CS259899B2 - Method of ergoline's new 1,2-disubstituted derivatives production - Google Patents

Abstract

Process for the production of new 1,2-disubstituted ergoline derivatives of formula I, wherein X is O or S, R * 1 is C 1 -C 4 -alkyl, R 2 = Hal, C 2 -C 8 -acyl, C 1 -C 6 -alkyl -alkyl, C2-C3-alkenyl, C2-C3-alkynyl, —S — R 5 wherein R 5 is C 1 -C 4 -alkyl which is optionally substituted with phenyl, or is phenyl, then R2 is a group of formula (a), -CHO or -CH 2 OH, R 3 C1-C4-alkyl or C2-C4-acyl, Et means ethyl and C 8-10 - C 10 means a single bond C-C or C-C double bond and when Co. C10 means a single bond C-C, then an atom hydrogen at position 10 occupies the " configuration " as well as pharmaceutically acceptable acid addition salts characterized by by taking the general compound formula III acts upon prior dithiol formation, the compound obtained, optionally in within the meaning of the general symbols to other compounds of formula I, obtained derivatives the ureas are optionally converted into derivatives thiourea and / or physiologically tolerable acid addition salts. Produced the compounds can be used as medicaments.

Description

The invention relates to a process for the production of new

1,2-substituted ergoline derivatives of the general formula I below which possess valuable pharmacological properties and can be used as medicaments.

The present invention provides a process for the preparation of the novel 1,2-disubstituted ergoline derivatives of formula (I)

in which

X represents an oxygen atom or a sulfur atom,

R ¹ represents an alkyl group having 1 to 4 carbon atoms,

R ² represents a halogen atom, an acyl group having 2 to 4 carbon atoms, alkyl of 1-4 carbon atoms, alkenyl having 2-3 carbon atoms, alkynyl with 2-3 carbon atoms, a group S-R ^5, wherein

R ⁵ represents a C 1 -C 4 alkyl group optionally substituted by a phenyl group, or represents a phenyl group, furthermore a group of the formula further represents a group -CHO or CH 2 OH, R ³ represents an alkyl group of 1 to 4 carbon atoms or an acyl group with 2 to 4 carbon atoms,

Et represents an ethyl group and represents a carbon-carbon single bond or a carbon = carbon double bond, and if

means a single carbon-carbon bond, then the hydrogen atom at the 10-position assumes the α-configuration as well as the pharmaceutically acceptable acid addition salts thereof.

C1-C4alkyl groups are, for example, methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl and tert-butyl.

Acyl groups are derived from aliphatic carboxylic acids preferably having 2 to 4 carbon atoms, examples of which are acetic acid, propionic acid and butyric acid.

Halogens in the substituents ^of R are preferably chlorine, bromine or iodine.

The pharmaceutically acceptable salts of the compounds of formula (I) which are prepared by the process of the invention are acid addition salts and are derived from commonly used acids. Such acids are, for example, inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, or organic acids such as aliphatic monocarboxylic or dicarboxylic acids, phenylsubstituted alkanecarboxylic acids, hydroxyalkanecarboxylic acids acids or alkanedicarboxylic acids, aromatic acids or aliphatic or aromatic sulfonic acids. Thus, physiologically acceptable salts of these acids are, for example, the following: sulphate, pyrosulphate, hydrogen sulphate, sulphite, hydrogen sulphite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate forinate, isobutyrate, caprylate, heptanoate, propolatelate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandate, butin-1,4-dioate, hexln-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dlnitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, N-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate-sulfonate-sulfonate-sulfonate-sulfonate-naphthalenesulfonate 1-naphthalenesulfonate

Compared to the known ergolines which are not substituted in the 2-position, such as, for example, lisuride and terguride, the compounds of formula I produced by the process of the invention exhibit central anti-dopaminergic activity and / or α 2 -receptor blocking activity.

Central blockade of dopamine receptors can be illustrated by an interaction test using a dopamine receptor agonist, i.e., apomorphine, in mice following a single pre-intraperitoneal administration (parameter: suppression of hypothermia induced by administration of 5 mg / kg i.p. apomorphine). Male mice (NMRI strain) are pretreated with various doses of a substance that does not itself affect the thermoregulation of the test animals or the vehicle. 30 minutes later, all animals are given apomorphine at a dose of 5 mg / kg i.p. 60 minutes after administration of the substance or vehicle (= 30 minutes after administration of apomorphine), the rectal temperature is measured using a thermosonde. While vehicle-treated mice show hypothermia, the dose-dependent effect of apomorphine on body temperature decrease was suppressed in the animals treated with the substance.

The central blocking a2 receptors may be illustrated by the interaction _{of the} test using clonidine as a A2a receptor agonist, in mice after a single intraperitoneal pretreatment (parameter: suppression of hypothermia induced by administration of 0.1 mg clonidine per kg ip). Male mice (NMRI strain) were pre-administered with different doses of a substance that did not itself affect the thermoregulation of the test animals or the vehicle. 30 minutes later, all animals received 0.1 mg / kg clonldin ip 60 minutes after administration of the substance or vehicle (-30 minutes after administration of clonidine) by measuring the temperature in the rectum with a thermosonde. While mice that were treated with vehicle only exhibited hypothermia, the dose-dependent effect of clonidine on the decrease in body temperature was suppressed in animals pretreated with the substance.

Based on these findings, the compounds produced by the process of the invention can be used as neuroleptics for the treatment of schizophrenic type psychoses, or as antidepressants.

The compounds of formula (I) may be prepared by methods known per se.

According to the invention, the compounds of the formula I as well as their pharmaceutically acceptable acid addition salts are prepared by the preparation of a compound of the formula III

NH ~ C / ~ NEt £

in which

X, Et and R ¹ are as defined above and R ³ 'is hydrogen or a C 1 -C 4 alkyl group, after previous formylation with dithiol, and optionally thereafter compounds so obtained in which R ² is a group of the formula are reductively converted to or methyl groups are hydrolyzed to formyl compounds and these are optionally reduced to compounds with the -CH 2 OH group and compounds in which R ³ is hydrogen are acylated and the compounds thus obtained are optionally converted to thiourea derivatives; and / or to physiologically compatible acid addition salts.

In the process according to the invention, the desired substituents are introduced into the 2-position.

Preparation of compounds of formula I wherein R ² represents a group of formula κ

is carried out, for example, by reacting compounds of formula III with ethyl formate and Lewis acids such as titanium tetrachloride at room temperature in inert solvents such as chloroform, methylene chloride and the like.

From the dithiolane derivative, the 2-methyl derivative can be obtained by reaction with Raney nickel at room temperature in inert solvents such as alcohols such as methanol, ethanol and the like.

The 2-formyl derivative can be obtained from the dithiolane derivative, for example by treatment with aqueous silica and subsequent reaction with sulfuryl chloride. The reaction is generally carried out at room temperature in inert solvents such as chlorinated hydrocarbons such as chloroform, methylene chloride, ethylene chloride and the like.

The aldehyde can be reduced to the corresponding alcohol, for example by treatment with lithium aluminum hydride in inert solvents such as ethers, for example tetrahydrofuran, diethyl ether and the like, or by treatment with sodium borohydride in solvents such as alcohols, for example methanol, ethanol and the like.

Conversion of the 8α-ureidoderivatives to the corresponding thlones is accomplished by treatment with phosphorus oxychloride followed by treatment with potassium xanthogenate. The reaction is carried out at low temperatures with occasional temperature increases in inert solvents such as ethers.

Thiourea derivatives can also be prepared by cleaving the urea followed by reaction of the amine with a thio-introducing agent and another amine.

All reactions are generally carried out under an atmosphere of an inert gas such as argon or nitrogen.

To form salts, the compounds of formula I are dissolved in a small amount of methanol or methylene chloride, and to the obtained solution is added a concentrated solution of the desired acid in methanol at room temperature.

The starting compounds are known or can be prepared according to known methods.

The following examples illustrate the invention but do not limit it in any way.

Example 1

To a solution of 6.9 g of 1,1-diethyl-3- (1,6-dimethyl-8α-ergolinyl) urea in 200 ml of chloroform at room temperature under argon was added successively 7 ml of formic acid epoxy ester and 3.6 ml (44 ml). mmol) of ethanedithiol. Then, 8.8 ml (80 mmol) of titanium tetrachloride dissolved in 100 ml of chloroform is slowly added dropwise. The reaction mixture was further stirred at room temperature for 20 hours. Although the starting material is not yet fully reacted at this point, the reaction mixture is worked up to prevent further formation of the disubstituted compound. To this end, the reaction mixture is cooled in an ice bath, and 50 ml of methanol and 40 ml of water are added dropwise thereto. The mixture was then basified with 25% ammonia solution and extracted with methylene chloride. The organic phase is washed with water and dried over magnesium sulphate. The evaporation residue is crystallized from boiling methanol / ethyl acetate. 3.0 g of 1,1-diethyl-3- [2- (1,3-dlthioian-2-yl) -1,6-dimethyl-8α-ergolinyl] urea are obtained (yield 37%).

[α] _D - 4-21 ° (0.5%, in chloroform. Example 2)

The Raney nickel suspension (7.5 ml) was washed four times with methanol (30 ml) each time. Then 15 ml of methanol are added followed by a solution of 690 mg (1.5 mmol) of 1,1-dlethyl-3- (2- (1,3-dithiolan-2-yl) -1,6-dimethyl-8α-ergolinyl The reaction mixture was stirred at room temperature for 3 hours and 7.5 ml of a Raney-nickel suspension, which had been previously washed as above with 4 times 30 ml of methanol, were added again after a further 2 hours of stirring at room temperature. The filtrate was evaporated and the residue was crystallized from a mixture of methanol and ethyl acetate to give 150 mg of 1,1-diethyl-1- (1,2,6-trimethyl-8a). -ergolinyl urea (27% yield).

[α] _D = 412 ° (0.5%, in chloroform).

Example 3

2.12 g (5 mmol) of 1,1-diethyl-3- [2- (1,3-dithiolan-2-yl) -6-methyl-8α-ergolinyl] urea were dissolved in 40 ml of chloroform under argon. To this solution was added 3.5 g of silica gel with vigorous stirring, dropwise as a suspension in 3.5 ml of water. A solution of 1.18 ml of sulfuryl chloride in 30 ml of chloroform was then added dropwise over 30 minutes. After stirring at room temperature for 3 hours, 7.5 g of potassium carbonate are added and the mixture is stirred vigorously for 20 minutes. The precipitate was filtered off and washed with chloroform. The precipitate is moistened with ethanol and added to 300 ml of saturated sodium chloride solution, which is then extracted several times with chloroform. The chloroform extracts and the chloroform filtrate were dried together with magnesium sulfate and evaporated. Crystallization is then carried out from ethyl acetate. 1.16 g of 1,1-diethyl-3- (6-methyl-2-formyl-8'-ergolinylurea) is obtained (yield 61%).

[α], ₃ = - (- 13 ° (0.5%, in chloroform. Example 4)

320 mg (8 mmol) of lithium aluminum hydride were suspended under argon in 20 ml of absolute freshly distilled tetrahydrofuran and a solution of 1.53 g (4 mmol) of 1,1-diethyl-3- (1,6-dimethyl-2-) was added dropwise at room temperature. Formyl-8α-ergolines of 1J urea in 40 ml of freshly distilled absolute tetrahydrofuran, then stirred at room temperature for 1¼ hours, then cooled in an ice bath and 20 ml of 1 N hydrochloric acid solution are added. 20 ml of 2N tartaric acid solution is added and the reaction mixture is covered with ethyl acetate, 80 ml of 1N ammonia solution are added dropwise to neutralize, the ethyl acetate phase is separated and the aqueous phase is further extracted with ethyl acetate. Silica gel, eluting with methylene chloride / methanol (95: 5) under pressure 1.0 g of crude The product was crystallized from ethyl acetate to give 0.72 g of 1,1-diethyl-3- (1,6-dimethyl-2-hydroxymethyl-8α-ergolinyl) urea (47% yield).

[α] _D = 4 ~ 19 ° (0.5%, in chloroform). Example 5

3- (6-Methyl-1-propyl-2-ethyl-8α-ergolinyl) -1,1-diethylthiourea

To 200 mg of 1,1-diethyl-3- (2-ethyl-6-methyl-1-propyl-8α-ergolinyl) urea in 10 ml of Me259899 thylene chloride was added 0.13 ml of phosphorus oxychloride at -12 ° C. The temperature of the reaction mixture was allowed to rise to room temperature over 1 hour and the reaction mixture was stirred at this temperature for 16 hours. After evaporation, the residue is triturated with ether, then the suspension is filtered and the solid is dried under vacuum over potassium hydroxide pellets. The dried substance is then mixed with a solution of 245 mg of potassium xanthogenate in 15 ml of acetonitrile at -10 ° C and stirred at this temperature for 2 hours. After evaporation, the mixture is partitioned between methylene chloride and sodium bicarbonate solution, the organic phase is concentrated and the residue is chromatographed over silica gel using a 10: 1 mixture of mothylene chloride and ethanol as eluent. Recrystallization from a small amount of ethanol / hexane gave 100 mg of 3- [6-methyl-1-propyl-2-ethyl-8a-ergolinyl] -1,1-diethylurea, m.p. 173-175 ° C.

Claims (2)

1. A process for the preparation of the novel 1,2-disubstituted ergoline derivatives of formula (I) means a carbon-carbon single bond or a carbon-carbon double bond, and if it is a carbon-carbon single bond, the hydrogen atom at the 10-position occupies the α-configuration as well as a pharmaceutically acceptable acid addition salt thereof, characterized in that it is a compound of formula III wherein: X represents an oxygen atom or a sulfur atom. R ¹ represents an alkyl group having 1 to 4 carbon atoms, R ² represents a halogen atom, an acyl group having 2 to 4 carbon atoms, alkyl of 1-4 carbon atoms, alkenyl having 2-3 carbon atoms, alkynyl with 2-3 carbon atoms, a group S-R ^5, wherein R ⁵ represents a C 1 -C 4 alkyl group optionally substituted by a phenyl group, or a phenyl group, furthermore a group of the formula S \ (lil) in which X, R @ ¹ and Et are as defined above and Ra ^'represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms is treated after previous formylation dithiol, and optionally then the compounds thus obtained, in which R ² represents a group of the formula below means -CHO or -CH? OH, R ³ is alkyl having 1 to 4 carbon atoms or an acyl group having 2 to 4 carbon atoms, Et is ethyl and where n is 2, they are reductively converted to methyl groups or hydrolyzed to formyl compounds and these are optionally reduced to compounds with the —CH2OH group and compounds in which R ³ 'is hydrogen are a259899 The compounds thus obtained are optionally converted to other compounds of the formula I within the meaning of the general symbols, optionally to thiourea derivatives and / or to physiologically tolerable acid addition salts. 2. A process according to claim 1, wherein the corresponding compounds of formula III are used as starting materials to give 1,1-diethyl-3- [2- (1,3-dithiolan-2-yl) -1,6]. -dimethyl-8α-ergolinyl] urea, 1,1-diethyl-3- (6-methyl-2-formyl-8α-ergolinyl) urea, 1,1-diethyl-3- (1,6-dimethyl-2- hydroxymethyl-8a-ergolinyl) urea.