CS268650B1 - Process for preparing new 4- (methylthiophenoxy) piperidines and their salts - Google Patents

Abstract

The solution falls into the field of drug synthesis. Its subject is a method for preparing new 4-(methylthiophenoxy)piperidines I and their salts, which consists in substitution reactions of fluorothioanisole II, where r2 is a methylthio group with 4-piperidinol III, where R is methyl, benzyl and R1 is hydrogen, phenyl in the presence of sodium hydride in dimethylformamide at temperatures of 70 to 130 °C and subsequent conversion of the obtained oily bases into crystalline salts by neutralization with pharmaceutically acceptable inorganic or organic acids. The substances according to the solution are intermediates in the preparation of pharmacodynamically active compounds; their salts themselves show properties in pharmacological studies indicating the possibility of their use in the treatment of mental depression.

Description

The invention relates to a process for the preparation of novel 4- (methylthiophenoxy) -piperidines of the general formula I, I (R ^).

N

I '

R

2 in which R is methyl or benzyl, R is hydrogen or phenyl and R is a methylthio group in position 2 or 4 of the benzene ring, and salts thereof, with pharmaceutically acceptable inorganic or organic acids.

The compounds of the formula I are intermediates in the synthesis of pharmacodynamically active compounds, while their salts themselves have properties indicating therapeutic efficacy in mental depression. This concerns mainly the efficacy in antireserpine assays in mice and in the yohimbine toxicity potentiation test in mice.

The individual substances according to the invention can be mentioned as follows (they have been tested by oral administration, administered in the form of salts and the stated doses are converted to bases);

4-Phenyl-1-methyl-4- (4-methylthio) phenoxy] piperidine was tested as hydrogen oxalate. In a mouse test of reserpine ptosis, it showed a statistically significant antagonism at a dose of 30 mg / kg. At a dose of 10 mg / kg, it antagonizes statistically significantly the hypothermic effect of reserpine in mice, the substance is also effective in the yohimbine toxicity potentiation test in mice) ED ₅₀ = 32.3 mg / kg.

1-Benzyl-4- (2- (methylthio) phenoxy) piperidine in 1 was tested as the hydrochloride id. In a mouse reserpine ptosis test, it showed statistically significant antagonism at a dose of 30 mg / kg.

1-Benzyl-4- (4- (methylthio) phenoxy) piperidine was tested as the hydrochloride. It antagonizes statistically significantly with reserpine ptosis in mice from a dose of 30 mg / kg. Shows effect in the test of potentiation of yohimbine toxicity on mice _5Q E0 = 63 mg / kg.

The process for the preparation of the compounds of the formula I according to the invention consists in the substitution reactions of fluorothioanisoles of the general formula II, ^F w. ² / A in which R is the same as in formula I, with 4-piperidinols of general formula III A OH 1 / (in) N

AND

R in which R and R ¹ denote the same as in formula I. These reactions take place in the presence of sodium hydride in dimethylformamide at temperatures of 70 to 120 ° C. The starting materials of formulas II and III have been described in the literature cited in the examples. Examples are given below

CS 268650 B1 details on the preparation of the compounds of formula I, but are only an illustration of the possibilities of the invention. The bases of the formula I obtained are neutralized with pharmaceutically acceptable inorganic or organic acids into the corresponding salts. All substances described in the invention are novel. Their identity was ensured by analytical and spectral methods.

Example i

1-Benzyl-4- (2- (methylthio) phenoxy) piperidine.

To a stirred solution of 5.75 g of 1-benzyl-4-piperidinol (U.S. Pat. No. 3,679,666) in 30 ml of dimethylformamide Ida was added 1.2 g of 80% sodium hydride (suspension in mineral oil) under a nitrogen atmosphere, and the mixture was stirred. 20 min at room temperature. 4.3 g of 2-fluorothioanisole (Yoder C.H. et al., O.Org. Chew. 41, 1511 (1976)) are then added and the mixture is heated at 100 DEG C. for 5 h with stirring. After cooling, the ee is diluted with water and extracted with ether. From the ether solution, the base is transferred by shaking to 100 ml of 3 M HCl, the separated acidic aqueous solution is basified with 20% sodium hydroxide solution and the base is re-extracted with ether. The extract was dried over anhydrous potassium carbonate and evaporated. 6.8 g (72%) of an oily base are obtained. This is dissolved in ether and the solution is neutralized with ethereal hydrogen chloride. The hydrochloride is obtained, which crystallizes from a mixture of ethanol and ether and melts at 189-197 ° C.

Example 2

1-Benzyl-4- (4-methylthio) phenoxy) piperidine.

As in the previous example, to a solution of 5.75 g of 1-benzyl-4-piperidinol in 30 ml of dimethylformamide was added 1.2 g of 80% sodium hydride and after 30 min. stirring 4.3 g of 4-fluorothloan isol (Zahn H., Zuber H., Chem. Ber. 86, 172 (1953)). The mixture is heated at 100 DEG C. for 6.5 h and worked up analogously to the previous example. 5.6 g (62%) of an oily base are obtained, which gives a crystalline hydrochloride, m.p. 198-203 ° C (ethanol).

Example 3.

4-Phenyl-1- (methyl-4- (4- (methylthio) phenoxy) piperidine).

similarly to the previous examples ae, 5.75 g of 4-phenyl-1-methyl-4-piperidinol are reacted (McElvain SM, Safranski JC, 3r., J.Am.chem.Soc. 72, 3134 (1950)) in 30 ml of dimethylformamide 1.2 g of 80% sodium hydride and 4.5 g of 4-fluorothioanisole (7 h at 120-130 ° C). Workup gave 3.4 g (36%) of an oily base which was crystallized by oxalic acid dihydrate to give crystalline hydrogen oxalate melting at 201-202 ° C (ethanol-acetone).

Claims (1)

OBJECT OF THE INVENTION Process for the preparation of novel 4- (methylthiophenoxy) piperidines of general formula I wherein R is methyl or benzyl, R ¹ is hydrogen or phenyl and R ² is methylthio in position 2 or 4 of the benzene ring, and salts thereof, characterized in that the fluorothioanisoles of formula ΐϊ, CS 268650 Bl o in which R represents the same as in formula I, is subjected to substitution reactions with 4-piperidinols of general formula III, (III) in which R and R ¹ denote the same as in formula I, in the presence of sodium hydride in dimethylformamide at temperatures of 70 to 130 ° C. The oily bases obtained are then converted into crystalline salts by neutralization with pharmaceutically acceptable inorganic or organic acids.