Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-12-21
1997-04-08
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514491, C07D26702, C07D28102, A61K 3155
Patent
active
056188080
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This is a 371 of PCT/US93/03389filed Apr. 14, 1993.
The present invention relates to novel substituted benzothiazepines and benzoxazepines, 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 cholecystokinin (CCK) 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)). 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 )). U.S. patent application 825,677, filed Jan. 27, 1992, refers to substituted hexahydroazepinones and tetrahydrobenzazepinones that are selective CCK-B receptor antagonists.
SUMMARY OF THE INVENTION
The present invention relates to compounds of the formula ##STR2## wherein X is oxygen, sulfur, sulfoxide or sulfone; ##STR3## R.sup.2 is phenyl optionally substituted with one or more substituents, preferably one or two substituents, independently selected from (C.sub.1 -C.sub.6)alkyl, nitro, amino, (C.sub.1 -C.sub.6)alkylamino, di-(C.sub.1 -C.sub.6)alkylamino, halo, hydroxy, CO.sub.2 H, CO.sub.2 (C.sub.1 -C.sub.6)alkyl, tetrazolyl, SO.sub.3 H, SO.sub.2 NH.sub.2, SO.sub.2 NH(C.sub.1 -C.sub.6)alkylamino, SO.sub.2 N-di-(C.sub.1 -C.sub.6)alkylamino and a group of the formula ##STR4## R.sup.3 and R.sup.5 are independently selected from (C.sub.1 -C.sub.6)alkyl, 1-adamantyl and 2-adamantyl; atoms and one nitrogen atom, wherein the nitrogen atom is the point of attachment, one of the carbon atoms may optionally be replaced by an oxygen or nitrogen atom, and one or more of said carbon atoms may optionally be substituted with one or two substituents independently selected from cyano and (C.sub.1 -C.sub.6)alkyl;
Examples of possible R.sup.6 groups are the groups having the formula ##STR5## wherein Z is NH or CH.sub.2 and R.sup.10, R.sup.11, R.sup.12 and R.sup.13 are independently selected from hydrogen and (C.sub.1 -C.sub.3)alkyl.
The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which 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, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combination
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Fuller Jr. Grover F.
Ginsburg Paul H.
Pfizer Inc.
Richardson Peter C.
Shah Mukund J.
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