N-(benzhydryloxyalkyl)-4-(carboxy/carbamoyl methyl)-piperidine d

Details N-(benzhydryloxyalkyl)-4-(carboxy/carbamoyl methyl)-piperidine d N-(benzhydryloxyalkyl)-4-(carboxy/carbamoyl methyl)-piperidine d

1996-10-16

1998-12-08

Chang, Ceila

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

514315, 514428, 546236, 548428, A61K 31445, C07D21134, C07D21170

Patent

active

058469800

DESCRIPTION:

BRIEF SUMMARY
The subject of the invention is new substituted nitrogenous heterocycle derivatives, their preparation and their biological and pharmaceutical applications.
The invention is more particularly targeted at substituted nitrogenous heterocycle derivatives, their isomers and their metabolites having a therapeutic activity, in particular a psychotropic activity and more especially an antidepressant activity.
Aryl-1,4-dialk(en)ylpiperazines (Eur. J. Med. Chem. 15, 363-370, 1980) are selective and powerful inhibitors of dopamine re-uptake, they exhibit a nanomolar affinity for this re-uptake site and also bind to the carrier for this amine (Neurochem. int. 15, 3, 325-332, 1989; Eur. J. Pharmacol. 177, 91-94, 1990) and are potential antidepressants. (Psychopharmacol., 101, 344-353, 1990) decreases the sleep induced by phenobarbital, increases the motor activity of the animals, induces stereotypic behaviors and decreases the immobility time of the mouse in the Porsolt behavioral despair test (Arch. Intern. Pharmacodyn. Therap., 225, 327, 1977) but antagonizes neither the ptosis nor the hypothermia induced by reserpine, nor the hypothermia induced by apomorphine. The behavioral despair test is the only predictive test for antidepressant activity with respect to which this product is active; however, the effect on the immobility time occurs at doses which cause an increase in the spontaneous motility of the animals, which is regarded as a bias and does not enable it to be irrefutably concluded that an antidepressant-type activity exists.
Selective or non-selective inhibitors of dopamine re-uptake are also active with respect to certain predictive tests for an activity in the treatment of Parkinson's disease (Psychopharmacol. Berl., 153-164-195; Psychopharmacol., 101, 344-195; Psychopharmacol., 101, 344-353, 1990). 1,2,3,4-tetrahydro-2-methyl-4-phenyl-8-isoquinolinamine inhibit dopamine and noradrenaline re-uptake (Drugs, 18, 1-24, 1979; Psychopharmacol., 101, 344-353, 1990). behavioral despair test; they also antagonize the ptosis and the hypothermia induced by reserpine and the hypothermia caused by apomorphine. The responses observed with respect to these pharmacological tests are predictive of an antidepressant activity; moreover, this effect is demonstrated in human clinical studies for 1,2,3,4-tetrahydro-2-methyl-4-phenyl-8-isoquinolinamine.
The studies carried out have made it possible to develop a family of substituted nitrogenous heterocycle derivatives endowed with inhibiting properties for dopamine, noradrenaline and serotonin re-uptake exhibiting, at low doses, the desired properties with respect to pharmacological tests predictive of an antidepressant activity.
The subject of the present invention is the use of the compounds of formula (I), which are substituted nitrogenous heterocycle derivatives, for the preparation of medicaments possessing psychotropic activity, in particular antidepressant activity, ##STR2## in which: R.sup.1 and R.sup.2, which are identical or different, represent a hydrogen atom, a halogen atom, a C.sub.1 -C.sub.6 alkyl group, a C.sub.2 -C.sub.6 alkoxy group or a trifluoromethyl group, chain, ##STR3## in which R.sup.9 represents alkyl, a C.sub.3 -C.sub.7 cycloalkyl, a C.sub.1 -C.sub.12 alkyl which is substituted by one or a number of optionally esterified alcohol functional groups or a C.sub.1 -C.sub.12 alkyl substituted by an --N(RaRb) group in which Ra and Rb, independently of one another, represent hydrogen or a C.sub.1 -C.sub.4 alkyl group or alternatively Ra and Rb, together with the nitrogen atom to wich they are bonded, form a 5- to 7-membered heterocycle optionally containing a second heteroatom, cation, one another, represent a hydrogen atom, a C.sub.1 -C.sub.12 alkyl, a C.sub.3 -C.sub.7 cycloalkyl, a C.sub.1 -C.sub.12 alkyl substituted by an --N(RaRb) group in which Ra and Rb are as defined above or a C.sub.1 -C.sub.12 alkyl substituted by one or a number of optionally esterified alcohol functional groups or alternatively Z.sub.2 and Z.sub.3, together with the nitrogen ato

REFERENCES:
patent: 4983614 (1991-01-01), Bizas
patent: 5053521 (1991-10-01), Pavia
patent: 5294623 (1994-03-01), Fukumi
Pavia et al. "Structure Activity studies on benzhydrol containing nipecotic acid . . . " J. Med. Chem. v.35, pp. 4238-4248, 1992.
Fumuki et al. "Preparation of antiallergic . . . " CA 114:42585, 1991.

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