BENZAMIDE COMPOUND AND MEDICINAL USE THEREOF

Abstract: Benzamide compounds of the formula wherein each symbol is as defined in the specification, isomers thereof and pharmaceutically acceptable acid addition salts thereof. Pharmaceutical compositions comprising a therapeutically effective amount of this compound and a pharmaceutically acceptable additive, and therapeutic agents for hypertension, therapeutic agents for angina pectoris, therapeutic agent for asthma, therapeutic agents for renal and peripheral circulatory disturbances and inhibitor of cerebral vasospasm, which comprise this compound. The compound of the present invention has strong smooth muscle relaxing action, and shows hypotensive action and cerebral · coronary vasodilating action like conventional calcium antagonists, as well as long-lasting renal and peripheral circulation improving action. Unlike calcium antagonists, it permits oral administration to suppress vascular contraction caused by various agonists, and is useful as a strong and long-acting agent for prophylaxis and treatment of circulatory diseases in coronary, cerebral, renal and peripheral arteries, as a therapeutic agent for hypertension, angina pectoris, and renal and peripheral circulation disorder, an inhibitor of cerebral vasospasm and the like. Moreover, the compound of the present invention is useful as a therapeutic agent for asthma.

Description: The present invention relates to a novel benzamide compound useful as pharmaceutical agents, an isomer thereof, pharmaceutically acceptable acid addition salts thereof and pharmaceutical use thereof. Background of the Invention One pathogenetic cause of hypertension and coronary · cerebral circulatory disturbances (e.g., angina pectoris, cerebral infarction and the like) which pose serious social problems as adult diseases is considered to be an abnormal contraction of smooth muscle. The contraction and relaxation of smooth muscle are mainly controlled by increase and decrease of intracellular calcium. The calcium which has flowed into smooth muscle cells binds with calmodulin to activate myosin light chain phosphorylation enzyme. As a result, myosin light chain is phosphorylated to cause contraction of smooth muscles (myosin phosphorylation theory). Taking note of this theory, various calcium antagonists have been developed which reduce intracellular calcium and distend blood vessels, and widely used for the therapy of hypertension, angina pectoris and the like. Inasmuch as a sustained contraction of smooth muscle of blood vessel, trachea and the like, which is characteristic of smooth muscle, is inexplicable by myosin phosphorylation theory alone, an involvement of contraction mechanism which is independent of intracellular calcium level, and calcium sensitivity reinforcing mechanism, have been suggested in recent years. Such involvement is supported by the occurrence of contraction of smooth muscle and diseases (e.g., cerebral vasospasm, asthma and the like) on which calcium antagonists are ineffective. Therefore, a pharmaceutical agent which only reduces intracellular calcium is insufficient to treat diseases caused by contraction of smooth muscle, and the development of a new smooth muscle relaxant has been awaited. Benzamide compounds as cardiotonics have been reported in Japanese Patent Unexamined Publication Nos. 158252/1987 and 158253/1987; as antiulcer agents in J. Med. Chem., 14 , 963 (1971); and as intestinal peristaltic movement inhibitors in Spanish patent No. 456,989. Yet, no reports have documented their smooth muscle relaxing action. On the other hand, WO 93/05021 discloses that 4-amino(alkyl)-cyclohexane-1-carboxamide compounds are useful as potent and long-acting anti-hypertensive agents, agents for prevention and treatment of circulatory diseases of coronary, cerebral, renal and peripheral arteries, and therapeutic agents for asthma. It is therefore an object of the present invention to provide an agent which can be administered orally, which has strong smooth muscle relaxing action, hypotensive action and cerebral · coronary vasodilating action like conventional calcium antagonists, as well as sustained renal and peripheral circulation improving action, and which also suppresses, unlike calcium antagonists, vasoconstriction caused by various agonists. Disclosure of the Invention The present inventors have conducted intensive studies and found that the benzamide compounds of the present invention, isomers thereof and pharmaceutically acceptable acid addition salts thereof can accomplish the above-mentioned objects and completed the present invention. It has been also found that the compound of the present invention has anti-asthma action based on the inhibitory action on experimental asthma in guinea pig which was induced by histamin inhalation, and on the inhibitory action on the contraction induced by acetylcholine in tracheal specimens extracted from guinea pig. Thus, the present invention relates to a benzamide compound of the formula (1) A benzamide compound of the formula or an isomer thereof or a pharmaceutically acceptable acid addition salt thereof. (2) A benzamide compound of (1), namely (R)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide or an isomer thereof or a pharmaceutically acceptable acid addition salt thereof. (3) A pharmaceutical composition comprising a therapeutically effective amount of the benzamide compound of (1) or (2), an isomer thereof or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable additive. (4) A therapeutic agent for hypertension, comprising the benzamide compound of (1) or (2), an isomer thereof or a pharmaceutically acceptable acid addition salt thereof. (5) A therapeutic agent for angina pectoris, comprising the benzamide compound of (1) or (2), an isomer thereof or a pharmaceutically acceptable acid addition salt thereof. (6) A therapeutic agent for asthma, comprising the benzamide compound of (1) or (2), an isomer thereof or a pharmaceutically acceptable acid addition salt thereof. (7) A therapeutic agent for renal and peripheral circulatory disturbances, comprising the benzamide compound of (1) or (2), an isomer thereof or a pharmaceutically acceptable acid addition salt thereof. (8) An inhibitor of cerebral vasospasm, comprising the benzamide compound of (1) or (2), an isomer thereof or a pharmaceutically acceptable acid addition salt thereof. As mentioned the present invention relates to a benzamide compound of the formula wherein R is a hydrogen; R 1 is a hydrogen; R 2 and R 3 are each hydrogen; R 4 is a hydrogen; R 5 is pyridine and A is the formula wherein R 10 and R 11 are different and one is hydrogen, and the other is methyl, and l and n are each 0, and m is 1, isomers thereof and pharmaceutically acceptable acid addition salts thereof. The present invention further provides pharmaceutical compositions containing a therapeutically effective amount of the compound of formula (I), an isomer thereof or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable additive; therapeutic agents for hypertension, angina pectoris, asthma, renal and peripheral circulation disorders, and cerebral vasospasm inhibitor containing a therapeutically effective amount of the compound of formula (I), an isomer thereof or a pharmaceutically acceptable acid addition salt thereof. The compound (I) of the present invention can be synthesized by the following route. Method 1 A method comprising reacting a carboxylic acid compound of the formula wherein R, R 1 , R 2 , R 3 and A are as defined above, or a reactive derivative thereof, with an amino compound of the formula wherein R 4 and R 5 are as defined above. The reactive derivative of carboxylic acid compound includes acid halide such as acid chloride, acid anhydride, mixed acid anhydride formed from ethyl chloroformate and the like, ester such as methyl ester, ethyl ester and the like, a reactive derivative produced from carbodiimide such as dicyclohexylcarbodiimide, and the like. The reaction is carried out in the presence of an inert solvent, which is generally an organic solvent without hydroxy such as tetrahydrofuran, ethyl acetate, benzene, toluene, carbon tetrachloride, chloroform, methylene chloride, dimethylfonnamide and dimethylimidazolidinone. The reaction proceeds at an optional temperature such as -10°C to 200°C, preferably from 0°C to 80°C. When the starting material is a reactive derivative (e.g., ester) having less greater reactivity, a high reaction temperature is used; when it is a reactive derivative having greater reactivity (e.g., mixed acid anhydride), a low reaction temperature is used. Where necessary, an organic base such as pyridine, triethylamine, diisopropylethylamine and the like may be used as a deacidifying agent. As occasion demands, the amino group of the formula (IV) can be protected with an amino-protecting group such as benzyloxycarbonyl and tert-butoxycarbonyl before reaction. Said protecting group can be removed after reaction by conventional method. The carboxylic acid compound of the formula (IV) which is a starting material of synthesis of the present invention can be easily synthesized from a commercially available starting material by a known method, or the method described in WO93/05021. An amine compound of the formula (V) which is the other synthesis starting material can be synthesized by the method described in WO93/05021. Method 2 A compound (I) wherein one of R and R 1 is hydrogen and the other is hydrogen can be produced by reacting an amine compound, wherein R and R 1 are hydrogen which is obtained by Method 1, of the formula wherein R 2 , R 3 , R 4 , R 5 and A are as defined above, and a halide compound, aldehyde compound or ketone compound. The halide compound to be used in this reaction is represented by the formula R 12 -Hal wherein R 12 is alkyl having 1 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl, phenyl or aralkyl optionally having substituent on the ring, and Hal is halogen, preferably chlorine or bromine; aldehyde compound is represented by the formula R 13 CHO wherein R 13 is hydrogen, alkyl having 1 to 5 carbon atoms, or phenyl or aralkyl optionally having substituent on the ring; and ketone compound is represented by the formula wherein R 14 and R 15 are the same or different and each is alkyl having 1 to 5 carbon atoms, or phenyl or aralkyl optionally having substituent on the ring, or R 14 and R 15 combinedly form together with carbonyl cycloalkyl having 3 to 7 carbon atoms. Compound (VIII) and halide compound may be reacted under the same conditions as in Method 1. It is preferable that deacidifying condensation be carried out in the presence of abase such as sodium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide, triethylamine and pyridine. Compound (VIII) and aldehyde or ketone are subjected to dehydrative condensation in a solvent hardly miscible with water, such as benzene, toluene, xylene, carbon tetrachloride, chloroform, dichloromethane and the like with reflux under heating. It is also beneficial to add a small amount of an acid such as p-toluenesulfonic acid. The compound obtained by the above condensation, such as alkylidene compound and phenylalkylidene compound, may be subjected to reduction to derive a compound such as alkyl compound and aralkyl compound. The reduction can be generally carried out in an alcohol such as methanol, ethanol, isopropyl alcohol and the like at -10 to 100°C, preferably 0 to 40°C. The reaction proceeds in the presence of a reducing agent such as sodium borohydride, or in the presence of a small amount of an acid such as hydrochloric acid, hydrobromic acid and acetic acid using a reducing agent such as sodium cyanoborohydride. When other groups of the objective compound are not affected, catalytic reduction using Raney nickel, palladium carbon, platinum oxide and the like may be employed. Alternatively, reductive amination can also produce the objective compound. In particular, the compound (I) of the present invention, having substituent on the benzene ring is converted to nitro by reacting the corresponding carboxylic acid or a derivative thereof with nitric acid/sulfuric acid, and converted to amine by various reductions with, for example, H 2 /Raney Ni, Zn/AcOH and the like. Then, the compound is treated with sodium nitrate in the presence of an acid such as hydrochloric acid and sulfuric acid to give a diazonium salt, which is subjected to Sandmeyer reaction with, for example, copper chloride, copper bromide and copper cyanide, to convert respective functional groups. An iodine compound can be obtained by' treating with potassium iodide. A fluorine compound can be synthesized by converting the diazonium salt to a borate with HBF 4 and heating the borate, or by treating with pyridine hydrofluoride. A carboxyl compound can be also obtained by hydrolysis of the nitrile compound obtained by Sandmeyer reaction, or directly by converting the benzene ring to.lithium compound and treating the compound with carbon dioxide. An ester or amide compound can be easily obtained by conversion from the carboxylic acid by a conventional method. A hydroxy compound can be synthesized by heating the diazonium salt in an aqueous acid solution. An alkyloxy compound and aralkyloxy compound can be easily synthesized by treating the hydroxyl group with the corresponding alkyl halide or aralkyl halide in the presence of a base. An alkyl compound and aralkyl compound can be. synthesized by Friedel-Crafts reaction using the corresponding alkyl, or aralkyl halide and AlCl 3 , or by a reaction using a Grignard reagent prepared from aromatic halide and magnesium, or by coupling reaction of aromatic halide and the corresponding alkyl or aralkyl boron compound using a palladium catalyst. The isomers encompassed in the compound (I) of the present invention can be prepared by isolation from mixtures of isomers by a conventional method, or by using various starting materials for isomers. The compound (I) thus obtained can be separated and purified from reaction mixtures by a method known per se such as recrystallization and chromatography. The compound (I) can be further converted to pharmaceutically acceptable acid addition salts by a conventional method. The acid to be used for forming acid addition salts may be appropriately selected from an inorganic acid (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid) and an organic acid (e.g., acetic acid, methanesulfonic acid, maleic acid and fumaric acid). These salts can be converted to the corresponding free base by a conventional method, such as reaction with alkali such as sodium hydroxide and potassium hydroxide. Further, a quaternary ammonium salt can be prepared. A compound (I) having a carboxyl group can be converted to a metal salt (e.g., sodium, potassium, calcium and aluminum) or salt with amino acid (e.g., lysine and ornithine). The effects afforded by the compound of the present invention are explained in detail by way of pharmacological experiments. Pharmacological Experiment 1 : hypotensive effects To spontaneously hypertensive rats (SHR) weighing 350-450 g (3-5 per group) was orally administered a test compound (30 mg/kg) dissolved in 0.5% hydroxypropylmethylcellulose, and systolic blood pressure at one hour after administration was determined by tail cuff method to examine hypotensive effects. The results are shown in Table 1. Compound Dose (mg/kg) hypotensive effect (mmHg) (SHR P.O.) Example 1 30 -116 Pharmacological Experiment 2 : vasodilating effects Male rabbits (body weight 1.9 - 3.0 kg) are anesthetized with sodium pentobarbital and killed by exsanguinity. The thoracic aorta is removed and about 2 mm wide ring specimens are prepared. The specimens are hung in a 40 ml Magnus bath filled with Krebs - Henseleit solution (NaCl 117 mM; KCl 4.7 mM; CaCl 2 2.5 mM; MgSO 4 1.2 mM; NaHCO 3 24.8 mM; KH 2 PO 4 1.2 mM; glucose 11.0 mM) at 37°C at a load of 2 g. The Magnus bath is constantly aerated with a mixed gas (95% oxygen+5% carbon dioxide). The tension of the specimens is measured by isometric transducer (TB-611T, Nihon Koden). The specimens are contracted with phenylephrine (10 -6 M) and when the contraction becomes constant, the compound is cumulatively added to observe relaxing response. The relaxing response by the compound is calculated relative to contraction by phenylephrine as 100% as the concentration necessary for 50% relaxation (IC 50 , µM). Pharmacological Experiment 3 : Effect on contraction caused by acetylcholine in tracheal specimen extracted from guinea pig Male Hartley guinea pigs (body weight 260-390 g) are anesthetized by intraperitoneal administration of pentobarbital sodium (100 mg/kg) and killed by exsanguinity. The trachea is removed and ventral cartilage is cut open and ligament is cut in 3 mm width to prepare specimens. The specimens are hung in a 40 ml Magnus bath filled with Krebs - Henseleit solution (NaCl 117 mM; KCl 4.7 mM; CaCl 2 2.5 mM; MgSO 4 1.2 mM; NaHCO 3 24.8 mM; KH 2 PO 4 1.2 mM; glucose 11.0 mM) at 37°C at a load of 1 g. The Magnus bath is constantly aerated with a mixed gas (95% oxygen+5% carbon dioxide). The tension of the specimens is measured by isometric transducer (TB-611T, Nihon Koden) and recorded on a recorder (Ti-102, Tokai Irika). The specimens are contracted with acetylcholine (10 -6 M) and when the contraction becomes constant, the compound is cumulatively added to observe relaxing response. The relaxing response by the compound is calculated relative to maximum response by papaverine (10 -4 M) as 100% as the concentration necessary for 50% relaxation (IC 50 , µM). Pharmacological Experiment 4 : Action on coronary blood flow Adult mongrel dogs (2-3 per group) are anesthetized by intravenous administration (30 mg/kg) of pentobarbital sodium, and left coronary artery is perfused according to the method of Yago et al. [Folia Pharmacologica Japonica, vol. 57, p. 380 (1961)], and the blood flow is measured. The test compound (10-300 µg) is administered into coronary artery. The effect on coronary blood flow of the test compound is expressed as ED 50 (µg) which is the dose necessary for increasing coronary blood flow to the level corresponding to the half of the effect achieved by administration of nifedipine [dimethyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate] (3 µg) into coronary artery. As the duration of the effect, half-life (T 1/2, min) is also determined. Pharmacological Experiment 5 : Cerebral, coronary or renal artery blood flow increasing action Adult mongrel dogs are anesthetized with 30 mg/kg, i.v. of pentobarbital sodium, and artificially respirated (20 ml/kg, 18 times/min) using an artificial respiratory apparatus (manufactured by Harvard). Left vertebral, left coronary circumflex branch and right renal artery are exposed, equipped with a blood flow probe, and blood flow is measured by electromagnetic flowmeter (Nihon Koden). The test compound is administered into vein from a cannula dwelled in femoral vein. The action of the test compound is expressed as a ratio of increase from the blood flow before administration of the test compound. Pharmacological Experiment 6 : Peripheral artery blood flow increasing action Male rats are anesthetized with pentobarbital sodium (50 mg/kg, i.p.) and fixed at a dorsal position. A probe is equipped at right planta, and blood flow is measured by a laser flowmeter (manufactured by Advance). The test compound is administered into vein from a cannula dwelled in femoral vein. The action of the test compound is expressed as a ratio of increase from the blood flow before administration of the test compound. The compound (I) of the present invention, isomers thereof and pharmaceutically acceptable acid addition salts thereof have strong smooth muscle relaxing action, and can increase coronary and cerebral blood flow like calcium antagonists. In addition, they have renal and peripheral circulation improving action which cannot be seen in conventional calcium antagonists, and the blood flow increasing action lasts for an extended period. They suppress not only smooth muscle contracting action associated with increase in intracellular calcium, but also contraction of smooth muscle caused by promotion of' sensitivity to calcium. Accordingly, the compound of the present invention is useful as a strong and long-acting agent for prophylaxis and treatment of circulatory diseases in coronary, cerebral, renal and peripheral arteries, as a therapeutic agent for hypertension, angina pectoris, and renal and peripheral circulation disorder, an inhibitor of cerebral vasospasm and the like. Moreover, the compound of the present invention shows the inhibitory action on experimental asthma in guinea pig which was induced by histamin inhalation and on the inhibitory action on the contraction induced by acetylcholine in tracheal specimens extracted from guinea pig, and is useful as a therapeutic agent for asthma. The compound (I) of the present invention, isomers thereof and pharmaceutically acceptable acid addition salts thereof are highly safe, and permit superior oral absorption, as is evident from the results of Pharmacological Experiment 1. When the compound (I) of the present invention is used as a pharmaceutical, an effective amount thereof is admixed with suitable, pharmacologically acceptable additives for pharmaceutical preparations, such as excipients, carriers, diluents and the like, and prepared into tablets, granules, powders, capsules, injections, inhalants, ointments, suppositories and the like which can be administered orally or parenterally. While the clinical dose varies depending on age, body weight, symptom and the like of patients, it is generally 1-500 mg daily for an adult by oral administration, which can be administered in a single dose or several doses. Best Mode for Embodying the Invention The present invention is specifically described by way of Examples, to which the invention is not limited. Example 1 (R)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide dihydrochloride monohydrate (Compound 2, R-configuration) (a) Thionyl chloride (1.43 ml) and dimethylformamide (2 drops) were added to a solution of (R)-(+)-4-(1-benzyloxycarbonylaminoethyl)-benzoic acid (2 g) in dichloromethane (20 ml), and the mixture was refluxed under heating for 1 hour. After the reaction, the solvent was evaporated under reduced pressure to give (R)-4-(1-benzyloxycarbonylaminoethyl)benzoyl chloride as crystals. Then, the crystals were dissolved in acetonitrile (10 ml) and the solution was dropwise added to a solution of 4-aminopyridine (525 mg) and diisopropylethylamine (1.17 ml) in acetonitrile (20 ml) under ice-cooling, which was followed by stirring at room temperature for 5 hours. After the reaction, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from methanol-ethyl acetate-hexane to give 1.87 g of (R)-N-(4-pyridyl)-4-(1-benzyloxycarbonylaminoethyl)benzamide. PMR (CDCl 3 /TMS) δ : 1.45(3H,d,J=6.8Hz), 4.84(1H,m), 5.03(1H,d,J=12Hz), 5.09(1H,d,J=12Hz), 5.18(1H,brs), 7.33(7H,m), 7.60(2H,d,J=5.9Hz), 7.77(2H,d,J=7.8Hz), 8.50(2H,d,J=5.9Hz). (b) (R)-N-(4-Pyridyl)-4-(1-benzyloxycarbonylaminoethyl)benzamide (1.87 g) and 10% palladium hydroxide carbon (300 mg) were added to methanol (20 ml), and the mixture was subjected to catalytic reduction in a stream of hydrogen. After the reaction, the catalyst was removed by filtration. The mixture was concentrated under reduced pressure, and a hydrochloric acid-methanol solution was added to the obtained crystals. The solvent was evaporated under reduced pressure. The obtained crystals were recrystallized from methanol-ethyl acetate to give 1.0 g of (R)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide dihydrochloride monohydrate having a melting point of 287-288°C. [α] D = +3.2° (methanol, c=1) PMR (DMSO-d 6 /TMS)δ: 1.53(3H,d,J=6.8Hz), 4.5(1H,brs), 7.70(2H,d,J=8.3Hz), 8.07(4H,m), 8.59(2H,d,J=5.8Hz), 8.69(2H,brs), 11.18(1H,brs) Example 2 (S)-(-)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide dihydrochloride, m.p. 278-279°C, [α] D =-5.6° (methanol, c=1) (Compound 2, S-configuration) Formulation Example 1: Tablet Compound of the present invention 10.0 mg Lactose 50.0 mg Corn starch 20.0 mg Crystalline cellulose 29.7 mg Polyvinylpyrrolidone K30 5.0 mg Talc 5.0 mg Magnesium stearate 0.3 mg 120.0 mg The compound of the present invention, lactose, corn starch and crystalline cellulose were mixed.. The mixture was kneaded with an adhesive solution of polyvinylpyrrolidone K30, and passed through a 20-mesh sieve to give granules. The. particles were dried at 50°C for 2 hours, and passed through a 24-mesh sieve. Talc and magnesium stearate were added, and the mixture was punched with a 7 mm diameter pounder to give tablets each weighing 120 mg. Formulation Example 2: Capsule Compound of the present invention 10.0 mg. Lactose 70.0 mg Corn starch 35.0 mg Polyvinylpyrrolidone K30 2.0 mg Talc 2.7 mg Magnesium stearate 0.3 mg 120.0 mg The compound of the present invention, lactose, corn starch and crystalline cellulose were mixed. The mixture was kneaded with an adhesive solution of polyvinylpyrrolidone K30, and passed through a 20-mesh sieve to give granules. The particles were dried at 50°C for 2 hours, and passed through a 24-mesh sieve. Talc and magnesium stearate were added, and the mixture was packed in hard capsule (No. 4) to give capsules each containing 120 mg.

Claims: A benzamide compound of the formula or an isomer thereof or a pharmaceutically acceptable acid addition salt thereof. A benzamide compound of claim 1, namely (R)-N-(4-pyridyl)-4-(1-aminoethyl)benzamide or an isomer thereof or a pharmaceutically acceptable acid addition salt thereof. A pharmaceutical composition comprising a therapeutically effective amount of the benzamide compound of claim 1 or 2, an isomer thereof or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable additive. A therapeutic agent for hypertension, comprising the benzamide compound of claim 1 or 2, an isomer thereof or a pharmaceutically acceptable acid addition salt thereof. A therapeutic agent for angina pectoris, comprising the benzamide compound of claim 1 or 2, an isomer thereof or a pharmaceutically acceptable acid addition salt thereof. A therapeutic agent for asthma, comprising the benzamide compound of claim 1 or 2, an isomer thereof or a pharmaceutical acceptable acid addition salt thereof. A therapeutic agent for renal and peripheral circulatory disturbances, comprising the benzamide compound of claim lor 2, an isomer thereof or a pharmaceutically acceptable acid addition salt thereof. An inhibitor of cerebral vasospasm, comprising the benzamide compound of claim 1 or 2, an isomer thereof or a pharmaceutically acceptable acid addition salt thereof.

Inventors: ARITA MASAFUMI, MINOGUCHI MASANORI, SAITOH TADAMASA, SATOH HIROYUKI, YAMAGAMI KEIJI, ARITA, MASAFUMI, MINOGUCHI, MASANORI, SAITOH, TADAMASA, SATOH, HIROYUKI, YAMAGAMI, KEIJI, ARITA, Masafumi, Yoshitomi Phar. Ind. Ltd., MINOGUCHI, Masanori, Yoshitomi Phar. Ind.Ltd., SAITOH, Tadamasa, Yoshitomi Phar. Ind. Ltd., SATOH, Hiroyuki, Yoshitomi Phar. Ind. Ltd., YAMAGAMI, Keiji, Yoshitomi Phar. Ind.Ltd.
Applicants: MITSUBISHI PHARMA CORP, MITSUBISHI PHARMA CORPORATION
Application year: 1995
Main classification: C07D213
IPC codes: C07D239, C07D213, C07D473, C07D215, C07D413, C07D487, C07D401, A61P9, C07D417, C07D471