CS213852B1 - 2,8 - Dissolved 6-methylergoline-I derivatives - Google Patents

Abstract

The invention relates to 2,8-disubstituted derivatives of 6-methylergoline-I of the general formula in which R denotes a methyl group, a chloromethyl group, a methylsulfonyloxymethyl group, a p-tolylsulfonyloxymethyl group or a carbamoylmethyl group and R' denotes a 1,3-dithiolan-2-yl group, as well as their pharmaceutically acceptable salts and organic and inorganic acids. The derivatives of the said general formula are both anti-indication and anti-lactation active, and thus serve as important products for the synthesis of other biologically active ergoline derivatives.

Description

The invention relates to 2,8-disubstituted 6-ethylergoline-I derivatives of the general formula I,

N-cHs

Kterém wherein R represents methyl, chloromethyl, methylsulfonyloxymethyl, p-tolylsulfonyloxymethyl or kerbamoylmethyl and R 'denotes 1,3-dithiolan-2-yl, as well as pharmaceutically acceptable salts thereof and organic and inorganic acids such as, for example, sulfonic acid, , wine, sulfur, phosphoric, etc.

The compounds of formula (I) and their salts, which are novel, have shown an inhibitory effect on adenohypophyseal prolactin secretion in animal pharmacological evaluations, which has been demonstrated, for example, by antinidative and antilactic effects; moreover, they are important intermediates for the preparation of other biologically active ergelin derivatives.

Compounds of formula (I) wherein R is methyl, chloromethyl or kerbamoylmethyl and R ^ ·, 1,3-dithiolan-2-yl may be prepared from compounds of formula (I) wherein R is as defined above and R'is hydrogen; Crafts reaction using titanium tetrachloride, for example 3 to 8 mol equivalents, and 2-methoxy-1,3-dithiolane, for example 2 to 4 mol equivalents, prepared in situ from 1,2-ethanedithiol and formic acid methyl ester, in the environment an inert solvent, preferably in chloroform, at a temperature of from 0 ° C to 40 ° C, preferably at room temperature.

Compounds of formula I wherein R is p-tolylsulfonyloxymethyl or methylsulfonylosymethyl and R 1 is 1,3-dithiolan-2-yl are prepared by reducing compounds of formula I wherein R is alkoxycarbonyl (e.g. 2- ( (3'-Dithiolan-2-yl) -8-methoxycarbonyl-6-ethylergolin-I, prepared according to P. Stutz and PAStadler, Helv. Chim. Aca 85, 75, 1972) and R is as defined above. using metal hydrides such as sodium borohydride in methanol, or using lithium aluminum hydride in an inert solvent such as tetrahydrofuran or 1,4-dioxane, and the alcohol thus prepared is reacted with p-tolylsulfonyl chloride or methylsulfonyl chloride in pyridine.

Further details of the two processes for the preparation of the compounds of the formula I according to the invention are given in the following examples.

Example 1

2- (13'-Dithiolan-2'-yl) -6,8-dimethylergolin-1

To a solution of 1.75 g (7.2 mmol) of 6,8-dimethylergoline-I in 110 ml of anhydrous chloroform was added 37 ml of methyl formate, 1.34 g (14.5 mmol) of ethanethithiol and stirred at room temperature. a solution of 3.2 ml (29 mmol) of titanium tetrachloride in 30 ml of anhydrous chloroform is added dropwise. The reaction mixture was stirred for 24 h, then cooled to -5 ° C, added dropwise with 20 ml of methanol, and concentrated ammonium hydroxide solution was added until strongly alkaline. The mixture was poured into a saturated aqueous sodium bicarbonate solution and shaken three times with 100 ml of chloroform. The combined chloroform extracts were dried over sodium sulfate, concentrated in vacuo to a water pump vacuum, and the residue was chromatographed on a silica gel column using chloroform.

213 852% methanol. Subsequent crystallization from ethanol gave the pure product with m.p. Mp 213-216 ° C.

Analogously prepare:

8-chloromethyl-2-ZL, 3'-dithiolan-2'-yl] -6-methylergolin-1, m.p. 236-239 ° C;

2- (1 *, 3 * -dithiolan-2 * -yl) -8-kerbamoylmethyl-6-methylergolin-1, m.p. Mp 262-267 ° C.

Example 2

2- [1,3-Dithiolan-2'-yl] -6-methyl-8-p-tolylsulfonylffixylmethylergoline-1

To a suspension of 0.76 g (20 mmol) of lithium aluminum hydride in 100 ml of anhydrous tetrahydrofuran and a solution of 3.88 g (10 mmol) of 2- (1 *, 3 * -dithiolan-2 * -yl) -6-methyl-8- was added dropwise with stirring. of methoxycarbonylergoline-I in 100 mL of anhydrous tetrahydrofuran. The mixture was stirred at room temperature for 2 h and after cooling to 0 ° C, 1 ml of water, 1 ml of 4N sodium hydroxide and 3 ml of water were added successively. The reaction mixture is filtered, the precipitate is extracted with tetrahydrofuran, the filtrate combined with the extract and evaporated to dryness under a water pump vacuum. The residue was dissolved in anhydrous pyridine (100 mL), cooled to 0 ° C and p-tolylsulfonyl chloride (2.1 g, 11 mmol) was added with shaking. After formation of a clear solution, the reaction mixture is allowed to stand at room temperature for 48 h, then poured into 1.2 liters of ice-water, the precipitate is filtered off with suction, dried under vacuum at 25 ° C and chromatographed on a silica gel column using chloroform. 1% by volume of methanol was crystallized from 96% ethanol to give the pure product with m.p. Mp 167-171 ° C.

2- (1 *, 3 * -Dithiolan-2 * -yl) -6-methyl-8-methylsulfonyloxymethylergoline-1, m.p. Mp 112-116 ° C.

Claims (1)

2,8-Disubstituted 6-methylergoline-I derivatives of formula I wherein R is methyl, chloromethyl, upin, methylsulfonyloxymethyl, p-tolylsulfonyloxymethyl or carbamoylmethyl and R 'is 1,3-dithiolan-2-yl as well as their pharmaceutically acceptable salts Suitable salts with organic and inorganic acids.