EP0401263A1 - New ergoline derivatives, process for producing them and their use as drugs - Google Patents

Abstract

Substituted ergolines of general formula (I) and their acid addition salts, where (a) and (b) represent a single bond CC or a double bond C = C, X represents oxygen or sulfur, R1 represents amino, nitro or the residue (c), R2 represents methylthio, if (a) is a double bond C = C, or a C1-C4 alkyl, R3 and R4 are different and represent a hydrogen, a C1-C4 alkyl or alternatively an acyl, or alternatively R3 and R4 each represent the same C1-C4 alkyl residue or form, together with the N atom of the residue (c), a cyclic trigonal to nonagonal compound. These compounds are produced by methods known per se and have, for example, hypotensive activity.

Description

 New ergoline derivatives, processes for their production and their use as medicines

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

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

The compounds from DE-OS 26 0 1 473 and DE-OS 32 05 169 predominantly have an antidepressant spectrum of activity, while the ergolines from DE-OS 33 09 493 show a pronounced cataleptogenic effect. A surprisingly predominantly hypotensive effect was found in the ergolines according to the invention.

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

and their acid addition salts, in which and are a CC single or C = C double bond and

X Sauerstroff or sulfur,

R ₁ amino, nitro or the rest

R _{2 is} methylthio if a C = C double bond or represents C ₁ -C ₄ alkyl,

R ₃ and R _{4 are} different and represent hydrogen, C ₁ -C ₄ alkyl, or acyl, or

R ₃ and R ₄ each represent the same radical C ₁ -C ₄ alkyl or together with

form the N atoms of a 3- to 9-glιedrι.gen 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, for example, hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, or organic acids, such as, for example, aliphatic mono- or dicarboxylic acids, phenyl-substituted alkane carboxylic acid, hydroxyaromatic carboxylic acids or alkane acids aliphatic or aromatic sulfonic acids. Physiologically acceptable salts of these acids are therefore, for example, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate , Isobutyrate, caproate, heptanoate, propiolate, malonate, succinate, suberate, sebacate, fumarate, halate, mandelate, butyne-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, ethylbenzoate, dinitrobenzoate, hydroxybenzoate, phthalate, methoxyben , Benzenesulfonate. Toluene sulfonate, chlorobenzene sulfonate, xylene sulfonate, phenylacetate, phenylpropionate. Phenylbutyrate, citrate, lactate, ß-hydroxybutyrate, glycollate, malate, tartrate, hethanesulfonate, propanesulfonate, naphthalene-1-sulfonate or naphthalene-2-sulfonate. The alkyl radicals with up to 4 carbon atoms are those which are derived from the aliphatic hydrocarbons, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isσbutyl, tert-butyl and cyclopropylmethyl.

If the alkyl chain on the amino nitrogen forms a ring with a C ₂ -C ₈ alkyl chain, the substituent is, for example, an aziridine, pyrrolidine or piperidine ring system which can also be substituted with alkyl groups.

Acyl is to be understood as acid residues such as alkanoyl with up to 5 carbon atoms, aroyl and aralkanoyl with 7-10 carbon atoms.

The alkanoyl radicals with 1 to 5 carbon atoms are derived from aliphatic carboxylic acids that are physiologically compatible, e.g. 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.

80o-ergolinyl urea derivatives are preferred compounds of this invention.

The compounds according to the invention showed a very good hypotensive activity in the dose range of 1 mg / kg body weight in SH rats. The hypotensive effects shown can be attributed to DA-agonistic effects of the compounds examined, which can be demonstrated in the electrically irritated rabbit ear arteries. Up to now, no antihypertensive agent that is effective exclusively via the DA ₂ receptor is known. The new connections of the

Formula I are surprisingly DA ₂ agonists.

Table 1: Blood pressure lowering effects Receptor binding data (Ki) DA ₂ binding (3H-NO437) - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Compound from Example 1 40%

Compound from Example 2 30%

Compound from Example 4 45% 28 n M

Compound from Example 5 35%

Compound from Example 6 50% 34 n M

The ergolinyl urea derivatives according to the invention would therefore be therapeutically applicable as antihypertensives. Because of their prolactin-lowering effect, they are also suitable as a weaning agent.

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

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

The compounds according to 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 α-permanent, 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.

To do this, an ergoline of the general formula II which is unsubstituted in the 2-position is used,

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

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

wherein R _{2 has} the meaning given above and which can be represented according to DE-OS 28 10 774, nitrided.

The nitration of the compounds of the formula III, which are also known from German patent application file number P 37 08 028.8, is optionally carried out after acetylation in the 1 position with nitric acid in the presence of sulfuric acid or acetic acid. The mono-nitration essentially follows the rules of electrophilic substitution of aniline, whereby the 2,3-dihydro-ergolines in the 13-position and the 9,10-didehydro-2,3-dihydro-ergolines in the 12- and 14-positions are mainly nitrided side by side. In addition, small amounts of the other positional isomers and double nitrated products can be formed. The separation is carried out by chromatography or crystallization.

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

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

The nitro group can be selectively reduced to the amino group at any stage, ie without reducing any 9.10 double bond which may be present with sodium borohydride in the presence of metal salts such as nickel (II) salts or tin (II) salts [(A. Nose et al ., Chem. Pharm. Bull. 29, 1155 (1981) and T. Satoh et al., Chem. Pharm. Bull. 21. 1443 (1981) j. If desired, the nitro compound reduced to the amino compound can be converted to the corresponding alkyl or acyl compounds by alkylation and acylation. If desired, an acylamino compound obtained in this way can be converted into the corresponding honalkylamino compounds by reduction with diisobutylaluminum hydride, with lithium aluminum hydride or with borane dimethyl sulfide.

The compounds thus obtained are used either as free bases or in the form of their acid addition salts, which if desired by reaction with a physiologically acceptable acid such as e.g. Tartaric acid, maleic acid or benzoic acid can be obtained, purified by recrystallization and / or chromatography.

To form salts, the compound obtained is dissolved in a little methanol and a concentrated solution of the desired organic acid in methanol is added 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

reacted in a manner known per se with dimethyl methylthiosulfonium tetrafluoroborate in tetrahydrofuran, then optionally reduced with NaBH ₄ in the presence of NiCl ₂ , optionally alkylated or acylated the aromatic amino compound obtained at -NH ₂ or optionally converted into a thiourea derivative with a thiolating agent or that an ergoline derivative of the general formula III

Example 1

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

315 mg of 1,1-diethyl-3- (6-methyl-13-nitro-8α-ergolinyl) urea (1 mmol) are dissolved in 25 ml of anhydrous THF and 1.0 g of dimethylmethylthiosulfonium tetra-fluoroborate is added in portions (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-8α-ergolinyl) -1,1-diethylurea

145 mg of the above nitro compound (0.34 mmol) are dissolved in 10 ml of methanol, 160 mg of nickel chloride (6 H ₂ O) and 76 mg of sodium borohydride are added in portions and the mixture is stirred with ice-cooling. After 30 min. is worked up as described above, the product is chromatographed on silica gel with methylene chloride / methanol and crystallized from ethyl acetate / diisopropyl ether. 21 mg of substance (14% of theory) are isolated.

Example 3

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

270 mg of 1,1-diethyl-3- (2,3β-dihydro-2,6-dimethyl-8α-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 Ziger nitric acid and 750 ml of conc. Sulfuric acid too. After 15 min. Stirring in an ice bath 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-Amirιo-2,3β-dihydro-2,6-dimethyl-8α-ergolinyl) -1,1-dimethyl urea

235 mg of the above nitro compound (0.58 mmol) are dissolved in 30 ml of methanol, 272 mg of nickel chloride (6 H ₂ O) 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-8α-ergolinyll-urea

1.10 g of 1,1-diethyl-3- (2,3β-dihydro-2,6-dimethyl-13-nitro-8α-ergolinyl) urea (2.75 mmol) is dissolved in 50 ml of THF, mixed with 1.1 ml of triethylamine and cools to -40 °. Then 0.33 ml of distilled tert. -Butyl hypochlorite (2.8 mmol), stirred for 15 min. at -40 ° and works 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-8α-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 H ₂ O) and 102 mg of sodium borohydride (2.7 mmol) are added in portions while cooling with ice. 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-8α-ergolinyl) urea

1 g (2.6 mmol) of 1,1-diethyl-3- (6-methyl-12-nitro-8α-ergolinyl) urea are dissolved in 50 ml of anhydrous tetrahydrofuran and added in portions with 1.24 g (6.3 mmol ) Dimethylmethylthiosulfonium tetrafluoroborate added 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.

Examples 8

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

431 mg (1 mmol) of 1,1-diethyl-3- (6-methyl-2-methylthio-12-nitro-βα-ergolinyl) urea are dissolved in 50 ml of methanol, with 473 mg (2 mmol) of nickel-II -chloride, hexahydrate and 113 mg (3 mmol) of sodium borohydride were 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).

Claims

Claims

1) substituted ergolines of the general formula I,

and their acid addition salts, in which and are a CC single or C = C double bond and

X Sauerstroff or sulfur, R ₁ amino, nitro or the rest

R _{2 is} methylthio if a C = C double bond, or C ₁ -C ₄ -

Represent alkyl, R ₃ and R _{4 are} different and for hydrogen, C ₁ -C ₄ alkyl. or acyl, or R ₃ and R ₄ each represent the same C ₁ -C ₄ alkyl radical or together with

form the N atoms of a 3- to 9-membered ring. 2) 1,1-Dιethyl-3- (6-methyl-2-methylthio-13-nitro-8α-ergolinyl) urea

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

4) 1,1-Diethyl-3- (2,3β-dihydro-2,6-dimethyl-13-nitro-8α-ergolinyl) urea

5) 3- (13-Amino-2,3β-dihydro-2,6-dimethyl-8α-ergolinyl) -1,1-diethylurea

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

7) 3- (13-Amino-2,6-dimethyl-8α-ergolinyl) -1,1-diethylurea

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

9) 3- (12-Amino-6-methyl-2-methylthio-8α-ergolinyl) -1,1-diethylurea

10) Medicament based on the compounds according to claims 1-9.

11) Process for the preparation of substituted ergolines of the general formula I

and their acid addition salts, in which and are a CC single or C = C double bond and

X Sauerstroff or sulfur,

R ₁ amino, nitro or the rest

R ₂ methylthio. if a C = C double bond, or C ₁ -C ₄ - Represent alkyl,

R ₃ and R _{4 are} different and represent hydrogen, C ₁ -C ₄ alkyl. or are acyl, or

R ₃ and R ₄ 5ever represent the same radical C ₁ -C ₄ alkyl or together with

form the N atoms of a 3- to 9-membered ring. characterized in that an ergoline of the general formula II which is unsubstituted in the 2-position

reacted in a manner known per se with dimethyl methylthiosulfonium tetrafluoroborate in tetrahydrofuran, then optionally reduced with NaBH ₄ in the presence of NiCl ₂ , optionally alkylated or acylated the aromatic amino compound obtained at -NH ₂ or optionally converted into a thiourea derivative with a thiolating agent or that an ergoline derivative of the general formula III

wherein R _{2 has} the meaning given above, nitrated in the usual manner, optionally in the 2,3-position with tert. -Butyl hypochlorite dehydrated, optionally converted into a thiourea derivative with a thiolating agent, optionally reduced with NaBH ₄ / NiCl ₂ , optionally alkylated or acylated on the -NH ₂ aromatic amino compound obtained.