Claims for Patent: 9,273,031

Summary for Patent: 9,273,031

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:	14/571,770
Patent Claims:	1. A method of treating a proliferative disease, disorder, or condition comprising: administering to a subject in need thereof a therapeutically effective amount of (a) an MDM2 inhibitor; and (b) an EGFR inhibitor; wherein the MDM2 inhibitor comprises a compound having a formula of: ##STR00268## or a stereoisomer or pharmaceutically acceptable salt thereof; wherein, X.sub.1 is selected from the group consisting of: hydrogen, 2-methly, 5-chloro, 5-nitro, and 6-hydroxyl; R2 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; 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; 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) ##STR00269## wherein R15, R16, and R17 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; (iii) a 3-thiophene ring of Formula (9) ##STR00270## wherein R18, R19, and R20 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; (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; and R21 is selected from the group consisting of: (i) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; (ii) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; (iii) 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; 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-6cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; 2,3-methylenedioxy; 3 4-methylenedioxy; 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-4lower alkyl optionally containing unsaturation; trifluoromethyl; trifluoromethoxy; difluoromethoxy; 3, 4-methylenedioxy; 2, 3-methylenedioxy; nitro; and halogen; (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; and (vii) a heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms. 2. The method of claim 1, wherein the proliferative disease, disorder, or condition comprises cancer. 3. The method of claim 1, wherein administering 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. 4. The method of claim 1, comprising administering to a subject in need thereof a therapeutically effective amount of (i) a pharmaceutical composition comprising an MDM2 inhibitor, an EGFR inhibitor, and a pharmaceutically acceptable carrier or excipient or (ii) a first pharmaceutical composition comprising an MDM2 inhibitor and a pharmaceutically acceptable carrier or excipient and a second pharmaceutical composition comprising an EGFR inhibitor and a pharmaceutically acceptable carrier or excipient. 5. The method of claim 1, wherein the subject has one or more of: (i) an inactivating P53 mutation or deletion in the subject; (ii) a defect in an upstream component of a p53 pathway; (iii) a defect in a downstream component of the p53 pathway; (iv) increased expression an MDM2 gene as compared to a control; (v) increased levels of MDM2 protein as compared to a control; or (vi) resistance to treatment with an EGFR inhibitor alone. 6. The method of claim 1, comprising selecting or modifying a treatment on the basis of detecting in a subject one or more of (i) an inactivating P53 mutation or deletion in the subject; (ii) a defect in an upstream component of a p53 pathway; (iii) a defect in a downstream component of the p53 pathway; (iv) increased expression an MDM2 gene as compared to a control; (v) increased levels of MDM2 protein as compared to a control; or (vi) resistance to treatment with an EGFR inhibitor alone. 7. The method 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. 8. The method of claim 1, wherein the EGFR inhibitor is erlotinib. 9. The method of claim 1, wherein the MDM2 inhibitor (i) inhibits MDM2 activity; (ii) increases phosphorylated p53; (iii) re-activates p53; (iv) inhibits binding of p53 and MDM2; or a combination thereof. 10. The method of claim 1, wherein the MDM2 inhibitor comprises a compound having a formula of: ##STR00271## or a stereoisomer or pharmaceutically acceptable salt thereof; wherein, X.sup.1 is selected from the group consisting of: hydrogen, 2-methyl, 5-chloro, 5-nitro, and 6-hydroxyl; 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; 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; 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) ##STR00272## 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; (iii) a 3-thiophene ring of Formula (9) ##STR00273## wherein R.sup.18, R.sup.19, and R.sup.20 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; (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; R.sup.22 is a C-1 to C-6 lower alkyl optionally substituted at C-1 or C-2 with at least one group selected from the group consisting of: (i) an unsubstituted phenyl ring; and (ii) 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: (a) straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; (b) C-1 to C-6 cycloalkyl optionally containing unsaturation or one oxygen or nitrogen atom; (c) aryl comprising a phenyl or heteroaryl five or six membered ring containing from 1 to 4 N, O, or S atoms; (d) 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; (e) 2,3-methylenedioxy; (f) 3,4-methylenedioxy; (g) dialkylamino having formula --NR.sub.13R.sub.14 wherein R.sub.13 and R.sub.14 are independently selected from hydrogen and straight chain or branched C-1 to C-4 lower alkyl optionally containing unsaturation; (h) trifluoromethyl; (i) trifluoromethoxy; (j) difluoromethoxy; (k) 3,4-methylenedioxy; (l) 2, 3-methylenedioxy; (m) nitro; and (n) halogen. 11. The method of claim 1, wherein the MDM2 inhibitor comprises a compound selected from the group consisting of: ##STR00274## 12. The method of claim 1 wherein the proliferative disease, disorder, or condition comprises one or more of the group consisting of cancer; blood vessel proliferative disorders; fibrotic disorders; mesangial cell proliferative disorders; psoriasis; actinic keratoses; seborrheic keratoses; warts; keloid scars; eczema; hyperproliferative diseases caused by virus infections; and papilloma virus infection. 13. The method of claim 1, wherein the EGFR inhibitor is erlotinib; and the proliferative disease, disorder, or condition comprises cancer. 14. The method of claim 10, wherein the EGFR inhibitor is erlotinib; and the proliferative disease, disorder, or condition comprises cancer.

Details for Patent 9,273,031

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