Methods of use of cyclopamine analogs

• US 8,227,509 B2
• Filed: 07/27/2011
• Issued: 07/24/2012
• Est. Priority Date: 12/28/2006
• Status: Active Grant

• Current Assignee: Royalty Security, LLC
• Original Assignee: Infinity Pharmaceuticals, Inc.
• Inventors: Castro, Alfredo C., Grogan, Michael J., Matsui, William, McGovern, Karen J., Tremblay, Martin R.
• Primary Examiner(s): Kosar, Andrew D
• Assistant Examiner(s): COVINGTON, RAYMOND K
• Application Number:
  US13/191,545
• Publication Number:
  US 20120077834A1
• Time in Patent Office: 363 Days
• Field of Search: 514/455, 514/47, 514/162, 514/278
• US Class Current: 514/455
• CPC Class Codes: A61K 31/17 having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64
• CPC Class Codes: A61K 31/196 the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/4355 the heterocyclic ring system containing a five-membered ring having oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/4745 condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines yohimbine derivatives, vinblastine A61K31/475; ergoline derivatives A61K31/48
• CPC Class Codes: A61K 31/519 ortho- or peri-condensed with heterocyclic rings
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 31/573 substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
• CPC Class Codes: A61K 31/58 containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/664 Amides of phosphorus acids
• CPC Class Codes: A61K 31/69 Boron compounds
• CPC Class Codes: A61K 31/704 attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin digitoxin A61K31/7048
• CPC Class Codes: A61K 31/7068 having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic acid
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 9/0014 Skin, i.e. galenical aspects of topical compositions non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00
• CPC Class Codes: A61N 5/10 X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy A61N5/01 takes precedence
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 35/04 : specific for metastasis
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 307/94 : spiro-condensed with carbocyclic rings or ring systems, e.g. griseofulvins
• CPC Class Codes: C07D 471/04 : Ortho-condensed systems
• CPC Class Codes: C07D 471/10 : Spiro-condensed systems
• CPC Class Codes: C07D 491/04 : Ortho-condensed systems
• CPC Class Codes: C07D 491/048 : the oxygen-containing ring being five-membered
• CPC Class Codes: C07D 491/10 : Spiro-condensed systems
• CPC Class Codes: C07D 491/107 : with only one oxygen atom as ring hetero atom in the oxygen-containing ring
• CPC Class Codes: C07J 69/00 : Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by contraction of only one ring by one atom and expansion of only one ring by one atom

Abstract

The invention provides methods for treating various conditions using derivatives of cyclopamine having the following formula:

Claims

1. A method for treating a cancer in a mammal, comprising administering to the mammal a compound selected from:

2. The method of claim 1, wherein each of the one or more other cancer treatments is chosen from one or more of:

one or more other chemotherapeutics;

radiation therapy;

a surgical treatment;

one or more biotherapeutics;

one or more anti-estrogens;

one or more anti-androgens;

endocrine therapy, or one or more LHRH agonists.

3. The method of claim 2, wherein at least one of the one or more other cancer treatments comprises administering one or more other chemotherapeutics.

4. The method of claim 3, wherein each of the one or more other chemotherapeutics is independently selected from gemcitabine, methotrexate, taxol, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposides, prednisolone, dexamethasone, cytarbine, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, asparaginase, vinblastine, vincristine, and vinorelbine.

5. The method of claim 3, wherein each of the one or more other chemotherapeutics is independently selected from a nitrogen mustard, a nitrosourea, an alkylsulphonate, a triazene, a platinum containing compound, a vinca alkaloid, a taxoid, an epipodophyllin, an anti-metabolite, a DHFR inhibitor, an IMP dehydrogenase Inhibitor, a ribonucleotide reductase inhibitor, a uracil analog, a cytosine analog, a purine analog, a Vitamin D3 analog, an isoprenylation inhibitor, a dopaminergic neurotoxin, a cell cycle inhibitor, an actinomycin, a bleomycin, an anthracycline, an MDR inhibitor, a Ca²⁺ ATPase inhibitor, imatinib, thalidomide, lenalidomide, erlotinib, gefitinib, sorafenib, sunitinib, and a proteasome inhibitor.

6. The method of claim 5, wherein each of the one or more other chemotherapeutics is independently selected from cyclophosphamide, Ifosfamide, Trofosfamide, Chlorambucil, Estramustine, Melphalan, carmustine (BCNU), Lomustine (CCNU), busulfan, Treosulfan, Dacarbazine, Temozolomide, Cisplatin, Carboplatin, oxaliplatin, Vindesine, paclitaxel, Docetaxol, etoposide, Teniposide, Topotecan, 9-Aminocamptothecin, Camptoirinotecan, Crisnatol, Mytomycin C, methotrexate, Trimetrexate, mycophenolic acid, Tiazofurin, Ribavirin, EICAR, hydroxyurea, Deferoxamine, Fluorouracil, Floxuridine, Doxifluridine, Ratitrexed, Capecitabine, cytarabine (ara C), Cytosine arabinoside, Fludarabine, mercaptopurine, Thioguanine, EB 1089, CB 1093, KH 1060, Lovastatin, 1-methyl-4-phenylpyridinium ion, staurosporine, Actinomycin D, Dactinomycin, bleomycin A2, Bleomycin B2, Peplomycin, daunorubicin, Doxorubicin (adriamycin), Idarubicin, Epirubicin, Pirarubicin, Zorubicin, Mitoxantrone, verapamil, and thapsigargin.

7. The method of claim 3, wherein each of the one or more other chemotherapeutics is independently selected from gemcitabine, Cisplatin, Epirubicin, and Fluorouracil.

8. The method of claim 3, wherein at least one of the one or more other chemotherapeutics is gemcitabine.

9. The method of claim 3, wherein at least one of the one or more chemotherapeutics is imatinib, thalidomide, lenalidomide, erlotinib, gefitinib, sorafenib, sunitinib, or bortezomib.

10. The method of claim 2, wherein at least one of the one or more other cancer treatments comprises administering one or more biotherapeutics.

11. The method of claim 10, wherein administering one or more biotherapeutics comprises administering one or more antibodies.

12. The method of claim 11, wherein at least one of the one or more antibodies is chosen from Avastin, Erbitux, Rituxan, or Bexxar.

13. The method of claim 2, wherein at least one of the one or more other cancer treatments comprises administering one or more anti-estrogens.

14. The method of claim 13, wherein at least one of the one or more anti-estrogens is chosen from Tamoxifen, Raloxifene, or Megestrol.

15. The method of claim 2, wherein at least one of the one or more other cancer treatments comprises radiation therapy or a surgical treatment.

16. The method of claim 1, wherein the method comprises administering the compound or pharmaceutically acceptable salt thereof in combination with a first other cancer treatment.

17. The method of claim 16, wherein the first other cancer treatment comprises administering one or more other chemotherapeutics.

18. The method of claim 17, wherein the first other cancer treatment comprises administering one chemotherapeutic.

19. The method of claim 18, wherein the chemotherapeutic is gemcitabine.

20. The method of claim 1, wherein the method comprises administering the compound or pharmaceutically acceptable salt thereof in combination with a first other cancer treatment and a second other cancer treatment.

21. The method of claim 20, wherein the first other cancer treatment comprises administering one or more other chemotherapeutics, and the second other cancer treatment comprises radiation therapy or a surgical treatment.

22. The method of claim 21, wherein at least one of the one or more other chemotherapeutics is gemcitabine.

23. The method of claim 1, wherein the cancer is chosen from one or more of:

a cancer of the pulmonary system, a brain cancer, a cancer of the gastrointestinal tract, a skin cancer, a genitourinary cancer, a pancreatic cancer, a lung cancer, a medullobastoma, a basal cell carcinoma, a breast cancer, a prostate cancer, an esophageal cancer, a hepatocellular cancer, a gastric cancer, a gastrointestinal stromal tumor (GIST), a colon cancer, a colorectal cancer, an ovarian cancer, a melanoma, head and neck cancer, polycythemia Vera, Waldenstrom'"'"'s macroglobulinemia, heavy chain disease, essential thrombocythemia, a soft-tissue sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, a chondrosarcoma, an osteogenic sarcoma, a chordoma, an angiosarcoma, an endotheliosarcoma, a lymphangiosarcoma, a lymphangioendotheliosarcoma, a synovioma, a mesothelioma, a leiomyosarcoma, a bladder carcinoma, a squamous cell carcinoma, a renal cell carcinoma, a hepatoma, a bile duct carcinoma, a neuroendocrine cancer, or a carcinoid tumor.

24. The method of claim 1, wherein the cancer is chosen from one or more of:

a cancer of the pulmonary system, a cancer of the gastrointestinal tract, a skin cancer, a genitourinary cancer, a pancreatic cancer, a lung cancer, a medullobastoma, a basal cell carcinoma, a prostate cancer, an esophageal cancer, a hepatocellular cancer, a gastric cancer, a gastrointestinal stromal tumor (GIST), a colon cancer, a colorectal cancer, an ovarian cancer, a melanoma, head and neck cancer, polycythemia Vera, essential thrombocythemia, a soft-tissue sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, a chondrosarcoma, an osteogenic sarcoma, a chordoma, an angiosarcoma, an endotheliosarcoma, a lymphangiosarcoma, a lymphangioendotheliosarcoma, a synovioma, a leiomyosarcoma, a bladder carcinoma, a squamous cell carcinoma, a hepatoma, a bile duct carcinoma, a neuroendocrine cancer, or a carcinoid tumor.

25. The method of claim 1, wherein the cancer is selected from of basal cell carcinoma, bile duct carcinoma, bladder carcinoma, breast cancer, chondrosarcoma, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, glioma, hepatocellular cancer, lung cancer, medulloblastoma, melanoma, neuroectodermal tumors, osteogenic sarcoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and testicular cancer.

26. The method of claim 1, wherein the cancer is selected from basal cell carcinoma, breast cancer, chondrosarcoma, colon cancer, esophageal cancer, gastric cancer, glioma, hepatocellular cancer, lung cancer, medulloblastoma, osteogenic sarcoma, ovarian cancer, pancreatic cancer, and prostate cancer.

27. The method of claim 1, wherein the cancer is pancreatic cancer.

28. The method of claim 1, wherein the cancer is chondrosarcoma.

29. The method of claim 1, wherein the cancer is lung cancer.

30. The method of claim 29, wherein the lung cancer selected from small cell lung cancer and non-small cell lung cancer.

31. The method of claim 1, wherein the cancer is basal cell carcinoma.

32. The method of claim 1, wherein the cancer is medulloblastoma.

33. The method of claim 1, wherein the cancer is ovarian cancer.

34. The method according to claim 1, wherein the cancer is osteogenic sarcoma.

35. The method according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof and the one or more other cancer treatments are administered concurrently.

36. The method according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof and the one or more other cancer treatments are administered within the same treatment protocol.

37. The method according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof and the one or more other cancer treatments are administered sequentially.

38. The method according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof and the one or more other cancer treatments are administered with a time interval in between.

39. The method according to claim 1, wherein the compound or pharmaceutically acceptable salt thereof is administered first followed by administration of the other cancer treatment.

40. The method according to claim 1, wherein the other cancer treatment is administered first followed by administration of the compound or pharmaceutically acceptable salt thereof.

41. The method of claim 1, wherein the compound or pharmaceutically acceptable salt thereof is administered locally to a tumor.

42. The method of claim 1, wherein the compound or pharmaceutically acceptable salt thereof is administered systemically.

43. The method of claim 1, wherein the mode of administration of the compound or pharmaceutically acceptable salt thereof is inhalation, oral, intravenous, sublingual, ocular, transdermal, rectal, vaginal, topical, intramuscular, intraperitoneal, epidural, subcutaneous, buccal, or nasal.

44. The method of claim 43, wherein the mode of administration is oral, intravenous, or topical.

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

46. A method for treating cancer, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the formula:

47. The method of claim 46, wherein each of the one or more other cancer treatments is chosen from one or more of:

one or more other chemotherapeutics;

radiation therapy;

a surgical treatment;

one or more biotherapeutics;

one or more anti-estrogens;

one or more anti-androgens;

endocrine therapy, or one or more LHRH agonists.

48. The method of claim 47, wherein at least one of the one or more other cancer treatments comprises administering one or more other chemotherapeutics.

49. The method of claim 48, wherein each of the one or more other chemotherapeutics is independently selected from gemcitabine, methotrexate, taxol, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposides, prednisolone, dexamethasone, cytarbine, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, asparaginase, vinblastine, vincristine, and vinorelbine.

50. The method of claim 48, wherein each of the one or more other chemotherapeutics is independently selected from a nitrogen mustard, a nitrosourea, an alkylsulphonate, a triazene, a platinum containing compound, a vinca alkaloid, a taxoid, an epipodophyllin, an anti-metabolite, a DHFR inhibitor, an IMP dehydrogenase Inhibitor, a ribonucleotide reductase inhibitor, a uracil analog, a cytosine analog, a purine analog, a Vitamin D3 analog, an isoprenylation inhibitor, a dopaminergic neurotoxin, a cell cycle inhibitor, an actinomycin, a bleomycin, an anthracycline, an MDR inhibitor, a Ca²⁺ ATPase inhibitor, imatinib, thalidomide, lenalidomide, erlotinib, gefitinib, sorafenib, sunitinib, and a proteasome inhibitor.

51. The method of claim 50, wherein each of the one or more other chemotherapeutics is independently selected from cyclophosphamide, Ifosfamide, Trofosfamide, Chlorambucil, Estramustine, Melphalan, carmustine (BCNU), Lomustine (CCNU), busulfan, Treosulfan, Dacarbazine, Temozolomide, Cisplatin, Carboplatin, oxaliplatin, Vindesine, paclitaxel, Docetaxol, etoposide, Teniposide, Topotecan, 9-Aminocamptothecin, Camptoirinotecan, Crisnatol, Mytomycin C, methotrexate, Trimetrexate, mycophenolic acid, Tiazofurin, Ribavirin, EICAR, hydroxyurea, Deferoxamine, Fluorouracil, Floxuridine, Doxifluridine, Ratitrexed, Capecitabine, cytarabine (ara C), Cytosine arabinoside, Fludarabine, mercaptopurine, Thioguanine, EB 1089, CB 1093, KH 1060, Lovastatin, 1-methyl-4-phenylpyridinium ion, staurosporine, Actinomycin D, Dactinomycin, bleomycin A2, Bleomycin B2, Peplomycin, daunorubicin, Doxorubicin (adriamycin), Idarubicin, Epirubicin, Pirarubicin, Zorubicin, Mitoxantrone, verapamil, and thapsigargin.

52. The method of claim 48, wherein each of the one or more other chemotherapeutics is independently selected from gemcitabine, Cisplatin, Epirubicin, and Fluorouracil.

53. The method of claim 48, wherein at least one of the one or more other chemotherapeutics is gemcitabine.

54. The method of claim 48, wherein at least one of the one or more chemotherapeutics is imatinib, thalidomide, lenalidomide, erlotinib, gefitinib, sorafenib, sunitinib, or bortezomib.

55. The method of claim 47, wherein at least one of the one or more other cancer treatments comprises administering one or more biotherapeutics.

56. The method of claim 55, wherein administering one or more biotherapeutics comprises administering one or more antibodies.

57. The method of claim 56, wherein at least one of the one or more antibodies is chosen from Avastin, Erbitux, Rituxan, or Bexxar.

58. The method of claim 47, wherein at least one of the one or more other cancer treatments comprises administering one or more anti-estrogens.

59. The method of claim 58, wherein at least one of the one or more anti-estrogens is chosen from Tamoxifen, Raloxifene, or Megestrol.

60. The method of claim 47, wherein at least one of the one or more other cancer treatments comprises radiation therapy or a surgical treatment.

61. The method of claim 46, wherein the method comprises administering the compound or pharmaceutically acceptable salt thereof in combination with a first other cancer treatment.

62. The method of claim 61, wherein the first other cancer treatment comprises administering one or more other chemotherapeutics.

63. The method of claim 62, wherein the first other cancer treatment comprises administering one chemotherapeutic.

64. The method of claim 63, wherein the chemotherapeutic is gemcitabine.

65. The method of claim 46, wherein the method comprises administering the compound or pharmaceutically acceptable salt thereof in combination with a first other cancer treatment and a second other cancer treatment.

66. The method of claim 65, wherein the first other cancer treatment comprises administering one or more other chemotherapeutics, and the second other cancer treatment comprises radiation therapy or a surgical treatment.

67. The method of claim 66, wherein at least one of the one or more other chemotherapeutics is gemcitabine.

68. The method of claim 46, wherein the cancer is chosen from one or more of:

a cancer of the pulmonary system, a brain cancer, a cancer of the gastrointestinal tract, a skin cancer, a genitourinary cancer, a pancreatic cancer, a lung cancer, a medullobastoma, a basal cell carcinoma, a breast cancer, a prostate cancer, an esophageal cancer, a hepatocellular cancer, a gastric cancer, a gastrointestinal stromal tumor (GIST), a colon cancer, a colorectal cancer, an ovarian cancer, a melanoma, head and neck cancer, polycythemia Vera, Waldenstrom'"'"'s macroglobulinemia, heavy chain disease, essential thrombocythemia, a soft-tissue sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, a chondrosarcoma, an osteogenic sarcoma, a chordoma, an angiosarcoma, an endotheliosarcoma, a lymphangiosarcoma, a lymphangioendotheliosarcoma, a synovioma, a mesothelioma, a leiomyosarcoma, a bladder carcinoma, a squamous cell carcinoma, a renal cell carcinoma, a hepatoma, a bile duct carcinoma, a neuroendocrine cancer, or a carcinoid tumor.

69. The method of claim 46, wherein the cancer is chosen from one or more of:

a cancer of the pulmonary system, a cancer of the gastrointestinal tract, a skin cancer, a genitourinary cancer, a pancreatic cancer, a lung cancer, a medullobastoma, a basal cell carcinoma, a prostate cancer, an esophageal cancer, a hepatocellular cancer, a gastric cancer, a gastrointestinal stromal tumor (GIST), a colon cancer, a colorectal cancer, an ovarian cancer, a melanoma, head and neck cancer, polycythemia Vera, essential thrombocythemia, a soft-tissue sarcoma, fibrosarcoma, myxosarcoma, liposarcoma, a chondrosarcoma, an osteogenic sarcoma, a chordoma, an angiosarcoma, an endotheliosarcoma, a lymphangiosarcoma, a lymphangioendotheliosarcoma, a synovioma, a leiomyosarcoma, a bladder carcinoma, a squamous cell carcinoma, a hepatoma, a bile duct carcinoma, a neuroendocrine cancer, or a carcinoid tumor.

70. The method of claim 46, wherein the cancer is selected from basal cell carcinoma, bile duct carcinoma, bladder carcinoma, breast cancer, chondrosarcoma, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, glioma, hepatocellular cancer, lung cancer, medulloblastoma, melanoma, neuroectodermal tumors, osteogenic sarcoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, and testicular cancer.

71. The method of claim 46, wherein the cancer is selected from basal cell carcinoma, breast cancer, chondrosarcoma, colon cancer, esophageal cancer, gastric cancer, glioma, hepatocellular cancer, lung cancer, medulloblastoma, osteogenic sarcoma, ovarian cancer, pancreatic cancer, and prostate cancer.

72. The method of claim 46, wherein the cancer is pancreatic cancer.

73. The method of claim 46, wherein the cancer is chondrosarcoma.

74. The method of claim 46, wherein the cancer is lung cancer.

75. The method of claim 74, wherein the lung cancer selected from small cell lung cancer and non-small cell lung cancer.

76. The method of claim 46, wherein the cancer is basal cell carcinoma.

77. The method of claim 46, wherein the cancer is medulloblastoma.

78. The method of claim 46, wherein the cancer is ovarian cancer.

79. The method according to claim 46, wherein the cancer is osteogenic sarcoma.

80. The method according to claim 46, wherein the compound or pharmaceutically acceptable salt thereof and the one or more other cancer treatments are administered concurrently.

81. The method according to claim 46, wherein the compound or pharmaceutically acceptable salt thereof and the one or more other cancer treatments are administered within the same treatment protocol.

82. The method according to claim 46, wherein the compound or pharmaceutically acceptable salt thereof and the one or more other cancer treatments are administered sequentially.

83. The method according to claim 46, wherein the compound or pharmaceutically acceptable salt thereof and the one or more other cancer treatments are administered with a time interval in between.

84. The method according to claim 46, wherein the compound or pharmaceutically acceptable salt thereof is administered first followed by administration of the other cancer treatment.

85. The method according to claim 46, wherein the other cancer treatment is administered first followed by administration of the compound or pharmaceutically acceptable salt thereof.

86. The method of claim 46, wherein the compound or pharmaceutically acceptable salt thereof is administered locally to a tumor.

87. The method of claim 46, wherein the compound or pharmaceutically acceptable salt thereof is administered systemically.

88. The method of claim 46, wherein the mode of administration of the compound or pharmaceutically acceptable salt thereof is inhalation, oral, intravenous, sublingual, ocular, transdermal, rectal, vaginal, topical, intramuscular, intraperitoneal, epidural, subcutaneous, buccal, or nasal.

89. The method of claim 88, wherein the mode of administration is oral, intravenous, or topical.

90. The method of claim 46, wherein the mammal is a human.

91. A method for treating pancreatic cancer, which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of the formula:

92. The method of claim 91, wherein the pharmaceutically acceptable salt is a hydrochloride salt.