Tetrahydronaphthalene derivatives and preparation thereof

Abstract: A tetrahydronaphthalene derivative of the formula: wherein R¹ is a substituted or unsubstituted phenyl group, naphthyl group, a sulfur- or nitrogen-containing heterocyclic group, a lower alkyl group or cycloalkyl group, and R² is hydroxymethyl group, carboxyl group, a lower alkoxycarbonyl group or a group of the formula: wherein R³ is hydrogen atom or a lower alkyl group, R⁴ is a lower alkoxycarbonyl-phenyl group, carboxy-phenyl group, a lower alkyl group, a lower alkoxycarbonyl-lower alkyl group or carboxy-lower alkyl group, and m and n are different and are 1 or 2, or a pharmaceutically acceptable salt thereof, which are useful as a platelet aggregation-inhibiting agent and as an agent for the treatment, amelioration and/or prophylaxis of a variety of thrombosis or embolism, coronary and cerebral vascular smooth muscle vellication, asthma, and the like, processes for the preparation thereof, and pharmaceutical composition containing said compound as an active ingredient.

Description: This invention relates to novel tetrahydronaphthalene derivatives, processes for preparation thereof and intermediates therefor. Thromboxan A₂ (hereinafter, referred to as "TxA₂") is a metabolite of arachidonic acid which exists widely in various organs of animals (e.g. liver, kidney, lung, brian etc.). Said TxA₂ is known to show platelet aggregation activity and induces a variety of thrombosis such as peripheral vascular thrombosis, pulmonary embolism, coronary artery thrombosis, myocardial infarction, transient ischemia, and the like. Therefore, 2-benzenesulfonylaminoethyl derivatives of phenoxyacetic acid or tetrahydronaphthyloxyacetic acid which have TxA₂-antagonistic activity have been suggested to be useful for therapuetic treatment of these diseases (cf. Thrombosis Research, 35, 379-395,1984, U.S. Patent No. 4868331). In EP-253257 there is described amino-5,6,7,8-tetrahydronaphyl-oxyacetic acids, processes for their preparation and use of them as medicaments. It is claimed that certain of the derivatives have TxA₂ antagonistic activity. In our earlier filed patent specification No. EP-317321 we describe novel indan derivatives and processes for preparing them. These indan derivatives show TxA₂ antagonistic activity. In another earlier filed patent specification of ours, EP-330380, we describe novel indanoxyacetic acid derivatives and processes for preapring the same. These indanoxyacetic acid derivatives show TxA₂ antagonistic activity. As a result of various investigation, there has been found novel tetrahydronaphthalene derivatives which show stronger TxA₂ antagonistic activity as compared with the above known compounds. Thus, the objects of the invention are to provide novel tetrahydronaphthalene derivatives and a pharmaceutical composition containing the same. Another object of the invention is to provide processes for preparing said compounds. A further object of the invention is to provide novel intermediates which are useful in the synthesis of the tetrahydronaphthalene derivatives of the invention. This invention relates to a tetrahydronaphthalene derivative of the formula: wherein R¹ is wherein R₆ is H, CH₃, Cl or -OCH₃ and R² is carboxyl or a group of the formula: wherein R³ is hydrogen and R⁴ is a carboxy-(C₁-C₆)-alkyl group and m=1 and n=2, or a pharmaceutically acceptable salt thereof. Said tetrahydronaphtalene derivative of the invention and pharmaceutically acceptable salts thereof show potent TxA₂ antagonistic and/or platelet aggregation-inhibiting activities and are useful for the therapeutic treatment, amelioration and/or prophylaxis of a variety of thrombosis or embolism, coronary and cerebral vascular smooth muscle vellication, asthma, and the like. Most preferred examples of the compounds of the invention are those of the formula (I) wherein R¹ is chlorophenyl group, and R² is a group of the formula: wherein R³ is hydrogen atom and R⁴ is carboxyethyl group or carboxypropyl group. The compounds (I) of the invention may exist in the form of two optically active isomers due to one asymmetric carbon atom, and this invention includes these optically active isomers and a mixture thereof. According to this invention, the compound (I) or salts thereof can be prepared by condensing an aminotetrahydronaphthalene derivative of the formula: wherein R², m and n are as defined above, or a salt thereof with a sulfonic acid compound of the formula: R¹SO₃H (III) wherein R¹ is as defined above, or a reactive derivative thereof. On the other hand, the compounds of the formula (I) wherein R² is a group of the formula: i.e. the compounds of the formula (I-c): wherein R¹, R³, R⁴, m and n are as defined above may be prepared by condensing a compound of the formula (I-b): wherein R¹, m and n are as defined above; or a reactive derivative at carboxyl group thereof with an amine compound of the formula: R³-NH-R⁴ (IV) wherein R³ and R⁴ are as defined above, or a salt thereof. Moreover, the compounds of the formula (I-c), may be prepared by hydrolyzing a compound of the formula (I-e): wherein R⁶ is a (C₁-C₆) alkoxycarbonyl-(C₁-C₆) alkyl group, and R¹,R³, m and n are as defined above. The condensation reaction of the aminotetrahydronaphthalene (II) or a salt thereof with the sulfonic acid compound (III) or a reactive derivative thereof can be carried out in the presence or absence of an acid acceptor. The reactive derivative of the compound (III) includes any conventional reactive derivatives, for example, the corresponding sulfonyl halide. The acid acceptor includes any conventional agents, for example, alkali metal carbonates alkali metal hydrogen carbonates, trialkylamines, pyridine, and the like. Examples of the salt of the starting compound (II) include mineral acid salts (e.g., hydrochloride, sulfate, etc.), organic acid salts (e.g., methanesulfonate, p-toluenesulfonate, dibenzoyltartrate etc.), and so forth. The reaction is preferably carried out in a suitable solvent (e.g. water, ethyl acetate) at a temperature of 0 to 200 °C. The reduction of the compound (I-b) can be carried out by treating it with a reducing agent. The reducing agent includes, for example, borane 1,4-oxathiane complex. This reduction is preferably carried out in an appropriate solvent (e.g. ether tetrahydrofuran) at a temperature of 0 to 50 °C. The condensation reaction of the compound (I-b) or a reactive derivative at carboxyl group thereof with the amine compound (IV) can be carried out by any conventional method. For example, the condensation reaction of the free carboxylic acid (I-b) and the compound (IV) can be carried out in the presence of a dehydrating agent. The dehydrating agent includes, for example, carbonyldiimidazole dicyclohexylcarbodiimide, and the like. Besides, the condensation reaction of the reactive derivative at carboxyl group of the compound (I-b) with the amine compound (IV) can be carried out in the presence or absence of an acid acceptor. A variety of the reactive derivative at the carboxyl group of the compound (I-b), including, for example, acid halides, activated esters may be used for the condensation reaction. The acid acceptor includes alkali metal carbonates, alkali metal hydrogen carbonates, trialkylamines, pyridine, and the like. These reactions are preferably carried out in an appropriate solvent (e.g. tetrahydrofuran, methylene chloride, ethyl acetate) at a temperature of 0 to 50 °C. The hydrolysis of the compound (I-e) can be carried out by conventional method, for example, by treating the compound with an alkali agent or an acid. Examples of the alkali agent are alkali metal hydroxides, and examples of the acid are mineral acids. The hydrolysis is preferably carried out in an appropriate solvent (e.g. water, a lower alkanol) at a temperature of 0 to 30 °C. All of the above reactions proceed without racemization, and hence, when an optically active compounds are used as the starting compounds, the desired compounds (I) can be obtained in the optically active form. The compounds (I) of this invention can be used for pharmaceutical use either in the free form or a pharmaceutically acceptable salt. Examples of the pharmaceuitcally acceptable salts include inorganic or organic salts such as alkali metal salts (e.g. sodium salt, potassium salt), alkaline earth metal salts (e.g. calcium salt, magnesium salt), heavy metal salts (e.g. zinc salt), ammonium salt, organic amine salts (e.g. triethylamine salt, pyridine salt, ethanolamine salt, a basic amino acid salt), and the like. These salts may readily be prepared by treading the compounds (I) with the corresponding inorganic or organic base in an appropriate solvent. The compounds (I) or a salt thereof may be administered either orally or parenterally to a warm-blooded animal, including human beings, and may also be used in the form of a pharmaceutical preparation containing the same compound in admixture with pharmaceutical excipients suitable for oral or parenteral administration. The pharmaceutical preparations may be in solid form such as tablets, capsules and powders, or in liquid form such as solutions, suspensions or emulsions. Moreover, when administered parenterally, it may be used in the form of injections. Because of the potent TxA₂ antagonistic activity, the compound (I) of the invention or a salt thereof are useful as platelet aggregation-inhibiting agent and for the treatment, amelioration and/or prophylaxis of a variety of thrombosis or embolism, such as cerebral thrombosis, coronary artery thrombosis, pulmonary thrombosis, pulmonary embolism, peripheral vascular embolism, thromboangiitis, and the like. The compound (I) or a salt thereof are also useful for prophylaxis of i) thrombosis which may be caused during extracorporeal circulation of blood and ii) thrombosis in case of an organ transplantation. Moreover, based on the potent TxA₂ antagonistic activity, the compound (I) or a salt thereof may be used for the treatment, amelioration and/or prophylaxis of myocardial ischemia, unstable angina pectoris, coronary vellication, cerebral blood vessel vellication after subarachnoid hemorrhage, cerebral hemorrhage, asthma, nephritis, renal failure, a shock, and the like. Besides, as some known TxA₂ antagonists show excellent TxA₂ antagonistic activity but at the same time show transient TxA₂-like activity, they are liable to side effects such as platelet aggregation-inducing activity, broncho-constriction activity, blood vessel constriction activity. As compared with the known antagonists, however, the compound (I) of this invention is quite advantageous for use by either oral or parenteral administration because it is substantially free from such TxA₂-like activity. The starting compound (II) wherein R² is carboxyl group can be prepared, for example, by hydrolysis of the corresponding compound (II) wherein R² is lower alkoxycarbonyl group, and may be, if required, further condensed with the amine compound (IV) to give the compound (II) wherein R² is a group of the formula: wherein R³ and R⁴ are as defined above. Experiment Effect on U-46619-induced platelet aggregation (in vitro) Nine volumes of blood collected from a healthy human were mixed with one volume of 3.8% (w/v) trisodium citrate solution, and the mixture was centrifuged to give platelet-rich plasma ("PRP") as the supernatant. The bottom layer was further centrifuged to give platelet-poor plasma ("PPP") as the supernatant. PRP was diluted with PPP so that the platelet count was 4x10⁵ cells/mm³. 25 µl of a test compound solution was added to 200 µl of said diluted PRP. After the mixture was stirred for 2 minutes at 37 °C, U-46619 solution (0.2 µg/ml solution) was added thereto to induce platelet aggregation. The degree of platelet aggregation was examined by Born's method (Nature, 194 , 927 (1962)), and the platelet aggregation-inhibiting activity of the test compound was estimated. The platelet aggregation-inhibiting activity of the test compound was expressed as IC₅₀, i.e., the concentration of the test compound required to induce 50% inhibition of U-46619-induced platelet aggregation. The results are shown in the following Table 1. Example 1 A solution of 1.94 g of 4-chlorophenylsulfonyl chloride in 20 ml of ethyl acetate is added to a mixture of 30 ml of ethyl acetate, 20 ml of water, 3.46 g of potassium carbonate and 2.25 g of ethyl 6-amino-5,6,7,8-tetrahydronaphthalene-2-acetate hydrochloride under stirring at room temperature. After the mixture is stirred at room temperature for 45 minutes, the organic layer is separated therefrom, washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform) to give 2.84 g of ethyl 6-(4-chlorophenyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-acetate as oil. Yield 83% Mass(m/z): 408 (M⁺+1) IR ν neat max (cm⁻¹): 3280, 1730, 1160 Example 2 28 ml of ethanol and 10 ml of a 2N aqueous sodium hydroxide solution are added to 2.81 g of ethyl 6-(4-chlorophenyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-acetate, and the mixture is stirred at room temperature overnight. After ethanol is removed from the mixture, water is added thereto, and the mixture is washed with methylene chloride. 10% hydrochloric acid is added to the water layer, and the mixture is extracted with ethyl acetate. The extract is washed, dried and evaporated to remove the solvent, and the residue is recrystallized from a mixture of ethyl acetate and n-hexane to give 2.16 g of 6-(4-chlorophenyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-acetic acid as pale brown prism. Yield 82% m.p. 152 - 154.5°C Mass(m/z): 380(M⁺+1) IR ν nujol max (cm⁻¹): 3240, 1710, 1330, 1160 Sodium salt: pale brown powder FABMass(m/z): 424, 402(M⁺+1) IR ν nujol max (cm⁻¹): 1580, 1380 Examples 3 to 7 The corresponding starting compounds are treated in the same manner as described in Example 2 to give the compounds shown in Table 2. Example of preparation 8 A mixture of 1.45 g of methyl 4-{[6-(2-thienyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-yl]acetylamino}benzoate, 10 ml of methanol, 9 ml of a 2N aqueous sodium hydroxide solution and 4 ml of tetrahydrofuran is stirred at room temperature overnight. Methanol and tetrahydrofuran are distilled off, and the residual mixture is washed and acidified. The precipitated crystals are collected by filtration, washed, dried and recrystallized from a mixture of tetrahydrofuran and isopropyl ether to give 1.33 g of 4-{[6-(2-thienyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-yl]acetylamino}benzoic acid as colorless crystals. Yield 94% m.p. 250 - 252°C FABMass(m/z): 471(M⁺+1) IR ν nujol max (cm⁻¹): 3320, 3220, 1690, 1600 Sodium salt: colorless crystals m.p. 267 - 269°C (decomp.) FABMass(m/z): 515, 493(M⁺+1) IR ν nujol max (cm⁻¹): 1680, 1600 Examples 9 to 16 The corresponding starting compounds are treated in the same manner as described in the Example of preparation 8 to give the compounds shown in Table 3. [Preparation of starting compounds] Preparation 1 (1) A solution of 5.4 g of oxalyl chloride in methylene chloride is added dropwise to a suspension of 6.67 g of monoethylester of 1,4-phenylenediacetic acid in methylene chloride under cooling and stirring. After one drop of dimethylformamide is added to the mixture, the mixture is stirred at room temperature for 3 hours and evaporated to remove the solvent. A solution of resulting yellow oil in methylene chloride is added dropwise to a suspension of 12.8 g of alminum chloride in methylene chloride under stirring at 0°C, and the mixture is stirred for 10 minutes. After ethylene gas is flowed into the mixture for 30 minutes, the mixture is stirred at room temperature for 3 hours. Water and ethyl acetate are added to the mixture under cooling, and the organic layer is separated therefrom, washed, dried and evaporated to remove the solvent. The resulting residue is purified by silica gel column chromatography to give 5.67 g of ethyl 6-oxo-5,6,7,8-tetrahydronaphthalene-2-acetate as colorless oil. FABMass(m/z): 233(M⁺+1) IR ν neat max (cm⁻¹): 1730 - 1720 (2) A solution of 6.36 g of the product obtained above, 9.5 ml of pyridine and 4.33 g of methoxylamine hydrochloride in methanol is refluxed for 2.5 hours under argon. After the solvent is distilled off, ethyl acetate and 10% hydrochloric acid are added to the residue. The organic layer is separated from the mixture, washed, dried and evaporated to remove the solvent. The resiual oil is purified by silica gel column chromatography to give 5.37 g of ethyl 6-methoxyimino-5,6,7,8-tetrahydronaphthalene-2-acetate as pale yellow oil. Mass(m/z): 261(M⁺) IR ν neat max (cm⁻¹): 1735, 1050 (3) 216 mg of platinum oxide (IV) and 540 mg of oxalic acid are added to a solution of 1.57 g of the product obtained above in ethanol, and the mixture is subjected to catalytic hydrogenation under hydrogen gas atmosphere at 202.65 kPa to 303.975 kPa (2 to 3 atm) overnight. After a solution of hydrogen chloride in ethanol is added to the mixture, the catalyst is filtered off. After the solvent is distilled off, the residue is recrystillied from a mixture of ethanol and ether to give 772 mg of ethyl 6-amino-5,6,7,8-tetrahydronaphthalene-2-acetate hydrochloride as pale brown prism. m.p. 217 - 221 °C (decomp.) Preparation 2 5.5 ml of 2M borane-methylsulfide complex in tetrahydrofuran are added to a solution of 1.31 g of ethyl 6-methoxyimino-5,6,7,8-tetrahydronaphthalene-2-acetate in tetrahydrofuran under argon at -5 to 0 °C, and the mixture is stirred at room temperature overnight. Ethanol and 9% hydrogen chloride-ethanol are added to the mixture under cooing and stirring, and the mixture is stirred at room temperature for 30 minutes. After the solvent is distilled off, the residue is crystallized with a mixture of ethanol and ether to give 990 mg of 2 -(6-amino-5,6,7,8-tetrahydronaphthalene-2-yl)ethanol hydrochloride as colorless solid. m.p. 221 - 224 °C (decomp.) Preparation 3 (1) 110.52 g of trifluoroacetic anhydride are added dropwise to a solution of 76.29 g of DL-N-(methoxycarbonyl)aspartic acid in ethyl acetate under cooling. After the mixturte is stirred at room temperature for 2 hours, a part of solvent is distilled off. n-hexane is added to the solution slowly under cooling, and the precipitated crystals are collected by filteration to give 65.54 g of DL-N-(methoxycarbonyl)aspartic anhydride as colorless prism. m.p. 102 - 103 °C (2) A mixture of 117.4 g of the product obtained above, 226.3 g of alminum chloride, 10.4 g of nitromethane and 270 g of benzene is refluxed for 3 hours. 10% hydrochloric acid is added to the reaction mixture, ethyl acetate and tetrahydrofuran are added thereto. The organic layer is separated from the mixture, dried and evaporated to remove the solvent. The residual solids, after the treatment of charcoal, are recrystallized from a mixture of ethyl acetate and n-hexane to give 147.9 g of 4-oxo-4-phenyl-2-methoxycarbonylaminobutyric acid as colorless prism. m.p. 132 - 135 °C (3) A suspension of 25.12 g of the product obtained above, 52.5 ml of 2N hydrochloric acid and 2.60 g of palladium-carbon in tetrahydrofuran is subjected to catalytic hydrogenation under hydrogen gas atmosphere (4 atm) for 10 hours. After the reaction, the catalyst is filtered off, and a part of solvent is distilled off. Ethyl acetate is added to the solution, the solution is washed, dried and a part of solvent is distilled off. n-hexane is added to the mixture and the precipitated crystals are collected by filtration to give 22.07 g of 4-phenyl-2-methoxycarbonylaminobutyric acid as colorless needles. m.p. 108.5 - 110 °C (4) A solution of 51.28 g of the product obtained above, 96.9 g of 2,2,2-trichloroethanol and 10.28 g of p-toluenesulfonic acid monohydrate in toluene is refluxed with Dean Strak apparatus for 5 hours. The reaction mixture is washed, dried and evaporated to remove the solvent, and the residue is distilled to give 71.5 g of 2,2,2-trichloroethyl 4-phenyl-2-methoxycarbonylaminobutyrate. b.p. 90 to 95 °C (0.6 mmHg) The product is allowed to stand to give colorless needles. m.p. 31 - 35 °C (5) A solution of 1.77 g of ethyl 2-chloro-2-methylthioacetate in methylene chloride and a solution of 5.22 g of tin chloride (IV) in methylene chloride are added dropwise to 3.69 g of the product obtained above at the same time under cooling and stirring. After the mixture is stirred at room temperature for 2 hours, water, chloroform and then 10% hydrochloric acid are added thereto. The organic layer is separated from the mixture, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography to give 4.37 g of ethyl 2-{4-[3-methoxycarbonylamino-3-(2,2,2-trichloroethoxycarbonyl)propyl]phenyl}-2-methylthioacetate as colorless oil. IR ν neat max (cm⁻¹): 3348, 1763, 1732 (6) A mixture of 1.81 g of the product obtained above, 475 mg of zink powder and 15 ml of acetic acid is stirred at room temperature for 30 minutes, and then refluxed for one hour. 475 mg of zink powder are added to the mixture, and the mixture is refluxed for 1.5 hour. Further 950 mg of zink powder are added to the mixture and the mixture is refluxed for 2 hours. Insoluble materials are filtered off, and the filtrate are condensed. The residue is extracted with ethyl acetate, washed, dried and evaporated to remove the solvent. The residue is purified by silica gel column chromatography, and recrystallized from a mixture of ethyl acetate and n-hexane to give 956 mg of ethyl 4-(3-carboxy-3-methoxycarbonylaminopropyl)phenylacetate. m.p. 108 - 110 °C (7) A solution of 1.62 g of the product obtained above, 0.66 ml of oxalyl chloride and a catalytic amount of dimethylformamide in methylene chloride is stirred under cooling for 5 minutes and then at room temperature for 3 hours. 2.68 g of alminum chloride are added to the mixture, and the mixture is stirred under cooling for one hour. Water and ethyl acetate are added to the mixture, and the organic layer is separated therefrom, washed, dried and evaporated to remove the solvent. The resulting oil is purified by silica gel column chromatography, and recrystallized from a mixture of ethyl acetate and n-hexane to give 983 mg of ethyl 8-oxo-7-methoxycarbonylamino-5,6,7,8-tetrahydronaphthalene-2-acetate as colorless needles. m.p. 95 - 97 °C (8) A suspension of 0.92 g of the product obtained above, 60 mg of sodium borohydride in methanol is stirred under cooling for 10 minutes. After the solvent is distilled off, ethyl acetate and water are added thereto. The organic layer is separated from the mixture. washed, dried and evaporated to remove the solvent. The resulting crystals are recrystallized from a mixture of ethyl acetate and n-hexane to give 700 mg of ethyl 8-hydroxy-7-methoxycarbonylamino-5,6,7,8-tetrahydronaphthalene-2-acetate as colorless prism. m.p. 99 - 100.5 °C (9) A suspension of 615 mg of the product obtained above, 180 mg of oxalic acid and 100 mg of 10% palladium-carbon in ethanol is subjected to catalytic hydrogenation under hydrogen gas atmosphere (4 atm) at 50 °C for 16 hours. The catalyst is filtered off. and the filtrate is condensed. Water is added to the residue and the solution is extracted with ethyl acetate, and the extract is washed, dried and evaporated to remove the solvent. The residue is recrystallized from a mixiture of toluene and n-hexane to give 500 mg of ethyl 7-methoxycarbonylamino-5,6,7,8-tetrahydronaphthalene-2-acetate. m.p. 89 - 90 °C (10) A solution of 586 mg of the product obtained above in 6N hydrochloric acid is refluxed for 13 hours. After the solvent is distilled off, 10% hydrogen chloride-methanol and methanol are added to the residue. The mixture is refluxed for 4 hours, and the solvent is distilled off. The residue is recrystallized from a mixture of methanol and ether to give 486 mg of metnyl 7-amino-5,6,7,8-tetrahydronaphthalene-2-acetate hydrochloride as colorless needles. m.p. 158 - 161.5 °C Concomitantly, ethyl 8-oxo-7-methoxycatbonylamino-5,6,7,8-tetrahydronaphthalene-2-acetate is treated in the same manner as described in (9) to give ethyl 7-methoxycarbonylamino-5,6,7,8-tetrahydronaphthalene-2-acetate.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LI, LU, NL, SE A tetrahydronaphthalene derivative of the formula: wherein R¹ is wherein R₆ is H, CH₃, Cl or -OCH₃, and R² is carboxyl or a group of the formula: wherein R³ is hydrogen and R⁴ is carboxy-(C₁-C₆)-alkyl group, and m=1 and n=2, or a pharmaceutically acceptable salt thereof. A tetrahydronaphthalene derivative as claimed in claim 1 in which R¹ is chlorophenyl, and R² is a group of the formula: wherein R³ is hydrogen and R⁴ is a carboxyethyl group or carboxypropyl. 4-([6-(4-chlorophenyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-yl]acetylamino)-n-butyric acid or a pharmaceutically acceptable salt thereof. 3-([6-(4-chlorophenyl)-sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-yl]acetylamino)-n-propionic acid or a pharmaceutically acceptable salt thereof. A process for preparing a tetrahydronaphthalene derivative of the formula: wherein R¹ is phenyl, methylphenyl, chlorophenyl, or methoxyphenyl and R² is carboxyl, or a group of the formula: wherein R³ is hydrogen atom and R⁴ is carboxy (C₁-C₆)-alkyl, and m is 1 and n is 2 or a pharmaceutically acceptable salt thereof, which comprises: condensing an aminotetrahydronaphthalene derivative of the formula: wherein R², m and n are as defined above, or a salt thereof with a sulfonic acid compound of the formula: R¹SO₃H (III) wherein R¹ is as defined above, or a reactive derivative thereof, and when compound (I) is a free form, optionally further converting the product into a pharmaceutically acceptable salt thereof. A process for preparing a tetrahydronaphthalene derivative of the formula: wherein R¹ is phenyl, methylphenyl, chlorophenyl, or methoxyphenyl. R³ is hydrogen atom and R⁴ is carboxy-(C₁-C₆)-alkyl, and m is 1 and n is 2 or a pharmaceutically acceptable salt thereof, which comprises: condensing a compound of the formula (I-b): wherein R¹, m and n are as defined above, or a reactive derivative at carboxyl group thereof with an amine compound of the formula: R³-NH-R⁴ (IV) wherein R³ and R⁴ are as definded above or a salt threof, and when compound (I-c) is a free form, optionally further converting the product into a pharmaceutically acceptable salt thereof. A process for preparing a tetrahydronaphthalene derivative of the formula: wherein R¹ is phenyl, methylphenyl, chlorophenyl, or methoxyphenyl R³ is hydrogen atom, R⁴ is carboxy-(C₁-C₆)-alkyl, and m is 1 and n is 2, or a pharmaceutically acceptable salt thereof, which comprises: hydrolyzing a compound of the formula (I-e): wherein R⁶ is (C₁-C₆) alkoxycarbonyl-(C₁-C₆)-alkyl group, and R¹, R³, m and n are as defined above, and when compound (I-c) is a free form, optionally further converting the product into a pharmaceutically acceptable salt thereof. A pharmaceutical composition which comprises an effective amount of the tetrahydronaphthalene derivative claimed in any one of claims 1 to 4 and a pharmaceutically acceptable carrier therefor. An aminotetrahydronaphthalene derivative of the formula: wherein R² is carboxyl, or a group of the formula: wherein R³ is hydrogen and R⁴ is carboxy-(C₁-C₆)-alkyl group, and m=1 and n=2 or a salt thereof. Claims for the following Contracting States : ES, GR A process for preparing a pharmaceutical composition, comprising mixing a tetrahydronaphthalene derivative of the formula: wherein R¹ is wherein R₆ is H, CH₃, Cl or -OCH₃ and R² is carboxyl or a group of the formula: wherein R³ is hydrogen and R⁴ is a carboxy-(C₁-C₆)-alkyl group and m=1 and n=2, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable carrier therefor. A process as claimed in claim 1 in which R¹ is chlorophenyl, and R² is a group of the formula: wherein R³ is hydrogen and R⁴ is a carboxyethyl or carboxypropyl. A process as claimed in claim 1 wherein the derivative of formula (1) is 4-([6-(4-chlorophenyl) sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-yl] acetylamino)-n-butyric acid or a pharmaceutically acceptable salt thereof. A process as claimed in claim 1 wherein the derivatice of formula (1) is 3-([6-(4-chlorophenyl)sulfonylamino-5,6,7,8-tetrahydronaphthalene-2-yl]acetylamino)-n-propionic acid or a pharmaceutically acceptable salt thereof. A process for preparing a tetrahydronaphthalene derivate of the formula: wherein R¹ is phenyl, methylphenyl, chlorophenyl, or methoxyphenyl and R² is carboxyl, or a group of the formula: wherein R³ is hydrogen and R⁴ is carboxy-(C₁-C₆)-alkyl, and m=1 and n=2 or a pharmaceutically acceptable salt thereof, which comprises: condensing an aminotetrahydronaphthalene derivative of the formula: wherein R², m and n are as defined above, or a salt thereof with a sulfonic acid compound of the formula: R¹SO₃H (III) wherein R¹ is as defined above, or a reactive derivative thereof, and when compound (I) is a free form, optionally further converting the product into a pharmaceutically acceptable salt thereof. A process for preparing a tetrahydronaphthalene derivative of the formula: wherein R¹ is phenyl, methylphenyl, chlorophenyl, or methoxyphenyl R³ is hydrogen and R⁴ is carboxy-(C₁-C₆)-alkyl, and m is 1 and n is 2 or a pharmaceutically acceptable salt thereof, which comprises: condensing a compound of the formula (I-b): wherein R¹, m and n are as defined above, or a reactive derivative at carboxyl group thereof with an amine compound of the formula: R³-NH-R⁴ (IV) wherein R³ and R⁴ are as definded above or a salt threof, and when compound (I-c) is a free form, optionally further converting the product into a pharmaceutically acceptable salt thereof. A process for preparing a tetrahydronaphthalene derivative of the formula: wherein R¹ is phenyl, methylphenyl, chlorophenyl, or methoxyphenyl R³ is hydrogen, R⁴ is carboxy-(C₁-C₆)-alkyl group, and m is 1 and n is 2, or a pharmaceutically acceptable salt thereof, which comprises: hydrolyzing a compound of the formula (I-e): wherein R⁶ is (C₁-C₆)alkoxycarbonyl-(C₁-C₆)-alkyl group, and R¹, R³, m and n are as defined above, and when compound (I-c) is a free form, optionally further converting the product into a pharmaceutically acceptable salt thereof.

Inventors: KOHNO HARUMICHI, NAKAI HIDEO, ODAWARA OKIO, SASAKI YASUHIKO, YAMASHITA TOYOHURA, KOHNO, HARUMICHI, NAKAI, HIDEO, ODAWARA, OKIO, SASAKI, YASUHIKO, YAMASHITA, TOYOHURA
Applicants: TANABE SEIYAKU CO, TANABE SEIYAKU CO., LTD.
Application year: 1990
Main classification: C07C311
IPC codes: C07C311, A61K31, C07D333, C07D213, A61P7, C07D521