CS258497B2 - Method of ergoline's new 2-substituted derivatives production - Google Patents

Abstract

Process for preparing new 2-substituted ergoline derivatives of the formula I in which X represents an oxygen atom or sulfur atoms, R1 denotes alkyl having 1 to 6 atoms carbon, Y is C2H4, -CH = CH- or -CBC-, R2 is optionally alkoxy C 1 -C 4 or nitrile a substituted phenyl group, thiophenyl or pyridinyl and Et is ethyl and means a single carbon-bond carbon or carbon-carbon double bond, and if Cg * - "'Customs is simple carbon-carbon bond, then a hydrogen atom in position 10 occupies the a-configuration as well as their pharmaceutically acceptable addition salts with acids, where X is oxygen atom, r! is methyl and - C 10 is a single bond, then Y-R2 is not -C2H4-phenyl or -CssC-phenyl characterized in that it is argolin derivatives of formula III, v wherein Z is a halogen atom or a group -C “CH, acts in the presence of a catalyst and a base with a compound of the formula Hal-R 2 or HC "C-R 2, wherein Hal represents a halogen atom, wherein one reactant each represents a compound containing halogen then optionally the CSC bond is hydrogenated or completely hydrogenated the urea derivatives are optionally converted to thiourea derivatives and / or obtained the compounds are optionally converted by treatment acid to its physiologically compatible acid addition salts. Produced compounds are used as medicines.

Description

The present invention relates to a process for the preparation of the novel 2-substituted ergoline derivatives of the following general formula (I) which have valuable pharmacological properties and can be used as medicaments.

The present invention provides a process for the preparation of novel 2-substituted ergoline derivatives of general formula (I)

X

NH-C-NEt ₂

in which

X

R ¹

Y

Et '10 represents an oxygen or sulfur atom, represents an alkyl group having 1 to 6 carbon atoms, represents a group C 1 H 4, -CH 2 CH- or a group -C 5 -C-, optionally represents an alkoxy group having 1 to 4 carbon atoms or an phenyl group substituted by phenyl a thiophenyl group, or. a pyridinyl group, represents an ethyl group, and represents a carbon-carbon single bond or a carbon = carbon double bond, and if C 8 - ---- - C ₁₀ represents a single carbon-carbon bond, then the hydrogen atom at the 10-position occupies the alpha configuration, and pharmaceutically acceptable the acid addition salts, wherein, if X is oxygen, R₁ is methyl, and C _g is a single carbon-carbon bond, then YR ² does CJH ^ -phenyl or C> C-phenyl.

Alkyl groups are alkyl groups having 1 to 6 carbon atoms, with alkyl groups having 1 to 4 carbon atoms being preferred, such as methyl, ethyl, isopropyl, n-propyl, n-butyl, isobutyl and tert. butyl group.

The aromatic group may be substituted at any position, one or more times with a C 1 -C 4 alkoxy or nitrile group.

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The pharmaceutically acceptable acid addition salts of the compounds of formula (I) which are prepared by the process of the invention are those 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 mono- or dicarboxylic acids, phenyl-substituted alkanecarboxylic acids, hydroxyalkanecarboxylic acids acids or alkenedicarboxylic acids, aromatic acids or aliphatic or aromatic sulfonic acids.

Thus, physiologically acceptable salts of these acids are, for example, sulphate, pyrosulphate hydrogen sulphate, sulphite, hydrogen sulphite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, , caproate, heptanoate, propionate, malonate, succinate, euberate. edbaleates, fumarate, maleate, manalate, Vatatin-1,4-dioate, hexin-1,6- <iiate, beftZate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzene , xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate or naphthalene-2-sulfonate.

Compared with the known ergolines which are not substituted in the 2-position, such as in comparison with lisuride or terguride, as well as in comparison with 1,1,1-diethyl-3- (2-phenylethynyl-6-methyl-8-alpha-ergolinyl) urea and the analogous 2-phenethylderivate known from European patent application 160 842, the compounds of the formula I produced by the process according to the invention are characterized by central dopaminergic activity.

Central blockade of dopamine A receptors can be illustrated by an interaction test using a dopamine receptor agonist, ie, apomorphine, in mice following a single pre-intraperitoneal administration (parameter: suppression of 5 mg / kg induced hypothermia).

i.p. Male mice (NMRI strain) are pretreated with various doses of Compound A, which does not itself affect the thermoregulation of the test animals, or the vehicle. 36 minutes later, all animals received apomorphine at a dose of 5 mg / kg i.p. 60 minutes after administration of Compound A or vehicle (= 30 minutes after administration of apomorphine), the rectal temperature is measured with a thermosonde. While vehicle-only mice exhibit hypothermia, dose-dependent effects of apomorphine on body temperature decrease were suppressed in animals treated with Compound A administration. (A test compound).

Based on these pharmacological findings, the compounds of the present invention can be used as neuroleptics for the treatment of schizophrenic psychoses.

The compounds of the formula I according to the invention are prepared by reacting with an ergoline derivative of the formula III

in which r! and X are as defined above and

Z represents a halogen atom or a -CsCH a group

Et represents an ethyl group, is active in the presence of a catalyst and a base compound of formula Hal - R @ ² or HCsC -R ² in which

Hal represents a halogen atom and o

R is as defined above, wherein each reactant is a compound containing a compound of formula (I); halogen, whereupon the CaC bond is optionally partially or completely hydrogenated, the urea derivatives are optionally converted to thiourea derivatives and / or the obtained compounds are optionally converted to their acid addition salts.

The preparation of compounds of the formula III is described, for example, in European Patent Applications Nos. 160 842, 56 358 and 141 387.

The reaction is carried out at temperatures from 0 ° C to 120 ° C, preferably at 70 ° C to 100 ° C, in an aprotic solvent such as dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile or dioxane.

The catalysts used are preferably palladium compounds, such as palladium salts or complex palladium compounds. Mention may be made, for example, of palladium acetate, trans-dichloro-bis- (tri-o-tolylphosphine) palladium (II) or trans-dichloro-bis- (triphenylphosphine) palladium (II) palladium (O) -tetrakis-triphenylphosphine. The catalyst is used in an amount of from 0.01 to 0.1 mol, based on the 2-halogenergoline used.

The reaction is stimulated by the addition of triarylphosphines. Catalytic amounts of copper (I) iodide or copper (I) bromide are added for ethynylation.

Suitable bases are secondary and tertiary amines such as dimethylamine, diethylamine, piperidine, triethylamine and tri-n-butylamine.

The halogenated compound preferably contains iodine or bromine.

The 2-ethynyl derivative can be completely or partially hydrogenated with catalytically activated hydrogen.

The full hydrogenation is carried out in the presence of a catalyst such as Raney nickel or palladium on various supports such as carbon at room temperature, optionally under elevated pressure in an inert solvent such as alcohols such as methanol, ethanol, propanol, ethers , such as dioxane, diethyl ether, acids such as glacial acetic acid and the like.

For the partial hydrogenation to the double bond, the catalysts used are, for example, palladium salts poisoned with quinoline or pyridine, but also lead or also palladium on various supports (Lindlar catalysts). The solvents used are alcohols or hydrocarbons.

However, the conversion of ethynyl derivatives to vinyl derivatives can also be accomplished by addition of organometallic compounds such as DIBAH diisobutylaluminum hydride and subsequent hydrolysis. Suitable solvents are hydrocarbons or ethers, such as hexane, toluene, tetrahydrofuran, diethyl ether and the like.

Conversion of the 8-alpha-urea derivatives to the corresponding thiones is carried out by reaction with phosphorus oxychloride followed by reaction with potassium xanthogenate. The reaction is carried out at low temperatures with occasional temperature increases in inert solvents such as ethers.

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

All reactions are generally carried out under a protective gas atmosphere, such as argon or nitrogen, partially under elevated pressure. The starting compounds are known or are prepared by methods known per se.

The following examples illustrate the invention. However, these examples do not limit the scope of the invention in any way.

He did

3- [N -methyl-2- (thien-2-ylethynyl) -8-alpha-ergolinyl] -1,1-diethylurea mg 3-Q6-methyl-2-ethynyl-8-alpha-ergolinyl3-1,11 The diethyl urea was heated in 2 ml of dimethylformamide with 2 ml of triethylamine, 1.5 mg of copper iodide, 0.069 ml of 2-iodo-thiophene and 4.8 mg of palladium (0) -tetrakis-trisphenylphosphine under argon for 2 hours at 80 ° C. After evaporation, the residue is taken up in ethyl acetate and the solution obtained is washed successively with dilute ammonia solution and saturated sodium chloride solution. Chromatography on silica gel (ethyl acetate / ethanol 1: 1) and recrystallization from ethanol / hexane gave 26 mg of 3-Q6-methyl-1- (thien-2-ylethynyl) -8-alpha. 252-156 ° C; -ergolins 1] -1,1-diethylurea.

The following compounds were prepared in an analogous manner:

3- [6-methyl-2- (3-pyridinylethynyl) -8-alpha-ergolinyl] -1,1-diethylurea, m.p.

226-229 [deg.] C, [alpha] _D3 +124.6 [deg.] (C &gt; 0.215, pyridine);

3- [2- (4-methoxy-phenylethynyl) -6-methyl-8-alpha-ergolinyl] -1,1-diethylurea, m.p.

210-211 DEG C. [.alpha ^ jj ^"0 +118 (e 0.2, pyridine).

Example 2

3- [2- (4-cyanophenylethynyl) -6-methyl-8-alpha-ergolinyl3,1,1-diethylurea

200 mg of 3-Q2-iodo-6-methyl-8-alpha-ergolinyl-2H-1,1-diethylurea is heated in 4 ml of dimethylformamide with 4 ml of triethylamine, 4 mg of copper iodide, 8 mg of (tetrakis-tris-phenylphosphine) palladium ( O) and 112 mg of 4-cyanophenylacetylene under argon for 2 hours at 80-90 ° C. After evaporation, the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution and the organic phase was washed with saturated sodium chloride solution. Chromatography on silica gel (methylene chloride / ethanol 10: 1) gave 87 mg of 3- [2- (4-cyanophenylethynyl) -6-methyl-8-alpha-ergolinyl] -1,1-diethylurea at a temperature of 87%. mp 150-151 ° C.

[α] _{D D} + +1 39.5 ⁰ (c = 0.2, pyridine).

The following compounds were prepared in an anological manner:.

3-] 2- (3-methyl-phenylethynyl) -6-methyl-8-alpha-ergolinyl-1,1,1-diethylurea, 3-Q2- (2-methyl-phenylethynyl) -6-methyl-8-alpha-ergolinyl] -1, 1-diethylurea and 3- [2- (4-chlorophenylethynyl) -6-methyl-8-alpha-ergolinyl] -1,1-diethylurea.

Example 3

3- [2- (4-methoxyphenethyl) -6-methyl-8-alpha-ergolinyl] -1,1-diethylurea

X 50 mg of 3- [4- (4-methoxyphenetinyl) -6-methyl-8-alpha-ergolinyl] -1,1-diethylurea in 20 ml of ethanol was added at the tip of a Raney nickel spatula and hydrogenated at room temperature and atmospheric pressure hydrogen for 1 hour. After filtering off the catalyst, the solvent was evaporated and the residue was recrystallized from ethyl acetate / hexane. 40 mg of 3- [2- (4-methoxyphenethyl) -6-methyl-8-alpha-ergolinyl] -1,1-diethylurea, m.p. 147-149 ° C, are obtained.

JjlfaJjj ^"0 +4.2 (0.2, pyridine).

Example 4

3- (9,10-Didehydro-6-methyl-2-phenylethynyl-8-alpha-ergolinyl) -1,1-diethylurea

150 mg of 2- (9,10-didehydro-2-bromo-6-methyl-8-alpha-ergolinyl-1,1-diethylurea is heated in 2 ml of dimethylformamide with 5 mg of cuprous iodide, 15 mg, (tetrakis-tris- phenylphosphine) palladium (0), ml of triethylamine and 0.12 ml of phenylacetylene for 6 hours at 90 DEG C. After filtration through silica gel, the filtrate is reheated with 5 mg of copper iodide, 15 mg of tetrakis-tris-phenylphosphine palladium (0) and 0.2 ml of phenylacetylene for 3 hours at 90 DEG C. The reaction mixture is then concentrated and the residue is partitioned between methylene chloride and saturated sodium bicarbonate solution and the organic phase is washed with saturated sodium chloride solution.

Chromatography on silica gel using methylene chloride / ethanol (10: 1) as the eluent and recrystallization from ethanol / hexane gave 50 mg of 3- (9 < 10-didehydro-2-phenylethynyl-8-alpha-ergolinyl) - M.p. 229-231 ° C.

(m / z) - +195.8 ⁰ (c 0.23, pyridine).

Example 5

3- {6-Methyl-2-phenylethynyl-8-alpha-ergolinyl} -1,1-diethylurea

X 200 g of 3- [6-methyl-2-phenylethynyl-8-alpha-ergolinyl-2H-1,1-diethylurea in 15 ml of methylenechoride was added at -12 ° C with 0.13 ml of phosphorus oxychloride. The mixture was allowed to warm to room temperature over 1 hour and stirred at room temperature for 16 hours. After evaporation of the methylene chloride, the residue is stirred in ether, the mixture is filtered and the residue is dried under vacuum over potassium hydroxide pellets. A solution of 245 mg of potassium xanthogenate in 15 ml of acetonitrile was then added at -15 ° C and the mixture was further stirred at room temperature for 2 hours.

After evaporation of the solvent, the residue was partitioned between ethyl acetate and saturated sodium bicarbonate solution and the organic phase was washed with saturated sodium chloride solution. After chromatography on silica gel twice, first using methylene chloride / ethanol (19: 1) and a second time using the same solvents (10: 1) as the eluent and recrystallizing from ethanol / hexane / ethyl acetate yields 60 mg of 3- [6]. -methyl-2-phenylethynyl-8-alpha-ergolinyl-1,1,1-diethylurea, m.p. 219-220 ° C.

Qalfa] _D ^«0 +195,8 (c 0.23, pyridine).

3- [6-Methyl-2-phenylethyl-8-alpha-ergolinyl] -1,1-diethylurea was prepared in an analogous manner.

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Example 6

3- (6-Methyl-2-phenylethyl-8-alpha-ergolinyl) -1,1-diethylurea

200 mg of 3- (6-methyl-2-phenylethynyl-8-alpha-ergolinyl) -1,1-diethylurea is added to a mixture of 150 g of palladium on barium carbonate (10%) in 30 ml of a solvent mixture consisting of 10 parts of hexane 2 parts of pyridine and 1 part of methanol, which mixture was pre-hydrogenated at room temperature and atmospheric pressure, were hydrogenated until the curve steeply rose. After filtering off the catalyst, the filtrate is concentrated and the residue is chromatographed on silica gel using a 2: 1 mixture of ethyl acetate and ethanol. Recrystallization gave 50 mg of 3- (6-methyl-2-phenetenyl-8-alpha-ergolinyl) -1,1-diethylurea as a mixture of Z- and E-derivative.

Example?

3- (6-Methyl-2-E-phenetenyl-8-alpha-ergolinyl) -1,1-diethylurea

To 160 mg of 3- (6-methyl-2-phenylethynyl-8-alpha-ergolinyl) -1,1-diethylurea under argon was added 3.5 ml of an approximately 1.2 M solution of DIBAH in toluene under 15 ml of absolute toluene. After stirring at room temperature for 10 minutes, the reaction mixture was heated to 80 ° C for 2 hours. After cooling, an aqueous hydrochloric acid solution was added to the mixture under a protective gas atmosphere, the mixture was stirred for 10 minutes, then basified with ammonia solution, filtered through silica gel, and the filtrate was then washed well with ethyl acetate. The organic phase is dried, concentrated and the residue is recrystallized from ethyl acetate / hexane. 89 mg of 3- (6-methyl-2-E-phenetenyl-8-alpha-ergolinyl) 1,1-diethylurea are obtained.

[.alpha.] D @ ²⁵ = +123 DEG (c = 0.2, pyridine).

Claims (3)

SUBJECT OF THE INVENTION A process for the preparation of novel 2-substituted ergoline derivatives of the general formula I X in which X represents an oxygen atom or a sulfur atom, R ¹ represents an alkyl group having 1 to 6 carbon atoms, Y is C ₂ H ₄ , -CH-CH- or -CaC-; R ² is optionally C 1 -C 4 alkoxy or a nitrile substituted phenyl, thiophenyl or pyridinyl group, Et represents an ethyl group, and '10 represents a single carbon-carbon bond or a carbon-carbon double bond and if Cg ~ - ~~ - ~ C ₁₀ represents a single carbon-carbon bond, then the hydrogen atom in position 10 assumes the a-configuration, and pharmaceutically acceptable acid addition salts, wherein, if X is oxygen, R ² is methyl, and -C = C ~~ ^ Q represents a single carbon-carbon bond, then YR ² does CJH ^ -phenyl, wherein by treating the ergoline derivatives of the general formula III in which R ^1, X 'and Et are as defined above and Z is halogen neoba -C ^ch, operating in the presence of a catalyst and a base of formula Hal - R ² optionally HCsC -R ² wherein R is as defined above and Hal represents a halogen atom, one reactant in each case being a halogen-containing compound, whereupon optionally the C1-C bond is partially or completely hydrogenated, the urea derivatives are optionally converted into thiourea derivatives and / or the resulting compounds are optionally converted by acid treatment to their physiologically tolerable addition salts with acids. 2. The process according to claim 1, wherein the corresponding compounds of formula III, Hal-R or HC-C-R are used as starting materials to form 3- [N -methyl-2- (thien-2-ylethynyl) -8-alpha-ergolinyl2] -1,1-diethylurea, 3- [N -methyl-2- (3-pyridinylethynyl) -8-alpha -ergolinyl2} 1,1-diethylurea, 3-Q2- (4-methoxyphenylethynyl) -6-methyl-8-alpha-ergolinyl-1,1,1-diethylurea, 3- [72- (4-cyanophenylethynyl) -6-methyl- 8-alpha-ergolinyl] -1,1-diethylurea; 3- [2- (4-methoxyphenethyl) -6-methyl-8-afla ergolinyl] -1,1-diethylurea. 3- (9,10-didehydro-6-methyl-2-phenylethynyl-8-alpha-ergolinyl) -1,1-diethylurea, 3- [6-methyl-2-phenylethynyl-8-alpha-ergolinyl] -1,1-diethylthiourea; and 3- (6-Methyl-2-phenylethenyl-8-alpha-ergolinyl) -1,1-diethylurea.