Disubstituted piperidine derivatives as neuroprotective agents

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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546209, A61K 31445, C07D41306

Patent

active

059689552

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BRIEF SUMMARY
The present invention relates to disubstituted piperidine derivatives, to a process for their preparation and to pharmaceutical compositions containing them.
These compounds possess selective neuroprotective activity and can therefore be useful in the prevention and/or treatment of neurotoxic injuries associated with neurological insults or neurodegenerative diseases.
The exicitatory amino acids (EAAs) L-glutamate and L-aspartate are the most abundant amino acids in brain and play a number of roles in maintaining neuronal function. For example, EAA neurotransmitters may contribute to the cellular abnormalities associated with epilepsy, the brain damage characteristic of neurodegenerative disorders such as, e.g., Huntington's, Alzheimer's and Parkinson's diseases, as well as disorders associated with ischemia,head injury and AIDS encephalopathy. Moreover, these trasmitters play a crucial role in learning and memory (Life Science, Vol. 54, pp. 135-148,1993).
Control of the above identified neurophatological processes and neurodegenerative consequences can be provided by compounds having activity as mediators or inhibitors of EAAs at the neuronal receptor sites.
There is therefore a need to find pharmacological agents able to antagonize or block neurotoxic action of EAAs at the EAA synaptic receptors of central neurons, in order to prevent and/or treat neurotoxic injuries associated with neurological insults or neurodegenerative diseases.
The compounds of the present invention fulfill such a need.
Accordingly, the present invention provides a 1,4-disubstituted piperidine derivative of formula (I) ##STR2## wherein R.sub.1 is hydrogen; bromo; chloro; a linear or branched C.sub.1 -C.sub.5 alkyl group; a linear or branched C.sub.1 -C.sub.5 alkoxy group; or an optionally substituted phenyl group of formula ##STR3## wherein Z is hydrogen, a linear or branched C.sub.1 -C.sub.5 alkyl group, a linear or branched C.sub.1 -C.sub.5 alkoxy group, bromo, chloro, fluoro, nitro or trifluoromethyl; an optionally substituted phenyl group as defined above; C.dbd.O or CH-A wherein A is an optionally substituted phenyl group as defined above;
Depending on the different meanings of the substituents X, R.sub.3 and/or Y, the compounds of formula (I) can have one or more asymmetric centers and can therefore exist in different stereoisomers which are also within the scope of the present invention.
A linear or branched C.sub.1 -C.sub.5 alkyl group may be, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl or n-pentyl; preferably, it is methyl, ethyl, propyl or iso-propyl.
A linear or branched C.sub.1 -C.sub.5 alkoxy group may be, for a example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy or n-pentoxy; preferably, it is a linear C.sub.1 -C.sub.5 alkoxy group, in particular a linear C.sub.1 -C.sub.3 alkoxy group, more particularly methoxy or ethoxy.
Preferred meanings of the Z substituent in an optionally substituted phenyl group of formula ##STR4## are hydrogen; chloro; bromo; fluoro; a linear C.sub.1 -C.sub.3 alkoxy group, in particular methoxy; and trifluoromethyl. Most preferred meanings of Z are fluoro and methoxy. Substituent Z may be in ortho, meta or para position of the phenyl ring; preferably, it is in para position.
As mentioned above, the present invention includes also in its scope 1,4-disubstituted piperidine derivatives of formula (I) in the form of pharmaceutically acceptable salts; these salts may be with pharmaceutically acceptable acids, both inorganic and organic acids. salts. hydrobromic, sulfuric, nitric or phosphoric acid; a pharmaceutically acceptable organic acid may be, e.g., malic, maleic, pamoic, succinic, gluconic, citric, tartaric, ascorbic, acetic, methanesulphonic or benzensulphonic acid.
A preferred class of compounds according to this invention are compounds of formula (I) wherein R.sub.1 is hydrogen; bromo; chloro; a linear C.sub.1 -C.sub.3 alkoxy group or an optionally substituted phenyl group of formula ##STR5## wherein Z is hydrogen, bromo, fluoro, a linear C.sub.1 -

REFERENCES:
patent: 4397853 (1983-08-01), Kawakita et al.
patent: 5338857 (1994-08-01), Ohto et al.
Chemical Abstracts, vol. 78, No. 25, Jun. 25, 1973, Columbus Ohio, US; 159582y, p. 415; XP002020897 see abstract & JP 48 026 759 A (Shionogi and Co., Ltd) Apr. 9, 1973.
Chemical Abstracts, vol. 84, No. 15, Apr. 12, 1976, Columbus, Ohio, US; abstract No. 99377x, p. 42; XP002020898 see abstract & JPN.J.Pharmacol., pp. 501-505, Toshio Yoshizaki et al: "Drug-induced adrenaline release and blood glucose in rats:3-phenyl-5-(2-piperidinoethyl)isoxazo le citrate".
Chemical Abstracts, vol. 67, No. 11, Sep. 11, 1967, Columbus, Ohio, US; abstract No. 54119x, p. 5092; XP002020899 see abstract & JP 42 003 496 B (Shionogi and Col, Ltd) May 6, 1967.

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