USE OF(S)-ENANTIOMERS OF 1,4-DIHYDROPYRIDINE DERIVATIVES FOR TREATING HEART FAILURE

Abstract: (S)-enantiomers of compounds (I), (Ph = phenyl, Ar = 2-nitrophenyl, 3-nitrophenyl, 2,3-dichlorophenyl or benzofurazan-4-yl, A = a C3-C6 branched chain alkylene group, R = C1-C6 alkyl optionally mono-substituted by C1-C6 alkoxy, R1 = H, OH or C1-C4alkyl, R2 = H or CH3) have a positive inotropic effect on cardiac contractility and are useful in the treatment of heart failure and in the preparation of medicaments for use in such treatments. The preparation of the (S)-enantiomers is also described.

Description: TΓΓLE USE OF (S)-ENANTIOMERS OF 1,4-DIHYDROPYRIDINE DERIVATIVES FOR TREATING HEART FAILURE DESCRIPTION The invention relates to the preparation of (S)-enantiomers of 1,4-dihydropyridines, to their use in the treatment of heart failure and to their use in the manufacture of medicaments for such treatment. 1 ,4-Dihydropyridines endowed with calcium antagonistic activity are widely used in the treatment of several cardiovascular diseases, for example hypertension and angina. An important limiting factor in the use of these compounds is the negative inotropic effect exerted by some of them, see S. Goldmann et al., Angew Chem. Int. Ed. Engl. , 30, 1559, (1991). This effect suggests a careful administration of these compounds to patients suffering from cardiac diseases, although a reduction of cardiac work could result beneficial for some of them. Most of the 1 ,4-dihydropyridine derivatives used for the treatment of cardiovascular diseases have an asymmetric carbon atom at position 4 in the dihydropyridine ring. Currently, all of them are used as racemates, containing both the (S)- and the (R)-enantiomer. U.S. Patent 4,705,797 and U.S. Patent 4,772,621 disclose asymmetric diesters of l,4-dihydro-2,6-dimethyl-4-aryl-pyridine-3,5-dicarboxylic acids and the stereoisomers or pharmaceutically acceptable salts thereof as compounds having antihypertensive and coronary dilating activity. It has now surprisingly been found that, besides the known potent effect in lowering the blood pressure already shown by their racemates, the (S)-enantiomers of such compounds also possess an unexpected positive inotropic effect. 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 coronary heart diseases in patients having impaired heart functions. The invention provides the use of an (S)-enantiomer of a compound having d e general formula I wherein Ph represents a phenyl group, Ar represents a 2-nitrophenyl, 3-nitrophenyl, 2,3-dichlorophenyl or benzofurazan-4-yl group, A represents a branched chain alkylene group having from 3 to 6 carbon atoms, R represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms, optionally mono-substituted by an alkoxy group having from 1 to 6 carbon atoms, Ri represents a hydrogen atom, a hydroxy group or an alkyl group having from 1 to 4 carbon atoms, and R 2 represents a hydrogen atom or a methyl group or of a salt, hydrate or solvate of such an (S)-enantiomer for the preparation of a medicament for the treatment of heart failure. The invention further provides a method for the treatment of a patient suffering from heart failure, the method comprising administering to the patient a therapeutically effective amount of an (S)-enantiomer of a compound having the general formula I as above defined or of a salt, hydrate or solvate of such an (S)-enantiomer. The invention also provides a process for the preparation of the (S)-enantiomers of the compounds of the general formula I, the process comprising the esterification of the (R)-enantiomer of a compound of the general formula II wherein R and Ar are as above defined with a compound of the general formula III HO — A — N — CH — CH2 — CH(Ph) 2 (III) I I R-] R2 wherein A, R l 5 R and Ph are as above defined. According to the invention, the (S)-enantiomer of the compound I may be administered to the patient as such, 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, sulphuric, maleic, succinic, citric, methanesulphonic and toluenesulphonic acids; they may be prepared from the free bases in conventional manner. Whatever the form (base, salt, hydrate or solvate), the active ingredient will usually be administered in admixture with a pharmaceutically acceptable carrier. Suitable administration routes include oral, parenteral, rectal and transdermal routes. The selection of the most suitable carrier will depend on the administration route. Carriers can be solid, semisolid or liquid diluents as well as capsules and may optionally provide modified release of the active drug. For example, a preparation to be administered orally in the form of tablets can include, in addition to the active ingredient, solubilizers (e.g. a polyethoxylated fatty acid), components which modify the drug release (e.g. hydroxypropylmethyl cellulose), fillers (e.g. lactose), binders (e.g. hydroxypropylmethyl cellulose) and/or lubricants (e.g. sodium stearylfumarate). The tablets can be coated with suspensions of colouring pigments (e.g. iron oxide) and film forming agents (e.g. cellulose derivatives). A preparation to be administered parenterally may be an aqueous solution of the active ingredient, possibly including a co-solvent such as polyethylene glycol. The amount of the active ingredient usually ranges between 0.1 and 99% by weight of the total formulation, preferably between 0.5 and 20% by weight in formulations for injection and between 2 and 50% by weight in formulations for oral administration. The daily dose of the active ingredient depends on individual needs (e.g. the patient's condition, body weight, age, gender etc.) as well as on the administration route. Generally, the oral dosage may range from 0.1 to 100 mg, preferably 1 to 20 mg, of active ingredient per day. In the process according to the invention, an (R)-enantiomer of a compound II is esterified with a compound III. The reaction may be performed in the presence of a coupling agent (e.g. dicyclohexylcarbodiimide, N,N'-carbonyldiimidazole or diethyl cyanophosphonate) optionally in the presence of a promoting agent (e.g. N-hydroxysuccinimide or 4-dimethylaminopyridine) in aprotic or chlorinated solvents (e.g. dimethylformamide or chloroform) at temperatures ranging from -10 to 140°C according to well known synthetic methods: Albertson, Org. React., Y2, 205-218 (1962); Doherty et al., J. Med. Chem. , 35, 2 (1992); Staab et al., Newer Methods Prep. Org. Chem., 5, 61 (1968); Ishihara, Chem. Pharm. Bull. , 39, 3236 (1991). Alternatively, the (R)-enantiomer of the compound II may first be reacted with an alkyl chloroformate in presence of a tertiary amine (e.g. triethylamine), subsequently adding the compound III at 0-80°C. Optionally, a promoting agent (e.g. 1-hydroxypiperidine) may be added before the compound III, see Albertson, Org. React. , _12, 157 (1962). Another alternative procedure is to convert the (R)-enantiomer of the compound II into the corresponding acyl halide using an inorganic halide (e.g. phosphorus pentachloride, phosphorus trichloride or thionyl chloride) in an aprotic solvent (e.g. chloroform, dichloroethane, dichloromethane, 1, 1, 1-trichloroethane or ethyl acetate), optionally in the presence of a promoting agent (e.g. dimethylformamide) at temperatures ranging between -10 and 65 °C, and then add the compound III. Isolation of the acyl halide before the addition of the compound III is optional. Whichever of these methods is used, the homo-chiral (S)-enantiomers of the compounds I which are obtained may be purified according to known methods, either as bases (e.g. by column chromatography) or as salts (e.g. by re-precipitation or crystallization). The (S)-enantiomers were investigated in vivo in dogs, at different doses in order to assess their pharmacological activity. Their effects on diastolic blood pressure and cardiac contractility were determined. The results show a positive inotropic effect on the heart contractility associated with the expected hypotensive effect. The positive inotropic effect suggests a potential use of these compounds as therapeutic agents for the treatment of heart failure. The invention is illustrated by the following Examples. EXAMPLE 1 S-(+)-methyl l,l . N-trimethyl-N-(3,3-diphenylpropyl)-2-aminoethyl 1,4-dihydro- -2,6-dimethyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate hydrochloride . 0.5 H 2 0. 0.13 ml of thionyl chloride was added at -10°C to a stirred suspension of 0.54 g of R-(-)-l,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-5-methoxycarbonyl-pyridine- -3-carboxylic acid [prepared as described in A. Ashimori et al., Chem. Pharm. Bull. , 39, 108-111, (1991)] in 2.9 ml of anhydrous dichloromethane and 0.75 ml of anhydrous dimethylformamide kept under nitrogen atmosphere and sheltered from direct light. After 1 hour at 0°C, a solution of 0.48 g of 2,N-dimethyl- -N-(3,3-diphenylpropyl)-l-amino-2-propanol (prepared as described in U.S. Patent 4,772,621) in 1 ml of dichloromethane was added at -5°C. After stirring for 3 hours at 0°C and standing overnight at 20-25 °C, the solvent was evaporated off in vacuo and the residue was dissolved in 20 ml of ethyl acetate. The organic phase was washed sequentially with brine (4 ml), 10% aqueous sodium carbonate solution (5 x 4 ml), brine (4 ml), IN hydrochloric acid (5 x 5 ml), brine (4 ml), 10% aqueous sodium carbonate solution (2 x 5 ml) and finally with brine (4 ml). The organic phase was dried over anhydrous sodium sulphate and evaporated to dryness in vacuo. The residue was purified by flash chromatography on a silica gel column eluting with petroleum etheπacetone 85: 15. The unitary TLC fractions (petroleum etheπacetone 7:3 by volume or chloroform:5N methanolic ammonia 99: 1 by volume) were evaporated to give a residue which was dissolved in 75 ml of diethyl ether containing 3 % of acetone. 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 0.66 g of the title compound. M.p. 115-125°C; [α D ] 25 = + 70.56° (MeOH, c = 0.981). Elemental analysis % for C 36 H 4 iN 3 O 6 .HCl. 0.5 H 2 O: Found: C, 65.47; H, 6.57; N, 6.29; Cl, 5.32; H 2 0, 1.68. Calc: C, 65.79; H, 6.60; N, 6.39; Cl, 5.39; H 2 0, 1.37. iH-NMR Spectrum of the base at 200 MHz (CDC1 3 , δ): 8.10 (m, 1H) nitrophenyl, 2-CH 7.97 (m, 1H) nitrophenyl, 4-CH 7,62 (m, 1H) nitrophenyl, 6-CH 7.33 (dd, 1H) nitrophenyl, 5-CH 7.29-7.10 (m, 10H) aromatic H atoms of CH(Ph) 2 5.79 (bs, 1H) pyridine, NH 5.05 (s, 1H) pyridine, 4-CH 3.92 (t, 1H) CH(Ph) 2 3.63 (s, 3H) COOCH 3 2.57 (m, 2H) OC(CH 3 ) 2 CH 2 N 2.40-2.23 (m, 2H) N(CH 3 )CH 2 CH 2 2.33/2.27 (2s, 6H) pyridine, 2-CH 3 and 6-CH 3 2.19-2.09 (m, 2H) N(CH 3 )CH 2 CH 2 2.17 (s, 3H) NCH 3 1.35-1.31 (2s, 6H) OC(CH 3 ) 2 CH 2 N EXAMPLE 2 2,2,N-trimethyl-N-(3,3-diphenylpropyl)-l-amino-3-propanol hydrochloride A mixture comprising N-methyl-3,3-diphenylpropylamine hydrochloride (2.61 g), acetic anhydride (1 ml) and formaldehyde (37% in water, 0.9 ml), was refluxed for 30 minutes. A solution of isobutyraldehyde (1 ml) in acetic anhydride (1 ml) was then added dropwise and the mixture was maintained at reflux temperature for further 30 minutes. The solvent was then evaporated off under vacuum and the residue was dissolved in water, alkalinized and extracted with diethyl ether. The organic layer was separated and dried and, after evaporation of the solvent, the residue was purified by silica gel chromatography eluting with dichlormethane: methanol (98:2 to 96:4). Pure fractions were collected and die solvent was evaporated to give 1.55 g of the Mannich base N-(3,3-diphenylpropyl)-2,2,N-trimethyl-3-aminopropionaldehyde, which was characterized by NMR spectrometry. i H-NMR at 60 MHz (CDCI 3 , δ): 9.5 (s, 1H) CHO 7.3 (s, 10H) aromatics 4.0 (t, 1H) CH(Ph) 2 2.7-1.9 (m, 9H) 3 CH 2 and NCH 3 1.0 (s, 6H) C(CH 3 ) 2 0.25 g of sodium borohydride were added at 0-3 °C to a solution of 1.5 g of the compound thus prepared in methanol (7 ml) cooled at 0-3 °C for 30 minutes. The mixture was then stirred at room temperature for 1 hour. The resulting solution was poured into 35 ml of water, the crude was extracted with diethyl ether and the organic layer was separated and extracted with a solution of oxalic acid (0.6 g in 35 ml of water). The initially acidic aqueous solution, after washing twice with diethyl ether and having been made alkaline with 30% sodium hydroxide (1 ml), was then extracted with diethyl ether. Hydrogen chloride in diethyl ether was added to the ethereal solution after drying over sodium sulphate. 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. i H-NMR at 60 MHz (CDC1 3 , δ): 10.8-9.9 (m, 1H) NH+ 7.7-7.2 (m, 10H) aromatics 5.0-4.4 (m, 1H) OH 4.1 (t, 1H) CH(Ph) 2 3.7 (s, 2H) CH 2 0 3.5-2.5 (m, 9H) 3 CH 2 and NCH 3 1.1 (s, 6H) C(CH 3 ) 2 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 .0.7 H 2 0 The title compound was prepared according to the method described in Example 1 , but using 2,2,N-trimethyl-N-(3,3-diphenylpropyl)-l-amino-3-propanol, prepared as described in Example 2, instead of 2,N-dimethyl-N-(3,3-diphenylpropyl)-l-amino- -2-propanol. The crude was purified by flash chromatography on silica gel column eluting with n-hexane: ethyl acetate graduated from 70:30 to 65:35. The fractions containing the pure base were pooled, the solvents were evaporated in vacuo to dryness, 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, m.p. 116-127°C. iH-NMR Spectrum at 200 Mhz (CDCI 3 , δ): 11.20-11.55 (bs, 1H) NH+ 8.06 (dd, 1H) nitrophenyl, 2-CH 7.90-8.03 (m, 1H) nitrophenyl, 4-CH 7.60-7.45 (dd, 1H) nitrophenyl, 6-CH 7.10-7.45 (m, 11H) nitrophenyl, 5-CH and aromatics of CH(Ph) 2 6.68-6.82 (d, 1H) pyridine, NH 5.07 (d, 1H) pyridine, CH in 4 3.85-4.15 (m, 3H) CH(Ph) 2 and COOCH 2 3.67 (s, 3H) COOCH 3 2.50-3.15 (m, 9H) CH 2 N(CH 3 )CH 2 CH 2 CH 2.34/2.41 (2d, 6H) pyridine, 2-CH 3 and 6-CH 3 1.70 (bs, 1.4H) H 2 0 0.98/1.18 (2d, 6H) C(CH 3 ) 2 EXAMPLE 4 Pharmacological tests The (S)-enantiomers of Examples 1 and 3 were tested for their in vivo pharmacological activity in dogs in comparison to the racemate of the compound of Example 1. Male beagle dogs weighing 11-13 kg, aged 12 months, from Green-Hill and Morini Allevamenti (Italy), were used. All dogs were anaesthetized with sodium pentobarbital (30 mg/kg i.v. for induction and 2 mg/kg/hour i.v. for maintenance), and artificially ventilated with a pump via a cuffed endotracheal tube. Intraventricular and arterial blood pressure were monitored by means of a Millar Mikro-Tip catheter with two pressor sensors inserted in the left ventricle via the left common carotid artery. The right femoral vein was cannulated to allow drug infusion. The following parameters were evaluated: systolic, diastolic and mean blood pressure, left ventricular systolic pressure and first derivative of left ventricular systolic pressure, dP/dt max as an index of cardiac contractility. The compounds were tested at the following dosages (intravenously administered in cumulative manner): Compound Dose (μg/kg) Example 1, Racemate 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 Figures 1 to 3, where percentage changes on diastolic blood pressure (DBP) and cardiac contractility at the different doses used are shown. In particular, Figures 1, 2 and 3 show the effects exerted on the haemodynamics parameters in the dog by the racemate of Example 1 , the (S)-enantiomer of Example 1 and the (S)-enantiomer of Example 3 respectively. Figure 1 clearly shows that the racemate of the compound of Example 1 has a potent blood pressure lowering effect (DBP) accompanied by a slight reduction of cardiac contractility (dP/dt max). By contrast, Figures 2 and 3 show that the noticeable blood pressure lowering effects of the compounds of Examples 1 and 3 are associated with an increase of dP/dt max, supporting a positive inotropic effect.

Claims: CLAIMS Use of an (S)-enantiomer of a compound having 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, A represents a branched chain alkylene group having from 3 to 6 carbon atoms, R represents a straight or branched chain alkyl group having from 1 to 6 carbon atoms, optionally mono-substituted by an alkoxy group having from 1 to 6 carbon atoms, Ri represents a hydrogen atom, a hydroxy group or an alkyl group having from 1 to 4 carbon atoms, and R 2 represents a hydrogen atom or a methyl group or of a salt, hydrate or solvate of such an (S)-enantiomer for the preparation of a medicament for the treatment of heart failure. 2. Use according to claim 1 of S-(+)-methyl l,l,N-trimethyl- -N-(3,3-diphenylpropyl)-2-aminoethyl l,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)- pyridine-3,5-dicarboxylate or S-(+)-methyl 2,2,N-trimethyl-N-(3,3-diphenylpropyl)- -3-aminopropyl l,4-dihydro-2,6-dimedιyl-4-(3-nitrophenyl)-pyridine-3,5-dicarboxylate. 3. Use of an (S)-enantiomer according to claim 1 or claim 2 for the preparation of a medicament which contains a pharmaceutically acceptable carrier. 4. Use of an (S)-enantiomer according to any preceding claim for the preparation of a medicament in a form suitable for oral administration. 5. Use of an (S)-enantiomer according to claim 4 for the preparation of a medicament which contains from 2% to 50% of the (S)-enantiomer. 6. Use of an (S)-enantiomer according to claim 4 or claim 5 for the preparation of a medicament which contains from 0.1 mg to 100 mg of the (S)-enantiomer in daily dose form. 7. Use of an (S)-enantiomer according to any of claims 4 to 6 for the preparation of a medicament which contains from 1 mg to 20 mg of the (S)-enantiomer in daily dose form. 8. Use of an (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 an (S)-enantiomer according to claim 8 for the preparation of a medicament which contains from 0.5% to 20% of the (S)-enantiomer. 10. A method for the treatment of a patient suffering from heart failure, the method comprising administering to the patient a therapeutically effective amount of an (S)-enantiomer of a compound having the general formula I as defined in claim 1 or of a salt, hydrate or solvate of such an (S)-enantiomer. 11. A process for the preparation of an (S)-enantiomer of a compound of the general formula I as defined in claim 1 , the process comprising the esterification of the (R)-enantiomer of a compound of the general formula II wherein R and Ar are as defined in claim 1 with a compound of the general formula III HO — A — N — CH — CH 2 — CH(Ph) 2 wherein A, R l5 R 2 and Ph are as defined in claim 1. 12. A process according to claim 11 in which the (R)-enantiomer of the compound of the general formula II is reacted with the compound of the general formula III in the presence of a coupling agent, and optionally in the presence of a promoting agent, in an aprotic or chlorinated solvent at a temperature of from -10 to 140°C. 13. A process according to claim 12 in which 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, and optionally in the presence of a promoting agent, and the compound of the general formula III is subsequently added. 14. A process according to claim 13 in which the (R)-enantiomer of the compound of the general formula II is first converted into the corresponding acyl halide using an inorganic acid halide in an aprotic solvent, optionally in the presence of a promoting agent, at a temperature of from -10 to 65 °C, and the compound of the general formula III is then added.

Inventors: LEONARDI AMEDEO, MOTTA GIANNI, TESTA RODOLFO, LEONARDI, AMEDEO, MOTTA, GIANNI, TESTA, RODOLFO
Applicants: RECORDATI CHEM PHARM, RECORDATI INDUSTRIA CHIMICA E FARMACEUTICA S.P.A., RECORDATI S.A., CHEMICAL AND PHARMACEUTICAL COMPAN
Application year: 1996
Main classification: A61K31
IPC codes: A61K31, A61P9, C07D211, C07D413