Enopeptins, uses thereof, and methods of synthesis thereto
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-038/08
C07K-007/56
A61K-038/15
A61K-031/407
C07D-498/14
C07D-498/22
A61K-038/12
A61K-045/06
A61K-038/00
출원번호
US-0924667
(2015-10-27)
등록번호
US-10106580
(2018-10-23)
발명자
/ 주소
Sello, Jason K.
출원인 / 주소
Brown University
대리인 / 주소
Wolf, Greenfield & Sacks, P.C.
인용정보
피인용 횟수 :
0인용 특허 :
30
초록
Provided herein are inventive enopeptin compounds of Formula (I): and pharmaceutically acceptable salts thereof, and pharmaceutical compositions thereof. Further provided are methods of preparation, use, and treatment.
대표청구항▼
1. A compound of Formula (III-a): or a pharmaceutically acceptable salt thereof; wherein: R1 is hydrogen or CH3;R7 is halogen, OH, —SH, —NH2, —CN, —NO2, —N3, —SO2H, —SO3H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted C2
1. A compound of Formula (III-a): or a pharmaceutically acceptable salt thereof; wherein: R1 is hydrogen or CH3;R7 is halogen, OH, —SH, —NH2, —CN, —NO2, —N3, —SO2H, —SO3H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted C2-6 alkyl, substituted C1 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;R5 is: x is an integer between 1 and 10, inclusive;R10a and R10b are independently hydrogen or optionally substituted alkyl;R9 is hydrogen, halogen, —CN, —NO2, —N3, substituted hydroxyl, substituted thiol, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;each instance of R6 is independently halogen, —OH, —SH, —NH2, —CN, —NO2, —N3, —SO2H, —SO3H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;m is 0 or an integer of between 1 and 5, inclusive;R11 is hydrogen; andR12 is —CH3. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein x is 1. 3. The compound of claim 2, or a pharmaceutically acceptable salt thereof, wherein each of R10a and R10b is hydrogen; and R9 is optionally substituted alkyl. 4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 2 and the group: 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1 and the group: 6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is halogen, optionally substituted c2-6 alkyl, substituted C1 alkyl, optionally substituted alkenyl, or optionally substituted alkynyl. 7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is halogen. 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is optionally substituted C2-6 alkyl. 9. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is halogen, —OH, —SH, —NH2, —CN, —NO2, —N3, —SO2H, —SO3H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted C2-6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. 10. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is substituted C1 alkyl. 11. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is fluoro or chloro. 12. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is halogen, —OH, —SH, —NH2, —CN, —NO2, —N3, —SO2H, —SO3H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl. 13. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R7 is fluoro. 14. A pharmaceutical composition comprising a compound of claim 1, or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 15. A method of preparing a compound of claim 1, the method comprising providing a compound of Formula (G): or salt thereof; and coupling the compound of Formula (G), or salt thereof, with a compound of Formula (H): or salt thereof; to provide a compound of Formula (I): or pharmaceutically acceptable salt thereof; wherein: R2 is hydrogen and the stereochemistry of the carbon attached to R2 and R3 is: R1 is hydrogen or —CH3;R3 and R4 are joined to form a substituted 6-membered heterocyclyl of formula: each instance of R7 is independently halogen, —OH, —SH, —NH2, —CN, —NO2, —N3, —SO2H, —SO3H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted C2-6 alkyl, substituted C1 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;R5 is: x is an integer between 1 and 10, inclusive;R10a and R10b are independently hydrogen or optionally substituted alkyl;R9 is hydrogen, halogen, —CN, —NO2, —N3, substituted hydroxyl, substituted thiol, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;each instance of R6 is independently halogen, —OH, —SH, —NH2, —CN, —NO2, —N3, —SO2H, —SO3H, substituted hydroxyl, substituted thiol, substituted amino, sulfonyl, sulfinyl, acyl, silyl, boronyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted carbocyclyl, optionally substituted heterocyclyl, optionally substituted aryl, or optionally substituted heteroaryl;m is 0 or an integer of between 1 and 5, inclusive;R11 is hydrogen; andR12 is —CH3. 16. A method of treating a microbial infection in a subject comprising administering an effective amount of a compound of claim 1, or pharmaceutically acceptable salt thereof, to the subject. 17. The method of claim 16, wherein the microbial infection is a bacterial infection. 18. The method of claim 17, further comprising administering the compound, or pharmaceutically acceptable salt thereof, in combination with an antibiotic. 19. The method of claim 18, wherein the antibiotic is a ribosome-targeting antibiotic. 20. The method of claim 17, wherein the bacterial infection is resistant to other treatments. 21. The method of claim 17, wherein the bacterial infection is multi-drug tolerant or multi-drug resistant. 22. A method of treating microbial virulence comprising contacting an effective amount of a compound of claim 1, or pharmaceutically acceptable salt thereof, to a microorganism. 23. The method of claim 22, wherein the compound, or pharmaceutically acceptable salt thereof, blocks virulence factor production.
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