Aminoalkyl-substituted thiazolin-2-ones, the preparation and use

Details Aminoalkyl-substituted thiazolin-2-ones, the preparation and use Aminoalkyl-substituted thiazolin-2-ones, the preparation and use

1993-12-13

1995-03-28

Gerstl, Robert

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

514252, 514326, 514333, 544367, 546209, 546280, 548189, C07D27734, C07D41706, A01K 31425

Patent

active

054017629

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to aminoalkyl-substituted thiazolin-2-ones, the preparation thereof and the use thereof for controlling diseases.
BE 829 071 describes 4-aryl-5-aminoalkylthiazolin-2-ones with pharmacological activities.
We have now found that aminoalkyl-substituted thiazolin-2-ones of the formula I ##STR2## where R.sup.1 is H or C.sub.1 -C.sub.5 -alkyl, ##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, C.sub.1 -C.sub.5 -alkylthio, trifluoromethyl or cyano, or is pyridyl, pyrimidinyl or thienyl, R.sup.3 is H or C.sub.1 -C.sub.5 -alkyl, and R.sup.4 is phenyl which is unsubstituted or monosubstituted by C.sub.1 -C.sub.5 -alkyl, C.sub.1 -C.sub.5 -alkoxy, halogen, hydroxyl or trifluoromethyl, or is thienyl, and their tautomers and salts of these compounds with physiologically tolerated acids have interesting pharmacological properties.
In the formula I, R.sup.1 is preferably H, R.sup.2 is preferably CH.sub.3, n is preferably 2, 3 or 4, and A is preferably ##STR4## where Ar is phenyl, pyridyl or pyrimidinyl, or ##STR5## where R.sup.3 is C.sub.1 -C.sub.3 -alkyl and R.sup.4 is phenyl or thienyl.
The tautomers derived from the compounds of the formula I have the formula Ia ##STR6##
The compounds of the formula I can be prepared by II ##STR7## where R.sup.1, R.sup.2 and n are as defined above, and X is a leaving group such as chlorine, bromine or R.sup.5 SO.sub.2 O--[R.sup.5 =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, when R.sup.1 is H, a tautomer of this compound, with an amine of the formula III ##STR8## where R.sup.2, R.sup.3, A and n are as defined above, and Hal is chlorine, bromine or iodine, or a hydrohalide of this compound, with a thiocarbamate of the formula V ##STR9## where R.sup.6 is C.sub.1 -C.sub.5 -alkyl, or with a tautomer of this compound, or ##STR10## where R.sup.2, A and n are as defined above, with an alkylating reagent R.sup.1 --X (X=Cl, Br, R.sup.5 SO.sub.2 O--) or R.sup.1.sub.2 SO.sub.4, where appropriate converting the resulting compounds into their salts with physiologically tolerated acids.
The reaction in process a) takes place in the melt, if required also in the presence of a solvent, e.g. ethanol, butanol, 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 crude product is isolated in a conventional way, e.g. by filtration, removal of the solvent by distillation, or extraction from the reaction mixture. The resulting compound is purified in a conventional way, for example by recrystallization from a solvent, chromatography or conversion into an acid addition compound.
The thiazolin-2-ones of the formula II used as starting materials can be prepared, for example, by halogenation of an .omega.-X-substituted ketone of the formula VII ##STR11## where R.sup.2, n and X have the stated meanings, and subsequently reacting the halo ketone with a thiocarbamate of the formula V.
The reactions in process b) are preferably carried out in a solvent at from room temperature to the boiling point of the solvent, in the presence or absence of an acid acceptor. Examples of solvents which can be used are aliphatic alcohols, dimethylformamide, glacial acetic acid, water or a solvent mixture, and of acid acceptors are inorganic bases such as sodium or potassium carbonate or tertiary organic bases such as triethylamine or pyridine. If used in excess, the latter can also act as solvent.
The .alpha.-halo ketones of the formula IV used as starting materials are obtained by halogenating the corresponding ketones of the formula VIII ##STR12## where R.sup.2, A

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