CS250596B1 - 1-(1-alkyl-8 alpha-ergolinyl)-3,3-diethylureas and method of their production - Google Patents

Description

1- (1-Alkyl-5a-ergolinyl) -3,3-ethylurea of formula I

Hí:>'' ⁷⁷ X ⁷ '' ý. 'Ϊ-, Κ fj í' T '' i '''s .✓. i π

? - ~ h ...... ' _z . \ (, i) in which

R is a C 1 -C 4 alkyl group, are dopamine agonists with dopamine antagonist effects in some parts of the CNS and can be used to treat hyperprolactinemia, acromegalia and parkinsonism.

They are prepared by demethylation of 1- (1-alkyl-6-methyl-8'-allergolinyl) -3,3-diethylmercuric cyanogen bromide and cleavage of the cyano group from the intermediate 6-cyander derivatives.

The invention relates to 1- (1-alkyl-8α-ergolinyl) -3,3-diethylureas of the formula I

in which

R represents a C 1 -C 4 alkyl group and a process for their preparation.

The term (C 1 -C 4) -alkyl denotes methyl, ethyl, n-propyl, n-butyl, isopropyl, isobutyl or sec-butyl.

Some similar, 6-position alkylated 1- (1-alkyl-8α-ergolinyl) -3,3-diethylureas are known to have dopaminergic activity, for example having a significant inhibitory effect on prolactin secretion (Cs. Certificate 231214). Some ergoline derivatives unsubstituted at the 6-position, such as 6-norlysergic acid methyl ester and 6-nor-9,10-dihydrolysergic acid, were prepared by applying von Braun's cyanogen bromide (Fehr T. et al., Helv. Chim. Acta 53, 2197). 1970). In the group of ergolinylureas, this method was used in MS. 232 301 and 232 303.

The 1-alkylated 8α-ergolinylureas of the formula I contain three chiral centers in the 5,8 and 10-positions in the molecule, the spatial arrangement of which is the same as that of 9,10-dihydroisolysergic acid-I: the hydrogen on the 5-position has a 3 'configuration (5R), the urea residue on carbon at the 8-position has the α (8S) configuration and hydrogen on the carbon at the 10-position has the α (10R) configuration.

According to the invention, 1- (1-alkyl-8α-ergolinyl) -3,3-diethylureas of the formula I can be prepared by the method of 1- (1-alkyl-6-methyl-8α-ergolinyl) -3,3-diethylurea of formula II

* K in which

R is as defined above, converted by treatment with cyanogen bromide to the 6-cyanergolinylureas of formula III

in which

R is as defined above, and from the compounds of formula III, a cyano group is reduced or hydrolytically cleaved to give 1- (1-alkyl-8α-ergolinyl) -3,3-diethylureas of formula I.

The demethylation according to the invention is carried out by treating excess solution of the cyanogen bromide with a solution of the ergolinylurea of the formula II in a suitable inert solvent at a temperature of from 0 to 100 ° C. As an inert solvent, halogenated aliphatic solvents such as dichloromethane, chloroform or carbon tetrachloride can be advantageously used. The reaction proceeds from several hours (heating to boiling in carbon tetrachloride) to several days (when carrying out the reaction at room temperature or at lower temperatures). The resulting 6-cyander derivatives of the formula III are neutral substances which can be easily separated from the starting basic compounds of the formula II by extraction with aqueous acid solutions and / or by column chromatography and crystallization.

The cleavage of the cyano group from the compounds of formula III can be carried out by reduction or hydrolysis methods. Reductive cleavage is carried out, for example, by zinc in acetic acid at boiling, or by treatment with alkali metals in hexamethylphosphoric triamide or hydrogenolytically in a suitable inert medium, such as dimethylformamide, in the presence of a catalyst such as Raney nickel. at 60 ° C.

The hydrolysis of the cyano group is carried out by treatment with an aqueous-alcoholic solution of alkali metal and alkaline earth metal hydroxides at elevated temperature, preferably at the boiling point of the reaction mixture, for 2 to 8 h. The alkali metal hydroxide is preferably sodium or potassium hydroxide, preferably solution in 20 to 80% (v / v) of an aqueous lower aliphatic alcohol such as methanol, ethanol or propanol at a concentration of 20 to 40% (w / v). Compared to reduction procedures, hydrolytic cleavage of the cyano group provides higher yields of the desired product.

The starting compounds of formula (II) are known compounds described in U.S. Pat. certificate.

The ergolinylureas of the formula I are colorless crystalline substances of basic nature which are isolated from the reaction mixture by conventional means, preferably by extraction, column chromatography and / or crystallization. With strong inorganic and organic acids, the compounds of formula I provide addition salts. For therapeutic purposes, water-soluble salts with pharmaceutically acceptable non-toxic acids such as hydrochloric, sulfuric, phosphoric, methanesulfonic, ethanesulfonic, maleic, malic, tartaric, citric and the like are suitable. Said salts may be prepared by treating at least 1 mole equivalent of acid per mole equivalent of a compound of formula I in a suitable inert solvent, preferably methanol, ethanol, acetone, water, or mixtures thereof.

The compounds of formula (I) are dopamine agonists with dopamine antagonistic effects in some parts of the CNS. Their dopaminergic effect is manifested both by inducing rotational movements in rats with unilateral damage to nigrostiatal structures and by inhibiting prolactin secretion and increasing secretion of gonadotropins, and can therefore be used in human and veterinary therapy for the treatment of parkinsonism, hyperprolactinemia and acromegaly, or induction female. For example, 1- (1-propyl-8 ' -ergolinyl) -3,3-diethylurea induces 0.5 mg / kg s. C. Contralateral rotation in rats with unilateral lesion of nigrostriatal pathways with 6-hydroxydopamine. This effect suggests a direct agonist effect on dopamine receptors, especially in the striatum. If the substance is administered prior to apomorphine in this test, potency is potentiated. The substance does not affect the body temperature of mice up to 1 mg / kg and this dose also does not affect apomorphine-induced hypothermia. In contrast, clonidine-induced hypothermia occurred after this dose. Thus, the substance has dopaminergic effects, but does not affect all structures where the dopamine system is applied. In addition, it affects adrenergic receptors.

The process for preparing 1- (1-alkyl-8α-ergolinyl) -3,3-diethylureas is illustrated by the following non-limiting Examples. The melting points of the compounds are determined on the Kofler block and are not corrected. Specific rotation values refer to crystal-free substances.

Example 1

1- (6-Cyano-1-methyl-8α-ergolinyl) -3,3-diethylurea

To a solution of 3.0 g (8.5 mmol) of 1- (1,6-dimethyl-8α-ergolinyl) -3,3-diethylurea in 170 ml of dichloromethane is added a solution of 2.1 with stirring at 20 to 23 ^° C. g (20 millimoles) of cyanogen bromide in 12 ml of dichloromethane and left to stand at room temperature in the dark for 4 days, extracted with 10% w / v aqueous tartaric acid, washed with dilute ammonia (9: 1) and water The crude product (2.7 gj was chromatographed on a silica gel column using toluene / acetone / conc. aqueous ammonia 50/30) to give the crude product.

: 0.3 to elute the substances. From the combined unitary fractions gave the title compound (1.97 g, yield 63.7%) which, after překrystallzování from acetone / hexane melts at 100-105 ° C and an optical rotation [ «] ^D20 - -99 4 ° (c = 0.2, pyridine). Example 2

1- (6-Cyano-1-ethyl-8H-ergolinyl) -3,3-diethylurea

A solution of 369 mg (1 mmol) of 1- (1-ethyl-6-methyl-8α-ergolinyl) -3,3-diethylurea in 25 ml of carbon tetrachloride was added dropwise over 1 hour to a boiling solution of 440 mg (4.15 mmol) of BrCN in 25 ml CCl 4. The reaction mixture was then refluxed for a further 3 hours, then cooled to room temperature and shaken with 30 ml of a 1% aqueous tartaric acid solution. The organic layer was separated, the solvent was distilled off under a water pump vacuum, and the residue was dissolved in dichloromethane (25 ml). This solution is shaken twice with 30 ml of a 1% aqueous tartaric acid solution, dried over sodium sulfate and the volatiles are evaporated off under a water pump vacuum. The residue is chromatographed on a silica gel column using chloroform with 2% methanol to elute the substances, the homogeneous fractions are combined, the volatiles are evaporated under a water pump vacuum and the residue is crystallized from acetone / hexane. Mp 162 DEG -163 DEG C., [ _.alpha. ] _D @ ²⁰ = + 122.2 DEG (c = 0.2, chloroform).

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Example 3

1- (6-Cyano-1-propyl-8α-ergolinyl) -3,3-diethylurea

In the same manner as in Example 2, but using l- (6-methyl-propyl-8of ergolinylj-3,3-diethylurea as a starting material to afford the title compound mp 148-150 BC [ce] _D ²⁰ = + 110.0 ° (c = 0.2, chloroform).

Example%

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

To 45 mL of a 30% (w / v) solution of potassium hydroxide in 50% (v / v) aqueous ethanol was added 1.85 g (5.06 mmol) of 1- (6-cyano-1-methyl-8α-) with stirring. ergolinyl) -3,3-diethylurea and the mixture is heated under reflux for 4 h. After cooling to room temperature, the precipitated ethanol layer was separated, the aqueous layer was extracted with chloroform, the combined organics were washed with water, dried over sodium sulfate and the solvents were distilled off under reduced pressure. The crude product is chromatographed on a silica gel column using chloroform / ethanol 9/1 to elute the compounds. Solvents were distilled off from the combined unitary fractions and the evaporation residue (1.36 g, 79.1% yield) was recrystallized from acetone. Mp 172-174 ° C; [α] _D ²⁰ = + 68.9 ° (c = 0.2, pyridine).

Example 5

In the same manner as in Example 4, but using 1- (6-cyano-1-ethyl-8of-ergolinyl) -3,3-diethylurea, respectively. 1- (6-Cyano-1-propyl-8α-ergolinyl) -3,3-diethylurea starting materials were obtained from:

1- (1-ethyl-8α-ergolinyl) -3,3-diethylurea, mp 148-152%, [α] _D ²⁰ = +33.4 ° (c = 0.2, chloroform);

1- (1-propyl-8'-allergolinyl) -3,3-diethylurea, mp 121-123%, [ _.alpha. ] _D @ ²⁰ = + 35.3 DEG (c = 0.2, chloroform).

SUBJECT

1- (1-Alkyl-8α-ergolinyl) -3,3-diethylureas of formula I

Claims (4)

in which R is as defined above by the action of cyanogen bromide to give 6-cyanergolinylureas of the formula III in which: R is C 1 -C 4 alkyl. 2. A process for the preparation of 1- (1-alkyl-8.alpha.-ergolinyl) -3,3-diethylureas having the general formula (1) according to claim 1, characterized in that 1- (1-alkyl-6-methyl-8.alpha.-ergolinyl) -3 3-Diethylureas of the general formula II in which R is as defined above, and the cyano group is reduced or hydrolytically cleaved from the compounds of formula III. 3. A process according to claim 2, wherein the removal of the cyano group is carried out hydrolytically by treatment with an aqueous ethanolic solution of alkali metal and alkaline earth metal hydroxides while boiling the reaction mixture. 4. The process of claim 3 wherein the aqueous-alcoholic alkali metal hydroxide solution used is 30% w / v. solution of potassium hydroxide in 50% v / v aqueous ethanol.