Aminoalkyl-substituted 2-amino-1,3,4-thiadiazoles, the preparati

Details Aminoalkyl-substituted 2-amino-1,3,4-thiadiazoles, the preparati Aminoalkyl-substituted 2-amino-1,3,4-thiadiazoles, the preparati

1993-12-13

1995-06-13

Gerstl, Robert

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

514256, 514318, 514326, 514333, 544245, 544367, 546193, 546209, 546277, C07D285135, A61K 3141

Patent

active

054243122

DESCRIPTION:

BRIEF SUMMARY
This application is 371 PCT/EP92/01028 filed May 11,1992.
The present invention relates to aminoalkyl-substituted 2-amino-1,3,4-thiadiazoles, the preparation thereof and the use thereof for controlling diseases.
GB 1 053 085 describes aminoalkylthiadiazoles which have antitussive, analgesic, antipyretic and hypoglycemic effects.
We have now found that aminoalkyl-substituted 2-amino-1,3,4-thiadiazole derivatives of the formula I ##STR2## where n is an integer from 2 to 6, and ##STR3## where Ar is phenyl which is unsubstituted or monosubstituted by C.sub.1 -C.sub.5 -alkyl, C.sub.1 -C.sub.5 -alkoxy, halogen, nitro, hydroxyl, trifluoromethyl or cyano, or is pyridyl, pyrimidinyl or thienyl, and the salts thereof with physiologically tolerated acids have interesting pharmacological properties.
A in the formula I is preferably ##STR4## where Ar is unsubstituted phenyl, pyridyl or pyrimidinyl, and n is preferably 2, 3 or 4.
The compounds of the formula I can be prepared by ##STR5## where n is as defined above, and X is a leaving group such as chlorine, bromine or RSO.sub.2 O--[R=C.sub.1 -C.sub.4 -alkyl or phenyl which is unsubstituted or substituted by C.sub.1 -C.sub.3 -alkyl or halogen], or a hydrohalide of this compound, with an amine of the formula III with physiologically tolerated acids.
The reactions in process a) take place in the melt, if required also in the presence of a solvent, e.g. ethyl acetate, tetrahydrofuran, dimethylformamide, dimethoxyethane, toluene or xylene, at from room temperature to the boiling point of the solvent, preferably in the presence of a base such as sodium methylate, sodium ethylate, sodium hydride, sodium carbonate, potassium carbonate, or of an amine, e.g. pyridine. It is also possible where appropriate for the amine component IV in excess to act as reagent, base and solvent.
The .omega.-X-alkylthiadiazoles of the formula II used as starting materials can be prepared, for example, by reacting .omega.-X-substituted carboxylic acids of the formula V carboxylic acids of the formula V are mostly known from the literature or can be prepared by known methods.
The reaction in process b) takes place in the presence of a diluent or solvent, preferably a strong acid, for example concentrated sulfuric acid, and expediently at from room temperature to the boiling point of the solvent. The reaction is generally complete in from 1 to 6 hours, depending on the precursors. The reaction product can be isolated and purified in conventional ways. The .omega.-amino carboxylic acids of the formula IV used as starting materials are known in some cases, or they can be prepared in a conventional way by reacting the .omega.-substituted carboxylic acids of the formula V with amines of the formula III.
The resulting compounds according to the invention are, where appropriate, converted into their addition salts with physiologically tolerated acids. Examples of suitable physiologically tolerated organic and inorganic acids are hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, oxalic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, adipic acid and benzoic acid. Others are to be found in Fortschritte der Arzneimittelforschung, Vol. 10, pp. 224 et seq., Birkhauser Verlag, Basel and Stuttgart, 1966.
The acid addition salts are usually obtained in a conventional way by mixing the free base or solutions thereof with the appropriate acid or solutions thereof in an organic solvent, for example a lower alcohol such as methanol, ethanol or propanol, a halohydrocarbon such as methylene chloride, an ether such as methyl t-butyl ether or diisopropyl ether, a ketone such as acetone or butanone or an ester such as ethyl acetate. It is also possible to use mixtures of the said solvents to improve crystallization. In addition, pharmaceutically acceptable aqueous solutions of acid addition compounds of the compounds I according to the invention can be prepared by dissolving the free bases in an aqueous acid solution.
The compounds according to the invention are suitable for controlling disea

REFERENCES:
patent: 4642132 (1987-02-01), Schirmer

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