JP2000514776A - Use of the (S) -enantiomer of a 1,4-dihydropyridine derivative for treating heart failure - Google Patents

Abstract

(57) [Summary] Compound (I) [Ph = phenyl, Ar = 2-nitrophenyl, 3-nitrophenyl, 2,3-dichlorophenyl or benzofurazan-4-yl, A = C ₃ -C ₆ branched alkylene group, R = necessary The (S) -enantiomer of C ₁ -C ₆ alkyl, R ₁ HH, OH or C ₁ -C ₄ alkyl, R ₂ HH or CH ₃ ] optionally monosubstituted with C ₁ -C ₆ alkoxy is It has a positive inotropic effect on cardiac contraction and is useful in the treatment of heart failure and in the manufacture of a medicament for use in such treatment. The preparation of the (S) -enantiomer is also described.

Description

DETAILED DESCRIPTION OF THE INVENTION Use of the (S) -Enantiomer of a 1,4-Dihydropyridine Derivative for the Treatment of Heart Failure The present invention relates to the preparation of the (S) -enantiomer of 1,4-dipidropyridine, their use in the treatment of heart failure And their use in the manufacture of a medicament for such treatment. 1,4-Dihydropyridines with calcium antagonist activity are widely used in the treatment of several cardiovascular diseases, such as hypertension and angina. An important limiting factor in the use of these compounds is the negative inotropic effect exerted by some of them. See Goldman et al., Angew Chem. Int. Ed. Engl., 30 , 1559, (1991). This effect facilitates the careful administration of these compounds to patients suffering from heart disease, but reduced cardiac work may be advantageous in some of them. Most 1,4-dihydropyridine derivatives used for the treatment of cardiovascular diseases have an asymmetric carbon atom at the 4-position of the dihydropyridine ring. Generally, all of them have been used as racemates containing both (S)-and (R)-enantiomers. U.S. Pat.Nos. 4,705,797 and 4,772,621 disclose the use of 1,4-dihydro-2,6-dimethyl-4-aryl-pyridine-3,5-dicarboxylic acids as compounds with antihypertensive and coronary vasodilating effects. Asymmetric diesters and stereoisomers or pharmaceutically acceptable salts thereof are disclosed. Now, surprisingly, in addition to the known potent antihypertensive effects already shown with their racemates, the (S) -enantiomer of such compounds also has an unexpected positive inotropic effect Was found to have This suggests their potential use in the treatment of patients affected by heart failure and in particular their preferred use for the treatment of hypertension and ischemic heart disease in patients with impaired cardiac function. The present invention provides compounds of the general formula I [Wherein, Ph represents a phenyl group, Ar represents a 2-nitrophenyl, 3-nitrophenyl, 2,3-dichlorophenyl or benzofurazan-4-yl group, and A represents 3 to 6 carbon atoms. R is a linear or branched chain having 1 to 6 carbon atoms, wherein R is mono-substituted with an alkoxy group having 1 to 6 carbon atoms as needed. R ₁ represents a hydrogen atom, a hydroxy group or an alkyl group having 1 to 4 carbon atoms, and R ₂ represents a hydrogen atom or a methyl group.] Provided is the use of a) -enantiomer or a salt, hydrate or solvate of such (S) -enantiomer in the manufacture of a medicament for treating heart failure. The present invention further provides a method of treating a patient suffering from heart failure, said method comprising the (S) -enantiomer of a compound having the general formula I as defined above or such (S) -enantiomer Administering to the patient a therapeutically effective amount of a salt, hydrate or solvate of The present invention also provides a process for the preparation of the (S) -enantiomer of a compound having the general formula I, comprising the steps of: Wherein R and Ar are defined as above, with the general formula III Wherein A, R ₁ , R ₂ and Ph are defined as above. According to the present invention, the (S) -enantiomer of Compound I can be administered to a patient neat or in the form of any of its pharmaceutically acceptable salts, hydrates or solvates. Preferred pharmaceutically acceptable acid addition salts include those formed with hydrochloric, sulfuric, maleic, succinic, citric, methanesulfonic, and toluenesulfonic acids; From the free base. Whatever the form (base, salt, hydrate or solvate), the active ingredient is usually administered in admixture with a pharmaceutically acceptable carrier. Suitable routes of administration include oral, parenteral, rectal, transdermal routes. The choice of the most suitable carrier will depend on the route of administration. The carrier can be a solid, semi-solid or liquid diluent, as well as a capsule, providing for modified release of the active agent, if necessary. For example, formulations for oral administration in the form of a tablet may contain, in addition to the active ingredient, a solubilizing agent (eg, a polyethoxylated fatty acid), a component that modulates drug release (eg, hydroxypropylmethylcellulose), an excipient (eg, Lactose), a binder (eg, hydroxypropyl methylcellulose) and / or a lubricant (eg, sodium stearyl fumarate). Tablets can be coated with a suspension of a coloring pigment (eg, iron oxide) and a film forming agent (eg, a cellulose derivative). Formulations to be administered non-daily may be aqueous solutions of the active ingredient, possibly with a co-solvent such as polyethylene glycol. The amount of active ingredient usually ranges from 0.1 to 99% by weight of the total formulation, preferably from 0.5 to 20% by weight for injectable formulations and from 2 to 50% by weight for oral formulations. The daily dose of the active ingredient depends on the individual requirements (eg, condition, weight, age, sex, etc. of the patient) and the route of administration. Generally, oral dosages may range from 0.1 to 100 mg, preferably 1 to 20 mg, of active ingredient per day. In the method of the present invention, the (R) -enantiomer of compound II is esterified with compound III. The reaction is carried out according to well-known synthetic methods: Albertson, Org. React., 12 , 205-218 (1962); Doherty et al. Med. Chem., 35 , 2 (1992); Staab et al., Newer Methods Prep. Org. Chem., 5 , 61 (1968); Ishihara, Chem. Pharm. According to Bull., 39 , 3236 (1991), in the presence of a coupling agent (eg, dicyclohexylcarbodiimide, N, N′-carbonyldiimidazole or diethylcyanophosphonate), an aprotic or chlorinated solvent (eg, The reaction can be carried out in dimethylformamide or chloroform), optionally in the presence of an accelerator such as N-hydroxysuccinimide or 4-dimethylaminopyridine, at a temperature ranging from -10 to 140 ° C. Alternatively, the (R) -enantiomer of compound II may be first reacted with an alkyl chloroformate in the presence of a tertiary amine (eg, triethylamine), and then compound II I may be added at 0-80 ° C. An accelerator (eg, 1-hydroxypiperidine) may optionally be added before compound III, see Albertson, Org. React., 12 . See 157 (1962). Other alternative procedures include inorganic halides (eg, phosphorus pentachloride, phosphorus trichloride or thionyl chloride) in aprotic solvents (eg, chloroform, dichloroethane, dichloromethane, 1,1,1-trichloroethane or ethyl acetate) Converting the (R) -enantiomer of compound II to the corresponding acyl halide, optionally in the presence of an accelerator (e.g., dimethylformamide), at a temperature in the range of -10 to 65 <0>C; Thereafter, compound III is added. Before adding compound III, the acyl halide may be isolated. Whichever of these methods is used, the resulting homo-chiral (S) -enantiomer of Compound I can be prepared as a base (eg, by column chromatography) or a salt (eg, reprecipitation or (Crystallization). To evaluate their pharmacological activity, the (S) -enantiomers were examined in dogs at different doses in vivo. Their effects on diastolic blood pressure and systole were measured. The results show a positive inotropic effect on systole, with the expected antihypertensive effect. Positive inotropic effects suggest the potential use of these compounds as therapeutics for the treatment of heart failure. The present invention is illustrated by the following examples. Example 1 S-(+)-methyl 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl 1,4-dihydro-2,6-dimethyl-4- (3- (Nitrophenyl) -pyridine-3,5-dicarboxylate hydrochloride. 0.5H ₂ O.0.13 ml of thionyl chloride was added at −10 ° C. to 0.54 g of R-(−)-1,4-dihydro-2,6-dimethyl in 2.9 ml of anhydrous dichloromethane and 0.75 ml of anhydrous dimethylformamide. -4- (3-Nitrophenyl) -5-methoxycarbonyl-pyridine-3-carboxylic acid [A. A. Ashimori et al., Chem. Pharm. BuII., 39 , 108-111, prepared as described in (1991)], maintained under a nitrogen atmosphere, and shielded from direct light. After 1 hour at 0 ° C., a solution of 0.48 g of 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol in 1 ml of dichloromethane (as described in US Pat. No. 4,772,621) Was added at -5 ° C. After stirring at 0 ° C. for 3 hours and standing at 20-25 ° C. overnight, the solvent was distilled off in vacuo and the residue was dissolved in 20 ml of ethyl acetate. The organic phase was washed with brine (4 ml), 10% aqueous sodium carbonate (5 × 4 ml), brine (4 ml), 1N hydrochloric acid (5 × 5 ml), brine (4 ml), 10% aqueous sodium carbonate (2 × 5 ml) and finally brine (4 ml) And washed one after another. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by flash chromatography on a silica gel column eluted with petroleum ether: acetone 85:15. Evaporation of a single TLC fraction (petroleum ether: acetone 7: 3 by volume or chloroform: 5N methanolic ammonia 99: l by volume) gave a residue which was reconstituted with 75 ml of diethyl ether containing 3% acetone. Dissolved in ether. After filtration, the solution was acidified with 3N ethereal hydrogen chloride, the precipitate was collected by suction and dried at 78 ° C./15 mmHg to give 0.66 g of the title compound. Mp ^{_{115-125 ℃; [α D] 25}} = + 70.56 ° (MeOH, c = 0 .981). _{C 36 H 41 N 3 O 6} .HCl.0.5H 2 O about Elemental analysis%: Found: C, 65.47; H, 6.57 ; N, 6.29; Cl, 5.32; H 2 O, 1.68. Calculated: C, 65.79; H, 6.60 ; N, 6.39; Cl, 5.39; H 2 O, 1.37. Base at 200MHz Example 2 2,2, N-trimethyl-N- (3,3-diphenylpropyl) -1-amino-3-propanol hydrochloride N-methyl-3,3-diphenylpropylamine hydrochloride (2.61 g) , Acetic anhydride (1 ml) and formaldehyde (37% in water, 0.9 ml) were refluxed for 30 minutes. Then a solution of isobutyraldehyde (1 ml) in acetic anhydride (1 ml) was added dropwise and the mixture was kept at reflux temperature for a further 30 minutes. Thereafter, the solvent was distilled off under vacuum, the residue was dissolved in water, made alkaline and extracted with diethyl ether. After separating and drying the organic layer and evaporation of the solvent, the residue was purified by silica gel chromatography, eluting with dichloromethane: methanol (98: 2 to 96: 4). The purified fractions were collected and the solvent was evaporated, yielding 1.55 g of Mannich base N- (3,3-diphenylpropyl) -2,2, N-trimethyl-3-aminopropionaldehyde, which was analyzed by NMR spectrometry. Characterized by At 60MHz 0.25 g of sodium borohydride was added to a solution of 1.5 g of the compound prepared above in methanol (7 ml) at 0-3 ° C and cooled at 0-3 ° C for 30 minutes. Then the mixture was stirred at room temperature for 1 hour. The resulting solution was poured into 35 ml of water, the crude product was extracted with diethyl ether, the organic phase was separated and extracted with oxalic acid solution (0.6 g in 35 ml of water). Next, the initial acidic aqueous solution was washed twice with diethyl ether, made alkaline with 30% sodium hydroxide (1 ml), and extracted with diethyl ether. Hydrogen chloride in diethyl ether was added to the ether solution after drying over sodium sulfate. The crude hydrochloride was collected by filtration and crystallized from acetone to give 1.26 g of the title product melting at 147-148 ° C. At 60MHz Example 3 S-(+)-methyl 2,2, N-trimethyl-N- (3,3-diphenylpropyl) -3-aminopropyl 1,4-dihydro-2,6-dimethyl-4- (3- (Nitrophenyl) -pyridine-3,5-dicarboxylate hydrochloride. 0.7H ₂ O. The title compound was prepared as described in Example 2 in place of 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol. Prepared according to the method described in Example 1, except using, 2, N-trimethyl-N- (3,3-diphenylpropyl) -1-amino-3-propanol. The crude product was purified by flash chromatography on a silica gel column eluted with a 70: 30-65: 35 gradient of n-hexane: ethyl acetate. Fractions containing the purified base were pooled, the solvent was evaporated to dryness under vacuum and the residue was dissolved in diethyl ether. After filtration, the solution was acidified with 3N ethereal hydrogen chloride and the precipitate was collected by suction and dried at 78 ° C / 15 mmHg to give the title compound, mp 116-127 ° C. At 200MHz Example 4 Pharmacological Testing In order to compare the racemic compound of the compound of Example 1, the (S) -enantiomers of Examples 1 and 3 were tested in dogs for their in vivo pharmacological activity. Male beagle dogs, weighing 11-13 kg, 12 months old, from Green-Hill and Morini Allevament i (Italy) were used. All dogs were anesthetized with sodium pentobarbital (30 mg / kg intravenously for induction and 2 mg / kg / hour intravenously for maintenance) and artificially pumped through a cuffed endotracheal tube. Ventilated. Intraventricular and arterial blood pressure were monitored by two pressure sensored Miller Mikro-Tip catheters inserted into the left ventricle via the left common carotid artery. The right femoral vein was cannulated for drug injection. The following parameters were evaluated: systolic, diastolic and mean blood pressure, left ventricular systolic pressure and the first derivative of left ventricular systolic pressure dP / dt max as an indicator of systole. Compounds were tested at the following doses (administered cumulatively intravenously). Compound dose (μg / kg) Example 1, racemic compound 3,10,30 Example 1, (S) -enantiomer 0.5,1,3,5 Example 3, (S) -enantiomer 1,3,5, 10 The results are reported in FIGS. 1-3, which show the percentage change in diastolic blood pressure (DBP) and systole at the different doses used. In particular, FIGS. 1, 2 and 3 show the effects of the racemic compound of Example 1, the (S) -enantiomer of Example 1 and the (S) -enantiomer of Example 3 on the hemodynamics of dogs, respectively. Is shown. FIG. 1 clearly shows that the racemate of the compound of Example 1 has a potent antihypertensive effect (DBP) with a slight decrease in cardiac contractility (dP / dt max). In contrast, FIGS. 2 and 3 show that the significant hypotensive effect of the compounds of Examples 1 and 3 is accompanied by an increase in dP / dt maximum, supporting a positive inotropic effect.

[Procedure for Amendment] Article 184-8, Paragraph 1 of the Patent Act [Date of Submission] July 1, 1997 (1997.7.1) [Content of Amendment] Description 1,4-dihydropyridine for treating heart failure The present invention relates to the preparation of the (S) -enantiomer of 1,4-dihydropyridine, their use in the treatment of heart failure and their use in the manufacture of a medicament for such treatment. 1,4-Dihydropyridines with calcium antagonist activity are widely used in the treatment of several cardiovascular diseases, such as hypertension and angina. An important limiting factor in the use of these compounds is the negative inotropic effect exerted by some of them. Goldman (S. Goldman) et al., Angew Chem. Int. Ed. Eng 1., 30 , 1559, (1991). This effect encourages the careful administration of these compounds to patients suffering from heart disease, but reduced cardiac work may be advantageous in some of them. Most 1,4-dihydropyridine derivatives used for the treatment of cardiovascular diseases have an asymmetric carbon atom at the 4-position of the dihydropyridine ring. Generally, all of them have been used as racemates containing both (S)-and (R)-enantiomers. U.S. Pat.Nos. 4,705,797 and 4,772,621 disclose the use of 1,4-dihydro-2,6-dimethyl-4-aryl-pyridine-3,5-dicarboxylic acids as compounds with antihypertensive and coronary vasodilating effects. Asymmetric diesters and stereoisomers or pharmaceutically acceptable salts thereof are disclosed. Now, surprisingly, in addition to the known potent antihypertensive effects already shown with their racemates, the (S) -enantiomer of such compounds also has an unexpected positive inotropic effect Was found to have This suggests their potential use in the treatment of patients affected by heart failure and in particular their preferred use for the treatment of hypertension and ischemic heart disease in patients with impaired cardiac function. The present invention provides compounds of the general formula I [Wherein, Ph represents a phenyl group, Ar represents a 2-nitrophenyl, 3-nitrophenyl, 2,3-dichlorophenyl or benzofurazan-4-yl group, and A represents 3 to 6 carbon atoms. R represents a linear or branched alkyl group having 1 to 6 carbon atoms, R ₁ represents a hydrogen atom, a hydroxy group or 1 to 4 Represents an alkyl group having a carbon atom, and R ₂ represents a hydrogen atom or a methyl group], the enantiomer having an (S) -configuration at the 4-position of the dihydropyridine ring, or such an enantiomer. Provided is the use of a salt, hydrate or solvate of the (S) -enantiomer in the manufacture of a medicament for treating heart failure. The present invention further provides a method of treating a patient suffering from heart failure, said method comprising the (S) -enantiomer of a compound having the general formula I as defined above or such (S) -enantiomer Administering to the patient a therapeutically effective amount of a salt, hydrate or solvate of The present invention also provides a process for preparing the (S) -enantiomer of a compound having the general formula I, comprising the steps of: The invention encompasses the esterification of the (R) -enantiomer of the compound of the present invention. Example 1 Methyl 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl)-(4S ) -Pyridine-3,5-dicarboxylate hydrochloride. 0.5H ₂ O.0.13 ml of thionyl chloride was added at −10 ° C. to 0.54 g of R-(−)-1,4-dihydro-2,6-dimethyl in 2.9 ml of anhydrous dichloromethane and 0.75 ml of anhydrous dimethylformamide. -4- (3-Nitrophenyl) -5-methoxycarbonyl-pyridine-3-carboxylic acid [A. A. Ashimori et al., Chem. Pharm. Bull., 39 , 108-111, (1991)], maintained under a nitrogen atmosphere and shielded from direct light. After 1 hour at 0 ° C., a solution of 0.48 g of 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol in 1 ml of dichloromethane (as described in US Pat. No. 4,772,621) Was added at -5 ° C. After stirring at 0 ° C. for 3 hours and standing at 20-25 ° C. overnight, the solvent was distilled off in vacuo and the residue was dissolved in 20 ml of ethyl acetate. The organic phase was washed with brine (4 ml), 10% aqueous sodium carbonate (5 × 4 ml), brine (4 ml), 1N hydrochloric acid (5 × 5 ml), brine (4 ml), 10% aqueous sodium carbonate (2 × 5 ml) and finally brine (4 ml). And washed one after another. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was purified by flash chromatography on a silica gel column eluted with petroleum ether: acetone 85:15. Evaporation of a single TLC fraction (petroleum ether: acetone 7: 3 by volume or chloroform: 5N methanolic ammonia 99: 1 by volume) yields a residue which is combined with 75 ml of diethyl ether containing 3% acetone. Dissolved in ether. After filtration, the solution was acidified with 3N ethereal hydrogen chloride, the precipitate was collected by suction and dried at 78 ° C./15 mmHg to give 0.66 g of the title compound. Mp ^{_{115-125 ℃; [α D] 25}} = + 70.56 ° (MeOH, c = 0.981). _{C 36 H 41 N 3 O 6} .HCl.0.5H 2 O about Elemental analysis%: Found: C, 65.47; H, 6.57 ; N, 6.29; Cl, 5.32; H 2 O, 1.68. Calculated: C, 65.79; H, 6.60 ; N, 6.39; Cl, 5.39; H 2 O, 1.37. Base at 200MHz 0.25 g of sodium borohydride was added to a solution of 1.5 g of the compound prepared above in methanol (7 ml) at 0-3 ° C and cooled at 0-3 ° C for 30 minutes. Then the mixture was stirred at room temperature for 1 hour. The resulting solution was poured into 35 ml of water, the crude product was extracted with diethyl ether, the organic phase was separated and extracted with an oxalic acid solution (0.6 g in 35 ml of water). Next, the initial acidic aqueous solution was washed twice with diethyl ether, made alkaline with 30% sodium hydroxide (1 ml), and extracted with diethyl ether. Hydrogen chloride in diethyl ether was added to the ether solution after drying over sodium sulfate. The crude hydrochloride was collected by filtration and crystallized from acetone to give 1.26 g of the title product melting at 147-148 ° C. At 60MHz Example 3 Methyl 2,2, N-trimethyl-N- (3,3-diphenylpropyl) -3-aminopropyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl)-(4S ) -Pyridine-3,5-dicarboxylate hydrochloride. 0.7H ₂ O. The title compound was prepared as described in Example 2 in place of 2, N-dimethyl-N- (3,3-diphenylpropyl) -1-amino-2-propanol. Prepared according to the method described in Example 1, except using, 2, N-trimethyl-N- (3,3-diphenylpropyl) -1-amino-3-propanol. The crude product was purified by flash chromatography on a silica gel column eluted with a 70: 30-65: 35 gradient of n-hexane: ethyl acetate. Fractions containing the purified base were pooled, the solvent was evaporated to dryness under vacuum and the residue was dissolved in diethyl ether. After filtration, the solution was acidified with 3N ethereal hydrogen chloride and the precipitate was collected by suction and dried at 78 ° C / 15 mmHg to give the title compound, mp 116-127 ° C. At 200MHz Claims 1. General formula I for the manufacture of a medicament for treating heart failure [Wherein, Ph represents a phenyl group, Ar represents a 2-nitrophenyl, 3-nitrophenyl, 2,3-dichlorophenyl or benzofurazan-4-yl group, and A represents 3 to 6 carbon atoms. R represents a linear or branched alkyl group having 1 to 6 carbon atoms, R ₁ represents a hydrogen atom, a hydroxy group or 1 to 4 Represents an alkyl group having a carbon atom, and R ₂ represents a hydrogen atom or a methyl group], the enantiomer having an (S) -configuration at the 4-position of the dihydropyridine ring, or such an enantiomer. Use of the salt, hydrate or solvate of the (S) -enantiomer. 2. Methyl 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl)-(4S) -Pyridine-3,5-dicarboxylate or methyl 2,2, N-trimethyl-N- (3,3-diphenylpropyl) -3-aminopropyl 1,4-dihydro-2,6-dimethyl-4- ( Use according to claim 1, of (3-nitrophenyl)-(4S) -pyridine-3,5-dicarboxylate. 3. Use of the (S) -enantiomer according to claim 1 or claim 2 for the preparation of a medicament comprising a pharmaceutically acceptable carrier. 4. Use of the (S) -enantiomer according to any of the preceding claims for the preparation of a medicament in a form suitable for oral administration. 5. Use of the (S) -enantiomer according to claim 4 for the preparation of a medicament comprising 2% to 50% of the (S) -enantiomer.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) C07D 211: 90 271: 12) (81) Designated country EP (AT, BE, CH, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG), AP (KE, LS, MW, SD, SZ, UG), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AM, AT, AU, AZ, BB, BG, BR, BY, CA, CH, CN, CZ, DE, DK, EE, ES, FI, GB, GE, HU, IS, JP, KE, KG, KP, KR, Z, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, TJ , TM, TR, TT, UA, UG, UZ, VN (72) Inventor Testa Rodolfo Italy-20060 Vignato Via Esse. Percini, 3/8

Claims (1)

Claims 1. General formula I for the manufacture of a medicament for treating heart failure [Wherein, Ph represents a phenyl group, Ar represents a 2-nitrophenyl, 3-nitrophenyl, 2,3-dichlorophenyl or benzofurazan-4-yl group, and A represents 3 to 6 carbon atoms. R is a linear or branched chain having 1 to 6 carbon atoms, wherein R is mono-substituted with an alkoxy group having 1 to 6 carbon atoms as needed. R ₁ represents a hydrogen atom, a hydroxy group or an alkyl group having 1 to 4 carbon atoms, and R ₂ represents a hydrogen atom or a methyl group.] Use of) -enantiomers or salts, hydrates or solvates of such (S) -enantiomers. 2. S-(+)-methyl 1,1, N-trimethyl-N- (3,3-diphenylpropyl) -2-aminoethyl 1,4-dihydro-2,6-dimethyl-4- (3-nitro (Phenyl) -pyridine-3,5-dicarboxylate or S-(+)-methyl 2,2, N-trimethyl-N- (3,3-diphenylpropyl) -3-aminopropyl 1,4-dihydro-2 Use according to claim 1, of 2,6-dimethyl-4- (3-nitrophenyl) -pyridine-3,5-dicarboxylate. 3. Use of the (S) -enantiomer according to claim 1 or claim 2 for the preparation of a medicament comprising a pharmaceutically acceptable carrier. 4. Use of the (S) -enantiomer according to any of the preceding claims for the preparation of a medicament in a form suitable for oral administration. 5. Use of the (S) -enantiomer according to claim 4 for the preparation of a medicament comprising 2% to 50% of the (S) -enantiomer. 6. Use of the (S) -enantiomer according to claim 4 or 5 for the preparation of a medicament comprising 0.1 mg to 100 mg of the (S) -enantiomer in a daily dose form. 7. Use of the (S) -enantiomer according to any of claims 4 to 6 for the preparation of a medicament comprising 1 mg to 20 mg of the (S) -enantiomer in a daily dose form. 8. Use of the (S) -enantiomer according to any of claims 1 to 3 for the preparation of a medicament in a form suitable for parenteral administration. 9. Use of the (S) -enantiomer according to claim 8 for the preparation of a medicament comprising 0.5% to 20% of the (S) -enantiomer. 10. A method of treating a patient suffering from heart failure, comprising the (S) -enantiomer or a salt, hydrate or solvate of such (S) -enantiomer of a compound having general formula I according to claim 1. Administering to a patient a therapeutically effective amount of 11. A process for preparing the (S) -enantiomer of a compound having the general formula I according to claim 1, comprising Wherein R and Ar are as defined in claim 1. The (R) -enantiomer of the compound of general formula III A process comprising esterifying with a compound of the formula: wherein A, R ₁ , R ₂ and Ph are defined as in claim 1. 12. The (R) -enantiomer of the compound of general formula II is combined with the compound of general formula III in an aprotic solvent or a chlorinated solvent in the presence of a coupling agent in the presence of an accelerator if necessary at -10 to 140 ° C. The method according to claim 11, wherein the reaction is carried out at a temperature of: 13. The (R) -enantiomer of the compound of the general formula II is first reacted with an alkyl chloroformate in the presence of a tertiary amine, if necessary in the presence of a promoter, and thereafter the compound of the general formula III is added. 13. The method according to 12. 14． The (R) -enantiomer of the compound of general formula II is first converted to the corresponding acyl halide, using an inorganic acid halide in an aprotic solvent and optionally in the presence of an accelerator at a temperature of -10 to 65 ° C. 14. The process according to claim 13, wherein the compound of general formula III is added.