Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-03-11
1999-03-16
Grumbling, Matthew V.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514253, 514318, 544182, 544357, 544238, 544360, 546194, C07D40314, C07D40114, A61K 3153, A61K 3150
Patent
active
058830944
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to novel pharmacologically active benzimidazolone derivatives and their acid addition salts. The compounds of this invention exhibit central dopaminergic activity and are useful in the treatment of central nervous system (CNS) disorders. They act preferentially on the D4 dopamine receptor.
It is generally accepted knowledge that dopamine receptors are important for many functions in the animal body. For example, altered functions of these receptors participate in the genesis of psychosis, addiction, sleep, feeding, learning, memory, sexual behavior, regulation of immunological responses and blood pressure. Since dopamine receptors control a great number of pharmacological events and, on the other hand, not all of these events are presently known, there is a possibility that compounds that act preferentially on the D4 dopamine receptor may exert a wide range of therapeutic effects in humans.
European Patent Application EP 526434, which was published on Feb. 3, 1993, refers to a class of substituted benzimidazolones that contain 1-(aryl and heteroaryl)-4-propyl piperidine substituents. These compounds were found to exhibit an affinity for the 5HT.sub.1A and 5HT.sub.2 serotonin receptors. German Patent Application DE 2714437, which was published on Oct. 20, 1977, refers to a series of s and reports that such compounds exhibited antihistamine activity when tested in mice. German Patent Application DE 2017265, which was published on Oct. 15, 1970, refers to a class of substituted found to exhibit bronchodilating effects in mice. European Patent Application EP 511074A1, which was published on Oct. 28, 1992, refers to benzimidazolone derivatives that are 5HT.sub.2 serotonin receptor antagonists useful in the treatment of a variety of CNS disorders.
The present invention relates to several substituted s that posess central dopaminergic activity and which have been found to have a preference for the D4 dopamine receptor.
SUMMARY OF THE INVENTION
This invention relates to compounds of the formula I ##STR2## wherein X.sup.1, X.sup.2 and X.sup.3 are independently selected from carbon and nitrogen; (e.g., chloro, fluoro, bromo or iodo), (C.sub.1 -C.sub.6)alkyl optionally substituted with from one to three fluorine atoms and (C.sub.1 -C.sub.6)alkoxy optionally substituted with from one to three fluorine atoms; moiety of said benzyl group may optionally be substituted with from one or more substituents, preferably with from one to three substituents, independently selected from halo (i.e., chloro, fluoro, bromo or iodo), cyano, (C.sub.1 -C.sub.6)alkyl optionally substituted with from one to three fluorine atoms, (C.sub.1 -C.sub.6)alkoxy optionally substituted with from one to three fluorine atoms, (C.sub.1 -C.sub.6)alkylsulfonyl, (C.sub.1 -C.sub.6)alkylamino, amino, di-(C.sub.1 -C.sub.6)alkylamino and (C.sub.1 -C.sub.6)carboxamido; (e.g., chloro, fluoro, bromo or iodo), cyano, (C.sub.1 -C.sub.6)alkyl optionally substituted with from one to three fluorine atoms, (C.sub.1 -C.sub.6)alkoxy optionally substituted with from one to three fluorine atoms, (C.sub.1 -C.sub.6)alkylsulfonyl, (C.sub.1 -C.sub.6)acylamino, and di-(C.sub.1 -C.sub.6)alkylamino; and
The compounds of formula I that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids. The acids that may be used to prepare pharmaceutically acceptable acid addition salts of those compounds of formula I that are basic in nature are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)! salts.
This inventi
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Faraci William S.
Fliri Anton F-J.
O'Neill Brian T.
Sanner Mark A.
Zorn Stevin H.
DeBenedictis Karen
Ginsburg Paul H.
Grumbling Matthew V.
Pfizer Inc.
Richardson Peter C.
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