Optically active 1,4-Dihydropyridine derivatives and methods of producing the same

Abstract: 1,4-dihydropyridine derivatives and optically active 1,4-dihydropyridine derivatives with the following formula, having vasodilating activity based on calcium antagonism, and PAF antaognism, and methods of producing the same are disclosed: wherein (*) indicates a chiral center in the case of the optically active 1,4-dihydropyridine derivatives.

Description: BACKGROUND OF THE INVENTION The present invention relates to optically active 1,4-dihydropyridine derivatives having (a) vasodilating activity based on calcium antagonism and (b) PAF antagonism. Generally it is known that 1,4-dihydropyridine derivatives are useful as remedies for diseases of circulatory system such as remedies for ischemic heart disease, cerebral circulatory disease and hypertension, since the 1,4-dihydropyridine derivatives have vasodilating activity based on the calcium antagonism thereof. It has been reported that it is essential that the 1,4-dihydropyridine derivatives have a 3,5-diester structure in order that the 1,4-dihydropyridine derivatives exhibit the above-mentioned actions. Representative examples of such 1,4-dihydropyridine derivatives are 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)-pyridine-3,5-dicarboxylic acid dimethyl ester (Generic name: "NIFEDIPINE" as described in U.S. Patent No. 3,644,627) and 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylic acid-3-[2-(N-benzyl-N-methylamino)ethyl]ester-5-methyl ester hydrochloride (Generic name: "NICARDIPINE" as described in Japanese Patent Publication 55-45075). Furthermore, as the conventional methods of producing optically active 1,4-dihydropyridine-3-carboxylate derivatives, there are known, for instance, (a) a method comprising the steps of subjecting 1,4-dihydropyridine-3-carboxylic acid derivatives to optical resolution to obtain optically active 1,4-dihydropyridine-3-carboxylic acid derivatives, (refer to T. Shibanuma et al., Chem. Pharm. Bull. 28, 2809 (1980)) to 1,4-dihydropyridine-3,5-dicarboxylate derivatives and (b) a method of subjecting diastereomers of 1,4-dihydropyridine-3,5-dicarboxylate derivatives to optical resolution (refer to Japanese Laid-Open Patent Application 56-36455). WO 86/04581 1,4-dihydropyridine-3,5-dicarbonic acid ester derivatives, the ester in position 3 being substituted by an aromatic group. In addition EP-A-0 145 956 and US-A-4 616 002 discose similar compounds substituted by an linear alkyl or a heterocyclic group. These compounds are considered to exhibit strong hypertensive and potensive action, negatively inotropic as well as negatively chronotropic effects, dilative action on the coronary vessels and inhibitory effect on K-reduced vasoconstriction. According to both documents all effects are due to the dihydropyridine compounds having calcium antagonist properties. Platelet-activating factor (PAF) is produced by many types of pre-phlogocytes, platelet and liver, liberated, and exhibits not only strong platelet aggregation activity, but also biological activities in a wide range, which are induced directly or through the liberation of other strong mediators such as thromboxane A 2 and leucotriene. Therefore it is considered that compounds having PAF antagonism are useful for remedies for varieties of allergic diseases, inflammatory diseases, and hyperexcretory diseases, such as asthma, arthritis, and bronchitis. Furthermore, recent studies have revealed that PAF is capable of inducing the reduction of the blood flow volume of coronary artery. Therefore it is also considered that PAF antagonists will be useful as remedies for angina pectoris. As PAF antagonists, varieties of compounds such as PAF analogues and benzodiazepine derivatives has been reported. However, a compound having (a) vasodilating activity based on calcium antagonism and (b) PAF antaognism have not yet been discovered. SUMMARY OF THE INVENTION It is therefore the object of the present invention to provide optically active 1,4-dihydropyridine derivatives having vasodilating activity based on calcium antagonism, and PAF antagonism. The present invention is based on the discovery that 1,4-dihydropyridine derivatives in which a specific amino acid derivatives are amido-bonded to position 3 of the 1,4-dihydropyridine ring exhibit antihypertensive action or PAF antagonism the same as or greater than that exhibited by the conventional 1,4-dihydropyridine-3,5-diester derivatives. The object of the present invention is achieved by optically active 1,4-dihydropyridine derivatives of formula (I): wherein R 21 is selected from the group consisting of NO 2 , Cl and CN and R 24 is selected from the group consisting of methyloxy, ethyloxy, isopropyloxy and 2-methoxyethyloxy, with the proviso that when R 21 is Cl or CN R 24 is methyloxy. The optically active 1,4-dihydropyridine derivatives of formula (I) are produced by any of the following three processes: Process 1 A keto-ester derivative of formula (II) is allowed to react with an optically active enamine derivative of formula (III) in the following reaction scheme: wherein R 21 , and R 24 are respectively the same as in formula (I), and R 17 and R 18 are different and independently represent an unsubstituted or substituted straight chain, branched chain or cyclic alkyl group, an unsubstituted or substituted aromatic hydrocarbon group, an unsubstituted or substituted aralkyl group, an unsubstituted or substituted straight chain, branched chain or cyclic alkoxycarbonyl group, or an unsubstituted or substituted straight chain, branched chain or cyclic aminocarbonyl group, and * indicates a chiral center. Process 2 An N-acylamino acid derivative of formula (VIII) is allowed to react with an optically active enamine derivative of formula (IX) in the following reaction scheme, followed by allowing the product to react with ammonia or an ammonium salt: wherein R 21 , R 24 , R 17 , and R 18 are respectively the same as previously defined, and * indicates a chiral center. [Process 6] A ketone derivative of formula (X) is allowed to react with an optically active acrylamide derivative of formula (XI) in the following reaction scheme, followed by allowing the product to react with ammonia or an ammonium salt: wherein R 21 , R 24 , R 17 , and R 18 are respectively the same as previously defined, and * indicates a chiral center. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS In the optically active 1,4-dihydropyridine derivatives of formula (I) wherein R 21 is selected from the group consisting of NO 2 , Cl and CN and and R 24 is selected from the group consisting of methyloxy, ethyloxy, isopropyloxy and 2-methoxyethyloxy, with the proviso that when R 21 is Cl or CN R 21 is methyloxy. Specific examples of the 1,4-dihydropyridine derivatives represented by the previously mentioned formula (I) are as follows: t-butyl 2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate, (+)-butyl 2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(S)-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate, t-butyl 2-[N-[1,4-dihydro-2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate, t-butyl 2-[N-[1,4-dihydro-2,6-dimethyl-5-isopropyloxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate, t-butyl 2-[N-[1,4-dihydro-2,6-dimethyl-5-(2-methoxyethyloxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate, The optically active 1,4-dihydropyridine derivatives of formula (I) are produced by any of the following three processes outlined above. Process 1: [Step A] The reaction in Step A in the above reaction scheme can be carried out by mixing the keto-ester derivative of formula (II) and the optically active enamine derivative of formula (III). The optically active enamine derivative of formula (III) can be easily obtained by allowing a commercially available keto-ester compound to react with an optically active amine compound. It is preferable to use a basic compound to carry out the reaction efficiently. Examples of the basic compound are n-butyl lithium, lithium diisopropylamide, sodium hydride, isopropyl magnesium halide, and phenyl magnesium halide. Such a basic compound is generally employed in an amount of 0.5 to 1.5 equivalents to the keto-ester derivative of formula (II). Furthermore, it is preferable that the above reaction be carried out in a non-protonic solvent. Examples of the non-protonic solvent are ethers such as diethyl ether, and tetrahydrofuran, and aromatic hydrocarbons such as benzene and toluene. The reaction proceeds at temperatures of -120° to 110°C, but it is preferable that the reaction be carried out in the temperature range of -100°C to -20°C to cause the reaction to proceed efficiently. Furthermore, it is preferable that the reaction be carried out under a water-free condition in an atmosphere of an inert gas such as nitrogen gas or argon gas in order to obtain the desired product in high yield. The product obtained by the above reaction is easily decomposed at room temperature and therefore difficult to identify. However the product is considered to have the following structure from the identification by use of a mass spectrum: wherein R 21 , and R 24 are respectively the same as in formula (I), and * indicates a chiral center. The above reaction product is then allowed to react with ammonia or an ammonium salt, whereby the optically active cyanoethylester of formula (IV) can be obtained. The ammonia and the ammonium salt employed in the above reaction are commercially available. Examples of the ammonium salt are ammonium acetate, and ammonium chloride. It is preferable that the ammonia or the ammonium salt be employed in an amount of 1.0 to 20 equivalents, more preferably in an amount of 1.2 to 5 equivalents, to the keto-ester derivative of formula (II) in order to obtain the optically active cyanoethyl ester of formula (IV) in high yield. It is also preferable that the reaction with the ammonia or the ammonium salt be carried out in a solvent. Examples of the solvent are alcohols such as ethanol, methanol and propanol; ethers such as diethyl ether and tetrahydrofuran; and hydrocarbons such as hexane, pentane, toluene and benzene. The reaction proceeds at temperatures of 0° to 60°C, but it is preferable that the reaction be carried out at room temperature because the operations are simple. Furthermore, the reaction in the above Step A can be carried out by replacing the keto-ester derivative of formula (II) and the optically active enamine derivative of formula (III) with a keto-ester derivative of formula (II') and an enamine derivative of formula (III') resectively, which are shown below: [Step B] The reaction in Step B can be carried out by mixing the optically active cyanoethyl ester derivative of formula (IV) with a basic compound. Examples of the basic compound employed in this reaction are sodium methylate, sodium hydroxide, and potassium hydroxide. It is preferable that the basic compound be employed in an amount of 1.0 to 3.0 equivalents, more preferably in an amount of 1.0 to 1.2 equivalents, to the optically active cyanoethyl ester derivative of formula (IV), to obtain the product of formula (V) in high yield. It is also preferable that the reaction be carried out in a solvent, such as water, an alcohol such as methanol, and ethanol, or a mixed solvent of these solvents, at temperatures of -20°C to 80°C, more preferably at temperatures of 0°C to 25°C to obtain the product of formula (V) in high yield. [Step C] The reaction in Step C can be carried out by subjecting the optically active carboxylic acid derivative of formula (V) obtained in the above Step B and the amine compound of formula (VI) to a condensation reaction. This condensation reaction can be carried out in a certain reaction temperature range, using a condensation agent and a reaction solvent. Examples of the condensation agents include carbodiimide agents-such as N,N-dicyclohexylcarbodiimide and 1-ethyl-3-(3-diethylaminopropyl)carbodiimide hydrochloride. The above reaction can be carried in an inert solvent at 0°C to 150°C, preferably at 20°C to 120°C. Examples of the inert solvent for use in the above reaction include halogenated hydrocarbons such as dichloromethane, chloroform, and 1,2-dichloroethane; hydrocarbons such as benzene, toluene and xylene; ethers such as ether, tetrahydrofuran, and dioxane; dimethylformamide; and diemthyl sulfoxide. It is also preferable that the above reaction be carried out in an atmosphere of an inert gas such as nitrogen gas or argon gas, and in the dark. The carboxyl group in the optically active carboxylic acid derivative of formula (V) is converted to a carboxylic halide group or an active ester group as in Process 3, and the thus obtained compound is allowed to react with the amine compound of formula (VI), whereby a 1,4-dihydropyridine derivative of formula (I) can be obtained. This reaction can be carried out in the same reaction temperature range, using the same carbodiimide agent and reaction solvents as above. The optically active 1,4-dihydropyridine derivatives of formula (I) can be synthesized more efficiently by the above Process 2 and Process 3 than by the above-mentioned Process 1: Process 2: The reaction can be carried out in the same reaction temperature range, using the same reaction solvents as in Step A in Process 1. Process 3 The above reaction can be carried out in the same reaction temperature range, using the same reaction solvents as in Step A in Process 1. The compounds produced in each of the above processes can be isolated by conventional separation methods, extraction, reprecipitation, recrystallization, and various types of chromatography. When necessary, the 1,4-dihydropyridine derivatives of formula (I) can be converted to the corresponding acid-addition salts by the reaction with pharmaceutically permissible acids. Examples of such acids are inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and nitric acid; and organic acids such as acetic acid, propionic acid, lactic acid, and citric acid. When the 1,4-dihydropyridine derivatives of formula (I) are used as hypotensor, vasodilator, cerebral circulation improvement agent, antithrombotic agent, antiasthmatic, antiinflammatory agent, and antiallergic agent, the derivatives can be administered perorally, intravenously, hypodermically, intramuscularly, or by inhalation. Therefore, the derivatives can be used in various administration forms including pellet, capsule, liquid, and suppository. Example 1 Synthesis of t-butyl 2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino] acetate: The above compound was prepared in accordance with the following reaction scheme by allowing the carboxylic acid to react with an amino acid of formula R 10 -H shown below: In the above formula, R 10 is Yield (%) 62.5 (recrystallized from acetonitrile) Melting point (°C) 143 - 146 IR (νKBr, cm -1 ) 3364, 1718, 1672, 1534, 1352 Mass spectrometry Based on Formula C 22 H 27 N 3 O 7 Calcd. 445.18484 Found 445.18523 NMR (δ, CDCl 3 ) 1.43 (9H, s), 2.29 (3H, s), 2.33 (3H, s), 3.65 (3H, s), 3.88 (2H, d, J=5Hz), 4.96 (1H, s), 5.90 (2H, m), 7.42 (1H, dd, J=8Hz, 8Hz), 7.68 (1H, d, J=8Hz), 8.03 (1H, d, J=8Hz), 8.13 (1H, s) Example 2 for Reference Synthesis of t-butyl 2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(2-nitrophenyl)pyridine-3-carbony]amino]acetate: A mixture of 0.498 g (2 mmol) of methyl 2-(2-nitrobenzylidene)acetoacetate and 0.428 g (2 mmol) of (s)-t-butyl 2-[N-(3-amino-2-butenoyl)amino]acetate was stirred in a light-shielding condition at 120°C for 15 minutes. After cooling to room temperature, the reaction mixture was chromatographed on a silica gel column for purification, whereby 0.63 g (70.9%) of the captioned compound was obtained as an oily material. IR (νKBr, cm -1 ) 3330, 1746, 1706, 1668, 1528, 1362 Mass spectrometry Based on Formula C 22 H 27 N 3 O 7 Calcd. 445.18484 Found 445.18513 NMR (δ, CDCl 3 ) 1.40 (9H, s), 2.28 (3H, s), 2.46 (3H, s), 3.52 (3H, s), 3.75 (1H, dd, J=18Hz, 5Hz), 3.98 (1H, dd, J=18Hz, 5Hz), 5.55 (1H, s), 5.74 (1H, s), 7.29 (1H, dd, J=8Hz, 8Hz), 7.46 (1H, t, J=5Hz), 7.52 (1H, dd, J=8Hz, 8Hz), 7.60 (1H, d, J=8Hz), 7.68 (1H, d, J=8Hz) Example 3 Synthesis of t-butyl 2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-chlorophenyl)pyridine-3-carbonyl]-amino]acetate: The above compound was prepared in accordance with the same reaction scheme as in Example 2 except that the ketone compound employed in Example 2 was replaced by ketone compound shown below. Specifically the reaction scheme in this example is as follows: wherein R 12 is and R 13 is -CH 3 . Yield (%) 89.8 Melting point (°C) oil IR (νKBr, cm -1 ) 3268, 1738, 1696, 1664 Mass spectrometry Based on Formula C 22 H 27 ClN 2 O 5 Calcd. 434.16080 Found 434.16166 NMR (δ, CDCl 3 ) 1.44 (9H, s), 2.30 (3H, s), 2.31 (3H, s), 3.66 (3H, s), 3.84 (1H, dd, J=18Hz, 5Hz), 3.92 (1H, dd, J=18Hz, 5Hz), 4.80 (1H, s), 5.30 (1H, s), 5.86 (1H, t, J=5Hz), 7.14 - 7.29 (4H, m) Example 4 Synthesis of t-butyl 2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-cyanophenyl)pyridine-3-carbonyl]amino]acetate: The above compound was prepared in the same reaction scheme as in Example 3 except that the ketone compound of formula (XIX) employed in Example 3 was replaced by a ketone compound of formula (XIX) in which R 12 is and R 13 is -CH 3 . Yield (%) 91.8 Melting point (°C) oil IR (νKBr, cm -1 ) 3352, 2232, 1746, 1682 Mass spectrometry Based on Formula C 23 H 27 N 3 O 5 Calcd. 425.19502 Found 425.19391 NMR (δ, CDCl 3 ) 1.45 (9H, s), 2.29 (3H, s), 2.33 (3H, s), 3.65 (3H, s), 3.88 (2H, d, J=5Hz), 4.87 (1H, s), 5.59 (1H, s), 5.84 (1H, t, J=5Hz), 7.36 (1H, dd, J=8Hz, 8Hz), 7.46 (1H, d, J=8Hz), 7.56 - 7.61 (2H, m) Example 5 Synthesis of t-butyl 2-[N-[1,4-dihydro-2,6-dimethyl-5-ethoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate: The above compound was prepared in the same reaction scheme as in Example 3 except that the ketone compound of formula (XIX) employed in Example 3 was replaced by a ketone compound of formula (XIX) in which R 12 is and R 13 is -C 2 H 5 . Yield (%) 74.2 Melting point (°C) oil IR (νKBr, cm -1 ) 3332, 1746, 1678, 1532, 1350 Mass spectrometry Based on Formula C 23 H 29 N 3 O 7 Calcd. 459.20049 Found 459.19889 NMR (δ, CDCl 3 ) 1.23 (3H, t, J=7Hz), 1.43 (9H, s), 2.29 (3H, s), 2.33 (3H, s), 3.87 (2H, d, J= 5Hz), 4.04 - 4.16 (2H, m), 4.96 (1H, s), 5.70 (1H, s), 5.85 (1H, t, J=5Hz), 7.44 (1H, dd, J=8Hz, 8Hz), 7.69 (1H, d, J=8Hz), 8.03 (1H, d, J=8Hz), 8.15 (1H, s) Example 6 Synthesis of t-butyl 2-[N-[1,4-dihydro-2,6-dimethyl-5-isopropyloxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate: The above compound was prepared in the same reaction scheme as in Example 3 except that the ketone compound of formula (XIX) employed in Example 3 was replaced by a ketone compound of formula (XIX) in which R 12 is and R 13 is Yield (%) 84.9 Melting point (°C) oil IR (νKBr, cm -1 ) 3332, 1746, 1676, 1532, 1350 Mass spectrometry Based on Formula C 24 H 31 N 3 O 7 Calcd. 473.21614 Found 473.21773 NMR (δ, CDCl 3 ) 1.12 (3H, d, J=6Hz), 1.25 (3H, d, J=6Hz), 1.43 (9H, s), 2.28 (3H, s), 2.33 (3H, s), 3.87 (2H, d, J=5Hz), 4.95 (1H, s), 4.92 - 5.03 (1H, m), 5.66 (1H, s), 5.84 (1H, t, J=5Hz), 7.42 (1H, dd, J=8Hz, 8Hz), 7.68 (1H, d, J=8Hz), 8.03 (1H, d, J=8Hz), 8.15 (1H, s) Example 7 Synthesis of t-butyl 2-[N-[1,4-dihydro-2,6-dimethyl-5-(2-methoxyethyloxycarbonyl)-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate: The above compound was prepared in the same reaction scheme as in Example 32 except that the ketone compound of formula (XIX) employed in Example 32 was replaced by a ketone compound of formula (XIX) in which R 12 is and R 13 is -(CH 2 ) 2 -OCH 3 . Yield (%) 79.2 Melting point (°C) oil IR (νKBr, cm -1 ) 3340, 1742, 1704, 1678, 1528, 1350 Mass spectrometry Based on Formula C 24 H 31 N 3 O 8 Calcd. 489.21106 Found 489.20856 NMR (δ, CDCl 3 ) 1.43 (9H, s), 2.30 (3H, s), 2.34 (3H, s), 3.36 (3H, s), 3.54 - 3.59 (2H, m), 3.87 (2H, d, J=5Hz), 4.98 (1H, s), 5.59 (1H, s), 5.88 (1H, t, J=5Hz), 7.42 (1H, dd, J=8Hz, 8Hz), 7.72 (lH, d, J=8Hz), 8.04 (1H, d, J=8Hz), 8.15 (1H, s) Example 8 Synthesis of (+)-t-butyl (S)-[2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridin-3-yl]-carbonyl]amino]acetate: The above compound was synthesized in accordance with the following reaction scheme: More specifically, under a light-shielding condition and in an atmosphere of an inert gas, a methylene chloride solution containing 1.91 g (11 mmol) of p-toluenesulfonyl chloride was added dropwise to an anhydrous methylene chloride solution containing 4.39 g (36 mmol) of N,N-dimethylaminopyridine. The reaction mixture was stirred for one hour under an ice-cooled condition. To the reaction mixture, 3.32 g (10 mmol) of (+)-(S)-1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)-pyridine-3-carboxylic acid was added and the reaction mixture was stirred for one hour. To the reaction mixture, an anhydrous methylene chloride solution containing 1.57 g (12 mmol) of glycine-t-butylester was added dropwise and the reaction mixture was further stirred for one hour. The solvent was distilled away under reduce pressure. Toluene was added to the residue and insoluble components were removed from the mixture by filtration. The insoluble components were washed with toluene and the toluene employed for the washing was combined with the above filtrate. The thus obtained toluene solution was washed with a saturated aqueous solution of ammonium chloride, with a dilute aqueous solution of sodium hydroxide and then with water, and dried over anhydrous sodium sulfate. The solvent was distilled away from the toluene solution under reduced pressure. The residue was chromatographed on a silica gel column for purification, whereby 4.00 g (90%) of the captioned compound with an optical rotation of [α] 25 / D=+18.0°(c=1.0031, ethanol) was obtained. The captioned compound with the following physical properties was obtained by recrystallization. Melting point (°C) 140.9 - 142.4°C IR (cm -1 , KBr) ν=3328, 1742, 1682, 1532, 1352 Mass spectrometry Based on Formula C 22 H 27 N 3 O 7 Calcd. 445.18484 Found 445.18726 NMR (δ, CDCl 3 ) 1.44 (9H, s), 2.31 (3H, s), 2.34 (3H, s), 3.66 (3H, s), 3.88 (2H, d, J=5Hz), 4.96 (1H, s), 5.62 (1H, s), 5.86 (1H, t, J= 5Hz), 7.42 (1H, dd, J=8Hz, 8Hz), 7.69 (1H, d, J=8Hz), 8.04 (1H, d, J=8Hz), 8.13 (1H, s) Optical rotation [α] 25 / D=+18.3° [c=1.0264, ethanol] Reference example 1 Synthesis of ethyl 2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino]acetate: Specifically the reaction scheme in this example is as follows: wherein R 15 is Yield (%) 75 Melting point (°C) oil IR (νKBr, cm -1 ) 3332, 1748, 1682, 1532, 1352 Mass spectrometry Based on Formula C 20 H 23 N 3 O 7 Calcd. 417.15352 Found 417.15282 NMR (δ, CDCl 3 ) 1.25 (3H, t, J=7Hz), 2.31 (3H, s), 2.34 (3H, s), 3.66 (3H, s), 3.98 (2H, d, J= 5Hz), 4.17 (2H, q, J=7Hz), 4.96 (1H, s), 5.83 (1H, s), 5.90 (1H, t, J=5Hz), 7.43 (1H, dd, J=8Hz, 8Hz), 7.69 (1H, d, J=8Hz), 8.05 (1H, d, J=8Hz), 8.14 (1H, s) Reference example 2 Synthesis of ethyl 2-[N-[1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carbonyl]amino] isobutyrate: The above compound was prepared in the same reaction scheme as above except that the amine compound was replaced by an amine compound Yield (%) 60 Melting point (°C) oil IR (νKBr, cm -1 ) 3332, 1740, 1682, 1532, 1352 Mass spectrometry Based on Formula C 22 H 27 N 3 O 7 Calcd. 445.18480 Found 445.18340 NMR (δ, CDCl 3 ) 1.21 (3H, t, J=7Hz), 1.43 (3H, s), 1.47 (3H, s), 2.22 (3H, s), 2.35 (3H, s), 3.63 (3H, s), 4.07 - 4.22 (2H, m), 4.93 (1H, s), 5.55 (1H, s), 5.91 (1H, s), 7.43 (1H, dd, J=8Hz, 8Hz), 7.66 (1H, d, J=8Hz), 8.05 (1H, d, J=8Hz), 8.12 (1H, s) Reference Example 3 Synthesis of 2-cyanoethyl methyl 1,4-dihydro-6-methyl-4-(3-nitrophenyl)-2-phenylpyridine-3,5-dicarboxylate: A toluene solution of 827 mg (3.8 mmol) of 2-cyanoethyl 3-amino-3-phenyl-2-propenoate and 952 mg (3.8 mmol) of methyl 2-(3-nitrobenzylidene) acetoacetate was refluxed for 3 hours. The reaction mixture was chromatographed on a silica gel column for purification, whereby 1.274 g (75%) of the captioned compound was obtained. NMR (δ, CDCl 3 ) 2.16 - 2.33 (2H, m), 2.41 (3H, s), 3.70 (3H, s), 3.91 - 4.08 (2H, m), 5.23 (1H, s), 5.98 (1H, s), 7.32 - 7.39 (2H, m), 7.42 - 7.52 (4H, m), 7.80 (1H, d, J=8Hz), 8.08 (1H, d, J=8Hz), 8.26 (1H, S) Reference Example 4 Synthesis of 2-cyanoethyl methyl 1,4-dihydro-4,6-dimethyl-2-phenylpyridine-3,5-dicarboxylate: The above compound was prepared in accordance with the same reaction scheme as in Reference Example 2 except that the ketoester derivative and the enamine derivative employed in Reference Example 2 were respectively replaced by a ketoester derivative of formula (XXI) and an enamine derivative of formula (XXII) shown below. Specifically the reaction scheme in this example is as follows: wherein R 17 in formula (XXI) is -CH 3 and R 18 in formula (XXII) is Yield (%) 78.9 NMR (δ, CDCl 3 ) 1.14 (3H, d, J=7Hz), 2.31 (3H, s), 2.32 (2H, t, J=6Hz), 3.75 (3H, s), 3.95 (1H, q, J=7Hz), 4.03 (1H, ddd, J=11Hz, 6Hz, 6Hz), 4.10 (1H, ddd, J=11Hz, 6Hz, 6Hz), 5.80 (1H, s), 7.28 - 7.35 (2H, m), 7.39 - 7.48 (3H, m) Reference Example 5 Synthesis of 2-cyanoethyl methyl 1,4-dihydro-2-(2-methoxy-4-methylthiophenyl)-6-methyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate: The above compound was prepared in the same reaction scheme as in Reference Example 4 except that the ketoester derivative and the enamine derivative employed in Reference Example 2 were respectively replaced by a ketoester derivative of formula (XXI) in which R 17 is and an enamine derivative of formula (XXII) in which R 18 is Yield (%) 84.7 NMR (δ, CDCl 3 ) 2.27 (2H, d, J=6Hz), 2.36 (3H, s), 2.53 (3H, s), 3.72 (3H, s), 3.85 (3H, s), 3.95 (1H, ddd, J=11Hz, 6Hz, 6Hz), 4.03 (1H, ddd, J=11Hz, 6Hz, 6Hz), 5.24 (1H, s), 5.91 (1H, s), 6.85 (1H, s), 6.87 (1H, d, J=8Hz), 7.11 (1H, d, J=8Hz), 7.44 (1H, dd, J=8Hz, 8Hz), 7.82 (1H, d, J=8Hz), 8.05 (1H, d, J=8Hz), 8.36 (1H, S) Reference Example 6 Synthesis of 2-cyanoethyl methyl 2-ethyl-1,4-dihydro-6-methyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate: The above compound was prepared in the same reaction scheme as in Reference Example 4 except that the ketoester derivative and the enamine derivative employed in Reference Example 4 were respectively replaced by a ketoester derivative of formula (XXI) in which R 17 is and an enamine derivative of formula (XXII) in which R 18 is -CH 2 CH 3 . Yield (%) 60.3 NMR (δ, CDCl 3 ) 1.26 (3H, t, J=7.4Hz), 2.38 (3H, s), 2.65 (2H, t, J=6Hz), 2.67 - 2.89 (2H, m), 3.66 (3H, s), 4.19 - 4.33 (2H, m), 5.10 (1H, s), 5.85 (1H, s), 7.40 (1H, dd, J= 8Hz, 8Hz), 7.67 (1H, d, J=8Hz), 8.02 (1H, d, J=8Hz), 8.10 (1H, S) Reference Example 7 Synthesis of 1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)-2-phenylpyridine-3-carboxylic acid: The above compound was obtained in accordance with the following reaction scheme: More specifically, 557 mg (2.89 mmol) of a 28% sodium methoxide was added to a dried mixed solution of methanol and methylene chloride (1 : 1) containing 1.174 g (2.62 mmol) of 2-cyanoethyl methyl 1,4-dihydro-6-methyl-4-(3-nitrophenyl)-2-phenylpyridine-3,5-dicarboxylate synthesized in Reference Example 3. The mixture was stirred at room temperature for 2 hours and 100 ml of methylene chloride was added thereto. The reaction mixture was then extracted with 100 ml of water. The water layer was acidified by 1N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, and the solvent was distilled away therefrom under reduced pressure, whereby 993 mg (96.2%) of the captioned compound was obtained. Melting point (°C) 183.3 - 185.9 IR (νKBr, cm -1 ) 3272, 1690, 1670, 1528, 1352 NMR (δ, Acetone-d6) 2.47 (3H, s), 3.67 (3H, s), 5.30 (1H, s), 7.32 - 7.48 (5H, m), 7.59 (1H, dd, J=8Hz, 8Hz), 7.89 (1H, d, J=8Hz), 8.07 (1H, d, J=8Hz), 8.23 (1H, s), 8.30 (1H, s), 10.10 (1H, br.S) Reference Example 8 Synthesis of 1,4-dihydro-5-methoxycarbonyl-4,6-dimethyl-2-phenylpyridine-3-carboxylic acid: The above compound was prepared in accordance with the same reaction scheme as in Reference Example 7 except that the cyanoethyl derivative employed in Reference Example 7 was replaced by a cyanoethyl derivative shown below. Specifically the reaction scheme in this example is as follows: wherein R 17 is and R 18 is Yield (%) 61.7 Melting point (°C) 172.1 - 175.7 IR (νKBr, cm -1 ) 3260, 1684, 1666 NMR (δ, CD 3 OD) 1.05 (3H, d, J=6Hz), 2.27 (3H, s), 3.72 (3H, s), 3.87 (1H, q, J=6Hz), 7.27 - 7.34 (2H, m), 7.34 - 7.41 (3H, m) Reference Example 9 Synthesis of 1,4-dihydro-5-methoxycarbonyl-2-(2-methoxy-4-methylthiophenyl)-6-methyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid: The above compound was prepared in the same reaction scheme as in Reference Example 8 except that the cyanoethyl derivative of formula (XXIV) employed in Reference Example 8 was replaced by a cyanoethyl derivative of formula (XXIV) in which R 17 is and R 18 is Yield (%) 67 Melting point (°C) 198.9 - 201.6 IR (νKBr, cm -1 ) 3340, 1714, 1682, 1530, 1352 NMR (δ, Acetone-d6) 2.39 (3H, s), 2.53 (3H, s), 3.69 (3H, s), 3.82 (3H, s), 5.12 (1H, s), 6.84 (1H, d, J=8Hz), 6.90 (1H, s), 7.14 (1H, d, J= 8Hz), 7.56 (1H, dd, J=8Hz, 8Hz), 7.92 (1H, d, J=8Hz), 8.04 (1H, d, J=8Hz), 8.07 (1H, s), 8.39 (1H, s), 9.95 (1H, br.S) Reference Example 10 Synthesis of 2-ethyl-1,4-dihydro-5-methoxycarbonyl-6-methyl-4-(3-nitrophenyl)pyridine-3-carboxylate: The above compound was prepared in the same reaction scheme as in Reference Example 8 except that the cyanoethyl derivative of formula (XXIV) employed in Reference Example 8 was replaced by a cyanoethyl derivative of formula (XXIV) in which R 17 is and R 18 is -CH 2 CH 3 . Yield (%) 96.4 Melting point (°C) 174.9 - 176.7 IR (νKBr, cm -1 ) 3348, 1660, 1532, 1352 NMR (δ, Acetone-d6) 1.21 (3H, t, J=7Hz), 2.37 (3H, s), 2.83 (2H, q, J=7Hz), 3.62(3H, s), 5.19 (1H, s), 7.52 (1H, dd, J=8Hz, 8Hz), 7.75 (1H, d, J=8Hz), 8.01 (1H, d, J=8Hz), 8.13 (1H, s), 8.16 (1H, s), 9.95 (1H, br. S) 1. Test for hypotensive activity The test was carried out by employing spontaneously hypertensive rats (aparalytice SHR; male) according to Nakao et al method. The blood pressures in the whole body of the rats were measured with a pressure transducer (MPU-0.5, made by Nihon Koden K.K.) through a canula inserted into the abdominal aorta through the aorta of its tail. Successively, 100 µg/kg of each compound to be tested was administrated into the vein of its tail of SHR through a canula (previously inserted), whereby the hypotensive activity of each compound was examined. The results are shown in Table 10. Compound of Example Hypotensive Activity (mmHg) 1 40 3 60 4 30 5 35 6 30 7 20 8 n.d 2. Test for platelet aggregation-inhibiting activity of rabit A blood of a rabbit (Japanese white; male; 2.5 - 3.0 kg) was exsanguinated from a carotid of the rabbit, and nine parts of the blood were mixed with one part of a 3.8% aqueous solution of sodium citrate. The mixture was centrifuged at 1100 rpm at 20°C for 15 minutes. The upper layer is a platelet rich plasma (PRP), and the lower layer was centrifuged at 2500 rpm at 20°C for 10 minutes, so that a platelet poor plasma (PPP) was obtained. 10 µl of a solution of the compound to be tested was added to 200 µl of PRP, and the mixture was subjected to incubation at 37°C for 10 minutes. To the mixture was added 10 µl of a platelet activating factor (PAF)(10 mg/ml). The agglutination was measured by Agricometer (NKK, PAT-4A). The Platelet aggregation-inhibiting concentration to each aggregation agent of each compound is shown in Table 11. Compound of Example Platelet Aggregation-Inhibiting Activity (%) 1 100 3 100 4 100 5 100 6 100 7 100 8 100 Ref. Ex. 1 64.3 Ref. Ex. 2 34.1 The optical active 1,4-dihydropyridine derivatives according to the present invention have vasodilating activity based on calcium antagonism, and PAF antaognism, so that these 1,4-dihydropyridine derivatives are useful as remedies for diseases of circulatory system, such as hypotensor, cerebral circulation improvement agent, and antithrombotic agent, and remedies for allergic diseases, such as antiasthmatic, anti-inflammatory agent, and antiallergic agent.

Claims: Claim for the following Contracting States : AT, BE, CH, LI, DE, DK, FR, GB, IT, LU, NL, SE 1,4-Dihydropyridine compounds of formula (I): wherein R 21 is selected from the group consisting of NO 2 , Cl and CN and R 24 is selected from the group consisting of methyloxy, ethyloxy, isopropyloxy and 2-methoxyethyloxy, with the proviso that when R 21 is Cl or CN R 24 is methyloxy. Claim for the following Contracting States : ES, GR A method for producing 1,4-dihydropyridine compounds of formula (I): wherein R 21 is selected from the group consisting of NO 2 , Cl and CN and R 24 is selected from the group consisting of methyloxy, ethyloxy, isopropyloxy and 2-methoxyethyloxy, with the proviso that when R 21 is Cl or CN R 24 is methyloxy, by 1. reacting a keto-ester derivative of formula (II) with an optically active enamine derivative of formula (III) wherein R 21 and R 24 are defined as above and R 17 and R 18 are different and independently represent an unsubstituted or substituted straight chain, branched chain or cyclic alkyl group, an unsubstituted or substituted aromatic hydrocarbon group, an unsubstituted or substituted aralkyl group, an unsubstituted or substituted straight chain, branched chain or cyclic alkoxycarbonyl group, or an unsubstituted or substituted straight chain, branched chain or cyclic aminocarbonyl group, and * indicates a chiral center, or 2. reacting an N-acylamino acid derivative of formula (VIII) with an optically active enamine derivative of formula (IX) followed by allowing the product to react with ammonia or an ammonium salt: wherein R 21 , R 24 , R 17 and R 18 are respectively the same as previously defined, and * indicates a chiral center, or 3. reacting a ketone derivative of formula (X) with an optically active acrylamide derivative of formula (XI) followed by allowing the product to react with ammonia or an ammonium salt: wherein R 21 , R 24 , R 17 and R 18 are respectively the same as previously defined, and * indicates a chiral center.

Inventors: IKAWA HIROSHI, KADOIRI AKIYOSHI, KASE NORIKO, KONAGAI YASUKO, YAMAURA TETSUAKI, IKAWA, HIROSHI,, KADOIRI, AKIYOSHI,, KASE, NORIKO,, KONAGAI, YASUKO,, YAMAURA, TETSUAKI,, IKAWA, HIROSHI, C/O FUJIREBIO INC., Kadoiri, Akiyoshi, c/o Fujirebio Inc., Kase, Noriko, c/o Fujirebio Inc., Konagai, Yasuko, c/o Fujirebio Inc., YAMAURA, TETSUAKI, C/O FUJIREBIO INC.
Applicants: FUJIREBIO KK, FUJIREBIO INC.
Application year: 1991
Main classification: C07D211
IPC codes: A61P25, A61P7, A61P37, A61K31, A61P11, A61P9, A61P29, C07D401, C07F7, C07D211, C07D473, C07D413, C07D405, C07D409, C07D417