DE3601411A1 - 3-Amino-1-(2-thiazolyl)-2-pyrazolines, process for their preparation and pharmaceutical preparations containing these - Google Patents

Abstract

The invention relates to novel 3-amino-1-(2-thiazolyl)-2-pyrazolines of the general formula I <IMAGE> and their acid addition salts, process for their preparation and pharmaceutical preparations containing these.

Description

The invention relates to 3-amino-1- (2-thiazolyl) pyrazolines and their physiologically tolerable acid addition salts, Process for their preparation and containing them pharmaceutical preparations and their use in the prophylaxis and therapy of inflammatory and allergic processes.

It is known that the degradation products of arachidonic acid metabolism as mediators are involved in numerous inflammatory and allergic processes. The biosynthesis caused by the enzyme cyclooxygenase leads to the prostaglandins, which are the cause of numerous diseases. It is known that the effect of most nonsteroidal anti-inflammatory agents is based on an inhibition of prostaglandin synthesis, which manifests itself in an anti-inflammatory effect. The non-steroidal anti-inflammatory agents have an inhibitory effect on the enzyme cyclooxygenase, the biocatalyst for the metabolism of arachidonic acid to the so-called endoperoxides PGG ₂ and PGH ₂ and their metabolites, which also include PGE ₂ . Since this prostaglandin has a protective effect on the gastric mucosa, the inhibition of its synthesis removes this protective effect and thereby causes the ulcerogenic side effect of numerous nonsteroidal anti-inflammatories.

Arachidonic acid is not only produced by cyclooxygenase, but also metabolized by the enzyme lipoxygenase. The resulting metabolites (leukotrienes) belong to on the one hand to the more important mediators of the inflammatory reaction, are on the other hand also for the appearance completely different clinical pictures, such as B. Bronchial asthma and allergic diseases. It exists therefore a need for orally active compounds that both the lipoxygenase and the cyclooxygenase in the required ratio that inhibit the side effects previously known connections no longer occur.

Substituted pyrazoline compounds as lipoxygenase inhibitors are known, z. B. 3-Amino-1- (3-trifluoromethylphenyl) - 2-pyrazoline from DE-OS 27 27 706 or 3-amino-1- (4,5,6,7- tetrahydro-2-benzothiazolyl) -2-pyrazoline from DE-OS 34 07 506.

It has now been found that 3-amino-1- (2-thiazolyl) -2-pyrazolines of the general formula I wherein
R ^{1 is} hydrogen, methyl, ethyl, propyl, butyl, adamantyl, carboxy, carboxyethyl, trifluoromethyl, phenyl, fluorophenyl, thienyl, pyridyl,
R ^{2 is} hydrogen, methyl, ethyl, propyl, butyl, benzyl, phenyl,
where R ¹ and R ^{2 must} not be hydrogen at the same time,
R ³ , R ^{4 are} hydrogen or methyl,
R ⁵ formyl, acetyl, propionyl, butyryl, methyl, ethyl, propyl, butyl,
R ^{6 is} hydrogen, methyl, ethyl, propyl, butyl
mean and their pharmaceutically acceptable acid addition salts have valuable pharmacological properties as dual inhibitors of lipoxygenase and cyclooxygenase.

Pharmaceuticals are also included in the invention usable acid addition salts of compounds of the formula I. These are, for example, with inorganic acids, such as mineral acids, e.g. B. sulfuric acid, phosphoric acid or hydrohalic acids, e.g. B. hydrochloric acid, with organic Carboxylic acids, such as lower alkane carboxylic acids, e.g. B. Acetic acid, such as optionally unsaturated dicarboxylic acids, e.g. B. oxalic, malonic, maleic or fumaric acid, or how  Hydroxycarboxylic acids, e.g. B. tartaric acid or citric acid, or with sulfonic acids, such as lower alkane or optionally substituted benzenesulfonic acids, e.g. B. methane or p-Toluenesulfonic acids formed.

Compounds according to the invention are, for example:
3-amino-5-methyl-1- (4,5-diphenyl-2-thiazolyl) -2-pyrazoline hydrochloride
3-formamido-5-methyl-1- (4-phenyl-5-methyl-2-thiazolyl) -2-pyrazoline
3-methylamino-5-methyl-1- (4-phenyl-5-methyl-2-thiazolyl) -2-pyrazoline hydrochloride
3-amino-1- (4,5-dibutyl-2-thiazolyl) -2-pyrazoline hydrochloride
3-amino-4-methyl-1- (4-methyl-5-benzyl-2-thiazolyl) -2-pyrazoline hydrochloride
3-N-methylbutylamino-5-methyl-1- (4-phenyl-5-methyl-2-thiazolyl) -2-pyrazoline hydrochloride
3-N-methylacetamido-1- (4-phenyl-2-thiazolyl) -2-pyrazoline hydrochloride
3-amino-5-methyl-1- (4,5-dimethyl-2-thiazolyl) pyrazoline
3-amino-4-methyl-1- (4,5-dimethyl-2-thiazolyl) -2-pyrazoline
3-amino-1- (4,5-dimethyl-2-thiazolyl) -2-pyrazoline
3-formamido-5-methyl-1 (4,5-dimethyl-2-thiazolyl) pyrazoline
3-methylamino-5-methyl-1 (4,5-dimethyl-2-thiazolyl) -2-pyrazoline
3-dimethylamino-5-methyl-1- (4,5-dimethyl-2-thiazolyl) -2-pyrazoline
3-N-Propylacetamido-5-methyl-1- (4,5-dimethyl-2-thiazolyl) -2-pyrazoline
3-N-butylethylamino-5-methyl-1- (4,5-dimethyl-2-thiazolyl) -2-pyrazoline
3-N-ethylformamido-5-methyl-1- (4,5-dimethyl-2-thiazolyl) -2-pyrazoline
3-amino-5-methyl-1- (4-phenyl-5-methyl-2-thiazolyl) -2-pyrazoline
3-amino-4-methyl-1- (4-phenyl-5-methyl-2-thiazolyl) -2-pyrazoline
3-amino-1- (4-phenyl-5-methyl-2-thiazolyl) -2-pyrazoline
3-amino-4-methyl-1- (4,5-diphenyl-2-thiazolyl) -2-pyrazoline
3-amino-1- (4,5-diphenyl-2-thiazolyl) -2-pyrazoline
3-acetamido-5-methyl-1- (4,5-diphenyl-2-thiazolyl) -2-pyrazoline
3-N-ethylformamido-5-methyl-1- (4,5-diphenyl-2-thiazolyl) -2-pyrazoline
3-formamido-5-methyl-1- (4,5-diphenyl-2-thiazolyl) -2-pyrazoline
3-amino-5-methyl-1- (4-trifluoromethyl-2-thiazolyl) -2-pyrazoline
3-amino-5-methyl-1- (4-phenyl-2-thiazolyl) -2-pyrazoline
3-amino-5-methyl-1- (4-phenyl-5-propyl-2-thiazolyl) -2-pyrazoline
3-amino-5-methyl-1- (4-adamantyl-2-thiazolyl) -2-pyrazoline
3-amino-5-methyl-1- (4-methyl-5-phenyl-2-thiazolyl) -2-pyrazoline
3-formamido-5-methyl-1- (4-methyl-5-phenyl-2-thiazolyl) -2-pyrazoline
3-methylamino-5-methyl-1- (4-methyl-5-phenyl-2-thiazolyl) -2-pyrazoline
3-amino-5-methyl-1- (4-carboxyethyl-2-thiazolyl) -2-pyrazoline
3-amino-5-methyl-1- (4-carboxy-2-thiazolyl) -2-pyrazoline
3-amino-5-methyl-1- (4-methyl-5-benzyl-2-thiazolyl) -2-pyrazoline
3-amino-1- (4-methyl-5-benzyl-2-thiazolyl) -2-pyrazoline
3-diethylamino-4-methyl-1- (4-methyl-5-benzyl-2-thiazolyl) -2-pyrazoline
3-N-ethylformamido-4-methyl-1- (4-methyl-5-benzyl-2-thiazolyl) -2-pyrazoline
3-amino-5-methyl-1- [4- (2-thienyl) -5-phenyl-2-thiazolyl] -2-pyrazoline
3-amino-5-methyl-1- (4,5-diethyl-2-thiazolyl) -2-pyrazoline
3-amino-5-methyl-1- [4- (3-pyridyl) -5-phenyl-2-thiazolyl] -o 2-pyrazoline
3-amino-5-methyl-1- (4,5-dibutyl-2-thiazolyl) -2-pyrazoline
3-amino-5-methyl-1- [4- (4-fluorophenyl) -2-thiazolyl] -2-pyrazoline
3-amino-5-methyl-1- (5-phenyl-2-thiazolyl) -2-pyrazoline
3-amino-5-methyl-1- (4-phenyl-5-ethyl-2-thiazolyl) -2-pyrazoline
3-amino-5-methyl-1- (4,5-dipropyl-2-thiazolyl) -2-pyrazoline

The compounds of formula I have valuable pharmacological Properties on. In particular, they inhibit the Lipoxygenase and cyclooxygenase degradation pathways of arachidonic acid metabolism and thus the formation of leukotrienes and prostaglandins, which act as mediators on inflammatory and allergic processes are involved. You are therefore as a medicine to treat inflammatory and allergic processes and can be used as anti-inflammatory drugs, Anti-inflammatory drugs, anti-atherosclerotic drugs, anti-thrombotic drugs, Antiallergic, antiasthmatic and gastroprotective Find use.

The compounds of the formula I according to the invention with R ⁵ = R ⁶ = H are prepared by methods known per se, for. B. after GF Duffin and JF Kendall, J. Chem. Soc. 1954, 408-415, by base-catalyzed cyclization of 2-hydrazinothiazoles of the formula II in which R ¹ , R ^{2 have} the meanings given in formula I, with unsaturated nitriles of the formula III wherein R ³ , R ^{4 have} the meanings given in formula I.

The reaction is carried out in a suitable solvent, predominantly in lower alcohols at temperatures of 50-100 ° C. in the presence of alkali alcoholate under a protective gas (nitrogen or argon). The compounds of the formula I with R ⁵ = R ⁶ = H become the compounds of the formula I with R ⁵ = C _1-4 -acal, R ⁶ = H according to known acylation processes with carboxylic acid halides or anhydrides in the presence or absence of a suitable solvent manufactured at 0-60 ° C.

The compounds of the formula I with R ⁵ = C _1-4 -alkyl, R ⁶ = H, are obtained by reducing acyl compounds of the formula I with R ⁵ = C _1-4 -acyl, R ⁶ = H.

All reduction processes for carboxamides can be used for this. It is advantageous to use complex metal hydrides, in particular lithium aluminum hydride, in a solvent. Normal and cyclic ethers such as diethyl ether, dioxanes and tetrahydrofuran are suitable for this at temperatures up to the boiling point of the solvent. Another variant is also convenient. Starting from compounds of the formula I with R ⁵ = C _1-4 -acyl, R ⁶ = C _1-4 -alkyl, the acyl radical is hydrolytically split off under acidic or alkaline conditions.

The compounds of the formula I according to the invention with R ⁵ = C _1-4 -acyl, R ⁶ = C _1-4 -alkyl and R ⁵ = C _1-4 -alkyl, R ⁶ = C _1-4 -alkyl are represented by Alkylation of the 3-acylamino or 3-alkylamino compounds with alkyl halides of the formula R ⁶ -Hal.

The reaction is carried out in the presence of a base in a aprotic solvent, for example dimethylformamide or dimethyl sulfoxide at room temperature up to 100 ° C and in reaction times from 15 minutes to Run 24 hours. Suitable bases are e.g. B. alkali amides, Alkoxides, mainly alkali metal hydrides, especially Sodium hydride.

The compounds according to the invention are purified by conventional methods, mainly by crystallization the acid addition salts or by chromatography.

The compounds of the invention can be in the form of their Bases or as acid addition salts.

The present invention also relates to pharmaceutical Preparations, which compounds of formula I or pharmaceutically acceptable acid addition salts of these compounds contain. In the pharmaceutical Preparations are enteral such as oral or rectal or parenteral administration, which are the active pharmaceutical ingredients alone or together with a customary, pharmaceutically usable carrier material  contain. The pharmaceutical is advantageously located Preparation of the active substance in the form of single doses before, which is tailored to the desired administration are, such as B. tablets, drages, capsules, suppositories. In the case of oral administration, the dosage of the compounds lies usually between 10-1000 mg per day, preferably between 30-300 mg and may be preferred one or more times two to three times a day.

The preparation of the compounds according to the invention explained in more detail by the following examples. The specified Melting points were measured using a Büchi 510 melting point determination apparatus measured and are given with ° C and not corrected.

The IR spectra were recorded on a Nicolet Model 3600 FT measured. The mass spectra were recorded using the Varian device MAT 311-A (70 eV) added.

example 1

3-amino-5-methyl-1- (4,5-diphenyl-2-thiazolyl) -2-pyrazoline- hydrochloride.

3.4 g of crotonic acid nitrile are added dropwise to a solution of 15.2 g of 2-hydrazino-4,5-diphenyl-thiazole hydrochloride in about 30 ml of ethanol while cooling with ice. An ethylate solution prepared from 2.3 g of sodium and 60 ml of ethanol is added to this mixture. The mixture is heated under reflux for 1.5 hours. The solvent is distilled off in vacuo and the residue is triturated well with water. The undissolved is filtered off and washed with isopropanol and ether. After drying, 6.7 g of base are obtained, which is converted into the hydrochloride using methanolic HCl in methanol. After recrystallization from ethanol, 6.5 g of white crystals of 3-amino-5-methyl-1- (4,5-diphenyl-2-thiazolyl) -2-pyrazoline hydrochloride, mp. 186-189 ° C.
IR (KBr): 1637 cm ^-1
MS: M⁺ and basepeak m / e 334

Example 2

3-formamido-5-methyl-1- (4-phenyl-5-methyl-2-thiazolyl) -2- pyrazoline.

5.4 g of 3-amino-5-methyl-1- (4-phenyl-5-methyl-2-thiazolyl) -2-pyrazoline are dissolved in 30 ml of 98% formic acid with stirring and heated to 60 ° C. under nitrogen . At this temperature, 20 ml of acetic anhydride are added dropwise. After 4 hours the mixture is evaporated to dryness in vacuo. The residue is taken up in water and a greasy solid is precipitated with ammonia, which is dissolved in dichloromethane after decanting off the water. The solution is washed with water, dried over sodium sulfate and evaporated in vacuo. 4.9 g of light beige crystals of 3-formamido-5-methyl-1- (4-phenyl-5-methyl-2-thiazolyl) -2-pyrazoline, mp 137-138 ° C., crystallize from ether.
IR (Krb): 1648, 1679 cm ^-1
MS: M⁺ and basepeak m / e 300.

Example 3

3-methylamino-5-methyl-1- (4-phenyl-5-methyl-2-thiazolyl) - 2-pyrazoline hydrochloride.

A solution of 3 g of 3-formamido-5-methyl-1- (4-phenyl-5-methyl-2-thiazolyl) -2-pyrazoline in 30 ml of absolute tetrahydrofuran is converted to a suspension of 1 at room temperature under a nitrogen atmosphere and with stirring , 5 g of lithium aluminum hydride added dropwise in 50 ml of tetrahydrofuran. The mixture is stirred for a further 5 hours and then water is added dropwise with ice cooling. It is extracted with ether, the organic phase is separated off, washed with water, dried over sodium sulfate and evaporated in vacuo. The hydrochloride is immediately prepared from the residue with methanolic HCl and recrystallized from isopropanol. 1.1 g of 3-methylamino-5-methyl-1- (4-phenyl-5-methyl-2-thiazolyl) -2-pyrazoline hydrochloride, mp. 217-220 ° C., are obtained.
IR (KBr): 1620, 1661 cm ^-1
MS: M⁺ and basepeak m / e 286.

Example 4

3-amino-3- (4,5-dibutyl-2-thiazolyl) -2-pyrazoline hydrochloride.

13.1 g of 2-hydrazino-4,5-dibutyl-thiazole hydrochloride are added to a sodium ethylate solution, prepared from 2.3 g of sodium and 60 ml of absolute ethanol, and after 15 minutes, with stirring, 2.7 g of acrylonitrile. The mixture is stirred under reflux for about 3 hours. The solvent is removed in vacuo and the residue is treated with water. It is extracted with ether, the organic phase is separated off, washed with water, dried over sodium sulfate and concentrated to dryness in vacuo. 5.6 g of pure base of mp 132-133 ° C. are obtained from hexane. The base dissolved in methanol is mixed with ethereal HCl up to pH 3-4. After filtering, washing with acetone and ether, 5.1 g of 3-amino-1- (4,5-dibutyl-2-thiazolyl) -2-pyrazoline hydrochloride, mp. 129-131 ° C., are obtained.
IR (KBr): 1647 cm ^-1
MS: M⁺ and basepeak m / e 304.

Example 5

3-amino-4-methyl-1- (4-methyl-5-benzyl-2-thiazolyl) -2- pyrazoline hydrochloride.

At 10 ° C., 3.4 g of methacrylonitrile is stirred with a mixture of 15 g of 2-hydrazino-4-methyl-5-benzylthiazole hydrobromide and sodium ethylate solution from 2.3 g of sodium and 100 ml of absolute ethanol in the course of 10 Dripped minutes. The mixture is heated at the boil for 2.5 hours with stirring. The hot solution is filtered, the filtrate is evaporated to dryness in vacuo and the residue is treated with water. The undissolved material is filtered off with suction, washed with water, suspended in methanol and mixed with methanolic HCl until a solution is obtained. The hydrochloride is precipitated by adding ether, filtered off and recrystallized from ethanol. 8.9 g of 3-amino-4-methyl-1- (4-methyl-5-benzyl-2-thiazolyl) -2-pyrazoline hydrochloride, mp. 139-141 ° C., are obtained.
IR (KBr): 1649 cm ^-1
MS: M⁺ and basepeak m / e 310.

Example 6

3-N-methylbutylamino-5-methyl-1- (4-phenyl-5-methyl-2- thiazolyl) -2-pyrazoline hydrochloride.

To 4.2 g of 3-methylamino-5-methyl-1- (4-phenyl-5-methyl-2-thiazolyl) -2-pyrazoline in 40 ml of dimethylformamide are added in portions 0.66 g of sodium hydride (55% Dispersion in mineral oil). After the evolution of hydrogen has ended, 2 g of 1-butyl bromide are added dropwise. The mixture is stirred at room temperature for 2 hours and heated at 100 ° C. for about 20 minutes. The mixture is poured onto ice and extracted with ether. The organic phase is separated off, washed, dried and concentrated. The hydrochloride is prepared from the residue with methanolic HCl and recrystallized from isopropanol. 3-N-Methylbutylamino-5-methyl-1- (4-phenyl-5-methyl-2-thiazolyl) -2-pyrazoline hydrochloride, mp 172-175 ° C., is obtained.
IR (KBr): 1623 cm ^-1
MS: M⁺ and basepeak m / e 342.

Example 7

3-N-methylacetamido 1- (4-phenyl-2-thiazolyl) -2-pyrazoline- hydrochloride.

A solution of 2.8 g of 3-acetamido-1- (4-phenyl-2-thiazolyl) -2-pyrazoline in 30 ml of dimethylformamide is added in portions under a nitrogen atmosphere to 0.44 g of sodium hydride (55% dispersion in mineral oil) . After about half an hour, 2.9 g of methyl iodide are added dropwise. The mixture is stirred at room temperature for 3 hours, briefly heated to 100 ° C. and, after cooling, poured onto ice water. The crystals are filtered off, washed with water and dried. The hydrochloride is prepared from the base with ethereal HCl in methanol. Recrystallization from ethanol gives 1.4 g of 3-N-methylacetamido-1- (4-phenyl-2-thiazolyl) -2-pyrazoline hydrochloride, mp. 207-209 ° C.
IR (KBr): 1689 cm ^-1
MS: M⁺ and basepeak m / e 300.

Example 8

Following the rules of Examples 1-7 were the following Connections established:

3-amino-5-methyl-1- (4,5-dimethyl-2-
thiazolyl) -2-pyrazoline hydrochloride mp. 257-260 ° C 3-amino-4-methyl-1- (4,5-dimethyl-2-
thiazolyl) -2-pyrazoline hydrochloride mp. 234-236 ° C 3-amino-1- (4,5-dimethyl-2-thiazolyl) -
2-pyrazoline hydrochloride mp. 265-267 ° C 3-formamido-5-methyl-1- (4,5-dimethyl-
2-thiazolyl) -2-pyrazoline mp. 148-150 ° C 3-methylamino-5-methyl-1- (4,5-dimethyl-
2-thiazolyl) -2-pyrazoline hydrochloride mp. 230 ° C (Z) 3-dimethylamino-5-methyl-1- (4,5-di-
methyl-2-thiazolyl) -2-pyrazoline hydrochloride mp. 222-224 ° C 3-N-propylacetamido-5-methyl-1- (4,5-
dimethyl-2-thiazolyl) -2-pyrazoline hydrochloride mp. 185-187 ° C 3-N-butylethylamino-5-methyl-1- (4,5-
dimethyl-2-thiazolyl) -2-pyrazoline hydrochloride mp. 162-164 ° C 3-N-ethylformamido-5-methyl-1- (4,5-
dimethyl-2-thiazolyl) -2-pyrazoline hydrochloride mp. 195-197 ° C 3-amino-5-methyl-1- (4-phenyl-5-methylzolyl-
2-pyrazoline hydrochloride mp. 163-166 ° C 3-amino-4-methyl-1- (4-phenyl-5-methyl-
2-thiazolyl) -2-pyrazoline hydrochloride mp. 157-159 ° C 3-amino-1- (4-phenyl-5-methyl-2-thiazolyl-
2-pyrazoline hydrochloride mp. 196-199 ° C 3-amino-4-methyl-1- (4,5-diphenyl-2-
thiazolyl) -2-pyrazoline hydrochloride mp. 177-179 ° C 3-amino-1- (4,5-diphenyl-2-thiazolyl) -
2-pyrazoline hydrochloride mp. 192-194 ° C 3-acetamido-5-methyl-1- (4,5-diphenyl-
2-thiazolyl) -2-pyrazoline hydrochloride mp. 152-154 ° C 3-N-ethylformamido-5-methyl-1- (4,5-
diphenyl-2-thiazolyl) -2-pyrazoline hydrochloride mp. 167-169 ° C 3-formamido-5-methyl-1- (4,5-diphenyl-
2-thiazolyl) -2-pyrazoline mp. 123-125 ° C 3-amino-5-methyl-1- (4-trifluoromethyl-
2-thiazolyl) -2-pyrazoline mp. 127-129 ° C 3-amino-5-methyl-1- (4-phenyl-2-thiazolyl-
2-pyrazoline hydrochloride mp. 168-171 ° C 3-amino-5-methyl-1- (4-phenyl-5-propyl-
2-thiazolyl) -2-pyrazoline hydrochloride mp. 238-240 ° C 3-amino-5-methyl-1- (4-adamantyl-2-
thiazolyl) -2-pyrazoline hydrochloride mp. 200-202 ° C 3-amino-5-methyl-1- (4-methyl-5-phenyl-
2-thiazolyl) -2-pyrazoline hydrochloride mp. 149-151 ° C 3-formamido-5-methyl-1- (4-methyl-5-
phenyl-2-thiazolyl) -2-pyrazoline hydrochloride mp. 177-179 ° C 3-methylamino-5-methyl-1- (4-methyl-5-
phenyl-2-thiazolyl) -2-pyrazoline hydrochloride mp. 147-150 ° C 3-amino-5-methyl-1- (4-carboxymethyl-
2-thiazolyl) -2-pyrazoline mp. 149-151 ° C 3-amino-5-methyl-1- (4-carboxy-2-thiazolyl-
2-pyrazoline hydrochloride mp. 175 ° C (Z) 3-amino-5-methyl-1- (4-methyl-5-benzyl-
2-thiazolyl) -2-pyrazoline hydrochloride mp. 151-153 ° C 3-amino-1- (4-methyl-5-benzyl-2-thiazolyl-
2-pyrazoline hydrochloride mp. 173-175 ° C 3-diethylamino-4-methyl-1- (4-methyl-5-
benzyl-2-thiazolyl) -2-pyrazoline hydrochloride mp. 134-136 ° C 3-N-ethylformamido-4-methyl-1- (4-
methyl-5-benzyl-2-thiazolyl) -2-pyrazoline hydrochloride mp. 138-140 ° C 3-amino-5-methyl-1- [4- (2-thienyl) -5-
phenyl-2-thiazolyl] -2-pyrazoline hydrochloride mp. 154-156 ° C 3-amino-5-methyl-1- (4,5-diethyl-2-
thiazolyl) -2-pyrazoline hydrochloride mp. 186-188 ° C 3-amino-5-methyl-1- [4- (3-pyridyl) -5-
phenyl-2-thiazolyl] -2-pyrazoline hydrochloride mp. 207-210 ° C 3-amino-5-methyl-1- (4,5-dibutyl-2-
thiazolyl) -2-pyrazoline hydrochloride mp. 107-109 ° C 3-amino-5-methyl-1- [4- (4-fluorophenyl) -
2-thiazolyl] -2-pyrazoline hydrochloride mp. 220-222 ° C 3-amino-5-methyl-1- (5-phenyl-2-
thiazolyl) -2-pyrazoline hydrochloride mp. 133-135 ° C 3-amino-5-methyl-1- (4-phenyl-5-ethyl-
2-thiazolyl) -2-pyrazoline hydrochloride mp. 220 ° C (Z) 3-amino-5-methyl-1- (4,5-dipropyl-2-
thiazolyl) -2-pyrazoline mp. 121-123 ° C

Claims (6)

1. 3-amino-1- (2-thiazolyl) -2-pyrazolines of the general formula I wherein
R ^{1 is} hydrogen, methyl, ethyl, propyl, butyl, adamantyl, carboxy, carboyethyl, trifluoromethyl, phenyl, fluorophenyl, thienyl, pyridyl,
R ^{2 is} hydrogen, methyl, ethyl, propyl, butyl, benzyl, phenyl,
where R ¹ and R ^{2 must} not be hydrogen at the same time,
R ^{3 is} hydrogen or methyl,
R ^{4 is} hydrogen or methyl,
R ⁵ formyl, acetyl, propionyl, butyryl, methyl, ethyl, propyl, butyl,
R ^{6 is} hydrogen, methyl, ethyl, propyl, butyl
mean,
and their pharmaceutically acceptable acid addition salts. 2. Process for the preparation of compounds of the formula I with R ⁵ = R ⁶ = H according to processes known per se, characterized in that 2-hydrazinothiazoles of the formula II in which R ¹ , R ^{2 have} the meanings given in formula I. , with unsaturated nitriles of the formula III, in which R ³ , R ^{4 have} the meanings given in formula I. converted into the compound of the formula I by base-catalyzed cyclization in a suitable solvent. 3. Process for the preparation of compounds of the formula I with R ⁵ = C _1-4 -acyl and R ⁶ = H, characterized in that compounds of the formula I with R ⁵ = R ⁶ = H according to known acylation processes with carboxylic acid halides or implemented anhydrides. 4. A process for the preparation of compounds of the formula I with R ⁵ = C _1-4 -alkyl and R ⁶ = H, characterized in that compounds of the formula I with R ⁵ = C _1-4 -acyl, R ⁶ = H reduced by known reduction processes for carboxamides. 5. A process for the preparation of compounds of formula I with R ⁵ = C _1-4 acyl and R ⁶ = C _1-4 alkyl and R ⁵ and R ⁶ = C _1-4 alkyl, characterized in that compounds of the formula I with R ⁵ = C _1-4 -acyl and R ⁶ = H or compounds of the formula I with R ⁵ = C _1-4 -alkyl and R = H with alkyl halides of the formula R ⁶ -Hal. 6. Medicines, characterized in that they have a compound of formula I or their pharmaceutically acceptable Acid addition salt as an active ingredient in a mixture with contain usual auxiliaries and carriers.