CS220139B1 - Amide of d-6-methyl-8beta-ergolin-1-yl propionic acid - Google Patents

Abstract

The invention relates to an amide, D.-6-methyl-8 (3-ergolin-1-ylpropionic acid) general pharmaceutically acceptable salts thereof with inorganic salts and organic acids. The amide of formula I is prepared from D-6-methyl-8, 3- (2-cyanoethyl) ergoline-I through free acid and its hydrazide method azide or directly hydrated corresponding nitrile under ionic extraction conditions couples. The amide of formula I significantly inhibits adenohypophyseal secretion depression.

Description

The present invention relates to a D-6-methyl-8/3-ergolin-1-ylpropionic acid amide of the formula I

its pharmaceutically acceptable salts with inorganic and organic acids.

The acid amide of formula (I) showed an inhibitory effect on adenohypophyseal prolactin secretion in experimental animals (Wistar Konarovice rats) in a biological evaluation. This effect is manifested in the target effect by, for example, antilactant and antinidative effects. Certain evaluation methodology for antinidative and antilactic effects has been previously described [see, eg, Černý A. et al .: Coll. Czechoslov. Chem. Commun. 41, 1042 (1976) and Aušková M. et al., Arzneim-Forsch. 23, 617 (1973)].

According to the invention, the D-6-methyl-8 (3-ergolin-1-yl-propionic acid amide of the formula I is prepared by hydrolyzing the corresponding nitrile of said acid, preferably by boiling with an aqueous methanolic or aqueous ethanolic potassium hydroxide solution to the corresponding carboxylic acid. and the acid or potassium salt thereof is converted to the corresponding acid methyl ester by boiling with methanolic hydrogen chloride and converted to the corresponding acid hydrazide by treatment with hydrazine hydrate, the hydrazide thus obtained is converted to the corresponding azide and treated with concentrated ammonia solution. the desired D-6-methyl-8/3-ergolin-1-ylpropionic acid amide of formula (I).

The D-6-methyl-8-benzolin-1-yl-propionic acid amide of the formula I can also be prepared from the corresponding nitrile of said acid by treatment with 2 to 20 mol equivalents of quaternary ammonium and quaternary ammonium, respectively. phosphonium base, in a mixture of pyridine with 10 to 50% water by volume at a temperature ranging from 20 ° C to the boiling point of the reaction mixture. D-6-methyl-8S-ergolin-1-yl-propionic acid nitrile is prepared according to our PV 7873-81.

Of the pharmaceutically acceptable salts of the compound of formula (I), normal tartrate is particularly preferred.

Further details of the preparation of the compounds of formula I will be apparent from the following non-limiting examples.

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Example 1!

D-6-Methyl-8 (3-ergolin-1-yl-propionic acid methyl ester)

A mixture of 2.79 g (0.01 mmol) of D-6-methyl-8 / 3- (2-cyanoethyl )ergoline-I, 10 g (0.18 mol) of potassium hydroxide, 44 ml of ethanol and 11 ml of water is refluxed under an atmosphere. After standing for 20 hours at 5 DEG C., the precipitated potassium salt of D-6-methyl-8/3-ergolin-1-ylpropionic acid is filtered off with suction, washed with ethanol and, after drying, suspended in 50 ml of methanol containing 2 g of hydrogen chloride. The mixture is then refluxed for 2 hours under nitrogen, evaporated to dryness in vacuo, the residue is dissolved in 300 ml of water, the solution is saturated with aqueous sodium carbonate solution and the precipitated product is filtered off with suction, washed with water and dried at 50 [ ^deg . in benzene system with 10% methanol and purified by crystallization from acetone: mp 191-192 ° C, [α] _D ^{20 -} 98.3 ° (c 0.2, pyridine).

D-6-methyl-8/3-ergolin-1-yl-propionic acid hydrazide

A mixture of 3.12 g (0.01 mmol) of methyl D-methyl-η 4 -ergolin-1-ylpropionate and 44 ml of 100% hydrazine hydrate is refluxed under a nitrogen atmosphere for 3 hours. It was washed with water and after drying purified by crystallization from a mixture of pyridine, ethanol and water: mp 176-177 ° C, [α] _D ²⁰ -95.0 ° (c 0.2, pyridine).

Example 3

D-6-methyl-8,3-ergolin-1-yl-propionic acid amide

(a) To a solution of D-6-methyl-8/3-ergolin-1-yl-propionic acid hydrazide (1.6 g, 5.1 mmol) in a mixture of 15 ml of dimethylformamide and 15 ml of glacial acetic acid are stirred and cooled to 0 ° 5.1 ml of 1N sodium nitrite solution was added dropwise. After standing at 0 ° C for 15 minutes, the mixture was poured into 500 mL of water and basified with solid sodium carbonate. The precipitated azide base is filtered off with suction and, after drying, stirred in an excess of concentrated aqueous ammonia solution. After standing at room temperature for 20 hours, the amide formed is washed with water and, after drying, purified by chromatography on a silica gel column using benzene / 20% ethanol and purified by crystallization from a mixture of ethanol, pyridine and water; mp 222-223 ° C, [α] _D ²⁰ -92.7 '(c 0.2, pyridine).

b) To a solution of 1.12 g (4 mmol) of D-6-methyl-8 (3- (2-cyanethyl) ergolin-I) in 52 ml of pyridine was added 11.8 g (55 mmol) of tetraethylammonium bromide and a solution of 3.08 g (55 mmol) of potassium hydroxide in 26 ml of water and the reaction mixture is refluxed under a nitrogen atmosphere for 7 hours, cooled, diluted with 40 ml of water, shaken with 10 ml of chloroform, evaporated to dryness and dissolved in benzene / 20%. The residue was purified by chromatography on a silica gel column and crystallized from ethanol / pyridine / water to give the product as described above.

c) Normal D-6-methyl-η-bergolin-1-ylpropionic amide tartrate was prepared using 2 mol equivalents of base and 1 mol equivalent of tartaric acid in ethanol; mp 204-206 ° C, [a] _D ²⁰ -46.2 ° (c 0.5, water).

Claims (1)

OBJECT OF THE INVENTION D-6-methyl-8 (3-ergolin-1-yl-propionic acid amide of the formula I) and pharmaceutically acceptable salts thereof with inorganic and organic acids.