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Details for Patent: 5,360,820

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Details for Patent: 5,360,820

Title: Medical use for tachykinin antagonists
Abstract:The present invention relates to the use of tachykinin antagonists, including substance P antagonists and other neurokinin antagonists, in the treatment of emesis. Also described are novel tachykinin antagonists of formula (I), processes for their preparation, pharmaceutical compositions containing them and their medical use. ##STR1## wherein R represents the ring A ##STR2## or 2-pyridinyl or 2-pyridinyl-N-oxide; R.sup.1 is selected from halogen atoms and C.sub.1-4 alkyl, C.sub.1-4 alkoxy, trifluoromethyl, and S(O).sub.n C.sub.1-4 alkyl groups; R.sup.2 and R.sup.3, which may be the same or different, each independently are selected from hydrogen and halogen atoms and C.sub.1-4 alkyl, C.sub.1-4 alkoxy, trifluoromethyl and cyano groups; n represents zero, 1 or 2; and pharmaceutically acceptable salts and solvates thereof.
Inventor(s): Hagan; Russell M. (Ware, GB3), Bunce; Keith T. (Ware, GB3), Naylor; Alan (Ware, GB3), Ladlow; Mark (Ware, GB3), McElroy; Andrew B. (Research Triangle Park, NC), Whittington; Andrew R. (Greenford, GB3), Coomber; Barry A. (Greenford, GB3)
Assignee: Glaxo Group Limited (London, GB)
Filing Date:Sep 18, 1992
Application Number:07/946,635
Claims:1. A method for the treatment of a mammal, suffering from emesis, wherein said emesis is induced by cancer chemotherapeutic agents, radiation sickness, radiation therapy, poisons, toxins, post-operative sickness or opioid analgesics, comprising administration of an effective amount of an NK.sub.1 receptor antagonist of formula H, V' or W: ##STR31## wherein in the antagonist of formula H: x is an integer from zero to four;

y is an integer from zero to four;

z is an integer from one to six;

the ring containing (CH.sub.2).sub.z may contain from zero to three double bonds, and one of the carbons of (CH.sub.2).sub.z may optionally be replaced by oxygen, sulfur or nitrogen;

m is an integer from zero to twelve, and any one of the carbon-carbon single bonds of (CH.sub.2).sub.m may optionally be replaced by a carbon-carbon double or triple bond and any one of the carbon atoms of (CH.sub.2).sub.m may optionally be substituted with R.sup.8 ;

R.sup.1 is hydrogen or (C.sub.1-6)alkyl optionally substituted with hydroxy, alkoxy or fluoro;

R.sup.2 is a radical selected from the group consisting of hydrogen, (C.sub.1-6) straight or branched alkyl, (C.sub.3-7)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, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl(C.sub.2-6 )alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl(C.sub.2-6)alkyl and benzhydryl groups may optionally be substituted with one or more substituents independently selected from the group consisting of halo, nitro, (C.sub.1-6)alkoxy, trifluoromethyl, amino, (C.sub.1-6)alkylamino, (C.sub.1-6)alkyl-O--C(O), (C.sub.1-6)alkyl-O--C(O)(C.sub.1-6)alkyl-CO.sub.2 --, (C.sub.1-6)alkyl-C(O)-(C.sub.1-6)alkyl-O--, (C.sub.1-6)alkyl-C(O)--, (C.sub.1-6)alkyl-C(O)-(C.sub.1-6)alkyl-, di-(C.sub.1-6)alkylamino, --CONH-(C.sub.1-6)alkyl, (C.sub.1-6)alkyl-CONH-(C.sub.1-6)alkyl, --NHC(O)H and --NHC(O)(C.sub.1-6)alkyl;

R.sup.5 is hydrogen or (C.sub.1-6)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; or cycloalkyl having from three to seven 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.3-7)cycloalkyl may optionally be substituted with one or two substituents, said substituents being independently selected from the group consisting of halo, nitro, (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, trifluoromethyl, amino, phenyl, (C.sub.1-6)alkylamino, --CONH-(C.sub.1-6)alkyl, (C.sub.1-6)alkyl-CONH-(C.sub.1-6)alkyl, --NHC(O)H and --NHC(O)-(C.sub.1-6)alkyl;

R.sup.4 may be attached to any atom of the nitrogen containing ring having an available bonding site and R.sup.7 may be attached to any atom of the (CH.sub.2).sub.z containing ring having an available bonding site;

R.sup.4, R.sup.6, R.sup.7 and R.sup.8 are each independently selected from the group consisting of hydrogen, hydroxy, halo, amino, carboxy, carboxyalkyl, (C.sub.1-6)alkylamino, di-(C.sub.1-6)alkylamino, (C.sub.1-6)alkoxy, (C.sub.1-6)alkyl-O--C(O)--, (C.sub.1-6)alkyl-O--C(O)-(C.sub.1-6)alkyl, (C.sub.1-6)alkyl-CO.sub.2, (C.sub.1-6)alkyl-C(O)-(C.sub.1-6)alkyl-O-(C.sub.1-6)alkyl-C(O)--, (C.sub.1-6)alkyl-C(O)(C.sub.1-6)alkyl, and the radicals set forth in the definition of R.sup.2, with the proviso that (a) when m is 0, 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, and (c) R.sup.4 and R.sup.7 can not be attached to the same carbon atom;

or a pharmaceutically acceptable salt thereof; ##STR32## wherein in the antagonist of formula V': Q is the residue of an optionally substituted azabicyclic ring system;

X represents oxa or thia;

Y represents H or hydroxy;

R.sup.1 and R.sup.2 independently represent phenyl or thienyl, either of which groups may be optionally substituted by halo or trifluoromethyl;

R.sup.3, R.sup.4 and R.sup.5 independently represent H, (C.sub.1-6)alkyl, (C.sub.2-6)alkenyl, (C.sub.2-6)alkynyl, halo, cyano, nitro, trifluoromethyl, trimethylsilyl, -OR.sup.a, SCH.sub.3, SOCH.sub.3, SO.sub.2 CH.sub.3, --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 ; and

R.sup.a and R.sup.b independently represent H, (C.sub.1-6)alkyl, phenyl or trifluoromethyl;

or a salt or prodrug thereof; ##STR33## ##STR34## wherein in the antagonist of formula W: 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 (CH.sub.2).sub.n may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of (CH.sub.2).sub.n may optionally be substituted with R.sup.4 and wherein any one of the carbon atoms of (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 (CH.sub.2).sub.m may optionally be substituted with R.sup.8 ;

R.sup.1 is hydrogen or (C.sub.1-8)alkyl optionally substituted with hydroxy, (C.sub.1-4)alkoxy or fluoro;

R.sup.2 is a radical selected from the group consisting of hydrogen, (C.sub.1-6) straight or branched alkyl, (C.sub.3-7)cycloalkyl wherein one of the CH.sub.2 groups in said cycloalkyl may optionally be replaced by NH, oxygen or sulfur; aryl selected from 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; phenyl-(C.sub.2-6)-alkyl, benzhydryl and benzyl, wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C.sub.2-6)-alkyl and benzhydryl may optionally be substituted with one or more substituents independently selected from the group consisting of halo, nitro, (C.sub.1-6)alkyl, (C.sub.1-6)alkoxy, trifluoromethyl, amino, (C.sub.1-6)alkylamino, (C.sub.1-6)alkyl-O--C(O)--, (C.sub.1-6)alkyl-O--C(O)-(C.sub.1-6)alkyl, (C.sub.1-6)alkyl-C(O)--O--, (C.sub.1-6)alkyl-C(O)-(C.sub.1-6)alkyl-O--, (C.sub.1-6)alkyl-C(O)--, (C.sub.1-6)alkyl-C(O)-(C.sub.1-6)alkyl-, di-(C.sub.1-6)alkylamino, --CONH-(C.sub.1-6)alkyl, (C.sub.1-6)alkyl-CONH-(C.sub.1-6)alkyl, NHC(O)H and --NHC(O)-(C.sub.1-6)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.1-6)alkyl; or

R.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 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 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.3-7) 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.1-6)alkyl, (C.sub.1-6)alkoxy, trifluoromethyl, amino, (C.sub.1-6)alkylamino, --CONH-(C.sub.1-6)alkyl, (C.sub.1-6)alkyl-C(O)--NH-(C.sub.1-6)alkyl, --NHC(O)H and --NHC(O)-(C.sub.1-6)alkyl; and

R.sup.4 and R.sup.7 each independently selected from the group consisting of hydroxy, hydrogen, halo, amino, oxo, cyano, methylene, hydroxymethyl, halomethyl, (C.sub.1-6)alkylamino, di(C.sub.1-6)alkylamino, (C.sub.1-6)alkoxy, (C.sub.1-6)alkyl-O--C(O)--, (C.sub.1-6)alkyl-O--C(O)-(C.sub.1-6)alkyl, (C.sub.1-6)alkyl-C(O), (C.sub.1-6)alkyl-C(O)-(C.sub.1-6)alkyl-O, (C.sub.1-6)alkyl-C(O), (C.sub.1-6)alkyl-C(O)-(C.sub.1-6)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.1-6)alkyl, hydrogen, phenyl or phenyl(C.sub.1-6)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 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 the group consisting of hydrogen, fluoro and (C.sub.1-6)alkyl, or R.sup.4 and R.sup.7, together with the carbon to which they are attached, form a (C.sub.3-6) saturated carbocyclic ring that forms a spiro compound with the nitrogen containing ring to which they are attached;

or a pharmaceutically acceptable acid addition salt thereof.

2. A method according to claim 1 wherein said emesis is induced by a cancer chemotherapeutic agent.

3. A method according to claim 2 wherein said cancer chematherapeutic agent is selected from cyclophosphamide, carmustine, lomustine, chloroambucil, dactinomycin, doxorubicin, mitomycin-C, bleomycin, cytarabine, methotrexate, 5-fluorouracil, etoposide, vinblastine, vincristine, cisplatin, dacarbazine, procarbazine, hydroxyurea, and combinations thereof.

4. A method according to claim 3 wherein said emesis is induced by cisplatin.

5. A method according to claim 3 wherein said emesis is induced by cyclophosphamide.

6. A method according to claim 1 wherein said emesis is induced by morphine, ipecacuanha or copper sulphate.

7. A method according to claim 1 wherein the NK, receptor antagonist is (2S,3S)-3-(2-methoxybenzylamino)-2-phenyl piperidine or a pharmaceutically acceptable acid addition salt thereof.

8. A method according to claim 1 wherein the NK.sub.1 receptor antagonist is a compound of formula H or V': ##STR35## or a pharmaceutically acceptable acid addition salt thereof.

9. A method according to claim 1 wherein the NK.sub.1 receptor antagonist is a compound of formula W ##STR36## or a pharmaceutically acceptable acid addition salt thereof.
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