Compounds and methods for preventing, treating and/or protecting against sensory hair cell death
원문보기
IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A01N-043/42
A61K-031/44
C07D-495/04
A61K-031/4365
A61K-031/496
A61K-031/5377
C07D-495/08
A61K-045/06
A61K-031/70
출원번호
US-0431025
(2013-09-27)
등록번호
US-9416141
(2016-08-16)
국제출원번호
PCT/US2013/062440
(2013-09-27)
국제공개번호
WO2014/052914
(2014-04-03)
발명자
/ 주소
Simon, Julian
Johnson, Graham
Rubel, Edwin
Chowdhury, Sarwat
Herr, R. Jason
Jiang, Qin
Chen, Xinchao
Owens, Kelly N
Raible, David
출원인 / 주소
University of Washington through its Center for Commercialization
대리인 / 주소
Wilson Sonsini Goodrich & Rosati
인용정보
피인용 횟수 :
1인용 특허 :
23
초록
Disclosed herein are compounds, and pharmaceutical compositions that include such compounds, for preventing, treating, and/or protecting against sensory hair cell death. Methods of using the compounds, alone or in combination with other therapeutic agents, are also disclosed.
대표청구항▼
1. A compound having the structure of Formula (III): wherein: X is a single bond, double bond, —CH2—, or —O—;R1 is C6-C10aryl or C3-C9heteroaryl, wherein C6-C10aryl and C3-C9heteroaryl are optionally substituted with one or more R4;R2 is H, C1-C6alkyl, C1-C6alkyl-OR6, C1-C6alkylC3-C6cycloalkyl, C1-
1. A compound having the structure of Formula (III): wherein: X is a single bond, double bond, —CH2—, or —O—;R1 is C6-C10aryl or C3-C9heteroaryl, wherein C6-C10aryl and C3-C9heteroaryl are optionally substituted with one or more R4;R2 is H, C1-C6alkyl, C1-C6alkyl-OR6, C1-C6alkylC3-C6cycloalkyl, C1-C6alkylC2-C7heterocycloalkyl, C1-C6alkyl-CO2R6, optionally substituted C1-C6alkylC6-C10aryl, or optionally substituted C1-C6alkylC3-C9heteroaryl;R3 are R5 are each independently H, or C1-C6alkyl; orR3 and R5 together form an optionally substituted C3-C6cycloalkyl ring, optionally substituted C2-C7heterocycloalkyl ring, optionally substituted C6-C10aryl ring, or an optionally substituted C3-C9heteroaryl ring;each R4 is independently selected from F, Cl, Br, I, —CN, —NO2, —CF3, —OR9, —OCF3, —NR8R9, —C(O)R10, —CO2R9, —C(O)NR8R9, —N(R8)C(O)R10, —N(R8)CO2R10, —NHS(O)2R10, —S(O)2NR8R9, C1-C6alkyl, C3-C6cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C7heterocycloalkyl, C6-C10aryl, and C3-C9heteroaryl;R6 is H, or C1-C6alkyl;R8 is H, or C1-C6alkyl;R9 is H, C1-C6alkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, C6-C10aryl, C3-C9heteroaryl, C1-C6alkylC6-C10aryl, or C1-C6alkylC3-C9heteroaryl;R10 is C1-C6alkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, C6-C10aryl, C3-C9heteroaryl, C1-C6alkylC6-C10aryl, or C1-C6alkylC3-C9heteroaryl;R11 is H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, C6-C10aryl, C3-C9heteroaryl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkylC6-C10aryl, or C1-C6alkylC3-C9heteroaryl;R12 is H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, C6-C10aryl, C3-C9heteroaryl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkylC6-C10aryl, or C1-C6alkylC3-C9heteroaryl;or R11 and R12 together with the nitrogen to which they are attached form an optionally substituted C2-C7heterocycloalkyl ring; andR13 are R14 are each independently H, or C1-C6alkyl;or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof. 2. The compound of claim 1 wherein R1 is phenyl optionally substituted with one or more R4. 3. The compound of claim 2 wherein R1 is substituted with one R4, wherein R4 is selected from F, Cl, Br, I, —CN, —CF3, —OR9, —OCF3, —C(O)R10, —CO2R9, and C1-C6alkyl. 4. The compound of claim 3 wherein R11 and R12 are each H. 5. The compound of claim 4 wherein R3 and R5 are each H. 6. The compound of claim 5 wherein R13 and R14 are each CH3. 7. The compound of claim 5 wherein R13 and R14 are each H. 8. The compound of claim 7 wherein X is a single bond. 9. The compound of claim 8 wherein R1 is 4-chlorophenyl. 10. The compound of claim 9 wherein R2 is H. 11. The compound of claim 9 wherein R2 is C1-C6alkyl. 12. The compound of claim 11 wherein R2 is CH3. 13. The compound of claim 9 wherein R2 is C1-C6alkylC3-C6cycloalkyl. 14. The compound of claim 13 wherein R2 is —CH2C3-C6cycloalkyl. 15. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, and a pharmaceutically acceptable excipient. 16. The pharmaceutical composition of claim 15 further comprising an aminoglycoside antibiotic. 17. A method for preventing, treating, and/or protecting against sensory hair cell death in an individual comprising administering to the individual a therapeutically effective amount of a compound of claim 1. 18. The method of claim 17 wherein the sensory hair cell death is associated with exposure to an ototoxic agent. 19. The method of claim 18 wherein the ototoxic agent is an aminoglycoside antibiotic. 20. A compound having the structure of Formula (I): wherein: R1 is C6-C10aryl or C3-C9heteroaryl, wherein C6-C10aryl and C3-C9heteroaryl are optionally substituted with one or more R4;R2 is H, C1-C4alkyl, or C2-C4alkenyl;R3 is C2-C6alkyl, C2-C6alkenyl, C1-C4haloalkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C7heterocycloalkyl, optionally substituted C6-C10aryl, —OR6, —NR5R6, —C(O)R7, —CO2R6, —C(O)NR5R6, —N(R5)C(O)R7, —N(R5)CO2R7, —NHS(O)2R7, —S(O)2NR5R6, or or R2 and R3 together form an optionally substituted C2-C7heterocycloalkyl ring;each R4 is independently selected from F, Cl, Br, I, —CN, —NO2, —CF3, —OR9, —OCF3, —NR8R9, —C(O)R10, —CO2R9, —C(O)NR8R9, —N(R8)C(O)R10, —N(R8)CO2R10, —NHS(O)2R10, —S(O)2NR8R9,C1-C6alkyl, C3-C6cycloalkyl, C1-C6heteroalkyl, C1-C6haloalkyl, C2-C7heterocycloalkyl, C6-C10aryl, and C3-C9heteroaryl;R5 is H, or C1-C6alkyl;R6 is H, C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C7heterocycloalkyl, optionally substituted C6-C10aryl, optionally substituted C3-C9heteroaryl, optionally substituted C1-C6alkylC6-C10aryl, or optionally substituted C1-C6alkylC3-C9heteroaryl;R7 is C1-C6alkyl, optionally substituted C3-C6cycloalkyl, optionally substituted C2-C7heterocycloalkyl, optionally substituted C6-C10aryl, C3-C9heteroaryl, optionally substituted C1-C6alkylC6-C10aryl, or optionally substituted C1-C6alkylC3-C9heteroaryl;R8 is H, or C1-C6alkyl;R9 is H, C1-C6alkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, C6-C10aryl, C3-C9heteroaryl, C1-C6alkylC6-C10aryl, or C1-C6alkylC3-C9heteroaryl;R10 is C1-C6alkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, C6-C10aryl, C3-C9heteroaryl, C1-C6alkylC6-C10aryl, or C1-C6alkylC3-C9heteroaryl;R11 is H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, C6-C10aryl, C3-C9heteroaryl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkylC6-C10aryl, or C1-C6alkylC3-C9heteroaryl;R12 is H, C1-C6alkyl, C1-C6haloalkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, C6-C10aryl, C3-C9heteroaryl, C1-C6alkylC3-C6cycloalkyl, C1-C6alkylC6-C10aryl, or C1-C6alkylC3-C9heteroaryl; or R11 and R12 together with the nitrogen to which they are attached form an optionally substituted C2-C7heterocycloalkyl ring;R13, R14, R15, and R16 are each independently H, or C1-C4alkyl;n is an integer selected from 0-4;p is an integer selected from 0-3; andq is an integer selected from 0-3;or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof.
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