Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1993-09-14
1994-12-06
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514255, 544360, 544379, 544398, 544401, 544402, A61K 31495, C07D295088, C07D29513, C07D295155
Patent
active
053710886
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to 1-aryl-4-piperazinylcyclohexanecarbonitriles, to processes for the preparation thereof and to the use thereof as drugs.
Derivatives of 4-amino-1-phenylcyclohexanecarbonitrile have been disclosed. Thus, ZA-C 66/5399 discloses compounds with morpholine- and mescalineantagonistic properties, and DE-B 17 93 383 discloses compounds with spasmolytic, hypotensive and neuroleptic properties. 4-Piperidinyl-1-phenylcyclohexanecarbonitriles with a strong antihistamine action have been described in EP-A 34 415.
In addition, a large number of substituted piperazines with antiarrhythmic or bloodflow-promoting properties has been disclosed. These are predominantly benzhydryl- or diarylbutylpiperazines, of which flunarizine is the best known compound. It is used for the therapy of disturbances of peripheral and cerebral blood flow (DE-A 19 29 330, DE-A 33 26 148, DE-A 25 47 570, EP-A 256 890, DE-A 36 00 390, EP-A 159 566, EP-A 285 219).
We have now found that 1-aryl-4-piperazinylcyclohexanecarbonitriles of the formula I ##STR2## where Ar is phenyl which is unsubstituted or monosubstituted by chlorine, methyl, methoxy or trifluoromethyl or mono- or disubstituted by fluorine, or is 2- or 3-thienyl or 2-, 3- or 4-pyridyl, nitro, cyano, acetyl, methoxycarbonyl or ethoxycarbonyl, be monosubstituted by oxo, hydroxyl, methoxy or acetoxy, and outstanding antihypoxic and antiischemic action.
Suitable physiologically tolerated acids are inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or organic acids such as tartaric acid, lactic acid, malic acid, citric acid, maleic acid, fumaric acid, oxalic acid, acetic acid, gluconic acid, mucic acid or methanesulfonic acid.
In formula I, Ar is preferably phenyl which is unsubstituted or monosubstituted by fluorine or chlorine, R.sup.1 is preferably hydrogen, fluorine or chlorine or methoxy, and P-Q is, in particular, alkyleneoxy or alkylenethio of 2 or 3 carbons, or 2-hydroxypropyleneoxy. R.sup.1 and R.sup.2 can be in positions 2, 3 or 4 on the phenyl ring.
If P contains hydroxyl, for example, the compounds of the formula I have a center of chirality. They therefore exist in the form of optical antipodes (enantiomers). These can be obtained by conventional methods, by salt formation with chiral auxiliaries such as tartaric acid, dibenzoyltartaric acid or mandelic acid and fractional crystallization followed by liberation of the bases from the salts, or else by synthesis from suitable chiral precursors.
Furthermore, because of the cyclohexane ring, the compounds may also occur as cis and trans isomers. These geometrical isomers can be obtained in a conventional manner by separation processes such as crystallization or chromatography at the final stage or at an earlier stage, or else by carrying out suitable reactions.
The present invention also relates to processes for preparing the compounds of the formula I, which comprise either ##STR3## where Ar has the stated meanings, with a piperazine derivative III ##STR4## where P, Q, R.sup.1 and R.sup.2 have the stated meanings, or b) reacting a compound of the formula IV ##STR5## where Ar again has the abovementioned meanings, with a compound of the formula V ##STR6## where P, R1 and R2 [sic] have the abovementioned meanings, and X is a reactive acid residue, or compound of the formula IV with a compound of the formula VI ##STR7## where Q, R.sup.1 and R.sup.2 have the abovementioned meanings, R.sup.3 is C.sub.1-4 -alkyl, and n is 1 or 2, physiologically tolerated acids into their salts.
The known reductive amination of compounds of the formula II with piperazines of the formula III can be carried-out with reducing agents such as catalytically activated hydrogen, in which case a noble metal catalyst such as palladium on carbon is preferably used, with complex metal hydrides such as sodium cyanoborohydride or else with formic acid in a suitable solvent at, preferably, from 0.degree.to 100.degree. C. Suitable solvents are acetonitrile, dimethylformamide, tetrahydrofuran, toluene or
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Hofmann Hans P.
Szabo Laszlo
Treiber Hans-Joerg
BASF - Aktiengesellschaft
Bernhardt Emily
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