CS217941B1 - Process for the preparation of 1- (D-6-methyl-8 and -ergolinyl) -3,3-diethylurea - Google Patents

Abstract

The invention relates to a new process for the production of significantly prolactin-inhibitingly active 1-(D-6-methyl-8alpha-ergolinyl)-3,3-diethylurea of formula I consisting in the condensation of D-6-methyl-8alpha-aminoergoline with diethylcarbamoyl chloride in the presence of a base.

Description

The present invention relates to a novel process for the preparation of a significantly prolactininhibitively active 1- (D-6-methyl-8alpha-ergolinyl) -3,3-diethylurea of the formula I

comprising condensing D-6-methyl-8alpha-aminoergoline with diethylcarbamoyl chloride in the presence of a base.

SUMMARY OF THE INVENTION The present invention provides a new economically advantageous process for the preparation of 1- (D-6-methyl-8alpha-ergolinyl) -3,3-diethylurea of the formula I

H,

N — CH ₃ h (I)

HN and its hydrogen maleate.

The substituted urea of formula I exhibits a significant inhibitory effect on prolactin and growth hormone secretion in animals and a gonadotropin secretion stimulating effect; its toxicity is significantly lower compared to the clinically used 1- (D-6-methyl-9,10-didehydro-8alpha-ergolinyl) -3,3-diethylurea (lisuride). Therapeutically, urea of formula I can be used wherever it is desirable to reduce secretion of prolactin or growth hormone, or to increase secretion of gonadotropins, for example, in human therapy for postpartum lactation , prostate hypertrophy, Parkinson's disease and other diseases, or in veterinary therapy to arrest lactation and heat-up in farm animals.

The compound of formula I and some methods for its preparation are known. According to the Czechoslovakian author's certificate No. 152 153 it can be produced by catalytic hydrogenation of lisuride in the presence of Raney nickel as a catalyst; The disadvantage of this process is that the corresponding 8beta-isomer is formed simultaneously with the compound of formula I and the mixture of isomers obtained must be separated by column chromatography.

In another method, the reduction of the lisuride double bond at the 9,10 position is carried out with alkali metals in liquid ammonia and in the presence of arylamines; this method does not produce the corresponding .beta.-isomer, but work in liquid ammonia is very technologically demanding. Subsequently, according to the Czechoslovak author's certificate No. 156 178, the urea of the formula I can be produced from the azide D-9,1O-dihydroisolysergic-I via the appropriate isocyanate; The disadvantage of this method is the simultaneous formation of further balastrations of substances which must be removed by column chromatography. The present inventors have now found that urea of the formula I can be prepared in high yield and good purity from readily accessible D-6-methyl-8alpha-aminoergoline.

According to the invention, 1- (D-6-methyl-8alpha-ergolinyl) -3,3-diethylurea of the above formula (I) can be produced by the process of D-6-methyl-8alpha-aminoergoline of formula II

H.

NH ₂

N — CH ₃ Ή (II)

HN reacts with the Ν, Ν-diethylcarbamoyl chloride of formula III

Cl-CO-N '(III)

in an inert solvent, and in the presence of a base for binding the resulting hydrogen chloride, and the base of the formula I obtained is optionally converted into a suitable addition salt with an organic or inorganic acid, preferably maleic acid.

The inert solvent used in the above reaction may be aromatic hydrocarbons such as benzene, toluene or xylene, chlorinated hydrocarbons such as methylene chloride, chloroform or 1,1,2,2-tetrachloroethane, or dipolar aprotic solvents such as dimethylformamide or dimethyl sulfoxide.

Either inorganic bases, such as alkali metal carbonates and bicarbonates, or organic bases, preferably tertiary amines, such as pyridine or triethylamine, can be used to bind hydrogen chloride.

The reaction can be carried out in a temperature range of -10 to +100 ° C, depending on the nature of the solvent used, preferably in an inert gas atmosphere such as nitrogen.

the desired product can be isolated from the reaction mixture by conventional means, for example by column chromatography and / or crystallization.

The starting D-6-methyl-8alpha-aminoergoline of formula III can be prepared in a known manner from the hydrazine of D-dihydroisolysergic acid-I (see A. Hofmann, Helv. Chim. Acta 30, 44 (1946)).

Further details of the process according to the invention will be apparent from the following non-limiting examples.

He did

Hydrogenmaleinam 1- (D-6-methyl-8alpha-ergolinyl) -3,3-diethylurea

To a solution of 2.41 g (10 mmol) of D-6-methyl-8alpha-aminoergoline in 12 ml of dimethylformamide was added 1.11 g (11 mmol) of triethylamine and then stirred and cooled at 0 to +4 ° C. , 1.49 g (11 mmol) of Ν, Ν-diethylcarbamoyl chloride was added dropwise. The reaction mixture was stirred at this temperature for 1 hour, then allowed to stand overnight at room temperature and poured into 60 ml of ice water. The aqueous mixture was basified with ammonia to pH about 7.5, the precipitate was filtered off and the crude product (2.9 g, yield 85%) was recrystallized from ethanol. 202 DEG-204 DEG C. and optical rotation [.alpha.] D @ 20 = + 29 DEG (c = 0.45, pyridine). Hydrogenmaleinam base I is prepared from an equimolar amount of both components in ethanol; mp 190-191 ° C (dec.);

Example 2

1- (D-6-Methyl-8α-ergolinyl) -3,3-diethylurea

To a slightly boiling solution of 0.48 g (2 mmol) of D-6-methyl-8alpha-aminoergoline in 50 ml of benzene was added, under a nitrogen atmosphere, a solution of 0.22 g (2.2 mmol) of triethylamine in 5 ml of benzene and then A solution of 0.30 g (2.2 mmol) of Ν, Ν-diethylcarbamoyl chloride in 5 ml of benzene was added dropwise. The reaction mixture was heated at reflux for 2 h, then the solvent was distilled off under reduced pressure, the residue was taken up in chloroform / benzene (2: 1) and the solution was chromatographed on a short silica gel column using the same solvent mixture as the eluent. From the combined fractions containing the desired product, the solvents were distilled off under reduced pressure, and the residue (0.27 g) was recrystallized from ethanol. The title compound was obtained with the same physicochemical constants as in Example 1.

Claims (3)

Process for the preparation of 1- (D-6-methyl-8alpha-ergolinyl) -3,3-diethylurea of the formula I JVHCON H (C ₂ H ₅₎ 2 (I) and its hydrogenmaleinanu, characterized in that D-6-methyl-8.alpha.-aminoergolin II N - CH, (II) reacts with Ν, Ν-diatylcarbamoyl chloride of formula III ' ^C 2 ^H 5 Cl-CO-N (III) ^C 2 ^H 5 in an inert solvent and in the presence of a base to bind the resulting hydrogen chloride, and optionally recovered urea of formula I is converted to a maleic acid addition salt. 2. The process according to claim 1, wherein the inert solvent is an aromatic hydrocarbon such as benzene, toluene or xylene, a chlorinated hydrocarbon such as methylene chloride, chloroform or 1,1,2,2-tetrachloroethane, or dipolar aprotic solvents, as dimethylformamide or dimethylsulfoxide. The process according to claim 1, characterized in that the base used for binding the hydrogen chloride is an inorganic base, such as an alkali metal carbonate or bicarbonate, or an organic base, preferably a tertiary amine, such as pyridine or triethylamine.