γ-diketones as Wnt/β-catenin signaling pathway activators

Patent metadata

Field	Value
Publication number	US-9951053-B2
Application number	US-201615356903-A
Country	US
Kind code	B2
Filing date	Nov 21, 2016
Priority date	Feb 22, 2013
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

The present disclosure provides γ-diketones or analogs thereof, that activate Wnt/β-catenin signaling and thus treat or prevent diseases related to signal transduction, such as osteoporosis and osteoarthropathy; osteogenesis imperfecta, bone defects, bone fractures, periodontal disease, otosclerosis, wound healing, craniofacial defects, oncolytic bone disease, traumatic brain injuries or spine injuries, brain atrophy/neurological disorders related to the differentiation and development of the central nervous system, including Parkinson's disease, strokes, ischemic cerebral disease, epilepsy, Alzheimer's disease, depression, bipolar disorder, schizophrenia; otic disorders like cochlear hair cell loss; eye diseases such as age related macular degeneration, diabetic macular edema or retinitis pigmentosa and diseases related to differentiation and growth of stem cell, such as hair loss, hematopoiesis related diseases and tissue regeneration related diseases.

First claim

What is claimed is:

1. A compound of Formula II:

or a pharmaceutically acceptable salt thereof,
wherein:
Ring C is a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon;
Ring D is selected from the group consisting of phenyl and a 5-6 membered heteroaryl, wherein a carbon atom on the ring is attached to the carbonyl carbon;
each R 4 is independently selected at each occurrence from the group consisting of H, unsubstituted —C 1-6 alkyl, —C 1-3 haloalkyl, halide, —OR 6 , CF 3 , and CN;
each R 5 is independently selected at each occurrence from the group consisting of H, unsubstituted —C 1-6 alkyl, —CH 2 OH, —CH 2 N(R 6b ) 2 , —C 1-3 haloalkyl, halide, —OR 6 , CF 3 , and CN;
each R 6 is independently selected from the group consisting of H, unsubstituted —C 1-6 alkyl, —C 1-3 haloalkyl, and CF 3 ;
each R 6b is independently selected from the group consisting of H and unsubstituted —C 1-3 alkyl;
p is an integer of 1 to 4; and
q is an integer of 1 to 5;
with the proviso that the compound of Formula II is not a compound selected from the group consisting of:

2. The compound of claim 1 , wherein Ring C is a 5-membered heteroaryl ring containing 1-3 heteroatoms selected from the group consisting of N, O, and S.

3. The compound of claim 2 , wherein

is selected from the group consisting of

and p is 1 or 2.

4. The compound of claim 3 , wherein is

5. The compound of claim 1 , wherein Ring C is a 6-membered heteroaryl ring containing 1-2 nitrogens.

6. The compound of claim 5 , wherein

is selected from the group consisting of

and p is 1 or 2.

7. The compound of claim 6 , wherein

8. The compound of claim 1 , wherein each R 4 is independently selected from the group consisting of H, F, Cl, Me, OMe, OH, CF 3 and CN.

9. The compound of claim 1 , wherein Ring D is phenyl.

10. The compound of claim 9 , wherein

is selected from the group consisting of

and q is 1 or 2.

11. The compound of claim 10 , wherein

is selected from the group consisting of

12. The compound of claim 1 , wherein Ring D is a 5-membered heteroaryl containing 1-3 heteroatoms selected from the group consisting of N, O, and S.

13. The compound of claim 12 , wherein

is selected from the group consisting of

and q is 1 or 2.

14. The compound of claim 13 , wherein

is selected from the group consisting of

15. The compound of claim 1 , wherein Ring D is a 6-membered heteroaryl containing 1-2 nitrogen atoms.

16. The compound of claim 15 , wherein

is selected from the group consisting of

and q is 1 or 2.

17. The compound of claim 16 , wherein

is selected from the group consisting of

and R 5 is H.

18. The compound of claim 1 , wherein R 5 is independently selected from the group consisting of H, F, Cl, Me, OMe, OH, CF 3 , and CN.

19. The compound of claim 1 , wherein Ring D is a phenyl or 6-membered heteroaryl; R 5 is selected from the group consisting of F, Cl, Me, OMe, OH, CF 3 and CN; q is 1; and R 5 is attached to an ortho carbon of the 6-membered ring.

20. The compound of claim 19 , wherein Ring D is a phenyl, R 5 is selected from the group consisting of F, Cl, Me, OMe, OH, CF 3 and CN; q is 1; and R 5 is attached to an ortho position of the phenyl ring.

21. The compound of claim 19 , wherein Ring D is a pyridine, R 5 is selected from the group consisting of F, Cl, Me, OMe, OH, CF 3 and CN; q is 1; and R 5 is attached to an ortho carbon of the pyridine ring.

22. The compound of claim 1 , wherein the compound of Formula II is selected from the group consisting of:

Assignees

• Samumed Llc

Inventors

• Kc Sunil Kumar
• Wallace David Mark
• Hood John
• Barroga Charlene F

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• C07D231/56

  Benzopyrazoles; Hydrogenated benzopyrazoles · CPC title

• C07D333/54

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring · CPC title

• C07D411/06 Primary

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D405/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title