DE3447075A1 - Tetrahydrobenzothiazoles, their preparation and their use as intermediates or as medicaments - Google Patents

Abstract

The present invention relates to novel tetrahydrobenzothiazoles of the general formula <IMAGE> in which R1 denotes a hydrogen atom, an alkyl group, an alkenyl or alkynyl group, an alkanoyl group, or a phenylalkyl or phenylalkanoyl group, R2 denotes a hydrogen atom or an alkyl group, R3 denotes a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl or alkynyl group, an alkanoyl group, or a phenylalkyl or phenylalkanoyl group, it being possible for the phenyl ring to be substituted by fluorine, chlorine or bromine atoms, R4 denotes a hydrogen atom, an alkyl group, or an alkenyl or alkynyl group, or R3 and R4, together with the nitrogen atom lying between them, denote a pyrrolidino, piperidino, hexamethylenimino or morpholino group, their enantiomers and their acid addition salts. The compounds of the above general formula I, in which one of the radicals R1 or R3 or both of the radicals R1 and R3 denote an acyl radical, are useful intermediates for the preparation of the other compounds of the general formula I, which have useful pharmacological properties, in particular an action on the central nervous system and/or the circulation. The novel compounds can be prepared by processes known per se.

Description

Tetrahydro-benzothiazoles, their production and their distribution

Use as intermediates or as pharmaceuticals The present invention relates to new tetrahydrobenzothiazoles of the general formula their enantiomers and their acid addition salts, in particular their physiologically acceptable acid addition salts with inorganic or organic acids, and processes for their preparation.

In the above general formula I means one of the radicals R1 or These compounds represent R3 or both of the radicals R1 and R3 an acyl radical of the general formula I valuable intermediates for the preparation of the rest Compounds of general formula I which have valuable pharmacological properties have, in particular an effect on the central nervous system and / or the circulation.

In the above general formula I, R1 denotes a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl or alkynyl group each with 3 to 6 carbon atoms, an alkanoyl group with 1 to 6 carbon atoms, a phenylalkyl or phenylalkanoyl group each having 1 to 3 carbon atoms in the alkyl part, R2 is a hydrogen atom or an alkyl group with 1 to 4 carbon atoms, R3 represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, an alkenyl or alkynyl group each with 3 to 6 carbon atoms, an alkanoyl group with 1 to 7 carbon atoms, a phenylalkyl or phenylalkanoyl groups each having 1 to 3 carbon atoms in the alkyl part, where the phenyl nucleus can be substituted by fluorine, chlorine or bromine atoms, R4 Hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an alkenyl or Alkynyl group each having 3 to 6 carbon atoms or R3 and R4 together with the nitrogen atom in between is a pyrrolidino, piperidino, hexamethyleneimino or morpholino group.

Preferred compounds of the above general formula I are those in which the group is in the 5 or 6 position.

For when defining the groups and comes for example for the -Group means 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, methyl-isopropylamino, ethyl-isopropylamino, allylamino, buten-2-ylamino, hexene -2-ylamino-, N-methyl-allylamino-, N-ethyl-allylamino-, Nn-propyl-allylamino-, Nn-butyl-allylamino-, propargylamino-, N-methylpropargylamino-, Nn-propyl-propargylamino-, formylamino -, acetylamino, propionylamino, butanoylamino, hexanoylamino, N-methyl-acetylamino, N-allyl-acetylamino, N-propargyl-acetylamino, benzylamino, N-methyl-benzylamino, l-phenylethylamino, 2-phenylethylamino, 3-phenyl-n-propylamino, benzoylamino, phenacetylamino or 2-phenylpropionylamino and for the Group of the 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, methylethylamino, methyl-n-propylamino, methyl-isopropylamino, ethyl-isopropylamino, allylamino, buten-2-ylamino , Hexen-2-ylamino-, diallylamino-, N-methyl-allylamino-, N-ethyl-allylamino-, Nn-propyl-allylamino-, Nn-butylallylamino-, propargylamino-, butin-2-ylamino-, hexyne-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-methylacetylamino, N-ethyl-acetylamino, Nn-propyl-acetylamino, N-allyl-acetylamino, benzoylamino Fluorobenzoyl amino, chlorobenzoylamino, bromobenzoylamino, phenylacetylamino, 2-phenylpropionylamino, N-methylbenzoylamino, N-ethylchlorbenzoylamino, dichlorobenzoylamino, N-cyclohexyl-acetylamino, benzylamino-, chlorobenzylamino- Phenylethylamino, 2-phenylethylamino, 2-phenyln-propylamino, 3-phenyl-n-propylamino, N-methyl-benzylamino, N-ethyl-benzylamino, N-ethyl-chlorobenzylamino, N-ethyl-2 -phenylethylamino, N-acetylbenzylamino, N-acetylchlorobenzylamino, N-allylbenzylamino, N-allylchlorobenzylamino, pyrrolidino, piperidino, hexamethyleneimino or morpholino groups.

However, particularly preferred compounds of the above general formula I are those compounds of the general formula in which R1 is a hydrogen atom, an alkyl group with 1 to 3 carbon atoms, an allyl, benzyl or phenylethyl group, R2 is a hydrogen atom, a methyl or ethyl group, R3 is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an allyl, propargyl -, Benzyl, chlorobenzyl, phenylethyl, cyclopentyl or cyclohexyl group, R4 a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or an allyl group or R3 and R4 together with the nitrogen atom in between a pyrrolidino, piperidino, hexamethyleneimino or Morpholino group mean, but especially those compounds in which the Group in the 6-position, and their acid addition salts, in particular their physiologically acceptable acid addition salts.

According to the invention, the new compounds are obtained by the following processes: a) Reaction of a cyclohexanone of the general formula in which R3 and R4 are as defined at the outset and X is a nucleophilic leaving group such as a halogen atom, e.g.

a chlorine or bromine atom, with a thiourea of the general formula in which R1 and R2 are defined as above.

The reaction is carried out in the melt or in a solvent or Solvent mixture such as water, ethanol, water / ethanol, pyridine, dioxane, dioxane / water, Glacial acetic acid, tetrahydrofuran or dimethylformamide expediently at temperatures between 0 and 1500C, preferably at temperatures between 20 and 1000C and optionally in the presence of a base, e.g. sodium hydroxide solution, sodium acetate, pyridine, triethylamine or N-ethyl-diisopropylamine carried out. - The ones used as raw materials Compounds of the general formula II do not have to be isolated here.

b) Implementation of a compound of the general formula in which R3 and R4 are as defined at the outset, with a formamidine disulfide of the general formula in which R1 and R2 are as defined at the outset and Y represents an anion of an inorganic or organic acid.

The reaction is preferably carried out in the melt or in a high-boiling point Solvents such as glycol, dimethylformamide, diphenyl ether or dichlorobenzene are expedient at temperatures between 25 and 200 ° C, preferably at temperatures between 70 and 1500C.

c) For the preparation of compounds of the general formula I in which at least one of the radicals R1, R2, R3 or R4 represents a hydrogen atom: cleavage of a protective radical from a compound of the general formula in which at least one of the radicals R1 'R2', R3 'or R4' is a protective group for an amino group such as an acyl or alkoxycarbonyl group, for example an acetyl, propionyl, methoxycarbonyl or ethoxycarbonyl group, or also R1 'and R2' or R3 'and R4' together with the nitrogen atom in between represent an imido radical, for example the phthalimido radical, and the rest of the radicals R1, R2, R3 or R4 have the meanings mentioned for R1 to R4 with the exception of the acyl radicals mentioned at the beginning.

A protective radical is preferably split off hydrolytically 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 acid or sulfuric acid in an aqueous solvent such as water / ethanol, Water / dioxane or water / tetrahydrofuran at temperatures between 50 and 1500C, preferably at the boiling point of the reaction mixture. One as a protective remnant Imido radical used, such as the phthalimido radical, is preferably combined with hydrazine in a solvent such as water, water / ethanol or water / dioxane at the boiling point split off the solvent used.

d) For the preparation of compounds of general formula 1 in which at least one of the radicals R1, R2, R3 or R4 is one of the alkyl, cycloalkyl, alkenyl or phenylalkyl groups mentioned at the outset: reduction of a compound of the general formula in which at least one of the radicals R111, R2 ", R3" or R4 "represents one of the acyl or phenylacyl radicals mentioned at the outset and the remaining radicals have the meanings mentioned for R1, R2, R3 and R4 at the beginning, with a metal hydride in a solvent .

The reduction is carried out in a suitable solvent such as diethyl ether, Tetrahydrofuran, glycol dimethyl ether or dioxane with a metal hydride, e.g. a complex metal hydride such as lithium aluminum hydride, at temperatures between 0 and 1000C, but preferably at temperatures between 20 and 80C.

For the preparation of compounds of general formula I in the one of the radicals R3 or R4 represents one of the acyl groups mentioned at the outset the reaction is particularly advantageous with lithium aluminum hydride at temperatures between 0 and 30 ° C., preferably at room temperature.

e) For the preparation of compounds of the general formula I in which at least one of the radicals R1, R2, R3 or R4 is one of the alkyl, cycloalkyl, alkenyl, alkynyl or phenylalkyl groups mentioned at the outset: reaction of a compound of the general formula in which at least one of the radicals R1 '", R2111, R3111 or R4 |" represents a hydrogen atom and the rest of the radicals R11 ", R2 11l t R3"' or R4 "'have the meanings mentioned for R1 to R4 with a compound of the general formula 5 z Z, (IX) in which R5 is one of the alkyl, cycloalkyl, alkenyl, alkynyl or phenylalkyl groups mentioned for R1 to R4 and Z is a nucleophilic leaving group such as a halogen atom or a sulfonic acid radical, e.g. Chlorine, bromine or iodine atom, a methoxysulfonyloxy or p-toluenesulfonyloxy group, or Z together with an adjacent hydrogen atom of the radical R5 denote an oxygen atom.

The reaction is carried out in a solvent such as water, methanol, ethanol, Tetrahydrofuran, dioxane, acetone, acetonitrile or dimethyl sulfoxide with an alkylating agent such as methyl iodide, dimethyl sulfate, ethyl bromide, diethyl sulfate, allyl iodide, benzyl bromide, 2-phenylethyl bromide 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 expediently at temperatures between -10 and 50 ° C., but preferably at Temperatures between 0 and 300C carried out. However, the implementation can also be done without Solvent to be carried out.

The alkylation of the nitrogen atom can also be carried out using formaldehyde / formic acid at elevated temperatures, e.g. at the boiling point of the reaction mixture, or with a corresponding carbonyl compound and a complex metal hydride such as sodium borohydride or sodium cyanoborohydride in a solvent such as water / methanol, Ethanol, ethanol / water, dimethylformamide or tetrahydrofuran at temperatures between 0 and 50 ° C., but preferably at room temperature.

According to the invention, a compound of the general formula is obtained I, in which at least one of the radicals R1, R2, R3 or R4 represents a hydrogen atom, this can be converted into a corresponding compound by means of appropriate acylation of the general formula I, in which at least one of the radicals R1, R2, R3 or R4 is a represents the acyl radicals mentioned at the outset, are converted.

The subsequent acylation is expediently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, Dioxane, glacial acetic acid, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid activating agent or a dehydrating agent By means, e.g. in the presence of ethyl chloroformate, thionyl chloride, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, or one which activates the amino group Means, 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 can also serve as a solvent, at temperatures between -250C and 2500C, but preferably at temperatures between -100C and the boiling point of the solvent used. The implementation can also be carried out without a solvent, furthermore it can be carried out during the reaction water produced by azeotropic distillation, e.g. by heating with toluene on the water separator or by adding a drying agent such as magnesium sulfate or molecular sieve are separated.

The compounds of general formula I obtained, which at least contain a chiral center, can be converted into their enantiomers by customary methods disconnect, for example by column chromatography on a chiral phase, by means of fractional crystallization of their diastereomeric salts or by means of column chromatography of their conjugates with optically active auxiliary acids such as tartaric acid, o, 0-dibenzoyl-tartaric acid, camphoric acid, camphorsulphonic acid or α-methoxyphenylacetic acid.

Furthermore, the compounds obtained can be converted into their acid addition salts, especially in their physiologically compatible acid addition salts with inorganic ones or convert organic acids. The acids here are, for example, hydrochloric acid, Hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, Succinic acid, maleic acid or fumaric acid into consideration.

The compounds of the general formulas used as starting materials II to IX are partly known from the literature or they are obtained from those known from the literature Procedure.

For example, a compound of the general formula is obtained in this way II by halogenation of the corresponding cyclohexanone, which in turn by Oxidation of the corresponding cyclohexanol and, if appropriate, subsequent alkylation and / or acylation is produced.

The compounds of the general formulas used as starting materials VI, VII and VIII are obtained by condensation of a corresponding α-bromo-cyclohexanone with a corresponding thiourea.

As already mentioned at the beginning, the connections represent the general Formula I, in which at least one of the radicals R to R4 is one of the groups mentioned at the outset Represents acyl radicals, valuable intermediates for the preparation of the compounds of the general formula I, in which R1 to R4 with Exception of Acyl radicals mentioned at the beginning have the meanings mentioned for R1 to R4 at the beginning. These compounds and their physiologically acceptable acid addition salts have valuable pharmacological properties, in particular an effect on the Blood pressure, a heart rate lowering effect and an effect on the central nervous system, especially a dopamine receptor stimulating effect.

For example, for the compounds A = 2-amino-6-dimethylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride, B = 2-amino-6-pyrrolidino-4,5,6,7-tetrahydro-benzthiazole dihydrochloride, C = 2-amino-6-n-propylamino-4,5,6,7-tetrahydro-benzthiazole dihydrochloride, D = 2-allylamino-6-dimethylamino-4,5,6,7-tetrahydrobenzthiazole dihydrochloride, E = 6- [N-Allyl-N- (4-chloro-benzyl) -aminoi -2-amino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride and F = 2-amino-6-diallylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride for Investigation of the influence of presynaptic dopamine receptors first the effect examined for the exploratory activity of mice and then, after clarification an effect on postsynaptic dopamine receptors (motility of those pretreated with reserpine Animals), the influence of dopamine turnover and dopamine synthesis as follows certainly: 1. Inhibition of exploratory activity The activity measurement took place in observation cages equipped with an infrared light barrier. The frequency with which the light beam is interrupted by a group is measured of 5 mice within 5 minutes. Groups of 5 animals each receive the substance to be examined, unless otherwise stated, in a dose of 10 mg / kg injected subcutaneously. 1 hour later, the animals are placed in the observation cages brought where immediately with the measurement of exploratory activity over 5 minutes is started. Parallel or alternating with groups treated with test substance Saline-treated control groups (0.9%; 0.1 m1 / 10 g body weight subcutaneous) examined.

The results are compiled in the following table: Substance dose1 Inhibition of activity (mg / kg sc) in percent versus saline treated Controls A 2.7 50 B 10.0 94 C 10.0 20 * D 10.0 76 * E 10.0 56 * F 10.0 60 * * Exploration measurement: 75 minutes after administration of the substance 1) read from the dose-effect curve in the range 1-10 mg / kg subcutaneously 2. Determination of the inhibition of dopamine turnover The inhibition of dopamine turnover was measured on mice. In animals treated with α-methyl paratyrosine (AMPT) (250 mg / kg intraperitoneally) at the time of 15 minutes of the experiment, the dopamine concentration in the whole brain falls as the duration of the experiment progresses. Substances that act on autoreceptors can prevent the drop in dopamine (compared to control animals treated with saline).

Test substances are used at time 0 of the experiment - if not otherwise stated - with 5 mg / kg s.c. applied.

At the time of 4 hours and 15 minutes of the experiment, the animals are sacrificed and the brains are subjected to dopamine determination by means of high pressure liquid chromatography with electrochemical detection. The percentage inhibition of the AMPT-induced decrease in dopamine caused by the test substance is determined. Substance dose% inhibition of (mg / kg sc) AMPT effect A 0.95 50 B 5 67 D 5 52 E 5 32 1) read from the dose-response curve in the range of 0.5-3 mg / kg sc

3. Determination of the dopamine synthesis inhibition For this purpose, 5 animals receive unless otherwise stated, 10 mg / kg s.c. the substance to be examined. After 5 Minutes the administration of 750 mg / kg i.p. y-butyrolactone, to block the presynaptic impulse conduction to reduce the influence of postsynaptic Eliminate feedback loops on the dopamine synthesis rate. this leads to a considerable increase in DOPA or dopamine synthesis. To inhibit the Decarboxylation of DOPA after a further 5 minutes 200 mg / kg i.p. 3-hydroxybenzyl hydrazine hydrochloride applied. The animals and the corpus are sacrificed 40 minutes after administration of the substance striatum prepared. The DOPA content is measured with the aid of HPLC electrochemical detection (standard: dihydroxibenzylamine).

The percentage inhibition caused by the test substance is determined the dopa accumulation stimulated by γ-butyrolactone compared to that with 0.9% of the Saline treated control animals.

The results of this experiment are summarized in the following table: Substance dose1 inhibition of dopa accumulators (mg / kg sc) formulation in% versus saline treated Controls A 0.55 50 C 10 60 1) read subcutaneously from the dose-effect curve in the range 0.1-1.0 mg / kg.

Furthermore, the compounds prepared according to the invention are largely non-toxic. Thus, when investigating the substances on mice with doses between 27 and 50 mg / kg p.o.

no deaths are noted.

Because of their pharmacological properties, they are suitable according to the invention prepared compounds of general formula I and their physiologically acceptable Acid addition salts for the treatment of central nervous, neuropsychiatric diseases, in particular schizophrenia, for the treatment of parkinsonism and / or for the treatment of circulatory diseases, especially hypertension.

The new compounds can be used for pharmaceutical purposes and their physiologically acceptable acid addition salts, optionally in combination with other active ingredients, in the usual galenic application forms such as coated tablets, Incorporate tablets, powders, suppositories, suspensions, drops or ampoules. The single dose is 1 to 4 times a day 0.01-0.5 mg / kg body weight, but preferably 0.1-0.3 mg / kg body weight.

The following examples are intended to explain the invention in more detail: example A 4- [N- (4-chloro-benzyl) -amino] -cyclohexanol 75.8 g (0.5 mol) of 4-amino-cyclohexanol hydrochloride are dissolved in 60 ml of water and after adding 36 g (0.26 mol) of potassium carbonate and 500 ml of toluene are boiled on the water separator until the water separates out. Then 71.7 g (0.5 mol) of 4-chlorobenzaldehyde are slowly added with further boiling on a water separator admitted. After the calculated amount of water has deposited, it becomes water given and the toluene phase separated and concentrated. The constriction residue will Dissolved in 500 ml of ethanol and with stirring in portions with 19 g (0.5 mol) of sodium borohydride offset. After standing overnight, the mixture is concentrated, water is added and chloroform is added extracted. After the extracts have been dried and concentrated, the residue is made up of ethyl acetate recrystallized.

Yield: 93.4 g (78% of theory), melting point: 103-1040C Calc .: C 65.12 H 7.57 N 5.84 C1 14.79 Found: 65.21 7.68 5.93 14.65 Analogously to Example A. using propionaldehyde produced the following compound: 4-n-propylamino-cyclohexanol Yield: 12.4% of theory, melting point: <200 ° C. Calc .: m / e = 157 found: m / e = 157 Example B 4- [N- (4-chloro-benzyl) -methylamino] -cyclohexanol 7.2 g (30 mmol) of 4- [N- (4-chloro-benzyl) -amino] -cyclohexanol are dissolved in 30 ml of dimethylformamide dissolved and after adding 2.2 g (16 mmol) of potassium carbonate dropwise with 4.26 g (30 mmol) of methyl iodide were added. After the slightly exothermic reaction has subsided is concentrated, mixed with water and extracted with chloroform. The narrowed ones For purification, extracts are chromatographed on silica gel (mobile phase: methylene chloride / methanol = 20/1).

Yield: 3.3 g (43.4% of theory), melting point: 74-750C Calc .: C 66.26 H 7.94 N 5.52 C1 13.97 Found: 66.36 7.95 5.46 13.81 Analogously to Example B. produced the following compounds: 4-hexamethyleneimino-cyclohexanol produced from 4-amino-cyclohexanol and 1,6-dibromohexane.

Yield: 47.3% of theory, melting point: <200 ° C. Calc .: m / e = 197 found: m / e = 197 4-diallylamino-cyclohexanol Manufactured from 4-aminocyclohexanol and allyl bromide.

Yield: 51% of theory, melting point: <200 ° C. Calc .: m / e = 195 Found: m / e = 195 4-Piperidino-cyclohexanol Manufactured from 4-Amino-cyclohexanol and 1,5-dibromopentane.

Yield: 65.8% of theory, melting point: <200 ° C. Calc .: m / e = 183 found: m / e = 183 4-pyrrolidino-cyclohexanol Manufactured from 4-amino-cyclohexanol and 1,4-dibromobutane.

Yield: 35.8% of theory, melting point: <200 ° C. Calc .: m / e = 169 found: m / e = 169 Example C 4-Diethylamino-cyclohexanol 28.75 g (0.25 mol) of 4-amino-cyclohexanol are dissolved in 150 ml of water with the addition of 20 g (0.5 mol) of sodium hydroxide and 65.6 ml (0.5 mol) of diethyl sulfate were added dropwise. This heats up the approach to 650C. The mixture is stirred for one hour at 70 ° C., then poured onto ice and extracted with chloroform.

Yield: 18.2 g (42.5% of theory), melting point: <200 ° C. Calc .: m / e = 171 found: m / e = 171 Example D 4- [N- (4-chloro-benzyl) -amino] -cyclohexanone 23.9 g (0.1 mol) 4- [N- (4-chlorobenzyl) -amino] -cyclohexanol are in Suspended 125 ml of ice water and mixed with 32 ml of concentrated sulfuric acid. Then 29.4 g (0.1 mol) of potassium dichromate are added in 2 portions and the mixture is heated 5 hours at 500C. It is then cooled, made alkaline with sodium hydroxide solution and extracted with chloroform. After concentration, a yellowish colored oily liquid is obtained.

Yield: 8.2 g (34% of theory), melting point: <200C Calc .: m / e = 237/239 Found: m / e = 237/239 Analogous to example D, the following compounds were made produced: 4- [N- (4-chloro-benzyl) -methylamino] -cyclohexanone Yield: 38% of the Theory, melting point: <200C Calc .: m / e = 251/253 Gef .: m / e = 251/253 4-diallylamino-cyclohexanone Yield: 21% of theory, melting point: <200 ° C. Calc .: m / e = 193, found: m / e = 193 4-piperidino-cyclohexanone Yield: 22.2% of theory, melting point: <200C Ber .: m / e = 181 Found: m / e = 181 4-pyrrolidino-cyclohexanone yield: 45.1% of theory, melting point: <200 ° C. Calc .: m / e = 167 Gef .: m / e = 167 4-diethylamino-cyclohexanone Yield: 49.7% of theory, melting point: <200 ° C. Calc .: m / e = 169 found: m / e = 169 4-n-propylamino-cyclohexanone Yield: 33% of theory, melting point: < 200C Calc .: m / e = 155 Det .: m / e = 155 Example E 4- [N- (4-chloro-benzyl) -methylamino] -cyclohexanone 8.4 g (35 mmol) 4- [N- (4-chloro-benzyl) -amino] -cyclohexanone are in Dissolved 50 ml of absolute dimethylformamide and, after adding 2.6 g (18.7 mmol) of potassium carbonate 5.0 g (35 mmol) of methyl iodide were added dropwise at 25-300C. After standing over It is concentrated overnight, water is added and the mixture is extracted with chloroform. The extracts are dried and concentrated.

Yield: 8.1 g (93% of theory), melting point: <200C Calc .: m / e = 251/253 Found: m / e = 251/253 The following were analogous to Example E Compounds made: 4- [N-Allyl-N- (4-chloro-benzyl) -amino] -cyclohexanone Yield: 70.7% of theory Melting point: <200 ° C. Calc .: m / e = 277/279 Det .: m / e = 277/279 4- [N- (4-chloro-benzyl) -ethylamino] -cyclohexanone Yield: 30% of theory Melting point: <200C Calc .: m / e = 265/267 Found: m / e = 265/267 Example F 4-Hexamethyleneimino-cyclohexanone For the suspension of 107.5 g (0.5 mol) of pyridinium chlorochromate and 40 g (0.5 mol) Sodium acetate in 700 ml of methylene chloride is added dropwise to the solution of 47 at 20-250C g (0.5 mol) of 4-hexamethyleneimino-cyclohexanol in 300 ml of methylene chloride. After an hour Stirring at 200 ° C. is added to ice water and sodium hydroxide solution and extracted with methylene chloride. After drying and concentrating the extracts, a colorless oily liquid remains.

Yield: 16.8 g (35.8% of theory), melting point: <20 "C calc .: m / e = 195 found: m / e = 195 Example 1 2-Amino-6-dimethylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride 2.82 g (0.02 mol) of 4-dimethylamino-cyclohexanone are dissolved in 20 ml of glacial acetic acid, 4.7 ml of 36% hydrobromic acid in glacial acetic acid were added and the mixture was cooled dropwise treated with a solution of 1.0 ml (0.02 mol) of bromine in 12 ml of glacial acetic acid. Afterward it is concentrated in vacuo and the residue is digested several times with diethyl ether. the Ether extracts are discarded and the residue is dissolved in 50 ml of ethanol. After adding 3.04 g (40 mmol) of thiourea is refluxed for 5 hours. Then it will be concentrated, made alkaline with sodium hydroxide solution and extracted with chloroform. To the drying and concentration of the extracts is carried out by column chromatography on silica gel cleaned (eluent: chloroform / methanol = 1/1). Then the base (melting point: 1910C) dissolved in acetone and converted into the dihydrochloride with isopropanolic hydrochloric acid convicted.

Yield: 1.09 g (20% of theory), melting point: 2720C, calc .: C 40.00 H 6.34 N 15.55 C1 26.24 Found: 39.63 6.55 15.31 26.29 From the corresponding retons the following tetrahydrobenzothiazoles were prepared analogously to Example 1: 2-Amino-6-diethylamino-4,5,6,7-tetrahydrobenzothiazole Yield: 25% of theory, melting point: 182-1830C, calc .: C 58.62 H 8.49 N 18.64 Found: 58.65 8.72 18.50 2-Amino-6-piperidino-4,5,6,7-tetrahydro-benzthiazole dihydrochloride Yield: 13% of theory, melting point: 2800 ° C. Calc .: C 46.45 H 6.82 N 13.55 C1 22.85 Found: 46.37 6.75 13.41 22.95 2-Amino-6-pyrrolidino-4,5,6,7-tetrahydro-benzothiazole Yield: 24.4% of theory, melting point: 204-2060C Calc .: C 59.15 H 7.67 N 18.81 Found: 59.50 7.74 18.95 2-Amino-6-diallylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride Yield: 19% of theory, melting point: 2420C, calc .: C 48.44 H 6.56 N 13.03 C1 22.00 found * 47.90 6.49 12.95 22.21 2-Amino-6- [N- (4-chloro-benzyl) -amino] -4,5,6,7-tetrahydrobenzthiazole Yield: 35% of theory, melting point: 1460C, calc .: C 57.23 H 5.49 N 14.30 C1 12.06 Found: 56.93 5.56 13.86 12.04 2-Amino-6- [N- (4-chloro-benzyl) -methylamino] -4,5,6,7-tetrahydro-benzothiazole Yield: 36% of theory, melting point: 1630 ° C. Calc .: C 58.69 H 5.89 N 13.64 C1 11.51 Found: 58.50 5.94 13.49 11.55 2-Amino-6- [N- (4-chloro-benzyl) -ethylamino] -4,5,6,7-tetrahydro-benzothiazole- dihydrochloride Yield: 49% of theory, melting point: 2580C (decomposition) Calc .: C 48.67 H 5.61 N 10.64 C1 26.94 Found: 48.30 5.85 10.57 26.97 2-Amino-6- [N-allyl-N- (4-chloro-benzyl) -amino] -4.5.6.7 tetrahydro-benzothiazole dihydrochloride Yield: 46.5% of theory, melting point: 2400C (decomposition) Calc .: C 50.19 H 5.45 N 10.33 C1 26.14 Found: 49.84 5.68 9.97 26.04 2-Amino-6-hexamethyleneimino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride Yield: 15.4% of theory, melting point: 2950C (decomposition) Calc .: C 48.17 H 7.14 N 12.95 Cl 21.86 Found: 47.90 7.34 12.44 21.64 2-Allylamino-6-dimethylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride Manufactured from 4-dimethylamino-cyclohexanone by bromination and subsequent Implementation with allyl thiourea.

Yield: 64% of theory, melting point: 2480 ° C. Calc .: C 46.45 H 6.82 N 13.54 C1 22.85 Found: 46.30 7.00 13.29 12.99 2-Amino-5-dimethylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride Made from 3-dimethylamino-cyclohexanone.

Yield: 33% of theory, melting point: 1940 ° C. Calc .: C 40.00 H 6.34 N 15.55 C1 26.24 Found: 39.74 6.37 15.15 25.96 2-Amino-5-morpholino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride Manufactured from 3-morpholino-cyclohexanone Yield: 7.4 g (20% of theory) Melting point: 237-2380C Calc .: C 42.31 H 6.13 N 13.46 Found: 42.00 6.29 13.13 Example 2 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride a) 4- (Phthalimido) cyclohexanol 75.5 g (0.5 mol) of 4-aminocyclohexanol hydrochloride and 74.0 g (0.5 mol) of phthalic anhydride are obtained after the addition of 65 g (0.5 mol) of ethyl diisopropyl amine and 1000 ml of toluene boiled on a water separator for 36 hours. Then with water added, the toluene phase separated and the aqueous phase several times with chloroform extracted. The organic phases are combined, dried and concentrated. Of the Concentration residue is recrystallized from isopropanol.

Yield: 95 g (77.8% of theory), melting point: 175-1760C b) 4- (phthalimido) cyclohexanone 95 g (0.388 mol) 4- (phthalimido) cyclohexanol are dissolved in 600 ml chloroform and after adding 450 ml of water and 120 ml of sulfuric acid in portions with 90 g (0.3 mol) of potassium dichromate were added. The internal temperature of the approach is here kept between 25 and 300C by slight cooling. The mixture is then stirred for 3 hours and separated then the chloroform phase and extracted twice with chloroform.

After drying and concentrating the extracts, 82 g (86.9 % of theory).

c) 2-Amino-6-phthalimido-4,5,6,7-tetrahydro-benzothiazole 48.6 g (0.2 Mol) 4- (phthalimido) cyclohexanone are analogous to Example 1 with 32 g (0.2 mol) of bromine brominated and then with thiourea into the 2-amino-6-phthalimido-4,5,6,7-tetrahydro-benzothiazole convicted.

Yield: 30 g (50% of theory), melting point: 244-2460C (decomposition) Calc .: C 60.18 H 4.38 N 14.04 Found: 60.05 4.25 13.95 d) 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride 9.5 g (31.7 mmol) of 2-amino-6-phthalimido-4,5,6,7-tetrahydrobenzthiazole are in Suspended 100 ml of ethanol and after adding 1.8 g (36 mmol) of hydrazine hydrate 2 Refluxed for hours. It is then concentrated and methanol in the mobile phase Purified by column chromatography on silica gel.

The dihydrochloride is then dissolved in ethanol with ethanolic hydrochloric acid pleases.

Yield: 2.0 g (26% of theory, melting point:> 3150C (decomposition) Calc .: C 34.72 H 5.41 N 17.35 C1 29.25 Found: 35.00 5.26 16.95 29.10 Example 3 6-Acetylamino-2-amino-4,5,6, 7-tetrahydro-benzothiazole hydrobromide To a solution of 155 g (1.0 mol) of 4-acetylamino-cyclohexanone in 1.5 l of glacial acetic acid 160 g (1.0 mol) of bromine are added dropwise.

The mixture is stirred at room temperature for 3 hours. To the reaction mixture will 152.0 g (2.0 mol) of thiourea and heated under reflux for 30 minutes. To After cooling, the precipitated crystals are filtered off with suction and washed with water and acetone washed.

Yield: 73 g (37% of theory), melting point: 292-293 ° C. (decomposition) Calc .: C 36.99 H 4.83 N 14.38 Found: 36.82 4.76 14.18 By stirring the hydrobromide the free potassium carbonate solution is obtained in aqueous potassium carbonate solution and then filtered off with suction Base with a melting point of 194-1960C (methanol).

The following compounds were prepared analogously to Example 3: 6-acetylamino-2-allylamino-4,5,6,7-tetrahydre-benzothiazole Yield: 46% of theory, melting point: 194-1960C Calc .: m / e = 251 Det .: m / e = 251 6-Acetylamino-2-methylamino-4,5,6,7-tetrahydro-benzothiazole Yield: 64% of the Theory, Melting Point: 238-2400C Calc .: C 53.30 H 6.71 N 18.65 Found: 53.18 6.78 18.41 6-acetylamino-2-dimethylamino-4,5,6,7-tetrahydrobenzthiazole yield: 51% of theory, Melting point: 170-1710C Calc .: C 55.20 H 7.16 N 17.56 Found: 55.15 7.17 17.58 example 4 2,6-diamino-4,5,6,7-tetrahydrobenzthiazole dihydrobromide 3 g (0.01 mol) 6-acetylamino-2-amino-4,5,6,7-tetrahydrobenzthiazole hydrobromide are dissolved in 20 ml of half-concentrated hydrobromic acid and taken for 6 hours Heated to reflux. The solution is then concentrated and the residue from methanol recrystallized.

Yield: 2.8 g (82% of theory), melting point:> 3150 ° C., melting point of the base: 233-2360C Calc .: C 25.39 H 3.96 N 12.69 Found: 25.34 3.93 12.51 Analogous to the example 4 the following compounds were prepared: 6-Amino-2-methylamino-4,5,6,7-tetrahydrobenzthiazole hydrobromide Yield: 57% of theory, melting point: 262-2630C Calc .: C 36.37 H 5.34 N 15.90 Found: 36.30 5.45 15.82 2-Allylamino-6-amino-4,5,6,7-tetrahydro-benzothiazole oxalate Yield: 52% of theory, melting point: 164-1650C (decomposition) Calc .: m / e = 209 Found: m / e = 209 6-Amino-2-dimethylamino-4,5,6,7-tetrahydro-benzothiazole Yield: 45% of theory, melting point:> 2700C (decomposition) Calc .: C 30.10 H 4.77 N 11.70 Found: 30.13 4.84 11.68 Example 5 2-Amino-6- [N- (2-phenyl-ethyl) -amino] -4,5,6,7-tetrahydrobenzthiazole dihydrochloride To a solution of 3.4 g (0.02 mol) of 2,6-diamino-tetrahydrobenzthiazole in 34 ml Dimethylformamide are 5 g (0.022 mol) of 2-phenylethyl bromide and 2.6 g of potassium carbonate given and the reaction mixture stirred at 1000C for 3 hours. Then will the precipitated potassium bromide is suctioned off and the solvent is distilled off. Of the The residue is chromatographed on silica gel (ethyl acetate / methanol = 80/20 + 3% ammonia). The addition of ethereal hydrochloric acid crystallizes the desired one Link.

Yield; 2.1 g (30% of theory), melting point: 289-2910C Calc .: C 52.02 H 6.11 N 12.13 Found: 51.82 6.13 12.16 Analogously to Example 5, the following were obtained Compounds made: 2-Amino-6-isopropylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride Yield: 28% of theory, melting point: 295-2960C (decomposition) Calc .: C 42.25 H. 6.74 N 14.78 Found: 41.95 7.09 14.50 2-Amino-6-isobutylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride Yield: 35% of theory, melting point: 2680C (decomposition) Calc .: C 44.29 H 7.10 N 14.09 Found: 43.97 7.17 13.97 6-Allylamino-2-amino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride Yield: 38% of theory, melting point: 282-2830C (decomposition) Calc .: C 42.56 H. 6.07 N 14.89 Found: 42.17 6.07 14.71 2-Amino-6- [N- (2-chloro-benzyl) -amino] -4,5,6,7-tetrahydro-benzothiazole dihydrochloride Yield: 40% of theory, melting point:> 2800C (decomposition) Calc .: C 45.85 H 4.95 N 11.45 Found: 45.50 4.86 11.08 2-Amino-6-propargylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride Yield: 35% of theory, melting point: 268-2700C (decomposition) Calc .: C 42.86 H. 5.40 N 15.00 Found: 42.78 5.59 14.79 2-Amino-6-methylamino-4,5,6,7-tetrahydro-benzthiazole-dihydrobromide Yield: 25% of theory, melting point: 312-3130C (decomposition) Calc .: C 27.84 H. 4.38 N 12.18 Found: 27.78 4.46 12.21 Example 6 2-Amino-6-di-n-propylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride monohydrate To a solution of 3.4 g (0.02 mol) of 2,6-diamino-4,5,6,7-tetrahydro -benzthiazole 10 g (0.08 mol) of n-propyl bromide and 11.1 g of potassium carbonate are dissolved in 50 ml of methanol given and refluxed for 3 days. 100 ml of water are then added and extracted with ethyl acetate. The solvent is distilled off and the residue is chromatographed on silica gel (mobile phase: methylene chloride / methanol = 80/20). The appropriate fraction is concentrated and the desired compound as the hydrochloride pleases.

Yield: 1.9 g (28% of theory) Melting point: 271-2730C Calc .: C. 45.34 H 7.90 N 12.20 Found: 45.00 7.98 12.00 Example 7 2-Amino-6-n-butylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride To a solution of 3.4 g (0.02 mol) of 2,6-diamino-4,5,6,7-tetrahydro-benzothiazole 1.8 g (0.022 mol) of n-butanal are added to 34 ml of dimethylformamide and then for 1 hour heated to 500C. After cooling, the reaction solution is 0.8 g (0.02 mol) Sodium borohydride is added and the mixture is heated to 50.degree. C. for 30 minutes. The solvent will largely removed in vacuo. The residue is mixed with 20 ml of water while cooling with ice and 2N hydrochloric acid added to pH = 1. The aqueous solution is made with ethyl acetate extracted. The organic phase is discarded. The aqueous phase is made with potassium carbonate added until an alkaline reaction and extracted with ethyl acetate. the organic phase is dried and concentrated. With the addition of ethereal hydrochloric acid the compound crystallizes.

Yield: 2.3 g (39% of theory), melting point: 254-2560C Calc .: C 44.29 H 7.10 N 14.09 Measured values: 44.44 7.31 14.07 Analogous to example 7 The following compounds were prepared: 2-Amino-6-ethylamino-4,5,6,7-tetrahydrobenzthiazole dihydrochloride Yield: 38% of theory, melting point: 296-2970C, calc .: C 40.00 H 6.34 N 15.55 Found: 39.97 6.41 15.35 2-Amino-6-n-pentylamino-4,5,6,7-tetrahydro-benzothiazole semifumarate Yield: 42% of theory, melting point:> 2700 ° C. Calc .: C 56.54 H 7.79 N 14.13 Found: 56.13 7.80 13.97 2-Amino-6-n-hexylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride Yield: 49% of theory, melting point: 272-2740C Calc .: C 47.85 H 7.72 N 12.88 Found: 47.96 7.65 12.71 2-Amino-6-n-propylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride Yield: 42% of theory, melting point: 286-2880C Calc .: C 42.25 H 6.74 N 14.78 Found: 42.05 6.77 14.57 2-Amino-6-cyclopentylamino-4,5,6,7-tetrahydro-benzothiazole dioxalate Yield: 36% of theory, melting point: 212-2130C, calc .: C 46.04 H 5.55 N 10.07 Found: 45.95 5.28 10.08 2-Amino-6-cyclohexylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride Yield: 38% of theory, melting point: 288-2900C Calc .: C 48.14 H 7.15 N 12.96 Found: 47.88 7.16 12.74 Example 8 6-Ethylamino-2-methylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride A solution of 1 g (0.0044 mol) 6-acetylamino-2-methylamino-4,5,6,7-tetrahydro-benzothiazole in 20 ml of absolute tetrahydrofuran with 0.4 g (0.01 mol) of lithium aluminum hydride added and heated under reflux for 2 hours. After cooling, 50 g of a 40% diammonium tartrate solution was added dropwise. The organic phase is separated off and narrowed. The residue is chromatographed on silica gel (mobile phase: methylene chloride / methanol = 80/20). The appropriate fraction is concentrated. With the addition of ethereal Hydrochloric acid crystallizes the compound.

Yield: 0.3 g (33% of theory), melting point:> 2600C Calc .: m / e = 211 Gef .: m / e = 211 Analogously to Example 8, the following compounds were made: 2-Allylamino-6-ethylamino-4,5,6,7-tetrahydro-benzthiazole dihydrochloride Yield: 37% of theory, Melting point: 218-2200C (decomposition) Calc .: C 46.45 H 6.82 N 13.54 Found: 46.60 7.03 13.66 2-Dimethylamino-6-ethylamino-4,5,6,7-tetrahydro-benzothiazole oxalate hydrate Yield: 20% of theory, melting point: 189-1900C, calc .: C 46.83 H 6.95 N 12.60 Found: 47.03 6.89 12.49 Example 9 6-Acetylamino-2-benzoylamino-4,5,6,7-tetrahydro-benzothiazole To a solution of 4.2 g (0.02 mol) of 6-acetylamino-2-amino-4,5,6,7-tetrahydro-benzothiazole in 100 ml of absolute tetrahydrofuran, 2.2 g of triethylamine and 3.1 g (0.022 mol) Given benzoyl chloride and heated under reflux for 3 hours.

The reaction mixture is mixed with water and with ethyl acetate extracted. The organic phase is concentrated. The residue is made from methanol recrystallized.

Yield: 3 g (48% of theory), melting point:> 2600 ° C. Calc .: m / e = 315 Gef .: m / e = 315 Analogously to Example 9, the following compounds were made: 2,6-Diacetylamino-4,5,6,7-tetrahydro-benzothiazole Yield: 50% of theory, melting point: 258-2590C Calc .: m / e = 252 Found: m / e = 252 6-acetylamino-2-propionylamino-4,5,6,7-tetrahyero-benzothiazole Yield: 44% of theory, melting point:> 2600C Calc .: m / e = 266 Gef .: m / e = 266 6-Acetylamino-2-phenylacetylamino-4,5'6'7-tetrahydro-benzothiazole Yield: 78 % of theory, melting point: 1120C Calc .: m / e = 329 Detected: m / e = 329 Example 10 2-Benzylamino-6-ethylamino-4,5,6,7-tetrahydro-benzothiazole dihydrochloride To a solution of 1.2 g (3.2 mmol) of 6-acetylamino-2-benzoylamino-4,5,6,7-tetrahydro-benzothiazole in 50 ml of absolute tetrahydrofuran are 0.24 g (64 mmol) of lithium aluminum hydride given and heated under reflux for 1 hour. The work-up is carried out analogously to the example 8th.

Yield: 0.4 g (34% of theory) Melting point: 242-2450C Calc .: C. 53.33 H 6.43 N 19.68 Found: 53.59 6.37 19.42 The following compounds were obtained analogously to Example 10 produced: 2,6-diethylamino-4,5,6,7-tetrahydrobenzthiazole dihydrochloride yield: 38% of theory, Melting point: 241-2430C Calcd .: C 44.29 H 7.10 N 14.09 Found: 44.06 7.27 13.85 6-Ethylamino-2-n-propylamino-4,5,6,7-tetrahyãro-benzothiazole dihydrochloride Yield: 32% of theory, melting point: 267-2680C Calc .: C 46.15 H 7.42 N 13.46 Found: 45.95 7.53 13.33 6-Ethylamino-2- [N- (2-phenyl-ethyl) -amino] -4,5,6,7-tetrahydrobenzthiazole dihydrochloride hemihydrate Yield: 26% of theory, melting point: 248-2510C Calc .: C 53.25 H 6.84 N 10.96 Found: 53.31 6.64 10.89 6-Acetylamino-2-ethylamino-4,5,6,7-tetrahyero-benzothiazole Prepared from 2,6-diacetylamino-4,5,6,7-tetrahydro-benzothiazole at room temperature.

Yield: 33% of theory, melting point: 234-2350C, calc .: m / e = 238 Found: m / e = 238 6-Acetylamino-2-benzylamino-4,5,6,7-tetrahydro-benzothiazole Prepared from 6-acetylamino-2-benzoylamino-4,5,6,7-tetrahydro-benzothiazole at room temperature.

6-Acetylamino-2-n-propylamino-4,5,6,7-tetrahydro-benzothiazole Prepared from 6-acetylamino-2-propionylamino-4,5,6,7-tetrahydro-benzothiazole at room temperature.

6-acetylamino-2- [N- (2-phenyl-ethyl) -amino] -4,5,6,7-tetrahydrobenzothiazole Example 11 6-Amino-2-ethylamino-4,5,6,7-tetrahydro-benzthiazole dihydrochloride Prepared from 6-acetylamino-2-ethylamino-4,5,6,7-tetrahydro-benzothiazole analogously to Example 4.

Yield: 45% of theory, melting point: 155-158 "C Calc .: C 40.00 H 6.34 N 15.55 Found: 39.86 6.31 15.26 Analogously to Example 11, the following compounds were obtained made: 6-amino-2-benzylamino-4,5,6,7-tetrahydro-benzthiazole-dihydrobromide 6-Amino-2-n-propylamino-4,5,6,7-tetrahydro-benzthiazole-dihydrobromide 6-Amino-2- [N- (2-phenyl-ethyl) amino] -4,5,6,7- tetrahydro-benzothiazole dihydrobromide Example 12 2-Benzoylamino-6-dimethylamino-4,5,6,7-tetrahydro-benzthiazole dihydrochloride 3.0 g (15 mmoles) of 2-amino-6-dimethylamino-4,5,6,7-tetrahydrobenzthiazole will dissolved in 15 ml of pyridine and treated dropwise with 2.1 g (15 mmol) of benzoyl chloride. After standing overnight, the mixture is concentrated, soda solution is added and the mixture is extracted with Chloroform. The chloroform extract is concentrated and then chromatographed on silica gel (mobile phase: methylene chloride / methanol = 9/1). The isolated base (melting point: 1740C) is dissolved in acetone and the dihydrochloride with isopropanolic hydrochloric acid pleases.

Yield: 2.8 g (49 * of theory), melting point: 2840C (decomposition) Calc .: C 51.33 H 5.65 N 11.23 C1 18.94 Found: 51.51 5.76 11.32 18.75 Example 13 6-Acetylamino-2-amino-4,5,6, 7-tetrahydro-benzothiazole 3.1 g (20 mmoles) of 4-acetylamino-cyclohexanone and 6.2 g (20 mmoles) of formamidine disulfide dihydrobromide are intimately mixed and placed in a heating bath at a temperature of 120-1300C for 2 hours heated with stirring. Then you take up with water, adjusts with ammonia alkaline and extracted with chloroform. After drying the extracts, it is concentrated, digested with acetone and filtered off with suction.

Yield: 1.8 g (42.6% of theory), melting point: 2300C (decomposition) Calc .: C 51.17 H 6.20 N 19.89 Found: 51.09 6.22 19.75 The starting point was analogous to Example 13 of 4-dimethylaminocyclohexanone prepared the following compound: 2-amino-6-dimethylamino-4,5,6,7-tetrahydro-benzothiazole Yield: 21% of theory, Melting point: 189-1900C. Calc .: C 54.80 H 7.66 N 21.29 Found: 54.71 7.53 21.12 Example I tablet core with 5 mg 2-Amino-6-dimethylamino-4,5,6,7-tetrahydro-benzthiazole-dihydrochloride Composition: 1 dragee contains: active substance 5.0 mg lactose 33.5 mg corn starch 10.0 mg Gelatin 1.0 mg Magnesium stearate 0.5 mg 50.0 mg Manufacturing process The mixture the active ingredient with lactose and corn starch is aqueous with a 10% gene Gelatin solution granulated through a sieve of 1 mm mesh size, dried at 40 ° C and rubbed through the above sieve again. The granules obtained in this way are made with magnesium stearate mixed and pressed into tablet cores. The production must take place in darkened rooms be made.

Core weight: 50 mg Punch: 5 mm, convex The tablet cores thus obtained are covered by a known method with a shell, which consists essentially of Consists of sugar and talc. The finished coated tablets are made with the help of beeswax polished.

Dragee weight: 100 mg Example II drops with 5 mg 2-Amino-6-dimethylamino-4,5,6,7-tetrahydrobenzthiazole dihydrochloride Composition: 100 ml of dropping substance contain: methyl p-hydroxybenzoate 0.035 g n-propyl p-hydroxybenzoate 0.015 g aniseed oil 0.05 g menthol 0.06 g pure ethanol 10.0 g active ingredient 0.5 g citric acid 0.7 g sodium phosphate sec. x 2 H2O 0.3 g sodium cyclamate 1.0 g glycerine 15.0 g dist. Water ad 100.0 ml Manufacturing process: The p-hydroxybenzoic acid ester, aniseed oil and menthol are dissolved in ethanol (solution I).

The buffer substances, the active substance and sodium cyclamate will be in least Dissolved water and added glycerine (solution II). Solution I becomes in solution II stirred in and the mixture with dist. Water made up to the given volume. The finished drop solution is filtered through a suitable filter. The production and filling of the drip solution must be carried out under protection from light and under protective gassing.

Example III Suppositories with 10 mg of 2-amino-6-dimethylamino-4,5,6,7-tetrahydro-benzthiazole-dihydrochloride id 1 suppository contains: active substance 10.0 mg suppository mass (e.g. Witepsol W 45) 1 690.0 mg 1 700.0 mg Manufacturing process: The finely powdered substance is mixed with With the help of an immersion homogenizer in the melted suppository mass, which has been cooled to 400C stirred in. The mass is poured into slightly pre-cooled molds at 350C.

Suppository weight: 1.7 g Example IV Ampoules with 5 mg of 2-amino-6-dimethylamino-4,5,6,7-tetrahydrobenzthiazole dihydrochloride 1 ampoule contains: active substance 5.0 mg citric acid 7.0 mg sodium phosphate sec. x 2 H2O 3.0 mg sodium pyrosulfite 1.0 mg dist. water ad 1.0 ml Manufacturing process: The Buffer substances, the active substance and sodium pyrosulfite dissolved. One fills with Boiled water to the given volume and filtered pyrogen-free.

Filling: in brown ampoules with protective gassing Sterilization: 20 minutes at 1200C The preparation and filling from the ampoule solution must be darkened Clearing.

Example V Dragees with 1 mg of 2-amino-6-dimethylamino-4,5,6,7-tetrahyd benzthiazole dihydrochloride 1 tablet core contains: active substance 1.0 mg lactose 35.5 mg corn starch 12.0 mg gelatin 1.0 mg magnesium stearate 0.5 mg 50.0 mg Manufacturing process: Analogous to example I.

Core weight: 50 mg Punch: 5 mm, domed Dragée weight: 100 mg

Claims (23)

Claims 1. Tetrahydro-benzothiazoles of the general formula in which R1 is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an alkenyl or alkynyl group with 3 to 6 carbon atoms each, an alkanoyl group with 1 to 6 carbon atoms, a phenylalkyl or phenylalkanoyl group with 1 to 3 carbon atoms each in the alkyl part, R2 Hydrogen atom or an alkyl group with 1 to 4 carbon atoms, R3 a hydrogen atom, an alkyl group with 1 to 7 carbon atoms, a cycloalkyl group with 3 to 7 carbon atoms, an alkenyl or alkynyl group with 3 to 6 carbon atoms each, an alkanoyl group with 1 to 7 carbon atoms, a phenylalkyl or phenylalkanoyl group with 1 to 3 carbon atoms in the alkyl part, where the phenyl nucleus can be substituted by fluorine, chlorine or bromine atoms, R4 is a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an alkenyl or alkynyl group with 3 to 6 carbon atoms or R3 and R4 together with the stick in between substance atom is a pyrrolidino, piperidino, hexamethyleneimino or morpholino group, and their acid addition salts. 2. Tetrahydro-benzothiazoles of the general formula I according to claim 1, in which the Group in the 5- or 6-position, and their acid addition salts. 3. Tetrahydro-benzothiazoles of the general formula in which R1 is a hydrogen atom, an alkyl group with 1 to 3 carbon atoms, an allyl, benzyl or phenylethyl group, R2 is a hydrogen atom, a methyl or ethyl group, R3 is a hydrogen atom, an alkyl group with 1 to 6 carbon atoms, an allyl, propargyl -, Benzyl, chlorobenzyl, phenylethyl, cyclopentyl or cyclohexyl group, R4 a hydrogen atom, an alkyl group with 1 to 3 carbon atoms or an allyl group or R3 and R4 together with the nitrogen atom in between a pyrrolidino, piperidino, hexamethyleneimino or Mean morpholino group, and their acid addition salts. 4. Tetrahydro-benzothiazoles of the general formula Ia according to claim 3, in which the Group is in the 6-position, and their acid addition salts. 5. Tetrahydro-benzothiazoles of the general formula Ia according to claim 3, in which R1 and R2 together with the nitrogen atom in between form an amino or allylamino group and R3 and R4 together with the intermediate nitrogen atom a dimethylamino, diethylamino, N-allyl-N- (4-chlorobenzyl) -amino-, n-propylamino- or represent a pyrrolidino group, and their acid addition salts. 6. 2-Amino-6-dimethylamino-4,5,6,7-tetrahydro-benzothiazole and its Acid addition salts. 7. 2-Amino-6-n-propylamino-4,5,6,7-tetrahydro-benzothiazole and its Acid addition salts. 8. Physiologically compatible acid addition salts with inorganic ones or organic acids of the compounds according to claims 1 to 7. 9. Medicament containing a compound according to claims 3 to 7 or a physiologically acceptable acid addition salt according to claim 8 alongside one or more inert carriers and / or diluents. 10. Use of a compound according to claims 3 to 7 or of a physiologically compatible acid addition salt according to claim 8 for treatment of central nervous neuropsychiatric diseases and / or for the treatment of Circulatory diseases. 11. A method for producing a medicament, characterized in that that by non-chemical means a compound according to claims 3 to 7 or a Physiologically acceptable acid addition salt according to claim 8 in one or more inert carriers and / or diluents is incorporated. 12. Process for the preparation of the tetrahydro-benzothiazoles according to Claims 1 to 8, characterized in that a) a cyclohexanone of the general formula in which R3 and R4 are as defined in claims 1 to 7 and X is a nucleophilic leaving group such as a halogen atom, e.g. a chlorine or bromine atom, with a thiourea of the general formula in which R1 and R2 are as defined in claims 1 to 7, is reacted or b) a compound of the general formula in which R3 and R4 are as defined in claims 1 to 7, with a formamidine disulfide of the general formula in which R1 and R2 are as defined in claims 1 to 7 and represents an anion of an inorganic or organic acid, is reacted or c) for the preparation of compounds of the general formula I in which at least one of the radicals R1, R2, R3 or R4 represents a hydrogen atom, a protective radical of a compound of the general formula in which at least one of the radicals R1 'R2', R3 'or R41 is a protective group for an amino group such as an acyl or alkoxycarbonyl group, e.g. an acetyl, propionyl, methoxycarbonyl or ethoxycarbonyl group, or also R1' and R2 'or R3' and R4 'together with the nitrogen atom in between represent an imido radical, for example the phthalimido radical, and the rest of the radicals R11, R2, R3 or R4 have the meanings mentioned for R1 to R4 in claims 1 to 7 with the exception of those in claims 1 and 2 acyl radicals mentioned are split off or d) for the preparation of compounds of the general formula I in which at least one of the radicals R1, R2, R3 or R4 is one of the alkyl, cycloalkyl, alkenyl or phenylalkyl groups mentioned in claims 1 to 7 means a compound of the general formula in which at least one of the radicals R1 ", R21, R3" or R4 "represents one of the acyl or phenylacyl radicals mentioned in claims 1 and 2 and the remaining radicals are those for R1, R2, R3 and R4 in claims 1 to 7 Have the meanings mentioned, is reduced with a metal hydride in a solvent or e) for the preparation of compounds of the general formula I in which at least one of the radicals R1, R2, R3 or R4 is one of the alkyl, cycloalkyl mentioned in claims 1 to 7 -, alkenyl, alkynyl or phenylalkyl groups means a compound of the general formula in which at least one of the radicals R11 ", R2 '", R3 "' or R4"'represents a hydrogen atom and the rest of the radicals R1 "', R21 nt R3t" or R4 'n are those for R1 to R4 in claims 1 to 7 have the meanings mentioned, with a compound of the general formula R5 Z, (IX) in which R5 has one of the alkyl, cycloalkyl, alkenyl, alkynyl or phenylalkyl groups mentioned for R1 to R4 in claims 1 to 7 and Z is a nucleophile Leaving group such as a halogen atom or a sulfonic acid radical, for example a chlorine, bromine or iodine atom, a methoxysulfonyloxy or p-toluenesulfonyloxy group, or Z together with an adjacent hydrogen atom of the radical R5 denote an oxygen atom, is reacted and, if desired, a compound obtained in this way general formula I, in which at least one of the radicals Rt, R2, R3 or R4 represent a hydrogen atom, by means of appropriate acylation into a corresponding compound of the general formula I in which at least one of the Re ste R1, R2, R3 or R4 represents one of the acyl radicals mentioned in claims 1 and 2, is converted or a compound of the general formula I obtained in this way, which contains at least one chiral center, is separated into its enantiomers or a compound of the general formula I is converted into their acid addition salts, in particular into their physiologically acceptable acid addition salts with organic or inorganic acids. 13. The method according to claim 12, characterized in that the implementation is carried out in a solvent. 14. The method according to claims 12a and 13, characterized in that that the reaction at temperatures between 0 and 150 ° C, preferably at temperatures between 20 and 1000C. 15. The method according to claims 12b and 13, characterized in that that the reaction at temperatures between 50 and 2000C, preferably at temperatures between 70 and 1500C. 16. The method according to claims 12c and 13, characterized in that that the cleavage of a protective radical hydrolytically in the presence of a base or an acid takes place. 17. The method according to claims 12c, 13 and 16, characterized in that that the reaction is carried out at temperatures between 50 and 1500C. 18. The method according to claims 12d and 13, characterized in that that the reduction is carried out with lithium aluminum hydride. 19. The method according to claims 12d, 13 and 18, characterized in that that the reduction at temperatures between 0 and 1000C, preferably at temperatures between 20 and 800C. 20. The method according to claims 12e and 13, characterized in that that the reaction, if X is a nucleophilic leaving group, at temperatures between -10 and 500C, preferably at temperatures between 0 and 300C performed will. 21. The method according to claim 20, characterized in that the implementation is carried out in the presence of a base. 22. The method according to claims 12e and 13, that the implementation, if the reaction is carried out with a carbonyl compound of the general formula IX is, in the presence of a complex metal hydride at temperatures between 0 and 500C, preferably at room temperature, is carried out. 23. The method according to claim 22, characterized in that as complex Metal hydride sodium borohydride or sodium cyanoborohydride is used.