CS195855B1 - Derivatives of 6-norfestuclavine pharmaceutical salts and process for preparing thereof - Google Patents

Description

The present invention relates to a 6-norfestulavin derivative of the formula I

in which

R is hydrogen, alkyl of 2 to 7 carbon atoms, ethoxycarbonylmethyl, 2- (ethoxycarbonyl) ethyl, 4- (ethoxycarbonyl) butyl or nitrile, their pharmaceutically acceptable salts, and methods of making these derivatives.

In the bioassay, the 6-norfestuklavin derivatives of formula I showed a significant inhibitory effect on adenohypophyseal prolactin secretion in experimental animals, which resulted in, for example, an antinidative effect in rats at doses of 0.1 to 1.0 mg ha animal ( about 200 g), administered orally, on day 5 after coupling. A significant antinidant effect at 0.1 mg / animal was found, for example, in 6-nor-6-ethylfestuklavin and 6-nor-6-propylfestuklavin, administered as aqueous tartrate solutions under these conditions.

The 6-norfestucline derivatives can be prepared according to the invention in several ways, depending on the nature of the substituent R in formula I.

In order to obtain a derivative of the formula I in which R is a nitrile group, festucline (D-6,8-dimethylergolin-I) is reacted with cyanogen bromide in an amount of 1 to 5 mol equivalents, preferably 1.5 mol equivalents, in an inert organic solvent such as a chlorinated aliphatic hydrocarbon, preferably dichloromethane, at temperatures of from 0 to 80 ° C, preferably at 20 to 25 ° C. Under these conditions, the reaction is complete in 1 to 7 days. After the reaction, the reaction mixture is worked up in the usual manner, for example by shaking the dichloromethane solution with an aqueous solution of tartaric acid (removal of unreacted starting material), evaporating the solvent and purifying the crude product obtained by crystallization from an organic solvent such as methanol or ethanol.

The starting material, i.e. festuclavin, is known;

it can be easily obtained, for example, according to es. Certificate No. 173 416.

According to the invention, a derivative of the general formula I in which R represents a hydrogen atom is prepared by reacting D-6-cyano-8-methylergoline-I with potassium in an amount of 2 to 20 mol equivalents in hexamethyltri, phosphoric acid amide , in an atmosphere of a non-oxidizing gas, for example nitrogen, at a temperature of from 20 to 100 ° C, preferably 30 to 50 ° C. 6-nor-6-cyanfestucline can also be used as starting materials in this process.

The reaction mixture is expediently worked up by pouring it into an excess of water, the precipitated microcrystalline product being separated and purified by crystallization from an organic solvent or mixture of solvents; a mixture of ethanol and chloroform is particularly suitable.

The method of reductive decyanization of said starting materials is advantageous as it is easy to carry out and provides a uniform end product in high yield. Cleavage of nitrile groups from both carbon and nitrogen atoms is selective and is not accompanied by a competitive reduction of the nitrile group to the primary amine. The starting material, i.e. D-6-cyano-8-cyanomethylergoline-I, is known, readily prepared in good yield and in a suitable purity from D-6-methyl-8-cyanomethylergoline. Reductive decyanization of D-6-cyano-8-cyanomethylergoline-I as a starting material is more economically advantageous for the preparation of a compound of formula I in which R is hydrogen because it provides the desired product in a reaction sequence of one step shorter.

The derivatives of the formula I in which R is an alkyl of 2 to 7 carbon atoms are prepared by alkylating a derivative of the formula I in which R is a hydrogen atom, i.e. 6-norfestulavine, in particular an alkyl halide or a dialkyl sulphate whose alkyl it has 2 to 7 carbon atoms, in an inert solvent such as dimethylformamide, in the presence of anhydrous potassium carbonate, at a temperature of from 20 ° C to the boiling point of the reaction mixture.

For the alkylation, 1 to 20 mol equivalents, preferably 2 mol equivalents, of an alkylating agent, e.g., alkyl esters of hydrochloric, hydrobromic or hydroiodic or dialkyl sulfuric esters can be used. The amount of anhydrous potassium carbonate required for the reaction is 1 to 10 mol equivalents, preferably 1.6 mol equivalents. The optimum reaction temperature is 80 ° C; when alkyl iodoic acid esters are used, it is also possible to operate at temperatures in the range of 20 to 25 ° C.

Derivatives of formula (I) wherein R is ethoxycarbonylmethyl, 2- (ethoxycarbonyl) ethyl or 4- (ethoxycarbonyl) butyl may be obtained under similar conditions as above except that the alkylation is carried out with ethyl bromoacetate, β-bromopropionate or ethyl ester; .alpha.-bromvaler. In a conventional embodiment, a compound of formula (I) wherein R is hydrogen with 1 to 20 mol equivalents of ω-halocarboxylic acid ethyl ester, preferably ω-bromocarboxylic acid, is reacted at a reaction time of 2 to 24 hours in an indifferent solvent, preferably dimethylformamide. in the presence of 1 to 10 mol equivalents of anhydrous potassium carbonate, preferably

1.6 mol equivalents, at a temperature from 20 ° C to the boiling point of the reaction mixture, preferably at 80 ° C.

After the above reactions are carried out, the reaction mixtures are worked up as required, e.g. after pouring the reaction mixture into water, the precipitate formed is filtered off with suction, washed with water and dried. The crude products are purified by crystallization from an organic solvent or solvent mixture, or by silica gel column chromatography, optionally using both methods.

The compounds of formula (I) are converted into pharmaceutically acceptable salts by reaction with organic or inorganic acids, for example in a lower alcohol such as methanol or ethanol. Sulfuric, hydrochloric and, in particular, organic tartaric, maleic, methane and ethanesulfonic acids are suitable inorganic acids. Particularly suitable salts suitable for pharmacological purposes are base tartrate. ·

In the examples, the specific rotation values of the substances were determined in pyridine and refer to solvent-free substances; temperature values are expressed in ° C.

Example 1

6-Nor-6-cyanfestucline

To a solution of festuclavine 240 mg (1 mmol) in dichloromethane (40 mL) was added cyanogen bromide (159 mg, 1.5 mmol) and the homogeneous reaction mixture was allowed to react at 20-25 ° C for 1 week, then shaken with 2 x 10 mL. 1% aqueous tartaric acid solution, the organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and crystallized to give 220 mg (88%) of the crude product, mp 277-278 ° C. Mp 279-281 ° C, [α] _D ²⁰ , + 78.8 ° (c = 0.370).

Example 2

6-Norfeetuklavin from D-6-cyano-8-cyanomethylergoline-I

To a solution of 276 mg (1 mmol) of D-6-cyano-8-methylergoline-I in 10 ml of ihexamethylphosphoric triamide was added, under vigorous stirring under a nitrogen atmosphere, 390 mg (10 mmol) of potassium in small portions and stirred. 3 hours at 40 ° C. After cooling to 20 ° C, the reaction mixture was added, with stirring, to 200 ml of water, the precipitate formed after 1 hour standing in a refrigerator at 5 ° C was aspirated and washed with 100 ml of water. After drying at 100 ° C under a water pump vacuum, 200 mg (88.5%) of the product with mp 238-240 ° C were obtained. Crystallization from chloroform-methanol (1: 1) afforded a preparation of mp 242-245 ° C, [α] _D ²⁰ , -35.7 °, (c = 0.350).

Example 3

6-Norfestulavin from 6-nor-6-cyanfestulavin

To a solution of 503 mg (2 mmol) of 6-nor-6-cyanfestucline in 30 mL of hexamethylphosphoric triamide was added portionwise 780 mg (20 mmol) of potassium in vigorous stirring under nitrogen and stirred at 20-25 ° C. After 3 hours, the reaction mixture was taken up in 300 ml of water, the precipitate was filtered off with suction, washed with 200 ml of water and treated as in Example 2. 402 mg (89%) of the crude product were obtained, mp 237-239 ° C. . Crystallization from chloroform-methanol (1: 1) gave a preparation of m.p. 242-245 ° C.

[α] _D ^{20 -} 35.9 °, (c - 0.346).

Example 4

6-Nor-6-ethylfestuklavin

To a solution of 226 mg (1 mmol) of 6-norfestulavine in 10 mL of anhydrous dimethylformamide was added 220 mg (1.6 mmol) of anhydrous potassium carbonate and 312 mg (2 mmol) of ethyl iodide, and the reaction mixture was stirred at 20-25 ° C for 7 hours, allowed to stand overnight and diluted with 100 ml of water. The precipitate was filtered off with suction and, after washing with 20 ml of water, dried at 80 DEG C. in a water pump vacuum. The crude product (220 mg, 86.6 proc.) Was recrystallized from chloroform-methanol (1: 1) to give a compound of mp 257-258 ° C, [α] _D 20, -107.7 °, (c = 0.343).

The following were also prepared in an analogous way:

6-Nor-6-propylfestuklavin: mp 188-190 ° C (benzene-methanol), Md ²⁰ , -76.1 °, (c = 0.396).

6-Nor-6-butylfestuccinine: mp 173-175 ° C (methanol), [α] D ²⁰ , -78.2 °, (c = 0.373).

Example 5

6-Nor-6-isopropylfestuklavin

Blavine in 15 ml of dimethylformamide was added 440 mg (3.2 mmol) of anhydrous potassium carbonate and 492 mg (4 mmol) of isopropylbroimide and the reaction mixture was stirred at 80 ° C for 16 hours. After cooling to 20-25 ° C, the reaction mixture was taken up in 200 ml of water and the precipitate formed was worked up analogously to Example 5. After chromatography of the crude product on a silica gel column using benzene + 1% methanol, the combined fractions yielded 210 mg. (39.2%) of the product which, after crystallization from benzene, gave a preparation of > mp 249 DEG-251 DEG C. [.alpha.] D = -95.6 DEG (c = 0.373).

The following were also prepared in an analogous way:

6-Nor-6-isobutylfestuklavin: mp 145-147 ° C (chloroform-methanol), [α] _D ²⁰ , -85.2 ° (c = 0.340).

6-Nor-6-heptylfestuklavin: mp 148-150 ° C (chloroform-methanol), [α] D ²⁰ , -55.7 ° (c = 0.403).

Example 6

6-Nor-6- (ethoxycarbonylmethyl) festuclavin

To a solution of 226 mg (1 mmol) of 6-norfestulavine in 8 mL of dimethylformamide was added 220 mg (1.6 mmol) of potassium carbonate> and 400 mg (2.4 mmol) of ethyl bromoacetate, and the reaction mixture was heated at 80 ° C for 16 hours and then worked up analogously to Example 5. After chromatography on benzene + 0.5% methanol, 228 mg (73%) of a uniform product was obtained, which after crystallization from chloroform-hexane (1: 5) gave the product mp 195-197 ° C, [α] _D ²⁰ , -63.06 ° (c = 0.333).

In an analogous way, for example:

6-Nor-6- (3-ethoxycarbonylethyl) festuclavin:

mp 120-122 ° C (benzene-hexane), [α] _D ²⁰ , -60.06 ° (c = 0.333).

6-Nor-6- (5-ethoxycarbonylbutyl) festuclavin:

mp 77-79 ° C (benzene-hexane), [α] _D ²⁰ , -56.2 ° (c = 0.373).

To a solution of 452 mg (2 mmol) of 6-norfest195855

Claims (6)

1. Derivatives of 6-norfestucline. of the general formula I in which R is hydrogen, alkyl of 2 to 7 carbon atoms, ethoxycarbonylmethyl, 2- (ethoxycarbonyl) ethyl, 4- (ethoxycarbonyl) butyl or nitrile, and pharmaceutically acceptable salts thereof. 2. A process for the preparation of a 6-norfestucline derivative of the formula I in which R is a nitrile group, characterized in that festucline is reacted with cyanogen bromide in an amount of 1 to 5 mol equivalents, preferably 1.5 mol equivalents, in an inert inert solvent. , for example of the chlorinated aliphatic hydrocarbon type, preferably dichloromethane, at temperatures from 0 to 80 ° C, preferably at 20 to 25 ° C. Celsius. VYNALEZU 3. A process for the preparation of a 6-norfestucline derivative of the formula I in which R is a hydrogen atom, which comprises reacting D-6-cyano-8-cyanomethylergoline-I, with potassium, in an amount of 2 to 20 mol equivalents. a hexamethylphosphoric triamide, in an atmosphere of a non-oxidizing gas such as nitrogen at a temperature of from 20 to 100 ° C, preferably 30 to 50 ° C. 4. Process according to claim 3, characterized in that 6-nor-6-cyanfestucline is used as the starting material. 5. A process for the preparation of 6-norfestucline derivatives of formula (I) wherein R is alkyl having 2 to 7 carbon atoms, characterized in that the derivative of formula (I) wherein R is hydrogen, i.e. 6-norfestucline, is alkylated, in particular an alkyl halide, or alkyl alkyl sulfate having 2 to 7 carbon atoms, in an inert solvent such as dimethylformamide, in the presence of anhydrous potassium carbonate, at a temperature of from 20 ° C to the boiling point of the reaction mixture. 6. A process for the preparation of a compound of formula (I) wherein R is ethoxycarbonyl-Imethyl, 2- (ethoxycarbonyl) ethyl or 4- (ethoxycarbonyl) butyl according to claim 5, wherein the alkylation is carried out with ethyl bromoacetate. , 3-bromoproplon or 6-bromvaler.