Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-06-20
1998-12-29
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540556, 540567, 540477, 544282, 544477, 546121, 514300, C07D47108, C07D48708, A61K 31435, A61K 31495
Patent
active
058542396
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
The present invention relates to diazabicyclic compounds, pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment and prevention of inflammatory and central nervous system disorders, as well as several other disorders. The pharmaceutically active compounds of this invention are substance P receptor antagonists.
Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being named because of their prompt stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmacologically active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence that is Illustrated by D. F. Veber et al. in U.S. Pat. No. 4,680,283. The wide involvement of substance P and other tachykinins in the pathophysiology of numerous diseases has been amply demonstrated in the art. For instance, substance P has been shown to be involved in the transmission of pain or migraine (see B. E. B. Sandberg et al., Journal of Medicinal Chemistry, 25, 1009 (1982)), as well as in central nervous system disorders such as anxiety and schizophrenia, in respiratory and inflammatory diseases such as asthma and rheumatoid arthritis, respectively, in rheumatic diseases such as fibrositis, and in gastrointestinal disorders and diseases of the GI tract such as ulcerative colitis and Crohn's disease, etc. (see D. Regoli in "Trends in Cluster Headache," edited by F. Sicuteri et al., Elsevier Scientific Publishers, Amsterdam, pp. 85-95 (1987)).
The following documents relate to compounds that exhibit activity as substance P receptor antagonists: U.S. Pat. No. 5,232,929; U.S. Pat. No. 5,138,060; WO 92/06079, published Apr. 16, 1992; WO 92/15585, published Sep. 17, 1992; WO 93/00330, published Jan. 7, 1993; WO 93/06099, published Apr. 1, 1993.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula ##STR2## or a pharmaceutically acceptable salt thereof wherein R.sup.1 is phenyl, thienyl or benzhydryl wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl and wherein said phenyl, thienyl and benzhydryl may be substituted with one or more substituents independently selected from halo, nitro, (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, amino, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)-alkylamino, (C.sub.1 -C.sub.6)alkyl--O--CO--, (C.sub.1 -C.sub.6)alkyl--CO--O--, (C.sub.1 -C.sub.6)alkyl--CO--, (C.sub.1 -C.sub.6)alkyl--O--, (C.sub.1 -C.sub.6)alkyl--CO--(C.sub.1 -C.sub.6)alkyl-, di-(C.sub.1 -C.sub.6)alkylamino, --CONH--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)-alkyl--CO--NH--(C.sub.1 -C.sub.6)alkyl, --NHCOH and --NHCO--(C.sub.1 -C.sub.6) alkyl;
R.sup.2 is hydrogen or (C.sub.1 -C.sub.6)alkyl, or R.sup.1 and R.sup.2, together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms;
A is phenyl, thienyl, benzothiazolyl or naphthyl wherein said phenyl, thienyl, benzothiazolyl and naphthyl may be substituted with one or more substituents independently selected from halo, nitro, (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, amino, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)-alkylamino, (C.sub.1 -C.sub.6)alkyl--O--CO--, (C.sub.1 -C.sub.6)alkyl--CO--O--, (C.sub.1 -C.sub.6)alkyl--CO--, (C.sub.1 -C.sub.6)alkyl--O--, (C.sub.1 -C.sub.6)alkyl--CO--(C.sub.1 -C.sub.6)alkyl-, di-(C.sub.1 -C.sub.6)alkylamino, --CONH--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)-alkyl--CO--NH--(C.sub.1 -C.sub.6)alkyl, --NHCOH and --NHCO--(C.sub.1 -C.sub.6)alkyl;
n is 0, 1 or2;
m is 0, 1 or 2;
the sum of n and m is
REFERENCES:
patent: 3494923 (1970-02-01), Gubitz et al.
Hirshfeld, A. and Taub, W. Bridged bicyclic compounds, Tetrahedron. vol. 28, pp. 1275-1287, 1972.
Howard Harry R.
Shenk Kevin D.
Creagan B. Timothy
Ginsburg Paul H.
Kifle Bruck
Pfizer Inc.
Richardson Peter C.
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