SMOOTHENED ANTAGONISM FOR THE TREATMENT OF HEDGEHOG PATHWAY-RELATED DISORDERS

• US 20110183962A1
• Filed: 09/28/2009
• Published: 07/28/2011
• Est. Priority Date: 10/01/2008
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Morrissey, Michael Patrick, Williams, Juliet, Pan, Shifeng, Dorsch, Marion, Monahan, John E.
• Granted Patent: US 8,778,927 B2
• Time in Patent Office: Days
• US Class Current: 514/211.08
• 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 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/366 having six-membered rings, e.g. delta-lactones
• CPC Class Codes: A61K 31/4184 condensed with carbocyclic rings, e.g. benzimidazoles
• CPC Class Codes: A61K 31/4402 only substituted in position 2, e.g. pheniramine, bisacodyl
• CPC Class Codes: A61K 31/4433 containing a six-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4545 containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
• 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 31/502 ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The invention provides methods for modulating, e.g., antagonizing, the activity of the Hedgehog signaling pathway, and for treating Hedgehog related disorders such as cancers (e.g., medulloblastoma). In particular, the invention provides methods for inhibiting aberrant growth states resulting from phenotypes such as Ptch loss-of-function, Hedgehog gain-of-function, smoothened gain-of-function or Gli gain-of-function by administering to a mammal combinations of Smoothened inhibitors (e.g., a compound of Formula I, Formula II, or Formula III, or any of the compounds listed herein or incorporated by reference) and cholesterol biosynthesis pathway inhibitors (e.g., statins), Gli inhibitors, and/or Phosphatidylinositol 3-kinase (PI3K) inhibitors.

Claims

1-32. -32. (canceled)

33. A method for treating a Hedgehog-related cancer in a patient in need thereof comprising administering to the patient a Smoothened inhibitor and a PI3 kinase inhibitor, wherein the Smoothened inhibitor is 2-methyl-4′

-trifluoromethoxy-biphenyl-3-carboxylic acid [6-(cis-2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, N-[4-chloro-3-(5-dimethylamino-1H-benzoimidazol-2-yl)-phenyl]-3,5-dimethoxy-benzamide, 2-[(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′

-yl]-propan-2-ol or a pharmaceutically acceptable salt thereof.

34. The method of claim 33, wherein the cancer is a medulloblastoma.

35. The method of claim 33, wherein the cancer is from a resistant tumor.

36. The method of claim 33, wherein the PI3 kinase inhibitor is selected from -methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl)-phenyl]-propionitrile, compound 8-(6-methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-1,3-dihydro-imidazo[4,5-c]quinolin-2-one BGT, 5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine or a pharmaceutically acceptable salt thereof.

37. A method for treating a Hedgehog-related cancer in a patient in need thereof comprising administering to the patient a Smoothened inhibitor and a Gli inhibitor, wherein the Smoothened inhibitor is 2-methyl-4′

-trifluoromethoxy-biphenyl-3-carboxylic acid [6-(cis-2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, N-[4-chloro-3-(5-dimethylamino-1H-benzoimidazol-2-yl)-phenyl]-3,5-dimethoxy-benzamide or 2-[(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′

-yl]-propan-2-ol or a pharmaceutically acceptable salt thereof.

38. The method of claim 37, wherein the cancer is a medulloblastoma.

39. The method of claim 37, wherein the cancer is from a resistant tumor.

40. The method of claim 37, wherein the Gli inhibitor is selected from GANT61 and GANT58.

41. The method of claim 37, wherein the Gli inhibitor is selected from zerumbone, zerumbone epoxide, staurosporinone, 6-hydroxystaurosporinone, arcyriaflavin C, and 5,6-dihydroxyarcyriaflavin A, physalin F, and physalin B.

42. A method for treating a Hedgehog-related cancer in a patient in need thereof comprising administering to the patient a Smoothened inhibitor and a statin, wherein the Smoothened inhibitor is 2-methyl-4′

-trifluoromethoxy-biphenyl-3-carboxylic acid [6-(cis-2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide, N-[4-chloro-3-(5-dimethylamino-1H-benzoimidazol-2-yl)-phenyl]-3,5-dimethoxy-benzamide, 2-[(R)-4-(6-benzyl-4,5-dimethyl-pyridazin-3-yl)-2-methyl-3,4,5,6-tetrahydro-2H-[1,2]bipyrazinyl-5′

-yl]-propan-2-ol or a pharmaceutically acceptable salt thereof.

43. The method of claim 42, wherein the cancer is a medulloblastoma.

44. The method of claim 42, wherein the cancer is from a resistant tumor.

45. The method of claim 42, wherein the statin is selected from pravastatin, simvastatin, lovastatin, fluvastatin, atorvastatin, cerivastatin, rosuvastatin, and pitavastatin.