Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-01-31
1999-03-30
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
544370, A01N 4360, C07D40300
Patent
active
058890106
DESCRIPTION:
BRIEF SUMMARY
This is a 371 application of PCT/IB95/00378, filed on May 18, 1995.
The present invention relates to novel pharmacologically active benzimidazole 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, leaming, 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 0526434, which was published on Feb. 3, 1993, referred to a class of substituted benzimidazol-2-ones that contain 1-(aryl and heteroaryl)4-propyl-piperidine substituents and states that such compounds were found to be centrally acting serotinergic agents. European Patent Application EP 0548813, which was published on Jun. 30, 1993, refers to a class of substituted indole derivatives that contain states that such compounds were found to be centrally acting serotinergic agents. German Patent Application DE 2017265, which was published on Oct. 15, 1970, refers to a class of substituted that such compounds were tested in mice and found to have bronchodilating effects. U.S. Pat. No. 4,200,641, which was issued on Apr. 29, 1980, and German Patent DE 2714437, which was published on May 11, 1989, refer to a series of s. These compounds were tested in mice and found to have antihistaminic activity. U.S. Pat. No. 4,954,503, which issued on Dec. 31, 1991, refers to a series of indazole derivatives that contain 1-(aryl and heteroaryl) 4propyl-piperidine substituents and states that such compounds were found to exhibit antipsychotic and analgesic activity in mice.
The benzimidazole and benzimidazolone moiety has been used as a generic substituent in the preparation of a variety of structurally different classes of compounds that exhibit activity on the CNS systems. Examples can be found in Belgium Patent Application BE 904,945, which was published on Dec. 18, 1986, U.S. Pat. No. 4,954,503, which issued on Dec. 31, 1991, and European Patent Application EP 200,322, which was published on Feb. 28, 1990. heteroaryl)-piperazin-1-yl!-3-(2-propyl-benzoimidazol-1-yl)-propan-2-ol; heteroaryl)-piperazin-1-yl!-2-hydroxy-propyl}-1,3-dihydro-benzoimidazol-2- heteroaryl)-piperazin-1-yl!-propyl!-1H-benzoimidazole derivatives that posses central dopaminergic activity. These compounds have a preference for D4-dopamine receptor.
SUMMARY OF THE INVENTION
This invention relates to compounds of the formula ##STR2## wherein each of the dotted lines represents an optional double bond;
X is carbon or nitrogen;
R.sup.1 (C.sub.1 -C.sub.4)alkyl is benzyl, aryl selected from phenyl, indanyl and naphthyl, or heteroaryl selected from pyridyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, quinolyl and imidazolyl, wherein each of the foregoing aryl, heteroaryl and (C.sub.1 -C.sub.4)alkyl groups, and the phenyl moiety of the benzyl group, may optionally be substituted with one or more substituents, preferably with from zero to two substituents, independently selected from halo (e.g., chloro, fluoro, bromo or iodo), (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, cyano, --C(.dbd.O)R.sup.8, aryl and heteroaryl, wherein said aryl is selected from phenyl, indanyl and naphthyl and said heteroaryl is selected from pyridyl, thienyl, furyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl
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Faraci William S.
Fliri Anton F. J.
O'Neill Brian T.
Sanner Mark A.
Zorn Stevin H.
Ginsburg Paul H.
Ngo Tamthom T.
Pfizer Inc.
Richardson Peter C.
Shah Mukund J.
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