DE3000901A1 - Anxiolytic and neuroleptic ergoline derivs. - prepd. from 8-beta-bromo-acetyl-ergoline and a piperazine - Google Patents

Abstract

8-beta-Acetylergoline derivs (I) are new (where R=H or CH3; R1=H or OCH3; R2=pyridyl, pyrazinyl, or pyridazinyl or phenyl opt. substd. by Cl, Br, F, 1-4C alkoxy, CH3 or CF3). The cpds. are useful as anxiolytics and neuroleptics. (I) is prepd. by reaction of 8-beta-bromoacetyl ergoline with a piperazine (II). The reaction is effected at ambient temp. or by heating to 60 degrees C for 1-6 hours.

Description

Ergoline derivatives, their production and use.

The invention relates to Sj3-acetylergoline derivatives and a Process for their manufacture.

The invention provides 8β-acetylergoline derivatives of the general formula I. wherein R is a hydrogen atom or a methyl group, R1 is a hydrogen atom or a methoxy group and R2 is a pyridyl, pyrazinyl or pyridazinyl group, an unsubstituted or substituted phenyl group in which the substituents are chlorine, bromine or fluorine atoms, alkoxy groups with 1-4 carbon atoms and Methyl and the trifluoromethyl group can be, as well as their pharmaceutically acceptable addition salts (acid addition salts).

Substituent R2 as an alkoxy-substituted phenyl group can therefore be a Be a phenyl group with the radicals methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy and i-butoxy may be substituted.

The invention also provides a process for the preparation of 8ß-acetylergoline derivatives of the general formula I, the process comprising reacting an 8ß-bromoacetyl-6-methylergoline (described in Belgian PS 861480) with a nucleophilic compound of the general formula II wherein R2 is as defined above. The reaction can take place either in the presence of a base such as trimethylamine or potassium carbonate or in the absence of a base. The reaction takes place in a solvent, such as. B. methanol, ethanol, acetone, dimethylformamide or chloroform at a temperature of about 25 0C - 60 0C for a period of 1 - 4 hours.

The products can be isolated and purified using known methods be e.g. B. using chromatography and / or crystallization as free bases or as salts of the pharmaceutically acceptable acids.

The compounds according to the invention and their pharmaceutically usable ones Addition salts find use as anxiolytic and neurolytic agents.

The action profiles of the central sedative pharmacological activity is obtained from Irwin's observations of the behavior of mice (Irwin S., Psychopharmacologia, Berl., 13, 222, 1968), with information on orientative acute toxicity as well 7 days of observation can be obtained, as well as by antagonism regarding central Amphetamine-induced hypothermia. The results of some compounds of the invention are given in Table 1.

To determine the antagonism in terms of the central amphetamine-induced Hypothermia (Janssen P.A.J., Niemegeers C.J.E., Schellekens K.H.L. and Lenaerts F., drug research. 17, (7) 841, 1967) the compounds became male mice administered orally at a dose between 1 -10 mg / kg, 30 minutes before intraperitoneal injection of 10 mg / kg d-amphetamine sulfate. The antagonism regarding Hypothermia was scored 60 minutes after the amphitamine administration.

The compounds of the invention were also found to be up to one oral dose of 25 mg / kg as inactive in inducing muscle relaxation (Irwin's Experiment in mice) and motor coordination in at ion "Rotarod" experiment in rats).

The reference numbers of the compounds are given in the examples below explained.

Table 1 Compounds Amphetamine antagonism Orientative acute toxicity (ED50, mg / kg po) (LD50, mg / kg po) 355/1083 4.2 600 355/1084 5.8> 800 355/1087 3.0> 800 The following examples serve to explain the invention in more detail.

Example 1 6-methyl-8ß- (4'-phenylpiperazine) acetylergoline (355/1083) A solution of 2.5 g of 88-bromoacetyl-6-methylergoline and 2.34 g of N-phenylpiperazine in 30 ml of ethanol the mixture was left to stand for 4 hours at room temperature. The solution was then evaporated in vacuo and the residue taken up with chlorofrom and washed with water washed. After evaporating the solvent in vacuo, the residue was chromatographed on a silica gel column using a mixture of chloroform: methanol (99: 1 volume ratio) as an eluent. The fractions that have the same product were combined and treated with 2 moles of methanesulfonic acid. The received Salt was recrystallized from ethanol and gave 3 g of 6-methyl-8ß- (4'-phenylpiperazine) -acetylergoline-bis-methanesulfonate, Bp. 219-221 OC Example 2 6-Methyl-8β-t4 '- (p.chlorphenyl) -piperazi7-acetylergoline (355/1084) The procedure was as in Example 1, except that N- (p-chlorophenyl) piperazine was used used. The bis-methanesulfonate of the title compound was obtained in 60% yield; Melting point: 242-2440 C.

Example 3 6-Methyl-8f3- £ 4 '- (p.methoxyphenyl) -piperazine-7-acetylergoline (355/1087) The procedure was as in Example 1, except that N- (p.Methoxyphenyl) -piperazine used; the bis-methanesulfonate of the title compound was obtained in 65% yield; Melting point: 216-2180 C.

Example 4 1g6-Dimethyl-8β- / 4 '(p.chlorphenyl) -piperazine-7-acetylergoline The procedure was as in Example 2, except that 8β-bromoacetyl-1,6-dimethylergoline was used used. The bis-methanesulfonate of the title compound was obtained in 60% yield; Melting point: 256-2580 C.

Example 5 6-methyl-10-methoxy-8β- (4'-phenylpiperazine) acetylergoline The procedure was as in Example 1, except that 8β-bromoacetyl-6-methyl-10-methoxyergoline was used and obtained the bis-methanesulfonate of the title compound in 70% yield.

Example 6 1,6-Dimethyl-10-methoxy-8β- (4'-phenylpiperazine) acetylergoline The procedure was as in Example 1, except that 8β-bromoacetyl-1,6-dimethyl-10-methoxyergoline was used used. The bis-methanesulfonate of the title compound was obtained in 67% yield.

Example 7 6-Methyl-8ß- [4 '- (2'-pyridyl) -piperazine] -actylergoline Man Worked as in Example 1, but used N- (2-pyridyl) -ei perazine and obtained the bis-methanesulfonate of the title compound in 60% yield,

Claims (4)

Claims 1. 8ß-acetylergoline derivative of the general formula where R is a hydrogen atom or a methyl group, R1 is a hydrogen atom or a methoxy group and R2 is a pyridil, parazinyl or pyridazinyl group, an unsubstituted or substituted phenyl group in which the substituents are chlorine, bromine or fluorine atoms, alkoxy groups with 1 - 4 carbon atoms, Methyl and the trifluoromethyl group can be, or their pharmaceutically acceptable addition salts. 2. Process for the preparation of 8ß-acetylergoline derivatives of the formula (I) according to claim 1, characterized in that an 8ß-bromoacetylergoline with a nucleophilic compound of the general formula wherein R2 is as defined above, is reacted, this reaction taking place in a protic or aprotic solvent at a temperature from room temperature to 600 ° C. over a period of 1 to 6 hours. 3 The method according to claim 2, characterized in that the reaction is carried out in the presence of a base. 4. Pharmaceutical preparations, characterized in that they contain at least a compound according to claim 1, optionally together with customary carriers, auxiliary respectively. Thinners.