Purine diones as wnt pathway modulators

Patent metadata

Field	Value
Publication number	US-2020190086-A1
Application number	US-201916716268-A
Country	US
Kind code	A1
Filing date	Dec 16, 2019
Priority date	May 23, 2013
Publication date	Jun 18, 2020
Grant date	—

Abstract

The invention relates to the use of compounds of general structure (I) in modulation of the Wnt pathway [Formula should be inserted here] wherein R 1 , R 2 , R 3 , R 4 and R 5 are each, independently, H or an alkyl group; D is selected from the group consisting of H, halogen, alkyl, cycloalkyl, aryl, and dialkylamino, each (other than H and halogen) being optionally substituted; Ar is an aryl or heteroaryl group, optionally substituted; Cy is an aryl, heteroaryl or a saturated ring containing at least one heteroatom, each being optionally substituted; and n is an integer from 1 to 3.

First claim

1 - 66 . (canceled)

67 . A method of treating a disease or condition associated with Wnt pathway activity, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I):

wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are each, independently, H or an alkyl group;
D is selected from the group consisting of H, halogen, alkyl, cycloalkyl, aryl, and dialkylamino, each (other than H and halogen) being optionally substituted;
Ar is a 6-membered heteroaryl ring having 1 or 2 nitrogen atoms having no substituents other than Cy and the amide nitrogen atom depicted in structure (I), these being in a 1,4-relationship on the ring; and
Cy is an aryl, heteroaryl or a saturated ring containing at least one heteroatom, each being optionally substituted; and
n is an integer from 1 to 2;
or an enantiomer, diastereomer or salt thereof.

68 . The method of claim 67 , wherein the compound of Formula (I) inhibits the Wnt pathway activity.

69 . The method of claim 67 , wherein the disease or condition is selected from the group consisting of cancer, fibrosis, a degenerative disease, diabetic retinopathy, stem cell retinopathy, rheumatoid arthritis, psoriasis, and myocardial infarction.

70 . The method of claim 67 , wherein the cancer is characterized by abnormal Wnt activity, optionally being high Wnt activity.

71 . The method of claim 67 , wherein the disease or condition is a cancer selected from the group consisting of cervical, colon, breast, bladder, head and neck, gastric, lung, ovarian, prostate, thyroid, non-small-cell lung, chronic lymphocytic leukemia, mesothelioma, melanoma, pancreatic adenocarcinoma, basal cell carcinoma, osteosarcoma, hepatocellular carcinoma, Wilm's tumor, and medulloblastoma.

72 . The method of claim 67 , wherein the fibrosis is selected from the group consisting of pulmonary fibrosis, liver fibrosis, skin fibrosis and renal fibrosis.

73 . A method of inhibiting Wnt signaling pathway, comprising contacting a cell with of a compound of Formula (I):

wherein:
R 1 , R 2 , R 3 , R 4 and R 5 are each, independently, H or an alkyl group;
D is selected from the group consisting of H, halogen, alkyl, cycloalkyl, aryl, and dialkylamino, each (other than H and halogen) being optionally substituted;
Ar is a 6-membered heteroaryl ring having 1 or 2 nitrogen atoms having no substituents other than Cy and the amide nitrogen atom depicted in structure (I), these being in a 1,4-relationship on the ring; and
Cy is an aryl, heteroaryl or a saturated ring containing at least one heteroatom, each being optionally substituted; and
n is an integer from 1 to 2;
or an enantiomer, diastereomer or salt thereof.

74 . The method of claim 73 , comprising contacting a Wnt protein associated with the cell with the compound of Formula (I).

75 . The method of claim 74 , wherein the Wnt protein is a Wnt-3A protein.

76 . The method of claim 73 , wherein the compound of Formula (I) inhibits the Wnt signaling pathway.

Assignees

• Agency Science Tech & Res

Inventors

• Ho Soo Yei
• Blanchard Stephanie Eliane
• Duraiswamy Athisayamani Jeyaraj
• Alam Jenefer
• Adsool Vikrant Arun

Classifications

• C07D473/08

  with methyl radicals in positions 1 and 3, e.g. theophylline · CPC title

• C07D473/06 Primary

  with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 · CPC title

• C07B2200/13

  Crystalline forms, e.g. polymorphs · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/522

  having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir · CPC title