IP Library › Granted Patent US 7,238,704

Granted Patent B2

US 7,238,704 · App. 11/003,560 · Granted Jul 3, 2007

Vinca derivatives

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Quick Facts

Patent No.: US 7,238,704
App. No.: 11/003,560
Granted: Jul 3, 2007
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 (243)

1. A compound of Formula (I) as follows:

where:

R 1 is:

alkyl;

alkenyl;

alkynyl;

aryl;

pyrazol-1-yl;

pyridyl;

thiophenyl;

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 could form a ring or R 6 and R 7 could 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 may be linked together with intervening atoms to form a ring; R 1 and R 8 may be linked together; or a pharmaceutically acceptable salt thereof, wherein the alkyl and alkenyl groups may be branched, 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 compound according to claim 1 , wherein R 3 =acetyl.

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

4. The compound according to claim 1 , wherein X=OMe.

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

6. The compound according to claim 1 , wherein R 2 =CH(O).

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

8. A compound of the following chemical formula:

9. A compound of the following chemical formula:

10. A compound of the following chemical formula:

11. A compound of the following chemical formula:

12. A compound of the following chemical formula:

13. A compound of the following chemical formula:

14. A compound of the following chemical formula:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

62. A compound having the following chemical formula:

63. A compound of the following chemical formula:

64. A compound of the following chemical formula:

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

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

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

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

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

70. A compound of the following chemical formula:

71. A compound of the following chemical formula:

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

73. A compound of the following chemical formula:

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

75. A compound of the following chemical formula:

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

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

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

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

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

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

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

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

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

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

86. A compound of the following chemical formula:

87. A compound of the following chemical formula:

88. A compound of the following chemical formula:

89. A compound of the following chemical formula:

90. A compound of the following chemical formula:

91. A compound of the following chemical formula:

92. A compound of the following chemical formula:

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

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

95. A complex comprising 2 structures of Formula I, according to claim 1 , joined together at their R 1 groups, wherein each R 1 is —S—.

96. A process for preparation of a derivative product compound of Formula (I) as follows:

where:

R 1 is:

alkyl;

alkenyl;

alkynyl;

aryl;

pyrazol-1yl;

pyridyl;

thiophenyl;

thiazolyl;

piperidinyl;

morpholinyl;

pyrrolidinyl;

azetidinyl;

CN;

CH(O);

COR 5 ;

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)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 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 and R 6 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;

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

converting an intermediate compound of formula:

wherein Y 1 is a halogen and Y 2 is a halogen or hydrogen,

under conditions effective to produce the product compound of Formula (I).

97. The process of claim 96 further comprising:

reacting a starting material compound of formula:

under conditions effective to form the intermediate compound.

98. The process of claim 97 , wherein the conditions effective to form the intermediate compound include using a halogenating agent selected from the group consisting of N-bromosuccinimide, N-iodo-succinimide, and iodine monochloride.

99. The process of claim 97 , wherein said converting comprises:

reacting the intermediate compound with a palladium catalyst reagent to produce the product of Formula (I).

100. The process of claim 99 , wherein the palladium catalyst reagent is selected from the group consisting of palladium acetate, tris(dibenzylideneacetone)dipalladium(0), 1,1′-bis(diphenylphosphino)ferrocene-dichloropalladium(II), tetrakis(triphenylphosphine)palladium, and bis(triphenylphosphine) palladium(II)dichloride.

101. A process for preparation of a product compound of Formula (I) as follows:

where:

R 1 is halogen;

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 and R 6 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;

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 may be linked together with intervening atoms to form a ring; R 1 and R 8 may be linked together; or a pharmaceutically acceptable salt thereof, wherein the alkyl and alkenyl groups may be branched or straight, with the proviso, that when R 8 =H, R 9 =OH, and R 10 =H, then R 1 ≠Br or I, said process comprising:

reacting a starting material compound of formula:

under conditions effective to form the product compound.

102. The process of claim 101 , wherein the conditions effective to form the intermediate compound include using a halogenating agent selected from the group consisting of N-bromosuccinimide, N-iodo-succinimide, and iodine monochloride.

103. A composition of matter comprising the compound of claim 1 and one or more excipients.

104. The composition according to claim 103 , wherein R 3 =acetyl.

105. The composition according to claim 103 , wherein R 4 =hydrogen.

106. The composition according to claim 103 , wherein X=OMe.

107. The composition according to claim 103 , wherein R 3 =acetyl, R 4 =hydrogen, and X=OMe.

108. The composition according to claim 103 , wherein R 2 =CH(O).

109. The composition according to claim 103 , wherein R 2 =alkyl.

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

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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

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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

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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

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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

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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.

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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.

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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

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RELEASE OF SECURITY INTEREST Recorded Jul 9, 2014

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To: ALBANY MOLECULAR RESEARCH, INC.

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SECURITY AGREEMENT Recorded Apr 20, 2012

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To: WELLS FARGO BANK, NATIONAL ASSOCIATION

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TERMINATION Recorded Apr 19, 2012

From: BANK OF AMERICA, N.A.