3-heteroarylidenyl-2-indolinone compounds for modulating protein kinase activity and for use in cancer chemotherapy

• US 20030191162A1
• Filed: 12/02/2002
• Published: 10/09/2003
• Est. Priority Date: 12/31/1998
• Status: Abandoned Application

• Current Assignee: Sugen Incorporated (Pharmacia Corp.)
• Original Assignee: Sugen Incorporated (Pharmacia Corp.)
• Inventors: Kwok, David Kevin, Hannah, Alison Lennox, Shawyer, Laura K., Tang, Peng Cho, Sun, Li, Langecker, Peter J.
• Application Number:
  US10/307,483
• Publication Number:
  US 20030191162A1
• Time in Patent Office: Days
• US Class Current: 514/363
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/40 having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
• CPC Class Codes: A61K 31/404 Indoles, e.g. pindolol
• CPC Class Codes: A61K 31/505 Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention relates to 3-heteroarylidenyl-2-indolinone compounds that modulate the enzymatic activity of protein kinases and therefore are expected to be useful in the prevention and treatment of protein kinase related cellular disorders such as cancer. Furthermore, these compounds are expected to enhance the efficacy of other chemotherapeutic agents, in particular, fluorinated pyrimidines, in the treatment of cancer.

Claims

1. A method for treating cancer comprising administering to a patient in need of such treatment a therapeutically effective amount of a fluorinated pyrimidine chemotherapeutic agent and a therapeutically effective amount of a compound having the chemical structure:

2. The method of claim 1 wherein said compound is selected from the group consisting of 5-hydroxy-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone, 4-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid, 4-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid methyl ester, 3-(5-hydroxymethyl-3-methyl-1H-pyrrol-2-ylmethylene)-1,3-dihydroindole-2-one and 4-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carbaldehyde or a physiologically acceptable salt or prodrug thereof.

3. The method of claim 1 wherein said compound is 3-[4-(2-carboxyethyl-3,5-dimethylpyrrol-2-yl)methylidenyl]-2-indolinone.

4. The method of claim 1 wherein said compound is 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone.

5. The method of claim 1 wherein said fluorinated pyrimidine chemotherapeutic agent is selected from the group consisting of carmofur, doxifluridine, fluorouracil, floxuridine, tegafur, capecitabine and uracil-ftorafur.

6. The method of claim 1 wherein said fluorinated pyrimidine chemotherapeutic agent is fluorouracil.

7. The method of claim 6 further comprising administering a therapeutically effective amount of leucovorin to said patient.

8. The method of claim 1 wherein said cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, renal cancer, hepatic cancer, pancreatic cancer, bladder cancer, prostate cancer and colorectal cancer.

9. A method for treating colorectal cancer comprising administering to a patient in need of such treatment a therapeutically effective amount of fluorouracil and a therapeutically effective amount of 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone.

10. The method of claim 9 further comprising administering a therapeutically effective amount of leucovorin to said patient.

11. The method of claim 9 wherein said therapeutically effective amount of said fluoruracil comprises from about 400 mg/m² to about 500 mg/m².

12. The method of claim 9 wherein said therapeutically effective amount of said fluorouracil is administered parenterally.

13. The method of claim 9 wherein said therapeutically effective amount of said 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone comprises from about 4 mg/m² to about 190 mg/m² per treatment.

14. The method of claim 9 wherein said therapeutically effective amount of said 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone comprises from about 72 mg/m² to about 145 mg/m² per treatment.

15. A method for treating cancer comprising a combination of 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone and at least one other chemotherapeutic agent.

16. The method of claim 15 wherein said other chemotherapeutic agent is selected from the group consisting of capecitabine, 5-FU, UFT, carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, a polyglutamated taxane, irinotecan, thalidomide, a COX-2 inhibitor, tamoxifen, leuprolide, angiostatin, endostatin, a matrix metalloprotease inhibitor, an interferon, doxorubicin, liposomal doxorubicin, daunorubicin, metoxantrone, estramucine and a vinca alkaloid, or combinations thereof.

17. A 3-heteroarylidenyl-2-indolinone compound selected from the group consisting of 5-hydroxy-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone, 4-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid, 4-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid methyl ester, 3-(5-hydroxymethyl-3-methyl-1H-pyrrol-2-ylmethylene)-1,3-dihydroindole-2-one and 4-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carbaldehyde or a physiologically acceptable salt or prodrug thereof.

18. A method for the modulation of the catalytic activity of a protein kinase comprising contacting said protein kinase with a compound, salt or prodrug of claim 17.

19. The method of claim 18 wherein said protein kinase is selected from the group consisting of receptor protein tyrosine kinase, cellular tyrosine kinase and serine-threonine kinase.

20. A pharmaceutical composition comprising:

a compound, salt or prodrug of claim 17;

and,

a pharmaceutically acceptable carrier or excipient.

21. A method for treating or preventing a protein kinase related disorder in an patient comprising administering a therapeutically effective amount of a compound, salt or prodrug of claim 17 to said patient.

22. The method of claim 21 wherein said protein kinase related disorder is selected from the group consisting of a receptor protein tyrosine kinase related disorder, a cellular tyrosine kinase disorder and a serine-threonine kinase related disorder.

23. The method of claim 21 wherein said protein kinase related disorder is selected from the group consisting of an EGFR related disorder, a PDGFR related disorder, an IGFR related disorder and a flk related disorder.

24. The method of claim 21 wherein said protein kinase related disorder is a cancer selected from the group consisting of squamous cell carcinoma, astrocytoma, glioblastoma, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer and glioma.

25. The method of claim 21 wherein said protein kinase related disorder is selected from the group consisting of diabetes, an autoimmune disorder, a hyperproliferation disorder, restenosis, fibrosis, psoriasis, osteoarthritis, rheumatoid arthritis, an inflammatory disorder and angiogenesis.

26. A method for treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of gemcitabine and a therapeutically effective amount of 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone.

27. The method of claim 26 wherein said cancer is pancreatic cancer.

28. The method of claim 26 further comprising a therapeutically effective amount of paclitaxel, carboplatin, liposomal doxorubicin, or topotecan.

29. The method of claim 28 wherein said cancer is selected from the group consisting of ovarian, small-cell lung and kidney cancer.

30. A method for treating cancer comprising administering to a patient in need of such treatment:

(a) therapeutically effective amount(s) of at least one agent selected from the group consisting of topoisomerase I inhibitors, chemotherapeutic agents, leucovorin, and combinations thereof; and

(b) a therapeutically effective amount of a compound comprising the chemical structure;

31. The method of claim 30 wherein said compound is selected from the group consisting of 5-hydroxy-3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone, 4-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid, 4-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid methyl ester, 3-(5-hydroxymethyl-3-methyl-1H-pyrrol- 2-ylmethylene)-1,3-dihydroindole-2-one and 4-methyl-5-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-1H-pyrrole-2-carbaldehyde, and physiologically acceptable salts or prodrugs thereof.

32. The method of claim 30,wherein said compound is 3-[4-(2-carboxyethyl-3,5-dimethylpyrrol-2-yl) methylidenyl]-2-indolinone.

33. The method of claim 30 wherein said compound is 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone.

34. The method of claim 30 wherein said agent comprises a topoisomerase I inhibitor.

35. The method of claim 34 wherein said topoisomerase I inhibitor is irinotecan.

36. The method of claim 35 wherein said irinotecan is administered orally.

37. The method of claim 35 wherein said irinotecan is administered parenterally.

38. The method of claim 30 wherein said agent comprises a chemotherapeutic agent selected from the group consisting of capecitabine, fluorinated pyrimidine chemotherapeutic agents, carboplatin, cisplatin, oxaliplatin, paclitaxel, docetaxel, polyglutamated taxanes, irinotecan, thalidomide, COX-2 inhibitor, tamoxifen, leuprolide, angiostatins, endostatins, matrix metalloprotease inhibitors, interferons, doxorubicin, liposomal doxorubicin, daunorubicin, metoxantrone, estramucine, a vinca alkaloid, gemcitabine, 2-methoxyestradiol, and combinations thereof.

39. The method of claim 38 wherein said chemotherapeutic agent is selected from the group consisting of cisplatin, a combination of carboplatin and paclitaxel, a fluorinated pyrimidine chemotherapeutic agent, and a combination of cisplatin and gemcitabine.

40. The method of claim 38 wherein said chemotherapeutic agent comprises cisplatin.

41. The method of claim 38 wherein said chemotherapeutic agent comprises a combination of carboplatin and paclitaxel.

42. The method of claim 38 wherein said chemotherapeutic agent comprises a fluorinated pyrimidine chemotherapeutic agent.

43. The method of claim 42 wherein said fluorinated pyrimidine chemotherapeutic agent is selected from the group consisting of carmofur, doxifluridine, fluorouracil, floxuridine, tegafur, capecitabine and uracil-ftorafur.

44. The method of claim 42 wherein said fluorinated pyrimidine chemotherapeutic agent is fluorouracil.

45. The method of claim 30 wherein said agent comprises a combination of cisplatin and gemcitabine.

46. The method of claim 30 wherein said cancer is a solid tumor cancer.

47. The method of claim 30 wherein said cancer is selected from the group consisting of breast cancer, gastric cancer, ovarian cancer, renal cancer, hepatic cancer, pancreatic cancer, bladder cancer, prostate cancer, colorectal cancer, and non-small cell lung cancer.

48. The method of claim 30 wherein said cancer is a colorectal cancer, said agent comprises a topoisomerase I inhibitor and a chemotherapeutic agent, and said compound is 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone.

49. The method of claim 48 wherein said topoisomerase I inhibitor is irinotecan and said chemotherapeutic agent is fluorouracil.

50. The method of claim 49 wherein the therapeutically effective amount of said compound is in the range from about 4 mg/m² to about 190 mg/m² per treatment.

51. The method of claim 50 wherein the therapeutically effective amount of irinotecan is in the range from about 75 mg/m² to about 400 mg/m² per treatment, the therapeutically effective amount of fluorouracil is in the range from about 375 mg/m² to about 600 mg/m² per treatment, and the therapeutically effective amount of leucovoran is in the range from about 20 mg/m² to about 200 mg/m² per treatment.

52. The method of claim 51 wherein the therapeutically effective amount of irinotecan is in the range from about 75 mg/m² to about 150 mg/m² per treatment, and wherein treatment with irinotecan occurs once weekly.

53. The method of claim 51 wherein the therapeutically effective amount of irinotecan is in the range from about 250 mg/m² to about 400 mg/m² per treatment, and wherein treatment with irinotecan occurs once every three weeks.

54. The method of claim 49 wherein administration is performed via continuous infusion.

55. The method of claim 49 wherein administration is performed via IV bolus.

56. The method of claim 49 wherein said irinotecan is administered orally.

57. The method of claim 49 wherein said irinotecan is administered parenterally.

58. The method of claim 30 wherein said cancer is a solid tumor, said agent comprises a topoisomerase I inhibitor and a chemotherapeutic agent, and said compound is 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone.

59. The method of claim 58 wherein said topoisomerase I inhibitor is irinotecan.

60. The method of claim 59 wherein said chemotherapeutic agent is cisplatin.

61. The method of claim 60 wherein the therapeutically effective amount of said compound is in the range from about 4 mg/m² to about 190 mg/m² per treatment.

62. The method of claim 60 wherein the therapeutically effective amount of irinotecan is in the range from about 75 mg/m² to about 400 mg/m² per treatment and the therapeutic effective amount of cisplatin is in the range from about 40 mg/m² to about 175 mg/m² per treatment.

63. The method of claim 62 wherein the therapeutically effective amount of irinotecan is in the range from about 75 mg/m² to about 150 mg/m² per treatment, and wherein treatment with irinotecan occurs once weekly.

64. The method of claim 62 wherein the therapeutically effective amount of irinotecan is in the range from about 250 mg/m² to about 400 mg/m² per treatment, and wherein treatment with irinotecan occurs once every three weeks.

65. The method of claim 62 wherein the therapeutically effective amount of cisplatin is in the range from about 40 mg/m² to about 110 mg/m² per treatment, and wherein treatment with cisplatin occurs once weekly.

66. The method of claim 62 wherein the therapeutically effective amount of cisplatin is in the range from about 75 mg/m² to about 175 mg/m² per treatment, and wherein treatment with cisplatin occurs once every three weeks.

67. The method of claim 60 wherein administration is performed via continuous infusion.

68. The method of claim 60 wherein administration is performed via IV bolus.

69. The method of claim 60 wherein said irinotecan is administered orally.

70. The method of claim 60 wherein said irinotecan is administered parenterally.

71. The method of claim 30 wherein said cancer is a solid tumor cancer, said agent comprises a topoisomerase I inhibitor, and said compound is 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone.

72. The method of claim 30 wherein said cancer is a colorectal cancer, said agent comprises a topoisomerase I inhibitor, and said compound is 3-[(2,4-dimethylpyrrol-5-yl) methylidenyl]-2-indolinone.

73. The method of claim 72 wherein said topoisomerase I inhibitor is irinotecan.

74. The method of claim 73 wherein the therapeutically effective amount of said compound is in the range from about 4 mg/m² to about 190 mg/m² per treatment.

75. The method of claim 73 wherein the therapeutically effective amount of irinotecan is in the range from about 75 mg/m² to about 400 mg/m² per treatment.

76. The method of claim 75 wherein the therapeutically effective amount of irinotecan is in the range from about 75 mg/m² to about 150 mg/m² per treatment, and wherein treatment with irinotecan occurs once weekly.

77. The method of claim 75 wherein the therapeutically effective amount of irinotecan is in the range from about 250 mg/m² to about 400 mg/m² per treatment, and wherein treatment with irinotecan occurs once every three weeks.

78. The method of claim 73 wherein administration is performed via continuous infusion.

79. The method of claim 73 wherein administration is performed via IV bolus.

80. The method of claim 73 wherein said irinotecan is administered orally.

81. The method of claim 73 wherein said irinotecan is administered parenterally.

82. The method of claim 30 wherein said cancer is a non-small cell lung cancer, said agent comprises a topoisomerase I inhibitor, and said compound is 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone.

83. The method of claim 82 wherein said agent further comprises a chemotherapeutic agent.

84. The method of claim 83 wherein said topoisomerase I inhibitor is irinotecan.

85. The method of claim 84 wherein said chemotherapeutic agent is cisplatin.

86. The method of claim 85 wherein the therapeutically effective amount of said compound is in the range from about 4 mg/m² to about 190 mg/m² per treatment.

87. The method of claim 85 wherein the therapeutically effective amount of irinotecan is in the range from about 75 mg/m² to about 400 mg/m² per treatment and the therapeutic effective amount of cisplatin is in the range from about 40 mg/m² to about 175 mg/m² per treatment.

88. The method of claim 87 wherein the therapeutically effective amount of irinotecan is in the range from about 75 mg/m² to about 150 mg/m² per treatment, and wherein treatment with irinotecan occurs once weekly.

89. The method of claim 87 wherein the therapeutically effective amount of irinotecan is in the range from about 250 mg/m² to about 400 mg/m² per treatment, and wherein treatment with irinotecan occurs once every three weeks.

90. The method of claim 87 wherein the therapeutically effective amount of cisplatin is in the range from about 40 mg/m² to about 110 mg/m² per treatment, and wherein treatment with cisplatin occurs once weekly.

91. The method of claim 87 wherein the therapeutically effective amount of cisplatin is in the range from about 75 mg/m² to about 175 mg/m² per treatment, and wherein treatment with cisplatin occurs once every three weeks.

92. The method of claim 85 wherein administration is performed via continuous infusion.

93. The method of claim 85 wherein administration is performed via IV bolus.

94. The method of claim 85 wherein said irinotecan is administered orally.

95. The method of claim 85 wherein said irinotecan is administered parenterally.

96. The method of claim 30 wherein said cancer is a non-small cell lung cancer, said agent comprises a chemotherapeutic agent, and said compound is 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone.

97. The method of claim 96 wherein said chemotherapeutic agent comprises a combination of carboplatin and paclitaxel.

98. The method of claim 97 wherein the therapeutically effective amount of said compound is in the range from about 4 mg/m² to about 190 mg/m² per treatment.

99. The method of claim 97 wherein the therapeutically effective amount of carboplatin is calculated to produce an AUC, calculated utilizing the Calvert formula, of about 6 mg/min/mL to about 8 mg/min/mL, and the therapeutic effective amount of paclitaxel is in the range from about 80 mg/m² to about 225 mg/m² per treatment.

100. The method of claim 97 wherein administration is performed via continuous infusion.

101. The method of claim 97 wherein administration is performed via IV bolus.

102. The method of claim 30 wherein said cancer is a solid tumor cancer, said agent comprises therapeutically effective amount of a chemotherapeutic agent, and said compound is 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]-2-indolinone.

103. The method of claim 30 wherein said solid tumor cancer is pancreatic cancer or a non-small cell lung cancer.

104. The method of claim 102 wherein said chemotherapeutic agent comprises a combination of cisplatin and gemcitabine.

105. The method of claim 104 wherein the therapeutically effective amount of said compound is in the range from about 4 mg/m² to about 190 mg/m² per treatment.

106. The method of claim 104 wherein the therapeutically effective amount of cisplatin is in the range from about 40 mg/m² to about 175 mg/m² per treatment, and the therapeutically effective amount of gemcitabine is in the range from about 750 mg/m² to about 1250 mg/m² per treatment.

107. The method of claim 104 wherein administration is performed via continuous infusion.

108. The method of claim 104 wherein administration is performed via IV bolus.

109. A combination useful for the treatment of cancer comprising:

(a) therapeutically effective amount(s) of at least one agent selected from the group consisting of topoisomerase I inhibitors, chemotherapeutic agents, leucovorin, and combinations thereof; and

(b) a therapeutically effective amount of a compound having the chemical structure;

110. A method f or the modulation of the catalytic activity of a protein kinase comprising contacting said protein kinase with a combination of claim 109.

111. The method of claim 110 wherein said protein kinase is selected from the group consisting of receptor protein tyrosine kinase, cellular tyrosine kinase and serine-threonine kinase.

112. A method for treating or preventing a protein kinase related disorder in an patient comprising administering a therapeutically effective amount of a combination of claim 109 to said patient.

113. The method of claim 112 wherein said protein kinase related disorder is selected from the group consisting of a receptor protein tyrosine kinase related disorder, a cellular tyrosine kinase disorder and a serine-threonine kinase related disorder.

114. The method of claim 112 wherein said protein kinase related disorder is a cancer selected from the group consisting of squamous cell carcinoma, astrocytoma, glioblastoma, lung cancer, bladder cancer, head and neck cancer, melanoma, ovarian cancer, prostate cancer, breast cancer, small-cell lung cancer, colorectal cancer, non-small-cell lung cancer, and glioma.

115. The method of claim 113 wherein said protein kinase related disorder is selected from the group consisting of diabetes, an autoimmune disorder, a hyperproliferation disorder, restenosis, fibrosis, psoriasis, osteoarthritis, rheumatoid arthritis, an inflammatory disorder and angiogenesis.

116. A method for treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a combination of claim 109.

117. The method of claim 116 wherein said cancer is pancreatic cancer.

118. The method of claim 117 wherein said agent comprises a chemotherapeutic agent selected from the group consisting of paclitaxel, carboplatin, liposomal doxorubicin, topotecan, and combinations thereof.

119. The method of claim 118 wherein said cancer is selected from the group consisting of ovarian, small-cell lung and kidney cancer.

120. A pharmaceutical composition comprising a combination of claim 109 and a pharmaceutically acceptable carrier or excipient.