CS262450B2 - Process for preparing new derivatives of 1-aryl-ergolinurea - Google Patents

Abstract

Compounds of the formula I <IMAGE> in which Ar represents an optionally substituted aryl or hetaryl radical and R<6> denotes lower alkyl and <IMAGE> can be a single or double bond, and their acid addition salts are described. These compounds have useful pharmacological properties.

Description

The invention relates to a process for the preparation of novel 1-arylergolinyl urea derivatives having valuable pharmacological properties and which can be used as medicaments.

We have found novel 1-arylergolinyl urea derivatives of general formula (I)

NH-CO-NEt2

in which

Ar represents a phenyl group which is optionally substituted by a nitro or amino group, a thiazolyl group, a pyrazinyl group or a pyrimidinyl group,

R ⁶ represents an alkyl group having 1 to 6 carbon atoms,

Et stands for ethyl group and taphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, proplonate, decanoate, caprylate, acrylate, formate, isobutyrate, caproate, heptanoate, propiolate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandate , butin-1,4-dloate, hexln-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dlbobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropyl, phenylpropyl, phenylpropyl, phenylbenzate O-hydroxybutyrate, glycolate, malate, tertrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, or naphthalene-2-sulfonate.

The compounds of formula (I) may be prepared by methods known per se.

It is an object of the present invention to provide a process for the preparation of novel 1-arylergolinyl urea derivatives of formula (I) which comprises:

C ₅ -C ₁₀ ----- represents a single or double bond, and their physiologically tolerated addition salts with acids.

The (C 1 -C 6) alkyl group may be straight-chain or branched. Examples which may be mentioned are preferably alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and sec-butyl.

The physiologically tolerable salts of the compounds of formula (I) produced by the process of the present 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, as well as phosphorous acid or organic acids such as aliphatic mono- or dicarboxylic acids, phenyl-substituted alkanecarboxylic acids , hydroxyalkanecarboxylic acids or alkene dicarboxylic acids, aromatic acids or aliphatic or aromatic sulfonic acids.

Thus, physiologically tolerable salts of these acids are, for example, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, in which:

R ⁶ represents an alkyl group having 1 to 6 carbon atoms and

Et is as defined above, aryl by treatment with a compound of formula III

Ar - X (III) in which

Ar is as defined above and

X is a halogen atom, whereupon the compounds are optionally converted into physiologically tolerable acid addition salts.

Suitable halogen atoms for X are fluorine, chlorine, bromine and iodine, in particular chlorine and bromine.

When introducing a substituted Ar group, such as a phenyl group which is substituted with a nitro group, the nitro group is optionally reduced and the amino group thus obtained is optionally replaced with hydrogen.

The arylation can be carried out, for example, in a basic medium in inert solvents at temperatures from 0 ° C to the boiling point of the reaction mixture, preferably at room temperature, for 1 to 20 hours.

Suitable inert solvents are aprotic solvents such as ethers, for example, diethyl ether, tetrahydrofuran, dioxane

or chlorinated hydrocarbons such as methylene chloride, dichloroethane and polar aprotic solvents such as dimethylformamide, dimethylsulfoxide, dimethylacetamide, N-methylpyrrolidone, acetonitrile, pyridine and others.

Alkali metal compounds such as sodium hydroxide or potassium hydroxide, sodium hydride, sodium carbonate or potassium carbonate can be added as bases. The arylation may optionally be carried out in the presence of phase transfer catalysts, such as crown ethers, such as 18-crown-6, dicyclohexyl-18-crown-6, dibenzo-18-crown-6, or tetraalkylammonium salts.

The reduction of the nitro group to the amino group is carried out, for example, catalytically in inert solvents at room temperature.

Preferably, the catalyst used is a supported palladium such as coal or platinum in finely dispersed form. In the case of halogen-containing compounds, Raney nickel is preferably used as the catalyst.

Solvents suitable for reduction are, for example, alcohols such as methanol, ethanol or ethers such as diethyl ether, tetrahydrofuran or mixtures thereof.

The hydrogenation can be carried out at atmospheric pressure or under hydrogen pressure.

For the purpose of desamination, for example, the diazo compound, which was obtained by treatment with nitrite, is reduced in the presence of cuprous and phosphoric acid at elevated temperature by boiling.

Suitably, the above-described reactions are carried out under an inert gas atmosphere, such as under nitrogen or argon.

In the preparation of physiologically compatible addition salts, the compound obtained is dissolved in a small amount of methanol, and to this solution is added a concentrated solution of the desired acid in methanol at room temperature.

In particular, the compounds of the formula (I) produced by the process according to the invention have the capability of centrally blocking α 2 -receptors, which effect is accompanied by only weak or absent antidopaminergic effects. This action profile predetermines these compounds as valuable substances for the treatment of psychiatric depressive disorders. The antidepressant effect of the compounds produced according to the invention lies in the central blockade of α 2 -receptors, which results in an increased release of norepinephrine in the brain and consequently an antidepressant effect.

Central α2-receptor blockade can be illustrated by the clonidine interaction assay as α2 -receptor agonist in mice following a single intraperitoneal pre-administration (parameter: suppression of 0.1 mg per kilogram of clonidine-induced hypothermia). Male mice (NMRI strain) are pre-treated with different doses of the test substance which does not itself affect the thermoregulation of the test animals or the vehicle. 30 minutes later, all animals received 0.1 mg / kg of clonidine i. P. 60 minutes after administration of the test substance or vehicle (= 30 minutes after administration of clonidine), the rectal temperature was measured with a thermosonde. While mice that were treated with vehicle only exhibited hypothermia, the dose-dependent effect of clonidine on body temperature decrease was suppressed in animals treated with the pre-substituted 1-substituted ergoline ureas of the invention.

As can be seen from the following Table 1, clonidine antagonistic effect after administration of 1-aminophenyl-TDHL at a dose of 0.39 mg / kg is statistically significant.

X X X X X X CM rH rd CM O O O O +1 +1 +1 +1 rd 00 00 what in M < M < M ⁴ WHAT WHAT what what

Antagonist effect of pretreatment (30 minutes, i.p.) with various doses of 1-substituted ergoline ureas on mouse hypothermia induced by clonidine (0.1 mg / kg ni.). The rectal temperature of the test animals is measured 30 minutes after administration of clonidine (= 60 minutes after administration of the test substance) (x: p <0.05; xx: p <0.01 compared to control; Dunnett's test of variation)

O

WHAT OJ rd ^ what O" O O" O* +1 +1 +1 +1 CD WHAT what rd M <* ME ME M <' WHAT what what WHAT

co rd CM o ”+1 CM O +1 what" 00 ME M < ME what what

čx CO * CO

CD 1П

o ea s 4- * Й o x CM

Co1 co M <”CO

X what rd X CM ~ what CD O" O" O" +1 +1 +1 +1 M < N FROM eo eo ” ME ME what* what WHAT WHAT what

CM o ”+1 CM ^ o ”+1 X CM <=) ”+1 CM o ” -H Ml rd in M ^ ME ME ME what* what WHAT what what

M < ? l rd ^ +1 00 ^ M < what* Me* what WHAT CM CM O* O" +1 +1 rd ^ rd M <* ME WHAT WHAT

X WHAT CM O" O" +1 +1 what M ^ ME what" what what X what rd O* O" +1 +1 00 ID what* what" what what ·

33.7 ± 0.2 33.7 ± 0.2 33.9 ± 0.1 34.3 ± 0.2 34.0 ± 0.2 34.3 ± 0.2x

00 eo

Based on these findings, the compounds produced by the process of the invention are therefore preferably used as antidepressants.

In order to use the compounds of the present invention as medicaments, they are converted into a pharmaceutical formulation which, in addition to the active ingredient, contains pharmaceutical, organic or inorganic inert carriers suitable for enteral or parenteral administration such as water, gelatin, acacia, lactose, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, etc. The pharmaceutical preparations may be present 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. These preparations additionally contain, if appropriate, auxiliaries such as preservatives, stabilizers, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers.

The preparation of the starting materials is known or can be carried out according to known methods. _to

The following examples illustrate the process of the invention in more detail.

Example 1 1,1-Diethyl-3- [6-methyl-1- (4-nitrophenyl) -

-8'-ergolmyl] urea

3.4 g of terguride (10 mmol) are dissolved in 200 ml of tetrahydrofuran, 0.4 g of tetrabutylammonium hydrogen sulfate, 5.0 g of solid, powdered potassium hydroxide and 5.3 ml (50 mmol) of 4-fluoronitrobenzene are added. The reaction mixture was stirred vigorously for 2 hours at room temperature under argon and then partitioned, if necessary after evaporation of a portion of the solvent, between ethyl acetate and saturated sodium chloride solution. The organic phase was dried over sodium sulfate and the filtrate was evaporated until crystals began to form. The mixture is then left to stand in an ice bath and the precipitated crystals are collected.

Yield 4.4 g (95%).

[α] _D = -37 ° (0.5% in chloroform).

Example 2

3- (1- (4-Aminophenyl) -6-methyl-8ce-

-ergolinyl] -1,1-diethylurea

2.3 g (5 mmol) of the compound prepared in Example 1 are dissolved in 35 ml of methanol and 35 ml of tetrahydrofuran, and 1.1 g of 10% palladium on carbon are added thereto, and hydrogenation is carried out at room temperature and atmospheric pressure. After 30 minutes, the catalyst is filtered off, the filtrate is evaporated and the residue is crystallized from ethyl acetate and diisopropyl ether.

Yield 1.9 g (88% of theory).

[α] _D = -16 ° (0.5% in chloroform).

Example 3 1,1-Diethyl-3- (6-methyl-1-phenyl-8a-)

-ergolinyl) urea

432 mg (1 mmol) of the compound of Example 2 are suspended in 8 ml of water and 3.8 ml of concentrated hydrochloric acid and 8 ml of water are added. The mixture is stirred for 10 minutes while cooling in an ice bath, then 74 mg (1.05 mmol) of sodium nitrite in 1 ml of water are added and the mixture is stirred for 30 minutes. Then 5 ml of 60% phosphoric acid and a copper oxide knife tip are added and the mixture is stirred at room temperature for 1 hour. The mixture was then basified by the addition of 5 ml of concentrated ammonia solution and extracted with methylene chloride. The organic phase was dried, evaporated and the residue chromatographed on silica gel using methylene chloride and methanol as eluent. 365 mg of product was isolated, which crystallized from ethyl acetate and diisopropyl ether.

Yield 223 mg (36% of theory).

[.alpha.] D = -13 DEG (0.5% in chloroform).

The following compounds were also prepared in an analogous manner to that described in Example 1.

Example 4 1,1-Diethyl-3- (6-methyl-1-pyrimidin-2-

-yl-8α-ergolinyl) urea

Terguride and 2-chloropyridine were used as starting materials.

Hydrochloride, m.p. 310 DEG-314 DEG.

[ _{i p} - Ψ46 ^υ (0.5% in pyridine).

Yield 38%.

Example 5 1,1-Diethyl-3- [6-methyl-1-pyrazine-2-

-yl-8α-ergolines 1) urea

Terguride and 2-chloropyrazine were used as starting materials.

Yield 56%.

[α] _D = -29 ° (0.2% in methanol).

Hydrochloride, m.p. 295-305 ° C.

Example 6 1,1-Diethyl-3- (6-methyl-1-thiazol-2-yl-86z-ergolinyl) urea

Terguride and 2-bromothiazole were used as starting materials.

Yield = 5%.

- 4-12 ° (0.5% in pyridine).

Mp 117-119 ^o C.

Example 7

1,1-Diethyl 1-3- [1- (3-nitrophenyl) -

-6-methyl-8α: -ergolinyl urea

Terguride and 3-fluoro-1-nitrobenzene were used as starting materials.

Example 8

1,1-diethyl-3- [1- (3-aminophenyl) -6-methyl-8α, -ergolinyl] urea

The title compound was prepared as described in Example 2.

Claims (3)

A process for the preparation of the novel 1-arylergolinyl urea derivatives of the general formula I NH -CO -NIN in which Ar represents a phenyl group which is optionally substituted by a nitro or amino group, a thiazolyl group, a pyrazinyl group or a pyrimidinyl group, ^Three R represents an alkyl group having 1 to 6 carbon atoms, Et represents an ethyl group and ^C 10 represents a single or double bond as well as their physiologically tolerable acid addition salts, characterized in that the compound of the formula II NH-CO-NEt2 OF THE INVENTION in which R ⁶ and Et, as defined above, aryl by the action of a compound of formula III Ar - X (III) in which Ar is as defined above and X represents a halogen atom, whereupon optionally the nitro group as an optional phenyl substituent of Ar is reduced and the amino group thus obtained is optionally diazotized and exchanged with hydrogen, and thereafter optionally converted to physiologically tolerable acid addition salts. 2. Process according to claim 1, characterized in that the corresponding compounds of the formulas II and III are used as starting materials 1,1-diethyl-3- [6-methyl-1- (4-nitrophenyl) -8a-ergolinyl] urea, 3- (1- (4-Aminophenyl) -6-methyl-8α-ergolinyl] -1,1-diethylurea, 1,1-diethyl-3- (6-methyl-1-phenyl-8α-ergolinyl) urea, 1,1-diethyl-3- (6-methyl-1-pyrimidin-2-yl-8α-ergolinyl) urea, 1,1-Diethyl-3- (6-methyl-1-pyrazinyl-8H-ergolinyl) urea a 1,1-diethyl-3- (6-methyl-1-thiazol-2-yl-8ceergolinyl) urea.