JPH0572907B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention is based on the general formula

The present invention relates to novel tetrahydro-benzthiazole compounds, their enantiomers and their acid addition salts with inorganic or organic acids, in particular their physiologically acceptable acid addition salts and processes for their preparation. When in the general formulas one of the radicals R ₁ or R ₃ or both radicals R ₁ and R ₃ represent an acyl group, the compounds of these general formulas exhibit useful pharmacological properties, especially in the central nervous system and (or) is a useful intermediate product for the preparation of other compounds of the general formula that have an effect on the circulatory system. In the above general formula, R 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, or represents a phenylalkyl or phenylalkanoyl group having 1 to 3 carbon atoms in the alkyl moiety and in which the phenyl nucleus may be substituted with 1 or 2 halogen atoms; R ₂ is a hydrogen atom or 1 R ₃ represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, each having 3 to 6 carbon atoms; alkenyl or alkynyl groups having carbon atoms, alkanoyl groups having 1 to 7 carbon atoms, or having 1 to 3 carbon atoms in the alkyl part and the phenyl nucleus is replaced by a fluorine, chlorine or bromine atom; _R4 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or an alkenyl or alkynyl group each having 3 to 6 carbon atoms; or R ₃ and R ₄ together with the nitrogen atom between them represent a pyrrolidino, piperidino or hexamethyleneimino group, and the -N ^R _3R4 group is bonded in the 6-position. base

[expression] and

As an example of the definition of [formula] The base

[Formula] is 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, N-n-propyl-allylamino, 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, represents a 1-phenylethylamino, 2-phenylethylamino, 3-phenyl-n-propylamino, benzoylamino, phenacetylamino or 2-phenylpropionylamino group;

[Formula] is amino, methylamino, ethylamino, n-propylamino, isopropylamino, n-butylamino, isobutylamino, tertiary
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, butyn-2-ylamino, hexyne-2-
ylamino, dipropargylamino, N-methyl-propargylamino, N-ethyl-propargylamino, cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, N-methyl-cyclohexylamino, N-ethyl-cyclohexyl Amino, formylamino, acetylamino, propionylamino, butanoylamino, pentanoylamino, hexanoylamino, heptanoylamino, N-methyl-acetylamino, N-ethyl-acetylamino, N-n-propyl-acetylamino, N-allyl-acetylamino, benzoylamino, fluorobenzoylamino, chlorbenzoylamino, bromobenzoylamino, phenylacetamide, 2-phenylpropionylamino, N-methylbenzoylamino, N-ethyl-chlorobenzoylamino, dichlor Benzoylamino, 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 or hexamethyleneimino groups. However, particularly preferred compounds of the general formula a

[Chemical formula] (wherein R ₁ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, allyl, benzyl, 2-chlorobenzyl, 4-chlorobenzyl, 3,4-
represents a dichlorobenzyl or phenylethyl group; R ₂ represents a hydrogen atom, methyl or ethyl group; R ₃ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, allyl, propargyl, benzyl,
represents a chlorobenzyl, phenylethyl, cyclopentyl or cyclohexyl group; R ₄ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or an allyl group; or R ₃ and R ₄ represent a nitrogen atom between them; taken together represent a pyrrolidino, piperidino or hexamethyleneimino group; and

[Formula] is bonded at the 6-position) and acid addition salts thereof, particularly physiologically acceptable acid addition salts thereof. These new compounds according to the invention are obtained by the following method: a General formula

[Chemical formula] (wherein R ₃ and R ₄ are as defined above,
and X represents a nucleophilically exchangeable group such as a halogen atom, such as a chlorine or bromine atom)
The general formula for cyclohexanone is

[In the formula, R ₁ and R ₂ are as defined above]
of thiourea. 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 at temperatures between 0 and 150°C, preferably at 20°C. ~
at a temperature of 100 °C, optionally with a base such as sodium hydroxide solution, sodium acetate, pyridine,
It is carried out in the presence of triethylamine or N-ethyl-diisopropylamine. Compounds of general formula used as starting materials do not need to be isolated. b General formula

[C] (In the formula, R ₃ and R ₄ are as defined above)
The compound with the general formula

[In the formula, R ₁ and R ₂ are as defined above,
and Y ^- represents an anion of an inorganic or organic acid) with formamidine disulfide. This reaction is preferably carried out in the melt or in a high boiling solvent such as glycol, dimethylformamide, diphenyl ether or dichlorobenzene, suitably at a temperature between 25 and 200°C, preferably
Carry out at a temperature of 70-150°C. c When producing a compound of the general formula in which at least one of the groups R ₁ , R ₂ , R ₃ or R ₄ represents a hydrogen atom, the general formula

[Chemical formula] (wherein at least one of the groups R' ₁ , R' ₂ , R' ₃ or R' ₄ is an acyl or alkoxycarbonyl group, for example an amino group such as an acetyl, propionyl, methoxycarbonyl or ethoxycarbonyl group) or R′ ₁ and R′ ₂
or R′ ₃ and R′ ₄ together with the nitrogen atom between them represent an imino group, for example a phthalimide group, and other groups R′ ₁ , R′ ₂ , R′ ₃ or R′ ₄
has the above-mentioned meanings for R ₁ to _{R 4} , except for the above-mentioned acyl group). Removal of the protecting group is preferably carried out using water/ethanol, water/dioxane or water/ethanol 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. 50 in an aqueous solvent such as tetrahydrofuran
This is carried out by hydrolysis at a temperature of -150 DEG C., preferably at the boiling temperature of the reaction mixture. Imide groups such as phthalimide groups used as protecting groups are preferably removed with hydrazine in a solvent such as water, water/ethanol or water/dioxane at the boiling temperature of the solvent used. d When preparing compounds of the general formula in which at least one of the groups R ₁ , R ₂ , R ₃ or R ₄ represents one of the alkyl or phenylalkyl groups mentioned above,
general formula

[Chemical formula] (In the formula, at least one of the groups R″ ₁ , R″ ₂ , R″ ₃ or R″ ₄ represents the above-mentioned acyl or phenyl acyl group, and the others are R ₁ , R ₂ , R ₃ and R ₄ (having the meaning given above) is reduced with a metal hydride in a solvent. This reduction is carried out with a metal hydride in a suitable solvent such as diethyl ether, tetrahydrofuran, glycol dimethyl ether or dioxane, e.g. with a complex metal hydride such as lithium aluminum hydride, at a temperature between 0 and 100°C.
Preferably it is carried out at a temperature of 20-80°C. When preparing compounds of the general formula in which the radical R ₃ represents one of the above-mentioned acyl groups, it is particularly advantageous to carry out the reaction with lithium aluminum hydride at a temperature of 0 to 30° C., preferably at room temperature. e at least one of the groups R ₁ , R ₂ , R ₃ or R ₄ is the above-mentioned alkyl, cycloalkyl, alkenyl,
When producing a compound of the general formula representing one of alkynyl or phenylalkyl groups,

[Chemical Formula] (In the formula, at least one of the groups R ₁ , R ₂ , R ₃ or R ₄ represents a hydrogen atom, and the other groups R ₁ , R ₂ , R ₃ or R ₄ are as defined above for R ₁ to R ₄ A compound of the general formula R ₅ -Z (in which R ₅ is an alkyl as defined above for R ₁ to _{R 4} )
represents one of the groups cycloalkyl, alkenyl, alkynyl or phenylalkyl, and Z represents a halogen atom or a sulfonic acid group, such as a chlorine, bromine or iodine atom, a methoxysulfonyloxy or p-toluenesulfonyloxy group, or Z together with the adjacent hydrogen of the group R ₅ represents oxygen). This reaction is carried out in solvents such as water, methanol, ethanol, tetrahydrofuran, dioxane, acetone, acetonitrile or dimethyl sulfoxide such as methyl iodide, dimethyl sulfate, ethyl bromide, diethyl sulfate, allyl iodide, benzyl bromide, 2-fluoride, enylethyl bromide or methyl-
using an alkylating agent such as p-toluenesulfonate, optionally with sodium hydroxide solution,
It is suitably carried out in the presence of a base such as potassium carbonate, sodium hydride, potassium tert-butoxide or triethylamine at a temperature of -10 DEG to 50 DEG C., preferably 0 DEG to 30 DEG C. however,
This reaction can also be carried out without using a solvent. This alkylation of the nitrogen atom can also be carried out using formaldehyde/formic acid at elevated temperatures, e.g. the boiling temperature of the reaction mixture, or with the corresponding carbonyl compound and complex metal hydrides such as sodium borohydride or sodium cyanoborohydride. 0-50°C in solvents like water/methanol, ethanol, ethanol/water, dimethylformamide or tetrahydrofuran using
It can also be carried out at a temperature of, preferably room temperature. If a compound of the general formula in which at least one of the radicals R ₁ or R ₃ represents a hydrogen atom is obtained according to the invention, this compound can be prepared by corresponding acylation in which at least one of the radicals R ₁ or R ₃ represents the above-mentioned acyl group. can be converted into the corresponding compound of the general formula representing one of the groups. This subsequent acylation may be performed in methylene chloride, chloroform, hydrogen tetrachloride, ether,
For example, ethyl chloroformate, thionyl chloride, N,N-
dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,N'-carbonyldiimidazole or N,N'-thionyldiimidazole or triphenylphosphine/in the presence of carbon tetrachloride, or with amino groups Auxiliary agents that activate
For example, in the presence of 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 be used as a solvent at the same time), from -25°C to 250°C. temperature in °C, preferably -10 °C
~The boiling temperature of the solvent used. This reaction can also be carried out without using a solvent,
Furthermore, any water produced during the reaction may be removed by azeotropic distillation, for example by heating with toluene using a water separator, or by adding a drying agent such as magnesium sulfate or molecular sieves. You can also do it. Compounds of the general formula having at least one chiral center can be prepared by conventional methods, for example by column chromatography on chiral phases, by fractional crystallization of diastereomeric salts or by tartaric acid,
Column chromatography of their conjugates with optically active auxiliary acids such as O,O-dibenzoyl-tartaric acid, camphoric acid, camphorsulfonic acid or α-methoxy-phenylacetic acid can resolve them into their enantiomers. The compounds can also be converted into their acid addition salts, especially physiologically acceptable acid addition salts, with inorganic or organic acids. Acids suitable for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid or fumaric acid. The compounds of the general formula ~ used as starting materials are in many cases known from the literature or can be obtained using methods known from the literature. Thus, for example, compounds of the general formula can be obtained by halogenation of the corresponding cyclohexanones, which can be prepared by oxidation of the corresponding cyclohexanols and optionally subsequent alkylation and/or acylation. The compounds of the general formula and used as starting materials can be obtained by condensing the corresponding α-bromo-cyclohexanone with the corresponding thiourea. As already mentioned above, compounds of the general formula in which at least one of the groups R ₁ to _{R 4} represents one of the above-mentioned acyl groups are those in which R ₁ to R ₄ are other than the acyl groups indicated above for R ₁ to R ₄ . It is a useful intermediate product for the preparation of compounds of the general formula having the meaning given above. These compounds and their physiologically acceptable acid addition salts have useful pharmacological properties, in particular effects on blood pressure, heart rate lowering and effects on the central nervous system, especially stimulatory effects on dopamine receptors. Thus, as an example, to assess the effects of the compounds listed below on presynaptic dopamine receptors, their effects on exploratory activity in mice were tested, and then any effects on postsynaptic dopamine receptors were determined. After treatment (by motility in animals pretreated with reserpine), the effects on dopamine conversion and dopamine synthesis were tested as follows: A = 2-amino-6-dimethylamino-4,
5,6,7-tetrahydrobenzthiazole-
Dihydrochloride; B = 2-amino-6-pyrrolidino-4,5,
6,7-tetrahydro-benzthiazole-2
Hydrochloride; C = 2-amino-6-n-propylamino-
4,5,6,7-tetrahydro-benzthiazole-dihydrochloride; D = 2-allylamino-6-dimethylamino-
4,5,6,7-tetrahydro-benzthiazole-dihydrochloride; E = 6-[N-allyl-N-(4-chloro-benzyl-)-amino]-2-amino-4,5,6,
7-tetrahydro-benzthiazole-dihydrochloride; and F = 2-amino-6-diallylamino-4,
5,6,7-tetrahydro-benzthiazole-dihydrochloride. 1. Inhibition of exploration activity This activity was measured in an observation cage with an infrared light barrier. The frequency of light interruptions within 5 minutes is determined by groups of 5 mice. Groups of 5 animals are administered the test substance by subcutaneous injection at a dose of 10 mg/Kg, unless otherwise stated. After 1 hour, animals are transferred to observation cages where their exploratory activity over a 5 minute period is immediately assessed. Parallel to or separately from the group treated with the test substance, a control group treated with saline is evaluated (0.9% solution; 0.1 ml/body weight
(administered subcutaneously at 10 g). The results are summarized in the table below:

[Table] 1 Dose by subcutaneous administration in the range of 1 to 10 mg/Kg/
Reading from the activity curve; 2 Measurement of exploration: 75 minutes after subcutaneous administration. 2 Evaluation of inhibition of dopamine turnover The inhibitory effect on dopamine turnover was measured in mice. In animals treated with α-methylparatyrosine (AMPT) (250 mg/Kg i.p.),
During the 15-minute experiment, dopamine levels throughout the brain decrease as the test progresses. This dopamine reduction (compared to control animals treated with saline solution) can be prevented by administration of substances that act on autoreceptors. Test substances are administered by subcutaneous route at time zero of the experiment at a dose of 5 mg/Kg unless otherwise stated. Animals are sacrificed 4 hours and 15 minutes into the experiment and their brains are measured for dopamine using high pressure liquid chromatography with electrochemical detection. This measure is the percent inhibition produced by the test substance on the dopamine decrease induced by AMPT.

[Table] Reading from the dose/activity curve
Ru.
3 Evaluation of the inhibitory effect on dopamine synthesis For this purpose, 5 animals are administered subcutaneously the test substance at a dose of 10 mg/Kg, unless otherwise stated. After 5 minutes, butyroacetone 750 mg/Kg was administered via the intraperitoneal route to control the rate of dopamine synthesis by blocking the presynaptic impulse line (feed).
back loops). This results in a significant increase in the synthesis of DOPA or dopamine. To prevent decarboxylation of DOPA, 200 mg/Kg of 3-hydroxybenzyl-hydrazine-hydrochloride is administered intraperitoneally after a further 5 minutes.
Five minutes after administering the test substance, animals are sacrificed and striatum preparations are made. DOPA content is determined by HPLC with electrochemical detection (standard: dihydroxybenzylamine). The % inhibition of butyroacetone-stimulated DOPA accumulation produced by the test substance compared to control animals treated with 0.9% saline solution is determined. The results of this experiment are shown in the following table:

[Table] Read from the dose/activity curve.
4 Evaluation of antiparkinsonism activity or activity against Parkinson's disease Neurotoxin 1-methyl-4-phenyl-1,2,
The discovery of 3,6-tetrahydropyridine (MPTP) (Langston et al., Science 219 , p. 979 (1983)) provided an animal model for Parkinson's disease. The irreversible neurological symptoms triggered by MPTP in humans and monkeys are conceptually similar to Parkinson's disease in its clinical, pathological, biochemical and pharmacological features. The reason for this demonstrable similarity is the fact that MPTP selectively destroys a small group of dopaminergic neurons in the substantia nigra of the brain, which is also affected by abnormal progression in spontaneous Parkinson's disease. Destroyed. It is even said that the etiology of idiopathic Parkinson's disease is MPTP or similar compounds produced in organs (Snyder, SH, Nature 311 , p. 514 (1984)). . Maybe MPTP
As a result of the specialized metabolism of MPTP-parkinsonian clinical features have so far been demonstrated only in monkeys and humans. Therefore, it was realized in the Rhesus monkey.
The MPTP model is uniquely suited for testing the activity of anti-Parkinsonian drugs. When MPTP was given to 7 Resus monkeys (1 x 0.15 mg/day for 3 days)
Kg, intramuscularly administered; 3 days off, then 1 x 0.30-0.40 mg/Kg administered daily for the next 3 days), showed the following symptoms: the animal was immobile and unable to take water or food. I can't. Animals exhibited a typical bowed posture; catalepsy occurred in some cases. The extremities showed stiffness interspersed with chronic spasms upon passive movement. In general, the buttocks and extremities cannot be stimulated even by very strong and painful stimuli. Intramuscular administration of test compound C (10-100 μg/Kg)
After an interval of 5-10 minutes, voluntary movements occur first, followed by a gradual strong normalization of motor function over the following 10-30 minutes. Animals can take food. The animals assume a fully upright and erect posture in their cages and are well behaved in terms of their alertness and species-specific behavior. The remaining symptoms recorded include a temporary slight resting tremor and a violent decrease in strength. These are not sedatives. It is seen that the circulation in the skin is increased compared to before administering Compound C. The effect of Compound C diminishes after about 5-7 hours and the animal returns to the parkinsonian symptoms described above; fresh readministration of the compound leads to improvement or virtual disappearance of the clinical pathology. Therefore,
The beneficial effects of this compound are reproduced several times in each animal. No side effects are detected at conventionally used doses. Furthermore, the compounds produced according to the present invention are largely non-toxic. That is, no mortality was recorded when the compound was tested in mice at doses of 27-50 mg/Kg (subcutaneous administration). In view of their pharmacological properties, the compounds of general formula and their physiologically acceptable acid addition salts prepared according to the present invention are useful for the treatment of diseases of the central nervous system, neurosynaptic system, especially schizophrenia, Parkinson's syndrome or Parkinson's disease. It is suitable for the treatment of phthisis and/or for the treatment of circulatory system disorders, especially hypertension. For use as a medicament, the novel compounds of the invention and their physiologically acceptable acid addition salts, optionally in combination with other active substances, can be prepared as simple or coated tablets, powders, suppositories, suspensions, drops. It can be formulated into conventional dosage forms such as tablets or ampoules. Each dose is administered 4 times a day;
0.01-0.5 mg/Kg body weight, preferably 0.1-0.3 mg/Kg body weight. The following examples are intended to illustrate the invention. Example A 4-[N-(4-chloro-benzyl)-amino]-
Cyclohexanol 4-Amino-cyclohexanol-hydrochloride 75.8
Dissolve g (0.5 mol) in 60 ml of water, add potassium carbonate
After addition of 36 g (0.26 mol) and 500 ml of toluene, it is boiled using a water separator until water separation is complete. Then 4-chlorobenzaldehyde
Slowly add 71.7 g (0.5 mol) while further boiling using a water separator. After the calculated amount of water has been separated off, the residue is added to water and the toluene phase is separated off and concentrated. Concentrate residue in ethanol
19g of sodium borohydride dissolved in 500ml
Add (0.5 mol) little by little while stirring. After standing overnight, the mixture is concentrated, mixed with water and extracted with chloroform. After drying and concentrating the extract, the residue is recrystallized from ethyl acetate. Yield: 93.4g (78% of theoretical amount) Melting point: 103-104℃ Calculated value: C65.12 H7.57 N5.84 Cl14.79 Actual value: 65.21 7.68 5.93 14.65 Propionaldehyde in the same manner as Example A The following compound is prepared using 4-n-propylamino-cyclohexanol Yield: 12.4% of theory Melting point: <20°C Calculated: m/e = 157 Found: m/e = 157 Example B 4-[N-(4-chloro-benzyl)-methylamino]-cyclohexanol 4-[N-(4-chloro-benzyl)-amino]-
Dissolve 7.2 g (30 mmol) of cyclohexanol in 30 ml of dimethylformamide, and dissolve potassium carbonate.
After adding 2.2 g (16 mmol) of methyl iodide
Add 4.26 g (30 mmol) dropwise. Once the slightly exothermic reaction has ended, the mixture is concentrated by evaporation, mixed with water and then extracted with chloroform. The concentrated extracts are purified by chromatography on silica gel (eluent: methylene chloride/methanol = 20/1) Yield: 3.3 g (43.4% of theory) Melting point: 74-75°C Calculated: C66.26 H7.94 N5.52 Cl13.97 Found: 66.36 7.95 5.46 13.81 The following compounds are prepared analogously to Example B: 4-hexamethyleneimino-cyclohexanol 4-amino-cyclohexanol and 1,6
- Manufactured from dibromohexane. Yield: 47.3% of theory Melting point: <20°C Calculated: m/e = 197 Found: m/e = 197 4-Diallylamino-cyclohexanol Prepared from 4-amino-cyclohexanol and allyl bromide. Yield: 51% of theory Melting point: <20°C Calculated value: m/e = 195 Actual value: m/e = 195 4-Piperidino-cyclohexanol 4-Amino-cyclohexanol and 1,5
- produced from dibromopentane. Yield: 65.8% of theory Melting point: <20°C Calculated value: m/e = 183 Actual value: m/e = 183 4-pyrrolidino-cyclohexanol 4-amino-cyclohexanol and 1,4
-dibromo-butane. Yield: 35.8% of theory Melting point: <20°C Calculated value: m/e = 169 Actual value: m/e = 169 Example C 4-Diethylamino-cyclohexanol 28.75 g of 4-amino-cyclohexanol
(0.25 mol) in 150 ml of water and 20 g of sodium hydroxide.
(0.5 mol) is added and dissolved, then 65.6 ml (0.5 mol) of dimethyl sulfate is added dropwise. The mixture is then heated to 65°C. Stir at 70°C for 1 hour, then pour onto ice and extract with chloroform. Yield: 18.2 g (42.5% of theory) Melting point: <20°C Calculated value: m/e = 171 Actual value: m/e = 171 Example D 4-[N-(4-chloro-benzyl)-amino ]−
Cyclohexanone 4-[N-(4-chloro-benzyl)-amino]-
23.9g (0.1mol) of cyclohexanol in 125ml of ice water
ml, then add 32 ml of concentrated sulfuric acid. 29.4 g (0.1 mol) of potassium dichromate are then added in two portions and the mixture is heated at 50° C. for 5 hours. It is then allowed to cool, made alkaline with sodium hydroxide solution and extracted with chloroform. After concentration, a yellowish oily liquid is obtained. Yield: 8.2 g (34% of theory) Melting point: <20°C Calculated value: m/e = 237/239 Actual value: m/e = 237/239 The following compound is prepared in the same manner as Example D. : 4-[N-(4-chloro-benzyl)-methylamino]-cyclohexanone Yield: 38% of theoretical amount Melting point: <20°C Calculated value: m/e=251/253 Actual value: m/e= 251/253 4-Diallylamino-cyclohexanone Yield: 21% of the theoretical amount Melting point: <20°C Calculated value: m/e = 193 Actual value: m/e = 193 4-Piperidino-cyclohexane yield: of the theoretical amount 22.2% Melting point: <20℃ Calculated value: m/e=181 Actual value: m/e=181 4-pyrrolidino-cyclohexanone yield: 45.1% of theoretical amount Melting point: <20℃ Calculated value: m/e= 167 Actual value: m/e = 167 4-diethylamino-cyclohexanone Yield: 49.7% of theory Melting point: <20°C Calculated value: m/e = 169 Actual value: m/e = 169 4-n-propylamino -Cyclohexanone Yield: 33% of theory Melting point: <20°C Calculated value: m/e = 155 Actual value: m/e = 155 Example E 4-[N-(4-chloro-benzyl)-methylamino] -Cyclohexanone 4-[N-(4-chloro-benzyl)-amino]-
Dissolve 8.4 g (35 mmol) of cyclohexanone in 50 ml of anhydrous dimethylformamide and dissolve potassium carbonate.
After the addition of 2.6 g (18.7 mmol), 5.0 g (35 mmol) of methyl iodide are added dropwise at 25-30°C. After standing overnight, the mixture is concentrated, mixed with water and then extracted with chloroform. The extract is dried and then concentrated. Yield: 8.1 g (93% of theory) Melting point: <20°C Calculated value: m/e = 251/253 Actual value: m/e = 251/253 The following compound was produced in the same manner as Example E. do: 4-[N-allyl-N-(4-chloro-benzyl)
-Amino]-cyclohexanone Yield: 70.7% of theory Melting point: <20°C Calculated value: m/e = 277/279 Actual value: m/e = 277/279 4-[N-(4-chloro-benzyl )-ethylamino]-cyclohexanone Yield: 30% of theory Melting point: <20°C Calculated value: m/e = 265/267 Actual value: m/e = 265/267 Example F 4-hexamethyleneimino-cyclohexanone At 20-25°C, 47 g (0.5 mol) of 4-hexamethyleneimino-cyclohexanol was dissolved in methylene chloride.
300 ml of the solution are added dropwise to a suspension of 107.5 g (0.5 mol) of pyridinium chlorochromate and 40 g (0.5 mol) of sodium acetate in 700 ml of methylene chloride. After stirring for 1 hour at 20°C, the mixture was poured onto ice water and sodium hydroxide solution,
Then extract with methylene chloride. After drying and concentrating the extract, a colorless oily liquid remains. Yield: 16.8 g (35.8% of theory) Melting point: <20°C Calculated value: m/e = 195 Actual value: m/e = 195 Example 1 2-amino-6-dimethylamino-4,5,
6,7-tetrahydro-benzthiazole-2
- Hydrochloride 4-dimethylamino-cyclohexanone 2.82g
(0.02 mol) in 20 ml of glacial acetic acid and 36 mol in glacial acetic acid.
Mix with 4.7ml of % hydrobromic acid, then 12ml of glacial acetic acid
A solution of 1.0 ml (0.02 mol) of bromine in the solution is added dropwise with cooling. The mixture is then evaporated under reduced pressure and the residue is triturated several times with diethyl ether. Discard the ether extract and dissolve the residue in 50 ml of ethanol. After adding 3.04 g (40 mmol) of thiourea, the mixture is refluxed for 5 hours. It is then concentrated by evaporation, made alkaline with sodium hydroxide solution and extracted with chloroform. After drying and concentrating the extract, the residue is purified by column chromatography on silica gel (eluent: chloroform/methanol=1/1). This base (melting point: 191°C) was then dissolved in acetone,
It is then exchanged into the dihydrochloride salt with isopropanolic hydrochloric acid. Yield: 1.09g (20% of theoretical amount), melting point: 272℃ Calculated value: C40.00 H6.34 N15.55 Cl26.24 Actual value: 39.63 6.55 15.31 26.29 In the same manner as Example 1, prepare the corresponding ketone. The following tetrahydrobenzthiazole compound is prepared from the compound: 2-amino-6-diethylamino-4,5,6,
7-Tetrahydro-benzthiazole Yield: 25% of theory Melting point: 182-183℃ Calculated value: C58.62 H8.49 N18.64 Actual value: 58.65 8.72 18.50 2-Amino-6-piperidino-4,5 ,6,7-
Tetrahydro-benzthiazole-dihydrochloride Yield: 13% of theory Melting point: 280℃ Calculated value: C46.45 H6.82 N13.55 Cl22.85 Actual value: 46.37 6.75 13.41 22.95 4-Amino-6-pyrrolidino -4,5,6,7-
Tetrahydro-benzthiazole Yield: 24.4% of theory Melting point: 204-206℃ Calculated value: C59.15 H7.67 N18.81 Actual value: 59.50 7.74 18.95. 2-Amino-6-diallylamino-4,5 ,6,
7-tetrahydro-benzthiazole-dihydrochloride Yield: 19% of theory Melting point: 242℃ Calculated value: C48.44 H6.56 N13.03 Cl22.00 Actual value: 47.90 6.49 12.95 22.21. 2-Amino- 6-[N-(4-chloro-benzyl)
-Amino]-4,5,6,7-tetrahydro-benzthiazole Yield: 35% of theoretical amount Melting point: 146℃ Calculated value: C57.23 H5.49 N14.30 Cl22.06 Actual value: 56.93 5.56 13.86 12.04. 2-Amino-6-[N-(4-chloro-benzyl)
-Methylamino]-4,5,6,7-tetrahydro-benzthiazole Yield: 36% of theoretical amount Melting point: 163℃ Calculated value: C58.69 H5.89 N13.64 Cl11.51 Measured value: 58.50 5.94 13.49 11.55. 2-Amino-6-[N-(4-chloro-benzyl)
-ethylamino]-4,5,6,7-tetrahydro-benzthiazole-dihydrochloride Yield: 49% of theory Melting point: 258℃ (decomposition) Calculated value: C48.67 H5.61 N10.64 Cl26 .94 Actual value: 48.30 5.85 10.57 26.97. 2-Amino-6-[N-allyl-N-(4-chloro-benzyl)-amino]-4,5,6,7-tetrahydro-benzthiazole-dihydrochloride Yield: 46.5% of theoretical amount Melting point: 240℃ (decomposition) Calculated value: C50.19 H5.45 N10.33 Cl26.14 Actual value: 49.84 5.68 9.97 26.04. 2-Amino-6-hexamethyleneimino-4 ，
5,6,7-tetrahydro-benzthiazole-
2-Alylamino-6-dimethylamino -4,
5,6,7-tetrahydro-benzthiazole-
Dihydrochloride Prepared by bromination of 4-dimethylamino-cyclohexanone and subsequent reaction with allylthiourea. Yield: 64% of theoretical amount Melting point: 248℃ Calculated value: C46.45 H6.82 N13.54 Cl22.85 Actual value: 46.30 7.00 13.29 22.99. Example 2 2,6-diamino-4,5,6, 7-tetrahydro-benzthiazole-2-hydrochloride a 4-(phthallimido)-cyclohexanol 4-aminocyclohexanol-hydrochloride 75.5g
(0.5 mol) and phthalic anhydride 74.0 g (0.5 mol)
ethyl-diisopropylamine 65g (0.5mol)
and 1000ml of toluene and boiled for 36 hours using a water separator. Water is then added, the toluene phase is separated and the aqueous phase is extracted several times with chloroform. The organic phases are collected, dried and concentrated. The concentrated residue is recrystallized from isopropanol. Yield: 95g (77.8% of theory) Melting point: 175-176℃ b 4-(phthalimide)-cyclohexanone 4-(phthalimide)-cyclohexanol-95
g (0.388 mol) in 600 ml of chloroform,
After addition of 450 ml of water and 120 ml of sulfuric acid, 90 g (0.3 mol) of potassium dichromate are added in portions. The internal temperature of the mixture is maintained at 25-30°C with slight cooling. The mixture is stirred for a further 3 hours, then the chloroform phase is separated and the mixture is extracted twice more with chloroform. After drying and concentrating the effluent, 82 g (86.9% of theory) are obtained. c 2-amino-6-phthalimide-4,5,
6,7-tetrahydro-benzthiazole 4-(phthalimido)-cyclohexanone 48.6g
(0.2 mol) is brominated analogously to Example 1 with 32 g (0.2 mol) of bromine and then converted to 2-amino-6-phthalimido-4,5,6,7-tetrahydro-benzthiazole with thiourea. Yield: 30g (50% of theoretical amount) Melting point: 244-246℃ (decomposition) Calculated value: C60.18 H4.38 N14.04 Actual value: 60.05 4.25 13.95 d 2,6-diamino-4,5, 6,7-tetrahydro-benzthiazole-dihydrochloride 2-amino-6-phthalimide-4,5,6,
7-tetrahydro-benzthiazole 9.5g
(31.7 mmol) is suspended in 100 ml of ethanol and refluxed for 2 hours after addition of 1.8 g (36 mmol) of hydrazine hydrate. The mixture is then concentrated and purified by column chromatography on silica gel using methanol as eluent.
The dihydrochloride salt is then precipitated in ethanol with ethanolic hydrochloric acid. Yield: 2.0g (26% of theoretical amount) Melting point: >315℃ (decomposition) Calculated value: C34.72 H5.41 N17.35 Cl29.25 Actual value: 35.00 5.26 16.95 29.10 Example 3 6-acetylamino- 2-amino-4,5,
6,7-tetrahydro-benzthiazole-hydrobromide 160 g (1.0 mol) of bromine in 1.5 ml of glacial acetic acid
Add dropwise to a solution of 155 g (1.0 mol) of acetylamino-cyclohexanone. Mixture at room temperature
Stir for an hour. 152.0g of thiourea in the reaction mixture
(2.0 mol) and the resulting mixture is refluxed for 30 minutes. After cooling, the precipitated crystals are filtered with suction,
Wash with water and acetone. Yield: 73g (37% of theoretical amount) Melting point: 292-293℃ (decomposition) Calculated value: C36.99 H4.83 N14.38 Actual value: 36.82 4.76 14.18 This hydrobromide salt was dissolved in an aqueous potassium carbonate solution. By stirring at and then filtering with suction, the free base is obtained; melting point: 194-196°C (methanol). Analogously to Example 3, the following compounds are prepared: 6-acetylamino-2-allylamino-4,
5,6,7-Tetrahydro-benzthiazole Yield: 46% of theory Melting point: 194-196°C Calculated value: m/e = 251 Actual value: m/e = 251 6-acetylamino-2-methylamino -4,
5,6,7-tetrahydro-benzthiazole Yield: 64% of theory Melting point: 238-240℃ Calculated value: C53.30 H6.71 N18.65 Actual value: 53.18 6.78 18.41 6-acetylamino-2- dimethylamino-4,
5,6,7-Tetrahydro-benzthiazole Yield: 51% of theory Melting point: 170-171℃ Calculated value: C55.20 H7.16 N17.56 Actual value: 55.15 7.17 17.58 Example 4 2,6-diamino -4,5,6,7-tetrahydro-benzthiazole-dihydrobromide 6-acetylamino-2-amino-4,5,
3 g (0.01 mol) of 6,7-tetrahydro-benzthiazole-hydrobromide was dissolved in semi-concentrated hydrobromic acid 20
ml and reflux for 6 hours. The solution is then concentrated by evaporation and the residue is recrystallized from methanol. Yield: 2.8 g (82% of theoretical amount) Melting point: >315°C Melting point of base: 233-235°C Calculated value: C25.39 H3.96 N12.69 Actual value: 25.34 3.93 12.51 Same as Example 4 , prepares the following compound: 6-amino-2-methylamino-4,5,6,7
-Tetrahydro-benzthiazole-hydrobromide Yield: 57% of theory Melting point: 262-263℃ Calculated value: C36.37 H5.34 N15.90 Actual value: 36.30 5.45 15.82 2-allylamino-6- Amino-4,5,6,7
-Tetrahydro-benzthiazole-oxalate Yield: 52% of theory Melting point: 164-165°C (decomposition) Calculated value: m/e = 209 Actual value: m/e = 209 6-amino-2-dimethyl Amino-4,5,6,
7-Tetrahydro-benzthiazole-dihydrobromide Yield: 45% of theory Melting point: >270°C (decomposed) Calculated: C30.10 H4.77 N11.70 Measured: 30.13 4.84 11.68. Example 5 2-Amino-6-[N-(2-phenyl-ethyl)-amino]-4,5,6,7-tetrahydro-benzthiazole-dihydrochloride 2,6-diamino-4, in 34 ml of dimethylformamide, To a solution of 3.4 g (0.02 mol) of 5,6,7-tetrahydro-benzthiazole are added 5 g (0.022 mol) of 2-phenyl-ethyl bromide and 2.6 g of potassium carbonate, and the reaction mixture is stirred at 100 DEG C. for 3 hours. The precipitated potassium bromide is filtered off with suction and the solvent is distilled off. The residue is chromatographed on silica gel (ethyl acetate/methanol = 80/20 + 3% ammonia). The desired compound is crystallized from ethanolic hydrochloric acid. Yield: 2.1g (30% of theoretical amount) Melting point: 289-291℃ Calculated value: C52.02 H6.11 N12.13 Actual value: 51.82 6.13 12.16 Produce the following compound in the same manner as Example 5. : 2-amino-6-isopropylamino-4,5,
6,7-Tetrahydro-benzthiazole-dihydrochloride Yield: 28% of theoretical amount Melting point: 295-296℃ (decomposition) Calculated value: C42.25 H6.74 N14.78 Actual value: 41.95 7.09 14.50 2- Amino-6-isobutylamino-4,5,
6,7-tetrahydro-benzthiazole-dihydrochloride Yield: 35% of theory Melting point: 268°C (decomposition) Calculated value: C44.29 H7.10 N14.09 Actual value: 43.97 7.17 13.97 6-allylamino- 2-amino-4,5,6,7
-Tetrahydro-benzthiazole-dihydrochloride Yield: 38% of theory Melting point: 282-283℃ (decomposition) Calculated value: C42.56 H6.07 N14.89 Actual value: 42.17 6.07 14.71. 2-Amino- 6-[N-(2-chloro-benzyl)
-Amino]-4,5,6,7-tetrahydro-benzthiazole-dihydrochloride Yield: 40% of theoretical amount Melting point: >280℃ (decomposition) Calculated value: C45.85 H4.95 N11.45 Actual measurement Value: 45.50 4.86 11.08 2-amino-6-propargylamino-4,5,
6,7-tetrahydro-benzthiazole-dihydrochloride Yield: 35% of theoretical amount Melting point: 268-270℃ (decomposition) Calculated value: C42.86 H5.40 N15.00 Actual value: 42.78 5.59 14.79 2- Amino-6-ethylamino-4,5,6,7
-Tetrahydro-benzthiazole-dihydrobromide Yield: 25% of theory Melting point: 312-313°C (decomposition) Calculated value: C27.84 H4.38 N12.18 Actual value: 27.78 4.46 12.21. Example 6 2-amino-6-di-n-propylamino-
4,5,6,7-tetrahydro-benzthiazole-dihydrochloride-monohydrate 2,6-diamino-4, in 50 ml of methanol
5,6,7-tetrahydro-benzthiazole
105 g (0.08 mole) of 2-propyl bromide and 11.1 g of potassium carbonate in a solution of 3.4 g (0.02 mole)
is added and the mixture is refluxed for 3 days. Then water 10
ml and the mixture is extracted with ethyl acetate. The solvent is evaporated and the residue is chromatographed on silica gel (eluent: methylene chloride/methanol = 80/20). The corresponding fractions are concentrated by evaporation and the desired compound is precipitated in the form of its hydrochloride. Yield: 1.9g (28% of theory) Melting point: 271-273℃ Calculated value: C45.34 H7.90 N12.20 Actual value: 45.00 7.98 12.00 Example 7 2-Amino-6-n-butylamino- 4,5,
6,7-tetrahydro-benzthiazole-2
Hydrochloride To a solution of 3.4 g (0.02 mol) of 2,6-diamino-4,5,6,7-tetrahydro-benzthiazole in 34 ml of dimethylformamide was added 1.8 g (0.022 mol) of n-butanol and the mixture was heated at 50°C. to 1
Heat for an hour. After cooling, the reaction solution was mixed with 0.8 g (0.02 mol) of sodium borohydride and heated to 50 °C.
Heat for 30 minutes. Most of the solvent is removed under reduced pressure. While cooling with water, pour the residue into 20 ml of water and
Mix with 2N hydrochloric acid to obtain PH1. This aqueous solution is extracted with ethyl acetate and the organic phase is discarded. The aqueous phase is mixed with potassium carbonate until an alkaline reaction is obtained and extracted with ethyl acetate. dry the organic phase;
Then concentrate. Add ethereal hydrochloric acid and crystallize the product. Yield: 2.3g (39% of theoretical amount) Melting point: 254-256℃ Calculated value: C44.29 H7.10 N14.09 Actual value: 44.44 7.31 14.07 Produce the following compound in the same manner as Example 7 : 2-amino-6-ethylamino-4,5,6,7
-Tetrahydro-benzthiazole-dihydrochloride Yield: 38% of theory Melting point: 296-297°C Calculated value: C40.00 H6.34 N15.55 Actual value: 39.97 6.41 15.35 2-amino-6-n- pentylamino-4,5,
6,7-Tetrahydro-benzthiazole-hemifumarate Yield: 42% of theory Melting point: >270°C Calculated value: C56.54 H7.79 N14.13 Actual value: 56.13 7.80 13.97 2-Amino-6 -n-hexylamino-4,5,
6,7-tetrahydro-benzthiazole-dihydrochloride Yield: 49% of theory Melting point: 272-274°C Calculated value: C47.85 H7.72 N12.88 Actual value: 47.96 7.65 12.71. 2-Amino- 6-n-propylamino-4,5,
6,7-tetrahydro-benzthiazole-dihydrochloride Yield: 42% of theory Melting point: 286-288℃ Calculated value: C42.25 H6.74 N14.78 Actual value: 42.05 6.77 14.57 (-)2- Amino-6-n-propylamino-
4,5,6,7-tetrahydro-benzthiazole-dihydrochloride Melting point: 270-272°C α ²⁰ _D = -56° (C = 1, methanol) (+) 2-Amino-6-n-propylamino −
4,5,6,7-tetrahydro-benzthiazole-dihydrochloride Melting point: 270-272°C α ²⁰ _D = +56° (C = 1, methanol) 2-amino-6-cyclopentylamino-4,
5,6,7-tetrahydro-benzthiazole-
2-oxalate yield: 36% of theoretical amount Melting point: 212-213℃ Calculated value: C46.04 H5.55 N10.07 Actual value: 45.95 5.28 10.08 2-Amino-6-cyclohexylamino-4,
5,6,7-tetrahydro-benzthiazole-
Dihydrochloride yield: 38% of theory Melting point: 288-290℃ Calculated value: C48.14 H7.15 N12.96 Actual value: 47.88 7.16 12.74 Example 8 6-ethylamino-2-methylamino-4,
5,6,7-Tetrahydro-benzthiazole-dihydrochloride A solution of 1 g (0.0044 mol) of 6-acetylamino-2-methylamino-4,5,6,7-tetrahydro-benzthiazole in 20 ml of anhydrous tetrahydrofuran is hydrogenated. Lithium aluminum chloride 0.4g
(0.01 mol) and refluxed for 2 hours. After cooling, 50 g of 40% diammonium tartrate solution are added dropwise. The organic phase is separated off and concentrated by evaporation. The residue is chromatographed on silica gel (eluent: methylene chloride/methanol=
80/20). The corresponding fractions are concentrated by evaporation. The product is crystallized by addition of ethereal hydrochloric acid. Yield: 0.3 g (33% of theory) Melting point: 260°C Calculated value: m/e = 211 Measured value: m/e = 211 Analogously to Example 8, the following compound is prepared: 2-allylamino -6-ethylamino-4,5,
6,7-tetrahydro-benzthiazole-dihydrochloride Yield: 37% of theoretical amount Melting point: 218-220℃ (decomposition) Calculated value: C46.45 H6.82 N13.54 Actual value: 46.60 7.03 13.66 2- dimethylamino-6-ethylamino-4,
5,6,7-tetrahydro-benzthiazole-
Oxalate hydrate yield: 20% of theory Melting point: 189-190℃ Calculated value: C46.83 H6.95 N12.60 Actual value: 47.03 6.89 12.49 Example 9 6-acetylamino-2-benzoylalumino- 4,5,6,7-Tetrahydro-benzthiazole 2.2 g of triethylamine in a solution of 4.2 g (0.02 mol) of 6-acetylamino-2-amino-4,5,6,7-tetrahydro-benzthiazole in 100 ml of anhydrous tetrahydrofuran. (0.022 mol) and 3.1 g (0.022 mol) of benzoyl chloride are added and the mixture is refluxed for 3 hours. The reaction mixture is mixed with water and extracted with ethyl acetate. The organic phase is concentrated by evaporation. The residue is recrystallized from methanol. Yield: 3 g (48% of theory) Melting point: >260°C Calculated value: m/e = 315 Actual value: m/e = 315 Analogously to Example 9, the following compound is prepared: 2,6 -Diacetylamino-4,5,6,7-tetrahydro-benzthiazole Yield: 50% of theory Melting point: 258-259°C Calculated value: m/e = 252 Actual value: m/e = 252 6-acetyl Amino-2-propionylamino-
4,5,6,7-tetrahydro-benzthiazole Yield: 44% of theory Melting point: >260°C Calculated value: m/e = 266 Actual value: m/e = 266 6-acetylamino-2-phenyl Enylacetylamino-4,5,6,7-tetrahydro-benzthiazole Yield: 78% of theory Melting point: 112°C Calculated value: m/e = 329 Actual value: m/e = 329 Example 10 2-benzyl amino-6-ethylamino-4,
5,6,7-tetrahydro-benzthiazole-dihydrochloride 6-acetylamino-2-benzoylamino-4,5,6,7 in 50 ml of anhydrous tetrahydrofuran
- 0.24 g of lithium aluminum hydride in a solution of 1.2 g (3.2 mol) of tetrahydro-benzthiazole
(64 mmol) is added and the mixture is refluxed for 1 hour. It is then worked up as in Example 8. Yield: 0.4g (34% of theory) Melting point: 242-245℃ Calculated value: C53.33 H6.43 N19.68 Actual value: 53.59 6.37 19.42 Produce the following compound in the same manner as Example 10. : 2,6-diethylamino-4,5,6,7-tetrahydro-benzthiazole-dihydrochloride Yield: 38% of theory Melting point: 241-243℃ Calculated value: C44.29 H7.10 N14.09 Actual value: 44.06 7.27 13.85 6-ethylamino-2-n-propylamino-
4,5,6,7-Tetrahydro-benzthiazole-dihydrochloride Yield: 32% of theory Melting point: 267-268℃ Calculated value: C46.15 H7.42 N13.46 Actual value: 45.95 7.53 13.33 6 -ethylamino-2-[N-(2-phenyl-ethyl)-amino]-4,5,6,7-tetrahydro-benzthiazole-dihydrochloride-hemihydrate Yield: 26% of theory Point: 248-251℃ Calculated value: C53.25 H6.84 N10.96 Actual value: 53.31 6.64 10.89. 2-(4-chloro-benzylamino)-6-ethylamino-4,5,6,7-tetrahydro -benzthiazole-dihydrochloride Yield: 65% of theory Melting point: >260℃ Calculated value: C48.67 H5.62 N10.64 Actual value: 48.79 5.80 10.60 2-(2-chloro-benzylamino)- 6-ethylamino-4,5,6,7-tetrahydro-benzthiazole-dihydrochloride Yield: 36% of theoretical amount Melting point: 251-253℃ Calculated value: C48.67 H5.62 N10.64 Actual value :48.57 5.78 10.57 2-(3,4-dichloro-benzylamino)-6-
ethylamino-4,5,6,7-tetrahydro-
Benzthiazole dihydrochloride Yield: 62.5% of theory Melting point: >260°C Calculated value: C44.77 H4.93 N9.79 Actual value: 44.85 4.82 9.96 6-acetylamino-2-ethylamino-4,
5,6,7-tetrahydro-benzthiazole 2,6-diacetylamino-4,5,6,7-
Prepared from tetrahydro-benzthiazole at room temperature. Yield: 33% of theoretical amount Melting point: 234-235°C Calculated value: m/e = 238 Actual value: m/e = 238 6-acetylamino-2-benzylamino-4,
5,6,7-tetrahydro-benzthiazole 6-acetylamino-2-benzoylamino-
Prepared from 4,5,6,7-tetrahydro-benzthiazole at room temperature. 6-acetylamino-2-n-propylamino-
4,5,6,7-Tetrahydro-benzthiazole Prepared from 6-acetylamino-2-n-propionylamino-4,5,6,7-tetrahydro-benzthiazole at room temperature. 6-acetylamino-2-[N-(2-phenyl-
ethyl)-amino]-4,5,6,7-tetrahydro-benzthiazole Example 11 6-amino-2-ethylamino-4,5,6,
7-tetrahydro-benzthiazole-dihydrochloride 6-acetylamino-2-
ethylamino-4,5,6,7-tetrahydro-
Manufactured from benzthiazole. Yield: 45% of theory Melting point: 155-158°C Calculated value: C40.00 H6.34 N15.55 Actual value: 39.86 6.31 15.26 The following compound is prepared in the same manner as in Example 11: 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-benzthiazole-dihydrobromide example 12 2-benzoylamino-6-dimethylamino-
4,5,6,7-tetrahydro-benzthiazole-dihydrochloride 2-amino-6-dimethylamino-4,5,
6,7-tetrahydro-benzthiazole 3.0g
(15 mmol) is dissolved in 15 ml of pyridine and then 2.1 g (15 mmol) of benzoyl chloride are added dropwise. After standing overnight, the mixture is concentrated, mixed with sodium hydroxide solution and then extracted with chloroform. The chloroform extract is concentrated and then chromatographed on silica gel (eluent: methylene chloride/methanol = 9/1). The isolated base (melting point: 174° C.) is dissolved in acetone and the dihydrochloride salt is precipitated with isopropanolic hydrochloric acid. Yield: 2.8g (49% of theory) Melting point: 284℃ (decomposition) Calculated value: C51.33 H5.65 N11.23 Cl18.94 Actual value: 51.51 5.76 11.32 18.75 Example 13 6-acetylamino-2 -amino-4,5,
6,7-tetrahydro-benzthiazole 4-acetylamino-cyclohexanone 3.1g
(20 mmol) and 6.2 g (20 mmol) of formamidine-disulfide dihydrobromide are intimately mixed and then heated in a heating bath at a temperature of 120-130° C. with stirring for 2 hours. The mixture is then taken up in water, made alkaline with ammonia and extracted with chloroform. After drying the extract, it is concentrated by evaporation, mixed with acetone and then filtered with suction. Yield: 1.8 g (42.6% of theory) Melting point: 195°C Calculated: C51.17 H6.20 N19.89 Found: 51.09 6.22 19.75 Same as Example 13 starting from 4-dimethylamino-cyclohexane to prepare the following compound: 2-amino-6-dimethylamino-4,5,6,
7-Tetrahydro-benzthiazole Yield: 21% of theory Melting point: 189-190°C Calculated value: C54.80 H7.66 N21.29 Actual value: 54.71 7.53 21.12 Example 2-Amino-6-dimethylamino-4 ,5,
6,7-tetrahydro-benzthiazole-2
Tablet core composition containing 5 mg of hydrochloride: One tablet core contains the following ingredients: 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 method: Active substance and lactose The mixture with corn starch and 10% aqueous gelatin was passed through a 1 mm mesh sieve to make granules, dried at 40°C,
Then strain through the sieve again. The granules thus obtained are mixed with magnesium stearate and compressed to form a tablet core. This tablet must be manufactured in a dark room. Weight of core: 50 mg Punch: 4 mm, convex The tablet core thus obtained is coated in the usual manner with a coating material consisting more essentially of sugar and talc. Polish the finished coated tablet with beeswax. Weight of coated tablet: 100mg Example 2-amino-6-dimethylamino-4,5,6,
Composition of drops containing 5 mg of 7-tetrahydro-benzthiazole-dihydrochloride: 100 ml of drops contains the following components: Methyl ester-p-hydroxybenzoate
0.035g n-propyl ester-p-hydroxybenzoate 0.015g Anisole 0.05g Menthol 0.06g Pure ethanol 10.0g Active substance 0.5g Citric acid 0.7g Sodium dibasic phosphate x 2H ₂ O 0.3g Sodium cyclamate 1.0g Glycerol 15.0g Distilled water Amount to bring the total volume to 100.0ml Manufacturing method: Dissolve hydroxybenzoate, anisole and menthol in ethanol (solution). Buffer substance, active substance and sodium cyclamate are dissolved in distilled water and glycerol is added (solution). Add the solution with stirring into the solution and make up the mixture with distilled water. The finished droplet solution is filtered through a suitable filter. The preparation and filling of the droplet solution must be carried out in the absence of light and under a protective gas atmosphere. Example 2-amino-6-dimethylamino-4,5,
6,7-tetrahydro-benzthiazole-2
One suppository containing 10 mg of hydrochloride contains the following ingredients: Active substance 10.0 mg Suppository mass (e.g. Witepsol W45) 169.0 mg 1700.0 mg Manufacturing process: Cooling of the active substance in fine powder form to 40°C. Add by stirring with an immersion homogenizer for the molten suppository mass. Pour the mass at 35°C into slightly cooled molds. Weight of suppository: 1.7g Example 2-amino-6-dimethylamino-4,5,6,
Ampoule containing 5 mg of 7-tetrahydro-benzthiazole-dihydrochloride One ampoule contains the following ingredients: Active substance 5.0 mg Citric acid 7.0 mg Sodium dibasic phosphate x 2 H ₂ O 3.0 mg Sodium pyrosulfate 1.0 mg Distilled water Amount to bring the total volume to 1.0 ml Preparation method: Buffer substance, active substance and sodium pyrosulfate are sequentially dissolved in cooled sodium pyrosulfate under a CO ₂ gas atmosphere. The solution is made up to volume with boiling water and filtered to remove pyrogens. Filling: Filling into brown ampoules under protective gas atmosphere Sterilization: 20 minutes at 120°C. The preparation and handling of ampoule solutions must be carried out in the dark. Example 2-amino-6-dimethylamino-4,5,6,
One coated tablet core containing 1 mg of 7-tetrahydro-benzthiazole-dihydrochloride contains the following ingredients: 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 method: Proceed as in the example. Weight of core: 50 mg Punch: 4 mm, convex Weight of coated tablet: 100 mg It is clear that instead of the compounds mentioned above, other compounds of the general formula, such as 2-amino-6
-n-propylamino-4,5,6,7-tetrahydro-benzthiazole-dihydrochloride can be incorporated as active substance in the formulation examples.

Claims (1)

[Scope of Claims] 1 General formula: (wherein R 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, 1 to 6
an alkanoyl group having 1 to 3 carbon atoms in the alkyl moiety, or a phenylalkyl or phenylalkanoyl group having 1 to 3 carbon atoms in the alkyl moiety, in which the phenyl nucleus may be substituted with 1 or 2 halogen atoms; _R2 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms; _R3 represents a hydrogen atom, an alkyl group having 1 to 7 carbon atoms, a cyclocarbon group having 3 to 7 carbon atoms; an alkyl group, an alkenyl or alkynyl group each having from 3 to 6 carbon atoms, an alkanoyl group having from 1 to 7 carbon atoms, or an alkyl group having from 1 to 3 carbon atoms in the alkyl part and in which the phenyl nucleus is fluorine , represents a phenylalkyl or phenylalkanoyl group optionally substituted with a chlorine or bromine atom; R ₄ is a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, or each having 3 to 6 carbon atoms or R ₃ and R ₄ together with the nitrogen atom between them represent a pyrrolidino, piperidino or hexamethyleneimino group, and the group [formula] is bonded in the 6 position; ) Tetrahydro-benzthiazole compounds, enantiomers thereof and acid addition salts thereof. 2 General formula a [Chemical formula] (wherein R ₁ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, allyl, benzyl, 2-chloro-benzyl, 4-chloro-benzyl, 3,4-
represents a dichlorobenzyl or phenylethyl group; R ₂ represents a hydrogen atom, a methyl or ethyl group; R ₃ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, allyl, propargyl, benzyl,
represents a chlorobenzyl, phenylethyl, cyclopentyl or cyclohexyl group; R ₄ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or an allyl group, or R ₃ and R ₄ represent a nitrogen atom between them; Tetrahydro-benzthiazole compounds, enantiomers thereof and acid addition salts thereof, of the formula: taken together represent a pyrrolidino, piperidino or hexamethyleneimino group, and the group is attached at the 6-position Compounds of range 1. 3 R ₁ and R ₂ together with the nitrogen atom between them represent an amino or allylamino group, and R ₃ and R ₄ together with the nitrogen atom between them represent dimethylamino, diethylamino, N-allyl. -N-(4-chloro-benzyl)-amino, n-
The compound according to claim 2, which represents a propylamino or piperidino group; is a tetrahydro-benzthiazole compound of general formula a, its enantiomers and its acid addition salts. 4 2-amino-6-dimethylamino-4,5,
The compounds of claim 1 which are 6,7-tetrahydro-benzthiazole compounds, enantiomers thereof and acid addition salts thereof. 5 2-amino-6-n-propylamino-4,
5,6,7-tetrahydro-benzthiazole,
Compounds of claim 1 which are enantiomers thereof and acid addition salts thereof. 6 Claims 1 to 6 are in the form of physiologically acceptable acid addition salts with inorganic or organic acids.
A compound according to any one of paragraph 5. 7 As an active substance, the formula a [Chemical formula] (wherein R ₁ is a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, allyl, benzyl, 2-chloro-benzyl, 4-chloro-benzyl, 3,4-
represents a dichlorobenzyl or phenylethyl group; R ₂ represents a hydrogen atom, a methyl or ethyl group; R ₃ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, allyl, propargyl, benzyl,
represents a chlorobenzyl, phenylethyl, cyclopentyl or cyclohexyl group; R ₄ represents a hydrogen atom, an alkyl group having 1 to 3 carbon atoms or an allyl group, or R ₃ and R ₄ represent a nitrogen atom between them; Tetrahydro-benzthiazole compounds, their enantiomers or their physiologically acceptable acids; A pharmaceutical composition for treating Parkinson's disease and central nervous system neuropsychiatric disorders, comprising an addition salt, optionally together with one or more inert carriers and/or diluents.