Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-03-18
1994-08-30
Bernhardt, Emily
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514218, 540575, 544396, A61K 31495, A61K 3155, C07D295088, C07D24308
Patent
active
053428390
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
The invention relates to 2-hydroxy-3-phenoxypropyl-substituted piperazines and homopiperazines, processes for the preparation thereof and the use thereof as drugs.
Numerous piperazines of various types have already been disclosed. Thus, for example, flunarizine and lidoflazine from the benzhydryl- and diarylbutylpiperazine series have been disclosed as therapeutics for cardiovascular and cerebrovascular disorders. Their mode of action is based on inhibition of the influx of calcium into the cell.
This mechanism of action also applies to the .omega.-phenoxy-alkyl-piperazines described in DE-A 3.600.390. The therapeutic aim of these compounds is, just like that of the benzhydryl-phenylalkanol-substituted piperazines described in DE-A 3.326.148, to treat disorders of the cerebral circulation.
N-Arylpiperazinealkanamides with diarylbutyl substituents on the piperazine ring (cf. EP-A 68544) improve the blood supply to the heart and protect it from the consequences of an ischemia, anoxia or hypoxia.
3-Aryloxy-2-propanol derivatives of phenylpiperazine have also been disclosed, but they display no calcium-antagonistic or antihypoxic effects (Arzneim. Forsch. (1978) 28 241-246).
It has now been found that 2-hydroxy-3-phenoxypropyl-substituted piperazines or homopiperazines of the formula I ##STR2## in which R.sup.1 and R.sup.2 denote hydrogen, fluorine or chlorine atoms, methoxy, methyl or trifluoromethyl groups, methyl, trifluoromethyl, cyano or nitro groups or a saturated or unsaturated alkoxy group with up to 3 C atoms, effect and which significantly improve the regional blood supply to the brain.
Thus the compounds according to the invention appear to be suitable for the therapy of cardiovascular disorders in general and in particular for treating acute and chronic oxygen deficiency states of the brain. By this are meant acute hypoxic or ischemic states occurring, for example, following cerebral infarct, craniocerebral trauma or vasospasms and following cardiovascular failure, e.g. associated with cardiac arrest, cardiac arrhythmias or circulatory failure. Examples of relevant syndromes with chronic oxygen deficiency states are: transient ischemic attacks (TIAs) and prolonged reversible ischemic neurological deficits (PRINDs), as well as multiinfarct dementia and atherosclerotic dementia, besides migraine and epilepsies.
Suitable physically 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 or mucic acid.
In the formula I, R.sup.1 and R.sup.2 are preferably hydrogen, fluorine or chlorine atoms, R.sup.3 and R.sup.4 are preferably hydrogen atoms, while R.sup.5 is, in particular, a fluorine or chlorine atom. n is preferably 2 and m is preferably 2 or 3. Y is, in particular, an oxygen atom. The substituents R.sup.1, R.sup.2 and R.sup.5 are, in particular, located in the 3 or 4 position of the phenyl rings. The 4 positions are preferred.
The compounds of the formula I have a center of chirality in the structural element of the aryloxypropanol. They therefore exist in the form of optical antipodes (enantiomers). The racemates can be obtained by conventional methods by salt formation with chiral auxiliary components such as dibenzoyltartaric acid, fractional crystallization and subsequent liberation of the bases from the salts or else by synthesis from suitable chiral precursors.
The invention also relates to processes for preparing the compounds of the formula I, which comprise reacting either ##STR3## in which R.sup.1, R.sup.2, m and n have the stated meaning, with an epoxide of the formula III ##STR4## in which Y, R.sup.3, R.sup.4 and R.sup.5 have the stated meaning, or b) a compound of the formula IV ##STR5## in which Y, R.sup.3, R.sup.4, R.sup.5 and n have the stated meaning, with a compound of the formula V ##STR6## where R.sup.1, R.sup.2, and m have the stated meaning, and X denotes a reactive acid
REFERENCES:
patent: 3133925 (1964-05-01), Cusic
patent: 4361562 (1982-11-01), Berthold
patent: 4831028 (1989-05-01), Lerch et al.
patent: 5087627 (1992-02-01), Morita et al.
Hofmann Hans P.
Raschack Manfred
Szabo Laszlo
Treiber Hans-Joerg
Unger Liliane
BASF - Aktiengesellschaft
Bernhardt Emily
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