[미국특허]
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
A61K-031/70
A61K-045/06
C07D-495/08
A61K-031/439
A61K-031/444
A61K-031/4545
A61K-031/4709
A61K-031/4725
C07D-495/18
출원번호
US-0214241
(2016-07-19)
등록번호
US-9902738
(2018-02-27)
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 :
0인용 특허 :
24
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 (Ia): 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-C6cycl
1. A compound having the structure of Formula (Ia): 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 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; andn is an integer selected from 0-4;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 C6-C10aryl. 3. The compound of claim 2 wherein R1 is phenyl. 4. The compound of claim 3 wherein R1 is substituted with one or more R4, wherein each R4 is independently selected from F, Cl, Br, I, —CN, —NO2, —CF3, —OR9, —OCF3, —NR8R9, —C(O)R10, —CO2R9, C1-C6alkyl, and C1-C6haloalkyl. 5. The compound of claim 4 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. 6. The compound of claim 4 wherein R1 is 4-fluorophenyl, 4-chlorophenyl, 3,4-dichlorophenyl, 4-bromophenyl, 4-iodophenyl, 3-cyanophenyl, 4-trifluoromethylphenyl, 4-trifluoromethoxyphenyl, 4-phenoxyphenyl, or 4-benzoylphenyl. 7. The compound of claim 6 wherein R1 is 4-chlorophenyl. 8. The compound of claim 7 wherein R11 and R12 are each H. 9. The compound of claim 8 wherein R13, R14, R15 and R16 are each H. 10. The compound of claim 9 wherein R2 is H. 11. The compound of claim 9 wherein R2 is methyl. 12. The compound of claim 10 wherein R3 is C2-C4alkyl, C3-C6cycloalkyl, C2-C7heterocycloalkyl, —OR6, —CO2R6, —C(O)NR5R6, —N(H)C(O)R7, —N(H)CO2R7, 13. The compound of claim 12 wherein R6 is H, C1-C6alkyl, or C1-C6alkylC6-C10aryl, and R7 is C1-C6alkyl, C6-C10aryl, C1-C6alkylC6-C10aryl, or C1-C6alkylC3-C9heteroaryl. 14. The compound of claim 9 wherein R2 and R3 together form an optionally substituted C2-C7heterocycloalkyl ring. 15. The compound of claim 14 wherein R2 and R3 together form an optionally substituted oxetane, pyrrolidine, piperidine, or tetrahydropyran ring. 16. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof, and a pharmaceutically acceptable excipient. 17. The pharmaceutical composition of claim 16 further comprising an aminoglycoside antibiotic. 18. 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 or a pharmaceutically acceptable salt, pharmaceutically acceptable solvate or hydrate, pharmaceutically acceptable salt hydrate, or pharmaceutically acceptable prodrug thereof. 19. The method of claim 18 wherein the sensory hair cell death is associated with exposure to an ototoxic agent. 20. The method of claim 19 wherein the ototoxic agent is an aminoglycoside antibiotic.
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