METHODS OF USE FOR CYCLOPAMINE ANALOGS

• US 20110230509A1
• Filed: 04/20/2011
• Published: 09/22/2011
• Est. Priority Date: 12/28/2006
• Status: Abandoned Application

• Current Assignee: Johns Hopkins University, Royalty Security, LLC
• Original Assignee: Royalty Security, LLC
• Inventors: Grogan, Michael J., Castro, Alfredo C., Tremblay, Martin R., Matsui, William, McGovern, Karen J.
• Application Number:
  US13/090,694
• Publication Number:
  US 20110230509A1
• Time in Patent Office: Days
• US Class Current: 514/278
• 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

1-21. -21. (canceled)

22. A method of treating cancer of the hematopoietic system comprising administering to a patient a therapeutically effective amount of a compound of the formula:

23. The method of claim 22, wherein R¹ is H, —

OR, amino, sulfonamido, sulfamido, OC(O)R⁵ or N(R⁵)C(O)R⁵.

24. The method of claim 22, wherein R¹ is sulfonamido.

25. The method of claim 22, wherein R² is H or heterocycloalkyl.

26. The method of claim 25, wherein R² is H.

27. The method of claim 22, wherein R³ is H.

28. The method of claim 22, wherein R⁴ is H, alkyl, aralkyl, —

[(W)—

C(O)N(R)]_qR⁵ or —

[(W)—

N(R)C(O)]_qR⁵.

29. The method of claim 28, wherein R⁴ is H.

30. The method of claim 22, wherein said compound is epimerically pure.

31. The method of claim 22, wherein the compound is:

32. The method of claim 22, wherein the compound is:

33. The method of claim 32, wherein the cancer of the hematopoietic system is myeloma, leukemia or lymphoma.

34. The method of claim 33, wherein the myeloma is multiple myeloma.

35. The method of claim 33, wherein the leukemia is acute lymphatic leukemia, acute myelocytic leukemia, chronic myelocytic leukemia or chronic lymphocytic leukemia.

36. The method of claim 33, wherein the lymphoma is non-Hodgkin'"'"'s lymphoma.

37. The method of claim 32, wherein the cancer of the hematopoietic system is myelodysplastic syndrome.

38. The method of claim 32, wherein the compound is used in combination with one or more other chemotherapeutic agent, anti-cancer agent or anti-cancer treatment.

39. The method of claim 38, wherein the chemotherapeutic agent is doxorubicin, dexamethasone, prednisolone, chlorambucil, methotrexate, vinblastine, bortezomib, melphalan, carmustine, cyclophosphamide, vincristine, lenalidomide, thalidomide, cytarabine, fludarabine or idarubicin.

40. The method of claim 38, wherein the other anti-cancer agent is a corticosteroid or an interferon.

41. The method of claim 38, wherein the other anti-cancer treatment is radiation or surgery.

42. The method of claim 32, wherein the compound is administered locally to a tumor.

43. The method of claim 32, wherein the compound is administered systemically.

44. The method of claim 32, wherein the mode of administration of said compound is inhalation, oral, intravenous, sublingual, ocular, transdermal, rectal, vaginal, topical, intramuscular, intra-arterial, intrathecal, subcutaneous, buccal, or nasal.

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

46. The method of claim 32, wherein the pharmaceutically acceptable salt is a hydrochloride salt.