DIHYDROPYRIDINE COMPOUNDS, THEIR PRODUCTION, PHARMACEUTICAL COMPOSITIONS CONTAINING THEM, AND METHODS OF PRODUCING THESE COMPOSITIONS

Abstract: Novel dihydropyridine compounds of the general for­ mula (I) and salts thereof: wherein A represents a straight or branched carbon chain alkylene group having 1 to 10 carbon atoms which may be interrupted by one or more oxygen atoms; R¹ and R⁴ are the same or different lower alkyl groups; R² represents an amino group, R³ represents a straight or branched carbon chain alkyl group having 1 to 10 carbon atoms which may be interrupted by one or more oxygen atoms, or R⁵ and R⁶ which may be the same or different, each represents a hydrogen atom, a nitro group, a halogen atom, a trifluoromethyl group, a cyano group, a lower alkyl group, a lower alkoxy group or a lower alkenyloxy group; R⁷ represents a hydrogen atom, a cyano group, a halogen atom, a lower alkoxy group or a lower alkanoyl group; R⁸ and R⁹, which may be the same or different, each represents a lower alkyl group or an aralkyl group; and n is 1 or 2. These compounds possess both Ca²⁺-antagonistic and adrenergic β-receptor blocking activities.

Description: It is known that certain dihydropyridine derivatives have a Ca²⁺-antagonistic action, and are highly useful for treating various cardiovascular disorders such as angina pectoris, myocardial infarction, hypertension and cardiac arrythmia; nifedipine and related 4-aryl-1,4-dihydropyridines having these properties are disclosed in US 3485847. It is further known that beta-adrenoceptor blocking agents are also useful for the treatment of such cardiovascular disorders; Propanolol and other beta-adrenergic blocking agents are discussed at length in Martindale, The Extra Pharmacopeia, 27th edition, 1977, pages 1311 to 1332. However, the mechanism of the actions of dihydropyridine derivatives is entirely different from that of beta-adrenocaptor blocking agents. That is, beta-adrenoceptor blocking agents reduce heart rate, cardiac output, stroke volume, cardiac work and myocardial oxygen demand, whereas ca²⁺-antagonists improve left ventricular function due to their coronary vasodilating and systemic vasodilating effect (reduction in afterload) and also inhibit coronary vasospasm. Recently it has been reported that a combined administration of a Ca²⁺-antagonist and a beta-blocker can achieve maximal symptomatic improvement in clinical angina pectoris. [Bassan, M., Weiler-Ravell, D. and Shalev, O.; Additive antianginal effect of verapamil in patients receiving propranolol; Br. Med. J., 284 , 1067 (1982)]. Further it has been reported that a combined administration of such two kinds of drug can be recommended for the treatment of hypertension, since the side effects of either drug are almost abolished or inhibited by the combined administration of both drugs. Thus, beta-blockers inhibit Ca²⁺-antagonist-induced reflex increase of heart rate and completely inhibit Ca²⁺-antagonist-induced increase of plasma renin activity. [Aoki, A., Kondo, S., Mochizuki, A., et al; Antihypertensive effect of Cardiovascular Ca²⁺-antagonist in hypertensive patients in the absence and presence of beta-adrenergic blockade; Am. Heart J., 96 , 218 (1978)] Thus compounds having both Ca²⁺-antagonistic and beta-blocking activities would be of interest in the management of ischemic heart diseases and hypertension. EP-A-0179386 and WO-A-86/02640 disclose compounds of respective formulae which are said to exhibit both of these activities. The compounds of the present invention are novel over those disclosed in the prior applications. The compounds of this invention are those of the general formula (I) and salts thereof: wherein A represents a straight or branched carbon chain alkylene group having 1 to 10 carbon atoms which may be interrupted by one or more oxygen atoms; R¹ and R⁴ are the same or different lower alkyl groups; R² represents an amino group, R³ represents a straight or branched carbon chain alkyl group having 1 to 10 carbon atoms which may be interrupted by one or more oxygen atoms, or R⁵ and R⁶, which may be the same or different, each represents a hydrogen atom, a nitro group, a halogen atom, a trifluoromethyl group, a cyano group, a lower alkyl group, a lower alkoxy group or a lower alkenyloxy group; R⁷ represents a hydrogen atom, a cyano group, a halogen atom, a lower alkoxy group or a lower alkanoyl group; R⁸ and R⁹, which may be the same or different, each represents a lower alkyl group or an aralkyl group; and n is 1 or 2; with the exception of any of the following compounds a] to j] wherein: a] R¹ and R⁴ are methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is ethyl or propyl, R³ is methyl, isopropyl or t-butyl; and R² is naphthyl-terminated; or b] R¹ and R⁴ are methyl, one of R⁵ and R⁶ is nitro and the other hydrogen; A is hexyl or 1-methyl ethyl; R³ is methyl; and R² is naphthyl-terminated; or c] R¹ and R⁴ are methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is pentyl; R³ is methyl, isopropyl or isobutyl; and R² is nahthyl-terminated; or d] R¹ and R⁴ are methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is 2,2-dimethyl pentyl; R³ is isopropyl; and R² is naphthyl-terminated; or e] R¹ and R⁴ are methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is butyl; R³ is methyl; and R² is naphthyl-terminated; or f] R¹ is methyl; R³ is methyl; R⁴ is methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is 1,1-dimethyl ethyl; and R⁷ is cyano; or g] R¹ is ethyl; R³ is methyl; R⁴ is methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is 1,1-dimethyl ethyl, ethyl or propyl; and R⁷ is cyano; or h] R¹ is ethyl; R³ is methyl; R⁴ is methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is 1,1-dimethyl ethyl; and R⁷ is bromo; or i] R¹ is isopropyl; R³ is methyl; R⁴ is methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is 1,1-dimethyl ethyl; and R⁷ is cyano; or j] R¹ is methyl; R³ is ethyl; R⁴ is methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is propyl; and R² is cyano. The above symbols have the same significances hereinafter. The compounds of this invention possess both Ca²⁺-antagonistic and adrenergic beta-receptor blocking activities. In a preferred group of compounds according to the invention, A is a straight or branched carbon chain alkylene group having 1 to 10 carbon atoms; R² is R³ represents a straight or branched carbon chain alkyl group having 1 to 4 carbon atoms; R⁵ and R⁶ are the same or different and selected from a hydrogen atom, a nitro group and C₁ to C₄ alkoxy groups. The term "lower alkyl" in the foregoing definitions for R¹, R⁴, R⁵, R⁶, R⁸ and R⁹ means a straight or branched carbon chain alkyl having 1 to 4 carbon atoms. Thus examples of the "lower alkyl" are methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and tert-butyl. The term "lower alkoxy" in the foregoing definitions for R⁵, R⁶ and R⁷ means an alkoxy having 1 to 4 carbon atoms. Thus examples of the "lower alkoxy" are methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, sec-butoxy, and tert-butoxy. The term "lower alkenyloxy" in the foregoing definitions for R⁵ and R⁶ means an alkenyloxy having 2 to 4 carbon atoms. Thus examples of the "lower alkenyloxy" are vinyloxy, 1-propenyloxy, allyloxy, 1-butenyloxy, 2-butenyloxy, and 3-butenyloxy. As examples of "lower alkanoyl" (i.e.C₁ to C₅ alkanoyl) in the definition for R⁷ there are formyl,acetyl,propionyl,butyryl(butanoyl) etc. As examples of "halogen" in the definition for R⁵, R⁶ and R⁷, there are chlorine, bromine, iodine,etc. As examples of "aralkyl" in the definitions for R⁸ and R⁹, there are benzyl, phenethyl, phenylpropyl, etc. As examples of "straight or branched carbon chain alkyl having 1 to 10 carbon atoms which may be interrupted by one or more oxygen atoms" in the definition for R³ there are methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl,sec-butyl, tert-butyl, pentyl(amyl), iso-pentyl, cert-pentyl, neo-pentyl, hexyl, iso-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1-dimethyl-butyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethy-2-methylpropyl, heptyl, 1-methylhexyl, 2-ethylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 1,1-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 3,3-dimethylpentyl, 3,4-dimethylpentyl, 1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, 1,2,2-trimethylbutyl, 2,2,3-trimethylbutyl, 1-ethyl-1-methylbutyl, 1-ethyl-2-methylbutyl, 1-ethyl-3-methylbutyl, 1-propylbutyl, 1-iso-propylbutyl, octyl, 6-methylheptyl, nonyl, 7-methyloctyl, decyl, 8-methylnonyl, etc.; and methoxymethyl, 1-methoxyethyl, 2-methoxyethyl, 1-methoxypropyl, 2-methoxypropyl, 3-methoxypropyl, 1-methoxy-1-methylethyl, 2-methxoy-1-methylethyl, 1-methoxybutyl, 2-methoxybutyl, 3-methoxybutyl, 4-methoxybutyl, 3-methoxy-1-methylpropyl, ethoxymethyl, 1-ethoxyethyl, 2-ethoxyethyl, 1-ethoxypropyl, 2-ethoxypropyl, 3-ethoxypropyl, propoxymethyl, iso-propoxymethyl, 1-propoxyethyl, 1-isopropoxyethyl, 2-propoxyethyl, 2-iso-propoxyethyl, 6-methoxyheptyl, 7-methoxyoxtyl, 8-methoxynonyl, etc. are straight or branched carbon chain divalent alkylene having 1 to 10 carbon atoms, and straight or branched carbon chain divalent alkylene having 2 to 10 carbon atoms interrupted by oxygen atom(s)(that is,ether type alkylene). As practical examples for these groups, there are methylene, methylmethylene ethylene, trimethylene, propylene tetramethylene, 1-methyltrimethylene 2-methyltrimethylene, 3-methyltrimethylene, 1-ethylethylene 2-ethylethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, decamethylene, 2-oxabutan-1,4-diyl (-CH₂OCH₂CH₂-), 3-oxapentan-1,5-diyl (-CH₂CH₂OCH₂CH₂-), 2-oxapentan-1,5-diyl (-CH₂OCH₂CH₂CH₂), 3-methyl-2-oxapentan-1,5-diyl 5-methyl-2-oxahexan-1,6-diyl etc. The salts of the compounds (I) include pharmaceutically acceptable nontoxic salts or pharmacologically acceptable salts. Examples of such salts are, for example, salts of inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; and salts of organic acids such as formic acid, acetic acid, oxalic acid, citric acid, succinic acid, fumaric acid, maleic acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, etc. The compounds of this invention include compounds having asymmetric carbon atom(s); in the case of such compounds, there are optical isomers. Thus this invention includes all of the isomers, individually and in any combination, e.g. racemic compound(s), optically active isomer(s), diastereoisomer(s), etc. The following disclosure of preparation, properties and uses of compounds of formula (I) is not subject to exclusions a] to j above except as indicated in the claims. The compounds of formula (I) can be produced by various processes; typical production processes are explained hereinafter: Process 1: In the above formulae, A, R¹, R², R³, R⁴, R⁵, R⁶, R⁷,R⁸, R⁹, and n are as defined above; X represents a halogen atom, R²a represents a hydrogen atom, , wherein R⁷ is as defined above, B represents an amino group or a protected amino group; and R²a represents a potassium atom when B represents a phthalimide group as protected amino. Compounds (I) can thus be produced by reacting dihydropyridine derivative (II) (which have halogenoalkyl (or halogenoalkoxyalkyl) ester group as the substituent at 5-position of the dihydropyridine ring] with amine compound or amine derivative (III) and then, if necessary (that is, when B is a protective amino group), releasing the protective group. Practical examples of "halogen" for X are chlorine, bromine, iodine; and practical examples of the protective group for an amino group are a toluenesulfonyl group, an acetyl group, a phenacylsulfonyl group, a trifluoromethanesulfonyl group, a bis-benzenesulfonyl group; further, potassium phthalimide is included in the compound R²a-B having a protected amino group - i.e. a Gabriel amine synthesis via phthalimide compound using potassium phthalimide can be applied for producing the compound (I). One of the above reactions is alkylation with compound (II). When reacting ammonia as the compound (III) to produce primary amine as the compound (I), there may be occur some side-reactions such as, particularly, polyalkylamine formation or amidation reaction; in such case, it is preferred to adopt the amino-protected compound (III) in order to produce the desired compound (I) selectively. When reacting a compound (III) other than ammonia, it is not always necessary to adopt the amino-protected compound (III). By adopting suitable reaction conditions, amino-protection is not needed. The reaction can be performed in the presence or absence of a solvent. It is preferred to perform the reaction in a solvent. Any solvents which do not take part in the reaction can be used. Examples of the solvent usually used are organic solvent such as benzene, toluene, xylene, dimethylformamide, dichloromethane, dichloroethane, methanol, ethanol. When adopting phthalimide compound as the compound (III) (the Gabriel method),dimethylformamide or xylene is usually used; particularly in the case dimethylformamide, the reaction can be performed under mild reaction conditions. The above solvents may be used alone or in appropriate combination. It is preferred that the reaction is performed by reacting the compound (II) with an equimolar or excessive molar amount of the compound (III). According to the kind of reaction, it may be preferred for smooth reaction to operate in the presence of a base. Examples of such a base are organic bases such as pyridine, picoline, N,N-dimethylaniline, N-methylmorpholine, dimethylamine (that is, secondary or tertiary amines); and inorganic bases such as sodium carbonate, potassium hydrogencarbonate. It may be preferred for smooth reaction to operate using an increased amount of the compound (III). Thus, various operation conditions may be adopted. The reaction is usually performed at room temperature or under heating, or under reflux. When using a protected amine compound as the compound (III), the compound (I) can be produced by hydrolysis in conventional manner. The hydrolysis may be acid- or alkali-hydrolysis, or preferably Ing-Manske hydrolysis using hydrazine. Starting materials [that is, the compounds (II)] are easily available since they are readily prepared by the methods described in U.S.Patent 3,985,758, i.e. by the Hantzsch synthesis or modifications thereof. Process 2. wherein Z represents an organic sulfonic acid radical; R²b represents a hydrogen atom, Compounds (I) can thus be prepared by reacting organic sulfonate compound (IV) with amine compound (v). Examples of the organic sulfonic acid radical are alkanesulfonic acid (alkylsulfonyl) radicals such as methanesulfonic acid radical (methanesulfonyl), ethanesulfonic acid radical (ethanesulfonyl); and aromatic sulfonic acid radicals such as toluenesulfonic acid radical (toluenesulfonyl), benzenesulfonic acid radical (benzenesulfonyl), etc. An equimolar or excess molar amount of the compound (v) is preferably reacted with the compound (IV). The reaction is usually performed at room temperature or under cooling. The reaction is usually performed in a solvent which does not take part in the reaction, and examples of the solvent are ether, methanol, ethanol, toluene tetrahydrofuran. The reaction time may be changed according to the kind of starting material and solvent, and the reaction conditions such as the reaction temperature. Process 3: wherein R²c represents a phenyl group, a phenoxymethyl group which may be substituted by an R⁷ group, or a naphthyloxymethyl group: and R⁷ is as defined above. The above compounds (I b ) [that is, the compounds (I) wherein R² is the above-defined group other than an amino group] can be produced by reacting a compound (I a ) [that is, a compound (I) wherein R² is an amino group] with an epoxy compound (VI). An equimolar or excess molar amount of either of the compounds (I a ) and (VI) is used for the reaction, and the reaction is performed in the absence or presence of a solvent which does not take part in the reaction. Examples of the solvent are organic solvents such as alcohol, (e.g. methanol, ethanol),ether (e.g. ethyl ether), tetrahydrofuran, ethyl acetate, etc. The reaction can be performed at room temperature or under heating. The reaction time may be changed according to other reaction conditions such as the solvent, etc. Process 4: wherein Z represents an organic sulfonic acid radical as defined above and R¹, R²c, R³, R⁴, R⁵, R⁶ are as defined above. The compounds (I b ) can be prepared by reacting a compound (I a ) with an organic sulfonic acid derivative (VII). An equimolar or excess molar amount of either of the compounds (I a ) and (VII) is used for the reaction, and the same solvent and the same reaction conditions as in the Process 2 can be adopted in the reaction. Starting materials (I a ) in the above Processes 3 and 4 may be produced by the method described in U.S. Patent 3,985,758 using the Hantzsch synthesis. However, these starting materials (I a ) are preferably produced by the method described in the Reference Examples of this application. This method described in the Reference Examples is based on a novel reaction for dihydropyridine ring formation which is novel per se.The new method has various advantages over known methods such as that of the U.S. Patent; thus in the novel method for dihydropyridine ring formation side-reactions scarcely occur and 5-aminoalkoxycarbonyl compounds (I a ) can be produced selectively in high yield. This method comprises reacting compound of formula (A) with compound of formula and releasing the amino-protecting group of the resulting compound of formula wherein A, R¹, R³, R⁴, R⁵, R⁶ are as defined above; starting material of formula (A) can be made by reacting compound of formula with compound of formula HO-A-protected amino and reacting the resulting compound of formula R₁COCH₂COO-A-protected amino with compound of formula wherein R x represents a hydrogen atom or an alkyl group of lower carbon content than R¹; in one particular example, A is (CH₂)₆₋, R¹, R³ and R⁴ are methyl, R⁵ is H, R⁶ is -CF₃, R x is H, and the protected amino group is phthalimido. A free form of the formula (I) compound or a salt of the compound (I) can be obtained after the above reactions. A salt of the formula (I) compound may be produced by performing the foregoing production process using a salt of the starting compound, or by applying a salt-forming reaction to the free formula (I) compound. The formula (I) compounds and salts can be separated and purified in ordinary manner, such as extraction with organic solvent, crystallization, column chromatography. The compounds of the formula (I) and salts thereof possess Ca²⁺-antagonistic activity and adrenergic beta-receptor blocking activity, and further possess intrinsic sympathomimetic activity (ISA). The compounds scarcely have side effects, and are useful for the treatment or prevention of ischemic heart-disases such as angina pectoris, and myocardial infarction, and also for the treatment or prevention of cardiovascular disorders such as hypertension and cardiac arrythmia. The compounds of formula (I) possess cerebral vasoconstriction-depressing action and central nervous system-improving action in addition to cardiovascular actions. An effective dose of the compounds of formula (I) is from 0.001 to 3 mg/kg (intravenous injection) for antihypertensive effect and coronary blood flow increasing effect; from 1 to 300 µg/kg (intracoronary injection) for coronary vasodilating effect; from 0.1 to 3 mg/kg (intravenous injection) for beta-blocking activity. In these cases it was also found that the compounds of formula (I) reduce cardiac work and myocardial oxygen demand. Moreover, it was found that the antihypertensive activity and coronary vasodilating activity of the compounds of formula (I) are effective for a longer period than in the case of known dihydropyridine compounds. The pharmacological effects of the compounds of formula (I) are shown in the following test results from the indicated test methods. Methods (1) Hemodynamic effects Mongrel dogs of either sex were anesthetized with pentobarbital sodium (30 mg/kg iv). The animals were artificially ventilated with room air. The chest was opened at the left 4th intercostal space. Mean arterial blood pressure (MBP), heart rate (HR), left ventricular pressure (LVP), max. dLVP/dt, mean pulmonary arterial blood pressure (MPAP), cardiac output (CO) and coronary blood flow (Cor. BF) were measured. The test compounds were injected into the femoral vein. Hemodynamic effects of these compounds were compared with that of well known Ca²⁺-antagonists. Table 1 (column 1) indicates the percent changes of MBP and Cor. BF from control values induced by intravenous injection of test compounds. (2) Coronary vasodilating effects Mongrel dogs of either sex were anesthetized and ventilated as previously described. A thoracotomy was performed at the 4th intercostal space. Following an intravenous injection of heparin (1000 units/kg), blood from the distal end of the cannulated carotid artery was pumped into circumflex branch of the left coronary artery using a servocontrolled peristaltic pump which. maintained a constant perfusion pressure of 120 mmHg by means of a pump controller. An electromagnetic flow probe was inserted in the circit to record blood flow through the cannulated coronary artery. The test compounds were administered directly into the rubber tubing connected close to the coronary artery cannula. Coronary vasodilating potency of the test compounds was assessed by calculating the dose required to produce 100% increase of Cor. HF (ED₁₀₀ pap), when the maximum responses to papaverine at a dose of 300 µg ia was expressed as 100% response. Table 1 (column 2) shows ED₁₀₀ pap and the duration of the coronary vasodilating effect of the test compounds. (3) Beta-adrenoceptor blocking effects Beta-adrenoceptor blocking effect of test compounds was determined according to the method of Tachikawa and Takenaka (Pharmacological studies on 1-(7-indenyloxy)-3-isopropylaminopropan-2-ol hydrochloride (YB-2); Arch. Int. pharmacodyn., 202, 79-92, 1973) using male Wistar rats. The rats were pretreated with reserpine (8 mg/Kg ip), 18 hr before experiments. The rats were anesthetized with pentobarbital sodium (55 mg/kg ip) and vagotomized bilaterally at the neck. The heart rate was measured with a cardiotachometer triggered by the QRS of the ECG (lead II) and recorded on a polygraph. After the control response to isoproterenol at a dose of 0.1 µg/kg iv was obtained, the test compound was injected iv in increasing doses at 20 min intervals. The mean dose producing 50% blockade of the positive chronotropic response to isoproterenol (ED₅₀) was estimated from dose-response curves obtained by plotting inhibition percentage against log cumulative dose of the test compound (Table 1, column 3). In this series of experiments, intrinsic sympathomimetic activity (ISA) was also evaluated. The results were shown in Table 1 (colum 4), wherein "-" represents that an increase in HR was scarcely observed; "+" represents that an increase in HR by 10 to 19 beats/min was observed; "++" represents that an increase in HR by 20 to 29 beats/min was observed; "+++" represents an increase in HR by above 30 beats/min. Ca-Antagonistic and beta-adrenoceptor blocking effects of a compound of this invention (in the case of the compound of Example 12, namely, 6-(2-hydroxy-3-phenoxypropylamino)hexyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate) were investigated by the following in vitro experiments. Ca²⁺-Antagonism: (1) Effect on KCl-induced contraction The experiment was performed according to the method of Terai, Takenaka and Maeno (Inhibition of calcium influx in rabbit aorta by nicardipine hydrochloride (YC-93); Bioch. Pharmacol., 30, 375-378, 1981). Herical strips were prepared from a rabbit thoracic aorta. The strips were incubated in 30ml Krebs-Henseleit solution which was maintained at 37 C and was constantly aerated with 95% O₂ and 5% CO₂ gas mixture. Isometric contractions were measured under a resting tension of 2.0 g. The strips were contracted by the addition of 50 ml KCl. Test compound was cumulatively added into the medium. The mean concentration producing a 50% inhibition of the KCl-induced contraction (IC₅₀) was estimated from dose-response curves (Table 2, column 1). (2) Effect on 3,4-diaminopyridine (3,4-DAP)-induced rythmic contraction The experiment was performed according to the method of Uchida and Sugimoyo (Mechanism of rythmic contraction of coronary artery and the effect of nicorandil (SG-75); Jap. J. Pharmacol., 34, Suppl. Abst. No. 0-151, 1984) using circular segments of dog coronary artery. The ring segments were cannulated with two triangle stainless-steel hooks and suspended vertically in Krebs-lienseleit solution under the conditions described previously. Preparations were set up under a resting tension of 1.0 g and rhythmic contractions were induced by application of 10 ml 3,4-DAP. Test compound was cumulatively added into the medium. IC₅₀ was estimated from dose-response curves (Table 2, column 2). (3) Effect on [³H]-nitrendipine binding The inhibitory effect of test compound on [³H]-nitrendipine binding to rat brain membrane was evaluated according to the method of Gould, Murphy and Snyder ([³H]-Nitrendipine-labeled calcium channels discriminate inorganic calcium agonosts and antagonists; Proc. Nati. Acad. Sci. USA, 79, 3656-3660, 1982). The IC₅₀ values, the concentration required to inhibit specific binding by 50%, were computed by logit-log analysis and then the inhibition constant (Ki) was obtained (Table 2, column 3). Beta-adrenoceptor blocking effect According to the method of Takenaka, Shiono, Honda, Asano, Miyazaki and Maeno (Antihypertensive and adrenoceptor blocking properties of new sulfonamide-substituted phenylethylamines; Clin. and Exper. Hyper.-Theory and Practice, A4, 125-137, 1982), isolated rat right atria were mounted in organ baths containing 30 ml of Krebs-Henseleit solution under conditions described previously. Beta-adrenoceptor blocking effect of test compounds was estimated by antagonism of (-)-isoproterenol-induced positive chronotropy. Antagonist dissociation constants (K B ) were determined at each concentration of test compound from dose-response curves and then pA₂ was calculated as -log K B (Table 3). Medicaments containing compounds of formula (I) may be prepared by conventional methods using conventional carriers or excipients. Medicants may contain one kind of the compound or many kinds of the compound of this invention. The compound may be in free form or a salt. They may for example be administered orally as tablets, pills, capsules, granules; parenterally by intravenous or intramuscular injection; or as suppositories. The appropriate dose is determined in each case considering factors such as the symptom, age and sex of the patient. For an adult a daily total of 1-200 mg is usually administered by intravenous injection in one to several doses. The invention is further illustrated by the following Reference Examples and Examples. The compounds per se of Examples 25 to 27 are not according to the invention. REFERENCE EXAMPLE In 290 ml of tetrahydrofuran were dissolved 48.3 g of 6-phthalimido-1-hexanol and 1.2 ml of triethylamine, and 18.1 g of diketene was added dropwise thereto under reflux over a period of 30 minutes. After refluxing the mixture for 1.5 hours, the mixture was cooled to room temperature, and then concentrated under reduced pressure. The residue was extracted with chloroform, and the extract was washed with dilute aqueous hydrochloric acid and water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide 61.2 g of a crude product of 6-phthalimidohexylacetoacetate. Thie crude product was used for the next reaction step, without purification. In 72 ml of dry benzene were dissolved 13.0 g of 6-phthalimidohexylacetoacetate, 6.85 g of m-trifluoromethylbenzaldehyde, 0.17 ml of piperidine and 0.51 ml of acetic acid. The mixture was refluxed under heating for 4.5 hours while removing formed water by a Dean-Stark trap. The reaction solution was cooled, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and the product was eluted with chloroform. 11.24 g of a crude product of 6-phthalimidohexyl 2-(m-trifluoromethylbenzylidene) aceto-acetate was obtained. This product was used for the following reaction, without purification In 92 ml of isopropylalcohol were dissolved 10.2 g of 6-phthalimidohexyl 2-(m-trifluoromethylbenzilidene)acetoacetate and 2.4 g of methyl 3-aminocrotonate, and the mixture was refluxed under heating for 3.5 hours. After coolin the reaction solution to room temperature, the solution was concentrated under reduced pressure to provide 12.5 g of a crude product of methyl 6-phthalimidohexyl 2,6-dimethyl-4-(m-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate. This product was used for the following reaction, without purification. A solution of 11.2 g of methyl 6-phthalimidohexyl 2,6-dimethyl-4-(m-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 10.1 g of hydrazine monohydrate in 330 ml of 95% ethanol (containing 5% water) was refluxed for 4 hours under heating. After cooling the reaction solution, the solution was concentrated under reduced pressure. The residue was extracted with chloroform, and the extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated. Crude crystals were recrystallized from chloroform-ether to provide 2.6 g of 6-aminohexyl methyl 2,6-dimethyl-4-(m-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate. Melting point: 119 -120.5°C. NMR (CDCl₃) δ : 2,33(6H,s), 2.66(2H,t), 3.65(3H,s), 3.93-4.13 (2H, m), 5.05(1H,s), 6.10 (1H, s) Example 1 In 20 ml of N,N-dimethylformamide were dissolved 14.3 g of 8-chlorooctyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 6 g of potassium phthalimide , and the mixture was refluxed for 3 hours under heating at 140-150°C. The reaction mixture was cooled to room temperature and after adding water thereto, the mixture was extracted with ether. The extract was washed with water, dried, and concentrated under reduced pressure to provide 16.1 g of a crude product of methyl 8-phthalimidooctyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. A solution of 16 g of methyl 8-phthalimidooctyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 6.8 g of hydrazine monohydrate in 160 ml of ethanol was refluxed for 2 hours under heating. Precipitate(solid) thue formed was removed by filtration. The filtrate was concentrated under reduced pressure and after adding chloroform to the residue, precipitates were again removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The product was eluted with chloroform-methanol (8:2 v/v), and crude crystals were recrystallized from ethanol - petroleum ether to provide 6 g of 8-aminooctyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. Melting point: 133-134°C. Example 2 In 50 ml of ethanol were dissolved 3 g of 8-aminooctyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 1 g of glycidyl phenyl ether, and the mixture was stirred at room temperature for 20 hours, After the reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography and the product was eluted with chloroform-methanol (95:5 v/v). 3.3 g of pale yellow powder of 8-(2-hydroxy-3-phenoxypropylamino)octyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate was obtained. The product was treated with an ethanol solution of hydrogen chloride to obtain 3 g of hydrochloric acid salt as amorphous powder. NMR (CDCl₃) ( free compound) 2.36(6H, s), 2.68(2H, s), 3.66(3H, s), 5.12(1H, s), 6.40(1H, s) Example 3 In 10 ml of N,N-dimethylformamide was dissolved 7.3 g of 2-(2-chloroethoxy)ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 3.4 g of potassium phthalimide, and the mixture was heated at 140-150° C for 3 hours. After cooling the mixture to room temperature and then adding thereto water, precipitates were extracted with chloroform. The extract was washed with a saturated aqueous sodium chloride , and concentrated under reduced pressure to provide 9.14 g of crude product of methyl 2-(2-phthalimidoethoxy)ethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate. A solution of 9.14 g of methyl 2-(2-phthalimidoethoxy)ethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 4,2 g of hydrazine monohydrate in 100 ml of ethanol was refluxed for 2 hours under heating. After cooling the reaction solution with ice and then adding thereto 100 ml of chloroform, precipitates were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The product was eluted with chloroform-methanol (8:2 v/v) and 4.8 g of 2-(2-aminoethoxy)ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1.4-dihydropyridine-3,5-dicarboxylate was obtained as liquid. NMR (CDCl₃) δ :2.36(3H, s), 2.86(2H, t), 3.66(3H, s), 4.24(2H, t), 5.12(1H, s), 6.50(1H, s) Example 4 In 20 ml of ethanol were dissolved 1.8 g of 2-(2-aminoethoxy)ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.64 g of glycidyl phenyl ether, and the solution was stirred at room temperature for 20 hours. The reaction solution was concentrated under reduced pressure and the residue was subjected to silica gel column chromatography. The product was eluted with chloroform-methanol (95:5 v/v), and 0.87 g of 2-[2-(2-hydroxy-3-phenoxypropylamino)ethoxy]ethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate was obtained. The product was treated with an ethanol solution of hydrochloric acid to provide 0.8 g of hydrochloric acid salt as amorphous powder. NMR (CDCl₃) ( free compound) δ : 2.36(6H, s), 2.68-3.08(4H), 3.64(3H, s), 3.80-4.40(5H), 5.12(1H, s), 5.94(1H, s) Example 5 a) In 30 ml of N,N-dimethylformamide were dissolved 18.4 g of 2-chloroethyl ethyl 2,6-dimethyl-4-(m-nitrophenyl)-1.4-dihydropyridin-3,5-dicarboxylate and 8.4 g of potassium phthalimide, and the solution was heated for 3 hours at 120-130°C. The reaction mixture was poured into 1000 ml of ice-water , and precipitated crystals were collected by filtration. The crystals were recrystallized from ether-ethyl acetate to provide 17 g of ethyl 2-phthalimidoethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridin-3,5-dicarboxylate. Melting point: 168-171° C. b) A solution of 17 g of ethyl 2-phthalimidoethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 8 ml of hydrazine monohydrate in 170 ml of ethanol was refluxed under heating for 30 minutes. Precipitated crystals were filtered hot, and the filtrate was concentrated under reduced pressure to remove the solvent. After adding water to the residue, the product was extracted with ethyl acetate, and the extract was washed with water, dried over anhydrous sodium sulfate, and concentrated to remove the the solvent. Crude crystals thus obtained were recrystallized from ethanol to provide 6,5 g of 2-aminoethyl ethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarbaxylate. Melting Point: 137-139°C NMR (CDCl₃) δ : 1.20 (3H, t), 2.32(6H, s), 2.86(2H, t), 4.08(2H, q), 5.08(1H, s), 5.84(1H, s) Example 6 In 25 ml of methanol was dissolved 1.95 g of 2-aminoethyl ethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate and after adding thereto 0.6 g of stylene oxide the mixture was allowed to stand for 2 days at room temperature. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography on silicagel (100 g) and the product was eluted with chloroform-methanol (98:2 v/v). Crude crystals were recrystallized from ethyl acetate, and 300 mg of ethyl 2-(β-hydroxyphenethylamino)ethyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate was obtained. Melting point: 108-109°c. NMR (CDCl₃) δ : 1.22(3H, t), 2.36(6H, s), 4.66(1H, m) 5.10 (1H, s), 6.12 (1H, s) Example 7 In 45 ml of methanol were dissolved 2.51 g of 6-aminohexyl methyl 2,6-dimethyl-4-(m-trifluoromethylphenyl)-1,4-dihydropyridine-3,5-dicarboxylate and 0.83 g of glycidyl phenyl ether, and the mixture was stirred for 45 hours at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. The product was eluted with chloroform-methanol (95:5 v/v), and 1.10 g of 6-(2-hydroxy-3-phenoxypropylamino)hexyl methyl 2,6-dimethyl-4-(m-trifluoromethylphenyl)-1,4-dihydropyridin-3,5-dicarboxylate was obtained. This product was treated with an ethanol solution of hydrogen chloride to obtain 1.16 g of hydrochloric acid salt as amorphous powder. NMR (CDCl₃) ( free compound) δ : 2.32(3H, s), 2,34(3H, s), 3.64(3H, s), 5.05(1H, s), 6.00(1H, s) By following the same procedure as in Examples 1 to 7, the following compounds were obtained. In the following examples, mp, Anal, NMR, Cal and Fond are abbreviations for melting point, elementary analysis values, nuclear magnetic resonance spectrum, calculated and found.

Claims: A dihydropyridine compound of the following general formula (I) or a salt thereof: wherein A represents a straight or branched carbon chain alkylene group having 1 to 10 carbon atoms which may be interrupted by one or more oxygen atoms; R¹ and R⁴ are the same or different C₁ to C₄ alkyl groups; R² represents an amino group, R³ represents a straight or branched carbon chain alkyl group having 1 to 10 carbon atoms which may be interrupted by one or more oxygen atoms, are the same or different and selected from a hydrogen atom, a nitro group, halogen atoms, a trifluoromethyl group, a cyano group, C₁ to C₄ alkyl groups, C₁ to C₄ alkoxy groups, and C₂ to C₄ alkenyloxy groups ; R⁷ represents a hydrogen atom, a cyano group, a halogen atom, a C₁ to C₄ alkoxy group or a C₁ to C₅ alkanoyl group; R⁸ and R⁹ are the same or different and selected from C₁ to C₄ alkyl groups and aralkyl groups; and n is 1 or 2; with the exception of any following compound a] to j] wherein: a] R¹ and R⁴ are methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is ethyl or propyl, R³ is methyl, isopropyl or t-butyl; and R² is naphthyl-terminated; or b] R¹ and R⁴ are methyl, one of R⁵ and R⁶ is nitro and the other hydrogen; A is hexyl or 1-methyl ethyl; R³ is methyl; and R² is naphthyl-terminated; or c] R¹ and R⁴ are methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is pentyl; R³ is methyl, isopropyl or isobutyl; and R² is naphthyl-terminated; or d] R¹ and R⁴ are methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is 2,2-dimethyl pentyl; R³ is isopropyl; and R² is naphthyl-terminated; or e] R¹ and R⁴ are methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is butyl; R³ is methyl; and R² is naphthyl-terminated; or f] R¹ is methyl; R³ is methyl; R⁴ is methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is 1,1-dimethyl ethyl; and R⁷ is cyano; or g] R¹ is ethyl; R³ is methyl; R⁴ is methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is 1,1-dimethyl ethyl, ethyl or propyl; and R⁷ is cyano; or h] R¹ is ethyl; R³ is methyl; R⁴ is methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is 1,1-dimethyl ethyl; and R⁷ is bromo; or i] R¹ is isopropyl; R³ is methyl; R⁴ is methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is 1,1-dimethyl ethyl; and R⁷ is cyano ; or j] R¹ is methyl; R³ is ethyl; R⁴ is methyl; one of R⁵ and R⁶ is nitro and the other hydrogen; A is propyl; and R⁷ is cyano. A compound according to claim 1 wherein A is a straight or branched carbon chain alkylene group having 1 to 10 carbon atoms; R² is R³ represents a straight or branched carbon chain alkyl group having 1 to 4 carbon atoms; R⁵ and R⁶ are the same or different and selected from a hydrogen atom, a nitro group and C₁ to C₄ alkoxy groups. A compound according to claim 1 which is one of the following compounds or a salt thereof: 4-(2-hydroxy-3-phenoxypropylamino)butyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate; 6-(2-hydroxy-3-phenoxypropylamino)hexyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate; 6-(2-hydroxy-3-phenoxypropylamino)hexyl methyl 2,6-dimethyl-4-(o-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate; 6-(2-hydroxy-3-phenoxypropylamino)hexyl methyl 2,6-dimethyl-4-(m-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylate; 6-(2-hydroxy-3-phenoxypropylamino)hexyl methyl 2,6-dimethyl-4-(o-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylate. A pharmaceutical composition containing as an active ingredient thereof at least one compound according to claim 1, 2 or 3. The use of a compound according to claim 1, 2 or 3 for the manufacture of a medicament having both Ca²⁺-antagonistic action and adrenergic beta-receptor blocking activity, and/or at least one of cerebral vasoconstriction-depressing activity and central nervous system-improving activity. The use of a compound according to claim 1, 2 or 3 for the manufacture of a medicament for the treatment or prevention of at least one of ischemic heart disease, cardiovascular disorder, cerebral vasoconstriction, and central nervous system disorder. A process for producing a compound according to claim 1 which is characterized by reacting a compound of the formula: with a compound of the formula: B - R²a wherein X represents a halogen atom; B represents an amino group or a protected amino group; and R²a represents a hydrogen atom, and may be a potassium atom when B represents a phthalimide group as protected amino; and R¹,R³,R⁴,R⁵,R⁶,R⁷ and A are as defined in claim 1; and further releasing the protective group when B is a protected amino group. A process for producing a compound according to claim 1 which is characterised by reacting a compound of formula: with a compound of the formula: H₂N-R²b wherein Z represents an organic sulfonic acid radical, R²b represents a hydrogen atom, and R¹, R³,R⁴,R⁵,R⁶,R⁷ and A are as defined in claim 1. A process for producing a compound according to claim 1 which is characterised by reacting a compound of formula: with a compound of the formula: wherein R²c represents a phenyl group, a phenoxymethyl group which may be substituted by R⁷, or a naphthyloxymethyl group; Z is an organic sulfonic acid radical; and R¹, R³, R⁴, R⁵, R⁶, R⁷, and A are as defined in claim 1. A process for producing a compound of the formula: which is characterised by reacting compound of formula (A) with compound of formula and releasing the amino-protecting group of the resulting compound of formula wherein A, R¹, R³, R⁴, R⁵, R⁶ are as defined in claim 7. A process according to claim 10 wherein the starting material of formula (A) is prepared by reacting compound of formula with compound of formula HO-A-protected amino and reacting the resulting compound of formula R₁COCH₂COO-A-protected amino with compound of formula wherein R x represents a hydrogen atom or an alkyl group of lower carbon content than R¹. A process according to claim 10 or 11 wherein A is (CH₂)₆₋, R¹, R³ and R⁴ are methyl, R⁵ is H, R⁶ is -CF₃, R x is H, and the protected amino group is phthalimido. The use, for the manufacture of a medicament having intrinsic sympathomimetic activity, of a compound of formula (I) or salt thereof wherein A represents a straight or branched carbon chain alkylene group having 1 to 10 carbon atoms which may be interrupted by one or more oxygen atoms; R¹ and R⁴ are the same or different C₁ to C₄ alkyl groups; R² represents an amino group, R³ represents a straight or branched carbon chain alkyl group having t to 10 carbon atoms which may be interrupted by one or more oxygen atoms, R⁵ and R⁶ are the same or different and selected from a hydrogen atom, a nitro group, halogen atoms, a trifluoromethyl group, a cyano group, C₁ to C₄ alkyl groups, C₁ to C₄ alkoxy groups, and C₂ to C₄ alkenyloxy groups; R⁷ represents a hydrogen atom, a cyano group, a halogen atom, a C₁ to C₄ alkoxy group or a C₁ to C₅ alkanoyl group; R⁸ and R⁹ are the same or different and selected from C₁ to C₄ alkyl groups and aralkyl groups; and n is 1 or 2 A process according to any of claims 7 to 12 including converting the 1,4-dihydropyridine product to or from salt form.

Inventors: ASANO, MASAHARU, FUJIKURA, TAKASHI, ITO, NORIKI, MATSUMOTO, YUZO, TAKENAKA, TOICHI
Applicants: YAMANOUCHI PHARMACEUTICAL CO. LTD.
Application year: 1985
Main classification: C07D211
IPC codes: A61K31, A61P3, A61P9, C07D401, C07D211, A61P25