IP Library › Granted Patent US 8,895,543

Granted Patent B2

US 8,895,543 · App. 11/697,415 · Granted Nov 25, 2014

Patent

Inventors: Ian L. Scott (Woodinville, WA); Jeffrey M. Ralph (Niskayuna, NY); Matthew E. Voss (Nassau, NY)

Assignee: Albany Molecular Research, Inc.

C07D519/04

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Quick Facts

Patent No.: US 8,895,543
App. No.: 11/697,415
Granted: Nov 25, 2014
Kind: B2

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Abstract

The present invention relates to derivatives of vinca alkaloids. Pharmaceutical compositions containing these compounds as well as processes of preparation and treatment of various conditions are also disclosed.

Claims (180)

1. A method for treating a condition selected from the group consisting of leukemia, carcinoma of the breast, lymphosarcoma, ovarian cancer, squamous cell cancer of the lung, and Hodgkin's disease in mammals comprising:

administering to a mammal a therapeutically effective amount of the compound of Formula (I) as follows:

where:

R 1 is:

alkyl;

alkenyl;

alkynyl;

aryl;

3-methylpyrazol-1-yl;

pyridyl;

thienyl;

thiazolyl;

piperidinyl;

morpholinyl;

pyrrolidinyl;

azetidinyl;

Cl;

Br;

CN;

C(O)NR 5 R 6 ;

C(O)NHR 5 ;

C(O)NH 2 ;

C(O)NHNH 2 ;

C(O)NR 5 NH 2 ;

C(O)NR 5 NHR 6 ;

C(O)NR 5 NR 6 R 7 ;

C(O)NHNHR 5 ;

C(O)NHNR 5 R 6 ;

C(O)NHOH;

SO 2 NHNH 2 ;

SO 2 NR 5 NH 2 ;

SO 2 NR 5 NHR 6 ;

SO 2 NR 5 NR 6 R 7 ;

SO 2 NHNHR 5 ;

SO 2 NHNR 5 R 6 ;

CO 2 R 5 ;

SR 5 ;

SSR 5 ;

SO 2 NHR 5 ;

SO 2 NR 5 R 6 ;

B(OR 5 ) 2 ;

CF 3 ;

SH;

SO 2 NH 2 ;

NH 2 ;

NHR 5 ;

NHSO 2 R 5 ;

NR 5 R 6 ;

NHCOR 5 ;

NR 5 COR 6 ; or

NR 5 SO 2 R 6 ;

R 2 =alkyl or CH(O);

R 3 =hydrogen, alkyl, or C(O)R 5 ;

R 4 =hydrogen or C(O)R 5 ;

R 5 , R 6 and R 7 each are independently alkyl, alkenyl, alkynyl, or aryl;

R 8 =hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, acyl, or thioalkyl;

R 9 ═OH and R 10 ═H or R 9 and R 10 together form a bridging double bond;

R 5 and R 6 can form a ring or R 6 and R 7 can form a ring;

X═OR 5 , NR 5 R 6 , NHNH 2 , NHNHC(O)R 5 , OH, NHR 5 , NH 2 , or NHNHC(O)H;

R 4 and X can be linked together with intervening atoms to form a ring; R 1 and R 8 can be linked together; or a pharmaceutically acceptable salt thereof, wherein the alkyl and alkenyl groups can be branched or straight, with the proviso, that when R 8 ═H, R 9 ═OH, and R 10 ═H, then R 1 ≠Br and the proviso that if R 1 is an unsubstituted aryl, then R 2 ≠CH 3 .

2. The method according to claim 1 , wherein R 3 =acetyl.

3. The method according to claim 1 , wherein R 4 =hydrogen.

4. The method according to claim 1 , wherein X═OMe.

5. The method according to claim 1 , wherein R 3 =acetyl, R 4 =hydrogen, and X═OMe.

6. The method according to claim 1 , wherein R 2 ═CH(O).

7. The method according to claim 1 , wherein R 2 =alkyl.

8. The method of claim 1 , wherein the mammal is human.

9. The method according to claim 1 , wherein the compound has the following chemical formula:

10. The method according to claim 1 , wherein the compound has the following chemical formula:

11. The method according to claim 1 , wherein the compound has the following chemical formula:

12. The method according to claim 1 , wherein the compound has the following chemical formula:

13. The method according to claim 1 , wherein the compound has the following chemical formula:

14. The method according to claim 1 , wherein the compound has a substituted form of R 1 with the following chemical formula:

15. The method according to claim 1 , wherein the compound has a substituted form of R 1 with the following chemical formula:

16. The method according to claim 1 , wherein the compound has a substituted form of R 1 with the following chemical formula:

17. The method according to claim 1 , wherein the compound has the following chemical formula:

18. The method according to claim 1 , wherein the compound has the following chemical formula:

19. The method according to claim 1 , wherein the compound has the following chemical formula:

20. The method according to claim 1 , wherein the compound has the following chemical formula:

21. A method for treating a condition selected from the group consisting of leukemia, carcinoma of the breast, lymphosarcoma, ovarian cancer, squamous cell cancer of the lung, and Hodgkin's disease in mammals comprising:

administering to a mammal a therapeutically effective amount of a compound having the following chemical formula:

22. A method for treating a condition selected from the group consisting of leukemia, carcinoma of the breast, lymphosarcoma, ovarian cancer, squamous cell cancer of the lung, and Hodgkin's disease in mammals comprising:

administering to a mammal a therapeutically effective amount of a compound having the following chemical formula:

23. A method for treating a condition selected from the group consisting of leukemia, carcinoma of the breast, lymphosarcoma, ovarian cancer, squamous cell cancer of the lung, and Hodgkin's disease in mammals comprising:

administering to a mammal a therapeutically effective amount of a compound having the following chemical formula:

24. A method for treating a condition selected from the group consisting of leukemia, carcinoma of the breast, lymphosarcoma, ovarian cancer, squamous cell cancer of the lung, and Hodgkin's disease in mammals comprising:

administering to a mammal a therapeutically effective amount of a compound having the following chemical formula:

25. A method for treating a condition selected from the group consisting of leukemia, carcinoma of the breast, lymphosarcoma, ovarian cancer, squamous cell cancer of the lung, and Hodgkin's disease in mammals comprising:

administering to a mammal a therapeutically effective amount of a compound having the following chemical formula:

26. A method for treating a condition selected from the group consisting of choricarcinoma, neuroblastoma, acute lung organs leukemia, chronic lung organs leukemia, testicular cancers, non-Hodgkin's lymphoma, acute childhood leukemia, lymphatic leukemia, Wilm's tumor, rhabdosarcoma, reticulum cell sarcoma, melanoma, and squamous cell cancer of the cervix in mammals comprising:

administering to a mammal a therapeutically effective amount of the compound of Formula (I) as follows:

where:

R 1 is:

alkyl;

alkenyl;

alkynyl;

aryl;

3-methylpyrazol-1-yl;

pyridyl;

thienyl;

thiazolyl;

piperidinyl;

morpholinyl;

pyrrolidinyl;

azetidinyl;

Cl;

Br;

CN;

C(O)NR 5 R 6 ;

C(O)NHR 5 ;

C(O)NH 2 ;

C(O)NHNH 2 ;

C(O)NR 5 NH 2 ;

C(O)NR 5 NHR 6 ;

C(O)NR 5 NR 6 R 7 ;

C(O)NHNHR 5 ;

C(O)NHNR 5 R 6 ;

C(O)NHOH;

SO 2 NHNH 2 ;

SO 2 NR 5 NH 2 ;

SO 2 NR 5 NHR 6 ;

SO 2 NR 5 NR 6 R 7 ;

SO 2 NHNHR 5 ;

SO 2 NHNR 5 R 6 ;

CO 2 R 5 ;

SR 5 ;

SSR 5 ;

SO 2 NHR 5 ;

SO 2 NR 5 R 6 ;

B(OR 5 ) 2 ;

CF 3 ;

SH;

SO 2 NH 2 ;

NH 2 ;

NHR 5 ;

NHSO 2 R 5 ;

NR 5 R 6 ;

NHCOR 5 ;

NR 5 COR 6 ; or

NR 5 SO 2 R 6 ;

R 2 =alkyl or CH(O);

R 3 =hydrogen, alkyl, or C(O)R 5 ;

R 4 =hydrogen or C(O)R 5 ;

R 5 , R 6 and R 7 each are independently alkyl, alkenyl, alkynyl, or aryl;

R 8 =hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, acyl, or thioalkyl;

R 9 ═OH and R 10 ═H or R 9 and R 10 together form a bridging double bond;

R 5 and R 6 can form a ring or R 6 and R 7 can form a ring;

X═OR 5 , NR 5 R 6 , NHNH 2 , NHNHC(O)R 5 , OH, NHR 5 , NH 2 , or NHNHC(O)H;

27. The method according to claim 26 , wherein R 3 =acetyl.

28. The method according to claim 26 , wherein R 4 =hydrogen.

29. The method according to claim 26 , wherein X═OMe.

30. The method according to claim 26 , wherein R 3 =acetyl, R 4 =hydrogen, and X═OMe.

31. The method according to claim 26 , wherein R 2 ═CH(O).

32. The method according to claim 26 , wherein R 2 =alkyl.

33. The method of claim 26 , wherein the mammal is human.

34. The method according to claim 26 , wherein the compound has the following chemical formula:

35. The method according to claim 26 , wherein the compound has the following chemical formula:

36. The method according to claim 26 , wherein the compound has the following chemical formula:

37. The method according to claim 26 , wherein the compound has the following chemical formula:

38. The method according to claim 26 , wherein the compound has the following chemical formula:

39. The method according to claim 26 , wherein the compound has a substituted form of R 1 with the following chemical formula:

40. The method according to claim 26 , wherein the compound has a substituted form of R 1 with the following chemical formula:

41. The method according to claim 26 , wherein the compound has a substituted form of R 1 with the following chemical formula:

42. The method according to claim 26 , wherein the compound has the following chemical formula:

43. The method according to claim 26 , wherein the compound has the following chemical formula:

44. The method according to claim 26 , wherein the compound has the following chemical formula:

45. The method according to claim 26 , wherein the compound has the following chemical formula:

46. A method for treating a condition selected from the group consisting of choricarcinoma, neuroblastoma, acute lung organs leukemia, chronic lung organs leukemia, testicular cancers, non-Hodgkin's lymphoma, acute childhood leukemia, lymphatic leukemia, Wilm's tumor, rhabdosarcoma, reticulum cell sarcoma, melanoma, and squamous cell cancer of the cervix in mammals comprising:

administering to a mammal a therapeutically effective amount of a compound having the following chemical formula:

47. A method for treating a condition selected from the group consisting of choricarcinoma, neuroblastoma, acute lung organs leukemia, chronic lung organs leukemia, testicular cancers, non-Hodgkin's lymphoma, acute childhood leukemia, lymphatic leukemia, Wilm's tumor, rhabdosarcoma, reticulum cell sarcoma, melanoma, and squamous cell cancer of the cervix in mammals comprising:

administering to a mammal a therapeutically effective amount of a compound having the following chemical formula:

48. A method for treating a condition selected from the group consisting of choricarcinoma, neuroblastoma, acute lung organs leukemia, chronic lung organs leukemia, testicular cancers, non-Hodgkin's lymphoma, acute childhood leukemia, lymphatic leukemia, Wilm's tumor, rhabdosarcoma, reticulum cell sarcoma, melanoma, and squamous cell cancer of the cervix in mammals comprising:

administering to a mammal a therapeutically effective amount of a compound having the following chemical formula:

49. A method for treating a condition selected from the group consisting of choricarcinoma, neuroblastoma, acute lung organs leukemia, chronic lung organs leukemia, testicular cancers, non-Hodgkin's lymphoma, acute childhood leukemia, lymphatic leukemia, Wilm's tumor, rhabdosarcoma, reticulum cell sarcoma, melanoma, and squamous cell cancer of the cervix in mammals comprising:

administering to a mammal a therapeutically effective amount of a compound having the following chemical formula:

50. A method for treating a condition selected from the group consisting of choricarcinoma, neuroblastoma, acute lung organs leukemia, chronic lung organs leukemia, testicular cancers, non-Hodgkin's lymphoma, acute childhood leukemia, lymphatic leukemia, Wilm's tumor, rhabdosarcoma, reticulum cell sarcoma, melanoma, and squamous cell cancer of the cervix in mammals comprising:

administering to a mammal a therapeutically effective amount of a compound having the following chemical formula:

Assignments (14)

ASSIGNMENT OF SECURITY INTEREST IN INTELLECTUAL PROPERTY, RECORDED ON SEPTEMBER 1, 2017, AT REEL/FRAME 043746/0621 Recorded Mar 17, 2025

From: BARCLAYS BANK PLC, AS EXISTING AGENT

To: APOLLO ADMINISTRATIVE AGENCY LLC, AS SUCCESSOR AGENT

Reel/Frame 070531/0279 →

SECURITY INTEREST Recorded Sep 6, 2021

From: CURIA GLOBAL, INC. (FKA ALBANY MOLECULAR RESEARCH, INC.); CURIA MASSACHUSETTS, INC. (FKA AMRI BURLINGTON, INC.); CURIA WISCONSIN, INC. (FKA CEDARBURG PHARMACEUTICALS, INC.); CURIA INDIANA, LLC (FKA AMRI SSCI, LLC); CURIA NEW MEXICO, LLC (FKA OSO BIOPHARMACEUTICALS MANUFACTURING, LLC); CURIA IP HOLDINGS, LLC

To: WILMINGTON TRUST, NATIONAL ASSOCIATION, AS COLLATERAL AGENT

Reel/Frame 057423/0665 →

RELEASE OF SECURITY INTEREST Recorded Oct 29, 2020

From: MORGAN STANLEY SENIOR FUNDING, INC., AS COLLATERAL AGENT

To: ALBANY MOLECULAR RESEARCH, INC.; AMRI BURLINGTON, INC.; CEDARBURG PHARMACEUTICALS, INC.; EUTICALS INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC

Reel/Frame 054252/0687 →

CORRECTIVE ASSIGNMENT TO CORRECT THE INCORRECT PATENT NO. 7541537 PREVIOUSLY RECORDED AT REEL: 034045 FRAME: 0951. ASSIGNOR(S) HEREBY CONFIRMS THE SECURITY INTEREST. Recorded Aug 14, 2018

From: ALBANY MOLECULAR RESEARCH, INC.; ALO ACQUISITION LLC; AMRI BURLINGTON, INC.; AMRI RENSSELAER, INC.; CEDARBURG PHARMACEUTICALS, INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC

To: BARCLAYS BANK PLC, AS THE COLLATERAL AGENT

Reel/Frame 046796/0352 →

SECOND LIEN SECURITY AGREEMENT Recorded Sep 1, 2017

From: ALBANY MOLECULAR RESEARCH, INC.; AMRI BURLINGTON, INC.; CEDARBURG PHARMACEUTICALS, INC.; EUTICALS INC.; OSO BIOPHARMACEUTICALS MANUFACTURING LLC-BY ITS SOLE MEMBER:ALO ACQUISITION LLC

To: MORGAN STANLEY SENIOR FUNDING, INC.

Reel/Frame 043746/0657 →

FIRST LIEN SECURITY AGREEMENT Recorded Sep 1, 2017

From: ALBANY MOLECULAR RESEARCH, INC.; AMRI BURLINGTON, INC.; CEDARBURG PHARMACEUTICALS, INC.; EUTICALS INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC-BY ITS SOLE MEMBER: ALO ACQUISITION LLC

To: BARCLAYS BANK, PLC AS COLLATERAL AGENT

Reel/Frame 043746/0621 →

RELEASE OF SECURITY INTEREST Recorded Aug 31, 2017

From: BARCLAYS BANK PLC, AS COLLATERAL AGENT

To: ALBANY MOLECULAR RESEARCH, INC.; ALO ACQUISITION LLC; AMRI BURLINGTON, INC.; AMRI RENSSELAER, INC.; CEDARBURG PHARMACEUTICALS, INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC; AMRI SSCI, LLC; EUTICALS INC.

Reel/Frame 043742/0085 →

SECURITY INTEREST Recorded Aug 5, 2015

From: ALBANY MOLECULAR RESEARCH, INC.; AMRI SSCI, LLC

To: BARCLAYS BANK PLC, AS THE COLLATERAL AGENT

Reel/Frame 036257/0914 →

SECURITY INTEREST Recorded Oct 24, 2014

From: ALBANY MOLECULAR RESEARCH, INC.; ALO ACQUISITION LLC; AMRI BURLINGTON, INC.; AMRI RENSSELAER, INC.; CEDARBURG PHARMACEUTICALS, INC.; OSO BIOPHARMACEUTICALS MANUFACTURING, LLC

To: BARCLAYS BANK PLC, AS THE COLLATERAL AGENT

Reel/Frame 034045/0951 →

RELEASE OF SECURITY INTEREST Recorded Jul 9, 2014

From: WELLS FARGO

To: ALBANY MOLECULAR RESEARCH, INC.

Reel/Frame 033283/0357 →

SECURITY AGREEMENT Recorded Apr 20, 2012

From: ALBANY MOLECULAR RESEARCH, INC.; AMRI BURLINGTON, INC.; AMRI BOTHELL RESEARCH CENTER, INC.; AMRI RENESSELAER, INC.

To: WELLS FARGO BANK, NATIONAL ASSOCIATION

Reel/Frame 028078/0227 →

TERMINATION Recorded Apr 19, 2012

From: BANK OF AMERICA, N.A.