Claims for Patent: 9,023,354

Summary for Patent: 9,023,354

Title:	Combination therapy with MDM2 and EFGR inhibitors
Abstract:	Provided is a method of treating a proliferative disease, condition, or disorder in a subject by administering a combination of an inhibitor of p53 and MDM2 binding and an EGFR inhibitor. Various embodiments of the disclosed methods provide a synergistic anti-proliferative or anti-apoptotic effect compared to administration of one agent alone.
Inventor(s):	Errico; Joseph P. (Warren, NJ), Mugrage; Benjamin (Cranbury, NJ), Turchi; Ignatius (Yardley, PA), Sills; Matthew (Berkeley Heights, NJ), Ong; Jane (Franklin Park, NJ), Allocco; John (Staten Island, NY), Wines; Pam (Manalapan, NJ), Bastos; Margarita (Plainsboro, NJ)
Assignee:	Errico; Joseph P. (Warren, NJ)
Application Number:	14/157,086
Patent Litigation and PTAB cases:	See patent lawsuits and PTAB cases for patent 9,023,354
Patent Claims:	1. A composition comprising: (a) an MDM2 inhibitor; and (b) an EGFR inhibitor, wherein the MDM2 inhibitor is a compound having a formula of ##STR00269## or a stereoisomer or pharmaceutically acceptable salt thereof; X is selected from the group consisting of hydrogen, 2-Methyl, 5-Chloro, 5-Nitro, and 6-Hydroxyl; R.sup.1 is selected from the group consisting of (i) a 2-Pyridyl ring of Formula (3) ##STR00270## wherein R.sup.23 is selected from the group consisting of hydrogen; fluoro; chloro; trifluoromethyl; methyl; ethyl; and methoxy; R.sup.3 is selected from the group consisting of hydrogen; fluoro; chloro; methyl; ethyl; methoxy; a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; aryl comprising a phenyl or heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms; and alkoxy --OR.sup.10 where R.sup.10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; R.sup.24 is selected from the group consisting of hydrogen; fluoro; chloro; and trifluoromethyl; and R.sup.4 is selected from the group consisting of hydrogen; methyl; a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; aryl comprising a phenyl or heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms; and alkoxy --OR.sup.10 where R.sup.10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; (ii) a 3-Pyridyl ring of Formula (4) ##STR00271## wherein R.sup.5, R.sup.6, and R.sup.7 are independently selected from the group consisting of hydrogen; trifluoromethyl; a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation, optionally containing one or more halogens; a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; Aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms; and Alkoxy --OR.sup.10 where R.sup.10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation, optionally containing one or more halogens; or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and (iii) a 4-Pyridyl ring of Formula (5) ##STR00272## wherein R.sup.8 and R.sup.9 are independently selected from the group consisting of a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms; and alkoxy --OR.sup.10 where R.sup.10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; (iv) a phenyl ring substituted with one or more groups selected from a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; aryl comprising a phenyl or heteroaryl containing from 1 to 4 N, O, or S atoms; alkoxy --OR.sup.10 where R.sup.10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; trifluoromethyl; trifluoromethoxy; difluoromethoxy; 3,4-methylenedioxy; 2,3-methylenedioxy; nitro; and halogen; and (v) an unsubstituted heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms; (vi) a substituted heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms substituted with one or more groups selected from the group consisting of straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; aryl comprising a phenyl or heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms; and alkoxy --OR.sup.10 where R.sup.10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and R.sup.2 is selected from the group consisting of (i) an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups independently selected from the group consisting of straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; aryl comprising a phenyl or heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms; hydroxy; alkoxy --OR.sup.10 where R.sup.10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; 2,3-methylenedioxy; 3,4-methylenedioxy; trifluoroethoxy; dialkylamino having formula --NR.sub.13R.sub.14 wherein R.sub.13 and R.sub.14 are independently selected from hydrogen; straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; trifluoromethyl; trifluoromethoxy; difluoromethoxy; 3,4-methylenedioxy; 2,3-methylenedioxy; nitro; and halogen; (ii) a 2-thiophene ring of Formula (8) wherein R.sup.15, R.sup.16, and R.sup.17 are independently selected from the group consisting of hydrogen; straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; alkoxy --OR.sup.10 where R.sup.10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; dialkylamino; trifluoromethyl; difluoromethyl; trifluoromethoxy; and halogen ##STR00273## (iii) a 3-thiophene ring of Formula (9) wherein R.sup.18, R.sup.19, and R.sup.20 are independently selected from the group consisting of straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; alkoxy --OR.sup.10 where R.sup.10 is a straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation or a C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; dialkylamino; trifluoromethyl; difluoromethyl; trifluoromethoxy; and halogen ##STR00274## (iv) an unsubstituted 2-Pyridyl ring or a 2-Pyridyl ring substituted at 4- or 6-position of the pyridine ring with one or more groups independently selected from the group consisting of straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation and C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; (v) an unsubstituted 3-Pyridyl ring or a 3-Pyridyl ring substituted at the 2-, 4- or 6-position of the pyridine ring with one or more groups independently selected from the group consisting of straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation and C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; and (vi) an unsubstituted 4-Pyridyl ring or a 4-Pyridyl ring substituted at the 2- or 6-position of the pyridine ring with one or more groups independently selected from the group consisting of straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation and C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; or a stereoisomer or pharmaceutically acceptable salt thereof. 2. The composition of claim 1, wherein a combination of the MDM2 inhibitor and the EGFR inhibitor results in a synergistic reduction in cell proliferation in a tumor of the subject or a synergistic increase in apoptosis in a tumor of the subject as compared to administration of either the MDM2 inhibitor or the EGFR inhibitor alone. 3. The composition of claim 1, wherein the EGFR inhibitor is selected from the group consisting of cetuximab, panitumumab, nimotuzumab, zalutumumab, matuzumab, potato carboxypeptidase inhibitor, gefitinib, lapatinib, and erlotinib, or a combination thereof. 4. The composition of claim 1, wherein the EGFR inhibitor is erlotinib. 5. The composition of claim 1, wherein the MDM2 inhibitor (i) inhibits MDM2 activity; (ii) increases phosphorylated p53; (iii) re-activates p53; or (iv) inhibits binding of p53 and MDM2; or a combination thereof. 6. The composition of claim 1, wherein the MDM2 inhibitor is a compound having a formula of: ##STR00275## or a stereoisomer or pharmaceutically acceptable salt thereof; wherein, X is selected from the group consisting of hydrogen, 2-Methyl, and 5-Chloro, R.sup.1 is selected from the group consisting of (i) a 2-Pyridyl ring of Formula (3) ##STR00276## wherein R.sup.23 is selected from the group consisting of hydrogen; fluoro; chloro; and methyl; R.sup.3 is selected from the group consisting of hydrogen; chloro; and methyl; R.sup.24 is selected from the group consisting of hydrogen; fluoro; chloro; and trifluoromethyl; and R.sup.4 is selected from the group consisting of hydrogen; and methyl; (ii) a 3-Pyridyl ring of Formula (4) ##STR00277## wherein R.sup.5, R.sup.6, and R.sup.7 are independently selected from the group consisting of hydrogen and trifluoromethyl and R.sup.2 is selected from the group consisting of (i) an unsubstituted phenyl ring or a phenyl ring substituted at the 2-, 3-, 4-, 5- or 6-position with one or more groups independently selected from the group consisting of methyl; methoxy; ethoxy; trifluoroethoxy; trifluoromethyl; hydroxy; trifluoromethoxy; Cl; and F; (ii) a 2-thiophene ring of Formula (8) wherein R.sup.15, R.sup.16, and R.sup.17 are independently selected from the group consisting of hydrogen and methyl ##STR00278## or a stereoisomer or pharmaceutically acceptable salt thereof. 7. The composition of claim 1, wherein the MDM2 inhibitor comprises a compound selected from the group consisting of: ##STR00279## ##STR00280## ##STR00281## ##STR00282## ##STR00283## ##STR00284## ##STR00285## ##STR00286## ##STR00287## ##STR00288## ##STR00289## ##STR00290## ##STR00291## ##STR00292## ##STR00293## 8. A kit comprising (a) a first composition comprising an MDM2 inhibitor and an EGFR inhibitor or (b) a second composition comprising an MDM2 inhibitor and a third composition comprising an EGFR inhibitor according to definitions of claim 1.

Details for Patent 9,023,354

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	02/12/2004		2039-02-26
Eli Lilly And Company	ERBITUX	cetuximab	Injection	125084	03/28/2007		2039-02-26
Amgen, Inc.	VECTIBIX	panitumumab	Injection	125147	09/27/2006		2039-02-26