Moenomycin analogs, methods of synthesis, and uses thereof
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07H-005/06
C07H-013/12
C07F-009/6558
출원번호
US-0390811
(2013-04-05)
등록번호
US-9273084
(2016-03-01)
국제출원번호
PCT/US2013/035416
(2013-04-05)
국제공개번호
WO2013/152277
(2013-10-10)
발명자
/ 주소
Kahne, Daniel Evan
Kahne, Suzanne Walker
Tsukamoto, Hirokazu
출원인 / 주소
President and Fellows of Harvard College
대리인 / 주소
Wolf, Greenfield & Sacks, P.C.
인용정보
피인용 횟수 :
2인용 특허 :
55
초록▼
The present invention provides compounds of Formula (I); or a pharmaceutically acceptable form thereof; wherein R1,R2,R3,R6,R7,R12,Ra, and Rb are as defined herein, and G is a group of Formula (a), (b), or (c): Formula (II), wherein X1; X2, X3, X4, X5, X6, X7, Y, RC, Rd, Rz, a, d, e, x, n, and m are
The present invention provides compounds of Formula (I); or a pharmaceutically acceptable form thereof; wherein R1,R2,R3,R6,R7,R12,Ra, and Rb are as defined herein, and G is a group of Formula (a), (b), or (c): Formula (II), wherein X1; X2, X3, X4, X5, X6, X7, Y, RC, Rd, Rz, a, d, e, x, n, and m are as defined herein. The present invention further provides pharmaceutical compositions comprising a compound of Formula (I), kits comprising such compositions, methods of use and treatment, and preparative methods.
대표청구항▼
1. A compound of Formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof;wherein: G is a group of Formula (a), (b), or (c): wherein a is 3, 4, or 5; wherein:X1, X2, X3, X4, X5, X6, and X7 are each independently hydrogen o
1. A compound of Formula (I): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof;wherein: G is a group of Formula (a), (b), or (c): wherein a is 3, 4, or 5; wherein:X1, X2, X3, X4, X5, X6, and X7 are each independently hydrogen or halogen;d is an integer between 1 and 25, inclusive; ande is an integer of between 2 and 25, inclusive;provided that at least one of X1, X2, X3, X4, X5, X6, and X7 is halogen; andthe sum of d and e is greater than 16; or wherein: Y is —O—, —S—, —NRY—, or an optionally substituted methylene group, wherein RY is hydrogen, optionally substituted aliphatic, or an amino protecting group;each instance of Rc is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —ORe, —SRe, —NHRe, or —N(Re)2, wherein each instance of Re is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two Re groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;each instance of Rd is independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —ORf, —SRf, —NHRf, or —N(Rf)2, wherein each instance of Rf is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two Rf groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;Rz is hydrogen, —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —ORg, —SRg, —NHRg, or —N(Rg)2, wherein each instance of Rg is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl or two Rg groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;each instance of n is, independently, 0, 1, 2, 3, or 4;each instance of m is, independently, 0, 1, 2, 3, or 4; andx is 1, 2, 3, 4, 5, or 6;Rxx is hydrogen, a hydroxyl protecting group, or a group of Formula: R12 is hydrogen, a hydroxyl protecting group, or the group (D): wherein R13, R14, R15, R16, and R17 are each independently hydrogen or a hydroxyl protecting group;R1, R2, R3, and R4 are each independently hydrogen or an amino protecting group;R5 is hydrogen, an amino protecting group, or the group (A): R6, R7, R8, R9, R10, and R11 are each independently hydrogen or a hydroxyl protecting group; andRa and Rb are each independently hydrogen or a hydroxyl protecting group. 2. The compound of claim 1 of Formula (II): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof. 3. The compound of claim 1 of Formula (III): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof; wherein R17 is hydrogen or a hydroxyl protecting group. 4. The compound of claim 1 of Formula (IV): or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof; wherein R18 is hydrogen or a hydroxyl protecting group. 5. The compound of claim 1 wherein G is a group of Formula (a). 6. The compound of claim 5, wherein the group of Formula (a) is selected from the group consisting of: 7. The compound of claim 1 wherein G is a group of Formula (b). 8. The compound of claim 7 wherein at least one of X1, X2, X3, X4, X5, X6, and X7 is halogen. 9. The compound of claim 7 wherein X1 and X2 are each hydrogen, X3 and X4 are each fluoro, and X5, X6, and X7 are each fluoro. 10. The compound of claim 7, wherein the group of Formula (b) is selected from the group consisting of: 11. The compound of claim 1 wherein G is a group of Formula (c). 12. The compound of claim 11, wherein the group of Formula (c) is selected from the group consisting of: wherein:Rc1, Rc2, Rc3, Rc4, Rc5, and Rc6, each independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —ORe, —SRe, —NHRe, or —N(Re)2, wherein each instance of Re is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two Re groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;Rd1, Rd2, Rd3, Rd4, Rd5, and Rd6, each independently —F, —Br, —I, —Cl, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, optionally substituted heteroaryl, —ORf, —SRf, —NHRf, or —N(Rf)2, wherein each instance of Rf is independently hydrogen, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted carbocycyl, optionally substituted heterocycyl, optionally substituted aryl, or optionally substituted heteroaryl, or two Rf groups are joined to form a 5- to 6-membered optionally substituted heterocycyl or optionally substituted heteroaryl ring;Y1, Y2, Y3, Y4, Y5, and Y6, each independently corresponds to —O—, —S—, —NRY—, or an optionally substituted methylene group, wherein RY is hydrogen, optionally substituted aliphatic, or an amino protecting group;n1, n2, n3, n4, n5, and n6 each independently 0, 1, 2, 3, or 4; andm1, m2, m3, m4, m5, and m6 each independently 0, 1, 2, 3, or 4. 13. The compound of claim 1 wherein G is selected from the group consisting of: 14. A pharmaceutical composition comprising an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof, and optionally a pharmaceutically acceptable excipient. 15. A method of treating a bacterial infection comprising administering to a subject an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof. 16. The method of claim 15, wherein the bacterial infection being treated is caused by Gram-positive bacteria. 17. The method of claim 15, wherein bacterial infection being treated is caused by Gram-negative bacteria. 18. The method of claim 15, wherein bacterial infection being treated is caused by vancomycin-resistant bacteria. 19. The method of claim 15, wherein bacterial infection being treated is caused by methicillin-resistant bacteria. 20. An in vitro method of inhibiting bacterial growth by contacting a bacterium with an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, solvate, hydrate, tautomer, isomer, enantiomer, diastereomer, or polymorph thereof. 21. The method of claim 15, wherein the bacterial infection being treated is caused by vancomycin-resistant Staphylococcus aureus, vancomycin-resistant Enterococci, or methicillin-resistant Staphylococcus aureus. 22. The compound of claim 1, wherein the compound is of Formula (I): or a pharmaceutically acceptable salt. 23. A pharmaceutical composition comprising an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and optionally a pharmaceutically acceptable excipient. 24. A method of treating a bacterial infection comprising administering to a subject an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof.
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