Treatment for osteoarthritis by intra-articular administration of a cis-imidazoline

Patent metadata

Field	Value
Publication number	US-9855266-B2
Application number	US-201715467129-A
Country	US
Kind code	B2
Filing date	Mar 23, 2017
Priority date	Jan 28, 2014
Publication date	Jan 2, 2018
Grant date	Jan 2, 2018

Abstract

Methods are provided herein for selectively killing senescent cells and for treating senescence-associated diseases and disorders by administering a senolytic agent. Senescence-associated diseases and disorders treatable by the methods using the senolytic agents described herein include cardiovascular diseases and disorders associated with or caused by arteriosclerosis, such as atherosclerosis; idiopathic pulmonary fibrosis; chronic obstructive pulmonary disease; osteoarthritis; senescence-associated ophthalmic diseases and disorders; and senescence-associated dermatological diseases and disorders.

First claim

The invention claimed is:

1. A method of treating osteoarthritis, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to Formula (I), or a pharmaceutically acceptable salt thereof:

wherein R is selected from saturated and unsaturated 5- and 6-membered rings containing at least one hetero atom, wherein the hetero atom is selected from S, N and O and is optionally substituted with a group selected from lower alkyl, cycloalkyl, —C═O—R 1 , hydroxy, lower alkyl substituted with hydroxy, lower alkyl substituted with lower alkoxy, lower alkyl substituted with —NH 2 , lower alkyl substituted with —C═O—R 1 , N-lower alkyl, —SO 2 CH 3 , ═O and —CH 2 C═OCH 3 ;
R 1 is selected from hydrogen, lower alkyl, —NH 2 , —N-lower alkyl, lower alkyl substituted with hydroxy, lower alkyl substituted with —NH 2 , and a 5- or 6-membered saturated ring containing at least one hetero atom selected from S, N and O;
X 1 and X 2 are each independently selected from hydrogen, lower alkoxy, —CH 2 OCH 3 , —CH 2 OCH 2 CH 3 , —OCH 2 CF 3 , and —OCH 2 CH 2 F; and
Y 1 and Y 2 are each independently selected from —Cl, —Br, —NO 2 , —C≡N, and —C≡CH.

2. The method of claim 1 , wherein R is piperazin-2-one.

3. The method of claim 1 , wherein Y 1 and Y 2 are both chloride.

4. The method of claim 1 , wherein X 1 and X 2 are —O—CH—(CH 3 ) 2 and —O—CH 3 respectively.

5. The method of claim 1 , wherein the compound is administered intra-articularly to an osteoarthritic joint in the subject.

6. The method of claim 1 , wherein the compound is formulated in a pharmaceutical composition that contains a hyaluronan.

7. The method of claim 1 , wherein the compound is formulated in a sustained release formulation that includes a gel, a polymeric matrix, or a microparticle.

8. The method of claim 1 , wherein the compound is administered as a single dose, followed by a non-treatment interval of at least two weeks.

9. The method of claim 5 , whereby erosion of a proteoglycan layer is inhibited in the osteoarthritic joint.

10. The method of claim 5 , whereby production of collagen Type II is promoted in the osteoarthritic joint.

11. The method of claim 5 , whereby symptoms of osteoarthritis being experienced by the subject in the joint are relieved.

12. The method of claim 5 , whereby pain being experienced by the subject in the joint is relieved.

13. The method of claim 1 , wherein the compound is 4-[[(4S,5R)-4,5-bis(4-chlorophenyl)-4,5-dihydro-2-[4-methoxy-2-(1-methylethoxy)phenyl]-1H-imidazol-1-yl]carbonyl]-2-piperazinone.

14. The method of any of claims 2 to 12 , wherein the compound is 4-[[(4S,5R)-4,5-bis(4-chlorophenyl)-4,5-dihydro-2-[4-methoxy-2-(1-methylethoxy)phenyl]-1H-imidazol-1-yl]carbonyl]-2-piperazinone.

Assignees

• Buck Inst Res Aging
• Unity Biotechnology Inc
• Mayo Found Medical Education & Res
• Univ Johns Hopkins
• Univ Johns Hopkins

Inventors

• Laberge Remi-Martin
• Campisi Judith
• Davalos Albert
• Demaria Marco
• David Nathaniel
• Vasserot Alain Philippe
• Kirkland James L
• Tchkonia Tamar
• Elisseeff Jennifer
• Kim Chaekyu
• Jeon Okhee
• Zhu Yi

Classifications

• A61K9/0073

  Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; (nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M) · 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

• A61K31/496 Primary

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/428

  condensed with carbocyclic rings · CPC title

• A61P19/02

  for joint disorders, e.g. arthritis, arthrosis · CPC title