and the residue is rinsed with n-hexane. Trifluoroacetic acid salt of this amine is dissolved in 10 ml of dichloromethane and 1.24 ml (8.9 mM) of triethylamine is added. Next, 0.68 ml (5.3 mM) of benzenesulfonyl chloride was added at 20 ° C., and stirred for 30 minutes at the same temperature. The reaction solution is added to 1N hydrochloric acid-ethyl acetate and separated. The organic layer was washed with 5% sodium bicarbonate and water in that order, dried over magnesium sulfate and concentrated under reduced pressure. The residue is subjected to column chromatography (SiO ₂ ), and the elution portion is collected by n-hexane-ethyl acetate (4: 1) to give 806 mg of the target substance in the oil phase. Yield 62.5%

Elemental analysis: C ₁₉ H ₂₅ NO ₄ S

Calculated (%): C; 62.78, H; 6.93, N; 3.85, S; 8.82

Found (%): C; 62.62, H; 6.97, N; 3.72, S; 8.70

IRνmax (CHCl ₃ ) cm ^-1 : 3390, 3280, 1733, 1160, 1093

NMRδ ppm (CDCl ₃ ): 0.85 to 2.00 (m, 10H), 2.18 (brs, 1H), 2.94 (d, J = 7 Hz, 2H), 2.98 (m, 1H), 3.68 (s, 3H), 5.01 (d , J = 7Hz, 1H), 5.27 ~ 5.58 (m, 2H), 7.43 ~ 7.61 (m, 3H), 7.82 ~ 7.95 (m, 2H)

② Preparation of Compound I a3-ac (2S ^* -t)

According to a conventional method, the sodium salt is used.

Elemental analysis: C ₁₈ H ₂₂ NO ₄ SNa · 0.8H ₂ O

Calculated (%): C; 56.03, H; 6.17, N; 3.63, S; 8.31

Found (%): C; 55.86, H; 6.04, N; 3.57, S; 8.36

IRνmax (KBr) cm ^-1 : 3400br, 3280, 1630sh, 1565, 1448, 1400sh, 1388, 1318, 1157, 1093

NMRδ ppm (D ₂ O + EXTTMS): 1.48 to 2.50 (m, 11H), 3.22 (m, 3H), 5.73 (m, 2H), 8.03 (m, 3H), 8.30 (m, 2H)

[Examples 32 to 35]

Using the compound IIa3 as a starting material, the following compounds as shown in Table 2 were prepared according to the method of Example 31 of Example I-1.

TABLE 2

[Examples 36 to 37]

The following compounds were prepared by reacting the brominated 3-methoxycarbonylbenzyltriphenylphosphonium according to the method of Example 30 of Example I-1 to the aldehyde prepared in Example 46 of Example I-2.

Example 36

① R ₁ = CH ₃

Elemental analysis: C ₂₄ H ₂₇ NO ₄ S · 0.1H ₂ O

Calculated (%): C; 67.45, H; 6.42, N; 3.28, S; 7.50

Found (%): C; 67.34, H; 6.46, N; 3.34, S; 7.34

IRνmax (CHCl ₃ ) cm ^-1 : 3400, 3285, 1605, 1584, 1165, 1095

¹ H-NMRδ ppm (CDCl ₃ ): 1.05-2.13 (m, 11H), 3.05 (m, 1H), 3.92 (s, 3H), 5.27-5.70 (m, 2H), 6.30 (d, J = 11.5 Hz, 1H), 7.40 (m, 5H), 7.90 (m, 4H)

R ₁ : H

mp. 160-162 ℃

Elemental Analysis C ₂₃ H ₂₅ NO ₄ S · 0.1H ₂ O

Calculated (%): C; 67.13, H; 6.12, N; 3.40, S; 7.79

Found (%): C; 66.92, H; 6.24, N; 3.34, S; 7.64

IRνmax (KBr) cm ^-1 : 3435, 3270, 2605, 2560, 1688, 1607, 1581, 1158, 1093

¹ H-NMRδ ppm (CDCl ₃ ): 1.03-2.25 (m, 11H), 3.05 (m, 1H), 4.97 (d, J = 7 Hz, 1H), 5.50 (t of d J = 7 Hz, 11.5 Hz, 1H) , 6.20 (br, 1H), 6.33 (d, J = 11.5 Hz, 1H), 7.47 (m, 5H), 7.90 (m, 4H)

Example 37

R ₁ = CH ₃

Elemental analysis: C ₂₄ H ₂₇ NO ₄ S · 0.1H ₂ O

Calculated (%): C; 67.45, H; 6.42, N; 3.28, S; 7.50

Found (%): C; 67.41, H; 6.56, N; 3.22

IRνmax (CHCl ₃ ) cm ^-1 : 3390, 3280, 1720, 1601, 1583, 1161, 1093, 965

¹ H-NMRδ ppm (CDCl ₃ ): 1.08-2.16 (m, 11H), 3.08 (m, 1H), 3.92 (s, 3H), 5.46 (d, J = 7 Hz, 1H), 5.90-6.36 (m, 2H ), 7.49 (m, 5H), 7.90 (m, 4H)

R ₁ : Na

Elemental analysis: C ₂₃ H ₂₄ NO ₄ SNa · 0.1H ₂ O

Calculated (%): C; 61.18, H; 5.80, N; 3.10, S; 7.10, Na; 5.09

Found (%): C; 61.38, H; 5.83, N; 3.10, S; 7.36, Na; 4.69

IRνmax (KBr) cm ^-1 : 3425, 3285, 1608, 1590, 1560, 1449, 1430, 1390, 1163, 1156, 1095, 967

¹ H-NMRδ ppm (d-methanol): 1.12-2.18 (m, 11H), 3.00 (m, 1H), 6.15 (m, 2H), 7.23-7.90 (m, 9H)

Example I-1

Example 38

Anhydrous 5-norbornene-2,3-dicarboxylic acid 1, 5.08 g (30 mM) is dissolved in 20 ml of methanol and heated to reflux for 7 hours. The crude crystal obtained by concentration under reduced pressure is recrystallized from a mixed solvent of ether and petroleum ether to obtain 5.65 g (96.0%) of compound 2.

Colorless columnar crystals. Melting point 72 ℃

¹ HNMR (CDCl ₃ ): δ 1.20 ~ 1.55 (m, 2H), 3.13 (brs, 2H), 3.27 (m, 2H), 3.55 (s, 3H), 6.23 (m, 2H), 10.27 (s, 1H )

Elemental Analysis: C ₁₀ H ₁₂ O ₄

Calculated (%): C; 61.21 H; 6.18

Found (%): C; 60.89 H; 6.10

Example 39

5.6 g (28.5 mM) of compound 2 was dissolved in 50 ml of acetone, and 5.2 ml (28.5 mM x 1.3) of triethylamine, 10 ml of water, and 3.54 ml of ethyl chlorocarbonate (28.5 mM x 1.3) were added at 0 deg. Stir for 15 minutes at. Next, 2.82 g (28.5 mM × 1.5) of sodium azide is dissolved in 15 ml of water and stirred at 0 ° C. for 30 minutes. It is partitioned between ether and dilute hydrochloric acid, the organic layer is washed with water, dried and concentrated under reduced pressure, and the residue is dissolved in 50 ml of benzene and heated to reflux for 30 minutes at 90 ° C. Next, 7 ml of benzyl alcohol and 5.2 ml of triethylamine were added, and the mixture was refluxed for 1.5 hours. The reaction solution was distributed between ethyl acetate and water (dilute hydrochloric acid), and the organic layer was washed with water, dried and concentrated under reduced pressure. The residue is subjected to column chromatography [silica gel, lova C, developed on n-nucleic acid-ethyl acetate (10%)] to give 5.96 g (67.0%) of compound 3. Colorless Prism Crystal, Melting Point 66 ℃

¹ HNMR (CDCl ₃ ): δ 1.20 to 1.58 (m, 2H), 3.10 (brs, 2H), 3.18 (dd, J = 3, 9 Hz, 1H), 3.50 (s, 3H), 4.60 (dt, J = 3, 9Hz, 1H), 5.06 (s, 2H), 5.27 (d, J = 9Hz, 1H), 6.06 ~ 6.45 (m, 2H), 7.32 (s, 5H)

Elemental Analysis: C ₁₇ H ₁₉ NO ₄

Calculated (%): C; 67.75, H; 6.37, N; 4.65

Found (%): C; 67.87, H; 6.30, N; 4.84

Example 40

1.0 g (3.31 mM) of Compound 3 is dissolved in 10 ml of toluene, 0.5 ml (3.31 mM) of diazabicycloundecene is added and heated to reflux for 3 days. After cooling, ethyl acetate was added, washed with 0.1N hydrochloric acid, water, dried and concentrated under reduced pressure. The residue is subjected to column chromatography [silica gel, lova B, developed on n-nucleic acid-ethyl acetate (25%)] to give 410 mg (yield 41.0%) of compound 4.

Colorless columnar crystals. Melting Point 76 ~ 77 ℃

¹ HNMR (CDCl ₃ ): δ 1.35 ~ 2.00 (m, 3H), 3.00 (brs, 2H), 3.68 (s, 3H), 4.58 (br, s, 2H), 5.08 (s, 2H), 6.08 ~ 6.55 (m, 2 H), 7.35 (s, 5 H)

Elemental Analysis: C ₁₇ H ₁₉ NO ₄

Calculated (%): C; 67.75, H; 6.37, N; 4.65

Found (%): C; 67.44, H; 6.46, N; 4.69

Example 41

3.01 g (10 mM) of compound 4 was dissolved in 40 ml of toluene, 18.0 ml (18 mM) of diisobutyl aluminum hydrogen (1.0 M in n-hexane) was added at -78 ° C, and stirred at the same temperature for 30 minutes. The reaction solution is partitioned between ethyl acetate and 80 mL of 1N hydrochloric acid, the organic layer is washed with water, dried and concentrated under reduced pressure to obtain a crude aldehyde. Separately, 11.79 g (35 mM) of methoxymethylphosphonium chloride was suspended in 60 ml of tetrahydrofuran, 17.48 ml of n-butyllithium (28 mM: in 1.6N-hexane solution) was added at 78 ° C, and stirred at 0 ° C for 20 minutes. . The first obtained aldehyde was dissolved in 20 ml of tetrahydrofuran, added at # 78 ° C, and warmed to 20 ° C over 30 minutes. Ethyl acetate is added to the reaction mixture, the mixture is washed with ice water, dried and concentrated under reduced pressure. The residue is subjected to column chromatography [neutral, great I, n-nucleic acid-ethyl acetate (5%)] to give 1.35 g (yield 45.2%) of compound 5. Colorless oily substance.

¹ HNMR (CDCl ₃ ): δ 1.10-1.75 (m, 3H), 2.54 (brs, 1H), 3.00 (brs, 1H), 3.50, 3.53 (s, x 2, 3H in total), 3.75-4.20 (m, 1H), 4.20-4.98 (m, 2H), 5.07 (s, 2H), 5.83-6.555 (m, 3H), 7.35 (s, 5H)

Example 42

1.35 g (4.5 mM) of compound 5 was dissolved in 7 ml of 90% formic acid, and left at 25 ° C for 15 minutes. Partition between ethyl acetate and 5% aqueous sodium hydrogen carbonate solution. The organic layer is washed with water, dried, and then concentrated under reduced pressure to obtain a crude aldehyde. The obtained aldehyde can be obtained by the method of Example 1-1 (the method of obtaining compound 8 from aldehyde), that is, a Wittig reaction, followed by methylation to obtain 650 mg (37.7%) of compound 6. Colorless oily substance.

¹ HNMR (CDCl ₃ ): δ 2.29 (t, J = 7Hz, 2H), 2.52 (brs, 1H), 2.97 (brs, 1H), 3.61 (s, 3H), 3.80 (td, J-3, 9Hz, 1H), 4.50 (d, J = 9 Hz, 1H), 5.05 (s, 2H), 5.30-5.60 (m, 2H), 5.95-6.635 (m, 2H), 7.31 (s, 5H)

Elemental Analysis: C ₂₃ H ₂₉ NO ₄

Calculated (%): C; 72.02, H; 7.64, N; 3.65

Found (%): C; 72.01, H; 7.66, N; 3.63

Example 43

I b-aa (2S ^* −t) at 6 is obtained by the method of Examples 6 and 7 of Example I-1. Yield 38.7%, colorless oily substance.

¹ HNMR (CDCl ₃ ): δ 2.27 (t, J = 7 Hz, 2H), 2.46 (brs, 1H), 2.71 (brs, 1H), 3.32 (td, J = 4, 9 Hz, 1H), 3.65 (s, 3H), 4.52 (d, J = 9 Hz, 1H), 5.05-5.45 (m, 2H), 5.80-6.60 (m, 2H), 7.40-8.05 (m, 5H)

Elemental analysis: C ₂₁ H ₂₇ NO ₄ S · H ₂ O

Calculated (%): C; 61.88, H; 7.18, N; 3.44, S; 7.87

Found (%): C; 61.86, H; 6.86, N; 3.22, S; 7.74

Compound I b-ab (2S ^* -t) is obtained from compound I b-aa (2S ^* -t) obtained by the method of Example 8 of Example I-1. (Yield 53.5%)

¹ HNMR (CDCl ₃ ): δ 0.85-2.25 (m, 9H), 2.32 (t, J = 7Hz, 2H), 2.45 (brs, 1H), 2.70 (brs, 1H), 3.32 (td, J = 4, 9 Hz, 1H), 4.71 (d, J = 9 Hz, 1H), 5.08-5.43 (m, 2H), 5.80-6.40 (m, 2H), 7.43-8.00 (m, 5H), 8.50 (brs, 1H)

Elemental analysis: C ₂₀ H ₂₅ NO ₄ S

Calculated (%): C; 63.96, H; 6.72, N; 3.73, S; 8.54

Found (%): C; 64.23, H; 6.86, N; 3.64, S; 8.36

Compound I b-ac (2S ^* -t) is obtained from compound I b-ab (2S ^* -t) in the usual manner. Yield 90.9%. Colorless powder.

[I-1]

Example 44

(+)-Campa is reacted according to the methods of Examples 1 to 14 of Example I-1 to obtain the following Compound I c (2S-t).

[The layout of the various subtitle centers of (+)-campa is maintained until the final product.]

Example I-2

Example 45

Preparation of Compound 5b

2.85 g (10 mM) of compound 5a obtained according to Example 3 of Example I-1 is dissolved in a mixture of 10 ml of anisole and 30 ml of trifluoroacetic acid and stirred at 45 ° C for 7 hours. The reaction mixture is concentrated under reduced pressure. To 30 mL of the dichloromethane solution of the residue, 4.18 mL (10 mM X 3) triethylamine and 1.09 mL (10 mM X 1.5) benzenesulfonyl chloride were added at 0 ° C. The mixture was stirred at 0 ° C. for 30 minutes and then partitioned between ethyl acetate and 1N hydrochloric acid. The ethyl acetate solution was washed with water, dried over sodium sulfate, depressurized / concentrated and the residue was separated by column chromatography [silica gel 50g: eluted with 10% ethyl acetate / n-hexane solution] to give 1.89 g of compound 5b as colorless. Obtained by columnar crystals (yield 65%). Melting point 84-87 degreeC.

IRνmax (CHCl ₃ ) cm ^-1 : 3395, 3285, 1642, 1449, 1157, 1094

¹ HNMR (CDCl ₃ ): δ ppm 1.00-2.15 (m, 11H), 3.02 (m, 1H), 4.78 (m, 2H), 5.50 (m, 2H), 7.55 (m, 3H), 7.93 (m, 2H)

Example 46

Preparation of Compound 7b

1.00 g (3.43 mM) of compound 5b is dissolved in 15 ml of dichloromethane, and 1.48 g (6.86 mM: purity 80%) of m-chloroperbenzoic acid are added at 0 ° C and stirred at 25 ° C for 2.5 hours. The reaction mixture is washed with 10% aqueous sodium thiosulfate solution and 5% aqueous sodium carbonate solution. The organic layer is concentrated under reduced pressure to obtain a crude epoxide. This epoxide is dissolved in 22 ml of dioxane, 1.56 g (6.86 mM) of periodic acid and 4 ml of water are added at 25 ° C. and stirred at 25 ° C. for 3 hours. The reaction mixture is poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over sodium sulfate, and concentrated under reduced pressure to obtain 1.00 g of compound 7b as a colorless oily substance. (Yield: 100%)

¹ HNMR (CDCl ₃ ): δ ppm 1.25-2.35 (m, 11H), 2.85 (m, 1H), 5.68 (d, J = 10 Hz, 1H), 7.45 (m, 3H), 7.83 (m, 2H), 9.52 (s, 1 H)

Example 47

(2S ^* )-2-exo-3-endo- (2-trimethylsilyloxy) -vinyl-3-benzenesulfonamidebicyclo [2,2,1] heptene IIIa2 '(2S ^* -t)

Trimethylsilylation of the compound 7b can be suitably achieved as follows.

1.13 g (9 mM) of trimethylsilyl chloride is dissolved in 8 ml of dichloromethane and stirred to add 1.25 ml (9 mM) of triethylamine immediately at 0 ° C. Complete complexation within 10 minutes. Separately, 852 mg (2.93 mM) of aldehyde 7b was dissolved in 1.5 ml of dichloromethane and added dropwise to the mixture obtained over 5 minutes. The reaction temperature is gradually warmed to room temperature, and the precipitation of triethylamine hydrochloride causes the reaction system to be non-uniform, so that the reaction is terminated by stirring well overnight.

After confirming by NMR spectrum that Compound 7b has been consumed completely, the solvent is distilled off completely under reduced pressure to obtain a crude solid residue. The residue is repeatedly triturated with anhydrous pentane to separate the desired enoltrimethylsilylether from the hydrochloride salt of triethylamine. By distilling off the pentane from the organic layer, 915 mg of the desired product IIIa2 '(2S ^* -t) is obtained as an almost pure crystalline residue. (Yield 86%)

NMR: δ ppm (CDCl ₃ ) 0.13 ~ 0.17 (two s, 9H), 1.0 ~ 2.35 (m, 9H), 3.03 (m, 1H), 4.28 (dd, J = 6Hz, J = 9Hz, 1H), 4.95 (m, 1H), 5.97 (dd, J = 6 Hz, J = 1.5 Hz, 1H), 7.43-7.63 (m, 3H), 7.77-7.97 (m, 2H)

Example 48

2 (S ^* )-2-exo-3-endo-2-formylfluoromethyl-3-benzenesulfonamidebicyclo [2,2,1,] pentane IIIa2 '(2S ^* -t)

365 mg (1 mmol) IIIa2 '(2S ^* -t) is dissolved in 1.5 mL dichloromethane or acetonitrile and 253 mg (1.48 mmol) crystalline fluorinated xenon is added once with stirring at 0 ° C. The reaction starts smoothly, generating gaseous xenon after a short induction period. After gas evolution has weakened, the reaction temperature is warmed to room temperature and left at room temperature for 2 hours to complete the reaction. The resulting pale yellow solution is then placed in cold water and extracted three times with ethyl acetate. The organic layer is dried over magnesium sulfate, distilled off under reduced pressure and an oily residue is obtained. The NMR spectrum of this residue shows the absorption of two characteristic aldehydes split at δ 9.51 and δ 9.68 with equal intensity, respectively, at the coupling constants of adjacent FH of 5.8 kPa and 6.5 kPa, respectively. This clearly shows that the desired fluorinated aldehyde has been produced in two isomeric mixtures.

The fluorinated aldehyde thus formed was separated by other small by-products such as IIIa2 '(2S'-t) or other unidentified products by silica gel column chromatography using toluene-ethyl acetate as the eluent, and 132 mg. The aldehyde IIIa2 '(2S ^* -t) of the oily phase is obtained. (Yield 45%)

The structure of aldehyde IIIa2 '(2S ^* -t) is clearly demonstrated by the following 19F-NMR spectrum.

19 F-NMR: δ C ₆ F ₆ (CDCl ₃ ) +31 ppm (dm, J = 43 Hz) and +38 ppm (0 ct., J = 43 Hz, J = 26 Hz, J = 6 Hz).

Compound IIIa2 '(2S ^* -t) is easily hydrolyzed by water or column chromatography, and is thus used for the next reaction without purification.

Example 49

Methyl 7- [2 (S ^* )-2-exo-3-endo-benzenesulfonamidebicyclo [2,2,1] pentan-2-yl]-(5z) -7-fluoro-pentenoic acid I a2 (2S ^* -t)

The yield used in the Wittig reaction is adjusted according to the well-known method of Corey as follows.

In a nitrogen atmosphere, 138 mg (3.4 mM) of sodium hydride suspension (in 60% mineral oil) was washed several times with anhydrous pentane, dried and 3.6 ml of dimethyl sulfoxide was added. Finally, the solution is completely dissolved in dimethyl sulfoxide at 60 to 70 ° C. to obtain a pale yellow solution of methylsulfinyl carboanion. The solution was cooled to 12 ° C. and about 846 mg (1.9 mM) of brominated 5- (methylpentenoic acid) triphenylphosphonium (commercially available) 3.6 ml of dimethyl sulfoxide solution was added immediately. The temperature of the solution is then slowly warmed to room temperature and held for 20 minutes to achieve the formation of illi. The color of the solution changes from pale yellow to quite reddish brown when the illi is produced. After 1.5 minutes of 175 mg (0.6 mM) fluorinated aldehyde solution of 1.5 ml dimethylsulfoxide was added to the above-mentioned illide solution maintained at 12 ° C, the temperature was gradually raised to room temperature. The color of the solution disappears immediately by the addition of aldehydes. After 30 minutes, the reaction solution was poured into cold saturated saline solution of hydrochloric acid, and extracted with ethyl acetate. After dimethyl sulfoxide is completely washed with cold water, the organic layer is dried over magnesium sulfate, filtered, and the solvent is distilled off under reduced pressure to obtain an oily preparation. It is dissolved in tetrahydrofuran without purification and esterified with diazomethane. Purification of the product by silica gel column chromatography using toluene-ethyl acetate as the elution solvent afforded 105 mg of the title compound easily. (Yield 43%)

It was confirmed that the physical constants of the obtained compound were the following target compounds.

NMR: δ ppm (CDCl ₃ ): 1.0 ~ 2.4 (m, 15H), 3.0 ~ 3.5 (m, 1H), 3.6 ~ 3.8 (2s, 3H), 4.0 ~ 5.0 (m, 1H), 5.8 ~ 5.8 (m , 3H), 7.40-7.70 (m, 3H), 7.80-8.10 (m, 2H)

IRνmax (CHCl ₃ ): 3600, 3375, 2950, 1730, 1580, 1440, 1320, 1160, 1095 cm ^-1

Mass (m / e): 409 (M), 389, 377, 358, 320, 315, 268, 248, 232, 91, 77, etc.

Example 50

Sodium 7- [endo-3-benzenesulfonamidebicyclo [2,2,1] hepto-exo-2-yl] -5-heptanate 44

100 mg of 10% palladium-carbon was added to a 5 ml solution of 200 mg of raw material 12a and water was added for 20 minutes. After the inorganic material is removed from the reaction solution, the filtrate is concentrated under reduced pressure. The residue was dissolved in 4 ml of water and lyophilized to give 189 mg of compound 44 as a white powder.

Elemental analysis: C ₂₀ H ₂₈ NSO ₄ Na · 0.7H ₂ O

Calculated (%): C; 58.00, H; 7.16, N; 3.38, S; 7.74

Found (%): C; 58.12, H; 7.02, N; 3.49, S; 7.57

IR (KBr) ν max: 3400, 3270, 1564, 1488, 1322, 1156, 1091.

¹ HNMR (D ₂ O + EXT · TMS) δ ppm: 1.5 ~ 2.67 (m, 21H), 3.30 (m, 1H), 8.07 (m, 3H), 8.63 (m, 2H)

Compounds of the present invention act as potent antagonists for the thromboxane A ₂ receptor, significantly inhibiting platelet aggregation due to thromboxane A ₂ . For this reason it is a compound that can be a useful antithrombotic antivascular contractor. In the representative compound, the platelet aggregation inhibitory effect in vitro is shown in the following experimental example.

[Test Materials and Test Methods]

In the carotid artery of a cohort rabbit (NIBS-JW, body weight 2.2-2.7kg), a 7.2 ml blood and 8 ml total amount of blood were collected in a plastic syringe containing 0.8 ml of 3.8% sodium citrate. The blood is placed in a plastic test tube, mixed inverted lightly and centrifuged at 20 ° C., 210 g for 10 minutes to obtain clear multi-platelet plasma [PRP (Platelet rich plasma)]. The remaining blood is centrifuged for 10 minutes at 20 ° C., 3000 rpm (about 1900 g) for 10 minutes to obtain platelet plasma [PPP (Platelet poor plasma)].

Dilute and adjust the platelet count of PRP to 50 ~ 55 × 10 ⁴ / μl with PPP and use it for the measurement of aggregation.

Platelet aggregation reaction is measured using A and meta (Model AUTO RAM-61, Ewha Electric Co., Ltd.) according to the method of warming (Born, GVR, Nature, 194,927-929 (1962)). That is, 400 μl of PRP adjusted to a platelet count of 50 to 55 × 10 ⁴ / μl was placed in a measuring cuvette, fixed in an agglomeration system, stirred at 37 ° C. for 1 minute (1200 rpm), and after preliminary warming, the test compound solution ( 50 μl when dissolved in physiological saline, 2 μl of the solution and 48 μl of physiological saline when soluble in dimethyl sulfoxide were added. After 2 minutes, adenosine 5'-diphosphate (ADP: PL-Biochemical Inc. .) Or 50 μl of collagen (Hormon-Chemie, Munchen) or arachidonic acid (sodium, sigma) is added to record the change in light transmittance caused by aggregation.

The aggregation rate of platelets sets the light transmittance of PRP and PPP to 0% and 100%, respectively, and makes the maximum light transmittance of PRP after addition of aggregating agent.

Percent aggregation inhibition is calculated from the ratio of the maximum aggregation rate of a test compound addition group to the maximum aggregation rate of a control group (carrier addition group).

[result]

The test results are shown in the table below. Prostaglandin (PG) E ₁ was used as standard.

TABLE 3a

(His 1)

* The compound number corresponds to the compound number in the examples.

TABLE 3b

(2) [Compound of Table 1)

* The compound number corresponds to the compound number in the examples.

The objective compound of the present invention showed strong inhibition on platelet aggregation by arachidonic acid, but did not show complete inhibition on primary aggregation by ADP.

The purpose of the present invention is to strongly inhibit platelet aggregation, hematopoiesis and contraction, and the application of the pharmacological effect is expected to be used for improvement of symptomatic treatment such as arteriosclerosis, myocardial infarction, acute myocardial ischemic angina, purifying machine shock, and sudden death. It is a compound.

The compound of interest of the present invention may also be obtained by oral administration or parenteral administration. Examples include tablets, capsules, pills, granules, fine granules, homemade, emulsions, suppositories, intravenous injections, intramuscular injections and subcutaneous injections. In formulating, a suitable carrier or excipient which is usually used is used. The compound of interest of the present invention is administered by oral administration about 10-800 mg per adult daily.

Claims (2)

Expression:

(Wherein R ₁ ′ is lower alkyl; R ₃ is hydrogen or methyl; R ₄ is hydrogen or fluorine; X is alkylene or alkenylene which may contain phenylene; Y is methylene or dimethylmethylene;

Is a single bond or a double bond; And are each represented by Formula Hal-SO ₂ -R ₂ Wherein R ₂ represents an alkyl, substituted or unsubstituted aryl, aralkyl or heteroaromatic hydrocarbon group; Hal represents halogen; respectively, and a deprotection reaction and / or salt formation reaction if necessary. Formula characterized in that

Wherein R ₁ is the same as R ₁ ′ or represents a hydrogen or salt forming group and R ₂ , R 3, R 4, X, Y and

Is the same as the above) method for producing a sulfonamide derivative or salt thereof expression

Wherein R2, R3, R4, and

Means the same as above)

Wherein Ar represents an aromatic hydrocarbon group; A represents alkylene or phenylene, respectively, and Hal and R ₁ ′ have the same meaning as described above. Formula characterized by reacting salt formation

Wherein R ₁ , R ₂ , R ₃ , R ₄ , X, Y and

Is the same as the above) method for producing a sulfonamide derivative or salt thereof.