Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-03-20
1999-11-02
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544360, 544295, 544292, 544293, 544357, 544369, 544368, 544370, 544296, 544284, 544364, 544405, 544336, 546264, 5462707, 5462701, 5462734, 5462704, 546194, 546209, 546198, 546199, 546256, 546257, 514253, 514254, 514332, 514256, 514275, 514260, 514342, 514338, 514318, 514326, 514321, 514322, 514333, 544328, 544331, A61K 31505, A61K 31495, C07D40302, C07D40312, C07D40314, C07D41702, C07D41712, C07D41714
Patent
active
059771100
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to novel substituted cyclohexylamines and derivatives thereof useful as pharmaceutical agents, to methods for their production, to pharmaceutical compositions which include these compounds and a pharmaceutically acceptable carrier, and to pharmaceutical methods of treatment. The novel compounds of the present invention are central nervous system agents. More particularly, the novel compounds of the present invention are both dopaminergic and serotonergic agents.
Compounds which interact with the dopamine D2 (DA D2) receptor have been shown to be efficacious in the treatment of psychiatric disorders such as schizophrenia. However, chronic administration of these agents causes various movement disorders both clinically and in animal models. It has been shown that administration of compounds that interact with the serotonin-1A (5-HT1A) receptor can block or prevent these extrapyramidal side effects in preclinical models (Neal-Beliveau B. S., et al., J. Pharm. Exp. Ther., 1993;265:207-17). Increases in both dopamine D2 and 5-HT1A receptor densities have been observed during postmortem studies of schizophrenic brains (Hashimoto T., et al., Life Sciences, 1991;48:355-363 and references cited therein). Thus, it seems likely both DA D2 and 5-HT1A receptors play an important role in the etiology of schizophrenia. Taken together, these studies suggest that compounds having the ability to interact with both dopamine D2 and 5-HT1A receptors will have increased efficacy in the treatment of schizophrenia while causing less side effects. The compounds of the present invention have potent binding affinity for both the dopamine D2 receptor and the 5-HT1A receptor. They also show activity in a behavioral paradigm predictive of antipsychotic efficacy.
A series of substituted cyclohexanols and cyclohexylamines represented by the formula ##STR1## wherein R is --OR.sup.3, wherein R.sup.3 is hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl lower alkyl, lower alkanoyl, aroyl, or aryl lower alkanoyl; ##STR2## wherein R.sup.4 and R.sup.5 are each independently hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, aryl lower alkyl, heteroaryl lower alkyl, lower alkanoyl, cycloalkanoyl, cycloalkylalkanoyl, aryl lower alkanoyl, heteroaryl lower alkanoyl, aroyl, heteroaroyl, or R.sup.4 and R.sup.5 are taken together with the nitrogen atom to which they are attached to form a ring denoted by ##STR3## wherein p is zero or an integer from 1 to 4 and R.sup.6 is hydrogen, lower alkyl, cycloalkyl, or cycloalkylalkyl ##STR4## wherein X is oxygen or sulfur or ##STR5## wherein R.sup.6 is as defined above, or ##STR6## wherein R.sup.4 and R.sup.5 are each independently hydrogen, lower alkyl, cycloalkyl, cycloalkylalkyl, aryl, aryl lower alkyl, lower alkanoyl, aryl lower alkanoyl, aroyl, or R.sup.4 and R.sup.5 are taken together with the oxygen and nitrogen atoms to which they are attached to form a ring denoted by ##STR7## wherein q is an integer from 2 to 3 and R.sup.6 is as defined above; substituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower akyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or 3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2- or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyl or 2-, 4-, or 5-thiazolyl substituted by lower alkyl or halogen; ##STR8## wherein R.sup.7 is aryl, 2-, 3-, or 4-pyridinyl or 2-, 3-, or 4-pyridinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-, 4-, or 5-pyrimidinyl or 2-, 4-, or 5-pyrimidinyl substituted by lower alkyl, lower alkoxy, or halogen, 2-pyrazinyl or 2-pyrazinyl substituted by lower alkyl, lower alkoxy, or halogen, 2- or 3-thienyl or 2- or 3-thienyl substituted by lower alkyl or halogen, 2- or 3-furanyl or 2- or 3-furanyl substituted by lower alkyl or halogen, 2-, 4-, or 5-thiazolyl or 2-, 4-, or 5-thia
REFERENCES:
patent: 5047406 (1991-09-01), Caprathe et al.
patent: 5478828 (1995-12-01), Mattson et al.
Wustrow et al., "Aminopyrimidines with High Affinity for Both Serotonin and Dopamine Receptors," J. Med. Chem., vol. 41, No. 5, pp. 760-771, 1998.
Belliotti Thomas R.
Kesten Suzanne R.
Pugsley Thomas A.
Wustrow David J.
Kessinger Ann M.
Shah Mukund J.
Tinney Francis J.
Warner-Lambert & Company
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