Cyclic protein tyrosine kinase inhibitors

• US 20040054186A1
• Filed: 03/24/2003
• Published: 03/18/2004
• Est. Priority Date: 04/15/1999
• Status: Active Grant

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Chen, Ping, Norris, Derek J., Wityak, John, Lombardo, Louis J., Das, Jagabandhu, Lee, Francis Y.F., Doweyko, Arthur M.P., Barrish, Joel C., Padmanabha, Ramesh
• Granted Patent: US 7,125,875 B2
• Time in Patent Office: Days
• US Class Current: 546/268.1
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07C 237/40 : having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07D 213/81 : Amides; Imides
• CPC Class Codes: C07D 213/82 : in position 3
• CPC Class Codes: C07D 231/38 : Nitrogen atoms nitro radicals C07D231/16
• CPC Class Codes: C07D 233/90 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 239/42 : One nitrogen atom nitro radicals C07D239/30
• CPC Class Codes: C07D 263/48 : Nitrogen atoms not forming part of a nitro radical
• CPC Class Codes: C07D 277/56 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 409/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/14 : containing three or more hetero rings

Abstract

Novel cyclic compounds and salts thereof, pharmaceutical compositions containing such compounds, and methods of using such compounds in the treatment of protein tyrosine kinase-associated disorders such as immunologic and oncologic disorders.

Claims

23. A method for the treatment of a protein tyrosine kinase-associated disorder, comprising the step of administering to a subject in need thereof an amount effective therefor of at least one compound of formula III or a salt thereof:

24. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is transplant rejection.

25. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is rheumatoid arthritis.

26. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is multiple sclerosis.

27. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is inflammatory bowel disease.

28. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is lupus.

29. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is graft vs. host disease.

30. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is a T-cell mediated hypersensitivity disease.

31. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is psoriasis.

32. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is Hashimoto'"'"'s thyroiditis.

33. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is Guillain-Barre syndrome.

34. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is a cancer.

35. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is contact dermatitis.

36. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is an allergic disease.

37. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is asthma.

38. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is ischemic or reperfusion injury.

39. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is atopic dermatitis.

40. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is allergic rhinitis.

41. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is chronic obstructive pulmonary disease.

42. The method of claim 23, wherein said protein tyrosine kinase-associated disorder is diabetic retinopathy.

43. The method of claim 23, wherein said protein tyrosine kinase is Lck.

44. The method of claim 23, wherein said protein tyrosine kinase is Fyn.

45. The method of claim 23, wherein said protein tyrosine kinase is Lyn.

46. The method of claim 23, wherein said protein tyrosine kinase is Hck.

47. The method of claim 23, wherein said protein tyrosine kinase is Fgr.

48. The method of claim 23, wherein said protein tyrosine kinase is Src.

49. The method of claim 23, wherein said protein tyrosine kinase is Yes.

50. The method of claim 23, wherein said protein tyrosine kinase is Blk.

51. The method of claim 23, wherein said protein tyrosine kinase is HER1.

52. The method of claim 23, wherein said protein tyrosine kinase is HER2.

53. The method of claim 23, wherein R₂ is other than heteroaryl and R₃ is aryl which is unsubstituted or substituted with Z₁, Z₂ and one or more groups Z₃.

54. The method of claim 23, wherein said compound of the formula III or salt thereof is administered, simultaneously or sequentially, with an antiinflammatory, antiproliferative, chemotherapeutic agent, immunosuppressant, anti-cancer, cytotoxic agent or PTK inhibitor other than a compound of the formula III or salt thereof.

55. The method of claim 54, wherein said compound of the formula III or salt thereof is administered with one or more of:

another PTK inhibitor;

cyclosporin A;

CTLA4-Ig;

antibodies selected from anti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, and monoclonal antibody OKT3;

agents blocking the interaction between CD40 and gp39;

fusion proteins constructed from CD40 and gp39;

inhibitors of NF-kappa B function;

non-steroidal antiinflammatory drugs (NSAIDs);

steroids;

gold compounds;

antiproliferative agents;

FK506 (tacrolimus, Prograf);

mycophenolate mofetil;

cytotoxic drugs;

TNF-α

inhibitors;

anti-TNF antibodies or soluble TNF receptor;

rapamycin (sirolimus or Rapamune);

leflunimide;

cyclooxygenase-2 inhibitors;

paclitaxel, cisplatin, carboplatin, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C, ecteinascidin 743, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin, etoposide, etoposide phosphate, teniposide, melphalan, vinblastine, vincristine, leurosidine, epothilone, vindesine, leurosine, or derivatives thereof.

56. A method for the treatment of a T cell mediated disorder, comprising the step of administering to a subject in need thereof an amount effective therefor of at least one compound of claim 23.

57. The method of claim 56, wherein T cell activation is inhibited.

59. A compound of formula II or salt thereof:

60. A compound of formula I or salt thereof

61. A compound of claim 60 wherein R₁ is hydrogen, halo, alkyl, aryl, alkoxy, alkoxycarbonyl, or aryloxycarbonyl.

62. A compound of claim 61 wherein R₁ is hydrogen.

63. A compound of claim 61 wherein R₂ is hydrogen.

64. A compound of claim 61 wherein R₄ is hydrogen.

65. A compound of claim 61 wherein R₅ is an aryl group which is substituted with Z₁, Z₂ and one or more groups Z₃.

66. A compound of claim 61 wherein R₁ is hydrogen or alkyl, R₂ and R₄ are independently hydrogen or alkyl, and R₅ is aryl which is unsubstituted or substituted with Z₁, Z₂ and one or more groups Z₃.

67. A compound of claim 66 wherein R₅ is aryl which is unsubstituted or independently substituted with one or more alkyl or halo.

68. A compound of claim 67 wherein R₃ is heteroaryl substituted optionally substituted with Z, and Z₂ and substituted with at least one group Z₃ where Z₃ is Z₆.

69. A compound of claim 68 wherein Z₆ is heterocyclo optionally substituted with one or more hydroxyalkyl.

71. A method for the treatment of a protein tyrosine kinase-associated disorder, comprising the step of administering to a subject in need thereof an amount effective therefor of at least one compound of claim 60 or claim 70.

72. A pharmaceutical composition for the treatment of a protein tyrosine kinase-associated disorder, comprising a pharmaceutically acceptable vehicle or diluent and at least one compound of claim 60 or claim 70.

70. A compound of formula I or salt thereof

73. A compound of formula II or salt thereof

74. A compound of claim 73 wherein R₁ is hydrogen or alkyl, R₂ and R₄ are independently hydrogen or alkyl, and R₅ is aryl which is unsubstituted or substituted with Z₁, Z₂ and one or more groups Z₃.

75. A compound of claim 74 wherein R₅ is aryl which is unsubstituted or independently substituted with one or more alkyl or halo.

76. A compound of claim 75 wherein R₃ is heteroaryl substituted optionally substituted with Z₁ and Z₂ and substituted with at least one group Z₃ where Z₃ is Z₆.

77. A compound of claim 76 wherein Z₆ is heterocyclo optionally substituted with one or more hydroxyalkyl.

78. A method for the treatment of a protein tyrosine kinase-associated disorder, comprising the step of administering to a subject in need thereof an effective amount of the compound of claim 73.

79. A method of claim 78 wherein the compound of claim 73 is administered with at least one additional therapeutic agent selected from cyclosporin A;

CTLA4-Ig;

antibodies selected from anti-ICAM-3, anti-IL-2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti-CD4, anti-CD80, anti-CD86, and monoclonal antibody OKT3;

agents blocking the interaction between CD40 and gp39;

fusion proteins constructed from CD40 and gp39;

inhibitors of NF-kappa B function;

non-steroidal antiinflammatory drugs;

steroids;

gold compounds;

antiproliferative agents;

FK506;

mycophenolate mofetil;

cytotoxic drugs;

TNF-α

inhibitors;

anti-TNF antibodies or soluble TNF receptor;

rapamycin;

leflunimide;

cyclooxygenase-2 inhibitors;

paclitaxel, cisplatin, carboplatin, doxorubicin, carminomycin, daunorubicin, aminopterin, methotrexate, methopterin, mitomycin C, ecteinascidin 743, porfiromycin, 5-fluorouracil, 6-mercaptopurine, gemcitabine, cytosine arabinoside, podophyllotoxin, etoposide, etoposide phosphate, teniposide, melphalan, vinblastine, vincristine, leurosidine, epothilone, vindesine, or leurosine.

80. A method of claim 79 wherein the portein tyrosine kinase-associated disorder is transplant rejection, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, lupus, graft vs. host disease, T-cell mediated hypersensitivity disease, psoriasis, Hashimoto'"'"'s thyroiditis, Guillian-Barre syndrome, contact dermatitis, allergic disease, asthma, ischemic or reperfusion injury, atopic dermatitis, allergic rhinitis, chronic obstructive pulmonary disease, or diabetic retinopathy.

81. A method of claim 78 wherein the portein tyrosine kinase-associated disorder is cancer.

82. A compound of formula III:

83. A method for the treatment of a protein tyrosine kinase-associated disorder comprising administering to a subject in need thereof an effective amount of the compound of claim 82.

84. The method of claim 83 wherein the protein tyrosine kinase-associated disorder is cancer.

85. The method of claim 84 wherein the cancer is chronic myelogenous leukemia (CML), gastrointestinal stromal tumor (GIST), small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), ovarian cancer, melanoma, mastocytosis, germ cell tumors, acute myelogenous leukemia (AML), pediatric sarcomas, breast cancer, colorectal cancer, pancreatic cancer, or prostate cancer.

86. The method of claim 84 wherein the cancer is sensitive to treatment by an inhibitor of BCR-ABL kinase.

87. The method of claim 84 wherein the cancer is resistant to treatment by an inhibitor of BCR-ABL kinase.

88. A method for the treatment of a protein tyrosine kinase-associated disorder comprising administering to a subject in need thereof an effective amount of the compound of formula IV:

89-1. The method of claim 89 wherein the cancer is chronic myelogenous leukemia (CML), gastrointestinal stromal tumor (GIST), small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), ovarian cancer, melanoma, mastocytosis, germ cell tumors, acute myelogenous leukemia (AML), pediatric sarcomas, breast cancer, colorectal cancer, pancreatic cancer, or prostate cancer.

92. A method for the treatment of a protein tyrosine kinase-associated disorder comprising administering to a subject in need thereof an effective amount of a therapeutic agent and an effective amount of a compound of formula III:

93. The method of claim 92 wherein the therapeutic agent is administered following administration of the compound of formula III.

94. The method of claim 92 wherein the therapeutic agent is administered prior to administration of the compound of formula III.

95. The method of claim 92 wherein the therapeutic agent is administered simultaneously with administration of the compound of formula III.

96. The method of claim 92 wherein the protein tyrosine kinase-associated disorder is cancer.

97. The method of claim 96 wherein the cancer is chronic myelogenous leukemia (CML), gastrointestinal stromal tumor (GIST), small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), ovarian cancer, melanoma, mastocytosis, germ cell tumors, acute myelogenous leukemia (AML), pediatric sarcomas, breast cancer, colorectal cancer, pancreatic cancer, or prostate cancer.

98. The method of claim 96 wherein the compound of formula III is the compound of formula IV:

99. The method of claim 97 wherein the compound of formula III is the compound of formula IV: