CS204530B1 - Esters of 1,4-disubstituted piperidin-4-o1 - Google Patents

Description

204530 describes the invention

REPUBLIC, 9> CERTIFICATE OF CERTIFICATE (11) (B,)

(61) (23) Show Priority (22) Registered 08 02 79 (21) (PV 891-79) (51) Int. Cl? OJ C 07 D 211/52

ÚftAD FOR INVENTIONS

& DISCOVERY (40) Posted on 31 07 80 (45) Published 29 10 82 (75)

Author of the invention RAJSNER MIROSLAV ing. CSc., PROTIVA MIROSLAV dr. DrSc.a DLABAC ANTONÍN MUDr. CSc., PRAGUE (54)

1,4-Disubstituted piperidin-4-ol esters

The invention relates to esters of 1,4-disubstituted-piperidin-4-ol of general formula 1

wherein R is alkyl of 1 to 9 carbon atoms or 3,4,5-trimethoxyphenyl, and salts thereof with pharmaceutically acceptable organic acids. The compounds of formula I are extremely long-acting antiemetic and antipsychotic agents. When used as a base, they are applied seintramuscularly in the form of solutions in plant oils or in miglyol artificial glyceride. Salts are administered orally. A particularly preferred compound of the invention is the decanoate of formula I wherein R = (CH2) KCHt. This highly lipophilic compound is highly soluble in said oils and is suitable for intramuscular administration as an extremely long-acting depot neuro-adhesive. Its solution in miglyol, containing 25 mgsubstance in 1 ml, was tested in dogs in which a standard dose of apomorphine was induced. The tested ester blocked the ability to induce an emetic response in dogs for a long time. Compared to the free alcohol of formula I where R = H, which is known as the long-acting neuroleptic preparation penfluridol (M. Rajshnerse sp., Collect. Czech. Chem. Commun. 43, 1760, 1978; J. Chem. Commun. 43, 1760, 1978; J. Metyš se sp., Activ. Nerv., 17, 219, 1975, used orally. In comparison with the decanoate, a solution of penfluridol in miglyol containing 25 mg of substance per ml was prepared.

Both penfluridoldecanoate and penfluridol were administered at a single intramuscular dose of 0.5 mg / kg to six-member groups of dogs, after which the standard dose of apomorphine was tested weekly. The effect was monitored for 10 weeks. Bázepenfluridol blocked 100% of the morphine response for the first three weeks, and less than 50% of the animals were present at week 5 and then recovered. After penfluridoldecanoate, 85% of the animals for the first time for two weeks (in 5 group 6 dogs) were blocked for the first time for 2 weeks. 100% blockade started at week 3 and 4 and 50% of the animals were prevented from apomorphine at week 7. Only in the 8th week did the percentage of protected animals fall below 50 and the effect of the 10th week passed away. The comparison showed that the effect of 204530 2 of penfluridoldecanoate develops more slowly than the free base, but lasts almost twice as long.

Thus, penfluridoldecanoate can be characterized as an extremely long-acting antiemetic because it is known that the results in the antiapo-morphine test in dogs are very well correlated with antipsychotic efficacy in schizophrenic patients.

The compounds of the invention, i.e., the esters of formula 1, are prepared from the alcohol of formula 1 wherein R = H, i.e., penfluridol (M. Rajshner et al., Already cited) by all conventional esterification procedures. For this purpose, the free acids of general formula II R-COOH (II) can be used, where R denotes the same as in formula I, or their reactive derivatives, namely chlorides, anhydrides and esters. When using the free acidic formula (II), esterification is carried out by acid catalysis or under azeotropic distillation conditions with benzene, toluene or xylene, by which the effluent is continuously removed by reaction. It is also possible to work under very mild conditions in the presence of scavenging agents, e.g. dicyclohexylcarbodiimide or carbonyldiimidazole. In the case of the use of lower acid esters of the formula II, it is carried out under the usual conditions for transesterification reactions. Very convenient is the use of the acid chlorides of formula (II) which react with penfluidol already at room temperature in an inert solvent, preferably in chloroform. This latter way is demonstrated in examples of implementation. The preparation of the acetate, decanoate and 3,4,5-trimethoxybenzoateupenfluridol has been shown to be of the invention.

The esters of general formula (I) are all oil-like compounds which can be isolated, purified and characterized by the formation of crystalline salts with some acids, and barium oxolates, which can also be used for oral administration, are particularly suitable. By decomposition of the pure oxalates by gentle alkylation, it is possible to obtain completely pure bases of the general formula I.

Further details of the preparation are apparent from the exemplary embodiments. Example 1 1- (4,4-Bis (4-fluorophenyl) butyl) -4-acetoxy-4- (4-chloro-3-trifluoromethylphenyl) piperidine To a solution of 26 g of 1- (4,4-bis (4- of fluorophenyl) butyl) -4- (4-chloro-3-trifluoromethylphenyl) piperidin-4-ol (base of penfluridol, M. Rajshner was added to a solution of 8.0 g of acetyl chloride in 30 ml of chloroform). 20 ml of chloroform and the mixture was allowed to stand at room temperature for 12 hours. The mixture was stirred with 100 ml of water for 1 hour, basified with sodium hydroxide solution and the chloroform layer was separated. Wash with water, dry over anhydrous potassium carbonate and evaporate under reduced pressure. The oily residue is dissolved in 40 ml of acetone, 6.0 g of oxalic acid dihydrate is added and dissolved by heating to 24 g of hydrogen genoxalate (74%) with a melting point of 175 to 178.5 ° C. The product is virtually pure since it does not increase further by further crystallization from acetone; The analytical preparation is 176-178 ° C. Example 2 1- (4,4-Bis (4-fluorophenyl) butyl) -4-decanoyl-4- (4-chloro-3-trifluoromethylphenyl) piperidine To a solution of 52 g of 1- (4,4-bis (4-fluorophenyl)) butyl 4- (4-chloro-3-trifluoromethylphenyl) piperidin-4-ol (base of penfluridol) in 80 ml of chloroform, a solution of 53 g of decanyl chloride is added with stirring (E. Fierz-David, W. Kuster, Chim.Acta 22, 82, 1939) in 40 ml of chloroform. After standing overnight, it was stirred with 400 ml of 4% sodium hydroxide solution for 3 hours. The chloroform solution was separated, washed with water, dried over anhydrous potassium carbonate and evaporated under reduced pressure. The oily residue was dissolved in 200 ml of acetone and the solution was neutralized by the addition of 13 g of oxalic acid dihydrate. A clear solution of hydrogen oxalate is formed with stirring. Most of the acetone was evaporated under reduced pressure, and a decimal amount of ether was added to the residue. Longer standing crystallizes 62 g (81%) of pure hydrogen oxalate, mp 126-128 ° C. The whole can be recrystallized by dissolving in 100 ml of acetone and adding 1.5 l of ether. 53 g of the desired solis are precipitated m.p. Mp 125-127 ° C. By decomposing the sodium hydrogen carbonate salt and extracting it with ether, it is possible to prepare a pure oily base which is suitable for preparing a solution in vegetable oils or in miglyol. Example 3 1- (4,4-Bis (4-fluorophenyl) butyl-4- (3,4,5-trimethoxybenzoyloxy) -4- (4-chloro-3-trifluoromethylphenyl) piperidine To a solution of 26 g l - [4,4-Bis (4-fluorophenyl) butyl] -4- (4-chloro-3-trifluoromethyl) piperidin-4-ol (base of penfluridol) in 30 ml of chloroform, a solution of 19 g of 3,4 is added by stirring. 5-trimethoxybenzoyl chloride (JT Marsh, H. Stephen, J. Chem. Soc. 127, 1635, 1925) in 50 ml of chloroform and left to stand overnight at room temperature. It is then stirred vigorously for 1 hour with a solution of 10 g of sodium hydroxide in 500 ml of water to quench the excess acid chloride. The chloroform solution is separated, washed with water, dried over potassium carbonate and the chloroform is evaporated off under reduced pressure. The oily residue is dissolved in 70 ml of acetone and the solution is neutralized by addition of 6.0 g of oxalic acid dihydrate. A warm solution is obtained which is partially evaporated and the residue is crystallized by addition of ether. In a yield of 25 g, the hydrogen oxalate of the product is obtained, which crystallizes as a monohydrate with m.p. 161-163 ° C. It can be recrystallized by dissolving it in triple ethanol and adding 20 times ether to the solution, i.e. it does not change by crystallization. 204530

Claims (1)

3 in which R is alkyl of 1 to 9 carbon atoms or 3,4,5-trimethoxyphenyl and salts thereof with pharmaceutically acceptable organic acids. SUMMARY OF THE INVENTION Esters of 1,4-disubstituted piperidin-4-olucco Formula I 3 N (I),. OCOR 204530