CS259898B2 - Method of ergoline's new 1,2-disubstituted derivatives production - Google Patents

Description

A process for producing novel 1,2-disubstituted ergoline derivatives of formula I wherein X represents O or S, ^R1 is Cl-Cd alkyl, R ² = Hal, C2-C4 acyl, Cl to C alkyl, C2- C3-alkenyl, C2-C3-alkynyl, -S-R ⁵ wherein R ⁵ is Cl-C alkyl, which is optionally substituted phenyl, or is phenyl, then R ² represents a group of formula (a), -CHO or - CH 2 OH, R ³ is C 1 -C 4 -alkyl or C 2 -C 4 -acyl, Et is ethyl and is a single C-C bond or a C-C double bond, and when

Cmc represents a single C-C bond, then the hydrogen atom at the 10-position assumes the α-configuration as well as the pharmaceutically acceptable acid addition salts thereof, characterized in that the compound of formula III is acylated, thlomethylated or halogenated and then optionally, the substituents in the obtained compound are converted to other substituents, and the obtained compounds are optionally converted into physiologically compatible acid addition salts. The compounds produced can be used as medicaments.

The present invention relates to a process for the preparation of the novel 1,2-disubstituted ergoline derivatives of the following general formula (I) which have valuable pharmacological properties and can be used as medicaments.

SUMMARY OF THE INVENTION The present invention provides a process for the preparation of novel 1,2-disubstituted ergoline derivatives of the general formula I _N H-CX-NEt?

AND

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 a phenyl group, furthermore a group of the formula

-CH 2 S further represents a group -CHO or CH 2 OH, R ³ represents an alkyl group having 1 to 4 carbon atoms or an acyl group having 2 to 4 carbon atoms,

Et is ethyl and

C 8 - C ₁₀ represents a carbon-carbon single bond or a carbon-carbon double bond, and if

(A) represents 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 such acids being 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 formate, isobutyrate, caprolate, heptanoate, propiolate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandate, butin-1,4-dioate, hexin-1,6-diate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesifonate, propanesulfonate-naphthalenesulfonate-naphthalenesulfonate-naphthalenesulfonate-naphthalenesulfonate-naphthalenesulfonate

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

Central blockade of dopamine 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 hypothermia induced by administration of 5 mg / kg i.p. apomorphine). Male mice (NMRI strain) are pre-treated with various doses of a substance that does not itself affect the thermoregulation of the test animals,

259833 optionally with a carrier. 30 minutes later, all animals are administered apomorphine at a dose of 5 mg / kg i.p. 60 minutes after administration of the substance or vehicle 30 minutes after administration of the apomorphine, the rectal temperature is measured using a thermosonde. While vehicle-only mice exhibited hypothermil, dose-dependent effects of apomorphine on body temperature decrease were suppressed in the animals treated with the substance.

Central α2-receptor blockade can be illustrated by the clonidine interaction assay as an α2 -receptor agonist in mice after single intraperitoneal pre-administration (parameter: suppression of 0.1 milligram per kg ip clonidine induced hypothermia). Male mice (NMRI strain). 30 minutes later, clonidine was administered to all animals at a dose of 0.1 mg / kg.

i. p. 60 minutes after administration of the substance or vehicle (- 30 minutes after administration of clonidine), the temperature in the rectum is measured with a thermosonde. While vehicle-only treated mice showed hypothermia, the dose-dependent effect of clonidine on body temperature decrease 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

in which

Et, X and R ¹ are as defined above, and R ³ 'is hydrogen or C 1 -C 4 alkyl, acylated, thiomethylated or halogenated, whereupon the compound of formula (I) wherein R ² is halogen, converted to the corresponding 2-lithiumergoline derivative and then reacted with an electrophilic reagent to give compounds of formula I wherein R ² is C 1 -C 4 alkyl or -SR ⁵ where R ⁵ is as defined above, or in the presence of a catalyst and a base are reacted with a C 2 -C 3 alkenylating agent or a C 2 -C 3 alkynylating agent to give compounds of formula I wherein R ² is C 2 -C 3 alkenyl or C 2 -C 3 alkynyl; 2 to 3 carbon atoms which are then optionally wholly or partially hydrogenated and the compounds thus obtained are optionally p are converted to thiourea derivatives and / or physiologically tolerated acid addition salts.

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

For example, the acyl group R ^{2 is} introduced by treating the ergoline of formula III with an acyl chloride in the presence of a Lewis acid such as aluminum chloride. If the acyl chloride is not a liquid, then the reaction may be carried out in inert solvents such as chlorobenzene or nitrobenzene.

Halogenation at position 2 can be carried out, for example, according to the procedure described in European Patent Application Publication No. 56,358.

The methylthiolation can be carried out, for example, in an inert solvent such as dioxane or tetrahydrofuran by treatment with a sulfonium salt such as dimethylmethylthiosulfonium fluoroborate, and is terminated after 0.5 to 2 hours at room temperature.

However, the alkylthiolation and arylthiolation may also be carried out via a 2-IIthiumergoline derivative and subsequent reaction with an electrophilic sulfur compound.

For this purpose, the 2-haloenergoline derivative of the formula I is reacted with lithiumergoline, preferably with alkyl lithium or phenyllithium, at low temperatures in an aprotic solvent to give the corresponding 2-lithiumergoline derivative. Suitable alkyllithiums are, in particular, tert-butyllithium (cf. European Patent Application No. 160,842).

The subsequent electrophilic substitution is carried out at low temperatures, preferably at temperatures between -110 ° C to -50 ° C in the same aprotic solvent. Suitable aprotic solvents are ethers or hydrocarbons such as tetrahydrofuran, dioxane, diethyl ether, toluene, hexane and the like.

Electrophilic agents preferably include thiosulfonic acid S-esters such as methanesulfonic acid S-methyl ester, toluene-thiosulfonic acid S-ethyl ester, toluene-thiosulfonic acid Sn-propyl ester or disulfides such as dibenzyl disulfide, diphenyldisulfide, tetraisopropylthiuramidisulfide or lower alkyl halides such as98 or lower alkyl halides. alkyl iodides or halogenated strong, such as lower alkylsilanes, such as trimethylchlorosilane.

In order to introduce a 2-alkenyl group or a 2-alkynyl group, a 2-haloenergoline derivative is reacted with a monosubstituted acetylene derivative or a monosubstituted vinyl derivative in the presence of a catalyst and a base.

The reaction is carried out at temperatures from 0 ° C to 120 ° C, preferably at temperatures of 70 ^C to 100 C 73, in an aprotic solvent such as dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile or dioxane.

Preferred catalysts are palladium compounds, such as palladium salts or complex palladium compounds. Examples which may be mentioned are palladium (II) acetate, trans-dichloro-bis- (tri-o-tolylphosphine) palladium (II) or trans-dichloro-bis- (triphenylphosphine) palladium (II) and palladium (O) -tetrakis-triphenylphosphine. it is used in an amount of from 0.01 to 0.1 mol, based on the 2-halogenergoline used.

Suitably, the reaction is carried out under an atmosphere of an inert gas such as nitrogen or argon, partly also at elevated pressure.

The reaction is stimulated by the addition of triarylphosphines.

Additions of catalytic amounts of copper salts, such as copper (I) iodide or copper (I) bromide, are suitable for ethinylation.

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

To produce 2-acetylene- or 2-vinylergoline derivatives which are not substituted in the acetylene or vinylene group, the proton is conveniently protected by a conventional protecting group, such as a trialkylsilyl group, which is optionally cleaved during the reaction mixture.

If the protecting group is a tetrahydropyranyl group, an acid such as pyridinium p-toluenesulfonate or dilute sulfuric acid in an alcohol at 70 to 100 ° C is used to cleave the latter.

By treatment with catalytically activated hydrogen, the 2-vinylderivatives can be completely or partially hydrogenated.

The complete hydrogenation is carried out in the presence of a catalyst such as Raneynicl 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, in acids such as glacial acetic acid and the like.

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

However, the conversion of the ethinyl derivative to the wool derivative can also be carried out by addition of organometallic compounds such as diisobutylaluminum hydride and subsequent hydrolysis. Suitable solvents are hydrocarbons or ethers.

The resulting 2-ethynyl and 2-hydroxypropargyl derivatives can be reacted with alkyl halides in the presence of lithium diisopropylamide or phase transfer catalysts to form alkylethnyl derivatives or alkyl propargyl ethers while simultaneously alkylating the 1-position, if unsubstituted.

Conversion of the 8α-ureldodrates to the corresponding thiones 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 a concentrated solution of the desired acid in methanol is added 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 1,1-Diethyl-3- (1,6-dimethyl-2-methylthio-8'-ergolinyl) urea

354 mg (1 mmol) of 1,1-diethyl-3- (1,6-dimethyl-8α-ergolinyl) urea are dissolved in 20 ml of tetrahydrofuran and 392 mg (2 mmol) of nitrogen are added to the solution at room temperature. dimethylmethylthiosulfonium tetrafluoroborate and 0.24 ml of 50% tetrafluoroboric acid. After stirring at room temperature for 30 minutes, the reaction mixture was partitioned between methylene chloride and sodium bicarbonate solution, the organic phase was combined, dried over sodium sulfate and evaporated. The crude product is chromatographed on silica gel using methylene chloride as eluent. Recrystallization yielded 276 mg (69%).

[α] _D - + 11 ° (0.5%, in chloroform).

From 3- (9,10-didehydro-1,6-dimethyl-8H-ergolinyl) -1,1-diethylurea, 3- (9,10-didehydro-1,6-dimethyl) was obtained according to the above procedure in the presence of tetrafluoroboronic acid. -2-methylthio-8 (N -ergolinyl) -1,1-diethylurea in 55% yield. Example 2

3- (2-bromo-9,10-didehydro-1,6-dimethyl-8α-ergolinyl) -1,1-diethylurea

Dissolve 352 mg (1 mmol) of 3- (9,10-didehydro-1,6-dimethyl-8α-ergolinyl) -1,1-diethylurea in 20 ml of anhydrous dioxane and add 484 mg (1.5 ml) of the obtained solution. mmole) of pyrrolidone hydroperbromide and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture is then poured onto saturated sodium bicarbonate solution, extracted with roethylene chloride and the organic phase is dried over sodium sulfate. After evaporation of the solvent, the residue is chromatographed on silica gel, and after crystallization, 345 mg of the desired compound is isolated (80% yield).

[α] β = + 299 ° (0.5%, in chloroform).

EXAMPLE 3 1,1-Diethyl-3- (1,6-dimethyl-2-phenylthio-8'-ergolinyl) urea

To 4 ml of anhydrous, freshly distilled toluene was added 0.3 ml (1.5 mmol) of distilled hexamethyldisilazane under argon and the mixture was cooled to 0 ^DEG C. Then 0.85 ml (1.4 mmol) of 15% butyllithium was added dropwise. in hexane and the mixture was further stirred at 0 ° C for 15 minutes, then a solution of 432 mg of 3- (2-bromo-1,6-dimethyl-8α-ergolinyl) -1,1-diethylurea ( 1 mmol) in 50 ml of anhydrous, freshly distilled toluene and stirred for a further 15 minutes at 0 DEG C. After addition of 1 ml of distilled tetramethylethylenediamine, the reaction mixture is cooled to -90 DEG C. At this temperature, 5 ml (7 ml) is added. tert-butyllithium (14% in hexane) was added and the mixture was further stirred for 2 minutes, then 1 g of diphenyldisulfide (5 mmol) was added, and after stirring at -70 ° C for 2 h, water was added for work-up. The organic phases are washed with saturated sodium bicarbonate solution The combined ethyl acetate phases were dried over sodium sulfate and concentrated to give 180 mg of the desired compound (39% of theory) after crystallization from ethyl acetate and tert-butyl methyl ether.

[Α] D - + 17 ° (0.5%, in chloroform).

In a completely analogous manner, the following ureas are prepared from the same starting material:

substitution with dibenzyl disulphide gave 3- (2-benzylthio-1,6-dimethyl-8-ergolinyl) -1,1-diethylurea in 47% yield;

using S-n-propyl p-toluenethiosulfonic acid ester was obtained

1.1-diethyl-3- (1,6-dimethyl-2-n-propylthio-8a-ergolinyl) urea, yield 65%.

If 3- (2-bromo-9,10-didehydro-1,6-dimethyl-8x-ergolinyl) -1,1-diethylurea is reacted with diphenyldisulfide, 3- (9,10-didehydro-1) is obtained. 6-dimethyl-2-phenylthio-8'-allergolinyl) -1,1-diethylurea in 47% yield.

Example 4

1,1-Diethyl-3- (2-vinyl-1-propyl-6-methyl-8α-ergolinyl) urea

1.15 g of 1,1-diethyl-3- (2-iodo-1-propyl-6-methyl-8α-ergolinyl) urea was heated in 10 ml of dimethylformamide together with 10 ml of trlethylamine, 53.5 mg of triorthotolylphosphine, 39.4 mg of palladium chloride and 1.34 ml of vinyltrimethylsilane for 3 hours at 115 ° C (bath temperature) in a small autoclave under argon atmosphere. After evaporation, the mixture was partitioned between methylene chloride and sodium bicarbonate solution. The organic phase is evaporated and the residue is chromatographed over silica gel using a 3: 1 mixture of ethyl acetate and ethanol. 218 mg of 1,1-diethyl-3- (2-trimethylsilylvinyl-1-propyl-6-methyl-8'-ergolinyl) urea and 230 mg of 1,1-diethyl-3- (2-vinyl-1-propyl) are obtained. 6-methyl-8-ergoninyl) urea as an oil.

Example 5

1,1-Diethyl-3- (2-ethyl-1-propyl-6-methyl-8α-ergolinyl) urea

150 mg of 1,1-diethyl-3- (2-vinyl-1-propyl-6-methyl-8α-ergolinyl) urea is hydrogenated in 20 ml of ethanol in the presence of 0.1 g of Raney-nickel at room temperature and atmospheric pressure hydrogen. Filtration of the catalyst through diatomaceous earth, evaporation of the filtrate and chromatography over silica gel using toluene / ethanol / water (80: 20: 1) as eluent gave 65 mg of 1,1-diethyl-3- (2-ethyl-1-). propyl-6-methyl-8α-ergolinyl urea as an oil.

if

Example 6

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 methylene 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 methylene chloride and ethanol as eluent. Recrystallization from a small amount of ethanol / hexane gave 100 mg of 3- (6-methyl-1-propyl-2-ethyl-8α-ergolinyl) -1,1-diethylthiourea, m.p. 173-175 ° C.

[Α] D = + 48 ° (c = 0.2, pyridine).

Example 7 1,1-Diethyl-3- {2-trimethylsilylethynyl-1-acetyl-6-methyl-8 (z-ergolinyl) urea

260 mg of 1,1-diethyl-3- (2-iodo-1-acetyl-6-methyl-8α-ergolinyl) urea are heated in 3 ml of dimethylformamide with 6 ml of triethylamine, 0.5 ml of trimethylsilylacetylene, 6 mg of copper iodide and 15 ml of bis-tri-orthotolylphosphine palladium (II) dichloride at 60 ° C under argon for 1.5 hours. After evaporation, the mixture was partitioned between ethyl acetate and sodium bicarbonate solution. The organic phase is chromatographed after evaporation through silica gel with methylene chloride / methanol 9: 1. 100 mg of 1,1-diethyl-3- (2-trimethylsilylethynyl-1-acetyl-6-methyl-8α-ergolinyl) urea is obtained as an oil.

Example 8 1,1-Diethyl-3- (2-ethynyl-1-propyl-6-methyl-8α-ergolinyl) urea

109 mg of 1,1-diethyl-3- (2-ethynyl-6-methyl-8α-ergolinyl) urea in 5 ml of absolute tetrahydrofuran was added dropwise at -30 degrees Celsius under argon to a solution of lithium diisopropylamide prepared over 15 minutes. minutes at 0 ° C from 0.15 ml of dilsopropylamine and 1.8 ml of a 0.6 M solution of n-butyllithium (hexane) in 3 ml of absolute tetrahydrofuran. After stirring for 30 minutes at -30 ° C, 0.07 ml of propyl iodide is added. The reaction mixture was stirred at -20 ° C for 1 hour and then stirred at room temperature overnight. After evaporation, extraction with ethyl acetate was carried out after addition of sodium bicarbonate solution and a small amount of ethanol. The organic phase is concentrated and chromatographed over silica gel using 10: 10: 1 toluene / ethyl acetate / water. 30 mg of 1,1-diethyl-3- (2-ethynyl-1-propyl-6-methyl-8a-ergolinylurea) are obtained in the form of an oil.

In the same manner, 1,1-diethyl-3- (2-propynyl-1,6-dimethyl-8α-ergolinyl) urea is obtained as the oil from the same starting material as above.

Claims (3)

A process for the preparation of novel 1,2-disubstituted ergoline derivatives of the general formula I NH-CX-NE ¹ ?. 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 a phenyl group, furthermore a group of the formula CH \ r * furthermore represents -CHO or CH 2 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 C ₁₀ represents a carbon-carbon single bond or a carbon = carbon double bond, and if it represents a carbon-carbon single bond, the hydrogen atom at the 10-position occupies the α-configuration as well as the pharmaceutically acceptable acid addition salts thereof, characterized by A compound of formula III in which: X and R ¹ are as defined above, and R ³ 'is hydrogen or C 1 -C 4 alkyl, with an agent selected from an acylating, thiomethylating or halogenating agent, whereupon the compounds of formula (I) thus obtained are: wherein R ² represents halogen, are converted into the corresponding 2-lithiumergolinu and then reacted with an electrophilic reagent to form compounds of formula I wherein R ^z is an alkyl group having 1 to 4 carbon atoms or a group -SR ^5, wherein R ⁵ as defined above, or reacted with a C 2 -C 3 alkenylating agent or a C 2 -C 3 alkynylating agent in the presence of a catalyst and a base to form compounds of formula I wherein R ² is a C 2 -C 3 alkenyl group C 3 or C 2 -C 3 alkynyl, which are then optionally wholly or partially hydrogenated, and the compounds thus obtained are optionally converted into other compounds of formula I, within the meaning of the general formulas, urea derivatives into thiourea derivatives and / or into physiologically tolerable acid addition salts. 2. A process according to claim 1, wherein the corresponding compounds of formula (III) are used as starting materials 3- (2-bromo-1,6-dimethyl-8α-ergolinyl) -1,1-diethylurea, 3- (2-bromo-1-methyl-8-n-propyl-8α-ergolinyl) -1,1-diethylurea, 1,1-diethyl-3- (1-propyl-2-iodo-6-methyl-8α-ergolinyl) urea, 1,1-diethyl-3- (1-methyl-2-ethynyl-6-methyl-8α-ergolinyl) urea, 1,1-diethyl-3- (1-propyl-2-ethyl-6-methyl-8o) -ergolinyl urea, 1,1-diethyl-3- (1-methyl-2-phenethyl-6-methyl-8α-ergolinyl) urea, 1,1-diethyl-3- (1-methyl-2-phenylethynyl-6-methyl-8'-ergolinyl urea), 1,1-diethyl-3- [1-methyl-2- (3-methoxypropinyl) -6-methyl-8α-ergolinyl] urea, 1,1-diethyl-3- (1,6-dimethyl-2-methylthio-8α-ergolinyl urea), 3- (9,10-didehydro-1,6-dimethyl-2-methylthio-8α-ergolinyl) -1,1-diethylurea, 3- (2-bromo-9,10-didehydro-1,6-dimethyl-8a-ergolinyl) -1,1-diethylurea, 1,1-diethyl-3- (1,6-dimethyl-2-phenylthio-8α-ergolinyl) urea, 3- (2-benzylthio-1,6-dimethyl-8a-ergolinyl) -1,1-diethylurea, 1,1-diethyl-3- (1,6-dimethyl-2-n-propylthio-8a-ergolinyl) urea, 3- (S, 10-didehydro-1,6-dimethyl-2-phenylthio-8a-ergolinyl) -1,1-diethylurea; 1,1-diethyl-3- (1,2,6-trimethyl-8α-ergolinyl) urea, 1,1-diethyl-3- (2-iodo-1-acetyl-6-methyl-8α-ergolinyl) urea, 1,1-diethyl-3- [1-acetyl-2- (3-tetrahydropyran-2-yloxy) -1-propynyl) -6-methyl-8a-ergolinyl] urea, 1,1-diethyl-3- (2-vinyl-1-propyl-6-methyl-8α-ergolinyl) urea, 1,1-diethyl-3- (2-ethyl-1-propyl-6-methyl-8α-ergolinyl) urea urea, 3- (6-methyl-1-propyl-2-ethyl-8α-ergolinyl) -1,1-diethylthiourea, 1,1-diethyl-3- (2-ethynyl-1-propyl-6-methyl-8α-ergolinyl) and urea and 1,1-diethyl-3- (2-propynyl-1,6-dimethyl-8α-ergolinyl) urea.