Compounds and uses thereof in modulating levels of various amyloid beta peptide alloforms
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
C07D-417/14
C07F-009/6558
출원번호
US-0806692
(2011-06-24)
등록번호
US-9403815
(2016-08-02)
국제출원번호
PCT/US2011/041905
(2011-06-24)
§371/§102 date
20130313
(20130313)
국제공개번호
WO2011/163636
(2011-12-29)
발명자
/ 주소
Wagner, Steven L.
Cheng, Soan
Mobley, William C.
Tanzi, Rudolph E.
출원인 / 주소
The Regents of the University of California
대리인 / 주소
Fish & Richardson P.C.
인용정보
피인용 횟수 :
1인용 특허 :
21
초록
The invention provides a novel compound having a structure corresponding to Formula (I): (A)-(B)-(C)-(D) (I) or a pharmaceutically acceptable salt or prodrug thereof and methods for using them.
대표청구항▼
1. A compound having a structure corresponding to Formula (I): (A)-(B)-(C)-(D) (I)or a pharmaceutically acceptable salt or prodrug thereof:Wherein A is: Wherein each E is independently N, NR, C, or CR1 , provided that two or three E's are N or NR;N is nitrogen; C is carbon; R is hydrogen, substitut
1. A compound having a structure corresponding to Formula (I): (A)-(B)-(C)-(D) (I)or a pharmaceutically acceptable salt or prodrug thereof:Wherein A is: Wherein each E is independently N, NR, C, or CR1 , provided that two or three E's are N or NR;N is nitrogen; C is carbon; R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;Each R1 is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;Wherein B is: Wherein each G is independently CR2;Each R2 is independently a hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfide, substituted or unsubstituted alkyl sulfinyl group, or substituted or unsubstituted alkyl sulfonyl group;Wherein B is: Wherein each G is independently CR3a;Each R3a is independently a hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfide, substituted or unsubstituted alkyl sulfinyl group, or substituted or unsubstituted alkyl sulfonyl group; Wherein each G is independently CR3b;Each R3b is independently a hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfide, substituted or unsubstituted alkyl sulfinyl group, or substituted or unsubstituted alkyl sulfonyl group; or Wherein each G is independently CR3c;Each R3c is independently a hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfide, substituted or unsubstituted alkyl sulfinyl group, or substituted or unsubstituted alkyl sulfonyl group; andWherein C is: Wherein R4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted alkoxy; andWherein D is: Wherein R5 is a hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;R6a and R6b are independently a hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; Wherein R7 is a hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;M is independently CHR8;Each R8 is independently a hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted alkoxy; or Where R9 is a hydrogen, halogen, or a substituted or unsubstituted alkyl;J is independently CH or N;Z is independently CHR10;Each R10 is independently a hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted alkoxy. 2. The compound of claim 1, wherein A of Formula (I) or a pharmaceutically acceptable salt thereof, is wherein Q is either CH or N. 3. The compound of claim 2, wherein R1 is a substituted or unsubstituted C1-C5 alkyl. 4. The compound of claim 3, having a structure corresponding to Formula (II): WhereinR4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted alkoxy;R5 is a hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;R6a and R6b are independently a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl;G is independently CR3c;Each R3c is independently a hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfide, substituted or unsubstituted alkyl sulfinyl group, or substituted or unsubstituted alkyl sulfonyl group; andQ is either CH or N; orhaving a structure corresponding to Formula (III): WhereinR4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted alkoxy;R5 is a hydrogen, a substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;R6a and R6b are independently a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl;G is independently CR3c;Each R3c is independently a hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfide, substituted or unsubstituted alkyl sulfinyl group, or substituted or unsubstituted alkyl sulfonyl group; andQ is either CH or N; orhaving a structure corresponding to Formula (IV): WhereinR4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted alkoxy;R5 is a hydrogen, a substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;R6a and R6b are independently a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl;G is independently CR3c;Each R3c is independently a hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfide, substituted or unsubstituted alkyl sulfinyl group, or substituted or unsubstituted alkyl sulfonyl group; andQ is either CH or N; orhaving a structure corresponding to Formula (V): WhereinR4 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted alkoxy;R5 is a hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;R6a and R6b are independently a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl;G is independently CR3c;Each R3c is independently a hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted alkylsulfide, substituted or unsubstituted alkyl sulfinyl group, or substituted or unsubstituted alkyl sulfonyl group; andQ is either CH or N. 5. The compound of claim 1 wherein D is selected from a group consisting of: 6. The compound of claim 4, having a structure corresponding to Formula (VI): Wherein R5 is a hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; andR6a and R6b are independently a hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl. 7. A compound having a structure corresponding to Formula (VII): Wherein R5 is a hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl. 8. The compound of claim 7, wherein said compound is selected from the group consisting of: 9. The compound of claim 6, wherein said compound is selected from the group consisting of: 10. The compound of claim 4, having a structure corresponding to Formula (VIII): Wherein R5 is a hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl; andR6a and R6b are independently a hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl. 11. A compound having a structure corresponding to Formula (IX): Wherein R5 is a hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl. 12. The compound of claim 11, wherein said compound is selected from the group consisting of: 13. The compound of claim 10, wherein said compound is selected from the group consisting of: 14. A compound selected from the group consisting of: 15. The compound of claim 1, wherein the unsubstituted alkyl group is methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, or tert-butyl group. 16. The compound of claim 1, wherein the prodrug has structure (X) or (XI): wherein:X is a hydrogen, halogen, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylsulfide, substituted or unsubstituted alkyl sulfinyl group, or substituted or unsubstituted alkyl sulfonyl group;R5 is a hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;R6a and R6b are independently a hydrogen, substituted or unsubstituted alkyl, or substituted or unsubstituted cycloalkyl;Ra and Rb are a C1-6 alkyl group; andL is a phosphono group. 17. A method of modulating levels of a highly fibrillogenic amyloid-beta (Aβ) peptide comprising contacting a protease which proteolyzes an amyloid precursor protein (APP) carboxyl-terminal fragment (CTF) or fragment thereof with an effective amount of a compound of claim 1 so as to modulate the levels of fibrillogenic amyloid-beta (Aβ) peptides. 18. A method of inhibiting production of Aβ42 or Aβ40 comprising contacting a protease which proteolyzes an amyloid precursor protein (APP) carboxyl-terminal fragment (CTF) or fragment thereof with an effective amount of a compound of claim 1 so as inhibit production of Aβ42 or Aβ40. 19. A method of promoting production of Aβ38 or Aβ37 comprising contacting a protease which proteolyzes an amyloid precursor protein (APP) carboxyl-terminal fragment (CTF) or fragment thereof with an effective amount of a compound of claim 1 so as promote production of Aβ38 or Aβ37. 20. A method for treating Alzheimer's Disease in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound of claim 1.
Eppstein Deborah A. (Los Altos CA) Fraser-Smith Elizabeth B. (Los Altos CA) Matthews Thomas R. (Los Gatos CA), Serial injection of muramyldipeptides and liposomes enhances the anti-infective activity of muramyldipeptides.
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