| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | December 12, 1989 |
| PATENT TITLE |
Tetrahydro-benzthiazoles, the preparation thereof and their use as intermediate products or as pharmaceuticals |
| PATENT ABSTRACT |
This invention relates to new tetrahydrobenzthiazoles of general formula ##STR1## wherein R.sub.1 represents a hydrogen atom, an alkyl group, an alkenyl or alkynyl group, an alkanoyl group, a phenyl alkyl or phenyl alkanoyl group, while the above mentioned phenyl nucleic may each be substituted by 1 or 2 halogen atoms, R.sub.2 represents a hydrogen atom or an alkyl group, R.sub.3 represents a hydrogen atom, an alkyl group a cycloalkyl group, an alkenyl or alkynyl group, an alkanoyl group, a phenyl alkyl or phenyl alkanoyl group, while the phenyl nucleus may be substituted by fluorine, chlorine or bromine atoms, R.sub.4 represents a hydrogen atom, an alkyl group, an alkyl or alkenyl group, or R.sub.3 and R.sub.4 together with the nitrogen atom between them represent a pyrrolidino, piperidino, hexamethyleneimino or morpholino group, the enantiomers and the acid addition salts thereof. The compounds of general formula I above in which one of the groups R.sub.1 or R.sub.3 or both groups R.sub.1 and R.sub.3 represent an acyl group are valuable intermediate products for preparing the other compounds of general formula I which have valuable pharmacological properties. The new compounds may be prepared using methods known per se. |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | October 12, 1988 |
| PATENT FOREIGN APPLICATION PRIORITY DATA | This data is not available for free |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
What is claimed is: 1. A tetrahydro-benzthiazole of the formula: ##STR16## wherein R.sub.1 is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl or alkynyl group each having 3 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part, wherein the above mentioned phenyl nuclei may be substituted by 1 or 2 halogen atoms; R.sub.2 is a hydrogen atom or an alkyl group with 1 to 4 carbon atoms; R.sub.3 is a hydrogen atom, an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms, an alkanoyl group having 1 to 7 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part, whilst the phenyl nucleus may be substituted by fluorine, chlorine or bromine atoms; and, R.sub.4 is a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms; or, R.sub.3 and R.sub.4 together with the nitrogen atom between them form a piperidino, hexamethyleneimino or morpholino group; or, an acid addition salt thereof. 2. A tetrahydro-benzthiazole of formula I, as claimed in claim 1, wherein the ##STR17## group is in the 5 or 6-position. 3. A tetrahydro-benzthiazole of the formula: ##STR18## wherein R.sub.1 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an allyl, benzyl, 2-chloro-benzyl, 4-chloro-benzyl, 3,4-dichloro-benzyl or phenylethyl group; R.sub.2 is a hydrogen atom, a methyl or ethyl group; R.sub.3 is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an allyl, propargyl, benzyl, chlorobenzyl, phenylethyl, cyclopentyl or cyclohexyl group; and, R.sub.4 is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or an allyl group; or, R.sub.3 and R.sub.4 together with the nitrogen atom between them form a piperidino, hexamethyleneimino or morpholino group; or, a pharmaceutically acceptable acid addition salt thereof. 4. A tetrahydro-benzthiazole of formula Ia, as claimed in claim 3 wherein the ##STR19## group is in the 6-position. 5. A tetrahydro-benzthiazole of formula Ia, as claimed in claim 3, wherein R.sub.1 and R.sub.2 together with the nitrogen atom between them form an amino or allylamino group; and, R.sub.3 and R.sub.4 together with the nitrogen atom between them form a dimethylamino, diethylamino, N-allyl-N-(4-chloro-benzyl)-amino, n- propylamino or group. 6. 2-Amino-6-dimethylamino-4,5,6,7-tetrahydro-benzthiazole, or a pharmaceutically acceptable acid addition salt thereof. 7. 2-Amino-6-n-propylamino-4,5,6,7-tetrahydro-benzthiazole, or a pharmaceutically acceptable acid addition salt thereof. 8. A pharmaceutical composition, suitable for the treatment of a disorder selected from the group consisting of high blood pressure, tachycardia, Parkinson's disease, Parkinsonism and schizophrenia, comprising a therapeutically effective amount of a compound according to claim 3 and a pharmaceutically acceptable carrier diluent. 9. A tetrahydrobenzthiazole of the formula ##STR20## wherein R is an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms, an alkanoyl group having 1 to 7 carbon atoms or a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl moiets, wherein the phenyl nucleus may be substituted by fluorine, chlorine or bromine atoms. 10. The compound of claim 9 wherein R is an alkyl group having 1 to 7 carbon atoms. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
This invention relates to new tetrahydrobenzthiazoles of general formula ##STR2## the enantiomers and acid addition salts thereof, particularly the pharmaceutically acceptable acid addition salts thereof with inorganic or organic acids, and processes for preparing them. Compounds of general formula I wherein R.sub.1 or R.sub.3 or both groups R.sub.1 and R.sub.3 represent an acyl group are valuable intermediate products for preparing other compounds of general formula I which have valuable pharmacological properties, particularly an effect on the central nervous system and/or the circulation. In general formula I above R.sub.1 represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl or alkynyl group each having 3 to 6 carbon atoms, an alkanoyl group having 1 to 6 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part, whilst the above mentioned phenyl nuclei may be substituted by 1 or 2 halogen atoms, R.sub.2 represents a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, R.sub.3 represents a hydrogen atom, an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms, an alkanoyl group having 1 to 7 carbon atoms, a phenyl alkyl or phenyl alkanoyl group having 1 to 3 carbon atoms in the alkyl part, whilst the phenyl nucleus may be substituted by fluorine, chlorine or bromine atoms, R.sub.4 represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an alkenyl or alkynyl group having 3 to 6 carbon atoms or R.sub.3 and R.sub.4 together with the nitrogen atom between them represent a pyrrolidino, piperidino, hexamethyleneimino or morpholino group. Preferred compounds of general formula I above are those wherein the group ##STR3## is in the 5 or 6-position. As examples of the definitions of the groups ##STR4## the ##STR5## group represents an amino, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert.butylamino, n-pentylamino, isoamylamino, n-hexylamino, dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, methyl-ethylamino, methyl-n-propylamino, methylisopropylamino, ethyl-isopropylamino, allylamino, buten-2-ylamino, hexen-2-ylamino, N-methylallylamino, N-ethyl-allylamino, N-n-propylallylamino, N-n-butyl-allylamino, propargylamino, N-methyl-propargylamino, N-n-propyl-propargylamino, formylamino, acetylamino, propionylamino, butanoylamino, hexanoylamino, N-methyl-acetylamino, N-allyl-acetylamino, N-propargyl-acetylamino, benzylamino, N-methyl-benzylamino, 2-chloro-benzylamino, 4-chloro-benzylamino, 4-fluoro-benzylamino, 3,4-dichloro-benzylamino, 1-phenylethylamino, 2-phenylethylamino, 3-phenyl-n-propylamino, benzoylamino phenacetylamino or 2-phenylpropionylamino group and the group ##STR6## may represent an amino, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tert.butylamino, n-pentylamino, isoamylamino, n-hexylamino, n-heptylamino, dimethylamino, diethylamino, di-n-propylamino, Di-n-butylamino, methyl-ethylamino, methyl-n-propylamino, methyl-isopropylamino, ethyl-isopropylamino, allylamino, buten-2-ylamino, hexen-2-ylamino, diallylamino, N-methyl-allylamino, N-ethyl-allylamino, N-n-propyl-allylamino, N-n-butyl-allylamino, propargylamino, butin-2-ylamino, hexin-2-ylamino, dipropargylamino, N-methyl-propargylamino, N-ethyl-propargylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, N-methyl cyclohexylamino, N-ethyl-cyclohexylamino, formylamino, acetylamino, propionylamino, butanoylamino, pentanoylamino, hexanoylamino, heptanoylamino, N-methyl-acetylamino, N-ethyl- acetylamino, N-n-propyl-acetylamino, N-allyl- acetylamino, benzoylamino, fluorobenzoylamino, chlorobenzoylamino, bromobenzoylamino, phenylacetamino, 2-phenylpropionylamino, N-methyl- benzoylamino, N-ethyl-chlorobenzoylamino, Dichlorobenzoylamino, N-cyclohexyl-acetylamino, benzylamino, chlorobenzylamino, bromobenzylamino, 1-phenylethylamino, 2-phenylethylamino, 2-phenyl-n-propylamino, 3-phenyl-n-propylamino, N-methyl-benzylamino, N-ethyl-benzylamino, N-ethyl-chlorobenzylamino, N-ethyl-2-phenylethylamino, N-acetyl-benzylamino, N-acetyl-chlorobenzylamino, N-allyl-benzylamino, N-allyl-chlorobenzylamino, pyrrolidino, piperidino, hexamethyleneimino or morpholino group. Particularly preferred compounds of general formula I are, however, the compounds of general formula Ia ##STR7## wherein R.sub.1 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an allyl, benzyl, 2-chloro-benzyl, 4-chloro-benzyl, 3,4-dichloro-benzyl or phenylethyl group, R.sub.2 represents a hydrogen atom, a methyl or ethyl group, R.sub.3 represents a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an allyl, propargyl, benzyl, chlorobenzyl, phenylethyl, cyclopentyl or cyclohexyl group, R.sub.4 represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or an allyl group or R.sub.3 and R.sub.4 together with the nitrogen atom between them represent a pyrrolidino, piperidino, hexamethyleneimino or morpholino group, but particularly the compounds wherein the group ##STR8## is in the 6-position, and the acid addition salts thereof, particularly the pharmaceutically acceptable acid addition salts. According to the invention the new compounds are obtained by the following methods: (a) Reacting a cyclohexanone of general formula ##STR9## wherein R.sub.3 and R.sub.4 are as hereinbefore defined and X represents a nucleophilically exchangeable group such as a halogen atom, e.g. a chlorine or bromine atom, with a thiourea of general formula ##STR10## wherein R.sub.1 and R.sub.2 are as hereinbefore defined. The reaction is carried out in a melt or in a solvent or mixture of solvents such as water, ethanol, water/ethanol, pyridine, dioxan, dioxan/water, glacial acetic acid, tetrahydrofuran or dimethylformamide, conveniently at temperatures of between 0.degree. and 150.degree. C., preferably at temperatures of between 20.degree. and 100.degree. C. and optionally in the presence of a base, e.g. sodium hydroxide solution, sodium acetate, pyridine, triethylamine or N-ethyl-diisopropylamine. The compounds of general formula II used as starting materials need not be isolated. (b) Reacting a compound of general formula ##STR11## wherein R.sub.3 and R.sub.4 are as hereinbefore defined, with a formamidine disulfide of general formula ##STR12## wherein R.sub.1 and R.sub.2 are as hereinbefore defined and Y.sup.- represents an anion of an inorganic or organic acid. The reaction is preferably carried out in a melt or in a high-boiling solvent such as glycol, dimethylformamide, diphenylether or dichlorobenzene, conveniently at temperatures of between 25.degree. and 200.degree. C., preferably at temperatures of between 70.degree. and 150.degree. C. (c) In order to prepare compounds of general formula I wherein at least one of the groups R.sub.1, R.sub.2, R.sub.3 or R.sub.4 represents a hydrogen atom; splitting off a protecting group from a compound of general formula ##STR13## wherein at least one of the groups R.sub.1 ', R.sub.2 ', R.sub.3 ' or R.sub.4 ' represents a protecting group for an amino group such as an acyl or alkoxycarbonyl group, e.g. an acetyl, propionyl, methoxycarbonyl or ethoxycarbonyl group, or R.sub.1 ' and R.sub.2 ' or R.sub.3 ' and R.sub.4 ' together with the nitrogen atom between them represent an imido group, e.g. the phthalimido group, and The other groups R.sub.1, R.sub.2, R.sub.3 or R.sub.4 have the meanings given for R.sub.1 to R.sub.4 hereinbefore, with the exception of the acyl groups mentioned hereinbefore. The splitting off of a protecting group is preferably carried out by hydrolysis in the presence of a base such as sodium hydroxide solution or potassium hydroxide solution or in the presence of an acid such as hydrochloric or sulphuric acid in an aqueous solvent such as water/ethanol, water/dioxan or water/tetrahydrofuran at temperatures of between 50.degree. and 150.degree. C., preferably at the boiling temperature of the reaction mixture. An imido group such as the phthalimido group used as a protecting group is preferably split off with hydrazine in a solvent such as water, water/ethanol or water/dioxan at the boiling temperature of the solvent used. (d) In order to prepare compounds of general formula I wherein at least one of the groups R.sub.1, R.sub.2, R.sub.3 or R.sub.4 represents one of the above-mentioned alkyl, or phenylalkyl group: Reduction of a compound of general formula ##STR14## wherein at least one of the groups R.sub.1 ", R.sub.2 ", R.sub.3 " or R.sub.4 " represents one of the acyl or phenylacyl groups mentioned hereinbefore and the other groups have the meanings given for R.sub.1, R.sub.2, R.sub.3 and R.sub.4 hereinbefore, with a metal hydride in a solvent. The reduction is carried out in a suitable solvent such as diethylether, tetrahydrofuran, glycoldimethylether or dioxan with a metal hydride, e.g. with a complex metal hydride such as lithium aluminium hydride, at temperatures of between 0.degree. and 100.degree. C., but preferably at temperatures of between 20.degree. and 80.degree. C. In order to prepare compounds of general formula I wherein one of the groups R.sub.3 or R.sub.4 represents one of the acyl groups mentioned hereinbefore, it is particularly advantageous to carry out the reaction with lithium aluminium hydride at temperatures of between 0.degree. and 30.degree. C., preferably at ambient temperature. (e) In order to prepare compounds of general formula I wherein at least one of the groups R.sub.1, R.sub.2, R.sub.3 or R.sub.4 represents one of the alkyl, cycloalkyl, alkenyl, alkynyl or phenylalkyl groups mentioned hereinbefore: Reacting a compound of general formula ##STR15## wherein at least one of the groups R.sub.1 "', R.sub.2 "', R.sub.3 "' or R.sub.4 "' represents a hydrogen atom and the other groups R.sub.1 "', R.sub.2 "', R.sub.3 "' or R.sub.4 "' have the meanings given for R.sub.1 to R.sub.4 hereinbefore, with a compound of general formula R.sub.5 -Z (IX) wherein R.sub.5 represents one of the alkyl, cycloalkyl, alkenyl, alkinyl or phenylalkyl groups mentioned for R.sub.1 to R.sub.4 hereinbefore and Z represents a nucleophili- cally exchangeable group such as a halogen atom or a sulfonic acid group, e.g. a chlorine, bromine or iodine atom, a methoxysulfonyloxy or p- toluenesulfonyloxy group, or Z together with an adjacent hydrogen of the group R.sub.5 represents an oxygen. The reaction is carried out in a solvent such as water, methanol, ethanol, tetrahydrofuran, dioxan, acetone, acetonitrile or dimethylsulfoxide with an alkylating agent such as methyliodide, dimethylsulfate, ethylbromide, diethylsulfate, allyliodide, benzylbromide, 2- phenylethylbromide or methyl-p- toluenesulfonate, optionally in the presence of a base such as sodium hydroxide solution, potassium carbonate, sodium hydride, potassium-tert.butoxide or triethylamine, conveniently at temperatures of between -10.degree. and 50.degree. C., but preferably at temperatures of between 0.degree. and 30.degree. C. However, the reaction may also be carried out without a solvent. Alkylation of the nitrogen atom may also be effected using formaldehyde/formic acid at elevated temperatures, e.g. at the boiling temperature of the reaction mixture, or with a corresponding carbonyl compound and a complex metal hydride such as sodiumborohydride or sodiumcyanoborohydride in a solvent such as water/methanol, ethanol, ethanol/water, dimethylformamide or tetrahydrofuran at temperatures of between 0.degree. and 50.degree. C., but preferably at ambient temperature. If according to the invention a compound of general formula I is obtained wherein at least one of the groups R.sub.1, R.sub.2, R.sub.3 or R.sub.4 represents a hydrogen atom, this may be converted by corresponding acylation into a corresponding compound of general formula I wherein at least one of the groups R.sub.1, R.sub.2, R.sub.3 or R.sub.4 represents one of the acyl groups mentioned herein before. The subsequent acylation is appropriately carried out in a solvent such as methylene chloride, chloroform, carbontetrachloride, ether, tetrahydrofuran, dioxan, glacial acetic acid, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid-activating agent or a dehydrating agent, e.g. in the presence of ethyl chloroformate, thionylchloride, N,N-dicyclohexylcarbodiimide, N,N'-dicyclohexyl carbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole or triphenylphosphine/carbontetrachloride, or an agent which activates the amino group, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or pyridine, which may simultaneously be used as solvent, at temperatures of between -25.degree. C. and 250.degree. C., but preferably at temperature of between -10.degree. C. and the boiling temperature of the solvent used. The reaction may also be carried out without a solvent and furthermore any water formed during the reaction may be removed by azeotropic distillation, e.g. by heating with toluene using a water separator, or by adding a drying agent such as magnesium sulphate or molecular sieve. The compounds of general formula I have at least one chiral center and can, therefore, exist in the form of various stereoisomers. Te invention embraces all of these stereoisomers and mixtures thereof. Mixtures of these stereoisomers can be resolved by conventional methods, e.g. by column chromatography on a chiral phase, by fractional crystallization of the diastereomeric salts or by column chromatography of their conjugates with optically active auxiliary acids such as tartaric acid, O,O-dibenzoyl-tartaric acid, camphor acid, camphorsulfonic acid or .alpha.-methoxy-phenylacetic acid. The compounds may also be converted into the acid addition salts thereof, particularly the pharmaceutically acceptable acid addition salts with inorganic or organic acids. Suitable acids for this include, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, citric, tartaric, succinic, maleic or fumaric acid. The compounds of general formulae II to IX used as starting materials are known from the literature in some cases or may be obtained using methods known from the literature. Thus, for example, a compound of general formula II is obtained by halogenation of the corresponding cyclohexanone, which is in turn prepared by oxidation of the corresponding cyclohexanol and optional subsequent alkylation and/or acylation. The compounds of general formulae VI, VII and VIII used as starting materials are obtained by condensation of a corresponding .alpha.-bromo-cyclohexanone with a corresponding thiourea. As already mentioned hereinbefore, the compounds of general formula I wherein at least one of the groups R.sub.1 to R.sub.4 represents one of the acyl groups mentioned above are valuable intermediate products for preparing the compounds of general formula I wherein R.sub.1 to R.sub.4 have the meanings given to R.sub.1 to R.sub.4 hereinbefore, with the exception of the acyl groups referred to hereinbefore. These compounds and the pharmaceutically acceptable acid addition salts thereof have valuable pharmacological properties, particularly a hypotensive effect on blood pressure, a heart rate lowering effect and an effect on the central nervous system, particularly a stimulant effect on the dopamine receptors. For example, therefore, in order to investigate the effect on presynaptic dopamine receptors, the following compounds A=2-amino-6-dimethylamino-4,5,6,7-tetrahydrobenzthiazol-dihydrochloride, B=2-amino-6-pyrrolidino-4,5,6,7-tetrahydrobenzthiazol-dihydrochloride, C=2-amino-6-n-propylamino-4,5,6,7-tetrahydrobenzthiazol-dihydrochloride, D=2-allylamino-6-dimethylamino-4,5,6,7-tetrahydro-benzthiazol-dihydrochlori de, E=6-[N-ally-N-(4-chloro-benzyl)-amino]-2-amino-4,5,6,7-tetrahydro-benzthiaz ol-dihydrochloride and F=2-amino-6-diallylamino-4,5,6,7-tetrahydrobenzthiazol-dihydrochloride were tested first for their effect on the exploratory activity of mice and then, after any effect on postsynaptic dopamine receptors had been clarified (motility in animals pretreated with reserpine), the effect on dopamine turnover and dopamine synthesis was determined, as follows: 1. Inhibition of the exploratory activity The activity was measured in observation cages fitted with an infra-red light barrier. The frequency of interruption of the light beam by a group of 5 mice within 5 minutes. Groups of 5 animals are given the test substance, unless otherwise specified, in a dosage of 10 mg/kg by subcutaneous injection. One hour later the animals are moved into the observation cages where their exploratory activity over a period of 5 minutes is immediately measured. In parallel or alternately with groups treated with test substance, control groups treated with common salt are investigated (0.9% solution; 0.1 ml/10 g of body weight by subcutaneous route). The results are assembled in the following table: ______________________________________ Inhibition of activity in percent compared Dosage with controls treated Substance (mg/kg s.c.) with common salt ______________________________________ A 2.7.sup.1 50 B 10.0 94 C 10.0 20.sup.2 D 10.0 76.sup.2 E 10.0 56.sup.2 F 10.0 60.sup.2 ______________________________________ .sup.1 read off from the dosage/activity curve in the range from 1-10 mg/kg subcutaneously .sup.2 measurement of exploration: 75 minutes after administration of the substance 2. Determining the inhibition of dopamine turnover The inhibition of dopamine turnover was measured in mice. In animals treated with .alpha.-methylparatyrosine (AMPT) (250 mg/kg by intraperitoneal route) 15 minutes into the experiment, the dopamine concentration throughout the brain decreases as the test progresses. By administering substances which act on autoreceptors, the dopamine reduction (compared with control animals treated with common salt solution) can be prevented. Test substances are administered at time O of the experiment in a dosage of 5 mg/kg s.c., unless otherwise stated. Four hours and 15 minutes into the experiment the animals are killed and the brains are subjected to dopamine determination using high pressure liquid chromatography with electrochemical detection. This determines the percentage inhibition, caused by the test substance, of the dopamine reduction induced by AMPT. ______________________________________ Dosage % inhibition of Substance (mg/kg s.c.) AMPT effect ______________________________________ A 0.95.sup.1 50 B 5 67 D 5 52 E 5 32 ______________________________________ .sup.1 read off from the dosage/activity curve in the range from 0.5-3 mg/kg s.c. 3. Determining the inhibiton of dopamine synthesis For this purpose, 5 animals are given the test substance in a dosage of 10 mg/kg s.c., unless otherwise stated. After 5 minutes, 750 mg/kg of .gamma.-butyrolactone are administered by intraperitoneal route in order to rule out the effect of postsynaptic feed back loops on the rate of dopamine synthesis by blocking the presynaptic impulse line. This results in a considerable increase in the synthesis of DOPA or dopamine. In order to inhibit the decarboxylation of DOPA, 200 mg/kg of 3-hydroxybenzyl-hydrazinhydrochloride are administered by intraperitoneal route after a further 5 minutes. Forty minutes after administration of the substance the animals are killed and the corpus striatum is prepared. The DOPA content is measured by HPLC with electrochemical detection (standard: dihydroxybenzylamine). The percentage inhibition, produced by the test substance, of the DOPA accumulation stimulated by .gamma.- butyrolactone compared with the controlled animals treated with 0.9% common salt solution is determined. The results of this experiment are shown in the following table: ______________________________________ Inhibition of DOPA accumulation in percent Dosage compared with controls Substance (mg/kg s.c.) treated with common salt ______________________________________ A 0.55.sup.1 50 C 10 60 ______________________________________ .sup.1 read off from the dosage/activity curve in the range from 0.1-1.0 mg/kg subcutaneous route. 4. Determining the anti-Parkinsonism activity or the activity against Parkinson's disease The discovery of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (Langston et al., Science 219, 979 (1983)) provided an animal model for Parkinson's disease. The irreversible neurological syndrome triggered by MPTP in man and in monkeys largely resembles the idiopathic Parkinson's disease in its clinical, pathological, biochemical and pharmacological characteristics (Markey et al., Nature 311, 464 (1984)). The reason for this convincing similarity is the fact that MPTP selectively destroys the small group of dopaminergic nerve cells in the substantia nigra of the brain which are also destroyed by degenerative processes in naturally occurring Parkinson's disease. There is even some speculation that the cause of idiopathic Parkinson's disease is MPTP or a similar compound forming in the organism (Synder, S.H., Nature 311, 514 (1984)). Possibly as a result of the specific metabolism of MPTP, the clinical impression of the MPTP-Parkinson picture has hitherto been demonstrated only in monkeys and man. The MPTP model realised in Rhesus monkeys is therefore exceptionally suitable for testing the activity of anti-Parkinson's disease drugs. Seven Rhesus monkeys were given MPTP (for 3 days 1.times.0.15 mg/kg i.m. daily, 3 days' break, then 3 days 1.times.0.30-0.40 mg/kg daily) and showed the following symptoms; the animals were akinetic and not capable of taking water or food. They showed a typical bowed posture; occasionally, cataleptic states occured. The extremities showed a rigor which was interspersed by clonic convulsions on passive movement. As a rule, voluntary movements of the rump and the extremities could not be triggered even by very powerful and painful stimulation. After intramuscular administration of compound C (10-100 .mu.g/kg) voluntary movements first occured after a time interval of 5 to 10 minutes, which were followed in the subsequent 10 to 30 minutes by a gradual, extensive normalisation of the motor function. The animals were capable of taking food. They stayed perfectly upright and straight inside their cages and were also satisfactory in terms of their vigilance and species-specific behaviour. The only residual symptoms recorded were an occasional transient and slight resting tremor and a reduction in rough strength. There was no sedation. Circulation in the skin appeared to be greater than before the compound C was administered. The effect of compound C diminished after about 5 to 7 hours and the animals reverted to the Parkinson symptoms described above; a fresh administration of this compound again leads to an improvement or substantial removal of the clinically pathological manifestations. The advantageous effects of the compounds were thus reproduced several times in each individual animal. No side effects were detected at the dosages used hitherto. Moreover, the compounds prepared according to the invention are largely non-toxic. Thus, when the substances were tested in mice at dosages of between 27 and 50 mg/kg s.c., no deaths were recorded. In view of their pharmacological properties, the compounds of general formula I prepared according to the invention and the pharmaceutically acceptable acid addition salts thereof are suitable for the treatment of central nervous, neuropsychiatric diseases, particularly schizophrenia, for the treatment of Parkinsonism or Parkinson's disease and/or for treating circulatory disorders, particularly hypertension. For pharmaceutical use, the new compounds and the pharmaceutically acceptable acid addition salts thereof, optionally combined with other active substances, may be incorporated in the conventional galenic preparations such as plain or coated tablets, powders, suppositories, suspensions, drops or ampoules. The individual dose is from 0.01 to 0.5 mg/kg of body weight, preferably 0.1 to 0.3 mg/kg of body weight, 1 to 4 times a day. |
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