Moenomycin analogs, methods of synthesis, and uses thereof
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-031/702
A61K-031/715
A61K-031/7016
A61K-031/7028
C07H-005/04
C07H-005/06
출원번호
US-0681052
(2008-10-03)
등록번호
US-8604004
(2013-12-10)
국제출원번호
PCT/US2008/078771
(2008-10-03)
§371/§102 date
20110104
(20110104)
국제공개번호
WO2009/046314
(2009-04-09)
발명자
/ 주소
Kahne, Daniel
Kahne, Suzanne Walker
Adachi, Masaatsu
Doud, Emma
Fuse, Shinichiro
Lin, Xiaonan
Zhang, Yi
Tsukamoto, Hirokazu
Ostash, Bohdan
출원인 / 주소
President and Fellows of Harvard College
대리인 / 주소
Wolf, Greenfield & Sacks, P.C.
인용정보
피인용 횟수 :
5인용 특허 :
54
초록▼
The present invention provides novel moenomycin analogs as well as pharmaceutical compositions thereof, methods of synthesis, and methods of use in treating an infection by administering an inventive compound to a subject in need thereof. The moenomycin analogs may be prepared synthetically, biosynt
The present invention provides novel moenomycin analogs as well as pharmaceutical compositions thereof, methods of synthesis, and methods of use in treating an infection by administering an inventive compound to a subject in need thereof. The moenomycin analogs may be prepared synthetically, biosynthetically, or semi-synthetically. The analogs are particularly useful in treating or preventing infections caused by Gram-positive organisms. Certain inventive compounds may have a broader spectrum of coverage, which includes Gram-negative organisms.
대표청구항▼
1. A compound of formula (I): or a pharmaceutically acceptable salt thereof; wherein: R1a and R1b are, independently, H, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic;each instanc
1. A compound of formula (I): or a pharmaceutically acceptable salt thereof; wherein: R1a and R1b are, independently, H, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic;each instance of R2, R4, and R5 is, independently, H, —ORz, —N(Rz)2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic, wherein Rz is H, a hydroxyl protecting group, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted aliphatic, optionally substituted heteroaliphatic, or a carbohydrate moiety;R3 is, independently, H, —OH, —NH2, —SH, —ORw, —NH(Rw), —N(Rw)2, —SRw, —O(C═O)Rw, —NH(C═O)Rw, —O(C═NH)Rw, —NH(C═NH)Rw, —S(C═NH)Rw, —NH(C═S)Rw, —S(C═O)Rw, —O(C═S)Rw, —S(═S)Rw, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic, wherein Rw is a carbohydrate moiety, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic;each instance of R6 and R7 is, independently, H, a hydroxyl protecting group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, optionally substituted heteroaliphatic, a carbohydrate moiety, —C(═O)N(RZ)2, —C(═O)ORZ, wherein Rz is H, a hydroxyl protecting group, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted aliphatic, optionally substituted heteroaliphatic, or a carbohydrate moiety; andeach instance of R8 is, independently, H, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, optionally substituted heteroaliphatic, a carbohydrate moiety, or —C(═O)Rw, wherein Rw is a carbohydrate moiety, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic;[Linker] is the group: wherein: Rc is hydrogen, halogen, optionally substituted heteroaryl, —ORq, —N(Rq)2, —SRq, —NO2, —CN, —N3, —N(Rq)═NRq, —CHO, —C(═O)Rq, —C(═S)Rq, —C(═NRq)Rq, —C(═O)ORq, —C(═NRq)ORq, —C(═NRq)N(Rq)2, —C(═O)N(Rq)2, —C(═S)ORq, —C(═O)SRq, —C(═S)SRq, —P(═O)(ORq)2, —P(═O)2(ORq), —S(═O)(ORq), —S(═O)2(ORq), —P(═O)N(Rq)2, —P(═O)2N(Rq)2, —C(═O)NRqS(═O)2Rq, —S(═O)N(Rq)2, —S(═O)2N(Rq)2, or optionally substituted heteroaryl; wherein each instance of Rq is H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or a protecting group;Ri is H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or a hydroxyl protecting group; andR9 is H or an optionally substituted C1-30 aliphatic moiety, wherein 0 to 10 methylene units are optionally replaced with —O—, —NRx, —S—, —C(═O)—, —C(═NRx)—, —S(═O)—, —S(═O)2—, —N═N—, —C(Ry)═C(Ry)—, an optionally substituted arylene, or an optionally substituted heteroarylene moiety, wherein each instance of Rx is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group, and each instance of Ry is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, or optionally substituted heteroaryl,R10 is —C(═O)NHR8, —CH2OR6, or —C(═O)OR6;R11 is —OR6 or —NHR8;R12 is —OR6 or —NHR8;with the proviso that the compound is not moenomycin A; moenomycin A1.2; moenomycin C1; moenomycin C3; moenomycin C4; AC326-alpha; pholipomycin; decahydromoenomycin A; decahydromoenomycin A1.2; decahydromoenomycin C1, decahydropholipomycin; octahydro-AC326-alpha; dihydromoenomycin A; [3H] moenomycin A; [2H] moenomycin A; or a moenomycin compound wherein R9 is: 2. A compound of formula (III): or a pharmaceutically acceptable salt thereof;wherein: R3 is, independently, H, —OH, —NH2, —SH, —ORw, —NH(Rw), —N(Rw)2, —SRw, —O(C═O)Rw, —NH(C═O)Rw, —O(C═NH)Rw, —NH(C═NH)Rw, —S(C═NH)Rw, —NH(C═S)Rw, —S(C═O)Rw, —O(C═S)Rw, —S(═S)Rw, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic, wherein Rw is a carbohydrate moiety, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic;each instance of R4 and R5 is, independently, H, —ORz, —N(Rz)2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic, wherein Rz is H, a hydroxyl protecting group, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted aliphatic, optionally substituted heteroaliphatic, or a carbohydrate moiety;each instance of R6 and R7 is, independently, H, a hydroxyl protecting group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, optionally substituted heteroaliphatic, a carbohydrate moiety, —C(═O)N(RZ)2, —C(═O)ORZ, wherein Rz is H, a hydroxyl protecting group, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted aliphatic, optionally substituted heteroaliphatic, or a carbohydrate moiety; andeach instance of R8 is, independently, H, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, optionally substituted heteroaliphatic, a carbohydrate moiety, or —C(═O)Rw, wherein Rw is a carbohydrate moiety, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic;[Linker] is the group: wherein: Rc is hydrogen, halogen, optionally substituted heteroaryl, —ORq, —N(Rq)2, —SRq, —NO2, —CN, —N3, —N(Rq)═NRq, —CHO, —C(═O)Rq, —C(═S)Rq, —C(═NRq)Rq, —C(═O)ORq, —C(═NRq)ORq, —C(═NRq)N(Rq)2, —C(═O)N(Rq)2, —C(═S)ORq, —C(═O)SRq, —C(═S)SRq, —P(═O)(ORq)2, —P(═O)2(ORq), —S(═O)(ORq), —S(═O)2(ORq), —P(═O)N(Rq)2, —P(═O)2N(Rq)2, —C(═O)NRqS(═O)2Rq, —S(═O)N(Rq)2, —S(═O)2N(Rq)2, or optionally substituted heteroaryl; wherein each instance of Rq is H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or a protecting group;Ri is H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or a hydroxyl protecting group; andR9 is H, unsubstituted or saturated hydrocarbon chain, unsubstituted or unsaturated hydrocarbon chain, substituted or unsaturated hydrocarbon chain, an optionally substituted aryl, or an optionally substituted heteroaryl moiety,whereineach instance of s and t is independently 0, 1, 2, 3, 4, or 5;each instance of Rx is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group, andeach instance of Ry is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, or optionally substituted heteroaryl;R10 is C(O)NHR8, —CH2OR6, or —C(═O)OR6; andR11 is —OR6 or —NHR8. 3. The compound according to claim 1, wherein R1a and R1b are, independently, H or the group: 4. The compound according to claim 1, wherein R2 is —CH3 or —CH2OH. 5. The compound according to claim 1, wherein R3 is —OH or —ORw. 6. The compound according to claim 1, wherein R3 is ORw, wherein Rw is a carbohydrate moiety. 7. The compound according to claim 1, wherein R4 and R5 are, independently, H, —CH3, —N(Rz)2, or —ORz. 8. The compound according to claim 1, wherein each instance of R6 is, independently, H or —C(═O)CH3. 9. The compound according to claim 1, wherein R7 is H, —C(═O)CH3, or —C(═O)NH2. 10. The compound according to claim 1, wherein R8 is H or —C(═O)CH3. 11. The compound according to claim 1, wherein Rc is —C(═O)H, —C(═O)OH, or —C(═O)NH2. 12. The compound according to claim 1, wherein Ri is H or a hydroxyl protecting group. 13. The compound according to claim 1, wherein R9 is an optionally substituted, optionally unsaturated, C10-20 hydrocarbon chain, wherein 0 to 8 methylene units are optionally replaced with —O—, —NRx—, —S—, —C(═O)—, —C(═NRx)—, —S(═O)—, —S(═O)2—, —N═N—, —C(Ry)═C(Ry), an optionally substituted arylene or an optionally substituted heteroarylene moiety. 14. The compound of claim 1, wherein R9 is an optionally substituted, optionally unsaturated, C10-C16 aliphatic moiety. 15. The compound of claim 1 wherein R9 is of one of the formulae: 16. The compound of claim 1, wherein R9 is a fluorinated, C8-C16 alkyl moiety. 17. The compound of claim 1, wherein R9 is of one of the formulae: 18. The compound of claim 1, wherein R9 is of one of the formulae: 19. The compound of claim 1, wherein R9 is of the formula: wherein each occurrence of Re is independently hydrogen or an optionally substituted aliphatic moiety. 20. The compound of claim 1, wherein [Linker] is of formula: 21. The compound of claim 1, wherein R10 is —C(═O)NHR8. 22. The compound of claim 1, wherein R10 is —C(═O)NH2. 23. The compound of claim 1, wherein R11 is —OR6. 24. The compound of claim 1, wherein R11 is —OH. 25. The compound of claim 1, wherein R12 is —OR6. 26. The compound of claim 1, wherein R12 is —OH. 27. A pharmaceutical composition comprising a compound of claim 1. 28. A compound of formula (IV): or a pharmaceutically acceptable salt thereof;wherein: R3 is, independently, H, —OH, —NH2, —SH, —ORw, —NH(Rw), —N(Rw)2, —SRw, —O(C═O)Rw, —NH(C═O)Rw, —O(C═NH)Rw, —NH(C═NH)Rw, —S(C═NH)Rw, —NH(C═S)Rw, —S(C═O)Rw, —O(C═S)Rw, —S(═S)Rw, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic, wherein Rw is a carbohydrate moiety, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic;each instance of R4 and R5 is, independently, H, —ORz, —N(Rz)2, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic, wherein Rz is H, a hydroxyl protecting group, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted aliphatic, optionally substituted heteroaliphatic, or a carbohydrate moiety;each instance of R6 and R7 is, independently, H, a hydroxyl protecting group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, optionally substituted heteroaliphatic, a carbohydrate moiety, —C(═O)N(RZ)2, —C(═O)ORZ, wherein Rz is H, a hydroxyl protecting group, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted aliphatic, optionally substituted heteroaliphatic, or a carbohydrate moiety; andeach instance of R8 is, independently, H, an amino protecting group, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, optionally substituted heteroaliphatic, a carbohydrate moiety, or —C(═O)Rw, wherein Rw is a carbohydrate moiety, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aliphatic, or optionally substituted heteroaliphatic;[Linker] is the group: wherein: Rc is hydrogen, halogen, optionally substituted heteroaryl, —ORq, —N(Rq)2, —SRq, —NO2, —CN, —N3, —N(Rq)═NRq, —CHO, —C(═O)Rq, —C(═S)Rq, —C(═NRq)Rq, —C(═O)ORq, —C(═NRq)ORq, —C(═NRq)N(Rq)2, —C(═O)N(Rq)2, —C(═S)ORq, —C(═O)SRq, —C(═S)SRq, —P(═O)(ORq)2, —P(═O)2(ORq), —S(═O)(ORq), —S(═O)2(ORq), —P(═O)N(Rq)2, —P(═O)2N(Rq)2, —C(═O)NRqS(═O)2Rq, —S(═O)N(Rq)2, —S(═O)2N(Rq)2, or optionally substituted heteroaryl; wherein each instance of Rq is H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or a protecting group;Ri is H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or a hydroxyl protecting group; andR9 is H, an optionally substituted C1-30 aliphatic moiety, wherein 0 to 10 methylene units are optionally replaced with —O—, —NRx—, —S—, —C(═O)—, —C(═NRx)—, —S(═O)—, —S(═O)2—, —N═N—, —C(Ry)═C(Ry)—, an optionally substituted arylene, or an optionally substituted heteroarylene moiety, wherein each instance of Rx is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, optionally substituted heteroaryl, or an amino protecting group, and each instance of Ry is, independently, H, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aryl, or optionally substituted heteroaryl;R10 is —C(O)NHR8, —CH2OR6, or —C(═O)OR6; andR11 is —OR6 or —NHR8.
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이 특허에 인용된 특허 (54)
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