Smoothened antagonism for the treatment of hedgehog pathway-related disorders

• US 8,778,927 B2
• Filed: 09/28/2009
• Issued: 07/15/2014
• Est. Priority Date: 10/01/2008
• Status: Active Grant

• Current Assignee: Novartis Ag
• Original Assignee: Novartis Ag
• Inventors: Dorsch, Marion, Monahan, John E., Morrissey, Michael Patrick, Pan, Shifeng, Williams, Juliet
• Primary Examiner(s): SHIAO, REI TSANG
• Application Number:
  US13/119,072
• Publication Number:
  US 20110183962A1
• Time in Patent Office: 1,751 Days
• Field of Search: 514/211.08, 514/235.5
• 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. A method for treating a brain cancer or tumor selected from medulloblastoma, glioblastoma or glioma 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 -bipheny-3-carboxylic acid [6-(cis-2,6-dimethyl-morpholin-4-yl)-pyridin-3-yl]-amide or a pharmaceutically acceptable salt thereof and the PI3 kinase inhibitor is 5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-vlamine, 2-methyl-2-[4-3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-1-yl) -phenyl]-propionitrile, or 8-(6-methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl -phenyl)-1,3-dihydro-imidazol[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the medulloblastoma is from a resistant tumor.

3. The method of claim 1, wherein the PI3 kinase inhibitor is 5-(2,6-di-morpholin-4-yl -pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine.

4. The method of claim 1, wherein the PI3 kinase inhibitor is 2-methyl-2[4-(3-methyl -2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-l-yl)-phenyl]-propionitrile.

5. The method of claim 1, wherein the PI3 kinase inhibitor is 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.

6. The method of claim 1, wherein the patient has medulloblastoma.

7. The method of claim 1, wherein the patient has glioblastoma.

8. The method of claim 1, wherein the patient has glioma.

10. The method of claim 1, wherein the patient has breast cancer.

11. The method of claim 1, wherein the patient has pancreatic cancer.

12. The method of claim 1, wherein the patient has colorectal cancer.

9. A method for treating Hedgehog pathway related breast cancer, pancreatic cancer or colorectal 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 or a pharmaceutically acceptable salt thereof and the PI3 kinase inhibitor is 5-(2,6-di-morpholin-4-yl-pyrimidin-4-yl)-4-trifluoromethyl-pyridin-2-ylamine, 2-methyl-2-[4-(3-methyl-2-oxo-8-quinolin-3-yl-2,3-dihydro-imidazo[4,5-c]quinolin-I-yl)-phenyl]-propionitrile, or 8-(6-methoxy-pyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethyl-phenyl)-I,3-dihydro-imidazo[4,5-c]quinolin-2-one, or a pharmaceutically acceptable salt thereof.