Claims for Patent: 9,427,479

Summary for Patent: 9,427,479

Title:	Tubulysin derivatives
Abstract:	Novel tubulysin derivatives which may be useful as cytotoxic agents to provide therapeutic benefits in the treatment of various types of cancers, alone, as drug conjugates or in combination with other chemotherapies are provided.
Inventor(s):	Gingipalli; Lakshmaiah (Waltham, MA), Toader; Dorin (Gaithersburg, MD), Wang; Fengjiang (Waltham, MA)
Assignee:	MedImmune LLC (Gaithersburg, MD)
Application Number:	14/683,196
Patent Claims:	1. A compound having the structure of Formula I: ##STR00111## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is CH.sub.3 or CH.sub.2CH.sub.3, R.sup.2 is H or CH.sub.3, R.sup.3 is H or NH.sub.2 and n is 1 or 2. 2. A compound of claim 1 wherein n is 1 and R.sup.1 is methyl. 3. A compound of claim 1 wherein R.sup.2 is methyl. 4. A compound of claim 1 wherein R.sup.3 is NH.sub.2. 5. A compound of claim 1 wherein n is 1, R.sup.1 is methyl, R.sup.2 is methyl and R.sup.3 is NH.sub.2. 6. A compound of claim 1 having the Formula (Ii) ##STR00112## 7. A compound of claim 1 having the Formula (Iii) ##STR00113## 8. A compound of claim 1 having the Formula (Iiii) ##STR00114## 9. A compound of claim 1 having the Formula (Iiv) ##STR00115## 10. A compound of claim 1 having the Formula (Iv) ##STR00116## 11. A compound of claim 1 having the Formula (Ivi) ##STR00117## 12. A compound having the structure of Formula II ##STR00118## or a pharmaceutically acceptable salt thereof, wherein: R.sup.1 is CH.sub.3 or CH.sub.2 CH.sub.3, R.sup.2 is H or CH.sub.3, R.sup.4 is CH.sub.3, (CH.sub.2).sub.4NH.sub.2, or (CH.sub.2).sub.3NHC(.dbd.O)NH.sub.2, R.sup.5 is H or CH(CH.sub.3)(CH.sub.3), R.sup.6 is NHC(.dbd.O) or CH.sub.2, n is 1 or 2; and m is 0, 1, 2 or 3. 13. A compound of claim 12 wherein n is 1 and R.sup.1 is methyl. 14. A compound of claim 12 wherein R.sup.2 is methyl. 15. A compound of claim 12 wherein n is 1, R.sup.1 is methyl, and R.sup.2 is methyl. 16. A compound of claim 12 wherein R.sup.4 is (CH.sub.2).sub.4NH.sub.2. 17. A compound of claim 12 wherein R.sup.5 is H. 18. A compound of claim 12 wherein R.sup.6 is CH.sub.2. 19. A compound of claim 12 wherein m is 1. 20. A compound of claim 12 wherein n is 1, m is 1, R.sup.1 is methyl, R.sup.2 is methyl, R.sup.4 is (CH.sub.2).sub.4NH.sub.2, R.sup.5 is H, and R.sup.6 is CH.sub.2. 21. A compound of claim 12 having the Formula (IIi) ##STR00119## 22. A compound of claim 12 having the Formula (IIii) ##STR00120## 23. A compound of claim 12 having the Formula (IIiii) ##STR00121## 24. A antibody-drug conjugate which is a conjugate of a compound having the structure of Formula II ##STR00122## wherein: R.sup.1 is CH.sub.3 or CH.sub.2 CH.sub.3, R.sup.2 is H or CH.sub.3, R.sup.4 is CH.sub.3, (CH.sub.2).sub.4NH.sub.2, or (CH.sub.2).sub.3NHC(.dbd.O)NH.sub.2, R.sup.5 is H or CH(CH.sub.3)(CH.sub.3), R.sup.6 is NHC(.dbd.O) or CH.sub.2, n is 1 or 2; and m is 0, 1, 2 or 3; and an antibody. 25. An antibody-drug conjugate of claim 24 wherein the antibody is a monoclonal antibody. 26. An antibody-drug conjugate of claim 24 wherein the antibody is specific to a cancer antigen. 27. An antibody-drug conjugate of claim 24 wherein the antibody is alemtuzumab, bevacizumab, brentuximab, cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, rituximab, tositumomab, or trastuzumab. 28. An antibody-drug conjugate of claim 24 which is a conjugate of a compound of the Formula (IIi) ##STR00123## and an antibody. 29. An antibody-drug conjugate of claim 24 which is a conjugate of a compound of the Formula (IIii) ##STR00124## and an antibody. 30. An antibody-drug conjugate of claim 24 which is a conjugate of a compound of the Formula (IIiii) ##STR00125## and an antibody. 31. A pharmaceutical composition containing a compound of claim 1. 32. A pharmaceutical composition containing an antibody-drug conjugate of claim 24. 33. A method of treating cancer by administering to a subject suffering from cancer, an effective amount of a compound of claim 1. 34. The method of claim 33 where the subject is suffering from squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial carcinoma, myeloma, salivary gland carcinoma, kidney cancer, basal cell carcinoma, melanoma, prostate cancer, vulval cancer, thyroid cancer, testicular cancer, esophageal cancer, head and neck cancers, mucinous ovarian cancer, cholangiocarcinoma or renal papillary carcinoma. 35. A method of treating cancer by administering to a subject suffering from cancer, an effective amount of a antibody-drug conjugate of claim 24. 36. The method of claim 35 where the subject is suffering from squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial carcinoma, myeloma, salivary gland carcinoma, kidney cancer, basal cell carcinoma, melanoma, prostate cancer, vulval cancer, thyroid cancer, testicular cancer, esophageal cancer, head and neck cancers, mucinous ovarian cancer, cholangiocarcinoma or renal papillary carcinoma. 37. A pharmaceutical composition containing a compound of claim 12. 38. A method of treating cancer by administering to a subject suffering from cancer, an effective amount of a compound of claim 12. 39. The method of claim 38 where the subject is suffering from squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, gastrointestinal cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma, pancreatic cancer, glioblastoma, glioma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, breast cancer, colon cancer, colorectal cancer, endometrial carcinoma, myeloma, salivary gland carcinoma, kidney cancer, basal cell carcinoma, melanoma, prostate cancer, vulval cancer, thyroid cancer, testicular cancer, esophageal cancer, head and neck cancers, mucinous ovarian cancer, cholangiocarcinoma or renal papillary carcinoma. 40. A compound having the Formula (IIiv) ##STR00126## 41. An antibody-drug conjugate which is a conjugate of a compound of the Formula (IIiv) ##STR00127##

Details for Patent 9,427,479

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2039-02-26
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2039-02-26
Genentech, Inc.	HERCEPTIN	trastuzumab	For Injection	103792	09/25/1998		2039-02-26