O-GlcNAc transferase inhibitors and uses thereof
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/496
A61K-031/4709
A61K-031/4725
C07D-401/12
C07D-401/14
C07D-409/14
C07D-215/36
C07D-417/12
C07D-405/12
출원번호
US-0375036
(2010-06-01)
등록번호
US-8957075
(2015-02-17)
국제출원번호
PCT/US2010/001596
(2010-06-01)
§371/§102 date
20120109
(20120109)
국제공개번호
WO2010/141074
(2010-12-09)
발명자
/ 주소
Kahne, Suzanne Walker
Lazarus, Michael Block
Gross, Benjamin J.
출원인 / 주소
President and Fellows of Harvard College
대리인 / 주소
Wolf, Greenfield & Sacks, P.C.
인용정보
피인용 횟수 :
1인용 특허 :
41
초록▼
The present invention provides inhibitors of O-GIcNAc transferase. Typically, the inhibitors are quinolinone-6-sulfonamides. The invention also provides pharmaceutical compositions thereof and methods for using the same in diabetes and complications thereof, neurodegenerative diseases, cancers, auto
The present invention provides inhibitors of O-GIcNAc transferase. Typically, the inhibitors are quinolinone-6-sulfonamides. The invention also provides pharmaceutical compositions thereof and methods for using the same in diabetes and complications thereof, neurodegenerative diseases, cancers, autoimmune diseases, and inflammatory diseases.
대표청구항▼
1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein denotes a single or double bond;R1 is cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; sub
1. A compound of formula (I): or a pharmaceutically acceptable salt thereof, wherein denotes a single or double bond;R1 is cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted, branched or unbranched arylalkyl; or substituted or unsubstituted, branched or unbranched heteroarylalkyl;R2 and R3 are independently cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted aryl; substituted or unsubstituted heteroaryl; substituted or unsubstituted, branched or unbranched arylalkyl; substituted or unsubstituted, branched or unbranched heteroarylalkyl; —C(═O)RB; —SORB; —SO2RB; or —C(RB)3; wherein each occurrence of RB is independently hydrogen; halogen; a protecting group; aliphatic; heteroaliphatic; acyl; aryl; heteroaryl; hydroxyl; alkoxy; aryloxy; amino; alkylamino; dialkylamino; or heteroaryloxy; orR2 and R3 may optionally be taken together with the intervening nitrogen to form a saturated or unsaturated, substituted or unsubstituted heterocyclic moiety;R4 is hydrogen, C1-6 aliphatic, or a protecting group;R5 is hydrogen, C1-6 aliphatic, or a protecting group;R6 is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —ORF; —C(═O)RF; —CO2RF; —C(═O)N(RF)2; —CN; —SCN; —SRF; —SORF; —SO2RF; —NO2; —N(RF)2; —NHC(O)RF; or —C(RF)3; wherein each occurrence of RF is independently hydrogen; halogen; a protecting group; aliphatic; heteroaliphatic; acyl; aryl moiety; heteroaryl; hydroxy; alkoxy; aryloxy; alkylthioxy; arylthioxy; amino; alkylamino; dialkylamino; heteroaryloxy; or heteroarylthioxy; andn is 0, 1, 2, or 3; wherein the compound of formula (I) is not one of the following: 2. The compound of claim 1, wherein the compound has the stereochemistry of formula (Ia): 3. The compound of claim 1, wherein the compound has the stereochemistry of formula (Ib): 4. The compound of claim 1 of formula: 5. The compound of claim 1 of formula: 6. The compound of claim 1 of formula: 7. The compound of claim 1 of formula: 8. The compound of claim 1 of formula: wherein RA is hydrogen; halogen; cyclic or acyclic, substituted or unsubstituted, branched or unbranched aliphatic; cyclic or acyclic, substituted or unsubstituted, branched or unbranched heteroaliphatic; substituted or unsubstituted, branched or unbranched acyl; substituted or unsubstituted, branched or unbranched aryl; substituted or unsubstituted, branched or unbranched heteroaryl; —OR; —C(═O)R; —CO2R; —C(═O)N(R)2; —CN; —SCN; —SR; —SOR; —SO2R; —NO2; —N(R)2; —NHC(O)R; or —C(R)3; wherein each occurrence of R is independently hydrogen; halogen; a protecting group; aliphatic; heteroaliphatic; acyl; aryl moiety; heteroaryl; alkoxy; aryloxy; alkylthioxy; arylthioxy; amino; alkylamino; dialkylamino; heteroaryloxy; or heteroarylthioxy; andm is 0-5, inclusive. 9. The compound of claim 1, wherein R2 and R3 are taken together to form a heterocyclic ring. 10. The compound of claim 1, wherein each of R2 and R3 is C1-6 alkyl, C1-6 heteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl. 11. The compound of claim 1, wherein one of R2 and R3 is C1-6 alkyl, C1-6 heteroalkyl, aryl, heteroaryl, arylalkyl, or heteroarylalkyl. 12. A compound having the formula: 13. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1; and a pharmaceutically acceptable excipient. 14. A method for treating an OGT-associated disease or condition in a subject comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound of claim 1. 15. The method of claim 14, wherein the subject is human. 16. The method of claim 14, wherein the OGT-associated disease or condition is cancer, diabetes mellitus type I, diabetes mellitus type II, insulin resistance, a complication of diabetes, or inflammatory disease. 17. The compound of claim 1, wherein is a single bond and R1 is not phenyl or benzyl. 18. The compound of claim 1, wherein is a double bond. 19. The compound of claim 1 of formula: 20. The compound of claim 1 of formula: 21. The compound of claim 20 of formula: 22. The compound of claim 20 of formula: 23. The compound of claim 7, wherein the compound has the stereochemistry of formula: 24. The compound of claim 7, wherein the compound has the stereochemistry of formula: 25. The compound of claim 8, wherein the compound has the stereochemistry of formula: 26. The compound of claim 8, wherein the compound has the stereochemistry of formula: 27. The compound of claim 8, wherein RA is halogen and m is 1. 28. The compound of claim 8, wherein RA is chloro or fluoro. 29. The compound of claim 9, wherein R2 and R3 are taken together to form a 6-membered heterocyclic ring. 30. The compound of claim 9, wherein R2 and R3 are taken together to form an optionally substituted pyrrolidine, piperidine, or homopiperidine ring. 31. The compound of claim 9, wherein R2 and R3 are taken together to form an optionally substituted piperazine ring. 32. The compound of claim 31, wherein the piperazine ring is substituted with an optionally substituted aryl or heteroaryl moiety. 33. The compound of claim 1, wherein at least one of R2 and R3 is aryl, arylalkyl, heteroaryl, or heteroarylalkyl. 34. The compound of claim 33, wherein each of R2 and R3 is arylalkyl or heteroarylalkyl. 35. The compound of claim 33, wherein each of R2 and R3 is heteroarylalkyl. 36. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 12; and a pharmaceutically acceptable excipient. 37. The pharmaceutical composition of claim 13, administered in an amount sufficient to deliver about 0.001 mg/kg to about 100 mg/kg of subject body weight per day.
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