Patent ID: 6326383
Filing Date: 2001-12-04
Classification: A61K,A61P,C07D,Y10S

Abstract:
A pharmaceutical composition for the treatment of emesis, comprsing:an effective amount of an NK.sub.1 receptor antagonist of formula W: ##STR31##wherein Y is (CH.sub.2).sub.n wherein n is an integer from 1 to 4, and wherein any one of the carbon-carbon single bonds in said (CH.sub.2).sub.n may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH.sub.2).sub.n may optionally be substituted with R.sup.4 and wherein any one of the carbon atoms of said (CH.sub.2).sub.n may optionally be substituted with R.sup.7 ;Z is (CH.sub.2).sub.m wherein m is an integer from 0 to 6, and wherein any one of the carbon-carbon single bonds of (CH.sub.2).sub.m may optionally be replaced by a carbon-carbon double bond or carbon-carbon triple bond, and any one of the carbon atoms of said (CH.sub.2).sub.m may optionally be substituted with R.sup.8 ;R.sup.1 is hydrogen or (C.sub.1 -C.sub.8) alkyl optionally substituted with hydroxy, (C.sub.1 -C.sub.4) alkoxy or fluoro;R.sup.2 is a radical selected from hydrogen, (C.sub.1 -C.sub.6) straight or branched alkyl, (C.sub.3 -C.sub.7) cycloalkyl wherein one of the CH.sub.2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulfur; aryl selected from phenyl and naphthyl; heteroaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isaoxazolyl, triazolyl, tetrazolyl and quinolyl; phenl-(C.sub.2 -C.sub.6)-alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C.sub.2 -C.sub.6)-alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from halo, nitro, (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkoxy, trifluoromethyl, amino, (C.sub.1 -C.sub.6)-alkylamino, (C.sub.1 -C.sub.6) alkyl-O--C(O)--, (C.sub.1 -C.sub.6)alkyl-O--C--(O)--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl-C(O)--O--, (C.sub.1 -C.sub.6)alkyl-C(O)--, (C.sub.1 -C.sub.6)alkyl-O--, (C.sub.1 -C.sub.6)alkyl-C(O)--, (C.sub.1 -C.sub.6)alkyl-C(O)--(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--CONH--(C.sub.1 -C.sub.6)alkyl, NHC(O)H and --NHC(O)--(C.sub.1 -C.sub.6) alkyl; andwherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;R.sub.5 is hydrogen, phenyl or (C.sub.1 -C.sub.6) alkyl; orR.sup.2 and R.sup.5, together with the carbon to which they are attached, form a saturated ring having from 3 to 7 carbon atoms wherein one of the CH.sub.2 groups in said ring may optionally be replaced by oxygen, NH or sulfur;R.sup.3 is aryl selected from phenyl and naphthyl; heteoaryl selected from indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl; tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of the (CH.sub.2) groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulfur;wherein each of said aryl and heteroaryl groups may optionally be substituted with one or more substituents, and said (C.sub.3 -C.sub.7) cycloalkyl may optionally be substituted with one or two substituents, each of said substituents being independently selected from halo, nitro, (C.sub.1 -C.sub.6) alkyl, (C.sub.1 -C.sub.6) alkoxy, trifluoromethyl, amino, (C.sub.1 -C.sub.6) alkylamino, --CONH--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl-C(O)--NH--(C.sub.1 -C.sub.6)alkyl, --NHC(O)H and --NHC(O)--(C.sub.1 -C.sub.6)alkyl; andR.sup.4 and R.sup.7 are each independently selected from hydroxy, hydrogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, (C.sub.1 -C.sub.6)alkylamino, di-(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkoxy, (C.sub.1 -C.sub.6)alkyl-O--C(O)--, (C.sub.1 -C.sub.6)alkyl-O--C(O)--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl-C(O), (C.sub.1 -C.sub.6)alkyl-C--(O)--(C.sub.1 -C.sub.6)alkyl-O, (C.sub.1 -C.sub.6)alkyl-C(O), (C.sub.1 -C.sub.6)alkyl-C(O)--(C.sub.1 -C.sub.6)alkyl--, andthe radicals set forth in the definition of R.sup.2, R.sup.6 is NHC(O)R.sup.9, --NHCH.sub.2 R.sup.9, SO.sub.2 R.sup.9 or one of the radicals set forth in any of the definitions or R.sup.2, R.sup.4 and R.sup.7 ;R.sup.8 is oximino (.dbd.NOH) or one of the radicals set forth in any of the definitions of R.sup.2, R.sup.4 and R.sup.7 ;R.sup.9 is (C.sub.1 -C.sub.6)alkyl, hydrogen, phenyl or phenyl(C.sub.1 -C.sub.6)alkyl; with the proviso that (a) when m is O, R.sup.8 is absent, (b) when R.sup.4, R.sup.6, R.sup.7, or R.sup.8 is as defined in R.sup.2, it cannot form, together with the carbon to which it is attached, a ring with R.sup.5, and (C) when R.sup.4 and R.sup.7 are attached to the same carbon atom, then either each of R.sup.4 and R.sup.7 is independently selected from hydrogen, fluoro and (C.sub.1 -C.sub.6) alkyl, or R.sup.4 and R.sup.7, together with the carbon to which they are attached, form a (C.sub.3 -C.sub.6) saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; and pharmaceutically acceptable acid addition salts thereof,in combination with an effective amount of a 5HT.sub.3 antagonist which is selected from the group consisting of ondansetron, metoclopramide and granisetron.