Compounds for treating eye disorders or diseases

Patent metadata

Field	Value
Publication number	US-10093694-B2
Application number	US-201715423359-A
Country	US
Kind code	B2
Filing date	Feb 2, 2017
Priority date	Feb 3, 2016
Publication date	Oct 9, 2018
Grant date	Oct 9, 2018

Abstract

Described herein are compounds that inhibit or prevent protein aggregation, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders associated with protein aggregation.

First claim

What is claimed is:

1. A method of treating an eye disease or disorder in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (Ic):

or a pharmaceutically acceptable salt thereof,
wherein the eye disease or disorder is selected from the group consisting of cataracts, congenital cataracts, cortical opacities, posterior subcapsular cataracts, presbyopia, nuclear sclerosis, retinal degenerative disorder, Refsum disease, Smith-Lemli-Opitz syndrome, Schnyder crystalline corneal dystrophy, drusen, age-related macular degeneration, and diabetic retinopathy; and wherein
X is —C(R 4 ) 2 —;
each R 4 is independently hydrogen, —OR e , optionally substituted C 1 -C 6 alkyl, or halogen; each R e is independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl;
Y is —CH 2 —, or —CH(R 5 )—;
R 5 is optionally substituted C 1 -C 6 alkyl or halogen;
R 6 and R 7 are each independently C 1 -C 3 alkyl;

R 8 is —OR h , or —N(R i ) 2 ;
R h is hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; each R i is independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or two R i are taken together with the N atom to which they are attached to form an optionally substituted heterocycloalkyl ring;
R 1 is —OR 10 , —SR 10 , —N(R 10 ) 2 , or halogen; and each R 10 is independently hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 heteroalkyl, optionally substituted C 3 -C 10 cycloalkyl, optionally substituted C 2 -C 10 heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; or two R 10 are taken together with the N atom to which they are attached to form an optionally substituted heterocycloalkyl ring.

2. The method of claim 1 , wherein the subject is having or at risk of developing an eye disease or disorder that affects the normal structure of the lens in the eye.

3. The method of claim 1 , wherein the compound, or the pharmaceutically acceptable salt thereof, inhibits crystallin protein aggregation.

4. The method of claim 3 , wherein the protein is an amyloid-forming protein selected from Hsp27, αA-crystallin, αB-crystallin, ßB2-crystallin, ßB1-crystallin, γD-crystallin, Hsp22, Hsp20, tau, alpha-synuclein, IAPP, beta-amyloid, PrP, huntingtin, calcitonin, atrial natriuretic factor, apolipoprotein AI, serum amyloid A, medin, prolactin, transthyretin, lysozyme, beta 2 microglobulin, gelsolin, keratoepithelin, cystatin, immunoglobulin light chain AL, and S-IBM.

5. The method of claim 3 , wherein the protein is a protein underlying a loss of function disease and is selected from the group consisting of mutant ß-glucosidase, cystic fibrosis transmembrane receptor, hexosaminidase A, hexosaminidase B, ß-galactosidase and alpha-glucosidase.

6. The method of claim 1 , wherein X is —CH 2 — or —CH(OR e )—.

7. The method of claim 6 , wherein R e is hydrogen.

8. The method of claim 1 , wherein R 5 is —Br, —F, methyl, or ethyl.

9. The method of claim 1 , wherein the compound has a formula of Formula (Id):

or the pharmaceutically acceptable salt thereof.

10. The method of claim 9 , wherein R h is hydrogen.

11. The method of claim 1 , wherein the compound, or the pharmaceutically acceptable salt thereof, is selected from:

12. The method of claim 1 , wherein R 1 is —OR 10 .

13. The method of claim 12 , wherein R 1 is —OH, —OMe, —OEt, or —O-n-Pr.

14. The method of claim 1 , wherein R 1 is —SR 10 or —N(R 10 ) 2 .

15. The method of claim 1 , wherein R 1 is halogen.

16. The method of claim 1 , wherein the compound, or the pharmaceutically acceptable salt thereof, is selected from:

17. The method of claim 16 , wherein the compound, or the pharmaceutically acceptable salt thereof, is selected from:

18. The method of claim 1 , wherein the therapeutically effective amount of the compound, or the pharmaceutically acceptable salt thereof, is administered as a pharmaceutical composition; and wherein the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.

Assignees

• Guangzhou Kangrui Biological Pharmaceutical Tech Co Ltd
• Univ California

Inventors

• Hou Rui
• Zhang Kang
• Li Gen

Classifications

• A61P27/12

  for cataracts · CPC title

• C07J33/002

  not condensed · CPC title

• C07J51/00

  Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00 · CPC title

• C07J17/00

  Normal steroids containing carbon, hydrogen, halogen or oxygen, having an oxygen-containing hetero ring not condensed with the cyclopenta(a)hydrophenanthrene skeleton (cardanolide, bufanolide C07J19/00) · CPC title

• C07J9/00 Primary

  Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane · CPC title