CS248739B2 - Production method of the new 2-substituted derivatives of ergoline - Google Patents

Abstract

Novel 2-substituted ergolines of the formula <IMAGE> in which C8---C9 and C9---C10 denote a CC single bond or a C=C double bond, but not a cumulated double bond, and the substituent in the 8-position is a- or b- if C8---C9 denotes a CC single bond, R<2> denotes CN, SR, SOR, <IMAGE> or -C(HOH)R where R denotes C1-4-alkyl, R<6> denotes C1-4-alkyl and R<8> denotes methyl or the group NH-CO-NEt2 or NH-CS-NEt2 and their salts are described, as well as their preparation by methods known per se from corresponding 2-unsubstituted ergolines by means of electrophilic substitution. The novel compounds have biological activity in the CNS field.

Description

The present invention relates to a process for the preparation of novel ergoline derivatives which are substituted in the 2-position. The compounds have valuable pharmacological properties and can be used as active ingredients of medicaments.

The object of the present invention is - a process for the production of the new 2-substituted-ergoline derivatives of the general formula - I means a single - carbon-carbon bond or a double-carbon-carbon bond, but not a cumulative - double bond - and - the substituent - at the 8-position - occupies the - and / or - position, if in the - position;

means - simple bond - carbon - carbon,

R ² represents a group - - CN, S CH, -SOCH3, -CR and - C (HOH) R

II

About taking

R is -alkyl-group having 1 to 4 carbon atoms,

К ⁶ represents an alkyl group -S 1 -to-C4 -carbon - -a

R 8 represents a methyl group or a group

NH - CO - N (C2 H5) 2 or

NH - CS - (C 2 H 5) and, as well as - their salts, which consist in that the ergoline of the formula II

which they are as defined above, treated with an electrophile selected from the group which is composed of chlorosulfonyl isocyanate (R ² = a nitrile group), dimethyl (methylthio) sulfoniumf luoroborátem (R ² = S CH) and an acyl chloride in the presence of a Lewis acid (R ² = CR) The carbonyl group at the 2-position substituent is then hydrogenated with a complex metal hydride or the methylthio group is oxidized with periodate and optionally the reaction product is converted into an acid addition salt by treatment with a physiologically tolerable acid.

Alkyl groups of up to 4 carbon atoms are those derived from aliphatic hydrocarbons. Such residues are, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.

The salts of the compounds of formula I which are produced by the process of the invention are acid addition salts and are derived from physiologically acceptable acids. Such physiologically acceptable acids are 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 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, decaonate, caprylate formate, isobutyrate, caproate, heptanoate, propiolate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandate, butin-1,4-dioate, hexin-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, 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 known ergolines which are not substituted in the 2-position, such as with Lisuride or Terguride, the compounds of formula I produced by the process of the invention are characterized by central anti-dopaminergic and / or α 2 -receptor blocking effects.

The central blockade of the 2-receptors, for example 1,1-diethyl-3- (6-methyl-2-methylthio-8α-ergolinyl) urea (A), can be illustrated by the interaction test using Clonidine as an α 2 -receptor agonist for of mice after single administration intraperitoneal pretreatment (parameter: suppression of 0.1 mg / kg ip of Clonidine induced hypothermia). Male mice (NMRI strain) were pre-treated with various doses of Compound A, which does not itself affect the thermoregulation of test animals or vehicle. 30 minutes later, all animals were administered Clonidine at a dose of 0.1 mg / kg i.p. 60 minutes after administration of A and / or vehicle (= 30 minutes after administration of Clonidine), the rectal temperature was measured using a thermosonde. While vehicle-treated mice showed hypothermia, dose-dependent effects of Clonidine on body temperature decrease were suppressed in animals pretreated with substance A. The effect of Compound A as a Clonidine antagonist was statistically significant as early as 0.2 mg / kg.

Central blockade of dopamine receptors of Compound A 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 of I. apomorphine). Male mice (NMRI strain) are pre-treated with various doses of Compound A, which does not itself affect the thermoregulation of the test animals or the vehicle. 30 minutes later, all animals are administered apomorphine at a dose of 5 mg / kg i.p. 60 minutes after administration of substance A or vehicle (= 30 minutes after administration of apomorphine), the temperature in the rectum is measured with a thermosonde. While vehicle-treated animals exhibit hypothermia, dose-dependent effects of apomorphine on body temperature decrease were inhibited in animals treated with Compound A administration. The effect of substance A as an apomorphine antagonist was statistically significant as early as 0.2 mg / kg.

Based on these findings, the compounds of the invention may be used as neuroleptics for the treatment of schizophrenic-type psychoses or as antldepressants.

The preparation of the compounds of the formula I according to the invention from the compounds of the formula II is carried out by methods known per se.

If R @ ^{2 is a} nitrile group, the process is carried out by reacting the ergoline of formula II in an inert solvent such as acetonitrile or. dimethylformamide, in the presence of a base such as trimethylamine or triethylamine, adds chlorosulfonyl isocyanate (cf. DE-OS 2 365 974).

The use of an inert gas atmosphere is expedient. The reaction is complete after 10 to 50 hours at room temperature.

When R2 is S-methyl, the process is carried out by mixing ergoline of formula II in an inert solvent such as dioxane or tetrahydrofuran with the addition of a sulfonium salt such as dimethylthiosulfonium fluoroborate. This reaction is complete after 0.5 and 2 hours at room temperature.

When R2 is an acyl group, the process is carried out by reacting the ergoline of formula II with an acyl chloride in the presence of a Lewis acid such as aluminum chloride. However, if the acyl chloride is not a liquid substance, for example, nitrobenzene or chlorobenzene may be used as the solvent.

The reaction is preferably carried out at temperatures below room temperature, such as at temperatures from -10 ° C to -5 ° C, and is complete after 1 to 5 hours.

A carbonyl group which is optionally present in the substituent R ² can be reduced to a hydroxy group with a complex · metal hydride such as sodium borohydride in a protic or else aprotic solvent such as tetrahydrofuran, acetonitrile, dioxane or dimethoxyethane, methanol, ethanol, isopropanol, optionally with the addition of anhydrous calcium chloride, preferably at the boiling point of the solvent or reaction mixture used.

Oxidation of the methylthio group to the sulfoxide group is accomplished by treatment with an aqueous solution of sodium periodate in acetonitrile. The reaction is complete after several hours at 50 ° C.

The compounds of formula I thus obtained are either in the form of the free bases or, optionally, in the form of their acid addition salts, obtained by reaction with a physiologically tolerated acid, such as tartaric acid or maleic acid, purification by recrystallization and / or chromatography.

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 materials required for carrying out the process of the invention are either known or can be prepared by methods known to those skilled in the art.

In order to form salts, the compounds of the present invention as medicaments are converted into pharmaceutical formulations containing, in addition to the active ingredient, a pharmaceutical, organic or inorganic inert carrier suitable for enteral or parenteral administration, such as water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations may be in solid form, for example in the form of tablets, dragees, suppositories, capsules or in liquid form, for example in the form of solutions, suspensions or emulsions. If desired, they also contain auxiliaries such as preservatives, stabilizers, wetting or emulsifying agents, salts for influencing the osmotic pressure or buffers.

The following examples illustrate the process in more detail, but do not limit its scope in any way.

Example · 1

680 mg of terguride [2 mmol] are dissolved in 120 ml of acetonitrile and 5.5 ml of triethylamine and a solution of 3.5 ml of chlorosulfonyl isocyanate in 40 ml of acetonitrile is added dropwise to the solution under ice-cooling and under argon. The ice bath was removed and the mixture was allowed to stand at room temperature for 2 days. In order to better isolate the polar by-products, 20 ml of diethylamine are added and the mixture is stirred at room temperature for 3 hours. The reaction mixture was then diluted with methylene chloride, shaken with 1N sodium hydroxide solution, and the aqueous phase was extracted again. The combined organic phases were dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel using methylene chloride / methanol as eluent. 229 mg (31% of theory) of crude 3- (2-cyano-6-methyl-8α-ergolinyl) -14-diethylurea were isolated. After crystallization from ethyl acetate, 92 mg of pure product is obtained.

[.alpha.] D = + 20 DEG (0.1% in chloroform).

The polar by-products are acylation products in position 1 and / or position 2.

Example 2

Dissolve 507 mg of lisuride (1.5 mmol) in 30 mL of tetrahydrofuran and add 588 mg of dimethylmethylthiosulfonium fluoroborate (3 mmol) at room temperature under a nitrogen atmosphere. After stirring at room temperature for 30 minutes, the mixture was partitioned between methylene chloride. and a bicarbonate solution, the organic phase was combined, dried over sodium sulfate and evaporated. The crude product was chromatographed on silica gel using methylene chloride and methanol as eluent. 506 mg (82% of theory) of 3- (9,10-didehydro-6-methyl-2-methylthio-8Xergolinyl) -1,1-diethylurea are obtained from which the tartaric acid salt is prepared.

Yield: 208 mg (55% of theory) [.alpha.] D = 226 DEG (0.5% in pyridine).

The following compounds were prepared in an analogous manner:

from terguride there were obtained 1H-diethyl-4-methyl-2-methylthio-8a: ergolmyl) urea, 58% yield (after chromatography), tartaric acid salt (79% yield), [α] D = - | - 23O (0.5% in pyridine);

from 8,9-didehydro-6,8-dimethylmethyloline 8,9-didehydryl-1,6,8-dimethyl-2-methylthioergoline is obtained, yield 95% (after chromatography), tartaric acid salt (48% yield), [α] D = - 772 ° (0.1% in pyridine);

starting from 3- (6-methyl-8α-ergolinyl) -1,1-diethylthiourea: 1,1-diethyl-3- (6-methyl-4-methylthio-N-ergolinylthiourea);

from 1,1-diethyl-3- (6-methyl-8ra-ergollnyl) urea, 1,1-diethyl-3- (6-methyl-2-methylthio-8/3-ergolinyl) urea is obtained, [a] D - 100 ° (0.1% in chloroform);

Zl, l-děethyl-3- (6-n-propyl-8a-ergolinyl) urea to afford l, l-diethyl-3- (2-methylthio-6ln-propyll8 _l of ergolínyí) urea.

Example 3

To 3 ml (42 mmol) of acetyl chloride · under ice-cooling · are added 0.467 g (3.5 mmol) of anhydrous aluminum chloride and at -10 ° C 0.477 g (1.4 mmol) of 3- (6-methyl-4-a) After stirring for 2.5 hours at -5 to 0 ° C, 30 ml of hexane are added and the oily precipitate is separated by decantation and then taken up in a mixture of methylene chloride and water. % sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and concentrated by column chromatography on 150 g of silica gel with methylene chloride / ethanol (10: 1) and recrystallization from ethanol / hexane to give 134 mg (25%). %) 3- (2-acetyl-6-methyl-8α-erginyl) -1,1-diethylurea.

[α] D = 4-51 ° (0.2% in pyridine).

The following compounds were prepared in an analogous manner:

from 8,9-didehydrol-16,8-dimethylergoline to give 2-acetyl-8,9-didehydro-6,8-dimethyl-goline, m.p. 168-169 ° C (from ethanol / hexane);

from terguride there is obtained 3- (2-propionyl-6-methyl-8α-ergolinyl) 11,1-diethylurea and from lisuride there is obtained 3- (2-acetyl-9,10-didehydr-6-methyl-1 - ( N - ((R) - (R) - (R) -1,1-Diethylurea).

Example 4 mg (0.149 mmol) of 3- (2-acetyl16-methyl-8α-ergolinyl) -1,1-diethylurea in 4 ml of absolute tetrahydrofuran was heated with 38 mg (1 mmol) of sodium borohydride and 18 mg (0.162 mmol) of anhydrous calcium chloride for 2 hours at reflux. After cooling to room temperature and after the addition of water, the reaction mixture is stirred for a further 10 minutes, the tetrahydrofuran is distilled off and methylene chloride is added to the residue. Washing the organic phase with saturated sodium chloride solution and drying over magnesium sulphate after concentration and column chromatography of the crude product over 75 g of silica gel using methylene chloride / ethanol (5: 1) as eluent gave 26 mg (46%). 6% of theory) 3- (2- (1-hydroxyethyl) -6-methyl-8-aergolinyl] -1,1-diethylurea as an oil which partially crystallizes.

Mp 175 ° C.

The following compounds are produced in an analogous manner:

3- (2- (1-hydroxyethyl) -9,10-didehydro-6-methyl-8α-ergolinyl) -1 was obtained from 3- (2-acetyl-9,10-didehydrol-16-methyl-8alergolinyl) -1,1-diethylurea. 1,1-methyl-urea;

3- (2-propionyl-6-methyl-8α-ergolinyl) -diethylurea yields 3- [2l (1-hydroxypropyl) -6-methyl-8α-ergolinyl] -1,1-diethylurea and 2-acetyl-8; 9-Didchydrol16,8-dimethylergoline yielded 2- (1-hydroxyethyl) 18,9-didehydro-6,8,4-dimethyl- ethylergoline.

Example 5

210 mg of 1,1-diethyl-3- (6-methyl-2-methylthio-8α-ergolinyl) urea were dissolved in ml of acetonitrile and 0.5 g of sodium periodate in 5 ml of water was added portionwise. The mixture was stirred for 16 hours at room temperature

114 DEG-116 DEG C., 50 DEG C., the residue was partitioned between 109 mg of 1,1-diethyl-3- (6-methylthylene chloride) and water, and the phase was purified with 2-methylsulfinyl. 8a-ergolinyl] urea, dried with sodium sulfate and evaporated, and the residue chromatographed on silica gel.

Claims (1)

A process for the preparation of novel 2-substituted ergoline derivatives of the general formula wherein: Cg, a R ⁶ represents a C 1 -C 4 alkyl group and R ⁸ represents a methyl group or a group NH - CO - N (C2 H5) 2 or NH-CS-N (C2H5) 2, and salts thereof, characterized in that the ergoline of formula (II) is a carbon-carbon single bond or a carbon-carbon double bond but not a cumulative double bond and the substituent at position 8 occupies a- or / S-position, if in which represents a single carbon-carbon bond, R ² is CN, SCH3, SOCH3, and -CR -C (HOH) R II o whereas R is C 1 -C 4 alkyl, as defined above, acting with an electrophilic agent selected from the group consisting of chlorosulfonyl isocyanate, dimethyl (methylthio) sulfonium fluoroborate and acyl chloride of up to 5 carbon atoms in the presence of a Lewis acid, optionally optionally carbonyl the group at the 2-substituent is hydrogenated with a complex metal hydride or the methylthio group is oxidized by treatment with periodate and optionally the reaction product is converted into an acid addition salt by treatment with a physiologically compatible acid.