INDOLE COMPOUNDS, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS COMPRISING THEM

Abstract: A substituted indole compound of formula (I) wherein R represents a linear or branched C₂-C₅ alkyl group which may be substituted by a phenyl or phenoxy group unsubstituted or substituted by an alkoxy group, R₁ repre­ sents a hydrogen atom, an alkyl group or a nitro group, A represents a direct bond or the group -CONH-, and n is an integer of 1 to 5; a process for the production thereof; and a pharmaceutical composition comprising the same.

Description: DESCRIPTION TITLE: "INDOLE COMPOUNDS, THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS COMPRISING BIEM" This invention relates to novel indole compounds having various pharmacological activities such as blood pressure lowering activity, vasodilating activity, adrenergic beta-blocking activity and blood flow increasing activity. The invention also relates to processes for the production of the aforesaid compounds. The compounds of this invention have not been described in the literature and are novel. They can be represented by the following formula (I). EMI1.1 In the formula, R represents a linear or branched C2-C5 alkyl group which may be substituted by a phenyl or phenoxy group unsubstituted or substituted by a lower alkoxy group, preferably a C1-C3 alkoxy group, R1 represents a hydrogen atom, a lower alkyl group, preferably a C1-C3 alkyl group, or a nitro group, A represents a direct bond or the bond -CONH-, and n is an integer of 1 to 5. It is an object of this invention therefore to provide the indole compounds of formula (I) and processes for their production. In formula (I), examples of the C2-C5 alkyl group are ethyl, n- or iso-propyl, and n-, iso-, sec- or tert-butyl. The alkyl group may be substituted by a phenyl or phenoxy group unsubstituted or substituted by a lower alkoxy group. The lower alkoxy group preferably has 1 to 3 carbon atoms, and a methoxy group is especially preferred. R1 in formula (I) maybe bonded not only to the 4-, 5-, 6- or 7-position of the indole ring, but also to the 2- or 3-position. The symbol n preferably represents an integer of 2 or 3. Specific examples of the compound of formula (I) are: 4- or 5-[(2-hydroxy-3-n- or iso-propylamino)propyloxy]-N-(2- or 3-nitroxyethyl or -nitroxypropyl)indole-2-carboxamide, 4- or 5-[(2-hydroxy-3-n-, iso-, sec- or tertbutylamino)propyloxy]-N-(2- or 3-nitroxyethyl or -nitroxypropyl)indole-2-carboxamide, 4- or 5-[(2-hydroxy-3-beta-phenethylamino)propyloxy]-N-(2- or 3-nitroxyethyl or -nitroxypropyl)indole-2-carboxamide, 4- or 5-I[(2-hydroxy-3-(beta-methoxyphenoxy)- ethylamino]propyloxy)-N-(2- or 3-nitroxyethyl or -nitroxypropyl) indole-2-carboxamide, 4- or 5-[(2-hydroxy-3-amylamino)propyloxy] -N-(2- or 3-nitroxyethyl or -nitroxypropyl)indole2-carboxamide, 4- or 5-[(2-hydroxy-3-n- or iso-propylamino)propyloxy]-7-nitro-N-(2- or 3-nitroxyethyl or -nitroxypropyl)indole-2-carboxamide, and 4- or 5-[(2-hydroxy-3-n- or iso-propylamino)propyloxy]-2-methyl-3(2- or 3-nitroxyethyl or -nitroxypropyl)indole. The compounds of formula (I) can be produced, for example, by the following process (a), (b), (c) or (d). Process (a) A compound of the following formula (II) EMI3.1 wherein R1, A and n are as defined herein above, is reacted with an amine compound of the following formula (III) H2N-R ...... (III) wherein R is as defined above. Process (b) A compound of the following formula (IV) EMI3.2 wherein R, R1, A and n are as defined herein above, is subjected to a nitrate ester-forming reaction. Process (c) A compound of the following formula (V) EMI3.3 wherein R and R1 are as defined above, and R' represents a hydrogen atom or a lower alkyl group, is reacted with a compound of the following formula (VI) EMI4.1 wherein n is as defined above. Process (d) A compound of the following formula (VIII) EMI4.2 wherein R1, A and n are as defined herein above, is subjected to an aminoalkanol-forming reaction. The compound of formula (II) used in process (a) can be produced by subjecting to a nitrate esterforming reaction a compound of the following formula (X) EMI4.3 wherein R1, A and n are as defined above, which can be obtained by subjecting a compound of the following formula (IX) EMI4.4 wherein R1, A and n are as defined above, to a glycidyl-forming reaction. The compound of formula (II) can also be produced by subjecting to a glycidyl-forming reaction the compound of formula (VIII) which can be obtained by subjecting the compound of formula (IX) to a nitrate ester-forming reaction. A -compound of formula (VIII) in which A is the bond -CONH- can be produced by reacting a hydroxyindole carboxylic acid derivative of the following formula (XI) EMI5.1 wherein R1 and R' are as defined above, with the compound of formula (VI). The compound of formula (VIII) which can be so produced may also be utilized as a starting compound in process (d). The compound of formula (IX) can be obtained by protecting the OH group of the compound of formula (XI) and then reacting the protected compound of formula (XI) with a compound of the following formula (VII) EMI5.2 wherein n is as defined above. The compound of formula (IV) used in process (b) can be produced by reacting the compound of formula (X) with the amine compound of formula (III). A compound of formula (IV) in which A is the bond -CONH- can be produced also by reacting the compound of formula (V) with the compound of formula (VII). The compound of formula (V) which can be used in the production of the compound of formula (IV) and also a8 a starting material in process (c) can be produced by reacting a compound of the following formula (XII) EMI6.1 wherein R and R' are as defined above, which can be obtained by subjecting the compound of formula (XI) to a glycidyl-forming reaction, with the amine compound of formula (III). The processes (a) to (d) are schematically shown below together with examples of producing the starting compounds used therefor. EMI7.1 <SEP> (VI) <SEP> H2N-(CH2)-n-ONO2 <tb> <SEP> (VII) <tb> # <SEP> H2N-(CH2)n-OH <SEP> # <SEP> nitrate <SEP> # <tb> H <SEP> (XI) <SEP> H <SEP> (IX) <SEP> ester- <SEP> H <SEP> (VIII) <tb> <SEP> forming <tb> <SEP> reaction <tb> glycidyl- <SEP> glycidyl- <SEP> glycidylforming <SEP> forming <SEP> forming <tb> reaction <SEP> reaction <SEP> reaction <tb> # <SEP> # <SEP> nitrate <SEP> # <tb> H <SEP> (XII) <SEP> H <SEP> (X) <SEP> ester- <SEP> H <SEP> (II) <tb> <SEP> forming <tb> <SEP> reaction <tb> <SEP> Process <SEP> (a) <tb> (III) <SEP> H2N-R <SEP> (III) <SEP> H2N-R <SEP> (III) <SEP> H2N-R <tb> Amination <SEP> Amination <SEP> Amination <tb> <SEP> Process <SEP> (b) <SEP> Process <SEP> (d) <tb> <SEP> nitrate <SEP> Aminoalkanol <SEP> ester- <SEP> forming <tb> <SEP> (VII) <SEP> forming <SEP> reaction <tb> # <SEP> H2N-(CH2)n-OH <SEP> # <SEP> reaction <SEP> (I) <tb> (V) <SEP> (IV) <tb> <SEP> (VI) <SEP> H2N-(CH2)n-ONO2 <tb> Process (c) In processes (a) to (d) and the production processes for starting compounds in these processes, the amination with the amine compound of formula (III), the amidation with the compound of formula (VI), the amidation with the compound of formula (VII), the nitrate ester-forming reaction, the aminoalkanol-forming reaction, and the glycidyl-forming reaction can be performed as shown below. 1. Amination The amination of the epoxy groupcontaining compound of formula (II), (X) or (XII) with the compound of formula (III) can be carried out by contacting the compound of formula (II), (X) or (XII) with the compound of formula (III) in a suitable solvent. The solvent may be an inert organic solvent. Specific examples include methanol, ethanol and isopropanol. The reaction is carried out preferably under heating, for example under refluxing temperature conditions, for example at a reaction temperature ranging from room temperature to about 150 0c. The reaction time can be selected properly, and is, for example, about 1 to about 5 hours. 2. Nitrate ester-forming reaction The nitrate ester-forming reaction of the hydroxyalkyl or hydroxyalkylamide derivative of formula (IV), (IX) or (X) can be carried out by contacting the compound of formula (IV), (IX) or (X) with a nitrating reagent such as fuming nitric acid or a mixture of fuming nitric acid and acetic anhydride in the presence or absence of a solvent. Examples of the solvent that may be used include acetonitrile, dioxane and tetrahydrofuran. Preferably, the reaction is carried out at relatively low temperatures, for example at about -400C to room temperature. The reaction time can be properly selected, and is, for example, several minutes to about 1 hours. When the compound of formula (VIII) is to be produced from the compound of formula (to), the nitrate ester-forming reaction is carried out after the hydroxyl group excepting -AtCH2 t OH is protected. Specific protective groups used for the protecting reaction include a chloroacetyl group,. a dichloroacetyl group and a trichloroacetyl group. 3. Amidation When the compound of formula (XI) or (V) is an indole carboxylic acid ester in which R' in the group -COOR' is a lower alkyl group, the amidation of the compound of formula (XI) or (V) with the nitroxyalkylamine of formula (VI) or the hydroxyalkylamine of formula (VII) can be carried out by contacting this ester with the compound of formula (VI) or (VII). The reaction temperature can be properly chosen and is, for example, room temperature to about 1300C, The reaction time can also be properly chosen, and is, for example, about 1 to about 6 hours. When R' in the group -COOR' in the compound of formula (XI) or (V) is a hydrogen atom (namely, when the group -COOR' is a free carboxyl group), the amidation reaction can be carried out by contacting the compound of formula (XI) or (V) with the compound of formula (VI) or (VII) in the presence of a suitable coupling reagent such as dicyclohexyl carbodiimide or carbonyl diimidazole at a relatively low temperature of, for example, about 0 to about 7000. In the reaction of the compound of formula (XI) with the compound of formula (VI) or (VII), the reaction is carried out preferably after the OH group other than -COOR' (R'=H) in formula (XI) is protected. The protecting reaction can be carried out in the same way as described hereinabove with regard to the nitrate ester-forming reaction in section 2 above. 4. Aminoalkanol-forming reaction The aminoalkanol-forming reaction of the compound of the formula (VIII) can be carried out by reacting it with an alkylaminoalkanol under ordinary conditions. 5. Glycidyl-forming reaction The glycidyl-forming reaction of the compound of formula (VIII), (IX) or (XI) can be carried out, for example, by contacting it with epichlorohydrin and piperidine or l,8-azabycyclo[5.4 .01 undec-7-ene (DBU) at a reaction temperature ranging from room temperature to about 1000C for about 1 to about 5 hours. The novel compounds of formula (I) which can be produced as described above show various pharmacological activities such as -blood pressure lowering activity, vasodilating activity, adrenergic betablocking activity and blood flow increasing activity and are useful, for example, as anti-angina pectoris agents, hypotensive agents, cerebral circulation improvers and antiarrhythmic agents. Accordingly, the present invention can also provide a pharmaceutical composition comprising an amount, effective for the treatment of cardiovascular diseases, of a compound of formula (I) and a pharmaceutically acceptable diluent or carrier. Liquid or solid carriers or diluents may be used in forming the pharmaceutical composition. They may include excipients, binders, lubricants, emulsifiers, etc. known in pharmaceutical production. Examples of these carriers or diluents include starches such as potato starch, wheat starch, corn starch and rice starch; sugars such as lactose, sucrose, glucose, mannitol and sorbitol; celluloses such as crystalline cellulose, calcium carboxymethyl cellulose and hydroxypropyl cellulose of a low degree of substitution; inorganic substances such as potassium phosphate, calcium sulfate, calcium carbonate and talc; binder compounds such as gelatin, gum arabic, methyl cellulose, sodium carboxymethyl cellulose, polyvinyl pyrrolidone and hydroxypropyl cellulose; polyhydric alcohol ester-type nonionic surfactants such as fatty acid monoglycerides, sorbitan fatty acid esters, sucrose and polyglycerol fatty acid esters; and polyoxyethylene-type noninonic surfactants. The pharmaceutical composition may be in any dosage forms known in the art of formulating pharmaceuticals, such as suppositories, powders, granules, tablets, sublingual tablets, liquid preparations, injectable preparations, and suspension. The pharmaceutical composition may be administered through any of peroral or parenteral routes, such as intravenous, sublingual or intrarectal administration. For long-term administration, the oral route is preferred. The dose may be changed as desired. For example, the compound of formula (I) may be administered in a dose of about 1 to about 100 mg/body/day, preferably about 5 to about 50 mg/body/day. The compounds of this invention have low toxicity. The compounds of formula (I) in accordance with this invention have been found to be active in the following pharmacological activity tests. Test 1: Blood pressure and heart rate using dogs. Test 2: 8-Blocking action using isolated atrial muscle of a guinea pigs. Test 3: Coronary blood flow using dogs. Example 1 5-[(2-Hydroxy-3-isopropylamino)propyloxy]-N (3-nitroxypropyl) indole-2-carboxamide of the formula: - EMI12.1 (1) A mixture of 10.57 g of ethyl 5-benzyloxyindole2-carboxylate and 16.80 g of 3-aminopropanol was stirred at 120 C for 3 hours. After cooling, water was added and the mixture was acidified with concentrated hydrochloric acid and then extracted with ethyl acetate. The extract was washed with water, dried and crystallized to give 8.41 g of colorless prismatic crystals having a melting point of 140 to 14500. The crystals were dissolved in 350 ml of ethanol, and 0.5 g of 108 palladium-carbon was added. The mixture was stirred for 5 hours under a hydrogen stream. The catalyst was removed by filtration. The reaction mixture was concentrated, and the resulting yellow oil was crystallized from ethyl acetate to give 7.00 g (yield 99.3%) of 5-hydroxy-N-(3-hydroxypropyl)indole-2-carboxamide as colorless prismatic crystals having a melting point of 186 to 18800. MS: m/e 234 [M+1 IR, vRBaX cm 1 3250 (NH, OH), 1610 (CONH), max 1050 (C=O). (2) Epichlorohydrin (21.65 g) was added to a solution of 2.74 g of the resulting 5-hydroxy-N-(3 hydroxypropyl)indole-2-carboxamide and 3.56 g of 1,8-diazabicyclol5.4.0]undec-7-ene (DBU) in 100 ml of methanol, and the mixture was stirred under refluxing for 3 hours. After the reaction, the solvent was evaporated under reduced pressure. An aqueous solution of sodium chloride was added to the resulting oily product, and the mixture was extracted with chloroform. The extract was washed with water and dried and the solvent was evaporated. The residue was crystallized from ethyl acetate to give 1.06 g (yield 31.326) of 5-(2,3-epoxypropyloxy)-N-(3-hydroxy propyl) indole-2-carboxamide as colorless needlelike crystals having a melting point of 99 to 10100. (3) A solution of 0.393 g of the resulting epoxy compound in 20 ml of acetonitrile was cooled to -30 C, and 0.496 g of an eguimolar mixture of acetic anhydride and fuming nitric acid was added, and the mixture was stirred for 10 minutes. After the reaction, an aqueous solution of sodium bicarbonate was injected into the reaction mixture, and it was extracted with ethyl acetate. The extract was washed with water, dried, and purified by silica gel column chromatography. Crystallization gave 0.073 g (yield 16.0%) of 5-(2,3-epoxypropyloxy)-N-(3-nitroxypropyl)indole-2-carboxamide as yellow prismatic crystals having a melting point of 148 to 14900. MS: m/e 335 [M+] 272 1M -HONO21 IR, ',KBr cm 1 3360 (CONH), 3260 (NH), max 1640 (CONH), 1620, 1280 (ONO2). (4) Methanol (10 ml) and 0.14 g of isopropylamine were added to 0.076 g of the resulting epoxy-nitroxy compound, and the mixture was heated under reflux for 3 hours with stirring. After the reaction, the solvent was evaporated, and the resulting oily product was separated by alumina thin-layer chromatography (developing solvent: chloroformmethanol=10/l) - to give 0.029 g (yield 32.48) of 5-[(2-hydroxy-3 isopropylamino)propyloxy)-N-(3-nitroxypropyl) indole- 2-carboxamide as a pale yellow powder. MS: m/e 331 [M+-HONO2] IR, VKBrmax cm-1 3240 (NH), 1640 (CONH, ONO2), 1280 (ONO2). 1H-NMR; #CDCl3 7.33 (1H, d, J=8Hz, HD) 7.07 (1H, d, J=2.0Hz, HB) 6.96 (2H, d,d, J=8.8Hz, J=2.2Hz, HC) 6.91 (1H, d, J=0.7Hz, HA) 4.57 (2H, t, J=6.4Hz, -CH2ONO2) 4.17-3.92 (3H, m, EMI14.1 3.53 (2H, t, J=6.6Hz, -CONHCH2-) 2.94-2.63 (3H, m, -CH2NHCH#) 2.07 (2H, q, J=6.6Hz7-CH2CH2CH2-) 1.12 (6H, d,d, J=6.5Hz, J=1.5Hz, EMI14.2 EMI14.3 The compounds in the following Examples were synthesized in the same way as in Example 1. Example 2 5-[3-t-butylamino-2-hydroxy)propoyloxy]-N (3-nitroxypropoyl) indole-2-carboxamide of the formula: EMI14.4 Property: Pale yellow prismatic crystals Melting point: 129-131 C MS: m/e 345 [M+-HONO2] IR: vmaxKBr cm-1: 3280 (NH, OH), 1630 (CONH, ONO2), 1280 (ONO2) 1HNMR: 6CDC13: 9.11 (1H, br.s, -CH2NH-) 7.32 (1H, d, Js8.8Hz, HD) 7.06 (lH, d, J=2.2Hz, HB) 6.99 (lH, d,d, J=8.8Hz, J=2.2Hz, HC) 6.75 (1H, s, HA) 6.34 (lH, br.s, -CONH-) 4.59 (2H, t, J=6.3Hz, -CH2ONO2) 4.08-3.92 (3H, m, EMI15.1 3.61 (2H, q, J=6.4Hz, -CH2CH2CH2O-) 2.97-2.67 (2H, m, -CH2N#) 2.10 (2H, q, J=6.4Hz, -CONHCH2CH2-) 1.14 (9H, s, -C(CH3)3) EMI15.2 Example 3 5-[(2-hydroxy-3-beta-phenethylamino)propyloxy] N-(3-nitroxypropyl)indole-2-carboxamide of the formula: EMI15.3 Property: Pale yellow powder Melting point: 134-136 C MS: m/e 393 [M+-HONO3] 302 [M+-HONO3, C7H7] IR: Vmax KBR cm-1: 3300 (OH), 3240 (NH), 1640 1640 (CONH), 1620, 1280 (ONO2) #CDCl3-CD3OD 7.40-6.87 (9H, m, aromatic ring H) 4.57 (2H, t, J=6.3Hz, -CH2ONO2) 4.25-3.94 (5H, m, EMI16.1 3.52 (2H, t, J=6.8Hz, -NHCH2-) 3.05-2.73 (4H, m, -CH2NHCH2-) 2.07 (2H, q, J=6.4Hz, -CH2CH2CH2-) Example 4 5-{[2-hydroxy-3-(beta-methoxyphenoxy)ethyl amino]propyloxy}-N-(3-nitroxypropyl)indole-2 carboxamide of the formula: EMI16.2 Property: Pale yellow powder Melting point: 128-131 C MS: m/e 439 [M+-BONO3] IR: #maxKBR cm-1: 1620 (CONH, ONO2), 1280 (ONO2) 1H-NMR: #CDCl3-CD3OD 7.33 (IR, d, J=8.8Hz, HD) 7.08 (lH, d, J=2.2Hz, HB) 7.00-6.77 (6H, m, HA, HB, EMI16.3 4.57 (2H, t, J=6.6Hz, -CH2ONO2) 4.28-3.64 (5H, m, EMI16.4 3.85 (3H, s, -OCH3) 3.53 (2H, t, J=6.6Hz, -CONHCH2-) 3.23-2.89 (4H, m, -CH2NHCH2-) 2.07 (2H, q, J=6.9Hz, -CH2CH2CH2-) EMI17.1 Example 5 4-[(2-hydroxy-3-isopropylamino)propyloxy-7 nitro-N-(3-nitroxypropyl)indole-2-carboxamide of the formula: EMI17.2 Property: Orange powder Melting point: 158-160 C MS: m/e 376 [M+-HONO3] IR: VmaxKBR cm 1 1630 (CONH), 1620 (ON02), 1560 (NO2), 1280 (ONO2) 1H-NMR: #CDCl3 8.15 (1H, d, J=9.3Hz, HC) 7.39 (lH, s, HA) 6,67 (1H, d, J=9.OHz, HB) 4.64 (2H, t, J=6.4Hz. -CH2ONO2) 3.95-3.78 (1H, m, EMI17.3 3.70-3.45 (7H, m, -CONHCH2-, EMI17.4 2.10 (2H, q, J=6.4Hz, -CH2CH2CH2-) 1.38-1.35 (6H, d,d, J=6.6Hz, EMI17.5 EMI18.1 Example 6 5-[(2-hydroxy-3-isopropylamino)propyloxy)-2 methyl-3-(2-nitroxyethyl)indole of the formula: - EMI18.2 Property: Yellow oil MS: m/e 351 [M+] IR: #maxfilm cm-1: 3280 (NH), 1610, 1260 (ONO2) 1H-NMR: #CDCl3 8.42 (lH, d, J=9.0Hz, HC) 7.00 (1H, d,d, J-9.0Hz, 2.4Hz, HB) 6.89 (lH, d, J=2.6Hz HA) 4.42-4.25 (lH, m, EMI18.3 4.00 (3H, d, J=2.5Hz, EMI18.4 3.68-3.49 (2H, m, -CH2CH2ONO2) 2.95-2.64 (3H, m, -CH2NHCH#) 2.64-2.45 (lH, m, -OHONO2) 2.03 (3H, s, EMI18.5 1.10 (6H, d, J=6.1Hz, EMI18.6 EMI18.7

Claims: CLAIMS 1. A substituted indole compound of formula (I) EMI19.1 wherein R represents a linear or branched C2-C5 alkyl group which may be substituted by a phenyl or phenoxy group unsubstituted or substituted by a lower alkoxy group, R1 represents a hydrogen atom, a lower alkyl group or a nitro group, A represents a direct bond or the group -CONH-, and n is an integer of 1 to 5. 2. A compound according to claim 1 wherein the lower alkoxy group in the definition of R is an alkoxy group having 1 to 3 carbon atoms, and the lower alkyl group for R1 is an alkyl group having 1 to 3 carbon atoms. 3. A compound according to claim 1 which is 5- t2-hydroxy-3-isopropylamino) propyloxy) -N- (3- nitroxypropyl)indole-2-carboxamide. 4. A compound according to claim 1 which is 5-[(2-hydroxy-3-tert-butylamino)propyloxy]-N- (3- nitroxypropyl)indole-2-carboxamide. 5. A compound according to claim 1 which is 5-1(2-hydroxy-3-beta-phenethylamino)propyloxy]-N-(3- nitroxypropyl)-indole-2-carboxamide. 6. A compound according to claim 1 which is 5-{[2-hydroxy-3-(beta-methoxyphenoxy)ethylamino] propyloxy}-N-(3-nitroxypropyl)indole-2-carboxamide. 7. A compound according to claim 1 which is 4- [ (2-hydroxy-3-isopropylamino)propyloxy]-7- nitro-N- (3-nitroxypropyl) indole-2-carboxamide. 8. A compound according to claim 1 which is 5-[(2-hydroxy-3-isopropylamino)propyloxy]-2methyl-3- (2-nitroxyethyl) indole. 9. A process for the production of a substituted indole compound as claimed in claim 1 which comprises (a) reacting a compound of formula (II) EMI20.1 wherein R1, A and n are as defined in claim 1, with an amine compound of formula (III) H2N-R (III) wherein R is as defined in claim 1; or (b) subjecting a compound of formula (IV) EMI20.2 wherein R, R1, A and n are as defined in claim 1, to a nitrate ester-forming reaction; or (c) reacting a compound of formula (V) EMI21.1 wherein R and R1 are as defined in claim 1, and R' represents a hydrogen atom or a lower alkyl group, with a compound of formula (VI) EMI21.2 wherein n is as defined in claim 1; or (d) subjecting a compound of formula (VIII) EMI21.3 wherein R1, A and n are as defined in claim 1, to an aminoalkanol-forming reaction. 10. A pharmaceutical composition comprising, as active ingredient, a substituted indole compound as claimed in any one of claims 1 to 8 in association with a pharmaceutically acceptable diluent or carrier.

Inventors: ISHIMAHA, HIROSHI, ONOGI, KAZUHIRO, SHIRATSUCHI, MASAMI
Applicants: KOWA COMPANY, LTD.
Application year: 1983
Main classification: C07D209
IPC codes: C07D405, C07D209, A61P9, A61K31, A61P25