DE3806374A1 - NEW ERGOLIN DERIVATIVES, PROCESS FOR THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS - Google Patents

Abstract

Substituted ergolines of general formula (I), and their acid addition salts, in which (a) and (b) denote a C-C single bond or a C=C double bond, X denotes oxygen or sulphur, R1 denotes amino, nitro or the (c) residue, R2 denotes methylthio, if (a) is a C=C double bond, or C1-C4 alkyl, R3 and R4 are different and denote hydrogen, C1-C4 alkyl, or acyl, or R3 and R4 each denote the same C1-C4 alkyl residue or together with the N atom of the (c) form a 3- to 9-membered ring. These compounds are produced by processes known per se and possess, for example, a hypotensive activity.

Description

The invention relates to new ergoline derivatives, processes for their preparation and drugs based on these compounds.

Ergolines with substituents in the aromatic part of the molecule are already out German Offenlegungsschriften DE-OS 26 01 473, 32 05 169 and 33 09 493 known.

The compounds from DE-OS 26 01 473 and DE-OS 32 05 169 predominantly have one antidepressant spectrum of activity, while the Ergonline from DE-OS 33 09 493 a show pronounced cataleptogenic effects. With the ergolines according to the invention surprisingly a predominantly hypotensive effect was found.

The invention relates to substituted ergolines of the general formula I.

and their acid addition salts,
wherein C₂C₃ and C₉C₁₀ are a CC single or C = C double bond and
X oxygen or sulfur,

R₂ is methylthio when C₂C₃ is a C = C double bond or is C₁-C₄ alkyl,
R₃ and R₄ are different and represent hydrogen, C₁-C₄-alkyl, or acyl, or
R₃ and R₄ each represent the same radical C₁-C₄-alkyl or together with the N atoms of

form a 3- to 9-membered ring.

The acid addition salts of the compounds according to the invention 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 mono- and dicarboxylic acids, phenyl-substituted alkanecarboxylic acid such Hydroxylalkancarbonsäuren or alkanedicarboxylic acids, aromatic acids or aliphatic or aromatic sulfonic acids. Physiologically acceptable salts of these acids are therefore z. B. the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, methaphosphate, pyrophosphate, chloride, bromite, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, Heptanoate, propiolate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, butyne-1,4-diocate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, tereulfonate, tereulfonate, tereulfonate, tereulfonate, tereulfate, tereulfate, Chlorobenzenesulfonate, xylenesulfonate, phenylsulfonate, phenylpropionate, phenylbutyrate, citrate, lactate, β- hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate or naphthalate-2-sulfonate.

The alkyl radicals with up to 4 carbon atoms are those that differ from the aliphatic Derive hydrocarbons such. B. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and cyclopropylmethyl.

If the alkyl chain on the amino nitrogen forms a ring with a C₂-C₈ alkyl chain, so the substituent z. B. an aziridine, pyrrolidine or piperidine ring system represents, which can also be substituted with alkyl groups.

Acyl includes acid residues such as alkanoyl with up to 5 carbon atoms, aroyl and Aralkanoyl with 7-10 C atoms to understand.

The alkanoyl radicals with 1 to 5 carbon atoms are derived from aliphatic carboxylic acids that are physiologically compatible, such as. B. acetyl, propionyl, n-butyryl and isobutyryl.

The aroyl residues and aralkanoyl residues with 7 to 10 carbon atoms are, for example Benzoyl, p-methylbenzoyl, 3,5-dimethylbenzoyl, phenylacetyl, phenylpropionyl and p-tolylacetyl.

8 α- Ergolinyl urea derivatives are preferred compounds of this invention.

The compounds according to the invention showed 1 mg / kg body weight in the dose range very good antihypertensive activity on SH rats. The shown hypotensive effects are due to DA₂-agonistic effects of the examined Connections attributed to what is due to the electrically irritated rabbit ear artery can be demonstrated.

The ergolinyl urea derivatives according to the invention would therefore be antihypertensive therapeutically applicable. They are suitable because of their prolactin-lowering But also effective as a weaning agent.  

For the use of the compounds according to the invention as pharmaceuticals, brought into the form of a pharmaceutical preparation that in addition to the active ingredient pharmaceutical, organic suitable for enteral or parenteral application or inorganic inert carrier materials, such as. B. water, gelatin, Gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, Contains polyalkylene glycols, etc. The pharmaceutical preparations can in solid form, e.g. B. as tablets, coated tablets, suppositories, capsules or in liquid form, e.g. B. present as solutions, suspensions or emulsions. If necessary, they also contain auxiliary substances such as preservatives, Stabilizing, wetting agents or emulsifiers, salts for changing the osmotic Pressure or buffer.

The dosage of the compounds according to the invention is in humans of 5-100 mg / day and a dosage form contains 1-20 mg of active ingredient.

The compounds of the invention are prepared by methods known per se. The starting material of formula II used is known. There are ergoline-diethylurea derivatives in which the ureido side chain is in the α position, which is saturated or unsaturated in the 9.10 position, substituted on the nitrogen atom in the 6 position with methyl and a nitro group on the aromatic in position 12, 13 or 14 are (e.g. DE-OS 33 09 493).

The nitrated ergolinyl-urea compounds can then be substituted in the 2-position will.

To do this, use a 2-position unsubstituted ergoline of the general Formula II,

in a manner known per se with dimethyl methylthiosulfonium tetrafluoroborate in Tetrahydrofuran.

In addition, an ergolinyl urea of the general formula III,

wherein R₂ has the meaning given above and which one according to DE-OS 28 10 774 can be nitrided.

The nitration of the compounds of formula III, also by the German Patent application file number P 37 08 028.8 are known, if necessary after acetylation in the 1-position with nitric acid in the presence of sulfuric acid or acetic acid. The mono-nitriding essentially follows the Rules of electrophilic substitution of aniline, taking the 2,3-dihydro-ergoline in the 13-position and the 9.10-didehydro-2.3-dihydro-ergoline in 12 and 14 positions are mainly nitrided side by side. Furthermore can contain small amounts of the other positional isomers and double nitrided products arise. The separation is carried out by chromatography or crystallization.  

The nitro compound which is unsubstituted in the 1 position can then be used again be oxidatively converted into the ergoline or indole system. For this, this Compound in an inert solvent, such as chlorinated hydrocarbons, with an oxidizing agent such as manganese dioxide, nickel peroxide, chromic acid derivatives, Phenylselenic anhydride, palladium salts, oxygen and catalysts or with dimethyl sulfide, tert-butyl hypochlorite and base.

The ergolinylureas of the formula I can be described in DE-OS 35 28 576 Processes are converted into ergolinylthioureas.

The nitro group can be selective at any stage to the amino group, i.e. H. without Reduction of an optionally present 9.10 double bond with sodium borohydride in the presence of metal salts such as nickel (II) salts or tin (II) salts can be reduced [(A. Nose et al., Chem. Pharm. Bull. 39, 1155 (1981) and T. Satoh et al., Chem. Pharm. Bull. 29, 1443 (1981)].  

If desired, the nitro compound reduced to the amino compound can by Alkylation and acylation to the corresponding alkyl or acyl compounds be implemented. An acylamino compound thus obtained can, if desired by reduction with diiosbutyl aluminum hydride, with lithium aluminum hydride or reacted with borane methyl sulfide in the corresponding monalkylamino compounds will.

The compounds thus obtained are either as free bases or in the form their acid addition salts, if desired by reaction with a physiologically acceptable acid, such as. B. tartaric acid, maleic acid or benzoic acid, are obtained, purified by recrystallization and / or chromatography.

To form salts, the compound obtained is dissolved in a little methanol and with a concentrated solution of the desired organic acid in methanol at room temperature.

The invention thus also relates to a process for the preparation of substituted Ergolines of the general formula I, which is characterized in that an ergoline of the general formula II which is unsubstituted in the 2-position  

in a manner known per se reacted with dimethyl methylthiosulfonium tetrafluoroborate in tetrahydrofuran, then optionally reduced with NaBH₄ in the presence of NiCl₂, optionally the aromatic amino compound obtained at -NH₂ alkylated or acyclized or optionally with a thiolating agent in a thiourea is converted or that an ergoline derivative of the general Formula III

wherein R₂ has the meaning given above, nitrated in a conventional manner, if appropriate dehydrated in the 2,3-position with tert-butyl hypochlorite, optionally with a thiolating agent in a thiourea derivative transferred, optionally reduced with NaBH₄ / NiCl₂, optionally the aromatic amino compound obtained alkylated or acylated on -NH₂.

Example 1 1,1-diethyl-3- (6-methyl-2-methylthio-13-nitro-8 α- ergolinyl) urea

315 mg of 1,1-diethyl-3- (6-methyl-13-nitro-8 α- ergolinyl) urea (1 mmol) are dissolved in 25 ml of anhydrous THF and 1.0 g of dimethylmethyltiosulfonium are added in portions. tetra-fluoroborate (5 mmol) at room temperature. After 16 hours the mixture is poured onto ice, made alkaline with 25% ammonia and extracted with methylene chloride. 281 mg (66% of theory), [ α ] _D = + 47 ° (0.25% in chloroform) crystallize from ethyl acetate / diisopropyl ether.

Example 2 3- (13-amino-6-methyl-2-methylthio-8 α- ergolinyl) -1,1-diethylurea

145 mg of the above nitro compound (0.34 mmol) are in 10 ml of methanol dissolved, with 160 mg of nickel chloride (6 H₂O) and in portions with 76 mg of sodium added borohydride and stirred with ice cooling. After 30 minutes it is as above described worked up the product on silica gel with methylene chloride / methanol chromatographed and crystallized from ethyl acetate / diisopropyl ether. Man isolated 21 mg substance (14% of theory).

Example 3 1,1-Diethyl-3- (2,3 b -dihydro-2,6-dimethyl-13-nitro-8 α -ergolinyl) urea

270 mg of 1,1-diethyl-3- (2,3 β- dihydro-2,6-dimethyl-13-nitro-8 α- ergolinyl) urea (0.75 mmol) is dissolved in 20 ml of conc. Sulfuric acid and adds 0.76 ml of a mixture of 75 ml of 65% nitric acid and 750 ml of conc. Sulfuric acid too. After stirring for 15 minutes in an ice bath, the mixture is worked up as described above and the residue is crystallized from ethyl acetate / diisopropyl ether. The yield is 188 mg (62% of theory), [ α ] _D = 69 ° (0.5% in chloroform).

Example 4 3- (13-amino-2,3 β- dihydro-2,6-dimethyl-8 α- ergolinyl) -1,1-diethyl urea

235 mg of the above nitro compound (0.58 mmol) are dissolved in 30 ml of methanol, 272 mg of nickel chloride (6 H₂O) and 66 mg of sodium borohydride are added in 2 portions with ice cooling. After the usual work-up, the residue is crystallized from ethyl acetate / diisopropyl ether, yield 170 mg (79% of theory), [ α ] _D = 55 ° (0.5% in chloroform).

Example 5 1,1-diethyl-3- (2,6-dimethyl-13-nitro-8 α- ergolinyl) urea

1.10 g of 1,1-diethyl-3- (2,3 β- dihydro-2,6-dimethyl-13-nitro-8 α- ergolinyl) urea (2.75 mmol) is dissolved in 50 ml of THF, mixed with 1.1 ml of triethylamine and cooled to -40 ° C. Then 0.33 ml of distilled tert-butyl hypochlorite (2.8 mmol) are added, the mixture is stirred at -40 ° for 15 min and worked up as described. 376 mg (14% of theory), [ α ] _D = -10 ° (0.5% in methanol) crystallize from the solution of the crude product in ethyl acetate / diisopropyl ether.

Example 6 3- (13-amino-2,6-dimethyl-8 a -ergolinyl) -1,1-diethylurea

365 mg of the above nitro compound (0.92 mmol) are dissolved in 120 ml of methanol, 430 mg of nickel chloride (6 H₂O) and 102 mg of sodium borohydride (2.7 mmol) are added in portions with ice cooling. Working up and chromatography are as described in Example 2. 90 mg of crystals (27% of theory) are obtained from ethyl acetate / diisopropyl ether, [ α ] _D = -1.5 ° (0.25% in chloroform).

Example 7 1,1-Diethyl-3- (6-methyl-2-methylthio-12-nitro-8 α -ergolininyl) urea

1 g (2.6 mmol) of 1,1-diethyl-3- (6-methyl-12-nitro-8 α -ergolinyl) urea are dissolved in 50 ml of anhydrous tetrahydrofuran and added in portions with 1.24 g (6.3 mmol) of dimethylthiosulfonium tetrate fluoroborate at room temperature. After 3 hours, the mixture is poured onto ice, made alkaline with 25% ammonia solution and shaken out with dichloromethane. The crude product is chromatographed on silica gel with dichloromethane / methanol (95/5) and crystallized from ethyl acetate / pentane. 810 mg (73% of theory) of yellow crystals are obtained.

Example 8 3- (12-amino-6-methyl-2-methylthio-8 α- ergolinyl) -1,1-diethylurea

431 mg (1 mmol) of 1,1-diethyl-3- (6-methyl-2-methylthio-12-nitro-8 α -ergolinyl) urea are dissolved in 50 ml of methanol, with 473 mg (2 mmol) of nickel II chloride, hexahydrate are added and 113 mg (3 mmol) of sodium borohydride are added in portions with ice cooling. After 10 minutes the mixture is worked up as described above, the crude product is chromatographed on silica gel with dichloromethane / methanol (95/5) and crystallized from ethyl acetate / pentane. 108 mg (30% of theory) of colorless crystals are obtained, [ α ] _D = + 46 ° (0.05% in chloroform).