KR790001695B1 - Process for the preparation of benz cycloamide derivatives - Google Patents

Abstract

Title compds. (I; R1 = H, C2-4 alkenyl or aralkyl; B = Et, Me, CH:C ; R4 = OR5 , N(R6)(R'); m+n 11) useful as antithrombosis agent, were prepd . Thus, (VI) was hydroysis to give (I-b) followed by the reaction with R5OH (A; R5 = C1-8 alkyl, ! cycloalkyl or aralkyl) to give (I) by alcohilysis of (VI) with (A) to give (I-a_, by the reaction of (I-a) with (III) to give (I-a), by the reaction of (I-a) with HN(R6)(R7) to give (I-c).

Description

Preparation of Benzcycloamide Derivatives

The present invention relates to a method for producing a novel benzcycloamide derivative represented by the following general formula having a useful effect in inhibiting platelet aggregation and useful as a preventive agent for thrombosis and embolism.

(여기서 R₂및 R₃는 서로 동일하거나 또는 상이한 것으로 각각 수소 또는 C₁－4알킬임), －CH=CH－이고; R₄는 OR₅(여기서 R₅는 수소, C_1－8알킬, 사이클로알킬 또는 아랄킬임) 또는

(여기서 R₆및 R₇은 동일하거나 또는 상이한 것으로 각각 수소, C_1－4알킬 또는 아랄킬이거나 또는 질소원자와 함께 5－ 또는 6－원 이종환식기 이 기는 또 질소원자, 산소원자 또는 유황원자를 함유할수 있음)를 형성할 수 있음)이고; m 및 n 는 각각 0 또는 양의 정수이고 m + n 는 11 이하이다.Wherein R ₁ is hydrogen, C _1-4 alkyl, C _2-4 alkenyl or aralkyl; B is —CH ₂ , —CH ₂ —CH ₂ — or —CH═CH—; A is

Wherein R ₂ and R ₃ are the same as or different from each other and are hydrogen or C _1-4 alkyl, respectively, —CH═CH—; R ₄ is OR ₅ where R ₅ is hydrogen, C _1-8 alkyl, cycloalkyl or aralkyl

Wherein R ₆ and R ₇ are the same or different and are hydrogen, C _1-4 alkyl or aralkyl, or a 5- or 6-membered heterocyclic group together with a nitrogen atom and also a nitrogen atom, an oxygen atom or a sulfur atom May contain); m and n are each 0 or a positive integer and m + n is 11 or less.

The present invention relates to a novel benzcycloamide derivative and a drug for treating thrombosis and embolism containing benzcycloamide derivative as an active ingredient.

In the past, many critical diseases have been treated by advanced treatment systems in the pharmaceutical and pharmaceutical industries. However, no effective and reliable treatment or treatment has been established for circulatory diseases, particularly ischemic diseases, arteriosclerosis and cerebral thrombosis. Since these circulatory diseases are often fatal, the development of reliable medicines to prevent and treat these critical diseases has been of great interest to many. The cause of these diseases is thought to be thrombosis as described in Hoving, T. [“platelet coalescence and aggregation” in thrombosis: measures (Manmen, EF, Anderson, GF & Barnhar, MI Eds.), P. 137 (1970); Bizzozero, J .: Virchows Arch., 90, 261 (1882); and Eberth, JC & Schimmelbusch, C .: Virchows Arch., 103, 39 (1886). .

A thrombus is a clot formed by the coagulation of blood flowing through a blood vessel, and the onset of the formation of a thrombus and a symptom due to a thrombus is called a thrombosis. Thrombus is useful for augmenting parts of damaged blood vessels and preventing continuous bleeding due to the action of platelets as triggers. On the other hand, a thrombus has a negative side that blocks blood vessels or blood vessels such as organs when it is transferred to another organ by blood transfer and causes embolus infarction. Therefore, thrombi formed in major organs, such as the heart, lungs, brain, etc., is accompanied by fatal effects such as cerebral infarction (embolism), myocardial infarction and pre-infarction.

In addition, in other diseases such as diabetes mellitus, malignancy, essential hypertension, heart valve disease, Basedow's disease, aorta syndrome mucous tumor, etc. Intrinsic properties such as coagulation acceleration and the like can be easily developed according to changes in the blood vessel wall. (Sozo Matsuoka, Factors on Bleeding and Thrombosis, p. 206, Published by Kinbara Publishing, 1969 and to Kanamegoda, “Thrombogenesis and Platelets,” Metabolism and Disease, Vol. 10, No. 2, p. 118, See 1973.)

Factors for thrombus formation include 1) changes in blood properties, 2) changes in blood transport, and 3) changes in blood vessel walls. (See Tadashima and Ketsueki To Myakkan (blood and blood vessels), Vol. 1, No. 4, pp 11-24, 1970). Normally flowing blood maintains a moderate dynamic equilibrium between coagulation and separation of blood, as well as coagulation and thrombosis. Thrombosis occurs when this equilibrium is lost due to stress or abnormal physiological conditions.

In recent years, modern foods tend to cause atherosclerosis diseases, and as a result, it is possible to increase the occurrence of thrombosis. Under these circumstances, the development of chemotherapy for preventing and treating thrombosis is greatly desired. For thrombosis, it is more effective to prevent the formation of tromby by inhibiting further development of tromby. Diseases caused by concomitantly formed trombi can be ameliorated by administering a trombin alleviator in combination with treatment of the underlying disease.

As a result of various studies on the development of effective reagents for the prevention and treatment of thrombosis, 5-(-2-hydroxy-3-tert-butylamino) -propoxy-3,4-dihydro having the following structural formula Carbostyryl

It has been found to be able to uniquely inhibit platelet aggregation of blood at low concentrations and to be extremely effective for the prevention and treatment of thrombosis when the compound is administered orally or intravenously to mammals including humans (Japanese Patent Publication No. 125,930). / 73).

It is an object of the present invention to provide novel benzcycloamide derivatives useful as preventive agents for thrombosis and embolism.

Another object of the present invention is to provide a drug containing a novel benzcycloamide derivative as an active ingredient.

Other objects and advantages of the present invention will become apparent from the following specification.

According to the present invention, a novel benzcycloamide derivative represented by the following general formula is provided.

(여기서 R₂및 R₃는 서로 동일하거나 상이한 것으로 각각 수소 또는 C₁－4알킬임) 또는 －CH=CH－이고; R₄는 －OR₅(여기서 R₅는 수소, C₁－8알킬, 사이클로알킬 또는 아랄킬임) 또는

(여기서 R₆및 R₇는 서로 동일하거나 또는 상이한 것으로 각각 수소, C₁－4알킬 또는 아랄킬이거나 또는 질소원자와 함께 5－또는 6－원 이종환식기(이 기는 질소원자, 산소원자 또는 유황원자를 함유 할 수 있음)를 형성할 수 있음)이고; m 및 n는 각각 0 또는 양의 정수이고 m + n는 11 이하이다.Wherein R ₁ is hydrogen, C _1-4 alkyl, C _2-4 alkenyl or aralkyl; B is —CH ₂ —, —CH ₂ —CH ₂ , or —CH═CH—; A is

Wherein R ₂ and R ₃ are the same or different from each other and are hydrogen or C _1-4 alkyl, respectively, or —CH═CH—; R ₄ is —OR ₅ , wherein R ₅ is hydrogen, C _1-8 alkyl, cycloalkyl or aralkyl

Wherein R ₆ and R ₇ are the same or different from each other and are hydrogen, C _1-4 alkyl or aralkyl or a 5- or 6-membered heterocyclic group together with a nitrogen atom (this group being a nitrogen atom, an oxygen atom or a sulfur atom May contain); m and n are each 0 or a positive integer and m + n is 11 or less.

The novel benzcycloamide derivative represented by the general formula (I) has excellent platelet aggregation-inhibiting action and is useful as a preventive agent for thrombosis and embolism. It has also been found that the benzcycloamide derivative represented by the general formula (I) has an anti-inflammatory effect.

In formula (I), R ₁ is a hydrogen atom, a lower alkyl group such as methyl, ethyl, propyl or butyl group, a lower alkenyl group such as allyl or crotyl group or an aralkyl group such as benzyl or phenethyl group. In A of Formula (I), R ₂ and R ₃ are each hydrogen atom or lower alkyl group such as methyl, ethyl, propyl or butyl group. In addition, R ₄ to R ₅ of formula (I) are hydrogen atoms or straight or branched chain alkyl groups such as methyl, ethyl, propyl, butyl, amyl, hexyl or octyl groups, or aralkyl groups such as benzyl or phenethyl groups, and R ₆ and R ₇ may be the same or different from each other and may be an aralkyl group such as a lower alkyl group such as methyl, ethyl, propyl or butyl group, benzyl or phenethyl group or together with a nitrogen atom to form a 5- or 6-membered heterocyclic group This group may also contain nitrogen, oxygen or sulfur atoms, such as piperidyl, morpholinyl, piperazyl or thiazolyl groups.

일 때에, R₂및 R₃가 결합되어 있는 것에서 탄소원자는 비대칭탄소원자일수 있으므로 이 유도체의 광학이성체(di－, d－및 1－)가 존재할 수 있다. 또한, A가 －CH=CH－일 때에, 이 유도체의 기하이성체(시스－ 및 트란스－)가 있다.In the benzcycloamide derivative of the present invention, A is

In this case, since the carbon atom may be an asymmetric carbon atom in which R ₂ and R ₃ are bonded, optical isomers (di-, d- and 1-) of this derivative may exist. Moreover, when A is -CH = CH-, there exist geometric isomers (cis- and trans-) of this derivative.

Benzcycloamide derivatives represented by general formula (I) can be prepared by the method according to the scheme shown below.

In the above structural formulas, A, B, R ₁ , R ₆ , R ₇ , m and n are as described above, and R ₅ ′ is C 1 _/SB>.SB>8 alkyl, cycloalkyl or aralkyl , X is halogen and M is an alkylmetal.

First, the compound represented by general formula (I-b) can be produced by hydrolyzing the benzcycloamide derivative represented by general formula (VI). The hydrolysis reaction can be carried out in the presence of a catalyst as a known method. As the catalyst, a conventional catalyst used in a normal hydrolysis reaction can be used. Specific examples of such catalysts include basic compounds such as sodium hydroxide, potassium hydroxide and barium hydroxide; mineral acids such as sulfuric acid, nitric acid, hydrochloric acid and phosphoric acid; Aromatic sulfonic acids such as naphthalenesulfonic acid and p-toluenesulfonic acid; Alkyl sulfonic acid like ethanesulfonic acid is mentioned.

In general, the hydrolysis reaction is carried out in a solvent. As a solvent, the conventional solvent used in normal hydrolysis reaction can be used. Specific examples of such solvents include alcohols such as methanol, ethanol, propanol, butanol and ethylene glycol; Ketones such as acetone and methyl ethyl ketone; And ethers such as dioxane and diethylene glycol monomethyl ether (monoglyme) and fatty acids such as acetic acid and propionic acid. The temperature of the electrical reaction is usually from room temperature to 200 ° C., preferably from 50 ° C. to 150 ° C., and the reaction time is from 3 to 48 hours, preferably from 3 to 30 hours.

If necessary, the compound represented by general formula (I-b) can be converted into the compound of general formula (I-a) by esterification with an alcohol represented by general formula R _{5 '} OH. In the alcohol represented by the general formula R _{5 '} OH, another starting material used in the esterification reaction, R ₅ ' is a linear or branched alkyl group such as methyl, ethyl, propyl, butyl, amyl, hexyl or octyl group, or benzyl Aralkyl groups like the phenethyl group. The reaction between the compound of the general formula (I-b) and the alcohol of the general formula R _{5 '} OH is carried out under a commercial esterification reaction. This reaction is carried out in the presence of a catalyst. As a catalyst, the conventional catalyst used in normal esterification reaction can be used. Specific examples of such a catalyst include hydrochloric acid gas; Inorganic acids such as concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride and perchloric acid; Organic acids such as trifluoroacetic acid, trifluoromethanesulfonic acid, naphthalenesulfonic acid, P-toluenesulfonic acid, benzenesulfonic acid and ethanesulfonic acid; Acid anhydrides such as trifluoromethanesulfonic anhydride and trichloromethanesulfonic anhydride; Thionyl chloride; Acetone dimethyl acetal; And acidic ion exchange resins. The above reaction can be carried out in the presence or absence of a solvent.

This solvent is a conventional solvent used in normal esterification reaction. Specific examples of such a solvent include aromatic hydrocarbons such as benzene, toluene and xylene; Halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and carbon tetrachloride; And ethers such as diethyl ether, tetrahydrofuran, dioxane and ethylene glycol monomethyl ether, and the like.

Moreover, it is advantageous to perform this reaction using a drying agent, such as anhydrous calcium chloride, anhydrous copper sulfate, anhydrous calcium sulfate, or phosphorus pentoxide. The ratio of the compound represented by general formula (I-b) and the alcohol represented by general formula R _{5 '} OH can be appropriately selected. However, when the reaction is carried out in the absence of a solvent, the alcohol is used in an excess amount in the case of the reaction in the presence of a solvent, where the alcohol is 1 to 5 times the mole number of the compound of the general formula (I-b), Is used in an amount of 1 to 2 times. Although reaction temperature is not specifically limited in an electrical reaction, Usually, it is -20 degreeC-200 degreeC, Preferably it is 0 degreeC-150 degreeC.

의 아민과 반응시켜 일반식(I－c)으로 표시되는 화합물을 얻는다. 이 반응은 용매존재하에서 행할 수 있다. 이와같은 용매의 예로 물, 메타놀 및 에타놀이 있다. 반응온도 및 반응시간 조건들은 특별히 한정되어 있지 않지만, 경우에 따라 적당히 선택될 수 있다. 그러나, 일반적으로, 이 반응은 실온내지 100℃사이의 온도에서, 적합하기로는 실온에서 수시간동안 행한다. 이 반응에서, 아민은 등몰량내지는 과잉량으로 사용한다. 일반적으로, 그러나 이 아민은 지방산에스테르유도체의 몰수에 대해 5∼10배의 양으로 사용한다.If necessary, the final compound of the present invention represented by general formula (I-a) may be converted into a compound represented by general formula (I-c). Thus, the compound represented by general formula (I'-a) is represented by general formula

It reacts with the amine of to obtain the compound represented by general formula (I-c). This reaction can be carried out in the presence of a solvent. Examples of such solvents are water, methanol and ethanol. The reaction temperature and reaction time conditions are not particularly limited, but may be appropriately selected depending on the case. In general, however, this reaction is carried out at temperatures between room temperature and 100 ° C., suitably for several hours at room temperature. In this reaction, the amine is used in an equimolar or excess amount. Generally, however, this amine is used in an amount of 5 to 10 times the number of moles of fatty acid ester derivative.

Optionally, the benzcycloamide derivative represented by general formula (I-a) may be obtained by alcoholizing the benzcycloamide derivative represented by general formula (VI) with an alcohol represented by general formula R _{5 '} OH and then adding water. This mixture can then be prepared by acid hydrolysis for 10 minutes at as low a temperature as possible, i.e. The reaction of the benzcycloamide derivative represented by the general formula (VI) with the alcohol represented by the general formula R _{5 '} OH is carried out under commercial alcohol decomposition reaction conditions. As the catalyst, a conventional catalyst used in a normal alcohol decomposition reaction can be used. Specific examples of such a catalyst include hydrogen chloride; Mines such as concentrated sulfuric acid, phosphoric acid, and nitric acid; And organic acids such as benzenesulfonic acid, p-toluenesulfonic acid and ethanesulfonic acid. The reaction is carried out in the presence or absence of a solvent. As a solvent, the conventional solvent used in normal alcohol decomposition reaction can be used. Specific examples of such solvents include ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diethylene glycol dimethyl ether (diglyme); Aromatic hydrocarbons such as benzene, toluene and xylene; and aliphatic hydrocarbons such as n-pentane and n-hexane. The ratio of the compound represented by the general formula (VI) and the alcohol represented by the general formula R _{5 '} OH can be appropriately selected within a wide range. In general, however, it is preferable to use the latter in an amount of 1 to 5 times and preferably 1 to 2 times the number of moles of the former. The reaction is carried out at a temperature of -50 ° to 100 ° C, preferably -20 ° to 50 ° C, for 1 to 24 hours, preferably 1 to 48 hours.

In addition, the benzcycloamide derivative represented by the general formula (I-a) may be prepared by reacting the halogenated fatty acid ester represented by the general formula (III) with the hydroxybenzcycloamide derivative represented by the general formula (II). . The fatty acid ester derivative of general formula (III) used here as a starting material is a known compound.

The reaction between the hydroxybenzcycloamide derivative represented by the general formula (II) and the halogenated fatty acid ester derivative represented by the general formula (III) is carried out under conventional dehydrohalogenation reaction conditions. Various basic compounds can be used as a dehalogenation agent. Specific examples of this dehalogenation agent include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and silver carbonate; Alkali metals such as sodium and potassium; Alcoholates such as sodium methylate and sodium ethylate; Organic bases such as triethylamine, pyridine and N, N-dimethylaniline. This reaction can be carried out in the presence or absence of a solvent. As the solvent, any solvent in which it does not participate in the reaction can be used. Specific examples of such solvents include alcohols such as methanol, ethanol, propanol, butanol and ethylene glycol; Ethers such as dimethyl ether, tetrahydrofuran dioxane and monoglyme; Ketones such as acetone and methyl ethyl ketone; Aromatic hydrocarbons such as benzene, toluene and xylene; Esters such as methyl acetate and ethyl acetate; And dipolar neutral solvents such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and hexamethylphosphoramide (HMPA). This reaction is also advantageously carried out in the presence of a metal iodide such as sodium iodide or potassium iodide.

The proportion of the compounds represented by the general formulas (II) and (III) can be appropriately determined. Normally, however, the latter is used in an amount of 1 to 5 times and preferably 1 to 2 times the number of moles of the former. Although reaction temperature is not specifically limited, Usually, it is room temperature to 200 degreeC, Preferably it is 50 degreeC-150 degreeC, The reaction time is generally 1-30 hours, Preferably it is 1-15 hours.

The benzcycloamide derivative represented by the general formula (VI) reacts the hydroxybenzcycloamide derivative represented by the general formula (II) with a compound of the general formula (V) to form a compound represented by the general formula (IV). This product can then be obtained by reacting with a metal cyanide represented by the general formula MCN. The hydroxybenzcycloamide represented by general formula (II) is a known compound. Alkyldihalides represented by the general formula (V) used as other starting materials in the reaction are known compounds.

The reaction between the hydroxy benzcycloamide represented by general formula (II) and the compound represented by general formula (V) is carried out under conventional dehydrohalogenation reaction conditions. As the dehalogenation agent, various basic compounds can be used. Specific examples of this dehalogenation agent include inorganic bases such as sodium hydroxide, potassium hydroxide, potassium hydrogencarbonate and silver carbonate; Alkali metals such as sodium and potassium; Alcoholates such as sodium methylate and sodium ethylate, organic bases such as triethylamine, pyridine and N, N-dimethylanyl and the like. This reaction can be carried out in the presence or absence of a solvent. As the solvent, any solvent can be used as long as it does not participate in the reaction. Specific examples of such a solvent include alcohols such as methanol, ethanol, propanol, butanol and ethylene glycol; Ethers such as dimethyl ether, tetrahydrofuran, dioxane, monoglyme or diglyme; Ketones such as acetone and methyl ethyl ketone; Aromatic hydrocarbons such as benzene, toluene and xylene; Esters such as methyl acetate and ethyl acetate; And bipolar neutral solvents such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and hexamethylphosphoramide (HMPA). This reaction is advantageously carried out in the presence of a metal iodide such as sodium iodide or potassium iodide. The proportion of the compounds represented by the formulas (II) and (V) can be appropriately determined. However, the latter is usually used in an amount of 1 to 5 times and suitably 1 to 2 times the number of moles of the former. Although reaction temperature is not specifically limited, Usually, it is room temperature to 200 degreeC, Preferably it is 50 degreeC-150 degreeC, The reaction time is generally 1-30 hours, Preferably it is 1-15 hours.

Next, the compound represented by formula (IV) is reacted with a metal cyanide represented by a general formula such as sodium cyanide, potassium cyanide, silver cyanide or copper cyanide, in the presence or absence of a solvent. In general, this reaction is preferably carried out in the presence of a solvent. As the solvent, any solvent can be used as long as it does not participate in the reaction. Specific examples of such a solvent include water; Methanol, ethanol; Alcohols such as protanol and ethylene glycol; Ketones such as acetone and methyl ethyl ketone; Ethers such as dioxane, tetrahydrofuran, monoglyme and diglyme; Aromatic hydrocarbons such as benzene, toluene and xylene; Bipolar neutral solvents such as M, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and hexamethylphosphoramide (HMPA); Liquid hydrogen cyanide; And liquid ammonia. This reaction is advantageously carried out in the presence of a metal iodide such as sodium iodide or potassium iodide. The proportion of the compounds represented by the formulas (IV) and MCN may be appropriately selected. However, it is usually preferable to use the latter in an amount of 1 to 5 times and suitably 1 to 2 times the number of moles of the former. Although reaction temperature is not specifically limited, Usually, room temperature is 250 degreeC, Preferably it is 50 degrees-150 degreeC, The reaction time is 30 minutes-30 hours, Preferably it is 30 minutes-15 hours.

The benzcycloamide derivative represented by the general formula (VI) may be prepared by reacting the benzcycloamide derivative represented by the general formula (II) with a compound represented by the general formula (VII). Cyano compounds represented by the general formula (VII) used as other starting materials in the reaction are known compounds. The reaction between the hydroxybenzcycloamide represented by the general formula (II) and the compound represented by the general formula (VII) is carried out under conventional dehydrohalogenation reaction conditions. As the dehalogenation agent, various basic compounds can be used. Specific examples of this dehalogenation agent include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and silver carbonate; Alkali metals such as sodium and potassium; Alcoholates such as sodium methylate and sodium ethylate; and organic bases such as triethylamine, pyridine and N, N-dimethylaniline. This reaction can be carried out in the presence or absence of a solvent. As the solvent, any solvent can be used as long as it is not involved in the reaction. Specific examples of such solvents include alcohols such as methanol, ethanol, propanol, butanol and ethylene glycol; Ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme and diclim; Ketones such as acetone and methyl ethyl ketone; Aromatic hydrocarbons such as benzene, toluene and xylene; Esters such as methyl acetate and ethyl acetate; And bipolar neutral solvents such as N, N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and hexamethylphosphoramide (HMPA). This reaction is advantageously carried out in the presence of metal iodides such as sodium iodide and potassium iodide. The proportion of the compounds represented by the general formulas (II) and (iii) can be appropriately determined. However, the latter is usually used in an amount of 1 to 5 times and suitably 1 to 2 times the number of moles of the former. Although reaction temperature is not specifically limited, Usually, room temperature-200 degreeC, Preferably it is 50 degrees-150 degreeC, Reaction time is 1-30 hours generally, Preferably it is 1-15 hours.

In addition, the compound represented by formula (IV) may be prepared by selectively reacting the hydroxybenzcycloamide derivative represented by formula (II) with acrylonitrile. This reaction is usually carried out in a solvent in the presence of a catalyst.

Examples of catalysts include sodium methylate, sodium ethylate, Triton B. Sodium hydroxide, potassium hydroxide and potassium carbonate. Examples of the solvent include benzene, dioxane, pyridine and acrylonitrile. Among these solvents, acrylonitrile is most suitable. In the above reaction, acrylonitrile is used in an amount of 1 to several times the number of moles of the hydroxybenzcycloamide derivative. Although reaction can be performed at room temperature to 150 degreeC, it is generally suitable to carry out between 50 degreeC-100 degreeC.

The benzcycloamide derivative represented by general formula (I-a) obtained by the present invention can be converted into the corresponding free carboxylic acid represented by general formula (I-b) by hydrolysis if necessary.

The above hydrolysis reaction is usually carried out by a known method in the presence of a catalyst. As a catalyst, the conventional catalyst used in normal hydrolysis reaction is used. Specific examples of such catalysts include basic compounds such as sodium hydroxide, potassium hydroxide and barium hydroxide; Mines such as sulfuric acid, hydrochloric acid and nitric acid; Organic acids such as acetic acid and aromatic sulfonic acid. In general, the reaction is carried out in the presence of a solvent. As a solvent, the conventional solvent used in normal hydrolysis reaction can be used. Specific examples of such a solvent include water, methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, dioxane, ethylene glycol and acetic acid. Although reaction temperature is not specifically limited in the above reaction, Room temperature-200 degreeC is preferable.

Benzcycloamide derivatives represented by the following general formula obtained by the present invention

(Wherein A, B, R ₅ ′, m and n are the same as above)

If necessary, the benzcycloamide derivative of the general formula (I-d) may be substituted with a general formula R _{1 '} X (wherein R ₁ ' is a C _1-4 alkyl, C _2-4 alkenyl or aralkyl group, and X is By reacting with a halogenated compound represented by

Wherein A, B, R ₅ ′, R ₁ ′, m and n are the same as above.

It can be converted into benzcycloamide derivative represented by. Thus, the benzcycloamide derivative represented by general formula (I-d) is formed of an alkali metal salt at its 1-position nitrogen and then concentrated with a halogenated compound of general formula R _{1 '} X to form a benz cycloamide derivative (I-e). Cycloamide derivatives can be obtained. In carrying out the above reaction, the alkali metal salt of compound (I-d) is a suitable solvent, for example, a benzene solvent (benzene, toluene or xylene) at 0 ° to 200 ° C, suitably at room temperature to 50 ° C. , n-hexane, cyclohexane, ether solvents (diethyl ether, 1,2-dimethoxyethane or dioxane) or dipolar neutral solvents (DMF, HMPA or DMSO), suitably DMF, DMSO or HMPA It is prepared by concentrating with an alkali metal compound such as sodium hydrogen compound, potassium hydrogen compound, sodium azide, sodium metal or potassium metal. Thus the alkali metal salt of the compound (I-d) and concentrated to reaction with the compound represented by the general formula R _1'X is successfully performed in the time to react at room temperature in a solvent such DMF examples of these two materials. In this case, the amount of the alkali metal compound is 1 to 5 times and suitably 1 to 3 times the number of moles of the compound of formula (I-d), while the amount of the halogenated compound is the number of moles of the compound of formula (I-d). It is 1 to 5 times with respect to, and 1 to 2 times suitably.

In addition, the following general formula obtained by the present invention

Wherein A, R ₅ , m and n are as defined above and R ₁ ″ is a hydrogen atom; a lower alkyl group such as methyl, ethyl, propyl or butyl group or an aralkyl group such as benzyl or phenethyl group)

Benzcycloamide derivative represented by the following general formula as needed

Wherein A, R ₁ ″, R ₅ , m and n are as defined above

It can be converted by the reduction reaction to the corresponding 3,4-dihydroxybenzcycloamide derivative represented by. The reduction reaction of the compound represented by the general formula (I-f) is usually carried out by hydrogenating the aforementioned compound in a suitable solvent in the presence of a conventional catalyst. Catalysts used in this case include, for example, platinum catalysts such as platinum wire, platinum rods, platinum sponges, platinum black powder, platinum oxides or platinum colloids; Palladium sponge, palladium black, palladium oxide, palladium barium sulfate, palladium carbonate, palladium carbon, palladium catalyst such as palladium silica gel or colloidal palladium, asbestos-adhesive rhodium, iridium, colloidal dium, ruthenium or colloidal iridium Platinum group metal catalysts such as; Nickel catalysts such as reduced nickel, nickel, oxide, la-ni nickel, Urushibara nickel, nickel formed by pyrolysis of nickel formate, or nickel borate; Cobalt catalysts such as reduced cobalt, la-nicobalt or urushibara cobalt; Iron catalysts such as reduced iron or lani iron; Copper catalysts such as reduced copper, la-ni copper or Ullmann copper; Or other metal catalyst such as zinc. In addition, the solvent used in this reaction may be, for example, lower alcohols such as methanol, ethanol or isopropanol; Water, acetic acid; Acetate esters such as methyl acetate or ethyl acetate; Ethylene glycol; Diethyl ether; Ethers such as tetrahydrofuran or dioxane; Toluene; Aromatic hydrocarbons such as benzene or xylene; Cycloalkanes such as cyclopentane or cyclohexane; Or n-alkanes such as n-hexane or n-pentane. This reaction is successfully carried out at atmospheric hydrogen pressure or preferably at a boiling point of 1 to 20 atm and room temperature to the solvent used, and suitably at room temperature to 100 ° C.

In addition, the 3,4-dihydrobenzcycloamide derivative represented by the following general formula obtained by the present invention

Wherein A, R ₁ , R ₅ , m and n are as defined above.

If necessary, by the dehydrogenation reaction,

Wherein A, R ₁ , R ₅ , m and n are as defined above.

It can be converted into benzcycloamide derivative represented by. The dehydrogenation reaction of compound (I-h) is performed using an oxidizing agent in a suitable solvent. The oxidizing agent used in the above reaction is benzoquinone such as DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) or chloranyl (2,3,5,6-tetrachlorobenzoquinone); Hydrogenation catalysts such as selenium dioxide, palladium carbon, palladium black, platinum oxide or la-ni nickel; Or brominating agents such as NBS (N-bromosuccinimide) or cancellation; In addition, the solvent used in the above reaction may be an ether such as dioxane, tetrahydrofuran, methoxyethanol or dimethoxyethane; benzene; Aromatic hydrocarbons such as toluene, xylene or cumene; And dipolar neutral solvents such as halogenated hydrocarbon DMF such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride, DMSO, or HMPA. The reaction temperature is in the range of room temperature to 300 deg. C, preferably 50 deg. C to 200 deg. C, and the reaction time is 1 to 48 hours, preferably 1 to 20 hours. The ratio of the oxidizing agent used is 1 to 5 times, preferably 1 to 2 times the molar number of the compound (I-i) in the case of benzoquinone or the brominating agent, and is usually the catalytic amount in the case of the hydrogenation catalyst.

All benzcycloamide derivatives represented by the general formula (1) described above are compounds having excellent platelet aggregation-inhibiting effect and useful as agents for preventing thrombosis. The platelet aggregation inhibitory effect and toxicity (LD ₅₀ mg / kg) of the representative derivatives among the novel benzcycloamide derivatives obtained by the present invention are shown below.

[Notified Compound:]

[Table 1]

[Table 2]

[Table 3]

The flocculation inhibiting effect was measured using an AG-II aggregometer (manufactured by Bryston Manufacturing Co.). Blood samples were taken from rabbits as a mixture of sodium citrate and volume ratio 1: 9 of whole blood and centrifuged at 1,000 rpm for 10 minutes to obtain platelet-rich plasma (PRP). The resulting PRP was isolated and the remaining blood sample was further centrifuged at 3,000 rpm for 15 minutes to obtain low platelet plasma (PPP).

The number of platelets in PRP was calculated by the Brecher-Clonkite method, PRP was diluted with PPP, and PRP containing 300,000 / mm ² amount of platelets for adenosine diphosphate (ADP) -induced coagulation test. A PRP sample containing a sample and a platelet amount of 450,000 / mm ² for collagen-induced coagulation test was prepared.

Then, 0.01 ml of a solution of the test compound having a measured concentration (shown in the table below) was added to 0.6 ml of the PRP sample obtained above, and the mixture was incubated at a temperature of 37 ° C. for 1 minute. Then 0.07 ml of ADP or collagen soln. Was added to this mixture. This mixture was then subjected to a transmission determination test and the change in the transmittance of this mixture was recorded using an agometer at agitation speed of 1,100 rpm. In this test, Auren Beronal buffer (pH 7.35) was used to prepare a solution of ADP collagen and test compound. ADP was adjusted to a concentration of 7.5 10 ⁻⁵ M, and the collagen solution was prepared by grinding 100 mg of collagen into 5 ml of the above buffer, and the obtained supernatant was used as a collagen inducer. Adenosine and acetylsalicylic acid were used as controls for the ADP-induced coagulation test and the collagen-induced coagulation test, respectively. The effect of inhibiting aggregation was determined by Percent inhibition (%) against the aggregation ratio of the control. The aggregation rate can be calculated by the following equation.

here,

"A" is the optical desiccation concentration of PRP and "b" is the blackening concentration of PRP combining the compound and coagulation inducer.

"C" is the blackening concentration of PPP.

The benzcycloamide compound of the present invention can be administered to animals, mammals and humans in dosage unit form in itself or in combination with conventional nutrient carriers. Oral dosage forms such as tablets, capsules, powder granules, and oral solutions in suitable dosage unit forms; Sublingual and buccal administration forms; And parenteral dosage forms useful for subcutaneous, intramuscular or intravenous administration. In order to achieve the desired effect, the dosage of the active ingredient may vary within a wide range of about 0.1 mg to about 100 mg per kg of body weight daily. Each granting unit may contain about 1 to 500 mg of active ingredient in combination with a pharmacological carrier. Such a suitable dosage can be administered 1 to 4 times a day.

In the preparation of solid compositions such as tablets, the active ingredient may be mixed with pharmacological bases such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic and the like. Tablets may be coated or otherwise treated with sucrose or other suitable material to provide sustainability and to continuously release a metered amount of drug. The preparation of the capsule is obtained by mixing the active ingredient with an inert pharmacological filler or diluent and then filling the resulting mixture into a hard gelatin mixture or soft capsule. Syrups or elixirs may contain sucrose or sweeteners, methyl- and propylparabens as preservatives, and suitable colorants and seasonings together with the active ingredient.

Non-oral solutions are prepared by dissolving the active ingredient in a sterilized liquid base. Suitable bases are water or brine. A composition having the desired transparency, stability, and parenteral application is prepared by dissolving about 0.1 mg to 3 g of the active ingredient in a non-volatile liquid-polyethylene glycol mixture having a molecular weight of 200 to 1,500 that is soluble in both water and organic liquid. do. It is advantageous to combine the resulting solution with a lubricant such as sodium carboxymethyl cellulose dragon, methyl cellulose, polyvinylpyrrolidone or polyvinyl alcohol. The solution may also contain fungicides and fungicides such as parabens, benzyl alcohol, phenol or thimerosal and the like. If desired, isotonic, local anesthetics, stabilizers or buffers such as sugar or sodium chloride may also be added thereto. To further increase the stability, parenterals can be removed from the water by freeze-drying methods, which are fully known in the art. Powder formed by freeze-drying can be converted just before use.

[Formulations of Tablets]

1,000 oral tablets each containing 5 mg of 6- (1-ethoxycarboxoxy) propoxy-3,4-dihydrocarbobostyryl were prepared from the following components.

(a) 5 g of 6- (1-ethoxycarboxy) propoxy-3,4-dihydrocarbobostyryl

(b) lactose, jay. blood. 50 g

(c) Coon Starch, J. blood. 25 g

(d) Crystalline cellulose, J. blood. 25 g

(e) methylcellulose, j. blood. 1.5 g

(f) magnesium stearate. second. blood. 1 g

Said 6- (1-ethoxy carboxy) propoxy-3,4-dihydro carabostyryl, lactose, cornon starch, and crystalline cellulose were fully mixed together. The resulting mixture was ground by adding 5.0% aqueous solution of methyl cellulose. The particles were carefully dried after passing through a 200 sieve. The dried particles were passed through a 200 mesh sieve, mixed with magnesium stearate and compressed into tablets.

[Formulation of Capsule]

Two oral hard gelatin capsules, each containing 10 mg of 6- (1-ethoxycarboxoxy) propoxy-3,4-dihydrocarabostyryl, each 10 mg, were prepared with the following components.

(a) 10 g of 6- (1-ethoxycarboxoxy) propoxy-3,4-dihydrocarbobostyryl

(b) lactose, jay. blood. 80 g

(c) starch, jay. blood. 30 g

(d) talc, jay. blood. 5 g

(e) magnesium stearate. second. blood. 1 g

The above components were finely ground, and the resulting particles were sufficiently mixed to obtain a uniform mixture. This mixture was then filled into simple gelatin capsules of suitable size to prepare capsules for oral administration.

[Formulation of injection]

A sterile aqueous solution suitable for parenteral use was prepared with the following ingredients.

(a) 1 g of 6- (1-ethoxycarboxoxy) propoxy-3,4-dihydrocarbobostyryl

(b) polyethylene glycol 4,000, j. blood. 0.3 g

(c) 0.9 g sodium chloride

(d) polyoxyethylene derivatives of sorbitan monooleate, j. blood. 0.4g

(e) sodium metabisulfite 0.1g

(f) methyl-parabens, J .; blood. 0.18 g

(g) Propyl-parabens, E. blood. 0.02

(h) 100 ml of distilled water sufficient to make an injection solution

The mixture containing paraben, sodium metabisphosphite and sodium chloride was dissolved in about 0.5 times the volume of distilled water for injection with stirring at 80 ° C. The resulting solution was cooled to 40 DEG C or lower, and the above-mentioned active ingredient, followed by polyoxyethylene derivative of polyethylene glycol 4,000 and sorbitan monooleate, was dissolved in this solution. Subsequently, distilled water for injection was added to this solution to adjust the final solution, followed by sterilization by sterile filtration through a suitable filter paper. 1 ml of the solution thus prepared contains 10 mg of 6- (1-ethoxycarboxoxypropoxy-3,4-dihydrocarabostyryl as an active ingredient.

Example 1

1.64 g of 5- (2′-cyanoethoxy) -3,4-dihydrocarabostyryl was added to 50 ml of concentrated hydrochloric acid, and the resulting mixture was refluxed for 5 hours. Thereafter, the reaction solution was cooled to deposit crystals. The precipitated crystals were collected by filtration and then recrystallized with water to obtain 1.5 g of 5- (2 ′)-carboxyoxytoxy-3,4-dihydrocarabostyryl as colorless needles. m.p. 221-224 캜.

Example 2

1 g of 6- (2′-cyanoethoxy) -3,4-dihydro carbostyryl was added to 30 ml of concentrated hydrochloric acid, and the resulting mixture was refluxed for 4 hours. Thereafter, the reaction solution was cooled to deposit crystals. The precipitated crystals were collected by filtration, and then recrystallized with water to obtain 0.2 g of 6- (2′-carboxyoxy-3-dihydrocaabostyryl as colorless needles. M.p. 188 to 190.5 ° C.

Example 3

0.4 g of 7- (2′-cyanoethoxy) -3,4-dihydrocarabostyryl was added to 25 ml of concentrated sulfuric acid, and the resulting mixture was refluxed for 4 hours. Thereafter, the reaction solution was concentrated under reduced pressure until drying, and the concentrate was recrystallized from water to obtain 0.2 g of 7- (2′-carboxyoxytoxy) -3,4-dihydrocarabostyryl as colorless scale crystals. . m.p. 161-164.5 degreeC.

Example 4

1 g of 8- (2′-cyanoethoxy) -3,4-dihydrocarabostyryl was added to 25 ml of concentrated hydrochloric acid, and the resulting mixture was refluxed for 5 hours. Thereafter, the reaction solution was cooled to deposit crystals. The deposited crystals were collected by filtration and then recrystallized with water to obtain 0.7 g of 8- (2′-carboxyoxytoxy) -3,4-dihydrocarabostyryl as colorless needles. m.p. 247-248.5 degreeC.

Example 5

18 g of N-ethyl-5 (3′-cyano) propoxy-3,4-dihydrocarabostyryl was added to 250 ml of a 2N-sodium hydroxide aqueous solution, and the resulting mixture was refluxed with stirring for 17 hours. Thereafter, the reaction solution was cooled and acidified by adding hydrochloric acid to deposit crystals. The precipitated crystals were collected by filtration, washed with water and recrystallized with ethyl acetate to give 14 g of N-ethyl-5- (3′-carboxy) propoxy-3,4-dihydro carbostyryl as colorless needle-like crystals. Got. m.p. 96-98 degreeC.

Example 6

18 g of 6- (3′-cyano) propoxy-3,4-dihydrocarabostyryl was added to 300 ml of a 2N-potassium hydroxide aqueous solution, and the resulting mixture was refluxed with stirring for 18 hours. Thereafter, the reaction solution was cooled and then acidified by adding hydrochloric acid to deposit crystals. The deposited crystals were collected by filtration, washed with water and recrystallized with methanol to give 17.5 g of 6- (3′-carboxy) propoxy-3,4-dihydrocarabostyryl as a colorless amorphous solid. m.p. 218-220 degreeC.

[Examples 7 to 37]

By Example 6, the compound as shown in Tables 4 and 5 was obtained.

[Table 4]

[Table 5]

Example 38

To 15 g of 5- (6′-cyano) hexyloxy-3,4-dihydro carabostyryl, 150 ml of water, 150 ml of dioxane and 25 g of sodium hydroxide were added to reflux with stirring for 20 hours. Thereafter, the reaction solution was cooled and acidified by adding hydrochloric acid to deposit crystals. The precipitated crystals were collected by filtration, washed with water, and recrystallized with methanol to obtain 13 g of 5- (6′-carboxy) hexyloxy-3,4-dihydrocarabostyryl as colorless needles. m.p. 138-142 degreeC.

[Examples 39 to 60]

By Example 5, the compounds as shown in Tables 6 and 7 were obtained.

[Table 6]

[Table 7]

Example 61

2.5 g of 5- (1′-carboxy) propoxy-3,4-dihydrocarabostyryl was added to 50 ml of ethanol saturated with hydrogen chloride, and the resulting mixture was refluxed for 10 hours. After the reaction, ethanol was removed under reduced pressure and the residue was dissolved in chloroform. The resulting solution was washed in the order of 5% aqueous sodium hydroxide solution and water. Thereafter, the chloroform layer was dried over anhydrous sodium sulfate, and then chloroform was removed by distillation. The residue was determined by petroleum ether and then recrystallized by chloroform-petroleum ether to give 2.1 g of 5- (1′-ethoxycarbonyl) propoxy-3,4-dihydrocarabostyryl as colorless acicular crystals. Obtained. m.p. 108 to 109 ° C.

Example 62

2.3 g of 6- (1′-carboxy) ethoxycarbostyryl and 1.5 g of cyclohexanol were added to 50 ml of benzene, and the resulting mixture was refluxed for 15 hours using a Dean stark apparatus ( On the one hand, the formed water was removed out of the system). After the reaction, the solvent was distilled off and the residue was dissolved in chloroform. The resulting solution was washed with 5% aqueous sodium hydrogen carbonate solution and water in that order, and the chloroform layer was dried over anhydrous sodium sulfate. Subsequently, the chloroform was removed by distillation, and the residue was then crystallized with petroleum ether and then recrystallized with chloroform-petroleum ether to give 6- (1′-cyclohexyloxycarbonyl) ethoxycara as colorless acicular crystal. 2.2 g of bostyryl was obtained. m.p. 162-163 캜.

Example 63

A small amount was added to a solution of 2 g of thionyl chloride in 20 ml of n-amyl alcohol while stirring 2.5 g of 7- (1′-carboxy) propoxy-3,4-dihydrocarabostyryl while cooling on the outside. The resulting mixture was stirred for 30 minutes at the temperature of electricity. After the reaction, the reaction solution was poured into 200 ml of ethyl acetate, washed in the order of ethyl acetate solution, 5% aqueous sodium hydroxide solution and water, and then dried over anhydrous sodium sulfate. Next, ethyl acetate was removed by distillation, the residue was crystallized with petroleum ether, and then recrystallized with chloroform-petroleum ether to give 7- (1′-n-amyloxycarbonanyl) prop as a colorless acicular crystal. 2.2 g of foxy-3,4-dihydrocarabobostyryls were obtained. m.p. 78 to 80 ° C.

[Examples 64 to 129]

By Example 61, the compounds as shown in Table 8 and Table 9 were obtained.

[Table 8]

[Table 9]

Example 130

4.0 g of 5- (4'-carboxy) butoxy-3,4-dihydro carbostyryl and 40 mg of p-toluenesulfonic acid were added to 40 ml of n-propanol, and the resulting mixture was refluxed for 10.5 hours. After cooling, the reaction solution was filled with 50 ml of chloroform and 50 ml of 5% aqueous sodium hydroxide solution, followed by shaking. Thereafter, the organic layer was separated, washed with 5% aqueous sodium hydroxide solution and water, and then dried over anhydrous sodium sulfate. Subsequently, the solvent was removed by distillation, and the residue was recrystallized with methanol to obtain 4.0 g of 5- (4′-porooxycarbonanyl) butoxy-3,4-dihydrocarabostyryl as colorless acicular crystals. .

m.p. 94-96 degreeC.

Example 131

2.7 g of 5- (3′-carboxy) propoxy-N-ethyl-3,4-dihydrocarabostyryl, 20 mg of p-toluenesulfonic acid and 0.9 g of n-amyl alcohol were added to 27 ml of purified benzene. The resulting mixture was refluxed with stirring for 13.5 hours using a Diine Starark apparatus. Thereafter, the solvent was distilled off and the residue was charged with 50 ml of chloroform and 50 ml of 5% aqueous sodium hydroxide solution and then shaken. The organic layer was separated and washed with 5% aqueous sodium hydroxide solution and then water. Subsequently, this solvent is removed by distillation, and the remaining moles are fractionally distilled to give 3.1 g of 5- (3′-amyloxycarbonanyl) propoxy-N-ethyl-3,4-dihydrocarabostyryl as colorless oil. Obtained. pb ₀ . ₅ 202-204 캜.

Example 132

A mixture obtained by adding 4.2 g of 6- (6′-carboxy) hexyloxy-3,4-dihydro carbostyryl, 40 mg of p-toluenesulfonic acid and 1.6 g of benzyl alcohol to 42 ml of purified benzene was obtained. It was refluxed for 15 hours using an arc device. After the reaction, the reaction solution was treated in the same manner as described in Example 131, and the residue was recrystallized from methanol to give 6- (6′-benzyloxycarbonyl) hexyloxy-3,4-di as colorless acicular crystals. 4.8 g of hydrocarbostyryl were obtained.

m.p. 98-100 degreeC.

[Examples 133 to 175]

By Example 130, the compounds as shown in Tables 10 and 11 were obtained.

[Table 10]

[Table 11]

Example 176

8 ml of ammonia water was added to 2.5 g of 5-ethoxycarbonylmethoxy-3,4-dihydrocarabostyryl and the resulting mixture was stirred at room temperature for 1.5 hours to deposit crystals. The precipitated crystals were collected by filtration and then recrystallized with methanol to obtain 1.5 g of material as colorless needles. 293-297 degreeC. NMR, IR and elemental analysis confirmed that the former substance was 5-carbamoylmethoxy-3,4-dihydrocarabostyryl.

Example 177

6.8 ml of isopropylamine and 10 ml of water were added to 2 g of 5-ethoxycarbonylmethoxy-3,4-dihydrocarabostyryl, and the resulting mixture was stirred at room temperature for 2 hours to deposit crystals. The precipitated crystals were collected by filtration and then recrystallized with methanol to give 0.5 g of material as colorless needles. m.p. 208.5-209.5 degreeC. NMR.IR and elemental analysis confirmed that the former material was 5- (N-isopropylcarabomoyl) methoxy-3,4-dihydrocarabobostyryl.

Example 178

10 ml of piperidine and 10 ml of water were added to 2 g of 5-ethoxycarbonylmethoxy-3,4-dihydrocarabostyryl, and the resulting mixture was stirred at room temperature for 2 hours. Thereafter, the reaction solution was concentrated to dryness, and the concentrate was dissolved in chloroform. The resulting solution was washed with water and then dried over anhydrous sodium sulfate, and chloroform was removed by distillation. This residue was recrystallized with ligroin-ethanol to give 0.3 g of the material as colorless needles. m.p. 179-180.5 degreeC. NMR.IR and elemental analysis confirmed that the former material was 5- (1′-piperidinocaaboyl) methoxy-3,4-dihydrocarabostyryl.

Example 179

To 2 g of 5-ethoxycarboylmethoxy-3,4-dihydrocarabostyryl, 6.9 ml of morpholine and 10 ml of water were added, and the resulting mixture was stirred at room temperature for 5 hours to deposit crystals. The deposited crystals were recovered and recovered and then recrystallized with ethanol to give 0.3 g of the material as colorless acicular crystals. m.p. 217-218.5 degreeC. NMR, IR and elemental analysis confirmed that the former material was 5- (1′-morpholinocarbonanyl) methoxy-3,4-dihydrocarabostyryl.

Example 180

8.7 ml of benzylamine and 13 ml of water were added to 2 g of 5-ethoxycarbonylmethoxy-3,4-dihydrocarabostyryl, and the resulting mixture was stirred at room temperature to deposit crystals. The deposited crystals were collected by filtration and then recrystallized with ethanol to give 1.9 g of material as colorless needles. m.p. 242-243 degreeC.

NMR, IR and elemental analysis confirmed that the former material was 5- (N-benzyl carbamoyl) methoxy-3,4-dihydrocarabobostyryl.

[Examples 181 to 187]

By Example 176, the compounds as shown in Table 12 were obtained.

[Table 12]

Example 188

10.5 ml of benzylamine and 10 ml of water were added to 2.6 g of N-ethyl-5- (3′-ethoxycarbonyl) propoxy-3,4-dihydrocarabostyryl, and the resulting mixture was stirred at room temperature for 2 hours. The crystals were deposited by stirring. The precipitated crystals were collected by filtration and recrystallized with ethanol to obtain 1.9 g of N-ethyl-5- (3'-benzylcarbamoyl) propoxy-3,4-dihydrocarabostyryl as a colorless amorphous solid. m.p. 131-134 ° C

Example 189

To 2.6 g of 8- (4'-ethoxycarbonyl) butoxycarbostyryl, 8 ml of an aqueous ammonia solution was added, and the resulting mixture was stirred at room temperature for 1.5 hours to deposit crystals. The deposited crystals were collected by filtration and then recrystallized with methanol to obtain 2.1 g of 8- (4′-carbamoyl) butoxycarabostyryl as colorless needles.

m.p. 178 ~ 180 ℃

By Example 188, the following compounds were obtained.

Example 190

6- [3 '-(N-n-propylcarbamoyl) -2'-methylpropoxy] -3,4-dihydrocarbobostyryl, colorless amorphous solid, m.p. 149-150 ℃

Example 191

5- (3'-carbamoyl) propoxycarbostyryl, colorless needle crystal, m.p. 252 ~ 255 ℃

Example 192

5 g of anhydrous hydrogen chloride was stirred in a solution containing 6 g of ethanol anhydride, 300 ml of anhydrous ether, and 25 g of 5- (4′-cyano) butoxy-3,4-dihydrocarabostyryl for at least about 4 hours. Was cooled with ice-methanol and injected while maintaining the temperature at -10 ° to -5 ° C. The solution was stirred at an electric temperature for 20 hours and then poured into 50 ml of 20% hydrochloric acid while maintaining the temperature at 30 ° to 40 ° C on the one hand. After stirring for 10 minutes at 30 DEG C-40 DEG C, the solution was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, saturated sodium bicarbonate solution and water in that order and dried over anhydrous sodium sulfate. Subsequently, the solvent was removed and the residue was recrystallized with methanol to obtain 12 g of 5- (4′-ethoxycarboyl) butoxy-3,4-dihydrocarabostyryl as colorless acicular crystals. m.p. 118 to 20 ° C.

Example 193

5 g of anhydrous hydrogen chloride was stirred in a solution containing 7 g of anhydrous ethanol, 300 ml of anhydrous ether, and 26 g of N-ethyl-5- (3'-cyano) propoxy-3,4-dihydrocarabostyryl for at least about 5 hours. On the other hand, the outside was cooled with ice-methanol and injected while maintaining the temperature at -10 to -5 占 폚. The solution was stirred at an electric temperature for 15 hours and then poured into 50 ml of 20% hydrochloric acid while maintaining the temperature at 30 ° to 40 ° C. After stirring for 10 minutes at the temperature above, the solution was extracted with ethyl acetate and the ethyl acetate layer was washed with water, saturated sodium bicarbonate solution and water in this order and dried over anhydrous sodium sulfate. Subsequently, the solvent was removed, and the residue was distilled off under reduced pressure to obtain 15 g of N-ethyl-5- (3'-ethoxycarbonanyl) propoxy-3,4-dihydrocarboxylryl as a colorless liquid. bp ₀ . ₉ 189-191 ° C.

[Examples 194-259]

By Example 193, the compounds as shown in Tables 13 and 14 were obtained.

[Table 13]

[Table 14]

Example 260

5 g of anhydrous hydrogen chloride was stirred in a solution containing 11 g of anhydrous amyl alcohol, 300 ml of anhydrous ether and 23 g of 6- (3′-cyano) propoxy-3,4-dihydrocarabostyryl for at least about 5 hours, The outside was cooled with ice-methanol and injected while maintaining the temperature at -10 to -5 占 폚. The solution was stirred for another 15 hours at an electric temperature and then poured into 50 ml of 20% hydrochloric acid while maintaining the temperature at 30 ° to 40 ° C. After stirring for 15 minutes at the temperature above, the solution was extracted with ethyl acetate and the organic layer was washed with water, saturated sodium bicarbonate solution and water in that order and dried over anhydrous sodium sulfate. Subsequently, this solvent was removed under reduced pressure, and the residue was recrystallized with ethanol to obtain 14 g of 6- (3′-amyloxycarbonanyl) propoxy-3,4-dihydrocarabostyryl as colorless needle-like crystals. m.p. 75-77 degreeC.

[Examples 216 to 303]

By Example 192, the compounds as shown in Tables 15 and 16 were obtained.

[Table 15]

[Table 16]

Reference Example 1

To a solution of sodium hydroxide 0.4 dissolved in 20 ml of water, 2 g of 6- (1'-ethoxycarboyl) -ethoxy-3,4-dihydrocarabostyryl was added and the resulting mixture was refluxed for 10 minutes. After cooling, the reaction solution was filled with concentrated hydrochloric acid to deposit crystals. The precipitated crystals were collected by filtration and then recrystallized with water to obtain 1.5 g of 6- (1'-carboxyoxy) ethoxy-3,4-dihydrocarbostyryl as colorless needles. m.p. 207-210.5 ° C.

Reference Example 2

300 mg of sodium hydride was added to a solution of 2.6 g of 5- (1′-ethoxycarboyl) ethoxy-3,4-dihydrocarabostyryl dissolved in 30 ml of dimethylformamide, and the resulting mixture was hydrogenated. It stirred until it was complete. Thereafter, 2.8 g of methyl iodide was charged to the mixture, followed by stirring at room temperature for 1 hour to deposit crystals of sodium iodide. The deposited crystals were collected by filtration and dimethylformamide was removed by distillation. The residue was then recrystallized with chloroform-petroleum ether to give 2.5 g of N-methyl-5- (1′-ethoxycarboyl) ethoxy-3,4-dihydrocarabostyryl as colorless acicular crystals. . Melting point 44-45 degreeC.

Reference Example 3

0.2 g of palladium black was added to a solution of 2.3 g of N-methyl-5- (1′-carboxy) ethoxycarbostyryl dissolved in 50 ml of methanol, and the resulting mixture was stirred for 50 hours under hydrogen pressure of 2.5 atm. Reduction was carried out at ℃. After that, the catalyst was filtered off and the filtrate was concentrated to dryness. The concentrate was then recrystallized with hydrous ethanol to give 1.8 g of N-methyl-5- (1′-carboxy) ethoxy-3,4-dihydrocarabostyryl as colorless needles. m.p. 148-149 degreeC.

Reference Example 4

0.1 g of palladium black was added to a solution of 2.5 g of 5- (4′-n-propoxycarboyl) -n-butoxycarbostyryl dissolved in 50 ml of methanol, and the resulting mixture was mixed for 8 hours under hydrogen pressure of 2.5 atm. Reduction at 50 ° C. After completion of the reaction, the catalyst was filtered off, and the filtrate was concentrated to dryness. The concentrate was then recrystallized with methanol to obtain 1.9 g of 5- (4'-n-propoxycarabosnil) -n-butoxy-3,4-dihydrocarabostyryl as colorless needle crystals. m.p. 94 ~ 96 ℃

Reference Example 5

To 50 ml of dioxane, 2.6 g of 6- (2′-ethoxycarbonyl) ethoxy-3,4-dihydrocarabostyryl and 3.8 g of 2,3-dichloro-5,6-dicyanobenzoquinone are added to each other. The resulting mixture was refluxed for 10 hours. Thereafter, the reaction solution was cooled to deposit crystals. The deposited crystals were filtered off and the filtrate was concentrated. The concentrate was dissolved in ethyl acetate, and the resulting ethyl acetate solution was washed in the order of 5% aqueous sodium carbonate solution and water, and then dried over anhydrous sodium sulfate. Subsequently, ethyl acetate was removed and the residue was subjected to silica gel column chromatography using ethyl acetate as a developing solvent. The resulting eluate was concentrated, and the concentrate was recrystallized with methanol to obtain 1.9 g of 6- (2'-ethoxycarboyl) ethoxycarbostyryl as colorless needles. m.p. 159-161 degreeC.

Example 304

－브로모아세테이트 21g을 또 채우고 4시간 동안 환류하여 취화나트륨을 침적시키고, 그 다음에 이것을 여과하여 제거한 다음에 여액을 냉각시켜 결정들을 침적시켰다. 침적된 결정들을 여과하여 분리하고, 그 다음에 에타놀로 재결정하여 무색 침상형 결정으로서 5－에톡시카아보닐메톡시－3,4－디하이드로카아보스티릴 20g을 수득했다. m.p. 146∼148℃A solution of 9.1 g of sodium ethylate dissolved in 200 ml of water was charged with 20 g of 5-hydroxy-4,3-dihydrocarabostyryl and refluxed for 2 hours. Ethyl in this solution

-21 g of bromoacetate was filled again and refluxed for 4 hours to deposit sodium embrittlement, which was then filtered off to remove the crystals by cooling the filtrate. The precipitated crystals were separated by filtration, and then recrystallized with ethanol to give 20 g of 5-ethoxycarboylmethoxy-3,4-dihydrocarabostyryl as colorless acicular crystals. mp 146-148 ° C

Example 305

－브로모프로피오네이트 10g을 채우고 5시간 동안 환류하여 취화나트륨을 침적시킨 다음에 이것을 여과하여 제거해서 여액을 감압하에서 농축하여 건조시켰다. 농축액을 에틸아세테이트에 용해시켜 생성되는 용액을 묽은 수산화나트륨 수용액으로 세척한 다음에 글라우버염(Glauber's salt)으로 건조시켜 에틸아세테이트를 제거했다. 이어서, 이 잔류물을 물 및 에타놀을 함유하는 혼합용매로 재결정하여 무색 비늘형 결정으로서 6－(1′－에톡시카아보닐)에톡시－3,4－디하이드로카아보스티릴 5g을 얻었다. m.p. 111∼113℃A solution of 3.4 g of sodium ethylate dissolved in 100 ml of ethanol was charged with 7.3 g of 6-hydroxy-3,4-dihydrocarabostyryl and refluxed for 2 hours. Ethyl in this solution

10 g of bromopropionate was charged and refluxed for 5 hours to deposit sodium embrittlement, which was then filtered off and the filtrate was concentrated to dryness under reduced pressure. The resulting solution was dissolved in ethyl acetate, and the resulting solution was washed with dilute aqueous sodium hydroxide solution and then dried with Glauber's salt to remove ethyl acetate. Subsequently, this residue was recrystallized with a mixed solvent containing water and ethanol to give 5 g of 6- (1′-ethoxycarbonanyl) ethoxy-3,4-dihydrocarabostyryl as colorless scale crystals. mp 111-113 degreeC

Example 306

－브로모이소부티레이트 10.7g을 채우고 6시간 동안 환류하여 취화나트륨을 침적시키고, 그 다음에 이것을 여과하여 제거하고, 여액을 감압하에서 건조시까지 농축시켰다. 농축액을 클로로포름에 용해시켜 생성되는 용액을 묽은 수산화나트륨 수용액으로 세척한 다음에 글라우버 염으로 건조시켜 클로로포름을 제거했다. 이어서, 이 잔류물을 물 및 에타놀을 함유하는 혼합용매로 재결정하여 무색 비늘형 결정으로서 7－(2′－에톡시카아보닐)이소프로폭시－3,4－디하이드로카아보스티릴 5g을 수득했다. m.p. 114∼115.5℃A solution of 3.4 g of sodium ethylate dissolved in 100 ml of ethanol was charged with 7.3 g of 7-hydroxy-3,4-dihydro carbostyryl and refluxed for 2 hours. Ethyl in this solution

-10.7 g of bromoisobutyrate was charged and refluxed for 6 hours to deposit sodium embrittlement, which was then filtered off and the filtrate was concentrated to dryness under reduced pressure. The resulting solution was dissolved in chloroform, and the resulting solution was washed with dilute aqueous sodium hydroxide solution and then dried with a glauber salt to remove chloroform. This residue was then recrystallized from a mixed solvent containing water and ethanol to give 5 g of 7- (2′-ethoxycarbonanyl) isopropoxy-3,4-dihydrocarabostyryl as colorless scale crystals. . mp 114 ~ 115.5 ℃

Example 307

A solution of 1.5 g of sodium ethylate dissolved in 50 ml of ethanol was charged with 3.3 g of 8-hydroxy-3,4-dihydrocarabostyryl and refluxed for 2 hours. The solution was charged with 5 g of ethyl α-bromoacetate and refluxed for 4 hours to deposit sodium embrittlement, which was then filtered off and the filtrate was concentrated to dryness under reduced pressure. The resulting solution was dissolved in ethyl acetate and the resulting solution was washed with dilute aqueous sodium hydroxide solution and then dried over anhydrous sodium sulfate to remove ethyl acetate. This residue was then recrystallized with ligroin to give 2.6 g of 8-ethoxycarboylmethoxy-3,4-dihydrocarabostyryl as colorless needles.

m.p. 92.5 ~ 94 ℃

Examples 308 to 315

By Example 304, the compounds as shown in Table 17 were obtained.

[Table 17]

Example 316

0.9 g of sodium metal was dissolved in a solution of 4.8 g of 5-hydroxycarbostyryl dissolved in 100 ml of ethylene glycol monomethyl ether. To this solution was charged 12 g of cyclohexyl α-bromopropionate while stirring at 85 to 90 ° C., and the resulting mixture was stirred at an electric temperature for 5 hours. After the reaction, the solvent was removed under reduced pressure and the residue was dissolved in 100 ml of chloroform. The resulting solution was washed in the order of 5% aqueous sodium carbonate solution and water. The chloroform layer was dried over anhydrous sodium sulfate and then chloroform was removed under reduced pressure. The residue was then crystallized with petroleum ether and then recrystallized with methanol to give 5.8 g of 5- (1′-cyclohexyloxycarbonanyl) ethoxycarbostyryl as colorless needles. m.p. 176 to 177 ° C

Example 317

－브로모부티레이트 10g을 충전하여 5시간 동안 환류하에 교반했다. 반응후에 용매를 증류에 의하여 제거하고, 잔류물을 클로로포름 100ml에 용해시켰다. 생성되는 용액을 5%수산화나트륨수용액 및 물의 순서로 세척하고 무수황산나트륨으로 건조시킨 다음에 클로로포름을 감압하에서 제거했다. 이어서, 이 잔류물을 석유에에테르로 결정시킨 다음에 메타놀로 재결정하여 무색침상형 결정으로서 6－(1′－프로폭시카아보닐)프로폭시－3,4－디하이드로카아보스티릴 5.1g을 수득했다. m.p.100∼101℃0.9 g of sodium metal was dissolved in a solution of 4.8 g of 6-hydroxy-3,4-dihydrocarabostyryl dissolved in 100 ml of n-propanol. N-propyl in this solution

10 g of bromobutyrate was charged and stirred under reflux for 5 hours. After the reaction, the solvent was removed by distillation and the residue was dissolved in 100 ml of chloroform. The resulting solution was washed in the order of 5% aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate and then chloroform was removed under reduced pressure. This residue was then crystallized with petroleum ether and then recrystallized with methanol to yield 5.1 g of 6- (1′-propoxycarbonaboyl) propoxy-3,4-dihydrocarabostyryl as colorless needle-like crystals. did. mp100 ~ 101 ℃

Example 318

－클로로프로피오네이트 5.5g을 채운뒤 5시간 동안 환류하에 가열했다. 반응 후에, 용매를 증류에 의해 제거하여 잔류물을 클로로포름 50ml에 용해시켰다. 생성되는 클로로포름 용액을 5% 수산화나트륨 수용액 및 물의 순서로 세척하고 무수 황산나트륨으로 건조시킨 다음에 클로로포름을 증류에 의해 제거했다. 이어서, 잔류물을 석유 에에테르로 결정시킨 다음에 메타놀로 재결정하여 무색판상형 결정으로서 8－(1′－메톡시카아보닐)에톡시－3,4－디하이드로카아보스티릴 3.8g을 수득했다. m.p. 103∼104℃3.2 g of 8-hydroxy-3,4-dihydrocarabostyryl and 1.3 g of sodium methylate were dissolved in 50 ml of methanol while heating. Methyl in the resulting solution

-5.5 g of chloropropionate was charged and heated under reflux for 5 hours. After the reaction, the solvent was removed by distillation to dissolve the residue in 50 ml of chloroform. The resulting chloroform solution was washed in the order of 5% aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate, and then chloroform was removed by distillation. The residue was then crystallized with petroleum ether and then recrystallized with methanol to yield 3.8 g of 8- (1′-methoxycarboyl) ethoxy-3,4-dihydrocarabostyryl as colorless plate crystals. mp 103-104 ℃

Example 319

－브로모부티레이트 25g을 채우고 8시간 동안 환류했다. 반응 후에 용매를 감압하에서 제거하고, 잔류물을 에틸아세테이트 300ml에 용해시켰다. 생성되는 용액을 5% 수산화나트륨 수용액 및 물의 순서로 세척한 뒤 무수 황산나트륨으로 건조시키고 나서 에틸아세테이트를 증류에 의해 제거했다. 이어서, 잔류물을 석유 에에테르로 결정시킨 다음에 에타놀로 재결정하여 무색판상형결정으로서 7－(1′－에톡시카아보닐)프로폭시－3,4－디하이드로카아보스티릴 21g을 수득했다. m.p. 83∼85℃16 g of 7-hydroxy-3,4-dihydrocarabostyryl and 9 g of sodium ethylate were dissolved in 200 ml of ethanol while heating. Ethyl in the resulting solution

25 g of bromobutyrate were charged and refluxed for 8 hours. After the reaction, the solvent was removed under reduced pressure, and the residue was dissolved in 300 ml of ethyl acetate. The resulting solution was washed with 5% aqueous sodium hydroxide solution and water, dried over anhydrous sodium sulfate, and ethyl acetate was removed by distillation. The residue was then crystallized with petroleum ether and then recrystallized with ethanol to give 21 g of 7- (1′-ethoxycarboyl) propoxy-3,4-dihydrocarabostyryl as colorless plate-like crystals. mp 83 ~ 85 ℃

[Examples 320 to 384]

Example 316 gave the compounds as shown in Tables 18 and 19.

[Table 18]

[Table 19]

Example 385

In 100 ml of dimethyl soxide, 19 g of N-ethyl-5-hydroxy-3,4-dihydrocarabostyryl, 10 g of sodium ethylate, and 2 g of sodium iodide were dissolved for 1 hour with stirring at 80 to 90 ° C. The resulting solution was charged with 32 g of ethyl γ-bromobutyrate and stirred at 100 to 110 ° C. for 10 hours. After the reaction, the reaction solution was poured into 1.5 L of saturated sodium chloride solution and then extracted with chloroform (300 ml × 4 times). The chloroform layer was washed in the order of saturated sodium chloride solution, 0.5N-sodium hydroxide aqueous solution and water, and then dried over anhydrous sodium sulfate. The chloroform layer was then concentrated, and the concentrate was distilled off under reduced pressure to obtain 21 g of N-ethyl-5- (3'-ethoxycarbonyl) propoxy-3,4-dihydrocarabostyryl as a colorless liquid form. bp ₀ . ₉ 189 ~ 190 ℃

Example 386

To 100 ml of ethanol was added 16 g of 5-hydroxy-3,4-dihydrocarabostyryl and 5.7 g of sodium hydroxide, and the resulting mixture was concentrated to dryness. Next, 100 ml of N, N-dimethylformamide, 2 g of potassium iodide and 45 g of propyl 5-bromovaleric acid were added to the concentrate, and the mixture was stirred at 100 to 110 ° C for 10 hours. After the reaction, the reaction solution was cooled and then inclined to 1 L of water to deposit crystals. The deposited crystals were collected by filtration and washed in the order of 0.5 N aqueous sodium hydroxide solution and water. Subsequently, these crystals were recrystallized with methanol to obtain 20 g of 5- (4′-propoxycarboyl) butoxy-3,4-dihydrocarabostyryl as colorless acicular crystals.

m.p. 94-96 degreeC.

Example 387

2.5 g of sodium metal and 16 g of 6-hydroxy-3,4-dihydrocarabostyryl were added to 100 ml of ethanol, and the resulting mixture was concentrated to dryness. Then, 100 ml of dimethyl sulfoxide and 2 g of sodium iodide were added to the concentrate, and the mixture was stirred at room temperature for 1 hour to prepare a solution. The solution was reacted with 40 g of ethyl 6-bromocaproate under stirring at 100-110 ° C. for 10 hours. After the reaction, the reaction solution was inclined to 1 L of water to deposit crystals. The precipitated crystals were collected by filtration, washed with 0.5N aqueous sodium hydroxide solution and water, and then recrystallized with methanol to give 6- (6′-ethoxycarbonyl) hexyloxy-3,4 as colorless acicular crystals. -19 g of dihydrocarbobostyryls were obtained. m.p. 103 to 105 ° C.

[Examples 388 to 430]

By Example 385, the compounds as shown in Tables 20 and 21 were obtained.

[Table 20]

[Table 21]

Reference Example 6

To 200 ml of ethanol was added 32 g of 5-hydroxy-3,4-dihydrocarabostyryl, 17 g of sodium ethylate, and 1 g of potassium iodide, and the resulting mixture was refluxed for 1 hour with stirring to prepare a solution. 56 g of 1,6-dibromohexane was added dropwise to this solution, and the resulting mixture was refluxed with stirring for 12 hours. After the reaction, the reaction solution was cooled to deposit crystals. The precipitated crystals were collected by filtration, washed with 0.5 N aqueous sodium hydroxide solution and water, and then recrystallized with ethanol to give 5- (6′-bromo) hexyloxy) -3,4- as colorless acicular crystals. 40 g of dihydrocarabostyryl was obtained.

m.p. 135-136 degreeC.

Reference Example 7

To 200 ml of dimethyl sulfoxide was added 26 g of 5- (6′-bromo) hexyloxy-3,4-dihydrocarabostyryl and 5.5 g of sodium cyanide powder to reflux the resulting mixture at 100 to 110 ° C. for 5 hours. did. After cooling, the reaction solution was inclined to 1.5 L of water to deposit crystals. The precipitated crystals were collected by filtration, washed with water and recrystallized with ethyl acetate to obtain 21 g of 5- (6'-cyano) hexyloxy-3,4-dihydrocarabostyryl as a colorless amorphous solid. m.p. 169-172 degreeC.

Reference Example 8

To a solution of 3.3 g of sodium metal dissolved in 200 ml of ethanol, 19 g of N-ethyl-5-hydroxy-3,4-dihydrocarabostyryl and 2 g of sodium iodide were added, and the resulting mixture was stirred at room temperature for 1 hour. This mixture was then charged with 24 g of 3-cyanopropyl bromide and refluxed with stirring for 10 hours. After the reaction, the reaction solution was concentrated, and the concentrate was dissolved in ethyl acetate. The ethyl acetate layer was washed with 0.5N aqueous sodium hydroxide solution and water and dried over anhydrous sodium sulfate. After ethyl acetate was concentrated to remove the residue, the residue was recrystallized with ligroin to yield 15 g of N-ethyl-5- (3'-cyano) propoxy-3,4-dihydrocarabostyryl as a colorless amorphous solid. m.p. 74 to 76 ° C.

Reference Example 9

A suspension of 11.4 g of 5-hydroxy-3,4-dihydrocarabostyryl suspended in 37.1 g of acetonitrile was charged with 2 ml of 40% methanol solution of triton B and refluxed for 8.5 hours. The reaction solution was cooled to deposit crystals, which was recovered by filtration and recrystallized with methanol to give 6.5 g of 5- (2'-cyanoethoxy) -3,4-dihydrocarabostyryl as colorless acicular crystals. Obtained. m.p. 217-222.5 degreeC.

Example 431

In 100 ml of dimethyl sulfoxide, 17 g of 5-hydroxy-3,4-dihydrocarabostyryl, 10 g of sodium ethylate, and 2 g of sodium iodide were dissolved with stirring at 80 to 90 ° C. for 1 hour. The resulting solution was charged with 31 g of ethyl r-bromocrotonate and stirred at 100 ° C. to 110 ° C. for 10 hours. After the reaction, the reaction solution was decanted into 1.5 L of saturated sodium chloride working solution and then extracted with chloroform. The chloroform layer was washed with saturated sodium chloride solution, 0.5N-aqueous sodium hydroxide solution and water in that order and dried over anhydrous sodium sulfate.

Subsequently, the chloroform layer was concentrated and then recrystallized with methanol to obtain 19 g of 5- (3'-ethoxycarbonanyl-2'-propenyloxy) -3,4-dihydrocarabostyryl as colorless acicular crystals. m.p. 152-153 캜.

Example 432

To 100 ml of ethanol was added 16 g of 6-hydroxy-3,4-dihydrocarabostyryl and 5.7 g of sodium hydroxide, and the resulting mixture was concentrated to dryness. Next, 100 ml of N, N-dimethylformamide, 2 g of potassium iodide and 40 g of ethyl r-bromocrotonate were added to the concentrate, and the resulting mixture was stirred at 100 to 110 ° C for 10 hours. After the reaction, the reaction solution was cooled and then decanted in 1 L of water to deposit crystals. The deposited crystals were filtered off and washed in the order of 0.5N aqueous sodium hydroxide solution and water. Subsequently, these crystals were recrystallized with methanol to obtain 18 g of 6- (3′-ethoxycarbonayl-2′-propenyloxy) -3,4-dihydrocarabostyryl as colorless acicular crystals. m.p. 151-152 캜.

Example 433

In Example 431, 6- (3'-ethoxycarbonayl-2'-propenyloxy) carbostyryl having m.p.213 to 215 ° C was obtained as colorless needles.

Example 434

3.2 g of 5-hydroxy-N-methyl-2-oxyindole was dissolved in 15 ml of dry dimethylformamide, and then 960 mg of a 50% aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature for 20 minutes. To the mixture thus obtained, 4.3 g of 3-bromo-butyrate was added dropwise with stirring at the same temperature for 30 minutes, followed by further stirring at 70 to 80 ° C for 30 minutes. After the reaction, the reaction mixture was dissolved in 300 ml of chloroform and the chloroform solution was washed with water (100 ml × 5 times) and then dried over anhydrous sodium sulfate. Subsequently, the residue obtained by distilling off chloroform was recrystallized from a mixture of benzene-hexane to obtain 3.5 g of 5- (3′-ethoxycarbonyl) propyloxy-N-methyl-2-oxyindole as colorless prismatic crystals. . m.p. 77.5-79 degreeC.

Example 435

3.0 g of 5-hydroxyindole was dissolved in 15 ml of a mixture of ethanol and dimethylformamide 2: 1, and then 1.0 g of sodium ethoxide was added thereto and stirred at room temperature for 20 minutes. To the mixture thus obtained, 4.0 g of ethyl 3-bromobutyrate was added dropwise with stirring for 30 minutes at the same temperature as before, followed by further stirring for 30 minutes at 70 ° C to 80 ° C. After the reaction, the reaction mixture was dissolved in 250 ml of chloroform and the chloroform solution was washed with water (100 ml × 5 times) and then dried over anhydrous sodium sulfate. Then, the residue obtained by distilling off chloroform was recrystallized with isopropyl ether to obtain 3.0 g of 5- (3′-ethoxycarbonyl) propyloxy-2-oxyindole as colorless microplate-like crystals. m.p. 104 to 106 ° C.

Claims (1)

The compound of the following general formula (I-b) obtained by hydrolyzing the compound of the following general formula (VI) is reacted with an alcohol of the following general formula (A), or the compound of the following general formula (VI) is Alcohol decomposition with alcohol of A) produces the compound of following general formula (I-a), or the compound of the following general formula (II) is made to react with the compound of the following general formula (III), and the following general formula (I-a) ) Or a compound of the following general formula (I-a) is reacted with an amine of the following general formula (B) to produce a compound of the following general formula (I-c) Method for preparing benzcycloamide derivative of I).

In each formula above, R ₁ is hydrogen, C ₁ ~ ₄ alkyl, C ₂ ~ ₄ alkenyl or aralkyl, B is —CH ₂ —, —CH ₂ —CH ₂ — or —CH═CH—, A is

And (wherein, R ₂ and R ₃ are each hydrogen or C ₁ ~ ₄ alkyl is the same or different from each other), or -CH = CH-, R ₄ is -OR ₅ (wherein, R ₅ is hydrogen, C ₁ ~ _8-alkyl, cycloalkyl or aralkyl kilim) or

ego R _'5 is a C ₁ ~ _8-alkyl, cycloalkyl or aralkyl, R ₆ and R ₇ may form a 5-or 6-membered heterocyclic dishes with each hydrogen, C ₁ ~ ₄ alkyl or aralkyl or or nitrogen atom is the same or different from each other, a group also a nitrogen atom, an oxygen atom or May contain sulfur atoms, m and n are each 0 or a positive integer, and m + n is 11 or less, X is halogen.