Patent ID: 6329394
Filing Date: 2001-12-11
Classification: A61K,A61P,Y10S

Abstract:
A pharmaceutical composition for the treatment of emesis, comprising:an effective amount of an NK.sub.1 receptor antagonist of formula J, N, S or G: ##STR26##whereinR.sup.1 is aryl selected from the group consisting of indanyl, phenyl and naphthyl; heteroaryl selected from the group consisting of thienyl, furyl, pyridyl and quinolyl; or cycloalkyl having 3 to 7 carbon atoms, wherein one of said carbon atoms may optionally be replaced by nitrogen, 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, said substituents being independently selected from the group consisting of chloro, fluoro, bromo, iodo, nitro, (C.sub.1 -C.sub.10)alkyl optionally substituted with from one to three fluoro groups, (C.sub.1 -C.sub.10)alkoxy optionally substituted with from one to three fluoro groups, amino, (C.sub.1 -C.sub.10)alkyl-S--, (C.sub.1 -C.sub.10)alkyl-S(O)--, (C.sub.1 -C.sub.10)alkyl-SO.sub.2 --, phenyl, phenoxy, (C.sub.1 -C.sub.10)alkyl-SO.sub.2 NH--, (C.sub.1 -C.sub.10)alkyl-SO.sub.2 NH--(C.sub.1 -C.sub.10)alkyl-, (C.sub.1 -C.sub.10)alkylamino-di(C.sub.1 -C.sub.10)alkyl-, cyano, hydroxy, cycloalkoxy having 3 to 7 carbon atoms, (C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)dialkylamino, HC(O)NH-- and (C.sub.1 -C.sub.10)alkyl-C(O)--NH--, wherein the nitrogen atoms of said amino and (C.sub.1 -C.sub.6)alkylamino groups may optionally be protected with an appropriate protecting group; andR.sup.2 is thienyl, benzhydryl, naphthyl or phenyl optionally substituted with from one to three substituents independently selected from the group consisting of chloro, bromo, fluoro, iodo, cycloalkoxy having 3 to 7 carbon atoms, (C.sub.1 -C.sub.10)alkyl optionally substituted with from one to three fluoro groups, and (C.sub.1 -C.sub.10)alkoxy optionally substituted with from one to three fluoro groups; ##STR27##whereinX.sup.1 is hydrogen, (C.sub.1 -C.sub.10)alkoxy optionally substituted with from one to three fluorine atoms or (C.sub.1 -C.sub.10)alkyl optionally substituted with from one to three fluorine atoms;X.sup.2 and X.sup.3 are independently selected from the group consisting of hydrogen, halo, nitro, (C.sub.1 -C.sub.10)alkyl optionally substituted with from one to three fluorine atoms, (C.sub.1 -C.sub.10)alkoxy optionally substituted with from one to three fluorine atoms, trifluoromethyl, hydroxy, phenyl, cyano, amino, C.sub.1 -C.sub.6)-alkylamino, di-(C.sub.1 -C.sub.6)alkylamino, --C(O)--NH--(C.sub.1 -C.sub.6)-alkyl, (C.sub.1 -C.sub.6)alkyl-C(O)--NH--C.sub.1 -C.sub.6)alkyl, hydroxy, (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkyoxy(C.sub.1 -C.sub.4)alkyl, --NH--C(O)H and --NHC(O)--(C.sub.1 -C.sub.6)alkyl; andQ is a group of the formula ##STR28##whereinR.sup.1 is a radical selected from the group consisting of furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl optionally substituted with one or two substituents independently selected from the group consisting of halo, (C.sub.1 -C.sub.10)alkyl optionally substituted with from one to three fluorine atoms, (C.sub.1 -C.sub.10)alkoxy optionally substituted with from one to three fluorine atoms, carboxy, benzyloxycarbonyl and (C.sub.1 -C.sub.3)alkoxy-carbonyl;R.sup.13 is selected from the group consisting of (C.sub.3 -C.sub.4) branched alkyl, (C.sub.5 -C.sub.6) branched alkenyl, (C.sub.5 -C.sub.7)cycloalkyl, and the radicals named in the definition of R.sup.1 ;R.sup.2 is hydrogen or (C.sub.1 -C.sub.6)alkyl;R.sup.3 is phenyl, biphenyl, naphthyl, pyridyl, benzhydryl, thienyl or furyl, and R.sup.3 may optionally be substituted with from one to three substituents independently selected from the group consisting of halo, (C.sub.1 -C.sub.10)alkyl optionally substituted with from one to three fluorine atoms and (C.sub.1 -C.sub.10)alkoxy optionally substituted with from one to three fluorine atoms;Y is (CH.sub.2).sub.l wherein l is an integer from one to three or Y is a group of the formula ##STR29##Z is oxygen, sulfur, amino, (C.sub.1 -C.sub.3)alkylamino or (CH.sub.2).sub.n wherein n is zero, one or two;o is two or three;p is zero or one;R.sup.4 is furyl, thienyl, pyridyl, indolyl, biphenyl, or phenyl optionally substituted with one or two substituents independently selected from the group consisting of halo, (C.sub.1 -C.sub.10)alkyl optionally substituted with from one to three fluorine atoms, (C.sub.1 -C.sub.10)alkoxy optionally substituted with from one to three fluorine atoms, carboxy, (C.sub.1 -C.sub.3)alkoxycarbonyl and benzyloxycarbonyl;R.sup.5 is thienyl, biphenyl or phenyl optionally substituted with one or two substituents independently selected from the group consisting of halo, (C.sub.1 -C.sub.10)alkyl optionally substituted with from one to three fluorine atoms and (C.sub.1 -C.sub.10)alkoxy optionally substituted with from one to three fluorine atoms;each of the two dashed lines in formula (N) and the dashed line in formula (II) represents an optional double bond that may optionally exist when Q is a group of the formula (II);X is (CH.sub.2).sub.q wherein q is an integer from 1 to 6, and wherein any one of the carbon-carbon single bonds in said (CH.sub.2).sub.q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH.sub.2).sub.q may optionally be substituted with R.sup.8, and wherein any one of the carbon atoms of said (CH.sub.2).sub.q may be substituted with R.sup.9 ;m is an integer from 0 to 8, and 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 a carbon-carbon triple bond, and any one of the carbon atoms of (CH.sub.2).sub.m may optionally be substituted with R.sup.11 ;R.sup.6 is a radical selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6) straight or branched alkyl, (C.sub.3 -C.sub.7) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from the group consisting of biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from the group consisting of thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl(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 the group consisting of halo, nitro, (C.sub.1 -C.sub.10)alkyl optionally substituted with from one to three fluorine atoms, (C.sub.1 -C.sub.10)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--C(O)--, (C.sub.1 -C.sub.6)alkyl-O--C(O)--C--(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, --C(O)NH--(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; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;R.sup.7 is hydrogen, phenyl or (C.sub.1 -C.sub.6)alkyl;or R.sup.6 and R.sup.7, together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;R.sup.8 and R.sup.9 are each independently selected from the group consisting of hydrogen, hydroxy, halo, amino, oxo (.dbd.O), nitrile, 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, 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)--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-, and the radicals set forth in the definition of R.sup.6 ;R.sup.10 is NHCR.sup.12, NHCH.sub.2 R.sup.12, NHSO.sub.2 R.sup.12, or one of the radicals set forth in any of the definitions of R.sup.6, R.sup.8 and R.sup.9 ;R.sup.11 is oximino (.dbd.NOH) or one of the radicals set forth in any of the definitions of R.sup.6, R.sup.8 and R.sup.9 ; andR.sup.12 is (C.sub.1 -C.sub.6)alkyl, hydrogen, phenyl(C.sub.1 -C.sub.6)alkyl or phenyl optionally substituted with (C.sub.1 -C.sub.6)alkyl, andwith the provisos that(a) when m is O, R.sup.11 is absent;(b) neither R.sup.8, R.sup.9, R.sup.10 nor R.sup.11 can form, together with the carbon to which it is attached, a ring with R.sup.7 ;(c) when Q is a group of the formula (VIII), R.sup.8 and R.sup.9 cannot be attached to the same carbon atom;(d) when R.sup.8 and R.sup.9 are attached to the same carbon atom, then either each of R.sup.8 and R.sup.9 is independently selected from hydrogen, fluoro, (C.sub.1 -C.sub.6)alkyl, hydroxy-(C.sub.1 -C.sub.6)alkyl and (C.sub.1 -C.sub.6)alkoxy-(C.sub.1 -C.sub.6)alkyl, R.sup.8 and R.sup.9, 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;(e) the nitrogen of formula (N) cannot be double bonded to both Q and the substituted benzyl group to which it is attached;(f) when Q is a group of the formula (VII) and q is 2 and either R.sup.8 or R.sup.9 is 5-hydroxy-(C.sub.1 -C.sub.6)alkyl or 5-(C.sub.1 -C.sub.6)alkoxy-(C.sub.1 -C.sub.6)alkyl, then the other of R.sup.8 or R.sup.9 is either 5-(C.sub.1 -C.sub.6)alkyl or hydrogen;(g) when Q is a group of the formula (VII) and q is 2, then neither R.sup.8 or R.sup.9 is 4-hydroxy-(C.sub.1 -C.sub.6)alkyl or 4-(C.sub.1 -C.sub.6)alkoxy-(C.sub.1 -C.sub.6)alkyl; and(h) when neither X.sup.1, X.sup.2 nor X.sup.3 is a fluorinated alkoxy group, at least one of R.sup.1, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and R.sup.13 is an aryl group substituted with a fluorinated alkoxy group;and pharmaceutically acceptable acid addition and base salts of compounds of the formula (N); ##STR30##whereinY is (CH.sub.2).sub.n wherein n is an integer from 1 to 6, 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 be substituted with R.sup.7 ;m is an integer from 0 to 8, and 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 a carbon-carbon triple bond, and any one of the carbon atoms of said (CH.sub.2).sub.m may be optionally substituted with R.sup.8 ;R.sup.1 is hydrogen or (C.sub.1 -C.sub.8)alkyl optionally substituted with hydroxy, alkoxy or fluoro;R.sup.2 is a radical selected from the group consisting of hydrogen, (C.sub.1 -C.sub.6) straight or branched alkyl, (C.sub.3 -C.sub.7)cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from the group consisting of phenyl and naphthyl; heteroaryl selected from the group consisting of indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl(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, --C(O)NH--(C.sub.1 -C.sub.6)alkyl-, (C.sub.1 -C.sub.6)alkyl-C(O)--NH--(C.sub.1 -C.sub.6)alkyl, --NH(O)CH and --NH(O)C-(C.sub.1 -C.sub.6) alkyl; and wherein one of the phenyl moieties of said benzhydryl may optionally be replaced by naphthyl, thienyl, furyl or pyridyl;R.sup.5 is hydrogen, phenyl or (C.sub.1 -C.sub.6)alkyl;or R.sup.2 and R.sup.5, together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur;R.sup.3 is aryl selected from the group consisting of phenyl and naphthyl; heteroaryl selected from the group consisting of indanyl, thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; and cycloalkyl having 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by nitrogen, 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 the group consisting of halo, nitro, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, trifluoromethyl, phenyl, amino, (C.sub.1 -C.sub.6)alkylamino, --C(O)NH--(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;R.sup.4 and R.sup.7 are each independently selected from the group consisting of hydrogen, hydroxy, halo, amino, oxo (.dbd.O), nitrile, (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)--O, (C.sub.1 -C.sub.6)alkyl-C(O)-(C.sub.1 -C.sub.6)alkyl-O, 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)alkyl-C(O)--, (C.sub.1 -C.sub.6)alkyl-C(O)-(C.sub.1 -C.sub.6)alkyl- and the 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 of 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 provisos that(a) when m is O, R.sup.8 is absent;(b) neither R.sup.4, R.sup.6, R.sup.7 nor R.sup.8 can form, together with the carbon to which it is attached, a ring with R.sup.5 ;(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 hydrogen, fluoro or (C.sub.1 -C.sub.6)alkyl, or R.sup.1 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;(d) when n is 2 and either R.sup.4 or R.sup.7 is 5-hydroxy(C.sub.1 -C.sub.6)alkyl or 5-(C.sub.1 -C.sub.6)alkoxy-C.sub.1 -C.sub.6)alkyl, then the other of R.sup.4 and R.sup.7 is hydrogen;(e) when n is 2, neither R.sup.4 nor R.sup.7 is 4-hydroxy(C.sub.1 -C.sub.6)alkyl or 4-(C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl; and(f) in all compounds of the formula (S), either R.sup.3 is aryl substituted with at least one phenyl group, or one or both of R.sup.4 and R.sup.7 is hydroxy-(C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy(C.sub.1 -C.sub.6)alkyl; ##STR31##whereinn is 1, 2 or 3 and where any carbon atom of (CH.sub.2).sub.n may be substituted by R.sup.4 and/or R.sup.5 ;X represents O or S;R.sup.1 represents phenyl optionally substituted by 1, 2 or 3 groups selected from the group consisting of C.sub.1-6 alkyl, C.sub.2-6 alkenyl; C.sub.2-6 alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, --OR.sup.a, SR.sup.a, SOR.sup.a, SO.sub.2 R.sup.a, --NR.sup.a R.sup.b, --NR.sup.a COR.sup.b, --NR.sup.a CO.sub.2 R.sup.b, CO.sub.2 R.sup.a, or --CONR.sup.a R.sup.b ;R.sup.2 represents aryl selected from the group consisting of phenyl and naphthyl; heteroaryl selected from the group consisting of indazolyl, thienyl, furyl, pyridyl, thiazolyl, tetrazolyl and quinolyl; benzhydryl; or benzyl; wherein each aryl or heteroaryl moiety may be substituted by C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo or trifluoromethyl;R.sup.4 and R.sup.5 each independently represent H, halo, CH.sub.2 OR.sup.9, C.sub.1-6 alkyl, oxo, CO.sub.2 R.sup.10 or CONR.sup.10 R.sup.11 ;R.sup.8 represents H, COR.sup.9, CO.sub.2 R.sup.10, COCONR.sup.10 R.sup.11, COCO.sub.2 R.sup.10 or C.sub.1-6 alkyl optionally substituted by a group selected from the group consisting of CO.sub.2 R.sup.10, CONR.sup.10 R.sup.11, hydroxy, cyano, COR.sup.9, NR.sup.10 R.sup.11, C(NOH)NR.sup.10 R.sup.11, CONHphenyl-(C.sub.1-4 alkyl), COCO.sub.2 R.sup.10, COCONR.sup.10 R.sup.11 and phenyl optionally substituted by one or more substituents selected from the group consisting of C.sub.1-6 alkyl, C.sub.1-6 alkoxy, halo and trifluoromethyl;R.sup.a and R.sup.b each independently represent H, C.sub.1-6 alkyl, phenyl or trifluoromethyl;R.sup.9 represents H, C.sub.1-6 alkyl or phenyl; andR.sup.10 and R.sup.11 each independently represent H or C.sub.1-6 alkyl;in combination with an effective amount of a 5HT.sub.3 antagonist which is selected from the group consisting of ondansetron, granisetron and metoclopramide.