CS196615B1 - Esters of n-/d-6-methyl-8-ergoline-i-yl-methyl/-carbamic acid and method for the production thereof - Google Patents

Description

The present invention relates to N- (D-6-methyl-8-ergolin-1-ylmethyl) carbamic esters of the general formula I

wherein R is straight or branched (C 1 -C 4) alkyl, (C 4 -C 8) cycloalkyl, 2-hydroxyethyl-, 2-methoxyethyl-, 2- (N-piperidino) ethyl-, allyl- or propargyl, their pharmaceutically acceptable of harmless salts with organic or inorganic acids and processes for their preparation.

Esters of formula (I) showed a significant inhibitory effect on biosynthesis and biosynthesis, respectively. secretion of adenohypophyseal prlactin in experimental animals (Wistar rats), which in the end resulted in, for example, anti-lactation and antinidation effects. Thereafter, the effect is exerted at a single dose of 0.06 to 0.1 mg of substance / animal (about 200 g), administered orally in the form of an aqueous solution of tartrate base, on the 5th day after animal copulation, for ethyl, allyl and N- (D-6-methyl-8-ergolin-1-ylmethyl) carbamic acid propargyl ester with 100% efficiency. The ethyl ester of this acid also induced a marked manifestation in rats suggesting stimulation of pituitary gonadotropin secretion, as demonstrated by a 10-day continuous administration of a daily dose of 0.1 mg and 0.1 mg, respectively. 0.02 mg substance / animal administered as an aqueous tartrate base solution.

Other esters of formula (I) exhibited a similar antlnidizing and stimulating effect at doses of 0.1 to 1.0 mg / animal.

According to the invention, esters of formula I are prepared by reacting N- (D-6-methyl-8-ergolin-1-ylmethyl) isocyanate with an alcohol of formula II

HO - R (II), in which R stands for the same as in Formula I, in an inert organic solvent of the aromatic type. or a halogenated hydrocarbon, preferably benzene, at temperatures from 20 ° C to the boiling point of the reaction mixture, in an atmosphere of a non-oxidizing gas, preferably nitrogen, whereupon the reaction products obtained in the form of bases are neutralized with organic or inorganic acids. salts.

The starting N- (D-6-methyl-8-ergolin-1-ylmethyl) isocyanate is preferably prepared by thermal degradation of the relatively stable N-O-methyl-8-ergolin-1-ylacetic acid azide, which is readily accessible as a base. or hydrochloride (M, Semonsky, N. Kucharczyk, Coli. Czechoslovak. Chem. Commun. 33, 577, 1968).

The thermal degradation of the D-6-methyl-8-ergolin-1-ylacetic acid azide base is carried out at 70 to 80 ° C in an inert solvent such as benzene, chlorobenzene, dimethylformamide and the like, preferably benzene at the boiling point of the reaction mixture. since the isocyanate formed is relatively well soluble in this solvent. The reaction is carried out for a period of 10 min to 1 h and is expediently carried out with the exclusion of atmospheric moisture and in a nitrogen atmosphere.

The reaction of the resulting isocyanate with the corresponding alcohols of the formula II is carried out. The reaction is carried out using at least 1 mol equivalent of this alcohol, preferably using an excess thereof, preferably in benzene, at the boiling point of the reaction mixture, for 1 to 24 hours. Upon completion, the reaction mixture is worked up by any of the usual methods, for example by distilling off the volatiles and purifying the crude product residue by silica gel column chromatography and crystallization of the combined uniform fractions from a suitable solvent or solvent mixture. ·

The alcohols of formula II are known and readily accessible.

The N- (D-6-methyl-8-ergolin-1-ylmethyl) carbamic acid esters of formula (I) are obtained in the form of bases which can be converted into pharmaceutically acceptable salts by reaction with organic or inorganic acids, preferably in lower alkanols, e.g. methanol or ethanol. Suitable inorganic acids are, for example, sulfuric or hydrochloric acid, and organic acids, for example, tartaric, maleic, methane and ethanesulfonic acids. Tartaric acid is a particularly suitable acid suitable for pharmacological purposes.

In the examples, the specific rotation values indicated were determined in pyridine and refer to solvent-free substances: temperature values are expressed in degrees Celsius.

Examples

Example 1

Cyclopentyl ester

N- (D-7-methyl-8-ergolin-1-ylmethyl) carbamic acid

A suspension of 618 mg (2 mmol) of D-6-methyl-8-ergolin-1-ylacetic acid azide base in 150 mL of benzene was refluxed for 20 min under nitrogen atmosphere, excluding air humidity. After cooling to temperature. 20 ml of cyclopentanol was added to the reaction mixture at 20-25 ° C, the mixture was refluxed for 1 h and then allowed to stand at 20-25 ° C for 2 h. After distilling off the volatiles in a water pump vacuum, the residue was chromatographed on a silica gel column using benzene + 3% methanol. Combined uniform fractions after crystallization from chloroform-hexane (1: 3) gave the product mp 146-148 ° C; [.alpha.] D @ ²⁰ = -75.8 DEG C. (c = 0.343). Reaction of the base with an equivalent of tartaric acid gave the normal tartrate with 1.1. about 165 ° C (with decomposition) and similarly methanesulfonate with mp about 190 ^and C) with decomposition).

The following N- (D-6-methyl-8-ergolin-1-ylmethyl) carbamic esters were prepared in an analogous manner:

methyl ester: mp 163-165 ° C (benzene);

[α] ²⁰ D, -90.0 ° C (c = 0.320).

ethyl ester: mp 186-188 ° C (benzene-hexane); (a) ²⁰ °, -88.0 ° C (c = 0.366).

propyl ester: mp 193-195 ° C (methanol);

(a) ² %, -83.7 ° C (c = 0.396).

n-butyl ester: mp 155-157 ° C (ethanol-benzene-hexane);

(a) ² %, -78.2 ° C (c = 0.400).

Isobutyl ester: mp 140-142 ° C (chloroform-hexane);

[α] ²⁰ D, -79.2 ° C (c = 0.410). .

allyester: mp 182-184 ° C (ethanol-benzene);

(a) ² %, -81.9 ° C (c = 0.360). propargyl ester: mp 184-186 ° C (methanol-benzene):

(«)’%, -82.5 ° C (c = 0.346). 2-methoxyethyl ester: mp 157-159 ° C (acetone-hexane);

(a) ² %, -76.5 ° C (c = 0.350). 2- (N-piperidino) ethyl ester: mp 154-156 ° C (chloroform-hexane):

[α] ²⁰ D, -71.4 ° C (c = 0.333).

Example 2

2-Hydroxyethyl acid ester

N- (D-6-methyl-8-ergolin-1-ylmethyl) carbamic acid

A suspension of 2474.4 mg (8 mmol) of D-6-methyl-8-ergolin-1-ylacetic acid azide base in 600 ml of benzene was converted to the isocyanate as described in Example 1. To the isocyanate solution at 20-25 ° C was added 30 ml of ethylene glycol, the reaction mixture was refluxed for 1 hour and allowed to stand for 20 hours at room temperature (20-25 ° C). at 5 ° C, aspirated, washed with 200 ml of water and dried. Chromatography on a silica gel column using benzene + 10% methanol and the combined combined fractions gave the product (yield 2.3 g, 83.8%) which, after crystallization from benzene-methanol (2: 1), had a mp of 190; up to 192 ° C; [α] ²⁰ D = -84.1 ° C (c = 0.392).

Claims (2)

N- (D-6-methyl-8-ergolin-1-ylmethyl) carbamic acid esters of the general formula I in which R represents straight or branched alkyl having 1 to 4 carbon atoms, cycloalkyl having 4 to 8 carbon atoms, 2- hydroxyethyl, 2-methoxyethyl, 2- (N-piperidino) ethyl, allyl or propargyl, and their pharmaceutically acceptable salts with organic or inorganic acids. VYNALEZU A process for the preparation of N- (D-6-methyl-8-ergolin-1-ylmethyl) carbamic acid esters of the general formula I, in which R is as defined above, and their pharmaceutically acceptable salts with organic or inorganic acids, according to The composition of claim 1, wherein the N- (D-6-methyl-8-ergolin-1-ylmethyl) isocyanate is reacted with an alcohol of formula II. HO-R (II), in which R is the same as in Formula I, in an inert inert solvent such as an aromatic or halogenated hydrocarbon, preferably benzene, at temperatures from 20 ° C to the boiling point of the reaction mixture, in a non-oxidizing gas atmosphere, preferably nitrogen, after which the reaction products obtained in the form of bases are converted by neutralization with organic or inorganic acids into the corresponding salts.