Purine diones as Wnt pathway modulators

Patent metadata

Field	Value
Publication number	US-10526335-B2
Application number	US-201815899675-A
Country	US
Kind code	B2
Filing date	Feb 20, 2018
Priority date	May 23, 2013
Publication date	Jan 7, 2020
Grant date	Jan 7, 2020

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 R1, R2, R3, R4 and R5 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

The invention claimed is:

1. A Wnt secretion modulating compound having structure (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 the Cy moiety and 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.

2. The compound of claim 1 , wherein R 1 and R 2 are either both methyl or both ethyl.

3. The compound of claim 1 , wherein n is 1.

4. The compound of claim 1 , wherein D is selected from H, methyl, cyclopropyl, trifluoromethyl, phenyl, dimethylamino, morpholin-N-yl, thiophene-3-yl, and bromo.

5. The compound of claim 1 , wherein D is H.

6. The compound of claim 1 , wherein R 5 is H.

7. The compound of claim 1 , wherein one of R 3 and R 4 is H and the other is selected from H, methyl, and ethyl.

8. The compound of claim 1 , wherein Ar is selected from the following:

wherein denotes the point of connection to the amide nitrogen atom depicted in structure (I) and * denotes the point of connection to the Cy moiety depicted in structure (I).

9. The compound of claim 1 , wherein Cy is a 5- or 6-membered aromatic ring having between 0 and 2 nitrogen atoms, 0 or 1 sulfur atoms, and 0 or 1 oxygen atoms.

10. The compound of claim 1 , wherein Cy is selected from the following:

wherein * denotes the point of connection to the Ar moiety of structure (I).

11. The compound of claim 1 , selected from:

12. The compound of claim 1 , wherein the compound is an anhydrous form of 2-(1,3-dimethyl-2,6-dioxo-1,2,3 ,6-tetrahydro-7H-purin-7-yl)-N-(6-phenylpyridazin-3-yl)acetamide free base, as represented by:

13. The anhydrous form compound of claim 12 , which is a non-hydrated single polymorph.

14. The anhydrous form compound of claim 12 , which is crystalline.

15. The anhydrous form compound of claim 14 , which shows on X-ray diffraction a peak on the 2theta scale at 22.2°±0.5°.

16. The anhydrous form compound of claim 14 , which shows on X-ray diffraction peaks on the 2theta scale at 5.5°±0.5° and 14.2°±0.5°.

17. The anhydrous form compound of claim 14 , which shows on X-ray diffraction at least four peaks on the 2theta scale selected from 5.5°±0.5°, 12.5°±0.5°, 14.2°±0.5°, 16.7°±0.5°, 17.7°±0.5°, 18.8°±0.5°, 22.4°±0.5°, 24.2°±0.5° and 31.7°±0.5°.

18. A pharmaceutical composition comprising a compound according to claim 1 together with one or more pharmaceutically acceptable carriers, diluents or adjuvants.

Assignees

• Agency Science Tech & Res

Inventors

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

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title