CS258270B1 - Process for preparing 1,6-disubstituted N- (8α-ergolinyl) -N ', N'-diethylureas - Google Patents

Abstract

A new method for the production of 1,· 6-disubstituted N-(8-alpha-ergolinyl)N',N^-diethylureas of the general formula I (see appendix), in which R1 denotes a lower alkyl group with 2 to 4 carbon atoms and R2 denotes an alkyl group with 1 to 4 carbon atoms, consisting in that the starting known N-(1- -alkyl-6-methyl-8-alpha-ergolinyl)-N',N'- -diethylurea of the general formula II is demethylated with cyanogen bromide, the cyano group is cleaved from the obtained 6-cyano derivative of the general formula III by alkaline hydrolysis and the resulting 6-norderivative of the general formula IV is alkylated. The substances of the general formula I exhibit high dopaminergic activity with low toxicity.

Description

The present invention relates to a process for the preparation of 1,6-disubstituted N- (8-alpha-ergolinyl) -N ', Ν'-diethylureas of the formula I

in which

R ³ represents a C 2 -C 4 alkyl group

R is C 1 -C 4 alkyl.

Compounds of formula I wherein R ³ is ethyl or propyl and R is methyl or ethyl have potent dopaminergic activity and are highly potent inhibitors of prolactin and growth hormone secretion in various animal species at relatively low toxicity and are described, together with the method their production, in MS.

AO 231 214. They can be produced by N-alkylation at the 1-position of unsubstituted N- (6-alkyl-8-alpha-ergolinyl) -N ', Ν'-diethylureas, preferably by treating the ureas in liquid ammonia with the appropriate alkyl halides in the presence of an alkali metal amide. A novel process has now been found in which the alkylation of N- (6-methyl-8-alpha-ergolinyl) -N ', Ν'-diethylurea to first is carried out and, after demethylation at the 6-position, alkylation to Njgj is carried out. This process has the advantage of better solubility of the synthesis intermediates and, in some cases, better accessibility of the starting N 3 -alkylated ureas.

According to the invention, the 1,6-disubstituted N- (8-alpha-ergolinyl) -N ', Ν'-diethylureas of the general formula I, in which R and R are as defined above, are produced by:

a) N- (1-alkyl-6-methyl-8-alpha-ergolinyl) -N ', Ν'-diethylurea of formula II

wherein R is as defined above, demethylates N - (1-alkyl-6-cyano-8-alpha-ergolinyl) -N ', N'-diethylurea of formula III by cyanogen bromide

H (III), wherein R is as defined above,

b) the compound of formula III is reductively or hydrolytically decyanized at the 6-position to give N- (6-alkyl-8-alpha-ergolinyl) -N ', Ν'-diethylurea of formula IV

(IV),

Wherein R ^z is as defined above, and

c) reacting a compound of formula IV with an alkylating agent of formula (V) wherein R ¹ is as defined for formula I and X is a halogen atom or an ester-linked aliphatic or aromatic sulfonic acid residue or an ester-linked acid residue sirové.

The starting compounds of the formula (II) can be prepared by known methods, e.g. AO 231,214.

In step a), the demethylation of the compound of the formula II is carried out by treating a solution of the substance in an inert solvent in the range of 1 to 4 mol equivalents, preferably 2 equivalents, of cyanogen bromide. temperatures from 0 to 100 ° C. Suitable inert solvents include, for example, dichloromethane, chloroform, dichloroethane, carbon tetrachloride or tetrachloroethane.

Upon completion of the reaction, the starting material residues are extracted with an aqueous solution of a strong organic or inorganic acid, preferably a tartaric acid solution, the organic portion is evaporated to dryness and the compound of formula III is purified by column chromatography and / or crystallization.

In step b), the decyanination of the compound of formula III is carried out either by reductive methods, for example zinc in acetic acid, alkali metals in hexamethyltriophosphoric acid or catalytic hydrogenation, for example in dimethylformamide in the presence of Raney nickel, or by alkaline hydrolysis. The hydrolysis is carried out by boiling with 20 to 40%, preferably 30%, aqueous or aqueous-alcoholic alkali metal hydroxide, preferably potassium hydroxide, for 2 to 10 h. The compound of formula IV has basic properties and can be isolated either in the form of base by extraction , chromatography and / or crystallization, or in the form of salts with inorganic or organic acids.

In step c), the alkylation of the compound of formula IV is carried out by treating with a solution of IV in an inert solvent such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, acetonitrile or nitromethane, 1 to 5 moles of alkylating agent V, preferably an alkyl bromide, alkyl iodide or dialkyl sulfate. at a temperature in the range of from 20 to 110 ° C, in the presence of acid-binding agents, for example in the presence of sodium or potassium carbonate or triethylamine. The compounds of formula (I) obtained are isolated by diluting the reaction mixture with water and extracting or filtering off the precipitated crude product; purification is accomplished by conventional laboratory techniques, for example, column chromatography and / or crystallization.

The intermediates of the synthesis of 1,6-disubstituted N- (8-alpha-ergolinyl) -N ', N'-diethylureas of the formula I according to the invention are novel substances which have not shown any remarkable biological activity in pharmacological testing.

Further details of the process according to the invention are given by the following non-limiting examples. Temperatures are given in degrees Celsius and specific rotation values refer to crystal free materials; percentages are by weight.

Example 1

N- (6-cyano-1-methyl-8-alpha-ergolinyl) -N ', Ν'-diethylurea

To a solution of 3.54 g (0.01 mol) of N- (1-methyl-8-alpha-ergolinyl) -N ', ,'-diethylurea in 200 ml of methylene chloride is added 2.1 g (0.02 mol) of cyanogen bromide and the reaction mixture was stirred at room temperature for 4 days under exclusion of light. The pale yellow solution was washed with 10% aqueous tartaric acid, diluted with aqueous ammonia (9: 1) and water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue (2.7 g, 87% yield) was dissolved in toluene / acetone / ammonia (5: 3: 0.03) and the solution was chromatographed on a silica gel column using the same solvent system to elute. The solvents were evaporated from the combined unitary fractions under reduced pressure and the residue was recrystallized from acetone-hexane. 102 DEG-105 DEG C. and .delta ^. ( ^{C =} 0.2, pyridine).

Example 2

In the same manner as in Example 1, but using N- (1-ethyl- or 1-propyl-8-alpha-ergolinyl) -N ', Ν'-diethyl urea instead of N- (1-methyl-8-alpha- ergolinyl) -N ', Ν'-diethylurea instead of N- (1-methyl-8-alpha-ergolinyl) -N', Ν'-diethylurea are prepared by:

N- (6-cyano-1-ethyl-8-alpha-ergolinyl) -N ', Ν'-diethylurea, mp 90-95 ° C (acetone-petroleum ether), ~ ⁺ 122.2 ° (c = 0.2 , chloroform) and N- (6-cyano-1-propyl-8-alpha-ergolinyl) -N ', N'-diethylurea, mp 148-150 ° C (acetone-petroleum ether), - + 110 ° (c = 0 , 2, chloroform).

Example 3

N- (1-methyl-8-alpha-ergolinyl) -N ', 4 ' -diethylurea

1.83 g (5 mmol) was added to 45 ml of 30% potassium hydroxide aqueous-ethanol solution.

N- (6-cyano-1-methyl-8-alpha-ergolinyl) -N ', N'-diethylurea and refluxed for 4 h; the progress of the reaction was monitored by thin layer chromatography on Silufol (Kavalier) in the chloroform-ethanol-triethylamine system 9: 1: 0.01. After cooling the reaction mixture to room temperature, the ethanol layer was separated, the aqueous portion was extracted with chloroform, the organics were combined, washed with water, dried over anhydrous sodium sulfate, and the solvents were distilled off under reduced pressure. The residue was dissolved in chloroform / ethanol 9: 1 and the solution was chromatographed on a silica gel column using the same solvent system to elute. The unitary fractions containing the product were combined, the solvents were evaporated under reduced pressure, and the residue (1.36 g, yield 80%) was recrystallized from acetone. The title compound of m.p. Mp 171-173 ° C and + 68.9 ° (c = 0.2, pyridine).

Example 4

In the same manner as in Example 3, but using N- (1-ethyl- or 1-propyl-6-cyano-8-alpha-ergolinyl) -N ', Ν'-diethyl urea instead of N- (6-cyano- 1-methyl-8-alpha-ergolinyl) -N ', N'-diethylurea prepared by: N- (1-ethyl-8-alpha-ergolinyl) -N', Ν'-diethylurea m.p. 148-152 ° C (acetone-petroleum ether), = + 33.4 ° (c = 0.2, chloroform) and N- (1-propyl-8-alpha5)

mp 121-123 ° C (acetone-petroleum ether), ^{= +} 35.3 ° (c = 0.2, chloroform).

Example 5

N- (1-methyl-6-propyl-8-alpha-ergolinyl) -N ', N'-diethylurea

To a solution of 0.34 g (1 mmol) of N- (1-methyl-8-alpha-ergolinyl) -N, Ν'-diethylurea in 10 ml of dimethylformamide was added 0.83 g (6 mmol) of anhydrous potassium carbonate, 37 g (3 mmol) of propyl bromide are added and the reaction mixture is heated to 70 ° C with stirring for 8 h. Dimethylformamide was distilled off under reduced pressure, the residue was stirred in water and the precipitate was dissolved in chloroform after drying. The solution is chromatographed on a silica gel column using the same solvent to elute. From the combined uniform fractions, after evaporation of the solvent and recrystallization of the residue from acetone yields the title compound, mp 117-119 ° ^{C = +} Md ° ^{26 '3} ° ^<C' 0.2, pyridine).

Example 6

In the same manner as in Example 5, but using ethyl iodide instead of propyl bromide, N- (1-methyl-6-ethyl-8-alpha-ergolinyl) -N ', Ν'-diethylurea, m.p. hexane), [Χ] ρθ ^{= + 2} θ » ³ ° (c ⁼ 0.2, pyridine).

Example 7

In the same manner as in Example 5, but using N- (1-ethyl- or 1-propyl-8-alpha-ergolinyl) -N ', Ν'-diethylurea instead of N- (1-methyl-8-alpha-ergolinyl) ) -N ', Ν'-diethylureas and the corresponding alkyl halides are prepared by:

N- (1-ethyl-6-propyl-8-alpha-ergolinyl) -N ', 4 ' -diethylurea, m.p. 85-86 ° C (acetone-hexane), "+ 30.4 ° (c = 0.2, pyridine):

N- (1-propyl-6-ethyl-8-alpha-ergolinyl) -N ', 4 ' -diethylurea, m.p. 63-65 ° C (ether-petroleum ether), 00 ° (c = 0.2, chloroform) a

N- (1,6-dipropyl-8-alpha-ergolinyl) -N ', Ν'-diethylurea, mp 59-61 ° C (acetone-hexane), ^{= + 30} ° ³ ° <9 "0.2, pyridine ).

Claims (4)

OBJECT OF THE INVENTION A process for the preparation of 1,6-disubstituted N- (8-alpha-ergolinyl) -N ', Ν'-diethylureas of formula I wherein: R 2 represents an alkyl group having 2 to 4 carbon atoms and R is C 1 -C 4 alkyl. characterized by: a) N- (1-alkyl-6-methyl-8-alpha-ergolinyl) -Ν ', Ν'-diethylurea of the formula II in which R is as defined above, demethylates with cyanogen bromide to give N- (1-alkyl- 6-cyano-8-alpha-ergolinyl) -N *, N'-diethylureas of formula III (III) wherein R is as defined above, b) a compound of formula III is reductively or hydrolytically dekyanizuje in position 6 to give N- (6-alkyl-8-alpha-erg.olinyl) -N ^- Ν'-diethylurea of the formula IV in which R has the abovementioned meaning, (IV), c) reacting a compound of formula IV with an alkylating agent of formula V R ¹ - X (V) wherein R is as defined for formula I and X represents a halogen atom or a ester-linked aliphatic or aromatic sulfonic acids or ester-linked radical of sulfuric acid. 2. Process according to claim 1, characterized in that in step a) the demethylation is carried out by treatment with 1 to 4 mol equivalents, preferably 2 mol equivalents, of cyanogen bromide in an inert solvent such as dichloromethane, chloroform, dichloroethane, carbon tetrachloride or tetrachloroethane. to 100 ° C. 3. Process according to claim 1, characterized in that in step b) the removal of the cyano group is carried out by alkaline hydrolysis, boiling with 20 to 40%, preferably 30% aqueous or aqueous-alcoholic potassium or sodium hydroxide for 2 to 10 h. 4. The process of claim 1, wherein step (c) of the alkylation is carried out with 1 to 5 moles of alkylating agent in an inert solvent such as dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, acetonitrile or nitromethane at a temperature in the range of 20. to 110 ° C, in the presence of acid liberating agents such as sodium carbonate, potassium carbonate or triethylamine.