Prodrugs of amino quinazoline kinase inhibitor

Patent metadata

Field	Value
Publication number	US-9586953-B2
Application number	US-201314397218-A
Country	US
Kind code	B2
Filing date	Sep 13, 2013
Priority date	Sep 13, 2012
Publication date	Mar 7, 2017
Grant date	Mar 7, 2017

Abstract

Disclosed are compounds having the formula:

wherein X is as defined herein, and methods of making and using the same.

First claim

What is claimed is:

1. A compound which is:

or a pharmaceutically acceptable salt thereof, or a hydrate thereof.

2. A compound which is 2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl dihydrogen phosphate or a pharmaceutically acceptable salt thereof.

3. The compound, or pharmaceutically acceptable salt thereof, according to claim 2 , which is 2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl dihydrogen phosphate.

4. A pharmaceutical composition comprising the compound, or pharmaceutically acceptable salt thereof, or hydrate thereof, according to claim 1 , and a pharmaceutically acceptable excipient.

5. A method of treating a disease mediated by RIP2 kinase comprising administering a therapeutically effective amount of the compound, or pharmaceutically acceptable salt thereof, or hydrate thereof, according to claim 1 to a human in need thereof, wherein the disease is selected from uveitis, dermatitis, acute lung injury, type 2 diabetes mellitus, arthritis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, early-onset inflammatory bowel disease, extraintestinal inflammatory bowel disease, prevention of ischemia reperfusion injury in solid organ transplant, non-alcohol steatohepatitis, autoimmune hepatitis, asthma, systemic lupus erythematosus, multiple sclerosis, sarcoidosis, Blau syndrome/early-onset sarcoidosis, Wegner's granulomatosis, and interstitial pulmonary disease.

6. The method according to claim 5 , wherein the disease is selected from uveitis, Blau Syndrome, early-onset sarcoidosis, ulcerative colitis, Crohn's disease, Wegener's granulomatosis and sarcoidosis.

7. The method according to claim 5 , wherein the disease is Crohn's disease.

8. The method according to claim 5 , wherein the disease is ulcerative colitis.

9. The method according to claim 5 , wherein the disease is Blau syndrome.

10. The method according to claim 5 , wherein the disease is rheumatoid arthritis.

11. The compound, or pharmaceutically acceptable salt thereof, or hydrate thereof, according to claim 1 , which is the pharmaceutically acceptable salt of said compound.

12. The compound, or pharmaceutically acceptable salt thereof, or hydrate thereof, according to claim 11 , wherein the pharmaceutically acceptable salt is a sodium salt.

13. The compound, or pharmaceutically acceptable salt thereof, or hydrate thereof, according to claim 1 , which is:

14. The compound, or pharmaceutically acceptable salt thereof, or hydrate thereof, according to claim 11 , wherein the pharmaceutically acceptable salt is a hydrochloride salt.

15. The compound, or pharmaceutically acceptable salt thereof, or hydrate thereof, according to claim 1 , which is a hydrate of a hydrochloride salt of said compound.

16. The compound, or pharmaceutically acceptable salt thereof, or hydrate thereof, according to claim 1 , which is 2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl dihydrogen phosphate hydrochloride monohydrate.

17. The compound, or pharmaceutically acceptable salt thereof, or hydrate thereof, according to claim 1 which is crystalline 2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl dihydrogen phosphate hydrochloride monohydrate having the PXRD of FIG. 2 .

18. The compound, or pharmaceutically acceptable salt thereof, or hydrate thereof, according to claim 11 , wherein the pharmaceutically acceptable salt is a calcium salt.

19. The compound, or pharmaceutically acceptable salt thereof, or hydrate thereof, according to claim 1 , which is a hydrate of a calcium salt of said compound.

20. The compound, or pharmaceutically acceptable salt thereof, or hydrate thereof, according to claim 1 , which is a hydrate of a hemi-calcium salt of said compound.

21. A compound which is:

or a pharmaceutically acceptable salt thereof, or a hydrate thereof, which is a trihydrate of a hemi-calcium salt of said compound.

22. The hemi-calcium salt trihydrate of the compound according to claim 1 which is crystalline calcium (I) 2-((4-(benzo[d]thiazol-5-ylamino)-6-(tert-butylsulfonyl)quinazolin-7-yl)oxy)ethyl hydrogen phosphate trihydrate having the PXRD of FIG. 1 .

23. A pharmaceutical composition comprising the hemi-calcium salt trihydrate of the compound according to claim 1 and a pharmaceutically acceptable excipient.

24. A method of treating a disease mediated by RTP2 kinase comprising administering a therapeutically effective amount of the hemi-calcium salt trihydrate of the compound according to claim 21 , to a human in need thereof, wherein the disease is selected from uveitis, dermatitis, acute lung injury, type 2 diabetes mellitus, arthritis, rheumatoid arthritis, ulcerative colitis, Crohn's disease, early-onset inflammatory bowel disease, extraintestinal inflammatory bowel disease, prevention of ischemia reperfusion injury in solid organ transplant, non-alcohol steatohepatitis, autoimmune hepatitis, asthma, systemic lupus erythematosus, multiple sclerosis, sarcoidosis, Blau syndrome/early-onset sarcoidosis, Wegner's granulomatosis, and interstitial pulmonary disease.

25. The method according to claim 24 , wherein the disease is selected from uveitis, Blau Syndrome, early-onset sarcoidosis, ulcerative colitis, Crohn's disease, Wegener's granulomatosis and sarcoidosis.

26. The method according to claim 24 , wherein the disease is Crohn's disease.

27. The method according to claim 24 , wherein the disease is ulcerative colitis.

28. The method according to claim 24 , wherein the disease is Blau syndrome.

29. The method according to claim 24 , wherein the disease is rheumatoid arthritis.

Assignees

• Glaxosmithkline Ip Dev Ltd

Inventors

• Casillas Linda N
• Haile Pamela A
• Marquis Jr Robert W

Classifications

• A61P37/06

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

• C07F9/6561

  containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings · CPC title

• A61P19/02

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

• A61K31/428

  condensed with carbocyclic rings · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title