Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-01-18
1997-04-08
Bond, Robert T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514221, 540523, 540524, 540527, A61K 3155, C07D22312
Patent
active
056188110
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel azepinones containing acid surrogates, pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment and prevention of central nervous system and gastrointestinal disorders. The pharmaceutically active compounds of this invention are selective CCK-B receptor antagonists.
Cholecystokinin (CCK) is a 33-amino acid peptide originally discovered and characterized in 1971. (See Mutt et al., Biochem. J., 125, 57 (1971)). It carries out its biological responses by binding to its two receptor types: CCK-A and CCK-B. The CCK-A receptor is located primarily in the gallbladder and pancreas, and mediates CCK-induced enzyme secretion and gallbladder contraction during a meal. The CCK-B receptor is located in the stomach, where it is involved in acid secretion, and in the brain, where it mediates pain and anxiety responses.
A number of potent and selective non-peptide antagonists for these two receptors are known (See M. G. Bock, Drugs of the Future, 16 (7), 631-640 (1991) and R. M. Freidinger, Med. Res. Rev., 9, 271-290 (1989)). Merck's L-364,718 (devazepide) is a selective CCK-A antagonist. (See O'Neill et al., Brain Res., 534, 287-290 (1990)). This compound, however, has proven not to be clinically useful. Merck's benzodiazepine L-365,260 is a selective CCK-B antagonist that was found to have an analgesic effect on squirrel monkeys. (See O'Neill et al., Brain Res., 534, 287-290 (1990)). Parke-Davis' CI-988 is a selective CCK-B antagonist that was found to reverse the pentagastrin-induced anxiogenic response in rats. (See Singh et al., Proc. Nat'l. Acad. Sci., U.S., 88, 1130-33 (1991)).
Other selective CCK-B antagonists are referred to in U.S. patent application 07/825,677, which was filed on Jan. 27, 1992 and PCT patent application PCT/US 92/10720, which was filed in the U.S. Receiving Office on Dec. 16, 1992.
The present invention relates to compounds of the formula ##STR2## wherein R.sup.1 is (C.sub.1 -C.sub.10)alkyl; R.sup.2 is phenyl or (C.sub.1 -C.sub.10)alkyl, each of which may be substituted by Y.sup.1 ; hydrogen, (C.sub.1 -C.sub.10)alkyl and phenyl, or may be taken together with the two carbons to which they are attached to form a phenyl which may be substituted by Y.sup.2 ; ##STR3## wherein W is selected from ##STR4## --SO.sub.2 (C.sub.1 -C.sub.8)alkyl, --SO.sub.2 NH(C.sub.1 -C.sub.8)alkyl, --SO.sub.2 CF.sub.3, ##STR5## --SO.sub.2 (phenyl), --SO.sub.2 (benzyl), --SO.sub.2 NH(phenyl), --SO.sub.2 NH(heteroaryl) and --SO.sub.2 (heteroaryl), wherein said heteroaryl is a 5 to 7 membered saturated or unsaturated hydrocarbon ring containing one to four heteroatoms selected from oxygen, nitrogen and sulfur and wherein the phenyl and heteroaryl moieties of W may optionally be substituted with one or two substituents independently selected from (C.sub.1 -C.sub.6)alkyl optionally substituted with from one to three fluorine atoms, phenyl, halo, (C.sub.1 -C.sub.6)alkoxy optionally substituted with from one to three fluorine atoms, ##STR6## --SO.sub.2, --SO.sub.2 NH.sub.2, --SO.sub.2 NH(C.sub.1 -C.sub.6)alkyl, ##STR7## cyano and --S(C.sub.1 -C.sub.6)alkyl; and Y.sup.1 and Y.sup.2 are independently selected from the group consisting of hydrogen, thienyl, pyridyl, furyl, and pyrimidyl, halo, (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, nitro, cyano, amino, --NH(C.sub.1 -C.sub.6)alkyl, --N[(C.sub.1 -C.sub.8)alkyl].sub.2, --S--(C.sub.1 -C.sub.8)alkyl, --SO--(C.sub.1 -C.sub.8)alkyl, --SO.sub.2 --(C.sub.1 -C.sub.8)alkyl, ##STR8## and phenyl, wherein said phenyl may optionally be substituted with one or two substituents independently selected from halo, (C.sub.1 -C.sub.6))alkyl, (C.sub.1 -C.sub.6)alkoxy, nitro, cyano, amino and trifluoromethyl;
Preferred compounds of formula I include those wherein R.sup.2 is phenyl, isopropyl or cyclohexyl.
Preferred compounds of formula I include those wherein R.sup.3 is hydrogen and R.sup.
Bond Robert T.
Ginsburg P. H.
Pfizer Inc.
Richardson P. C.
Zielinski B. C.
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