GB2123826A

GB2123826A - Esters of epinine

Info

Publication number: GB2123826A
Application number: GB08319111A
Authority: GB
Inventors: Cesare Casagrande; Vittorio Vecchietti
Original assignee: SIMES
Current assignee: SIMES
Priority date: 1982-07-22
Filing date: 1983-07-14
Publication date: 1984-02-08
Also published as: CH660359A5; DE3326364A1; BE897314A; JPS5946250A; IT1190925B; FR2531949B1; IT8222515A1; GB8319111D0; FR2531949A1; IT8222515A0

Abstract

Esters of epinine of formula <IMAGE> (R=cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, alkoxy, amino, alkylamino, dialkylamino or optionally substituted heterocyclic, other than pyridyl) may be prepared by reacting epinine with an acid RCOOH or a reactive derivative thereof. The process, the esters, their pharmaceutically acceptable salts, and pharmaceutical compositions containing the esters or salts are all claimed. The esters are useful in cardiovascular and renal therapy.

Description

SPECIFICATION Esters of epinine The invention relates to esters of epinine and their pharmaceutically acceptable salts, to a process for their preparation and to pharmaceutical compositions containing them.

The invention provides esters of epinine having the general formula I

wherein R represents a cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aralkenyl, alkoxy, amino, alkylamino, dialkylamino or optionally substituted heterocyclic group, with the proviso that R does not represent a pyridyl group, and further provides pharmaceutically acceptable acid addition salts thereof. The salts may be salts of inorganic or organic acids, such as hydrochloric, methanesulphonic, citric and tartaric acids.

The compounds of the invention may be prepared by reacting epinine with an acid of the general formula RCOOH, wherein R is as above defined, or with a reactive derivative of such an acid.

The undesired contemporaneous acylation of the amino group, which is present in the epinine moiety, can be avoided by using an N-protected derivative of epinine or by carrying out the reaction in a strongly acid medium so that the amino group is completely protonated. Suitable acids are mineral acids, such as hydrogen halides, and organic acids, such as trifluoracetic and methanesulphonic acids, or an excess of the same acid which is used to esterify epinine. When an appropriate excess of the acid RCOOH is used it acts both as diluent and as protonating agent of the amino group. A suitable N-protected derivative of epinine is N-benzyloxycarbonylepinine. The benzyloxycarbonyl protecting group can be easily removed by hydrogenation when the esterification of the phenol hydroxy groups is complete.

Esterification with the acid RCOOH may be carried out in the presence of a condensing agent, such as dicyclohexylcarbodiimide, at a temperature of from OOC to the reflux temperature of the reaction mixture.

Reactive derivatives of the acid RCOOH include its halides preferably its chloride or bromide, and its simple and mixed anhydrides and its activated esters. The reaction may be conducted at a temperature of from --1 50C to the reflux temperature of the reaction mixture. The reaction can be promoted by adding suitable basic compounds which bind the hydrogen halide which is formed, such as alkali and alkaline earth carbonates and bicarbonates or organic bases, e.g. pyridine, dimethylamine, triethylamine and dimethylamino-pyridine; obviously the base is not added when the protonation of the epinine amino group is made in acid medium, but only when the epinine amino group is protected by means of a suitable protecting group; the volatile organic bases such as pyridine may be used in excess, then they act also as solvents.The reaction may be carried out in an inert organic solvent, such as a hydrocarbon, more particularly a halogenated hydrocarbon such as methylene dichloride, an acyclic or cyclic ether such as diethyl ether, tetrahydrofuran and dioxan, an ester such as ethyl acetate, or an amide such as dimethylformamide.

In vivo and in vitro tests in animals have shown that the compounds of the general formula I and their salts are endowed with diuretic activity and with selective vasodilating activity on vital circulatory districts such as the renal, mesenterial, coronary arteries and with positive inotrope activity. They are therefore useful in the therapy of cardiac decompensation, renal insufficiency hypertension, pathologic syndromes characterized from water and saline retention and pathologic syndromes characterized from the insufficient perfusion of the vital organs. The compounds of the invention are active also when orally administered.

The invention further provides a pharmaceutical composition comprising a compound having the general formula I as herein defined or a pharmaceutically acceptable salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.

The pharmaceutical compositions according to the invention may be in solid form such as tablets, dragees, capsules, powders, granulations, suppositories and candles, or in liquid form such as solutions, suspensions and emulsions, or in semisolid form such as creams and ointments.

They may be also prepared in such a way that the release of the drug is prolonged after the administration. They may contain the usual carrier materials and may include auxiliary substances such as preserving, stabilizing, wetting or emulsifying agents, salts for regulating the osmotic pressure, buffers, dyestuffs and flavouring agents. They are prepared according to known methods and may further contain other therapeutic agents.

The following Examples illustrate the invention.

Example 1 A solution of 11.1 g (76 mmol) of cyclohexanecarboxylic acid chloride and of 4.4 g (21.6 mmol) of epinine hydrochloride in 30 ml of trifluoroacetic acid was maintained under stirring at room temperature for 4 hours. After evaporating off the solvent, the residue was taken up in dichloromethane, washed with 1 M aqueous sodium bicarbonate, dried over anhydrous sodium sulphate, and filtered. The solvent was again evaporated off and the residue, dissolved in ethyl acetate, was treated with an excess of the solution of hydrogen chloride in diethyl ether. The mixture was evaporated to dryness and the residue was crystallized form ethyl acetate: ethanol; 3,4-0-dicyclo hexanecarboxyl-epinine hydrochloride (m.p. 138-1 400C, yield 79%) was thus obtained.

Example 2 Following the procedure described in Example 1, but replacing the cyclohexanecarboxylic acid chloride with an equivalent amount of cyclopentanecarboxylic acid chloride, 3,4-0- dicyclopentanecarboxyl-epinine hydrochloride (m.p. 147--1490C; from ethyl acetate) was obtained.

Example 3 Following the procedure described in Example 1, but replacing the cyclohexanecarboxylic acid chloride with an equivalent amount of cyclobutanecarboxylic acid chloride, 3,4-0- dicyclobutanecarboxyl-epinine hydrochloride (m.p. 160--1620C from ethyl acetate: ethanol) was obtained.

Example 4 Following the procedure described in Example 1, but replacing the cyclohexanecarboxylic acid choride with an equivalent amount of cyclopropanecarboxylic acid chloride, 3,4-0- dicyclopropanecarboxyl-epinine hydrochloride (m.p. 165-1 670C from ethyl acetate: ethanol) was obtained.

Example 5 Following the procedure described in Example 1, but maintaining the temperature at 800C for 1 5 hours and replacing the cyclohexanecarboxylic acid chloride with an equivalent amount of benzoyl chloride, 3,4-0-dibenzyoyl-epinine hydrochloride (m.p. 1 56-1 580C from ethyl acetate: ethanol) was obtained.

Example 6 Following the procedure described in Example 1, but maintaining the temperature at 700C for one hour and replacing the cyclohexanecarboxylic acid chloride with an equivalent amount of p methoxybenzoyl chloride, 3,4-0-di-p- methoxybenzoyl-epinine hydrochloride (m.p.

1 54--1 560C from ethyl acetate: ethanol) was obtained.

Example 7 Following the procedure described in Example 1, but maintaining the temperature at 800C for two hours and replacing the cyclohexanecarboxylic acid chloride with an equivalent amount of p-toluenecarboxylic acid chloride, 3,4-0-di-p-tolyl-epinine hydrochloride (m.p. 1 78--1800C from ethyl acetate: ethanol) was obtained.

Example 8 Following the procedure described in Example 1, but replacing the cyclohexanecarboxylic acid chloride with an equivalent amount of phenylacetyl chloride, 3,4-0-di-(phenylacetyl)- epinine hydrochloride (m.p. 187--1890C from ethyl acetate) was obtained.

Example 9 Following the procedure described in Example 1, but replacing the cyclohexanecarboxylic acid chloride with an equivalent amount of cinnamoyl chloride, 3,4-0-dicinnamoyl-epinine hydrochloride (m.p. 125-1 2700 from ethyl acetate) was obtained.

Example 10 Following the procedure described in Example 1, but reducing the reaction time to 3 hours and replacing the cyclohexanecarboxylic acid chloride with an equivalent amount of 3-phenylpropionyl chloride, 3,4t0-di-(3-phenylpropionyl)-epinine hydrochloride (m.p. 110-1 1200from ethyl acetate) was obtained.

Example 11 Following the procedure described in Example 1, but replacing the cyclohexanecarboxylic acid chloride with an equivalent amount of 4phenylbutyryl chloride, 3,4-0-di-(4-phenylbutyryl)- epinine hydrochloride (m.p. 1 13--1 150C from ethyl acetate) was obtained.

Example 12 Following the procedure described in Example 1, but replacing the cyclohexanecarboxylic acid chloride with an equivalent amount of 2-phenyl2-methyl-propionyl chloride, 3,4-0-di-2-phenyl2-methyl-propionyl)-epinine hydrochloride (m.p.

94--960C from ethyl acetate) was obtained.

Example 13 Following the procedure described in Example 1, but replacing the cyclohexanecarboxylic acid chloride with an equivalent amount of 2,2dimethyl-3-phenyl-propionyl chloride, 3,4-0-di (2,2-dimethyl-3-phenyl-propionyl)-epinine hydrochloride (m.p. 19419600 from ethyl acetate) was obtained.

Example 14 Following the procedure described in Example 1, but increasing the reaction time to 5 hours and replacing the cyclohexanecarboxylic acid chloride with an equivalent amount of alphathiophenecarboxylic acid chloride, 3,4-0-di(alphathiophenecarboxyl)-epinine hydrochloride (m.p.

142--1440C from ethyl acetate: ethanol) was obtained.

Example 15 A solution of 12 g (39.8 mmol) of Nbenzyloxycarbonyl-epinine and 16 g (148 mmol) of dimethylcarbamoyl chloride in 200 ml of pyridine was maintained at 800C for 12 hours.

The mixture was evaporated to dryness, and the residue was taken up in dichloromethane. The mixture was washed with water, with 1 M hydrochloric acid with 1 M aqueous sodium carbonate solution and again with water until neutralization. The mixture was dried over anhydrous sodium salphate, filtered and evaporated. The purification was carried out by chromatography on a silica gel column (eluent, dichloromethane), 3,4-0-di-(dimethylcarbamoyl)- N-benzyloxycarbonyl-epinine was separated (yield 37%) in an oily form chromatographically pure (thin layer chromatography on silica gel, solvent dichloromethane: ethyl acetate 45:5 by volume; detection with iodine; mass spectrum M+ at 433 m/e).

Example 16 Following the procedure described in Example 15, but replacing the dimethylcarbamoyl chloride with an equivalent amount of diethylcarbamoyl chloride, 3,4-0-di-(diethylcarba moyl)-N- benzyloxycarbonyl-epinine was obtained in an oily form chromatographically pure (thin layer chromatograph on silica gel solvent dichloromethane:ethyl acetate 95:5 by volume: detection with iodine; mass spectrum M+ at 499 m/e).

Example 17 3.5 g (7.8 mmol) of 3,4-0-di (dimethylca rbamoyl)-N-benxyloxycarbonylepinine prepared as described in Example 15, was hydrogenated at atmospheric pressure, at room temperature, for one hour in the presence of 1 g of 10% by weight palladium-on-charcoal in 100 ml of acetic acid. After filtration and evaporation, the residue was isolated and purified as described in Example 1. 3,4-0-di-(dimethylcarbamoyl)- epinine hydrochloride (m.p. 135-1 370C from ethyl acetate; yield 55%) was obtained.

Example 18 Following the procedure described in Example 17, but replacing the 3,4-0-di (dimethylcarbamoyl)-N-benzyloxycarbonyl epinine with an equivalent amount of 3,4-0-di (diethylcarbamoyl)-N-benzyloxycarbonyl-epinine, prepared as described in Example 16, 3, 4-0-di- (diethylcarbamoyl)-epinine in an oily form, chromatographically pure, was obtained (thin layer chromatography on silica gel, solvent water: acetic acid: butanol:acetone:toluene=1 :1:1:1:1 by volume; detection with iodine; mass spectrum M+ at 365 m/e).

Claims

1. An ester of epinine having the general formula I as herein defined, or a pharmaceutically acceptable acid addition salt thereof.

2. 3,4-Di-O-dicyclohexanecarboxyl-epinine or its hydrochloride.

3. 3,4-Di-O-dicyclopentanecarboxyiepinine or its hydrochloride.

4. 3,4-Di-O-dicyclobutanecarboxyl-epinine or its hydrochloride.

5.3,4-Di-O-dicyclopropanecarboxyl-epinine or its hydrochloride.

6. 3,4-Di-O-dibenzoyl-epinine or its hydrochloride.

7. 3,4-Di-O-di-p-methoxybenzoyl-epinine or its hydrochloride.

8. 3,4-Di-O-di-p-toyl-epinine or its hydrochloride.

9. 3,4-Di-O-di-(phenylacetyl)-epinine or its hydrochloride.

10. 3,4-Di-O-dicinnamoyl-epinine or its hydrochloride.

11.3,4-Di-O-di-(3-phenylpropionyl)-epinine or its hydrochloride.

12.3,4-Di-O-di-(4-phenylbutyryl)-epinine or its hydrochloride.

13.3,4-Di-O-di-(2-phenyl-2-methyl- propionyl)-epinine or its hydrochloride.

14. 3,4-Di-0-di-(2,2-dimethyl-3-phenyl- propionyl)-epinine or its hydrochloride.

15. 3,4-Di-O-di-(alpha-thiophenecarboxyl)- epinine or its hydrochloride.

1 6. 3,4-Di-0-di-(dimethylcarbamoyl)-epinine or its hydrochloride.

17. 3.4-Di-O-di-(diethylcarbamoyl)-epinine or its hydrochloride.

1 8. A pharmaceutical composition comprising an ester of epinine according to any preceding claim or a pharmaceutically acceptable acid addition salt thereof in admixture with a pharmaceutically acceptable diluent or carrier.

1 9. A process for the preparation of an ester of epinine according to claim 1, the process comprising reacting epinine with an acid of the general formula RCOOH as herein defined or with a reactive derivative of such an acid.

20. A process according to claim 19 in which the reaction is carried out in the presence of a protonating agent.

21. A process according to claim 20 in which the protonating agent is hydrochloric, methanesulphonic or trifluoroacetic acid.

22. A process according to claim 20 or claim 21 in which the protonating agent is an excess of the acid RCOOH.

23. A process according to claim 19 in which the amino group of the epinine is protected before the esterification, and the protecting group is removed after the esterification.

24. A process according to claim 23 in which the amino group of the epinine is protected by a benzyloxycarbonyl group.

25. A process according to claim 24 in which the benzyloxycarbonyl group is removed by hydrogenation.

26. A process according to any of claims 19 to 25 in which the epinine is reacted with the acid RCOOH in the presence of a condensing agent and of a diluent at a temperature of from OOC to the reflux temperature of the reaction mixture.

27. A process according to claim 26 in which the condensing agent is dicyclohexylcarbodiimide.

28. A process according to any of claims 19 to 25 in which the epinine is reacted with a halide, an anhydride or an ester of the acid RCOOH.

29. A process according to any of claims 23 to 25 in which the N-protected epinine is reacted with an acid chloride RCOCI in the presence of a hydrochloric acid binding agent.

30. A process according to claim 29 in which the binding agent is an alkali or an alkaline earth carbonate or bicarbonate dimethylamine or pyridine.

31. A process according to any of claims 28 to 30 in which the reaction is carried out in the presence of a diluent at a temperature of from 15 C to the reflux temperature of the reaction mixture.

32. A process according to claim 31 in which the diluent is methylene dichloride, diethyl ether, tetrahydrofuran, dioxan, ethyl acetate or dimethylformamide.

33. A process according to claim 19, the process being substantially as described herein with reference to any of the Examples.