SULFONAMIDE DERIVATIVE AND PHARMACEUTICAL COMPOSITION CONTAINING THE SAME

Abstract: This invention relates to a sulfonamide derivative of general formula (I) and an antiasthmatic having a bronchodilator activity and containing said derivative as the active ingredient (I), wherein X represents a quinoline residue of formula (II) or an isoquinoline residue of formula (III) (wherein R¹ represents a hydrogen or halogen atom, or a lower alkyl or lower alkoxy group, and R² represents a hydrogen atom or a hydroxy group); and when X is a quinoline residue (II), n is 0 or 1 provided that when n is 0, R⁴ represents an (un)substituted diazacycloalkyl group, while when n is 1, R³ represents a hydrogen atom or a lower alkyl group and R⁴ represents an (un)substituted aralkylamino group or an (un)substituted diazacycloalkyl group; or when X is an isoquinoline residue (III), n is 1, R³ represents a hydrogen atom or a lower alkyl group, and R⁴ represents a 3,4-methylene-dioxyphenethylamino group, a 3,4-methylenedioxy-benzylamino group or an (un)substituted diazacycloalkyl group, provided that when R⁴ is an (un)substituted diazacycloalkyl group, said diazacycloalkyl group is bonded to the main chain at the nitrogen atom of said group.

Description: Technical Field The present invention relates to a novel sulfonamide derivative and a pharmaceutical composition comprising the same. More particularly, the present invention is concerned with a sulfonamide derivative which contains an unsubstituted or substituted diazacycloalkyl group or an unsubstituted or substituted aralkylamino group and is substituted with a quinoline residue or an isoquinoline residue, or an acid addition salt thereof. The sulfonamide derivative or an acid addition salt thereof of the present invention affects the bronchial smooth muscle of a mammal and is effective as an active ingredient of a pharmaceutical composition for the prevention and treatment of respiratory diseases, such as asthma. The present invention also relates to a pharmaceutical composition comprising the above-mentioned novel sulfonamide derivative or an acid addition salt thereof as an active ingredient. Background Art Various compounds have been proposed as a drug for treatment of circulatory organ diseases, particularly as a drug for treatment of peripheral circulatory disorders, cerebral circulation disorders, angina and the like. In this connection, reference may be made to, for example, European Patent No. 0061673 (U.S. Patent No. 4,456,757, U.S. Patent No. 4,560,755, U.S. Patent No. 4,525,589, Japanese Patent Application Laid-Open Specification No. 57-156463, Japanese Patent Application Laid-Open Specification No. 57-200366, Japanese Patent Application Laid-Open Specification No. 58-121278, Japanese Patent Application Laid-Open Specification No. 58-121279), European Patent No. 0109023 (U.S. Patent No. 4,634,770, U.S. Patent No. 4,709,023, Japanese Patent Application Laid-Open Specification No. 59-93054, Japanese Patent Application Laid-Open Specification No. 60-81168), U.S. Patent No. 4,678,783 (Japanese Patent Application Laid-Open Specification No. 61-152658, Japanese Patent Application Laid-Open Specification No. 61-227581), U.S. Patent No. 4,798,897 (Japanese Patent Application Laid-Open Specification No. 62-103066, Japanese Patent Application Laid-Open Specification No. 62-111981), Journal of Medicinal Chemistry, 32 , 42-50 (1989), Agents Actions, 28 (3-4), 173-184 (1989) and Pharmacology, 37 (3), 187-194 (1988). It is known that N-(2-aminoethyl)-N-hexyl-5-isoquinolinesulfonamide, 1-(5-isoquinolinesulfonyl)-3-aminopiperidine and the like described in U.S. Patent No. 4,798,897, and N-(2-guanidinoethyl)-5-isoquinolinesulfonamide described in Agents Actions, 28 (3-4), 173-184 (1989), Pharmacology, 37 (3), 187-194 (1988) and European Patent No. 0109023 have not only vasodiletic activity but also bronchodilating activity. However, the bronchodilating effect exhibited by the above-mentioned compound is unsatisfactory. Bronchodilators, such as xanthine type medicines and β-receptor stimulants, are widely used as a clinical, therapeutic agent for treatment of respiratory diseases, such as asthma. It is believed that these medicines increase the concentration of a cyclic adenosine 3',5'-mono-phosphate. As a representative example of the xanthine type medicines, aminophylline can be mentioned. Further, as a representative example of the β-receptor stimulants, isoproterenol can be mentioned. However, these xanthine type medicines and β-receptor stimulants have side effects on heart and the like, and an intractable asthma which is not remitted by these medicines has emerged. Therefore, these medicines do not always satisfy the demand of clinicians. Further, EP-A-0 061 673 discloses N-(aminoalkyl)isoquinoline sulfonamides and pharmaceutically acceptable salts thereof, wherein the compounds have a relaxatory action for vascular smooth muscle and are useful as a vasodilator and a hypotensor. US-A-4 857 301 describes inter alia 5-(4-piperidinylmethyl)aminosulfonylisoquinoline and teaches that the isoquinoline group may be replaced by a quinoline group in order to obtain further bronchodilating compounds. EP-A-0 287 696 discloses isoquinoline sulfonamides which are useful as vasodilators and bronchodilators. The second alkyl group is bound to the nitrogen atom of the sulfonamide group and the benzyl and phenethyl groups are not substituted. There has, however, still been a demand for improving the prior art. In such a situation, the present inventors have made extensive and intensive studies with a view toward developing a bronchodilator which is more useful for treating respiratory diseases, such as asthma. As a result, it has been found that a sulfonamide derivative which contains an unsubstituted or substituted diazacycloalkyl group or an unsubstituted or substituted aralkylamino group and is substituted with a quinoline residue or an isoquinoline residue, and an acid addition salt thereof have bronchodilatational activity and strongly prevent bronchoconstriction by prostaglandin F 2α (hereinafter referred to as "PGF 2α ") which is almost not remitted by the conventional xanthine type bronchodilators. Based on these finding, the present invention has been completed. Accordingly, it is an object of the present invention to provide a sulfonamide derivative substituted with a quinoline residue or an isoquinoline residue, and an acid addition salt thereof, which not only have excellent bronchodilating activity and no side effect to heart, but also are effective as an active ingredient of medicines for treating an intractable asthma which is not remitted by the xanthine type medicines. It is another object of the present invention to provide a pharmaceutical composition comprising the above-mentioned derivative or an acid addition salt thereof as an active ingredient, which not only has excellent bronchodilating activity and no side effect to heart, but is also effective for treating an intractable asthma which is not remitted by the xanthine type medicines. The foregoing and other objects, features and advantages of the present invention will be apparent from the following detailed description and appended claims. Disclosure of The Invention According to the present invention, there is provided a sulfonamide derivative represented by formula (I) or a pharmaceutically acceptable acid addition salt thereof wherein X represents a quinoline residue represented by formula (II) or an isoquinoline residue represented by formula (III) where R¹ is a hydrogen atom, a halogen atom, a C₁₋₆-alkyl group or a C₁₋₆-alkoxy group, or where R² is a hydrogen atom or a hydroxyl group, and wherein: when X is the quinoline residue (II), n is 1, in which R³ is a hydrogen atom or C₁₋₆-alkyl group and R⁴ is a substituted aralkylamino group in which a substituted aralkyl moiety of the substituted aralkylamino group is represented by the following formula (IV): wherein p represents an integer of from 1 to 3, each of R⁵ and R⁶ independently represents a hydrogen atom, a C₁₋₃-alkyl group, a C₁₋₃-alkoxy group, a halogen atom or a trifluoromethyl group, with the exception that R⁵ and R⁶ cannot be simultaneously a hydrogen atom, and R⁵ and R⁶ may be directly bonded with each other to form a methylenedioxy group; and when X is the isoquinoline residue (III), n is 1, in which R³ is a hydrogen atom or a C₁₋₆-alkyl group and R⁴ is a 3,4-methylenedioxyphenethylamino group or a 3,4-methylenedioxybenzylamino group. In the above formula (II), R¹ is a hydrogen atom, a halogen atom, a C₁₋₆-alkyl group or a C₁₋₆-alkoxy group. Of these, a halogen atom and a C₁₋₆-alkoxy group are most preferred. Examples of halogen atoms include a chlorine atom and a bromine atom. The numbers of carbon atoms of the C₁₋₆-alkyl group and the C₁₋₆-alkoxy group are in the range of from preferably 1 to 3. Examples of C₁₋₆-alkyl groups include a methyl group and an ethyl group. Examples of C₁₋₆-alkoxy groups include a methoxy group and an ethoxy group. In the above formula (I), R³ is a hydrogen atom or a C₁₋₆-alkyl group. Of these, a hydrogen atom is most preferred. The number of carbon atoms of the lower alkyl group is in the range of from preferably 1 to 3. Examples of C₁₋₆-alkyl groups include a methyl group and an ethyl group. Examples of substituted aralkylamino groups include 3,4-dimethoxyphenethylamino group, 4-methoxyphenethylamino group, 3-chlorophenethylamino group, 4-trifluoromethylphenethylamino group, 3,4-methylenedioxyphenethylamino group, 3,4-dimethoxybenzylamino group, 4-methoxybenzylamino group, 3-chlorobenzylamino group and 3,4-methylenedioxybenzylamino group. Examples of sulfonamide derivatives represented by formula (I) of the present invention include the following compounds. (1) N-[2-(3,4-methylenedioxyphenethylamino)ethyl]-5-isoquinolinesulfonamide (2) N-[2-(3,4-methylenedioxyphenethylamino)ethyl]-1-hydroxy-5-isoquinolinesulfonamide hydrochloride (3) N-[2(3,4-methylenedioxybenzylamino)ethyl]-5-isoquinolinesulfonamide (4) N-[2-(3,4-methylenedioxybenzylamino)ethyl]-1-hydroxy-5-isoquinolinesulfonamide hydrochloride (5) N-[2-(4-methoxyphenethylamino)ethyl]-8-chloro-5-quinolinesulfonamide (6) N-[2-(4-chlorophenethylamino)ethyl]-8-chloro-5-quinolinesulfonamide (7) N-[2-(4-trifluoromethylphenethylamino)ethyl]-8-chloro-5-quinolinesulfonamide (8) N-[2-(3,4-dimethoxyphenethylamino)ethyl]-8-chloro-5-quinolinesulfonamide (9) N-[2-(3,4-methylenedioxyphenethylamino)ethyl]-8-chloro-5-quinolinesulfonamide (10) N-[2-(3-chlorobenzylamino)ethyl]-8-chloro-5-quinolinesulfonamide (11) N-[2-(4-methoxybenzylamino)ethyl]-8-chloro-5-quinolinesulfonamide (12) N-[2-(3,4-dimethoxybenzylamino)ethyl]-8-chloro-5-quinolinesulfonamide (13) N-[2-(3,4-methylenedioxybenzylamino)ethyl]-8-chloro-5-quinolinesulfonamide (14) N-[2-(4-methoxyphenethylamino)ethyl]-8-ethoxy-5-quinolinesulfonamide (15) N-[2-(4-chlorophenethylamino)ethyl]-8-ethoxy-5-quinolinesulfonamide (16) N-[2-(4-trifluoromethylphenethylamino)ethyl]-8-ethoxy-5-quinolinesulfonamide (17) N-[2-(3,4-dimethoxyphenethylamino)ethyl]-8-ethoxy-5-quinolinesulfonamide (18) N-[2-(3,4-methylenedioxyphenethylamino)ethyl]-8-ethoxy-5-quinolinesulfonamide (19) N-[2-(3-chlorobenzylamino)ethyl]-8-ethoxy-5-quinolinesulfonamide (20) N-[2-(4-methoxybenzylamino)ethyl]-8-ethoxy-5-quinolinesulfonamide (21) N-[2-(3,4-dimethoxybenzylamino)ethyl]-8-ethoxy-5-quinolinesulfonamide (22) N-[2-(3,4-methylenedioxybenzylamino)ethyl]-8-ethoxy-5-quinolinesulfonamide (23) N-[2-(3,4-methylenedioxybenzylamino)ethyl]-5-quinolinesulfonamide (24) N-[2-(3,4-dimethoxyphenethylamino)-2-methylethyl]-8-chloro-5-quinolinesulfonamide Further, according to the present invention, there is also provided an acid addition salt of the sulfonamide derivative represented by the above-mentioned formula (I). This salt is a pharmacologically acceptable, non-toxic salt. Examples of salts include salts with inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and organic acids, such as acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, fumaric acid, maleic acid and methanesulfonic acid. The sulfonamide derivative of the present invention can be produced by various methods and is not particularly limited. For example, there can be mentioned a method in which a substituted quinolinesulfonic acid or isoquinolinesulfonic acid which has the above-mentioned substituent R¹ or R² is reacted with thionyl chloride or the like to thereby convert the sulfonic acid group to a sulfonyl chloride group to obtain a sulfonyl chloride compound and then, the obtained sulfonyl chloride compound is reacted with a hydroxylamine having the above-mentioned substituent R³ and paratoluenesulfonyl chloride and the resultant reaction product is then reacted with a compound corresponding to substituents R⁴ mentioned above, that is an aralkylamine, 3,4-methylenedioxyphenethylamine or 3,4-methylenedioxybenzylamine to thereby obtain a sulfonamide derivative. The acid addition salt of the sulfonamide derivative of the present invention can readily be prepared by reacting the sulfonamide derivative obtained by the method mentioned above with an inorganic acid or an organic acid. When the produced compound per se is an acid addition salt, the corresponding compound in free form can easily be formed by treating with an alkali. Hereinbelow, representative examples of methods for producing the sulfonamide derivative and acid addition salt thereof of the present invention are described in detail. (Method 1): Production of the sulfonamide derivative represented by formula (I), wherein X is isoquinoline residue (III), n is 1, R² is a hydrogen atom, R³ is a hydrogen atom or a C₁₋₆-alkyl group and R⁴ is a 3,4-methylenedioxyphenethylamino group or a 3,4-methylenedioxybenzylamino group, or wherein X is quinoline residue (II), n is 1, R¹ is a hydrogen atom, a halogen atom, a C₁₋₆-alkyl group or a C₁₋₆-alkoxy group, R³ is a hydrogen atom or a C₁₋₆-alkyl group and R⁴ is an aralkylamino group which is substituted at its aromatic ring. 5-Isoquinolinesulfonic acid or 8-R'-substituted 5-quinolinesulfonic acid is reacted with thionyl chloride in the presence of a catalytically effective amount (usually 0.5 to 5 % by volume based on the amount of thionyl chloride) of N,N-dimethyl-formamide, thereby obtaining 5-isoquinolinesulfonyl chloride or 8-R'-substituted 5-quinolinesulfonyl chloride represented by the following formula (V): wherein R¹ has the same meaning as defined for formula (II) and A and B each represent a nitrogen atom or carbon atom with the proviso that when A is a nitrogen atom, B is a carbon atom and when A is a carbon atom, B is a nitrogen atom. The compound of formula (V) is then reacted with the compound represented by the following formula (VI), thereby obtaining a compound represented by the following formula (VII): wherein R³ has the same meaning as defined in formula (I), wherein R¹, R³, A and B have the same meanings as defined above. Representative examples of compounds represented by formula (VI) which may be employed include ethanolamine, 2-hydroxypropylamine and 2-hydroxybutylamine. The reaction between the compound of formula (V) and the compound of formula (VI) may be carried out in the presence or absence of an acid acceptor. Examples of acid acceptors which may be employed include alkali metal compounds, such as sodium hydrogencarbonate, sodium hydroxide, potassium carbonate, sodium carbonate, potassium hydroxide and sodium methylate, and organic tertiary amines, such as pyridine, trimethylamine and triethylamine. The reaction between the compound of formula (V) and the compound of formula (VI) may be carried out in a solvent. Examples of solvents which may be employed include halogenated hydrocarbons, such as dichloromethane and chloroform; ethers such as tetrahydrofuran, dioxane and diethyl ether; dimethyl sulfoxide; N,N-dimethylformamide; acetonitrile and water. These solvents may be used individually or in mixture. The amount of the compound of formula (VI) may be in the range of from 1 to 20 mols, preferably from 1 to 10 mols per mol of the compound of formula (V). It is more preferred that the amount of the compound of formula (VI) be in the range of from 2.5 to 5 mols per mol of the compound of formula (V) when an acid acceptor is absent, and in the range of from 1 to 3 mols per mol of the compound of formula (V) when an acid acceptor is present. When an acid acceptor is employed, the amount of the acid acceptor may be in the range of from 1 to 10 mols, preferably 1 to 6 mols per mol of the compound of formula (VI). The reaction temperature is generally in the range of from -30 to 120°C, preferably -20 to 50°C. The reaction time is generally 0.5 to 48 hours, preferably 0.5 to 6 hours. The compound of formula (VII) is then reacted with paratoluenesulfonyl chloride to obtain a compound represented by the formula (VIII). This reaction may be conducted according to the method described in L.F. Fieser and M. Fieser, "Reagent for Organic Synthesis", Volume 1, p.1180. wherein R¹, R³, A and B have the same meanings as defined above. For example, the compound of formula (VII) is dissolved in pyridine, and to the resultant solution is added paratoluenesulfonyl chloride in an amount of 1 to 2 mols per mol of the compound of formula (VII). The reaction is allowed to proceed at 10 to 80 °C for 2 to 8 hours, whereby the compound of formula (VIII) is obtained in high yield. Next, the compound of formula (VIII) is reacted with 3,4-methylenedioxyphenethylamine or 3,4-methylenedioxybenzylamine when A is a carbon atom and B is a nitrogen atom, or with an aralkylamine which is substituted at its aromatic ring when A is a nitrogen atom and B is a carbon atom, thereby obtaining the desired compound. Examples of employable aralkylamines having an substituted aromatic ring, include 3,4-dimethoxyphenethylamine, 4-methoxyphenethylamine, 3-chlorophenethylamine, 4-trifluoromethylphenethylamine, 3,4-methylenedioxyphenethylamine, 3,4-dimethoxybenzylamine, 4-methoxybenzylamine, 3-chlorobenzylamine and 3,4-methylenedioxybenzylamine. These amines are generally used in an amount of from 1 to 10 mols per mol of the compound of formula (VIII). This reaction is preferably conducted in a sealed vessel, since this reaction is likely to proceed slowly. It is preferred that this reaction be carried out in a solvent. Examples of solvents which can be employed include alcohols, such as methanol, ethanol and butanol; halogenated hydrocarbons, such as dichloromethane and chloroform; and ethers, such as tetrahydrofuran, dioxane and diethyl ether. These solvents may be used individually or in mixture. The reaction temperature is generally in the range of from 10 to 120 °C, preferably 60 to 110 °C. The reaction time is generally 0.5 to 72 hours. (Method 2): Production of the acid addition salt of the sulfonamide derivative represented by formula (I), wherein X is isoquinoline residue (III), n is 1, R² is a hydroxyl group, R³ is a hydrogen atom or a C₁₋₆-alkyl group and R⁴ is a 3,4-methylenedioxyphenethylamino group or a 3,4-methylenedioxybenzylamino group. The reaction is conducted in substantially the same manner as in Method 1 except that 1-chloro-5-isoquinoline sulfonic acid is employed instead of 5-isoquinoline sulfonic acid or an 8-R'-substituted 5-quinoline sulfonic acid used in Method 1. The resultant compound is treated with an aqueous solution of an inorganic acid to effect hydrolysis, thereby obtaining the desired compound in which R² is a hydroxyl group and which is in the form of an acid addition salt. Examples of inorganic acids include hydrochloric acid, sulfuric acid and hydrobromic acid. The concentration of the inorganic acid is preferably 0.25 to 10 mols/liter. The reaction temperature is generally in the range of from 50 to 100 °C. The reaction time is generally 2 to 6 hours. (Method 3): Production of an acid addition salt from each of the sulfonamide derivatives obtained in Method 1. The compound obtained in Method 1 is dissolved in an alcohol, such as methanol and ethanol, to obtain a solution. Then, an equivalent or several fold amount of an acid is added to the solution, to form an acid addition salt. Examples of usable acids include inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid, and organic acids, such as acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, fumaric acid, maleic acid and methanesulfonic acid. The sulfonamide derivative and the pharmaceutically acceptable acid addition salt thereof of the present invention exert an excellent bronchial smooth muscle relaxation action. Accordingly, these compounds are useful substances for prevention and treatment of respiratory organ diseases, such as asthma. Accordingly, in a further aspect of the present invention, there is provided a pharmaceutical composition comprising the sulfonamide derivative represented by formula (I) or a pharmaceutically acceptable acid addition salt thereof, and at least one pharmaceutically acceptable carrier or diluent. Examples of carriers which may be employed include vehicles, such as lactose, sucrose, glucose, starch and crystalline cellulose; binders, such as hydroxypropyl cellulose, carboxymethyl cellulose, starch, gum arabic, gelatin, glucose, sucrose, tragacanth and sodium alginate; disintegrators, such as carboxymethyl cellulose, starch and calcium carbonate; lubricants, such as magnesium stearate, refined tarc, stearic acid and calcium stearate; additives such as lecithine, soybean oil and glycerin. Examples of diluents include distilled water, physiological saline, Ringer's solution, ethanol, vegetable oil, and mixtures thereof. In the case where the compounds of the present invention are formulated into an inhalant, e.g. polychloromonofluoromethane may be used as a solvent. Further, the compound of the present invention may be used in combination with other drugs, depending on the symptoms of a patient. For example, the compound may be used in combination with other bronchodilators, antiallegic agents, steroids, expectorants and antibiotics. When the compound of the present invention administered to human, the compound may be orally administered in the form of tablet, powder, granule, capsule, sugar-coated tablet, suspension and syrup, or parenterally administered in the form of solution or suspension for injection, cream and spray. The dose is varied depending on the age, weight or condition of the patient. However, the dose may generally be 3 to 300 mg per day for an adult. The daily dose may be administered at one time, or it may also be devided into 2 or 3 portions and these portions are administered at intervals. The administration is generally continued for a period of from several days to 2 months. The daily dose and the administration period are varied to some extent depending on the condition of the patient. The bronchial smooth muscle-relaxing action of the sulfonamide derivative of the present invention was evaluated by the effect on suppression of KCl-induced contraction and PGF 2α -induced contraction of bronchial specimens excised from guinea pigs. The results are as follows. The compound of the present invention not only inhibits the contraction induced by the action of KCl which is a bronchial smooth muscle-contracting substance, but also strongly inhibits the contraction induced by the action of PGF 2α . For example, the concentrations (hereinafter referred to as "ED₅₀") of 1-(8-chloro-5-quinolinesulfonylaminoethyl)-4-(3,4-methylenedioxybenzyl)homopiperazine (38) which are effective for attaining a 50 % relaxation of the bronchial smooth muscles contracted by KCl and PGF 2α , respectively, are 26 µM and 74 µM. The ED₅₀ values of N-[2-(3,4-methylenedioxybenzylamino)ethyl]-5-isoquinolinesulfonamide (3) in respect of the inhibitions of KCl-induced contraction and PGF 2α -induced contraction are 5.2 µM and 23 µM, respectively. By contrast, aminophylline which is a xanthine derivative does not exhibit a 50 % relaxation of PGF 2α -induced contraction even when administered in an amount as large as 200 µM. The ED₅₀ values of N-(2-aminoethyl)-N-hexyl-5-isoquinolinesulfonamide hydrochloride [comparative compound (1)] and 1-(5-isoquinolinesulfonyl)-3-aminopiperidine hydrochloride [comparative compound (2)], which are conventional compounds, in respect of the inhibition of PGF 2α -induced contraction, are 101 µM and 93 µM, respectively. Further, the inhibiting action of the compound of the present invention on the histamine-induced contraction of the trachea of a guinea pig was examined by in vivo experiment. As a result, the in vivo bronchodilation action was confirmed. That is, in the in vivo experiment on the trachea of a guinea pig, 1-(8-chloro-5-quinolinesulfonylaminoethyl)-4-(3,4-methylenedioxybenzyl)homopiperazine (38) and N-[2-(3,4-methylenedioxybenzylamino)ethyl]-5-isoquinolinesulfonamide (3) respectively suppressed 45 % and 36 % of the bronchial contraction induced by intravenous administration of 1 mg/kg of histamine. By contrast, aminophylline, comparative compound (1) and comparative compound (2), which were used as controls, respectively suppressed only 7 %, 9 % and 12 % of the bronchial contraction induced by intravenous administration of 1 mg/kg of histamine. As described above, the sulfonamide derivative of the present invention exhibits an excellent bronchial smooth muscle relaxation action, suggesting that it is a useful substance as a medicine for the prevention and treatment of respiratory organ diseases, such as asthma. Particularly, in view of the fact that in recent years, a number of publications report that prostaglandins have some part in respiratory diseases, such as asthma [see Lambley, J.E. and Smith, A.P., European Journal of Pharmacology, Vol. 30, pp. 148-153 (1975) and Orehek, J. et al., Journal of Pharmacology & Experimental Therapeutics, Vol. 194, pp. 554-564 (1975)], it is strongly suggested that the compound of the present invention which exhibits strong inhibitory action not only on the KCl or histamine-induced bronchial contraction, but also on the PGF 2α -induced bronchial contraction which is almost not affected by any conventional bronchodilator, has clinical usefulness. Best Mode for Carrying Out the Invention In each of the following Examples, the yields of the desired compounds of the present invention as shown in Tables 2, 4, 6, 8, 10, 12 and 14 are determined relative to the amount of a sulfonamide which is used in each Example for the reaction between the sulfonamide and an amine for bonding R⁴ shown in formula (I). On the other hand, the yields of desired compounds of the present invention as shown in Table 16 are determined relative to the amount of 8-ethoxy-5-quinolinesulfonic acid or 5-quinolinesulfonic acid which is used in each Example shown in Table 16. Hereinbelow, the present invention will be described in detail with reference to the following Examples. Example 1 52.8 g of 5-isoquinolinesulfonyl chloride hydrochloride was dissolved in 200 ml of water and extracted with 300 ml of dichloromethane. The resultant aqueous layer was taken out and adjusted to pH 5 with a saturated aqueous sodium hydrogencarbonate solution, and subjected to extraction with 200 ml dichloromethane. Then, the dichloromethane layers were mixed together and added dropwise to a dichloromethane solution (300 ml) containing 24.4 g of ethanolamine over 30 minutes while cooling with ice. The precipitated crystal was subjected to filtration, washed successively with 300 ml of water and 200 ml of ethyl acetate, and dried under reduced pressure at 40 °C, to thereby obtain 40.0 g of N-(2-hydroxyethyl)-5-isoquinolinesulfonamide (yield: 79 %). The thus obtained 40.0 g of the N-(2-hydroxyethyl)-5-isoquinolinesulfonamide was dissolved in 103 ml of pyridine. To the resultant solution was added 33.3 g of paratoluenesulfonyl chloride and stirred at room temperature for 24 hours. After completion of the reaction, the pyridine was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was dissolved in 500 ml of chloroform and extracted with 300 ml of water. The chloroform layer was dried over anhydrous magnesium sulfate. Then, the chloroform was removed by distillation under reduced pressure to obtain a residue as crystals. The thus obtained residual crystals were suspended in acetone and subjected to filtration, followed by vacuum drying, to thereby obtain 46.5 g of N-(2-paratoluenesulfonyloxyethyl)-5-isoquinolinesulfonamide (yield: 72 %). To 4.06 g of the thus obtained N-(2-paratoluenesulfonyloxyethyl)-5-isoquinolinesulfonamide was added 40 ml of tetrahydrofuran containing 4.53 g of 3,4-methylenedioxybenzylamine. The resultant mixture was heated in a sealed vessel at 100 °C for 17 hours and then, the solvent was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was subjected to purification by means of a column for chromatography packed with 200 g of silica gel (Wacogel C-200, manufactured by Wako Pure Chemical Industries, Ltd., Japan) using, as an eluent, a mixture of methanol and chloroform (0.5 % methanol) to obtain 1.84 g of N-[2-(3,4-methylenedioxybenzylamino)ethyl]-5-isoquinolinesulfonamide (3) (yield: 48 %). NMR spectrum (δppm)(CDCl₃/CD₃OD): 2.5-3.5(6H), 5.9(2H), 6.6-6.8(3H), 7.5-7.8(1H), 8.2-8.8(4H), 9.3(1H). IR spectrum(cm⁻¹): 2930, 1620, 1510, 1340, 1250, 1160, 1140, 1020. Mass spectrum (m/e): 385 Example 2 Substantially the same procedure as in Example 1 was repeated except that 4.96 g of 3,4-methylenedioxyphenethylamine was used instead of 3,4-methylenedioxybenzylamine, to thereby obtain 1.95 g of N-[2-(3,4-methylenedioxyphenethylamino)ethyl]-5-isoquinolinesulfonamide (1) (yield: 49 %) NMR spectrum (δ ppm)(CDCl₃/CD₃OD): 2.4-3.1(8H), 5.9(2H), 6.5-6.8(3H), 7.5-7.8(1H), 8.1-8.7(4H), 9.2(1H) IR spectrum (cm⁻¹): 2930, 1615, 1510, 1330, 1250, 1160, 1140, 1010 Mass spectrum (m/e): 399 Example 3 To 14.2 g of 8-chloro-5-quinolinesulfonic acid were added 142 ml of thionyl chloride and 1.42 ml of dimethylformamide. The resultant mixture was heated under reflux for 3 hours and the thionyl chloride was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was dissolved in 100 ml of ice water and adjusted to pH 6 with a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with 100 ml of dichloromethane. The dichloromethane layer was added dropwise to 100 ml of a dichloromethane solution containing 3.56 g of ethanolamine and 5.6 g of triethylamine over 30 minutes while cooling with ice. The mixture was stirred at a temperature of 15 °C to 20 °C for 2 hours. After completion of the reaction, the resultant mixture was washed with 200 ml of water and dried over anhydrous magnesium sulfate. Then, the solvent was removed by distillation under reduced pressure, to thereby obtain 14.0 g of N-(2-hydroxyethyl)-8-chloro-5-quinolinesulfonamide (yield: 84 %). To 5.74 g of N-(2-hydroxyethyl)-8-chloroquinolinesulfonamide was added 80 ml of pyridine. Then, to the mixture was added 7.6 g of paratoluenesulfonyl chloride and stirred at a temperature of 15 °C to 20 °C for 24 hours. After completion of the reaction, the resultant mixture was put into 200 g of ice water and extracted twice with 200 ml of dichloromethane, followed by drying over anhydrous magnesium sulfate. Then, the solvent was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was subjected to purification by means of a column for chromatography packed with 250 g of silica gel (Wacogel C-200, manufactured by Wako Pure Chemical Industries, Ltd., Japan) using chloroform as an eluent, to thereby obtain 6.25 g of N-(2-paratoluenesulfonyloxyethyl)-8-chloro-5-quinolinesulfonamide (yield: 71 %). 3.32 g of N-(2-paratoluenesulfonyloxyethyl)-8-chloro-5-quinolinesulfonamide was reacted with 30 ml of a tetrahydrofuran solution containing 3.41 g of 3,4-methylenedioxybenzylamine in a sealed vessel at 70 °C for 17 hours, and the solvent was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was subjected to purification by means of a column for chromatography packed with 200 g of silica gel (Wacogel C-200, manufactured by Wako Pure Chemical Industries, Ltd., Japan) using, as an eluent, a mixture of methanol and chloroform (5 % methanol) to thereby obtain 1.80 g of N-[2-(3,4-methylenedioxybenzylamino)ethyl]-8-chloro-5-quinolinesulfonamide (13) (yield: 57 %) NMR spectrum (δ ppm)(CDDl₃/CD₃OD): 2.5-3.5(6H), 5.9(2H), 6.6-6.8(3H) 7.2-8.2(3H), 8.9-9.1(2H). IR spectrum (cm⁻¹): 2930, 1490, 1330, 1260, 1150, 1135, 1020, 910. Mass spectrum (m/e): 419 Example 4 Substantially the same procedure as in Example 3 was repeated except that 3.41 g of 4-methoxyphenethylamine was used instead of 3,4-methylenedioxybenzylamine, to thereby obtain 2.05 g of N-[2-(4-methoxyphenethylamino)ethyl]-8-chloro-5-quinolinesulfonamide (5) (yield: 65 %). NMR spectrum (δ ppm)(CDCl₃/CD₃OD): 2.3-3.2(6H), 3.7(2H), 6.6-7.1(3H) 7.3-8.2(3H), 8.0-9.2(2H). In spectrum (cm⁻¹): 2930, 1485, 1330, 1260, 1150, 1140, 910. Mass spectrum (m/e): 419 Examples 5 to 11 Substantially the same procedure as in Example 3 was repeated except that 4-chlorophenethylamine, 4-trifluorophenethylamine, 3,4-dimethoxyphenethylamine, 3,4-methylenedioxyphenethylamine, 3-chlorobenzylamine, 4-methoxybenzylamine and 3,4-dimethoxybenzylamine were individually used in place of 3,4-methylenedioxybenzylamine, to thereby obtain compounds (6), (7), (8), (9), (10), (11) and (12). The reaction conditions are shown in Table 1. The yields and analytical data of these compounds are shown in Table 2. Compound No. Yield (%) Mass spectrum (m/e) NMR spectrum (δ ppm) (CDCl₃/CD₃OD) Example 5 (6) 72 424 2.3-3.2(8H),6.8-7.1(4H) 7.4-8.2(3H),8.9-9.2(2H) Example 6 (7) 75 457 2.3-3.1(8H),6.6-7.1(4H) 7.5-8.2(3H),8.9-9.2(2H) Example 7 (8) 66 449 2.5-3.2(8H),3.8(6H), 6.4-6.8(3H),7.4-8.2(3H), 8.9-9.2(2H) Example 8 (9) 75 433 2.4-3.1(8H),5.9(2H), 6.5-6.8(3H),7.4-8.1(3H), 8.9-9.2(2H) Example 9 (10) 45 410 2.5-3.5(6H),6.5-6.8(3H), 6.9-7.3(1H),7.5-8.1(3H), 8.9-9.2(2H) Example 10 (11) 50 405 2.5-3.5(6H),3.7(3H), 6.4-6.7(4H),7.4-8.2(3H), 8.9-9.3(2H) Example 11 (12) 52 435 2.4-3.5(6H),3.8(6H), 6.4-6.8(3H),7.4-8.2(3H) 8.9-9.2(2H) Examples 12 to 20 Substantially the same procedure as described in Examples 3 to 11 was repeated except that 8-ethoxy-5-quinolinesulfonic acid was used instead of 8-chloro-5-quinolinesulfonic acid in order to obtain N-[2-(paratoluenesulfonyloxy)ethyl]-8-ethoxy-5-quinolinesulfonamide and 3.39 g of the thus obtained sulfonamide was used, to thereby obtain compounds (14) to (22), respectively. The reaction conditions are shown in Table 3 and the yields and analytical data of these compounds are shown in Table 4. Compound No. Yield (%) Mass spectrum (m/e) NMR spectrum (δ ppm) (CDCl₃/CD₃OD) Example 12 (16) 65 429 1.5-2.0(3H),2.3-3.2(8H) 3.7(3H),4.1-4.6(2H), 6.8-8.2(7H),8.9-9.2(2H) Example 13 (17) 69 433 1.5-2.0(3H),2.3-3.1(8H), 4.1-4.6(2H),6.6-8.2(7H), 8.9-9.2(2H) Example 14 (18) 59 467 1.5-2.0(3H),2.5-3.2(8H), 4.1-4.6(2H),6.6-8.2(7H), 8.9-9.2(2H) Example 15 (19) 71 459 1.5-2.0(3H),2.5-3.2(8H), 3.8(6H),4.1-4.6(2H), 6.5-8.1(6H),8.9-9.2(2H) Example 16 (20) 63 443 1.5-2.0(3H),2.5-3.3(8H), 4.1-4.6(2H),5.9(2H), 6.5-8.1(6H),8.9-9.2(2H) Example 17 (21) 59 419 1.5-2.0(3H),2.5-3.5(6H), 4.1-4.6(2H),6.5-8.2(7H), 8.9-9.3(2H) Example 18 (22) 48 415 1.5-2.0(3H),2.5-3.5(6H), 3.7(3H),4.1-4.6(2H), 6.4-8.2(7H),8.9-9.2(2H) Example 19 (23) 51 445 1.5-2.0(3H),2.4-3.5(6H), 3.8(6H),4.1-4.6(2H) 6.4-8.2(6H),8.9-9.2(2H) Example 20 (24) 55 429 1.5-2.0(3H),2.5-3.5(6H), 4.1-4.6(2H),5.9(2H), 6.6-8.2(6H),8.9-9.2(2H) Example 21 Compound (23) was obtained in substantially the same manner as described in Example 3 except that 5-quinolinesulfonic acid was used in place of 8-chloro-5-quinolinesulfonic acid (yield: 52 %). NMR Spectrum (δ ppm) (CDCl₃/CD₃OD): 2.5-3.5(6H), 5.9(2H), 6.6-6.8(3H) 7.4-8.0(2H), 8.2-8.6(2H), 8.8-9.2(2H) IR absorption spectrum (cm⁻¹): 2940, 1490, 1340, 1260, 1150, 1135 Mass spectrum (m/e):385 Example 22 8.0 g of 1-chloro-5-isoquinolinesulfonylchloride hydrochloride was dissolved in 40 ml of iced water and the pH of the solution was adjusted to 6 with a saturated aqueous sodium hydrogencarbonate solution, followed by extraction with 67 ml of dichloromethane. The resultant dichloromethane layer was added dropwise into 67 ml of a dichloromethane solution containing 1.69 g of ethanolamine and 2.7 g of triethylamine for 20 minutes and then the mixture was stirred for two hours at 15 to 20 °C while cooling with ice. After completion of the reaction, the mixture was washed with 100 ml of distilled water and was dried over anhydrous magnesium sulfate. Then, the dichloromethane was removed under reduced pressure to obtain 5.74 g of N-(2-hydroxylethyl)-1-chloro-5-isoquinolinesulfonamide (yield: 74 %). To 5.74 g of N-(2-hydroxyethyl)-1-chloro-5-isoquinolinesulfonamide was successively added 80 ml of pyridine and 7.62 g of p-toluenesulfonylchloride and the mixture was stirred at 15 to 20 °C for 24 hours. After completion of the reaction, the mixture was cooled with 200 g of ice water and the mixture was subjected to extraction with 200 ml of dichloromethane twice. The resultant dichloromethane layer was dried over anhydrous magnesium sulfate and the residue was subjected to purification by means of a chromatography column packed with 200 g of silica gel (Wacogel C-200, manufactured by Wako Pure Chemical Industries, Ltd., Japan) using chloroform as an eluent to obtain 6.61 g of N-(2-paratoluenesulfonyloxyethyl)-1-chloro-5-isoquinolinesulfonamide (yield: 75 %). 30 ml of a tetrahydrofuran solution containing 3.3 g of N-(2-paratoluenesulfonyloxyethyl)-1-chloroisoquinoline and 1.13 g of 3,4-methylenedioxybenzylamine was kept in a sealed vessel at 70 °C for 8 hours to advance a reaction. The solvent was removed under reduced pressure and the residue was subjected to purification by means of a chromatography column packed with 200 g of silica gel (Wacogel C-200, manufactured by Wako Pure Chemical Industries, Ltd., Japan) using, as an eluent, a mixture of methanol and chloroform (5 % methanol) to thereby obtain 1.57 g of N-[2-(3,4-methylenedioxybenzylamino) ethyl]-1-chloro-5-isoquinolinesulfonanide (yield: 50 %). 20 ml of (6 mol/liter) hydrochloric acid was added to 1.50 g of N-[2-(3,4-methylenedioxybenzylamino) ethyl]-1-chloro-5-isoquinolinesulfonamide, and the mixture was heated at 65 °C for 6 hours. The resultant crystalline precipitate was filtered off, and washed with 10 ml of ice water twice and then washed with 10 ml of ethanol twice, followed by drying, to thereby obtain 1.3 g of N-[2-(3,4-methylenedioxybenzylamino)-ethyl]-1-hydroxy-5-isoquinolinesulfonamide hydrochloride (4) (yield: 83 %). NMR spectrum (δ ppm) (DMSO-d₆): 3.1-3.8(6H), 6.0(2H), 6.7-6.9(3H), 7.0-7.7(3H), 8.2-8.6(2H) IR spectrum (cm⁻¹) 2940, 1685, 1630, 1540, 1350, 1260, 1150, 1130, 1070 Mass spectrum (m/e): 437 Example 23 Compound (2) as obtained in substantially the same manner as described in Example 22 except that 3,4-methylenedioxyphenethylamine was used in place of 3,4-methylenedioxybenzylamine. The reaction conditions are shown in Table 5, and the yields and analytical data are shown in Table 6. Compound No. Yield (%) Mass spectrum (m/e) NMR spectrum (δ ppm) (DMSO-d₆) Example 23 (2) 34 451 2.9-3.8(8H), 6.0(2H), 6.7-6.9(3H), 7.0-7.7 (3H), 8.2-8.6(2H) Example 24 Substantially the same procedure as described in Example 3 was repeated except that 4.38 g of 2-hydroxypropylamine was used instead of ethanolamine, to thereby obtain 14.1 g of N-(2-hydroxypropyl)-8-chloro-5-quinolinesulfonamide (yield: 80 %). To 14.1 g of N-(2-hydroxypropyl)-8-chloro-5-quinolinesulfonamide were added 180 ml of pyridine and 17.87 g of paratoluenesulfonyl chloride, followed by stirring for 24 hours at a temperature of 15 °C to 20 °C. After completion of the reaction, to the reaction mixture was added 450 g of ice water, followed by extraction twice each with 500 ml of dichloromethane. The dichloromethane layer was dried over anhydrous magnesium sulfate to obtain a residue. The thus obtained residue was subjected to purification by silica gel column chromatography (Wacogel C-200, 750 g; solvent: chloroform) to obtain 15.0 g of N-(2-paratoluenesulfonyloxypropyl)-8-chloro-5-quinolinesulfonamide (yield: 70 %) 50 ml of a tetrahydrofuran solution containing 4.58 g of N-(2-paratoluenesulfonyloxypropyl)-8-chloro-5-quinolinesulfonamide and 4.95 g of 3,4-dimethoxyphenethylamine was heated at 70 °C for 8 hours in a sealed vessel. Then, the solvent was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was subjected to purification by silica gel column chromatography [Wacogel C-200, 200 g; solvent: a mixture of methanol and chloroform (5 % methanol)] to obtain 2.37 g of N-[2-(3,4-dimethoxyphenethylamino)-2-methylethyl]-8-chloro-5-quinolinesulfonamide (24) (yield: 51 %). NMR spectrum (δ ppm)(CDCl₃/CD₃OD): 0.9(3H), 2.3-3.1(7H), 3.8(6H), 6.5-6.8(3H), 7.8-8.2(3H), 8.9-9.2(2H). IR spectrum (cm⁻¹): 2930, 1490, 1330, 1260, 1150, 1140, 1020, 915. Mass spectrum (m/e): 463. Example 25 1.0 g of N-[2-(3,4-methylenedioxybenzylamine)ethyl]-5-isoquinolinesulfonamide (3) obtained in Example 1 was dissolved in 10 ml of methanol. To the solution was added an equal amount of aqueous hydrochloric acid, and the mixture was stirred for 10 minutes. Then, the solvent was removed by distillation under reduced pressure to obtain a residue. The thus obtained residue was subjected to recrystallization from a mixture of methanol and ether to obtain 0.86 g of N-[2-(3,4-methylenedioxybenzylamino)ethyl]-5-isoquinolinesulfonamide hydrochloride (yield: 79 %). Elementary analysis (%) of hydrochloride of compound (3) Calculated: C: 54.09, H: 4.78, N: 9.96, Cl: 8.40 Found: C: 54.31, H: 4.52, N: 10.11, Cl: 8.62 Application Example 1 Inhibitory effect on KCl-induced contraction of tracheal specimens excised from guinea pigs According to a method in which tracheal specimens excised from guinea pigs were used (Takagi and Ozawa, "Yakubutsugaku Jikken (Experiments in Pharmacology)", pp.100-102, 1960, published by Nanzando Japan; and Fujiwara and Shibata, "Yakurigaku Kiso Jikenho (Methods of Fundamental Experiments in Pharmacology)" pp.131-134, 1982, published by Kyourin, Japan), relaxing effect of sulfonamide derivatives of the present invention on bronchial smooth muscle was examined. Of compounds (1) to (24) shown herein, compounds other than acid addition salts were individually used in the form of a hydrochloride which was obtained by the same method as described in Example 25. From male guinea pigs weighing 350 to 500 g (Hartley strain, Kuroda Junkei Dobutsu), tracheas were excised and each of the excised tracheal specimens was hung in 20 ml of a Magnus tube filled with Krebs-Henseleit solution under isotonic conditions and the solution temperature was kept at 37 °C. An aqueous KCl solution was dropwise added into the Magnus tube (final KCl concentration: 20 mM) to contract the tracheal specimen. After the KCl-induced contraction became stable, each of the compounds of the present invention was dissolved in distilled water or physiological saline, and the compound solution was cumulatively added into the Magnus tube. The relaxing effect of each of the compounds of the present invention on contracted tracheal specimens was evaluated and a dose-response curve was obtained. A dose required for relaxing KCl-induced contraction to 50 %, i.e., ED₅₀ was calculated from the dose-response curve. For comparison, the same method as described above was repeated except that aminophylline was used, to thereby determine an ED₅₀. The number of tracheal specimens in each group was 3. The results are shown in Table 7. Effect on KCl-induced contraction Compound No. ED₅₀ (µM) Compound No. ED₅₀ (µM) Compound No. ED₅₀ (µM) (1) 7.4 (19) 128 (2) 15 (20) 131 (3) 5.2 (21) 163 (4) 10 (22) 31 (5) 28 (6) 60 (7) 70 (23) 86 (8) 120 (9) 30 (10) 120 (11) 125 (12) 160 (13) 28 (14) 35 (15) 71 (16) 75 (17) 125 (18) 38 (24) 110 Application Example 2 Inhibitory effect on PGF 2α -induced contraction of tracheal specimens excised from guinea pigs Tracheal specimens excised from male guinea pigs weighing 350 to 500 g (Hartley strain, Kuroda Junkei Dobutsu) were contracted in substantially the same manner as in Application Example 1 except that PGF 2α (final concentration: 1 µm) was used instead of KCl. After the contraction of the tracheal specimens became stable, each of the compounds (hydrochloride) of the present invention was dissolved in distilled water or physiological saline, and the compound solution was cumulatively added into the Magnus tube in the same manner as in Application Example 1. The relaxing effect of each of the compounds of the present invention on the contracted specimens was evaluated and a dose-response curve was obtained. The dose required for relaxing PGF 2α -induced contraction to 50 %, i.e., ED₅₀ was calculated form the dose-response curve. Of compounds (3) and (4), which were individually used herein, compounds other than acid addition salts were used in the form of a hydrochloride which was obtained in the same manner as described in Example 25. For comparison, the same procedure as described above was repeated except that aminophylline, comparative compound (1) and comparative compound (2) were individually used instead of the compound of the present invention, to obtain an ED₅₀. The number of specimens in each group was 3. The results are shown in Table 8. Application Example 3 Effect on trachea in vivo According to a modified method of Konzett-Rössler method [see J. Martinez et al, Bronchial Arterial Injections, vol. 33, 295, (1961); Masaaki Takai et al, Oyo Yakuri (Applied Pharmacology), vol. 17, p.345, (1979)], effect of the compounds of the present invention on trachea in vivo was examined. Of compounds (3) and (4), which were used herein, compounds other than acid addition salts were individually subjected to testing in the form of a hydrochloride which was obtained in the same manner as described in Example 25. Urethane was intraperitoneally administered to male guinea pigs weighing 350 to 600 g (Hartley strain, Kuroda Junkei Dobutsu) in an amount of 1.5 g/kg of body weight to anesthetize the animals. Then, cannulae were inserted into the trachea and femoral vein of each animal under urethane anesthesia and fixed. The inserted tracheal cannula was connected to a respirator for small animal (model 1683, manufactured by Harvard Co., Ltd.) and a pneumotachometer (model MHF-1200, manufactured by Nihon Kohden Corp.) through a bottle containing water, the water surface of which was adjusted to a level which is 10 cm high from the bottom, and a respiratory volume was determined. Each of the above-mentioned compounds of the present invention was administered to guinea pigs through the femoral vein in an amount of 1 mg/kg of body weight. After 3 minutes from the administration, histamine was administered to the same guinea pigs through the femoral vein in an amount of 20 µg/kg of body weight, to thereby induce contraction of trachea and the inhibition of the histamine-induced tracheal contraction by each of the above-described compounds of the present invention was determined. For comparison, the inhibition of histamine-induced tracheal contraction by each of aminophylline, comparative compound (1) and comparative compound (2) was determined in substantially the same manner as described above. As a solvent for each compound, physiological saline was used. The number of the guinea pigs tested in each group was 3. The results are shown in Table 9. Comparative compound (2): 1-(5-isoquinolinesulfonyl)-3-aminopiperidine hydrochloride Industrial Applicability A pharmaceutical composition containing the novel sulfonamide derivative of the present invention or a pharmaceutically acceptable acid addition salt thereof as an active ingredient exhibits excellent bronchodilating effect, but does not exhibit adverse effect on heart. In addition, the compounds of the present invention are useful as an effective medicine for prevention and treatment of respiratory diseases, such as an intractable asthma which is not relieved by the treatment of a xanthine derivative.

Claims: Claims for the following Contracting States : DE, NL, GB, CH, LI, FR, LU, SE, AT, BE, IT, DK A sulfonamide derivative represented by formula (I) or a pharmaceutically acceptable acid addition salt thereof: X-SO₂-(NH-CH₂-CR³H) n -R⁴ (I) wherein X represents a quinoline residue represented by formula (II) or an isoquinoline residue represented by formula (III) where R¹ is a hydrogen atom, a halogen atom, a C₁₋₆-alkyl group or a C₁₋₆-alkoxy group, or where R² is a hydrogen atom or a hydroxyl group, and wherein: (a) when X is a quinoline residue (II), n is 1, in which R³ is a hydrogen atom or a C₁₋₆-alkyl group and R⁴ is a substituted aralkylamino group, in which, a substituted aralkyl moiety of the substituted aralkylamino group is represented by the following formula (IV): wherein p represents an integer of from 1 to 3, each of R⁵ and R⁶ independently represents a hydrogen atom, a C₁₋₃-alkyl group, a C₁₋₃-alkoxy group, a halogen atom or a trifluoromethyl group, with the exception that R⁵ and R⁶ cannot be simultaneously a hydrogen atom, and R⁵ and R⁶ may be directly bonded with each other to form a methylenedioxy group, and (b) when X is an isoquinoline residue (III), n is 1, in which R³ is a hydrogen atom or a C₁₋₆-alkyl group and R⁴ is a 3,4-methylenedioxyphenethylamino group or a 3,4-methylenedioxybenzylamino group. The sulfonamide derivative or pharmaceutically acceptable acid addition salt thereof according to claim 1, wherein X represents an isoquinoline residue represented by formula (III), R³ is a hydrogen atom, and R⁴ is a 3,4-methylenedioxyphenethylamino group or a 3,4-methylenedioxybenzylamino group. The sulfonamide derivative or pharmaceutically acceptable acid addition salt thereof according to any one of claims 1 and 2, wherein X represents an isoquinoline residue represented by formula (III) where R² is a hydrogen atom. The sulfonamide derivative or pharmaceutically acceptable acid addition salt thereof according to any one of claims 1 or 2, wherein X represents an isoquinoline residue represented by formula (III) where R² is a hydroxyl group. A pharmaceutical composition comprising the sulfonamide derivative or pharmaceutically acceptable acid addition salt thereof according to any one of claims 1 to 4, and at least one pharmaceutically acceptable carrier or diluent. Claims for the following Contracting State : ES A process for preparing a pharmaceutical composition, characterized in that it comprises admixing with at least one pharmaceutically acceptable carrier and/or diluent a sulfonamide derivative represented by formula (I) or a pharmaceutically acceptable acid addition salt thereof wherein X represents a quinoline residue represented by formula (II) or an isoquinoline residue represented by formula (III) where R¹ is a hydrogen atom, a halogen atom, a C₁₋₆-alkyl group or a C₁₋₆-alkoxy group, or where R² is a hydrogen atom or a hydroxyl group, and wherein: (a) when X is quinoline residue (II), n is 1, in which R³ is a hydrogen atom or a C₁₋₆-alkyl group and R⁴ is a substituted aralkylamino group, in which a substituted aralkyl moiety of the substituted aralkylamino group is represented by the following formula (IV): wherein p represents an integer of from 1 to 3, each of R⁵ and R⁶ independently represents a hydrogen atom, a C₁₋₃-alkyl group, a C₁₋₃-alkoxy group, a halogen atom or a trifluoromethyl group, with the exception that R⁵ and R⁶ cannot be simultaneously a hydrogen atom, and R⁵ and R⁶ may be directly bonded with each other to form a methylenedioxy group, and (b) when X is an isoquinoline residue (III), n is 1, in which R³ is a hydrogen atom or a C₁₋₆-alkyl group and R⁴ is a 3,4-methylenedioxyphenethylamino group or a 3,4-methylenedioxybenzylamino group. The process according to claim 1, characterized in that said pharmaceutically acceptable carrier is at least one member selected from the group consisting of a vehicle, a binder, a disintegrator, a lubricant, and an additive. The process according to claim 2, characterized in that said vehicle is at least one member selected from the group consisting of lactose, sucrose, glucose, starch and crystalline cellulose. The process according to claim 2, characterized in that said binder is at least one member selected from the group consisting of hydroxypropyl cellulose, carboxymethyl cellulose, starch, gum arabic, gelatin, glucose, sucrose, tragacanth and sodium alginate. The process according to claim 2, characterized in that said disintegrator is at least one member selected from the group consisting of carboxymethyl cellulose, starch and calcium carbonate. The process according to claim 2, characterized in that said lubricant is at least one member selected from the group consisting of magnesium stearate, refined tarc, stearic acid and calcium stearate. The process according to claim 2, characterized in that said additive is at least one member selected from the group consisting of lecithine, soybean oil and glycerin. The process according to claim 1 or 2, characterized in that said pharmaceutically acceptable diluent is at least one member selected from the group consisting of distilled water, physiological saline, Ringer's solution, ethanol, vegetable oil, and polychloromonofluoromethane. The process according to claim 1, wherein X represents an isoquinoline residue represented by formula (III), R³ is a hydrogen atom, and R⁴ is a 3,4-methylenedioxyphenethylamino group or a 3,4-methylenedioxybenzylamino group. The process according to claim 9, wherein X represents an isoquinoline residue represented by formula (III) where R² is a hydrogen atom. The process according to claim 9, wherein X represents an isoquinoline residue represented by formula (III) where R² is a hydroxyl group.

Inventors: KAJIHARA AKIRO - - SORYO-MACHI, MIYOSHI SHIRO - - - NISHI-KASH, KAJIHARA, AKIRO 19-8-203, SORYO-MACHI, MIYOSHI, SHIRO 2-3-1-809, NISHI-KASHIWADAI
Applicants: ASAHI CHEMICAL IND, ASAHI KASEI KOGYO KABUSHIKI KAISHA
Application year: 1990
Main classification: C07D215
IPC codes: C07D405, C07D215, C07D217, A61K31, C07D401