Methods using a combination of a 3-heteroaryl-2-indolinone and a cyclooxygenase-2 inhibitor for the treatment of neoplasia
AssigneePharmacia Corporation
InventorsJaime L. Masferrer, Julie M. Cherrington, Kathleen M. Leahy, Ben S. Zweifel
Life of this patent
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Abstract
The present invention provides methods and compositions useful for treatment or prevention of neoplasia by administering a combination comprising a 3-heteroaryl-2-indolinone compound and a COX-2 selective inhibitor. Further provided are compositions, pharmaceutical compositions, and kits for treatment and prevention of neoplasia.
Claims74
A method for treating or preventing a neoplasia disorder in a subject in need of such treatment or prevention, said method comprising treating the subject with a therapeutically-effective amount of a combination comprising a 3-heteroaryl-2-indolinone compound or pharmaceutically acceptable salt or prodrug thereof and a cyclooxygenase-2 selective inhibitor or pharmaceutically acceptable salt or prodrug thereof.
A composition for the treatment or prevention of neoplasia comprising a 3-heteroaryl-2-indolinone compound or pharmaceutically acceptable salt or prodrug thereof and a cyclooxygenase-2 selective inhibitor or pharmaceutically acceptable salt or prodrug thereof.
A pharmaceutical composition comprising a 3-heteroaryl-2-indolinone compound or pharmaceutically acceptable salt or prodrug thereof, cyclooxygenase-2 selective inhibitor or pharmaceutically acceptable salt or prodrug thereof;
- and a pharmaceutically-acceptable excipient.
A kit that is suitable for use in the treatment, prevention or inhibition of neoplasia, wherein the kit comprises a first dosage form comprising a 3-heteroaryl-2-indolinone or pharmaceutically acceptable salt or prodrug thereof, and a second dosage form comprising a cyclooxygenase-2 selective inhibitor or pharmaceutically acceptable salt or prodrug thereof, in quantities which comprise a therapeutically effective amount of the combination of the compounds for the treatment or prevention of neoplasia.
A composition for the treatment, prevention or inhibition of neoplasia disorder in a subject in need of such treatment, comprising a cyclooxygenase-2 inhibitor or a pharmaceutically acceptable sale, ester or prodrug thereof in a first amount and a 3-heteroaryl-2-indolinone compound or pharmaceutically acceptable salt or prodrug thereof in a second amount, wherein said first amount together with said second amount comprises a therapeutically effective amount for the treatment, prevention or inhibition of neoplasia disorder in said subject.
A composition for the treatment, prevention or inhibition of neoplasia disorder in a subject in need of such treatment comprising a cyclooxygenase-2 inhibitor or a pharmaceutically acceptable salt, ester or prodrug thereof selected from the group consisting of substituted benzothiopyrans, dihydroquinolines, and dihydronaphthalenes in a first amount and a 3-heteroaryl-2-indolinone compound or pharmaceutically acceptable salt or prodrug therof in a second amount, wherein said first amount together with said second amount comprises a therapeutically effective amount for the treatment, prevention or inhibition of neoplasia disorder in said subject.
A composition for treating neoplasia disorder comprising administering to a subject in need thereof, a cyclooxygenase-2 (COX-2) inhibitor in a first amount and a 3-heteroaryl-2-indolinone compound or pharmaceutically acceptable salt or prodrug therof in a second amount, wherein said first amount together with said second amount is a therapeutically effective amount of said COX-2 inhibitor and said 3-heteroaryl-2-indolinone, and wherein said COX-2 inhibitor is represented by Formula (I):
- 50
- or an isomer, a pharmaceutically acceptable salt, ester, or prodrug thereof;
- wherein:
- G is O, S or NRa;
- Ra is alkyl;
- R1 is H or aryl;
- R2 is carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl or alkoxycarbonyl;
- R3 is haloalkyl, alkyl, aralkyl, cycloalkyl or aryl optionally and independently substituted with one or more radicals selected from alkylthio, nitro and alkylsulfonyl;
- n is an integer which is 1, 2, 3, or 4;
- and
- each R4 is independently H, halo, alkyl, aryl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, mono- or dialkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, hydroxyarylcarbonyl, nitroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, alkylcarbonyl, aryl, or heteroaryl;
- wherein said aryl and heteroaryl radicals are optionally and independently substituted with one or more radicals which are alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy or alkylthio;
- or wherein R4 together with the atoms to which R4 is attached and the remainder of ring E forms a naphthyl radical.
A composition for the treatment, prevention or inhibition of neoplasia disorder in a subject in need of such treatment comprising a cyclooxygenase-2 inhibitor or a pharmaceutically acceptable salt, ester or prodrug thereof selected from the group consisting of tricylic COX-2 inhibitors in a first amount and a 3-heteroaryl-2-indolinone compound or pharmaceutically acceptable salt or prodrug therof in a second amount, wherein said first amount together with said second amount comprises a therapeutically effective amount for the treatment, prevention or inhibition of neoplasia disorder in said subject.
A composition for treating neoplasia disorder comprising administering, to a subject in need thereof, a cyclooxygenase-2 (COX-2) inhibitor in a first amount and a 3-heteroaryl-2-indolinone compound or pharmaceutically acceptable salt or prodrug therof in a second amount, wherein said first amount together with said second amount is a therapeutically effective amount of said COX-2 inhibitor and said 3-heteroaryl-2-indolinone compound or pharmaceutically acceptable salt or prodrug therof, and wherein said COX-2 inhibitor is represented by Formula (11):
- 51
- or an isomer, a pharmaceutically acceptable salt, ester, or prodrug thereof,
- wherein:
- D is a partially unsaturated or saturated heterocyclyl ring or a partially unsaturated or saturated carbocyclic ring;
- R13 is heterocyclyl, cycloalkyl, cycloalkenyl and aryl, wherein R13 is optionally substituted at a substitutable position with one or more radicals which are alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy or alkylthio;
- R14 is methyl or amino;
- and
- R15 is H, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, or N-alkyl-N-arylaminosulfonyl.
A composition for treating neoplasia disorder comprising a cyclooxygenase-2 (COX-2) inhibitor in a first amount and a 3-heteroaryl-2-indolinone compound or pharmaceutically acceptable salt or pro-drug therof in a second amount, wherein said first amount together with said second amount is a therapeutically effective amount of said COX-2 inhibitor and said 3-heteroaryl-2-indolinone compound or pharmaceutically acceptable salt or prodrug therof, and wherein said COX-2 inhibitor is represented by Formula (III):
- 52
- or an isomer, a pharmaceutically acceptable salt, ester, or prodrug thereof,
- wherein:
- R16 is methyl or ethyl;
- R17 is chloro or fluoro;
- R18 is hydrogen or fluoro;
- R19 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy or hydroxy;
- R20 is hydrogen or fluoro;
- and
- R21 is chloro, fluoro, trifluoromethyl or methyl,
- provided that R17, R18, R19 and R20 are not all fluoro when R16 is ethyl and R19 is H.
A composition for treating neoplasia disorder comprising administering, to a subject in need thereof, a cyclooxygenase-2 (COX-2) inhibitor in a first amount and a 3-heteroaryl-2-indolinone compound or pharmaceutically acceptable salt or prodrug therof in a second amount, wherein said first amount together with said second amount is a therapeutically effective amount of said COX-2 inhibitor and said 3-heteroaryl-2-indolinone compound or pharmaceutically acceptable salt or prodrug therof, and wherein said COX-2 inhibitor is represented by Formula (IV):
- 53
- or an isomer, a pharmaceutically acceptable salt, ester, or prodrug thereof,
- wherein:
- X is O or S;
- J is a carbocycle or a heterocycle;
- R22 is NHSO2CH3 or F;
- R23 is H, NO2, or F;
- and
- R24 is H, NHSO2CH3, or (SO2CH3)C6H4.
A composition for treating neoplasia disorder comprising administering, to a subject in need thereof, a cyclooxygenase-2 (COX-2) inhibitor in a first amount and a 3-heteroaryl-2-indolinone compound or pharmaceutically acceptable salt or prodrug therof in a second amount, wherein said first amount together with said second amount is a therapeutically effective amount of said COX-2 inhibitor and said 3-heteroaryl-2-indolinone compound or pharmaceutically acceptable salt or pro-drug therof, and wherein said COX-2 inhibitor is represented by Formula (V):
- 54
- or an isomer, pharmaceutically acceptable salt, ester, or prodrug thereof, wherein:
- T and M independently are phenyl, naphthyl, a radical derived from a heterocycle comprising 5 to 6 members and possessing from 1 to 4 heteroatoms, or a radical derived from a saturated hydrocarbon ring having from 3 to 7 carbon atoms;
- Q1, Q2, L1 or L2 are independently hydrogen, halogen, lower alkyl having from 1 to 6 carbon atoms, trifluoromethyl, or lower methoxy having from 1 to 6 carbon atoms;
- and
- at least one of Q1, Q2, L1 or L2 is in the para position and is —S(O)n—R, wherein n is 0, 1, or 2 and R is a lower alkyl radical having 1 to 6 carbon atoms, a lower haloalkyl radical having from 1 to 6 carbon atoms, or an —SO2NH2;
- or,
- Q1 and Q2 are methylenedioxy;
- or
- L1 and L2 are methylenedioxy;
- and
- R25, R26, R27, and R28 are independently hydrogen, halogen, lower alkyl radical having from 1 to 6 carbon atoms, lower haloalkyl radical having from 1 to 6 carbon atoms, or an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl and pyridyl;
- or,
- R25 and R26 are O;
- or,
- R27 and R28 are O;
- or,
- R25, R26, together with the carbon atom to which they are attached, form a saturated hydrocarbon ring having from 3 to 7 carbon atoms;
- or,
- R27, R28, together with the carbon atom to which they are attached, form a saturated hydrocarbon ring having from 3 to 7 carbon atoms.
Dependencies are inferred from the claim text.