Patent
Compounds as hypoxia mimetics, and compositions and uses thereof
| العنوان: | Compounds as hypoxia mimetics, and compositions and uses thereof |
|---|---|
| Patent Number: | 8,742,138 |
| تاريخ النشر: | June 03, 2014 |
| Appl. No: | 13/384097 |
| Application Filed: | July 14, 2010 |
| مستخلص: | This invention relates to new compounds that can serve as hypoxia mimetics. This invention also relates to methods of increasing HIF levels or activity in a subject or treating a condition associated with HIF levels or activity in a subject by administering to the subject at least one of these compounds. |
| Inventors: | Kang, Xinshan (Beijing, CN); Long, Wei (Beijing, CN); Ma, Cunbo (Beijing, CN); Wang, Yanping (Nanjing, CN); Cao, Hong (Beijing, CN); Wang, Yinxiang (Beijing, CN); Tan, Fenlai (Beijing, CN); Hu, Yunyan (Beijing, CN) |
| Assignees: | Betta Pharmaceuticals Co., Ltd. (Hangzhou, Zhejiang, CN), Kang, Xinshan (Beijing, CN) |
| Claim: | 1. A compound of Formula I: [chemical expression included] or a pharmaceutically acceptable salt thereof, wherein: n is 1; R 1 is OH; R 2 and R 3 are each H; R 4 is H or unsubstituted alkyl; R 5 is OH or lower alkoxy; R 6 and R 7 are each H; R 8 is heteroaryl, substituted heteroaryl, phenyl or phenyl substituted by halogen alkyl, alkoxy, haloalkyl, or haloalkoxy and R 9 is H; or R 8 is H and R 9 is substituted phenyl. |
| Claim: | 2. The compound of claim 1 , wherein R 3 and R 4 are each H. |
| Claim: | 3. The compound of claim 1 , wherein R 5 is OH. |
| Claim: | 4. The compound of claim 1 , wherein at least one of R 8 and R 9 is halo or a moiety substituted with at least one halo. |
| Claim: | 5. The compound of claim 1 , wherein at least one of R 8 and R 9 is aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, and substituted heterocycloalkyl. |
| Claim: | 6. The compound of claim 1 , wherein at least one of R 8 and R 9 is substituted aryl, or substituted heteroaryl. |
| Claim: | 7. The compound of claim 1 , wherein at least one of R 8 and R 9 is substituted phenyl or substituted pyridyl. |
| Claim: | 8. The compound of claim 1 , wherein at least one of R 8 and R 9 is phenyl and substituted with halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy at the para- and/or meta-position. |
| Claim: | 9. The compound of claim 1 , wherein R 8 is pyridyl substituted with halogen, alkyl, haloalkyl, alkoxy, or haloalkoxy at the para- and/or meta-position. |
| Claim: | 10. The compound of claim 1 , wherein the compound is of Formula II: [chemical expression included] wherein: R 21 is H, halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy; R 22 is H, halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy; Z 1 is CR 23 ; and R 23 is H, halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy; provided that at least one of R 21 and R 22 and R 23 (if present) is halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy. |
| Claim: | 11. The compound of claim 10 , wherein each of R 21 , R 22 , and R 23 (if present) is independently H, Cl, F, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy. |
| Claim: | 12. The compound of claim 10 , wherein one of R 21 , R 22 , and R 23 is halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy; and the other two of R 21 , K 22 , and R 23 are both H. |
| Claim: | 13. The compound of claim 10 , wherein one of R 21 and R 23 is halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy; and the other one of R 21 and R 23 is H; R 22 is H. |
| Claim: | 14. The compound of claim 10 , wherein two of R 21 , R 22 , and R 23 are each independently halogen, lower alkyl, lower haloalkyl, lower alkoxy, and lower haloalkoxy; and the other one of R 21 , R 22 , and R 23 is H. |
| Claim: | 15. The compound of claim 10 , wherein R 21 , R 22 , and R 23 are each independently halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy. |
| Claim: | 16. The compound of claim 10 , wherein the compound is of Formula IIa: [chemical expression included] wherein: R 21 is H, halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy; and R 22 is H, halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy; provided that at least one of R 21 and R 22 is halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy. |
| Claim: | 17. The compound claim 16 , wherein R 21 is H; and R 22 is lower alkyl or lower haloalkyl. |
| Claim: | 18. The compound of claim 16 , wherein R 21 is H; and R 22 is C 1-3 alkyl or C 1-3 haloalkyl. |
| Claim: | 19. The compound of claim 18 , wherein R 22 is methyl or C 1-2 haloalkyl. |
| Claim: | 20. The compound of claim 18 , wherein R 22 is methyl or ethyl. |
| Claim: | 21. The compound of claim 16 , wherein R 22 is H; and R 21 is lower alkyl or lower haloalkyl. |
| Claim: | 22. The compound of claim 16 , wherein R 21 and R 22 are each independently halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy. |
| Claim: | 23. The compound of claim 16 , wherein R 21 is methyl or ethyl. |
| Claim: | 24. The compound of claim 16 , wherein R 21 is methyl or C 1-2 haloalkyl. |
| Claim: | 25. The compound of claim 16 , wherein R 21 and R 22 are each independently C 1-2 alkyl or C 1-2 haloalkyl. |
| Claim: | 26. The compound of claim 1 , wherein the compound of Formula III: [chemical expression included] wherein: R 24 ; and R 25 are each independently H, halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy; Z 2 is N or CR 26 ; and R 26 is H, halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy; provided that at least one of R 24 and R 25 and R 26 (if present) is halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy. |
| Claim: | 27. The compound of claim 26 , wherein Z 2 is CR 26 . |
| Claim: | 28. The compound of claim 26 , wherein each of R 24 , R 25 , and R 26 (if present) is H, Cl, F, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, or trifluoromethoxy. |
| Claim: | 29. The compound of claim 26 , wherein Z 2 is CR 26 ; one of R 24 , R 25 , and R 26 is halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy; and the other two of R 24 , R 25 , and R 26 are both H. |
| Claim: | 30. The compound of claim 26 , wherein Z 2 is CR 26 ; one of R 24 and R 26 is halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy; and the other one of R 24 and R 26 is H; and R 25 is H. |
| Claim: | 31. The compound of claim 26 , wherein Z 1 is CR 26 ; two of R 24 , R 25 , and R 26 are each independently halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy; and the other one of R 24 , R 25 , and R 26 is H. |
| Claim: | 32. The compound of claim 26 , wherein Z 2 is CR 26 ; R 24 , R 25 , and R 26 are each independently halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy. |
| Claim: | 33. The compound of claim 26 , wherein Z 2 is N. |
| Claim: | 34. The compound of claim 26 , wherein Z 2 is N; one of R 24 and R 25 is halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy; and the other of R 24 and R 25 is H. |
| Claim: | 35. The compound of claim 26 , wherein the compound is of Formula IIIa [chemical expression included] wherein: R 24 is H, halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy; and R 25 is H, halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy; provided that at least one of R 24 and R 25 is halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy. |
| Claim: | 36. The compound of claim 35 , wherein R 24 is H; and R 25 is lower alkyl or lower haloalkyl. |
| Claim: | 37. The compound of claim 35 , wherein R 24 is H; and R 25 is C 1-3 alkyl or C 1-3 haloalkyl. |
| Claim: | 38. The compound of claim 37 , wherein R 25 is methyl and C 1-2 haloalkyl. |
| Claim: | 39. The compound of claim 37 , wherein R 25 is methyl or ethyl. |
| Claim: | 40. The compound of claim 35 , wherein R 25 is lower alkyl or lower haloalkyl. |
| Claim: | 41. The compound of claim 35 , wherein R 24 is methyl or C 1-2 haloalkyl. |
| Claim: | 42. The compound of claim 35 , wherein R 24 is methyl or ethyl. |
| Claim: | 43. The compound of claim 35 , wherein R 24 and R 25 are each independently halogen, lower alkyl, lower haloalkyl, lower alkoxy, or lower haloalkoxy. |
| Claim: | 44. The compound of claim 35 , wherein R 24 and R 25 are each independently C 1-2 alkyl or C 1-2 haloalkyl. |
| Claim: | 45. The compound of claim 1 , wherein the compound is: 2-(4-hydroxy-2-oxo-7-phenyl-2H-chromene-3-carboxamido)acetic acid; 2-(7-(2-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(7-(3-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(7-(4-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-(3-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-(4-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-(3-(trifluoromethoxy)phenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-(4-(trifluoromethoxy)phenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(7-(3,4-dichlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(7-(3,4-difluorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-(3,4,5-trifluorophenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-7-(3-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-7-(4-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-m-tolyl-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-p-tolyl-2H-chromene-3-carboxamido)acetic acid; 2-(8-(2-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(8-(3-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(8-(4-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-8-(3-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-8-(4-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-8-(3-(trifluoromethoxy)phenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-8-(4-(trifluoromethoxy)phenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(8-(3,4-dichlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(8-(3,4-difluorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-8-(3,4,5-trifluorophenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-8-(3-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-8-(4-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-8-m-tolyl-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-8-p-tolyl-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-7-(6-methoxypyridin-3-yl)-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-(pyridin-4-yl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-(pyridin-3-yl)-2H-chromene-3-carboxamido)acetic acid; or 2-(4-hydroxy-2-oxo-8-(3-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic acid. |
| Claim: | 46. A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient, adjuvant or carrier, and a therapeutically effective amount of a compound of claim 1 . |
| Claim: | 47. The pharmaceutical composition of claim 46 , wherein the compound of claim 1 is: 2-(4-hydroxy-2-oxo-7-phenyl-2H-chromene-3-carboxamido)acetic acid; 2-(7-(2-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(7-(3-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(7-(4-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-(3-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-(4-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-(3-(trifluoromethoxy)phenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-(4-(trifluoromethoxy)phenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(7-(3,4-dichlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(7-(3,4-difluorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-(3,4,5-trifluorophenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-7-(3-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-7-(4-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-m-tolyl-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-p-tolyl-2H-chromene-3-carboxamido)acetic acid; 2-(8-(2-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(8-(3-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(8-(4-chlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-8-(3-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-8-(4-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-8-(3-(trifluoromethoxy)phenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-8-(4-(trifluoromethoxy)phenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(8-(3,4-dichlorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(8-(3,4-difluorophenyl)-4-hydroxy-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-8-(3,4,5-trifluorophenyl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-8-(3-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-8-(4-methoxyphenyl)-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-8-m-tolyl-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-8-p-tolyl-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-7-(6-methoxypyridin-3-yl)-2-oxo-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-(pyridin-4-yl)-2H-chromene-3-carboxamido)acetic acid; 2-(4-hydroxy-2-oxo-7-(pyridin-3-yl)-2H-chromene-3-carboxamido)acetic acid; or 2-(4-hydroxy-2-oxo-8-(3-(trifluoromethyl)phenyl)-2H-chromene-3-carboxamido)acetic acid. |
| Claim: | 48. The pharmaceutical composition of claim 46 , further comprising an erythropoiesis stimulating agent or a chemotherapeutic agent. |
| Claim: | 49. The pharmaceutical composition of claim 46 , wherein the compound of claim 1 is present in an amount effective for the treatment of diabetes, cancer, ischemia, anemia, or thalassemia. |
| Current U.S. Class: | 549/285 |
| Patent References Cited: | 8324405 December 2012 Ho et al. WO 03/080649 October 2003 WO 2007/070359 June 2007 WO 2008/119744 October 2008 WO 2009/100250 August 2009 |
| Other References: | Takechi et al. Chem.Phar.Bull., 2000, 48(11), 1702-1710. cited by examiner Bonsignore, et al., Heterocycles (1997), 45(11), 2131-2136. cited by examiner Wolff, Burger's medicinal Chemistry and Drug Discovery, vol. 1, Principles and Practice, John Wiley & sons, New York, 1997. cited by examiner West, Solid State Chemistry and Its Applications, John Wiley & Sons, 1984. cited by examiner Dorwald F. A. Side Reactions in Organic Synthesis, 2005, Wiley: VCH, Weinheim p. IX of Preface p. 1-15. cited by examiner Venkatesh et al., Role of the Development Scientist in Compound Lead Selection and Optimization J. Pharm. Sci. 89, 145-54 (2000). cited by examiner Takechi, Haruko et al. Screening search for organic fluorophores: syntheses and fluorescence properties of 3-azolyl-7-diethylaminocoumarin derivatives. Chemical & Pharmaceutical Bulletin, 2000, vol. 48, No. 11, pp. 1702-1710. cited by applicant |
| Primary Examiner: | Chandrakumar, Nizal |
| Attorney, Agent or Firm: | Rao, Weisun Greenberg Traurig, LLP |
| رقم الانضمام: | edspgr.08742138 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |