DE3413659A1 - Novel 2-substituted ergoline derivatives - Google Patents

Abstract

2-Substituted ergolines of the general formula I <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 the group COR%, (R%=OH, OC1-4-alkyl or NH2), the group CH=CH-CO2R_ or CH2-CH2-COR_ (R_=C1-4-alkyl, the group CIC-R_% or HC=CH-R_% (R_%=hydrogen, C1-4-alkyl, phenyl, CH2OH, <IMAGE> CO2R_, CH2NR_2 and <IMAGE> where R_=C1-4-alkyl), R<6> denotes lower alkyl having up to 4 C atoms and R<8> denotes methyl or the group NH-CO-NEt2 or NH-CS-NEt2 and their salts are described, which can be prepared in a manner known per se by electrophilic substitution of the corresponding 2-haloergolines in the presence of a palladium catalyst. The novel compounds are biologically active in the CNS field.

Description

New 2-substituted

Ergoline derivatives The invention relates to new ergoline derivatives of the formula I, which are substituted in the 2-position, their preparation according to per se known methods and their use as medicaments based on these compounds.

Alkyl radicals with up to 4 carbon atoms are those that differ from aliphatic Derive hydrocarbons, e.g.

Methyl, ethyl, n-propyl, isopropyl, n-butyl and tert-butyl.

The salts of the compounds of the formula I according to the invention are acid addition salts and are derived from physiologically harmless acids. Such. physiological harmless acids are inorganic acids such as hydrochloric acid, Nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydriodic acid, nitrous acid or phosphorous acid, or organic acids such as aliphatic mono- or dicarboxylic acids, phenyl-substituted alkanecarboxylic acids, hydroxyalkanecarboxylic acids or alkanedicarboxylic acids, aromatic acids, or aliphatic or aromatic Sulfonic acids. Physiologically harmless salts of these acids are therefore e.g. Sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, Dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, Acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, Propiolate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, butyne-1,4-dioate, Hexyne-1,6-dioate, benzoate, chlorobinzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, Toluenesulfonate, Chlorobenzene sulfonate, xylene sulfonate, phenyl acetate, phenyl propionate, phenyl butyrate, Citrate, lactate, ß-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, Naphthalene-1-sulfonate or naphthalene-2-sulfonate.

Compared to known ergolines unsubstituted in the 2-position, such as, for example, the lisuride or the terguride, the compounds according to the invention are distinguished of formula I by a centrally antidopaminergic and / or a2 receptor blocking agent Effectiveness.

The central dopamine receptor blockade, e.g. of 1.l-diethyl- (6-methyl-2-ethynyl-8a-ergolinyl) urea (A) was in an interaction test with the dopamine receptor agonist apomorphine shown in mice after a single i.p. pretreatment (parameter: abolition of the by apomorphine 5 ng / kg i.p. caused hypothermia). Male NMRI mice were used with different doses of A, which itself did not affect the thermoregulation of the test animals influence, or pretreated with carrier medium. 30 minutes later everyone received Animals apomorphine 5 mg / kg i.p. 60 minutes after administration of A or carrier medium (= 30 Minutes after apomorphine), the rectal temperature was measured using a thermal probe measured. While the mice pretreated with the carrier medium exhibited hypothermia, was the body temperature lowering effect in 2-ethynyl -TDjIL-pretreated animals of apomorphine dose-dependently canceled.

The apomorphine-antagonistic effect of A was already in the dosage 0.2 mg / kg statistically significant.

The central a2 receptor blockade of A was tested in an interaction test with the 2-receptor agonist olonidine on pliiuses after a single i.p. pretreatment (Parameter: Abolition of those caused by clonidine 0.1 mg / kg i.p. Hypothermia). Male NMRI mice were given various doses of A, self do not influence the thermoregulation of the test animals or with the carrier medium pretreated. 30 minutes later, all animals received clonidine 0.1 mg / kg i.p.

60 minutes after administration of A or carrier medium (= 30 minutes after clonidine) the rectal temperature was measured with the help of a thermal probe. While the with Mice pretreated with carrier medium exhibited hypothermia In animals, the body temperature-lowering effect of clonidine was lifted in a dose-dependent manner. The clonidine antagonistic effect of A was already at the dose of 0.2 mg / kg statistically significant.

On the basis of these findings, the compounds according to the invention can therefore as neuroleptics for the treatment of psychoses of the schizophrenic type or used as antidepressants.

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

For this purpose, a 2-iodine or 2-bromine ergoline is used with an electrophile Reagent such as benzyl alcohol under a carbon monoxide atmosphere, an acrylic ester or a monosubstituted acetylene either without a solvent, in the corresponding amine or in an aprotic, water-miscible solvent, in the presence of a secondary or tertiary amine, at temperatures above room temperature in the range from 40 ° C to the boiling point of the reaction mixture in the presence of a palladium catalyst, brought to reaction.

Acrylic esters are to be understood as meaning those esters of acrylic acid which by esterification with a lower aliphatic alcohol with up to 3 carbon atoms such as the ethyl acrylate.

Monosubstituted acetylene is used to denote ethynyl derivatives, in which one H atom is replaced by C1-3-alkyl, phenyl, hydroxymethyl, tetrahydropyranyloxy, C1-3 alkoxycarbonyl, di-Cl 3-alkylaminomethyl and C1-3-alkyldimethylsilyl substituted is.

Examples of aprotic, water-miscible solvents are called dimethylformamide, N-methylpyrrolidone, tetrahydrofuran, acetonitrile and dioxane.

Secondary and tertiary amines are, for example, dimethylamine, diethylamine, Piperidine, triethylamine and tri-n-butylamine.

Palladium salts and palladium complex compounds are used as palladium catalysts in question. Examples include palladium-II-acetate, trans-dichloro-bisttri-o-tolyl-phosphine) -palladium (II) or trans-dichloro-bis (triphenylphosphine) -palladium (II) and palladium (O) -tetrakis-triphenylphosphine. The catalyst is used in an amount of 0.01 to 0.1 mol based on the 2-halo-ergoline applied.

In some of the reactions, the addition of copper-I-iodide has proven itself or of tri-o-tolylphosphine.

The reactions are expediently carried out with the exclusion of air, but sometimes also under increased pressure, i.e.

under an inert gas atmosphere and in an autoclave.

If the substituent R 'is optionally hydroxy, the corresponding Benzyl 2-carboxylate in a protic solvent such as an aliphatic Alcohol, e.g. methanol, in the presence of finely divided palladium, such as palladium black, hydrogenated with hydrogen under normal pressure at room temperature.

If the substituent R 'is optionally the amino group, then the corresponding 2-benzyl ester with ammonia in a protic solvent such as in an alcohol, preferably ethylene glycol, at an elevated temperature to the corresponding Carboxamide implemented.

If the substituent in the 2-position contains an exocyclic C = C double bond or C = C triple bond, the unsaturated bond can e.g. with Raney nickel or palladium / carbon in an aliphatic alcohol at room temperature under normal pressure be wholly or partially easily reduced to the corresponding hydrogenation product.

If the ethynyl substituent in the 2-position contains a protecting group, such as a SiMe2R "group, this can be done with a weak base such as sodium or potassium carbonate at room temperature, but also with acids or fluoride ions (cesium fluoride or tetrabutylammonium fluoride) removed. If the ethynyl group is protected on one side as an acetone addition product, so the protecting group is created by boiling with a strong base such as potassium or sodium hydroxide removed at 100 oC.

If the protective group is the tetrahydropyranyl radical, then one uses for Cleavage of an acid such as pyridinium p-toluenesulfonate or dilute sulfuric acid, in an alcohol at 70-10000.

The compounds of formula I obtained in this way are either as free Bases or, if desired, in the form of their acid addition salts, which are obtained by reaction with a physiologically compatible acid such as tartaric acid or maleic acid, are obtained, purified by recrystallization and / or chromatography.

To form salts, the compounds of formula I are in little Dissolved methanol or methylene chloride and with a concentrated solution of the desired Acid in methanol is added at room temperature.

The ones required to carry out the inventive method Starting compounds are either known or can be known to the person skilled in the art Methods are made.

Preparation of the starting material 1 mmol of terguride is anhydrous in 20 ml Dissolved dioxane, mixed with approx. 1.5 ml of N-iodosuccinimide at room temperature and 30 Stirred for minutes. The reaction mixture is then poured into a saturated one Bicarbonate solution, extracted with methylene chloride and dried the organic phase with magnesium sulfate. After evaporation of the solvent, the residue becomes on silica gel chromatographed. 1,1-Diethyl-3- (2-iodo-6-methyl-8α-ergolinyl) urea is obtained in 76% yield [α] D = +37.3 ° C = 0.2 in pyridine.

In an analogous manner, lisuride and N-bromosuccinimide are obtained 1.l-Diethyl-3- (2-bromo-6-methyl-9.10-didehydro-8a-ergolinyl) urea (23%) [α] D = +247 ° C = 0.2 in pyridine.

For the use of the compounds according to the invention as medicaments these are brought into the form of a pharmaceutical preparation, which in addition to the Active ingredient a pharmaceutical suitable for enteral or parenteral administration, organic or inorganic inert carrier materials, such as water, gelatin, Gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols etc. contains. The pharmaceutical preparations can be in solid form, e.g. as tablets, Dragees, suppositories, capsules or in liquid form, e.g. as solutions, suspensions or emulsions are present. If necessary, they also contain auxiliaries such as preservatives, stabilizers, wetting agents or emulsifiers, salts for change osmotic pressure or buffer.

The following examples are intended to explain the process according to the invention.

Example 1 300 mg (0.644 mmol) 3- (2-iodo-6-methyl-8a-ergolinyl) -l.l-diethylurea are in 4 ml of benzyl alcohol after the addition of 0.169 ml (0.709 mmol) of tri-n-butylamine heated, under a carbon monoxide atmosphere with 7 mg (0.031 mmol) palladium-II-acetate added and kept at 100-110 ° C. for 2.5 hours with vigorous stirring. After this Cooling to room temperature, the reaction solution is diluted with ethyl acetate and with saturated sodium hydrogen carbonate solution and saturated sodium chloride solution shaken out. After drying over magnesium sulfate, the ethyl acetate is under reduced pressure and then the benzyl alcohol is distilled off in a high vacuum. After column chromatography on 150 g of silica gel in the system, the crude product is obtained Dichloromethane / ethanol = 10: 1 and recrystallization from ethanol / hexane 166 mg 8a- (3.3-diethylureido) 6-methyl-ergoline-2-carboxylic acid benzyl ester (54.5%).

M.p. 226-229 ° C [α] D = +43.2 ° (c = 0.25% in pyridine).

Example 2 104 mg (0.22 mmol) of 8α- (3.3-Diethylureido) -6-methyl-ergoline-2 -carboxylic acid benzyl ester are dissolved in 20 ml of methanol and, after adding 50 mg of palladium black hydrogenated for 30 min at room temperature under normal pressure. After filtering off of the catalyst and concentration gives 8a- (3. 3-Die thylureido) -6-methyl-ergoline-2-carboxylic acid in 100% yield.

F .: Decomposition above 230 ° C.

Example 3 150 mg (0.31 mmol) of 8a- (3.3-diethylureido) -6-methyl-ergoline-2-carboxylic acid benzyl ester are in 3 ml of a saturated solution of ammonia in ethylene glycol for 3 hours heated to 100 OC. After dilution with water, it is extracted with ethyl acetate and the organic phase washed with saturated sodium chloride solution over magnesium sulfate dried, filtered and concentrated. The residue is dried over silica gel with methylene chloride / ethanol = 8: 1 chromatographed.

After trituration in ethanol / hexane / ether, 90 mg of 8a- (3,3-diethylureido) -6-methylergoline) -2-carboxamide are obtained of melting point 171-173 ° C, [α] D = +42.5 ° (c = 0.2% in pyridine).

Example 4 261 mg (0.56 mmol) 3- (2-iodo-6-methyl-8a-ergolinyl) -l.l-diethylurea, 7, omg (0.023 mmol) tri-o-tolylphosphine, 4.7 mg (0.006 mmol) trans-dichloro-bis (tri-otolylphosphine) -palladium (II) and 0.075 ml (0.69 mmol) of ethyl acrylate are dissolved in 1.5 ml of dimethylformamide and 0.7 ml of triethylamine dissolved and after purging with argon in the autoclave for 4 hours heated to 100 0. After concentrating the reaction solution under reduced pressure is taken up in ethyl acetate and washed with saturated sodium chloride solution. That obtained after drying the ethyl acetate phase over magnesium sulfate and concentrating the solution The crude product is poured over 150 g of silica gel with dichloromethane / ethanol 10: 1 as the solvent chromatographed.

3- (2-Ethoxyearbonylvinyl-6-methyl-8α-ergolinyl) -l.l-diethylurea is obtained.

Yield: 115 mg (47%) F .: 223-225 ° C (ethanol / hexane) [α] D = +115 ° (c = 0.2% in pyridine).

Example 5 178 mg (0.406 mmol) 3- (2-ethoxycarbonylvinyl) -6-methyl-8α-ergolinyl) -l.l-diethylurea are dissolved in 20 ml of ethanol and after the addition of 0.1 g of Raney nickel for 1 hour Hydrogenated room temperature under normal pressure. After filtering off the catalyst 86 mg of 3- [2- (2-ethoxycarbonylethyl) -6-methyl-8α-ergolinyl / -1.1-diethylurea are obtained by recrystallization from ethyl acetate / flexan (48%).

F. 160-161 ° C.

[α] D = +22 ° (c = 0.2% in pyridine).

Example 6 933 mg (2.0 mmol) 3- (2-iodo-6-methyl-8a-ergolinyl) -1.1-diethylurea are dissolved in a mixture of 5 ml of dimethylformamide and 10 ml of triethylamine and after adding 0.610 ml (4.4 mmol) ethynyltrimethylsilane, 19 mg (0.1 mmol) Copper (I) iodide and 47.2 mg (0.06 mmol) trans-dichloro-bis (tri-o-tolylphosphine) -palladium (II) Heated to 60 0 under argon for 3 hours. After concentration under reduced pressure and Taking up the residue in ethyl acetate / water, the organic phase is saturated with Washed sodium chloride solution, dried over magnesium sulfate and evaporated. After column chromatography over 150 g of silica gel with methylene chloride / ethanol 10: 1 486 mg of 3- (2-ethynyl-trimethylsilyl-6-methyl-8a-ergolinyl) -1.1-diethylurea are used as the eluent (55.7 9s) obtained as an oil.

The following are prepared in an analogous manner: 3- {6-Hethyl-2- [3- (tetrahydropyran-2-yloxy) propynyl] -8α-ergolinyl,} -1.1-diethylurea M.p. 188OC [α] D = +64 ° (c = 0.2% in pyridine); 3- (2-propynyl-6-methyl-8α-ergolinyl) -l.l-diethylurea, 3- [2- (1-Dimethylaminopropin-3-yl) -6-methyl-8α-ergolinyl] -l.l-diethylurea, 3- [2- (1-Carbethoxyethin-2-yl) -6-methyl-8α-ergolinyl] -l.l-diethylurea, 3- (2-trimethylsilylethynyl-6-methyl-8ß-ergolinyl) -1.1-diethylurea, 3- (2-trimethylsilylethynyl-6-methyl-8a-ergolinyl) -1.1-diethylthiourea, 3- (2-trimethylsilylethynyl-1.6-dimethyl-8a-ergolinyl) -1 .1-diethylurea, 8.9-didehydro-6.8-dimethyl-2-phenylethynylergoline F .: from 118 ° C (with decomposition) and 3- (2-trimethylsilylethynyl-6-n-propyl-8a-ergolinyl) -1.1-diethylurea.

Example 6a Starting from 3- (2-bromo-6-methyl-8α-ergolinyl) -1.1-diethylurea with 3- (tetrahydropyran-2-yloxy) -1-propyne the 3- {9 {9.10-didehydro-6-methyl-2 - [- 3- (tetrahydropyran-2-yloxy) -1-propynyl] -8α- ergolinyl} -1.1-diethylurea (25%) and with 3-hydroxy-3-methyl-l-butyne the 3-9.lo-didehydro 2- (3-hydroxy-3-methyl-1-butynyl) -6-methyl-8 «-ergolinylS- ll-diethylurea (31 96) obtained.

Example 7 262 mg (0.6 mmol) 3- (2-ethynyltrimethylsilyl-6-methyl-8a-ergolinyl) -l.l-diethylurea are dissolved in a mixture of 9 ml of ethanol and 1 ml of water and after addition of 104 mg (0.75 mmol) anhydrous potassium carbonate for 16 hours at room temperature touched. The solvent is distilled off, taken up in ethyl acetate and shaken with saturated sodium chloride solution.

After drying the ethyl acetate solution over magnesium sulfate, distill off of the solvent and column chromatography of the crude product on 150 g of silica gel with toluene, ethanol, water in a ratio of 80: 20: 1 as eluent, 81 mg 3- (2-Ethynyl-6-methyl-8α ergolinyl) -l.l-diethylurea (37%) by recrystallization obtained from ethanol / hexane.

F .: 192 oC [α] D = 60.6 ° (c = 0.175% in pyridine) In analogous Ways are made: 3- (2-ethynyl-6-methyl-8a-ergolinyl) -1.1-diethylthiourea, 3- (2-ethynyl-1.6-dimethyl-8a-ergolinyl) -1.1-diethylurea and 3- (2-ethynyl-6-n-propyl-8a-ergolinyl) -1.1-diethylurea, F.: 126 ° C.

Example 8 122 mg (0.29 mmol) 3- [9.10-Didehydro-2- (3-hydroxy-3-methyl-1-butynyl) -6-methyl-8α-ergolinyl] -1.1-diethylurea are in 15 ml of absolute toluene after addition of 64 mg (1.6 mmol) of powdered sodium hydroxide Heated under reflux for 2 hours under nitrogen. Then the solvent distilled off and the residue in ethyl acetate with water and saturated sodium chloride solution shaken out. That from the ethyl acetate solution after drying with magnesium sulfate and The crude product obtained is concentrated by column chromatography on 80 g of silica gel Purified with ethyl acetate / ethanol 2: 1 as the eluent. By reprecipitation from ethyl acetate / ether / hexane one obtains 3- (9.10-didehydro-2-ethynyl-8-ergolinyl) -l.l-diethylurea in 25% strength Yield.

Example 9 213 mg (0.45 mmol) 3- {6-methyl-2- [3- (tetrahydropyran-2-yl-oxy) -propinyt8-ergolinyl3 -l.l-diethylurea are dissolved in 10 ml of ethanol with 2 ml of water and 176 mg (0.7 mmol) Pyridinium p-toluenesulfonate was refluxed under argon for 1 hour. After evaporation and distributing in ethyl acetate and saturated bicarbonate solution becomes the organic Phase washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The residue is first over silica gel with ethyl acetate: acetone = 1: 1 and later chromatographed with methylene chloride: acetone = 12: 1. After recrystallization 90 mg (51 ° Wi) 3-g2- (1-hydroxypropyn-3-yl) 6-methyl-8a-ergoliny1- are obtained from ethyl acetate / hexane 1.1-the thylurea.

F.: 151-154 OC [α] D = +71.2 ° (c = 0.219% in pyridine).

The following is prepared in an analogous manner: 3- [2- (1-Hydroxypropin-3-yl) -9.10-didehydro-6-methyl-8α-ergolinyl] -1.1-diethylurea [α] D = + 404 ° (c = 0.2 in pyridine) F .:> 129 ° C.

Example 10 140 mg (0.084 mmol) 3- (2-ethynyl-6-methyl-8a-ergolinyl) -l.l-diethylurea are in 20 ml of ethanol after the addition of 0.1 g of Raney nickel in 45 minutes at room temperature and normal pressure hydrogenated. After filtering off the catalyst and concentrating the solution is recrystallized from ethanol / hexane. Yield: 119 mg of 3- (2-ethyl-6-methyl-8a-ergolinyl) -1.1-diethylurea (84%).

F.: 165-168 OC [α] D = + 25 ° (c = 0.22 in pyridine).

Example 11 200 mg of 3- (2-ethynyl-6-methyl-8α-ergolinyl) -1.1-diethylurea are in 35 ml of ethanol with 200 mg of palladium / calcium carbonate (2%) and 200 mg of quinoline hydrogenated at room temperature and normal pressure. After filtering off the catalyst evaporated. The residue is chromatographed over silica gel with methylene chloride / ethanol 6: 1. 30 mg of 3- (6-methyl-2-vinyl-8α-ergolinyl) -1.1-diethylurea are obtained as Oil.

Claims (5)

Claims 1. Ergolines of the general formula I substituted in the 2-position where C8 ### C9 and C9 ### C10 denote a CC single or a C = C double bond, but not a cumulative double bond and the substituent in the 8-position is α or β, if C8 --- Cg means a CC single bond, R2 the grouping COR ', (R' = OH, OC1-4-A1ky1 or NH2, the grouping CH = CH-CO2R "and CH2-CH2-COR" (R "= C1-4 alkyl ), the grouping C # C-R '''and HC = CH-R''' (R '''= hydrogen, C1-4-alkyl, phenyl, CH2OH, CO2R ", CH2NR" 2 and where R "= C1-4-alkyl, lower alkyl with up to 4 carbon atoms and R8 represent ethyl or the grouping NH-CO-NEt2 or NH-CS-NEt2, and their salts. 2. 1.1-Diethyl- (6-methyl-2-ethynyl-8α-ergolinyl) urea 3. 1.1-Diethyl- (6-methyl-2-ethyl-8α-ergolinyl) urea 4. Process for the preparation of ergolines of the general formula I substituted in the 2-position where C8 ### C9 and C9 ### C10 denote a CC single or a C = C double bond, but not a cumulative double bond and the substituent in the 8-position is α or β if a CC single bond R2 means the grouping COR ', (R' = OH, OC1-4-alkyl or NH2, the grouping CH = CH-CO2R "and CH2-CH2-COR" (R "= C1-4-alkyl), the grouping C # C-R '''and HC = CH-R''' (R '''= hydrogen, C1-4-alkyl, phenyl, CH2OH, CO 2R ''', CH2NR "2 and where R "= C1-4-alkyl R6 lower alkyl with up to 4 carbon atoms and R8 represent methyl or the grouping NH-CO-NEt2 or Nit-CS-NEt2, and their salts, characterized in that a 2-iodine or 2-bromo-ergoline of the general formula II wherein C8 ### C9, C9 ### C10, R6 and R8 have the meaning given above, with an electrophilic reagent from the group consisting of benzyl alcohol / carbon monoxide, acrylic ester CH2 = CH-CO2R "and ethynyl derivative CH-CR"', wherein R "and R" have the meaning given above, in the presence of a palladium catalyst and a secondary or tertiary amine without a solvent or in an aprotic, water-miscible solvent at temperatures above room temperature in the range from 40 oO to the boiling point of the reaction mixture , if desired, then hydrogenated the 2-benzyl group with palladium to form the carboxyl compound or reacted with ammonia to form the 2-carboxamide group or hydrogenated an exocyclic multiple bond with Raney nickel or palladium on a support to form a CC single bond or double bond or a SiNe2R "protective group with a Base or a tetrahydropyranyl protective group with pyridine ptoluenesulfonate is split off and optionally the so The compounds obtained are converted into the corresponding acid addition salt with a physiologically acceptable acid. 5. Use of the compounds according to claims 1-3 as medicaments.