NOVEL CYCLIC AMINOPHENYLACETIC ACID DERIVATIVE, PRODUCTION THEREOF, AND IMMUNE RESPONSE MODULATOR CONTAINING THE SAME AS ACTIVE INGREDIENT

Abstract: A novel cyclic aminophenylacetic acid derivative which has an immune response modulatory activity, represented by general formula (1), an optical isomer thereof and salts thereof, a process for producing the same, and a remedy for autoimmune diseases containing the same as an active ingredient. In Formula (1), R and R¹ represent each independently hydrogen or C₁ to C₃ lower alkyl; R² represents trifluoromethyl or phenyl which may be substituted by one to three groups selected among halogen, methoxy and combinations thereof; and X represents hydrogen, C₁ to C₃ lower alkyl, C₁ to C₃ lower alkoxy, cyano, thiocyano, trimethylsilylethynyl, phenyl which may be substituted by one to three groups selected among halogen, methoxy, methyl and combinations thereof, carbamoyl, carboxyl, C₁ to C₃ lower alkoxycarbonyl, acetyl, benzoyl, nitro, amino, C₁ to C₃ lower alkanoylamino, benzoylamino which may be substituted, phenylsulfonylamino which may be substituted, C₁ to C₃ lower alkylthio, C₁ to C₃ lower alkylsulfinyl, C₁ to C₃ lower alkylsulfonyl or halogen.

Description: Field of the invention The present invention relates to novel cyclic aminophenylacetic acid derivatives having immune response-modulating action, their optical isomers and salts, their preparative processes, and therapeutic agents for autoimmune diseases containing them as effective ingredients. Background For the therapy of chronic diseases (rheumatoid arthritis and autoimmune diseases) with which the immune response is concerned, anti-inflammatory agents, immunomodulators, etc. are used. The formers are for symptomatic therapy, thus cannot become fundamental therapeutic agents. Whereas, the latters, in which gold salt and D-penicil-lamine, levamisole, lobenzarit, etc. are known, have attracted an attention for the last several years. The inventors have also studied diligently for the purpose of developing a more effective and safer antirheumatic agent and have found previously that the cyclic anthranilic acid derivatives have immunomodulatory action and inducing ability for suppressor T cells, and that they have therapeutic effect against rheumatoid arthritis (Japanese Unexamined Patent Publication No. Hei 1-279867 corresponding to US-A-4 956 372 and EP-A-0 310 096). However in cyclic aminophenylacetic acid derivatives, compounds having such action are not known. In cyclic aminophenylacetic acid derivatives having different substituent from the compounds in this invention, those having anti-inflammatory, antipyretic and analgesic actions are described in Japanese Unexamined Patent Publication No. Sho 58-116466 and US-A-3,778,511 (1973), but the immuno-modulatingaction is not referred at all. These publicly known compounds, with which a possibility to cause gastrointestinal injury is suggested, belong to a category of non-steroidal anti-inflammatory drugs having cyclooxygenase-inhibitory action, and their usefulness is not satisfactory from the points of efficacy and toxicity. Moreover, cyclic aminophenylacetic acid derivatives exhibiting monoamineoxydase-inhibitory action are also known (Chemical Abstract, Vol. 64, 1753c (1966), ibid Vol. 70, 10292f(1969)), but these also differ from the compounds of the invention in the structure and action. US-A-3,897,436 discloses quinolineacetic compounds or pharmaceutically acceptable non-toxic salts thereof having anti-inflammatory and analgesic activity. Moreover, they are active ingredients of pharmaceutical compositions and can be used for the relief and removal of pain as well as for the treatment of rheumatic, arthritic and other inflammatory complaints. US-A-3,897,436 does not disclose an immunomodulating activity of the compounds. Simularly the quinolyl acetic acids of EP-A-0 083 222 are not described to have immunomodulating activity. Disclosure of the invention The inventors have found that novel cyclic aminophenylacetic acid derivatives represented by a general formula (1) [wherein X denotes a bromine atom or chlorine atom] , their optical isomers and their salts have conspicuous modulating action on immune response, have excellent inhibitory action also against acute inflammation, which cannot be seen with conventional immunomodulatory drugs, and yet do not exhibit cyclooxygenase-inhibitory action. Further, the inventors have found that they exhibit fast-acting and persistent therapeutic effect against adjuvant arthritis being a typical pathologic model of rheumatoid arthritis. Further, the inventors have come to confirm the safety, too, leading to the completion of the invention. According to the invention, the compounds represented by the general formula (1) can be prepared through processes, for example, as described below. Namely, by reducing quinoline derivatives represented by a general formula (2) [wherein X denotes a bromine atom or chlorine atom and X 1 denotes a hydrogen atom, chlorine atom or bromine atom], the compounds represented by a general formula (1) can be prepared. This reduction can be carried out at a temperature of ambient temperature to 80 °C and a pressure of atmospheric pressure to 50 kg/cm under hydrogen gas stream in the presence of a catalyst, for example, palladium carbon, dissolving the compounds of the general formula (2) into a suitable solvent, for example, methanol, ethanol, isopropanol. Also, they can be prepared by reacting with sodium borocyanohydride in a suitable solvent, for example, methanol, ethanol, acetic acid. Moreover, by reacting the compound represented by formula (1b) with a corresponding halogenating agent, for example, chlorine, bromine, corresponding hypohalogenous acid, corresponding N-halogenosuccinimide, halogen-pyridine type chlorine complexes in an inert solvent, the compounds represented by a general formula (1) can be prepared. Next, ester derivatives represented by a general formula (1f) [wherein R denotes an alkyl group having 1 to 3 carbon atoms and X denotes the same meanings as above] can be derived easily to the inventive compounds represented by the general formula (1) [wherein X denotes same meanings as above] by hydrolyzing with acid or alkali according to usual methods. Besides, the important intermediates of the invention represented by the general formula (2) can be prepared through publicly known process (process A shown below). On the other hand, the compounds represented by the general formula (2), are preferable to be prepared via a process (process B shown below) developed newly by the inventors. Namely, by reacting aminophenylacetic acid derivatives (4) with equimolar or a slight excess alkyl ester of 3-trifluoro-methylpropiolic acid (5) at 0 °C to boiling point of solvent used, preferably room temperature in a suitable solvent, for example, methanol, ethanol, isopropanol, acetonitrile, dioxane the alkyl ester of 3-(substituted phenylamino)-3-trifluoromethylacrylic acid (6=6') can be prepared in high yield. In the inventive process, the reaction temperature is milder and the reaction time is also shorter compared with the former process (process A). And, it gives less side reaction and higher yield generally. [wherein R 1 denotes a lower alkyl group and R, X and X 1 denote same meanings as above], Moreover, for the inventive compounds represented by the general formula (1), two optical isomers exist, because they have one asymmetric carbon; the invention includes those optical isomers and the racemate. With respect to the synthesis of optically active substances, by applying, for example, the method of optical resolution against diastereoisomers of tetrahydroquinoline derivatives using N-tosyl-L-proline described in Journal of Medicinal Chemistry, Vol. 30, 839 (1987), the optical isomers of the inventive compounds can be synthesized. Next, the compounds represented by the general formula (1) can be converted to their salts, for example, salts with hydrochloric acid, sulfuric acid, phosphoric acid, methanesulfonic acid, lactic acid, citric acid, tartaric acid, as acid adducts, and metal salts with sodium, potassium, magnesium, as alkali salts. In the following, the invention will be illustrated by examples. Reference Example 1: Ethyl 2-(2-fluorophenyl)-1,2,3,4-tetrahydroquinoline-6-acetate (not claimed) Ethyl p-aminophenylacetate (8 g), ethyl 2-fluoro-benzoylacetate (10 g) and p-toluenesulfonic acid (1 g) were dissolved into benzene (150 ml) and, providing Dean Stalk dehydrating apparatus placed molecular sieve (MS 4 angstroms) therein, the solution was refluxed for 4.5 hours under heat. Solvent was distilled off under reduced pressure and water was added to the residue, which was extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate, and then concentrated. After diphenyl ether (60 ml) was added to the residue, the mixture was stirred at 240 to 250 °C for 30 minutes under heat. After cooling, ether was added and the crystals deposited were collected by filtration to obtain crude ethyl 2-(2-fluorophenyl)-4-hydroxyquinoline-6-acetate (9.5 g). After phosphorus oxychloride (40 ml) was added thereto, the mixture was refluxed for 2 hours under heat. After cooling, this was thrown into ice and extracted with methylene chloride. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain ethyl 4-chloro-2-(2-fluorophenyl)quinoline-6-acetate (9.2 g). This was dissolved into ethanol (200 ml) and, after 10 % palladium carbon (1 g) was added, hydrogenation was conducted at a hydrogen pressure of 40 kg/cm 2 and at 80 °C. Catalyst was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by means of silica gel column chromatography (development solvent: methylene chloride) to obtain aimed product (3.7 g) as a pale yellow oily substance. Reference Example 2: Ethyl 8-chloro-2-(2-fluorophenyl)-1,2,3,4-tetra-hydroquinoline-6-acetate (not claimed) The compound (2.4 g) of Reference Example 1 was dissolved into d imethylformamide (30 ml) and, after N-chlorosuccimide (1.1 g) was added, the mixture was stirred at 80 °C for 2 hours under heat. After cooling, ice water was added and the reaction liquor was extracted with methylene chloride. The organic layer was washed with saturated saline solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by means of siLica gel column chromatography (development solvent: methylene chloride) to obtain aimed product (1.5 g) as a pale yellow oily substance. Elemental analysis (%): As C 19 H 19 ClFNO 2 C H N Calculated 65.61 5.51 4.03 Observed 65.51 5.52 3.88 Intermediate 1: Methyl 1,2,3,4-tetrahydro-2-trifluoromethyl-quinoline-6-acetate · Process A Methyl p-aminophenylacetate (7 g), ethyl trifluoroaceto-acetate (8.19 g) and p-toluenesulfonic acid (500 mg) were dissolved into benzene (100 ml) and, providing Dean Stalk dehydrating apparatus placed molecular sieve (MS 4 angstroms) therein, the solution was refluxed for 10 hours under heat. Solvent was distilled off under reduced pressure and the residue was purified by means of silica gel column chromatography (development solvent: ethyl acetate:hexane = 1:4) to obtain methyl 3-(4-methoxycarbonylmethylphenylamino)-3-trifluoromethylacrylate (7.18 g) as colorless prismatic crystals. Melting point: 50 - 51 °C (recrystallization solvent: ethyl acetate-n-hexane) Elemental analysis (%): As C 14 H 14 F 3 NO 4 C H N Calculated 53.00 4.45 4.41 Observed 52.90 4.38 4.53 To this was added diphenyl ether (30 ml), and the mixture was stirred at about 250 °C for 45 minutes under heat. After cooling, hexane was added and the crystals deposited were collected by filtration and dried to obtain crude methyl 4-hydroxy-2-trifluoromethylquinoline-6-acetate (4.75 g). Melting point: 192 - 193 °C (recrystallization solvent: methanol), colorless needle-like crystals Elemental analysis (%): As C 13 H 10 F 3 NO 3 C H N Calculated 54.74 3.53 4.91 Observed 54.39 3.47 4.92 To this were added phosphorus pentachloride (3.81 g) and phosphorus oxychloride (20 ml), and the mixture was stirred at 100 °C for 1 hour. Phosphorus oxychloride was distilled off and water was added to the residue, which was neutralized with sodium bicarbonate. This was extracted with chloroform and the organic layer was washed with water, then with saturated saline solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by means of silica gel column chromatography (development solvent: ethyl acetate:hexane = 1:4) to obtain methyl 4-chloro-2-trifluoromethylquinoline-6-acetate (4.88 g). Melting point: 108 - 109 °C (recrystallization solvent: ethyl acetate-n-hexane), white flocky crystals Elemental analysis (%): As C 13 H 9 ClF 3 NO 2 C H N Calculated 51.42 2.99 4.61 Observed 51.27 2.86 4.67 Methyl 4-chloro-2-trifluoromethylquinoline-6-acetate (12.35 g) thus obtained, triethylamine (5.96 ml) and 10 % palladium carbon (600 mg) were added to methanol (200 ml) and the hydrogenation was conducted at a hydrogen pressure of 50 kg/cm 2 and at room temperature for 3 hours. Catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved by adding ether, washed with water, then with saturated saline solution, dried over anhydrous sodium sulfate and then concentrated to obtain aimed product (10.29 g) as white crystals. · Process B Into 30 ml of methanol were dissolved 2.17 g (13.2 mmol) of methyl-p-aminophenylacetate, and, under stirring and cooling with ice, a solution of 2.00 g (13.2 mmol) of methyl 3-trifluoromethylpropiolate in 10 ml of methanol was added dropwise. After 30 minutes, solvent was distilled off to obtain methyl 3-(4-methoxycarbonylmethylphenylamino)-3-trifluoromethylacrylate (4.17 g) as a yellow oily substance. H-NMR (CDCL 3 ) δ:3.62(2H, s, CH 2 ), 3.70, 3.75 (6H, S, CO 2 CH 3 x 2), 5.34 (1H, s, H ), 7.08 - 7.31 (4H, m, ArH), 9.76 (1H, bs, NH) When recrystallizing from ethyl acetate-n-hexane, this oily substance becomes colorless prismatic crystals. This was allowed to react successively according to process A to obtain aimed product. Intermediate 2: Methyl 8-chloro-1,2,3,4-tetrahydro-2-trifluoro-methylquinoline-6-acetate The compound (2 g) of intermediate 1 was treated similarly to Reference Example 2 to obtain aimed product (1.87 g) as a colorless oily substance (purified by means of silica gel column chromatography (development solvent: ethyl acetate:hexane = 1:4). Example 1: 8-Chloro-1,2,3,4-tetrahydro-2-trifluoromethyl-quinoline-6-acetic acid The compound (1.58 g ) of intermediate 2 was added to a mixed liquor of aqueous solution (5 ml) containing sodium hydroxide (310 mg) with ethanol (5 ml) and the mixture was stirred at room temperature for 1 hour. Water (20 ml) was added and the reaction mixutre was brought to pH 4 with concentrated hydrochloric acid, which was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain aimed product (1.41 g) as white crystals. When recrystallizing from ethyl acetate-hexane, these give a melting point of 127 - 128 °C. Elemental analysis (%): As C 12 H 11 ClF 3 NO 2 C H N Calculated 49.08 3.78 4.77 Observed 49.09 3.72 4.70 Intermediate 3: 1,2,3,4-Tetrahydro-2-trifluoromethylquinoline-6-acetic acid The compound of intermediate 1 was treated similarly to Example 1 to obtain aimed product as white prismatic crystals (recrystallization solvent: ethyl acetate-hexane). Melting point: 118 - 119 °C Elemental analysis (%): As C 12 H 12 F 3 NO 2 C H N Calculated 55.60 4.67 5.40 Observed 55.73 4.62 5.28 Intermediates 4: Methyl 1-[N-tosyl-L-prolyl]-1,2,3,4-tetrahydro-2-trifluoromethylquinoline-6-acetate (synthesis of diastereoisomers) The compound (100 mg) of intermediate 1 and N-tosyl-L-prolyl chloride (316 mg) were added to anhydrous toluene (0.2 ml) and the mixture was heated at 60 °C for 12 hours and further at 80 °C for 5 hours while stirring. After cooling, the reaction liquor was poured into a saturated aqueous solution of sodium bicarbonate, which was extracted with ethyl acetate. The extracted solution was washed with saturated aqueous solution of sodium bicarbonate and with saturated saline solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by means of silica gel column chromatography (development solvent: ethyl acetate:hexane = 2:3 to 3:2) to obtain isomer A (83 mg) from early eluted fraction and isomer B (49 mg) from late eluted fraction. Isomer A: Colorless prismatic crystals (recrystallization solvent; ethyl acetate), Melting point: 204 - 205 °C Elemental analysis (%): As C 25 H 27 F 3 N 2 O 5 S C H N Calculated 57.24 5.19 5.34 Observed 57.24 5.12 5.33 Isomer B: Colorless foamy substance Elemental analysis (%): As C 25 H 27 F 3 N 2 O 5 S C H N Calculated 57.24 5.19 5.34 Observed 57.32 5.19 5.17 Intermediate 5: 1,2,3,4-Tetrahydro-2-trifluoromethylquinoline-6-acetic acid (+) isomer The isomer A (56 mg) or Reference Example 6 was added to 20% aqueous solution of sodium hydroxide (5 ml) and the mixture was heated at 100 °C for 3 hours while stirring. Ice pieces were added to the reaction liquor, which was brought to pH 3 to 4 with concentrated hydrochloric acid and extracted with ethyl acetate. The extracted solution was washed with saturated saline solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by means of silica gel column chromatography (development solvent: ethyl acetate:hexane = 1:1 to ethyl acetate alone) to obtain aimed product (14.9 mg) as colorless flaky crystals (recrystallication solvent; methylene chloride-hexane). Melting point: 107 - 108 °C Specific rotation [α] 25 / D 17.9° (c = 0.223, chloroform) Intermediate 6 : 1,2,3,4-Tetrahydro-2-trifluoromethylquinoline-6-acetic acid (-) isomer The isomer B (41 mg) of intermediate 4 was treated similarly to Reference Example 7 to obtain aimed product (7.8 mg) as colorless flaky crystals (recrystallication solvent; methylene chloride-hexane). Melting point: 105 - 107 °C Specific rotation [α] 25 / D-15.3° (c = 0.222, chloroform) Example 2 : 8-Chloro-1,2,3,4-tetrahydro-2-trifluoromethyl-quinoline-6-acetic acid (+) isomer The compound (14.8 mg) of intermediate 5 was dissolved into anhydrous N,N-dimethylformamide (0.2 ml) and, after N-chlorosuccimide (8.4 mg) was added thereto, the mixture was heated at 70 °C for 30 minutes in argon stream while stirring. The reaction liquor was dissolved into ethyl acetate (15 ml), which was washed with water and with saturated saline solution, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by means of silica gel column chromabography (development solvent; ethyl acetate:hexane = 1:4 to ethyl acetate alone) to obtain aimed product (9.2 mg) as colorless crystals. Melting point: 110 - 112 °C Specific rotation [α] 25 / D -21.2° (c = 0.613, chloroform) Example 3 : 8-chloro-1,2,3,4-tetrahydro-2-trifluoromethyl-quinoline-6-acetic acid (-) isomer The isomer A (7.8 mg) of intermediate Reference Example 8 was treated similarly to Example 2 to obtain aimed product (4.5 mg) as colorless crystals. Melting point: 108 - 111 °C Specific rotation [α] 25 / D-19.3° (c = 0.3, chloroform) Intermediate 6: Methyl 8-bromo-1,2,3,4-tetrahydro-2-trifluoro-methylquinoline-6-acetate Into 30 ml of DMF were dissolved 3.18 g of the compound of intermediate 1, and, undet stirring at -5 to 0°C, a solution of 2.07 g of NBS (N-bromosuccimide) in 30 ml of DMF was added dropwise over 1 hour. After dropwise addition, 20 ml of ice water were added to stop the reaction. After 100 ml of water was added further, the reaction mixture was extracted with ethyl acetate (300 ml). The organic layer was washed with water (300 ml x 3 times) and with saturated saline solution (150 ml x 1) and then dried over anhydrous sodium sulfate. Solvent was distilled off and the residue was purified by means of silica gel column chromatography (development solvent: ethyl acetate:hexane = 1:4) to obtain 3.62 g of aimed product as faintly yellow oily substance. Example 4 : 8-Bromo-1,2,3,4-tetrahydro-2-trifluoromethyl-quinoline-6-acetic acid The compound of intermediate 6 was treated similarly to Example 1 to obtain aimed product as faintly yellow crystals (recrystallization solvent: ethyl acetate-hexane). Melting point: 111 - 112 °C Elemental analysis (%): As C 12 H 11 BrF 3 NO 2 C H N Calculated 42.63 3.28 4.14 Observed 42.89 3.13 4.10 Next, test examples with animals will be shown. Test example 1 : Inhibitory effect on vascular permeability Male ddY-strain mice were orally administered with the compound of examples in 5 % arabic gum suspension. After 45 minutes, 1 % Evans Blue dissolved in saline (0.1 ml/10 g body weight) was injected into tail vein, and immediately, 1 % of acetic acid diluted in saline (0.1 ml/10 g body weight) was injected into peritoneal cavity. Thirty minutes later, each mouse was sacrificed and peritoneal cavity was washed with saline (2 ml/10 g body weight). Peritoneal exuded fluid was collected and centrifuged at 3,000 rpm for 10 minutes. The optical density of supernatant was read at 630nm. The volume of Evans Blue was determined from the calibration curve and the inhibition ratio was calculated. As shown in Table 1, the inventive compounds have remarkable inhibitory action on vascular permeability. Number of example Dose (mg/kg, p.o.) Inhibition ratio (%) Ex. 1 100 29.1 Ex. 4 100 38.6 Test example 2 : Therapeutic effect on the adjuvant arthritis in rats Heat-killed Mycobacterium butyricum (0.6 mg/rat) suspended in liquid paraffin was injected intradermally into right hind paw of female SD-strain rats. Test compounds suspended in 0.3 % CMC solution were administered orally once a day for 7 days from 14 days to 20 days after the injection of adjuvant. The swelling of non-injected hind paw was measured by the water displacement method. Inhibition ratio on swelling at 18 days, 21 days and 27 days after the injection of adjuvant are shown in Table 2. As shown in Table 2, the inventive compound have remarkable inhibitory effect on the adjuvant arthritis in SD-strain rats. Furthermore even after the end of administration of the inventive compounds, the therapeutic effect was lasted. Number of example Dose (mg/kg/day) Inhibition ratio of swelling (%) 18 days 21 days 27 days Ex. 1 12.5 21 36 50 25 39 45 52 50 39 56 58 Test example 3: Effect on IgM antibody-producing cells in vitro The spleen cells of BDF 1 -strain mice were isolated by finely mincing the spleen, centrifuged, and suspended in medium (RPMI-1640 + 10 % FCS). Each 50 µl of spleen cell suspension (2 x 10 7 cells/ml) and sheep erythrocyte suspension (1 x 10 7 cells/ml) was spread on a 96-well plate. Test compounds were dissolved in DMSO and diluted in medium. Then, 100 µl of medium containing test compounds were added to the 96-well plate. After the plate was incubated at 37 °C for 5 days in 5 % CO 2 incubator,the number of IgM antibody-producing cells was counted by Jerne method. The results are shown in Table 3. Effect on IgM antibody-producing cells in vitro Number of example Concentration (M) n IgM-PFC/culture (mean±S.E.) Inhibition ratio (%) Reference Ex. 1 - 6 82±15 - 2 x 10 -6 6 24±3 71 5 x 10 -5 6 31±9 62 The inventive compounds significantly inhibited the appearance of anti-sheep erythrocyte IgM antibody-producing cells in vitro. Test example 4 Effect on IgM antibody-producing cells in vivo To a BALB/c-strain mice were intraperitoneally injected with 5 x 10 8 /0.1 ml of sheep erythrocytes. The test compound was administered orally once a day for 4 days since the erytyrocyte injection. On the next day of final administration, the spleen cells were isolated by finely mincing the spleen, centrifuged and suspended in medium (RPMI-1640 + 10 % FCS). The number of IgM antibody-producing cells was counted by Jerne method. The results are shown in Table 4. Effect on IgM antibody-producing cells in vivo Number of example Dose (mg/kg/day) n IgM-PFC/spleen (× 10 2 ) (mean±S.E.) Inhibition ratio (%) Reference ― 7 995±55 - Ex. 1 12.5 7 651±49 35 The inventive compound significantly inhibited the appearance of anti-sheep erytyrocyte IgM antibody-producing cells also in vivo. Utilizability in the industry As described above, the compounds of the invention represented by the general formula (1) have a modulating action on the immune response together with a prompt therapeutic effect against the inflammatory model. Despite, they do not exhibit any cyclooxygenase-inhibitory action. Hence, the compounds of the present invention can be useful as therapeutically effective agents not only for rheumatoid arthritis but also for various autoimmune diseases.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LI, LU, NL, SE Cyclic aminophenylacetic acid derivatives represented by the general formula (1) [wherein X denotes abromine atom or chlorine atom], their optical isomers and their salts. A process for preparing cyclic aminophenylacetic acid derivatives represented by the general formula (1) as defined in claim 1 and their salts, characterized in that quinoline derivatives represented by the general formula (2) [wherein X has the same meanings as defined in claim 1 and X 1 denotes a hydrogen atom, chlorine atom or bromine atom], are hydrogenated. A process for preparing cyclic aminophenylacetic acid derivatives represented by the general formula (1) as defined in claim 1, their optical isomers and their salts, characterized in that , with cyclic aminophenylacetic acid derivatives represented by the formula (1b) a corresponding halogenating agent is reacted. A process for preparing cyclic aminophenylacetic acid derivatives represented by the general formula (1) as defined in claim 1, their optical isomers and their salts, characterized in that cyclic aminophenylacetic acid derivatives represented by the general formula (1f) [wherein X has the same meanings as defined in claim 1, and R denotes an alkyl group having 1 to 3 carbon atoms], are hydrolyzed. Quinoline derivatives represented by the general formula (2a-1) wherein R and X are as defined in claim 4 and X 2 denotes a hydrogen atom, chlorine atom, bromine atom or hydroxyl group, and their salts. Aminophenylacetic acid derivatives represented by the general formula (3) wherein R and X are defined as in claim 4 and R 1 denotes an alkyl group having 1 to 3 carbon atoms or a benzyl group. A process for preparing aminophenylacetic acid derivatives represented by the general formula (3) as defined in claim 6, characterized in that , with aminophenylacetic acid derivatives represented by the general formula (4) [wherein R and X have the same meanings as in claim 4], a trifluoromethyl-propiolic acid ester represented by the general formula (5) CF 3 C≡CCOOR 1 [wherein R 1 has the same meaning as according to claim 6, is reacted. An antirheumatic agent and a therapeutic agent for autoimmune diseases having at least one kind or more of cyclic aminophenylacetic acid derivatives represented by the general formula (1) as defined in claim 1, their optical isomers and their salts as effective ingredient(s). Claims for the following Contracting State : ES The use of at least one kind or more of cyclic aminophenylacetic acid derivatives represented by the general formula (1) [wherein X denotes a bromine atom or chlorine atom], their optical isomers and their salts as effective ingredient(s) for preparing an antirheumatic agent and a therapeutic agent for autoimmune diseases. A process for preparing cyclic aminophenylacetic acid derivatives represented by the general formula (1) as defined in claim 1 and their salts, characterized in that quinoline derivatives represented by the general formula (2) [wherein X has the same meanings as defined in claim 1 and X 1 denotes a hydrogen atom, chlorine atom or bromine atom], are hydrogenated. A process for preparing cyclic aminophenylacetic acid derivatives represented by the general formula (1) as defined in claim 1. their optical isomers and their salts, characterized in that , with cyclic aminophenylacetic acid derivatives represented by the formula (1b) a corresponding halogenating agent is reacted. A process for preparing cyclic aminophenylacetic acid derivatives represented by the general formula (1) as defined in claim 1, their optical isomers and their salts, characterized in that cyclic aminophenylacetic acid derivatives represented by the general formula (1f) [wherein X has the same meanings as defined in claim 1, and R denotes a alkyl group having 1 to 3 carbon atoms], are hydrolyzed. A process for preparing aminophenylacetic acid derivatives represented by the general formula (3) [wherein R and X are defined as in claim 4 and R 1 denotes an alkyl group having 1 to 3 carbon atoms or a benzyl group], characterized in that , with aminophenylacetic acid derivatives represented by the general formula (4) [wherein R and X have the same meanings as above], a trifluoromethyl-propiolic acid ester represented by the general formula (5) CF 3 C≡CCOOR 1 [wherein R 1 has the same meaning as above], is reacted. Claims for the following Contracting State : GR Cyclic aminophenylacetic acid derivatives represented by the general formula (1) [wherein X denotes a bromine atom or chlorine atom], their optical isomers and their salts. A process for preparing cyclic aminophenylacetic acid derivatives represented by the general formula (1) as defined in claim 1 and their salts, characterized in that quinoline derivatives represented by the general formula (2) [wherein X has the same meanings as defined in claim 1 and X 1 denotes a hydrogen atom, chlorine atom or bromine atom], are hydrogenated. A process for preparing cyclic aminophenylacetic acid derivatives represented by the general formula (1) as defined in claim 1, their optical isomers and their salts, characterized in that , with cyclic aminophenylacetic acid derivatives represented by the formula (1b) a corresponding halogenating agent is reacted. A process for preparing cyclic aminophenylacetic acid derivatives represented by the general formula (1) as defined in claim 1, their optical isomers and their salts, characterized in that cyclic aminophenylacetic acid derivatives represented by the general formula (1f) [wherein X has the same meanings as defined in claim 1, and R denotes a alkyl group having 1 to 3 carbon atomsl, are hydrolyzed. Quinoline derivatives represented by the general formula (2a-1) [wherein R a and X are defined as in claim 4 and X 2 denotes a hydrogen atom, chlorine atom, bromine atom or hydroxyl group], and their salts. Aminophenylacetic acid derivatives represented by the general formula (3) [wherein R and X are defined as in claim 4, R 1 denotes a alkyl group having 1 to 3 carbon atoms or a benzyl group. A process for preparing aminophenylacetic acid derivatives represented by the general formula (3) as defined in claim 6, characterized in that , with aminophenylacetic acid derivatives represented by the general formula (4) [wherein R and X have the same meanings as in claim 4], a trifluoromethyl-propiolic acid ester represented by the general formula (5) CF 3 C≡CCOOR 1 [wherein R 1 has the same meaning as according to claim 6], is reacted. The use of at least one kind or more of cyclic aminophenylacetic acid derivatives represented by the general formula (1) as defined in claim 1, their optical isomers and their salts as effective ingredient(s) for preparing an antirheumatic agent and a therapeutic agent for autoimmune diseases.

Inventors: AWANO KATSUYA, ISHIZAKI TAKAYOSHI, KOHNO YASUSHI, KOJIMA EISUKE, KUDOH SHINJI, SAITO KOJI, SAKOE YASUHIKO, AWANO, KATSUYA, ISHIZAKI, TAKAYOSHI, KOHNO, YASUSHI, KOJIMA, EISUKE, KUDOH, SHINJI, SAITO, KOJI, SAKOE, YASUHIKO, AWANO, KATSUYA, 352-22, KIZAWA, ISHIZAKI, TAKAYOSHI, 4-9-6, SAKURADA, KOHNO, YASUSHI, 1-10-5, AKATSUKI, KOJIMA, EISUKE, 2412-3, OOAZA-NAKATA, KUDOH, SHINJI, 661-14, OOAZA MARUBAYASHI, SAITO, KOJI, 1-6-8, AKATSUKI, SAKOE, YASUHIKO, 510-3, OTOME
Applicants: KYORIN SEIYAKU KK, KYORIN PHARMACEUTICAL CO., LTD.
Application year: 1992
Main classification: C07D215
IPC codes: A61P29, C07C317, A61P37, C07F7, C07D215, C07C331, A61K31, C07D498, C07C323, C07C311