Diazole amides

Patent metadata

Field	Value
Publication number	US-9750722-B2
Application number	US-201514878784-A
Country	US
Kind code	B2
Filing date	Oct 8, 2015
Priority date	Dec 21, 2012
Publication date	Sep 5, 2017
Grant date	Sep 5, 2017

Abstract

Compounds are provided that act as potent antagonists of the CCR1 receptor, and have in vivo anti-inflammatory activity. The compounds are diazole lactam derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated disease, and as controls in assays for the identification of competitive CCR1 antagonists.

First claim

What is claimed is:

1. A method of treating CCR1-mediated diseases or conditions, wherein said CCR1-mediated diseases or conditions are selected from the group consisting of transplant rejection, dermatitis, inflammatory bowel disease, asthma, Alzheimer's disease, psoriasis, encephalomyelitis, rheumatoid arthritis, multiple sclerosis, multiple myeloma, osteoporosis, and leukemia comprising administering to a subject in need thereof a therapeutically effective amount of the compound represented by the structure:

wherein
each A is independently selected from the group consisting of N and CH;
A 1 is N or C(R 5 );
A 2 is N or C(R 7 );
Z is phenyl and is optionally substituted with 1-3 R a ;
R 3 is a member selected from the group consisting of halogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, —OR a , —NR a R b , and phenyl, and wherein the alkyl, cycloalkyl, and phenyl portions of R 3 are optionally further substituted with 1-3 R 3 ;
R 4 is a member selected from the group consisting of H and C 1-8 alkyl;
R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, halogen, C 1-8 alkyl, and C 1-8 haloalkyl optionally further substituted with 1-3 R a ; and optionally, R 4 and R 5 , are connected to form an additional 5- or 6-membered ring which is saturated, unsaturated or aromatic having carbon atom ring vertices;
each R a and R b is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylalkyl, amino, C 1-8 alkylamino, di C 1-8 alkylamino, carboxamide, carboxy C 1-4 alkyl ester, carboxylic acid, and —SO 2 —C 1-8 alkyl;
or a pharmaceutically acceptable salt thereof.

2. A method in accordance with claim 1 , wherein said CCR1-mediated disease or condition is selected from the group consisting of transplant rejection, dermatitis, inflammatory bowel disease, asthma, Alzheimer's disease, psoriasis, and encephalomyelitis.

3. A method in accordance with claim 1 , wherein said CCR1-mediated disease or condition is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, multiple myeloma and osteoporosis.

4. A method in accordance with claim 1 , wherein said administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical.

5. A method in accordance with claim 1 , wherein said compound is administered in combination with an anti-inflammatory agent, analgesic agent, an anti-proliferative agent, a metabolic inhibitor, a leukocyte migration inhibitor or an immuno modulator.

6. A method in accordance with claim 1 , wherein said CCR1-mediated disease or condition is rheumatoid arthritis.

7. A method in accordance with claim 1 , wherein said CCR1-mediated disease or condition is selected from the group consisting of multiple myeloma and leukemia.

8. A method of treating CCR1-mediated diseases or conditions, wherein said CCR1-mediated diseases or conditions are selected from the group consisting of transplant rejection, dermatitis, inflammatory bowel disease, asthma, Alzheimer's disease, psoriasis, encephalomyelitis, rheumatoid arthritis, multiple sclerosis, multiple myeloma, osteoporosis, and leukemia comprising administering to a subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

9. A method in accordance with claim 8 wherein the compound is:

or a pharmaceutically acceptable salt thereof.

10. A method in accordance with claim 8 wherein the compound is:

or a pharmaceutically acceptable salt thereof.

11. A method in accordance with claim 8 , wherein said CCR1-mediated disease or condition is selected from the group consisting of transplant rejection, dermatitis, inflammatory bowel disease, asthma, Alzheimer's disease, psoriasis, encephalomyelitis, rheumatoid arthritis, multiple sclerosis, multiple myeloma and osteoporosis.

12. A method in accordance with claim 8 , wherein said CCR1-mediated disease or condition is rheumatoid arthritis.

13. A method in accordance with claim 11 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

14. A method in accordance with claim 12 , wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

15. A method in accordance with claim 8 , wherein said administering is oral, parenteral, rectal, transdermal, sublingual, nasal or topical.

16. A method in accordance with claim 8 , wherein said compound is administered in combination with an anti-inflammatory agent, an analgesic agent, an anti-proliferative agent, a metabolic inhibitor, a leukocyte migration inhibitor or an immuno modulator.

17. A method of modulating CCR1 function comprising administering to a subject in need thereof a therapeutically effective amount of the compound represented by the structure:

wherein
each A is independently selected from the group consisting of N and CH;
A 1 is N or C(R 5 );
A 2 is N or C(R 7 );
Z is phenyl and is optionally substituted with 1-3 R a ;
R 3 is a member selected from the group consisting of halogen, C 1-8 alkyl, C 3-8 cycloalkyl, C 1-8 haloalkyl, —OR a , —NR a R b , and phenyl, and wherein the alkyl, cycloalkyl, and phenyl portions of R 3 are optionally further substituted with 1-3 R a ;
R 4 is a member selected from the group consisting of H and C 1-8 alkyl;
R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, halogen, C 1-8 alkyl, and C 1-8 haloalkyl optionally further substituted with 1-3 R a ; and optionally, R 4 and R 5 , are connected to form an additional 5- or 6-membered ring which is saturated, unsaturated or aromatic having carbon atom ring vertices;
each R a and R b is independently selected from the group consisting of hydrogen, hydroxyl, halogen, cyano, C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylalkyl, amino, C 1-8 alkylamino, di C 1-8 alkylamino, carboxamide, carboxy C 1-4 alkyl ester, carboxylic acid, and —SO 2 —C 1-8 alkyl;
or a pharmaceutically acceptable salt thereof.

18. A method in accordance with claim 17 wherein said subject has an inflammatory condition or an immunoregulatory disorder.

19. A method in accordance with claim 17 , wherein said subject has a disease or condition selected from the group consisting of transplant rejection, dermatitis, inflammat

Assignees

• Chemocentryx Inc

Inventors

• Chen Xi
• Dragoli Dean R
• Fan Pingchen
• Jaen Juan C
• Li Yandong
• Powers Jay P
• Malathong Viengkham
• Punna Sreenivas
• Tanaka Hiroko
• Zhang Penglie

Classifications

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P37/06

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

• A61P37/08

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

• A61P37/00

  Drugs for immunological or allergic disorders · CPC title