CCR1 antagonists and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9334283-B2
Application number	US-201414172398-A
Country	US
Kind code	B2
Filing date	Feb 4, 2014
Priority date	Nov 13, 2002
Publication date	May 10, 2016
Grant date	May 10, 2016

Abstract

The invention provides compounds having the formula:

wherein R 1 is halogen. The invention also provides compositions comprising the compounds, and methods of treating diseases or disorders that comprise administering one or more of the compounds to a subject in need thereof. The disclosed compounds have CCR1 antagonist activity.

First claim

What is claimed is:

1. A method for treating an inflammatory disease, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising
(S)-5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a, d]cycloheptene-7-carboxylic acid or physiologically acceptable salt thereof,
(R)-5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cycloheptene-7-carboxylic acid or physiologically acceptable salt thereof, and a physiologically acceptable carrier or excipient, wherein the ratio of (S)-enantiomer to (R)-enantiomer is at least about 5:1.

2. The method of claim 1 , wherein the ratio of (S)-enantiomer to (R)-enantiomer is at least about 10:1.

3. The method of claim 1 , wherein the ratio of (S)-enantiomer to (R)-enantiomer is at least about 20:1.

4. The method of claim 1 , wherein the ratio of (S)-enantiomer to (R)-enantiomer is at least about 50:1.

5. The method of claim 1 , wherein the inflammatory disease is an acute or chronic inflammatory disease.

6. The method of claim 1 , wherein the inflammatory disease is selected from the group consisting of inflammatory arthritis, inflammatory demyelinating disease, atherosclerosis, arteriosclerosis, restenosis, ischemia/reperfusion injury, diabetes mellitus, psoriasis, inflammatory bowel diseases, rejection of a transplanted graft, graft versus host disease, allergy and asthma.

7. A method for treating an inflammatory disease, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising
(S)-5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-1-oxy-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cycloheptene-7-carboxylic acid or physiologically acceptable salt thereof,
(R)-5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-1-oxy-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cycloheptene-7-carboxylic acid or physiologically acceptable salt thereof, and a physiologically acceptable carrier or excipient, wherein the ratio of (S)-enantiomer to (R)-enantiomer is at least about 5:1.

8. The method of claim 7 , wherein the ratio of (S)-enantiomer to (R)-enantiomer is at least about 10:1.

9. The method of claim 7 , wherein the ratio of (S)-enantiomer to (R)-enantiomer is at least about 20:1.

10. The method of claim 7 , wherein the ratio of (S)-enantiomer to (R)-enantiomer is at least about 50:1.

11. The method of claim 7 , wherein the inflammatory disease is an acute or chronic inflammatory disease.

12. The method of claim 7 , wherein the inflammatory disease is selected from the group consisting of inflammatory arthritis, inflammatory demyelinating disease, atherosclerosis, arteriosclerosis, restenosis, ischemia/reperfusion injury, diabetes mellitus, psoriasis, inflammatory bowel diseases, rejection of a transplanted graft, graft versus host disease, allergy and asthma.

Assignees

• Millennium Pharm Inc

Inventors

• Carson Kenneth G
• Harriman Geraldine C B
• Ghosh Shomir

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P37/06

  Immunosuppressants, e.g. drugs for graft rejection · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P43/00

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title