IPC분류정보
국가/구분 |
United States(US) Patent
등록
|
국제특허분류(IPC7판) |
|
출원번호 |
US-0978314
(2010-12-23)
|
등록번호 |
US-8710092
(2014-04-29)
|
발명자
/ 주소 |
- Zhang, Jian
- Cook, Robert O.
- Armer, Thomas A.
- Kosarev, Sergey Alexandrovich
- Xie, Dejian
|
출원인 / 주소 |
- Map Pharmaceuticals, Inc.
|
대리인 / 주소 |
|
인용정보 |
피인용 횟수 :
12 인용 특허 :
85 |
초록
▼
Provided herein are substituted indolo4,3-fgquinolines of Formula (I) and (II) where R1-R6 and R13 are as defined in the specification and pharmaceutical compositions thereof which are useful in treating, preventing, or ameliorating a variety of medical disorders such as, for example, migraine. In
Provided herein are substituted indolo4,3-fgquinolines of Formula (I) and (II) where R1-R6 and R13 are as defined in the specification and pharmaceutical compositions thereof which are useful in treating, preventing, or ameliorating a variety of medical disorders such as, for example, migraine. In other embodiments, provided herein are methods of agonizing receptors such as, for example, the 5-HT1D and or 5-HT1B receptor using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of antagonizing or inhibiting activity at receptors such as, for example, the 5-HT2B receptor using the compounds and compositions disclosed herein. In still other embodiments, provided herein are methods of regulating serotonin transport using the compounds and compositions disclosed herein.
대표청구항
▼
1. A compound of Formula (I): or pharmaceutically acceptable salts, hydrates or solvates thereof wherein:R1 is (C1-C4) alkyl, substituted (C1-C4) alkyl or (C1-C4) perfluoroalkyl;R2 is alkyl, substituted alkyl, acyl, substituted acyl, halo, heteroalkyl, substituted heteroalkyl, —NO2, —N3, —OH, —S(O)k
1. A compound of Formula (I): or pharmaceutically acceptable salts, hydrates or solvates thereof wherein:R1 is (C1-C4) alkyl, substituted (C1-C4) alkyl or (C1-C4) perfluoroalkyl;R2 is alkyl, substituted alkyl, acyl, substituted acyl, halo, heteroalkyl, substituted heteroalkyl, —NO2, —N3, —OH, —S(O)kR100, —OR101, —NR102R103, —CONR104R105, —CO2R106 or —OC(O)R107;R3 and R4 are independently hydrogen, deuterium, fluoro, hydroxy or methoxy;R5 is hydrogen, (C1-C3) alkyl, substituted (C1-C4) alkyl or (C1-C3) perfluoroalkyl;R6 is R7 is sec-butyl, isobutyl, t-butyl, benzyl, (C2-C4) alkenyl or (C2-C4) alkynyl;R8 is hydrogen, (C1-C4) alkyl, substituted (C1-C4) alkyl, benzyl or substituted benzyl;R9 is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, benzyl, (C2-C4) alkenyl or (C2-C4) alkynyl;R10 is hydrogen, OH, ═O, (C1-C4) alkyl, (C1-C4) substituted alkyl, —CO2R108 or —CONR109R110;R11 is hydrogen, OH, ═O, (C1-C4) alkyl, (C1-C4) substituted alkyl, —CO2R111 or —CONR112R113;R12 is hydrogen, OH, ═O, (C1-C4) alkyl, (C1-C4) substituted alkyl, —CO2R114 or —CONR115R116;R13 is hydrogen or halogen;R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R113, R114, R115 and R116 are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; andk is 0, 1 or 2;n is 0, 1, 2 or 3;wherein substituted with reference to a saturated carbon atom is limited to —Ra, halo, —O−, ═O, —ORb, —SRb, —S−, ═S, —NRcRc, ═NRb, ═N—ORb, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)2Rb, —S(O)2NRb, —S(O)2O−, —S(O)2ORb, —OS(O)2Rb, —OS(O)2O−, —OS(O)2ORb, —P(O)(O−)2, —P(O)(ORb)(O−), —P(O)(ORb)(ORb), —C(O)Rb, —C(S)Rb, —C(NRb)Rb, —C(O)O−, —C(O)ORb, —C(S)ORb, —C(O)NRcRc, —C(NRb)NRcRc, —OC(O)Rb, —OC(S)Rb, —OC(O)O−, —OC(O)ORb, —OC(S)ORb, —NRbC(O)Rb, —NRbC(S)Rb, —NRbC(O)O−, —NRbC(O)ORb, —NRbC(S)ORb, —NRbC(O)NRcRc, —NRbC(NRb)Rb and —NRbC(NRb)NRcRc, where Ra is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each Rb is independently hydrogen or Ra; and each Rc is independently Rb or alternatively, the two Rcs are taken together with the nitrogen atom to which they are bonded form a 4-, 5-, 6- or 7-membered cycloheteroalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S; and substituted with reference to an unsaturated carbon atom or an nitrogen atom in a heteroalkyl group is limited to —Ra, halo, —O−, —ORb, —SRb, —S−, —NRcRc, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, —N3, —S(O)2Rb, —S(O)2O−, —S(O)2ORb, —OS(O)2Rb, —OS(O)2O−, —OS(O)2ORb, —P(O)(O−)2, —P(O)(ORb)(O−), —P(O)(ORb)(ORb), —C(O)Rb, —C(S)Rb, —C(NRb)Rb, —C(O)O−, —C(O)ORb, —C(S)ORb, —C(O)NRcRc, —C(NRb)NRcRc, —OC(O)Rb, —OC(S)Rb, —OC(O)O−, —OC(O)ORb, —OC(S)ORb, —NRbC(O)Rb, —NRbC(S)Rb, —NRbC(O)O−, —NRbC(O)ORb, —NRbC(S)ORb, —NRbC(O)NRcRc, —NRbC(NRb)Rb and —NRbC(NRb)NRcRc where Ra, Rb and Rc are as defined above; provided that when R2, R3, R4, R10, R11, R12 and R13 are hydrogen and R6 is O that:R1 is not allyl;provided that when R1 is (C1-C4) alkyl and R2, R3, R4, R10, R11, R12 and R13 are hydrogen that:R6 is not provided that when R1 and R5 are methyl and R2, R3 and R4 are hydrogen that: R6 is not provided that when R1 and R5 are methyl and R2, R3 and R4 are hydrogen that: R6 is not provided that when R1 and R5 are methyl and R2, R3 and R4 are hydrogen that: R6 is not 2. The compound of claim 1, wherein R1 is (C1-C4) alkyl or (C1-C4) perfluoroalkyl and R6 is 3. The compound of claim 1, wherein R1 is —CH3, —C2H5, —C3H7, i-C3H7, —CF3, —C2F5, —C3F7 or i-C3F7 and R6 is 4. The compound of claim 1, wherein R1 is —CH3, —C2H5, —C3H7, i-C3H7, —CF3, —C2F5, —C3F7 or i-C3F7, R2 is (C1-C4) alkyl, (C1-C4) substituted alkyl, (C1-C4) acyl, (C1-C4) substituted acyl, halo, —NO2, —OR101, —NR102R103, —CONR104R105, —CO2R106 or —OC(O)R107, n is 0 or 1, R3 and R4 are independently hydrogen or deuterium, R5 is —CH3, —C2H5, —C3H7, —CF3, C2F5 or —C3F7, R6 is R10, R11 and R12 are independently hydrogen, OH or (C1-C4) alkyl; and R13 is hydrogen or bromine. 5. The compound of claim 1 having the structure: 6. The compound of claim 1 having the structure: wherein z is 5 or 8. 7. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable vehicle. 8. A compound of Formula (II): or pharmaceutically acceptable salts, hydrates or solvates thereof wherein:R1 is (C1-C4) alkyl, substituted (C1-C4) alkyl or (C1-C4) perfluoroalkyl;R2 is alkyl, substituted alkyl, acyl, substituted acyl, halo, heteroalkyl, substituted heteroalkyl, —NO2, —N3, —OH, —S(O)kR100, —OR101, —NR102R103, —CONR104R105, —CO2R106 or —OC(O)R107;R5 is hydrogen, (C1-C3) alkyl, substituted (C1-C3) alkyl, or (C1-C3) perfluoroalkyl;R6 is R7 is (C1-C4) alkyl;R8 is hydrogen, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl, substituted (C1-C4) alkyl, (C2-C4) alkenyl or (C2-C4) alkynyl, benzyl or substituted benzyl;R9 is methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, (C2-C4) alkenyl or (C2-C4) alkynyl;R10 is hydrogen, OH, ═O, (C1-C4) alkyl, (C1-C4) substituted alkyl, —CO2R108 or —CONR109R110;R11 is hydrogen, OH, ═O, (C1-C4) alkyl, (C1-C4) substituted alkyl, —CO2R111 or —CONR112R113;R12 is hydrogen, OH, ═O, (C1-C4) alkyl, (C1-C4) substituted alkyl, —CO2R114 or —CONR115R116;R13 is hydrogen or halogen;R101, R102, R103, R104, R105, R106, R107, R108, R109, R110, R111, R112, R113, R114, R115 and R116 are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; andk is 0, 1 or 2;n is 0, 1, 2 or 3;wherein substituted with reference to a saturated carbon atom is limited to —Ra, halo, —O−, ═O, —ORb, —SRb, —S−, ═S, —NRcRc, ═NRb, ═N—ORb, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, ═N2, —N3, —S(O)2Rb, —S(O)2NRb, —S(O)2O−, —S(O)2ORb, —OS(O)2Rb, —OS(O)2O−, —OS(O)2ORb, —P(O)(O−)2, —P(O)(ORb)(O−), —P(O)(ORb)(ORb), —C(O)Rb, —C(S)Rb, —C(NRb)Rb, —C(O)O−, —C(O)ORb, —C(S)ORb, —C(O)NRcRc, —C(NRb)NRcRc, —OC(O)Rb, —OC(S)Rb, —OC(O)O−, —OC(O)ORb, —OC(S)ORb, —NRbC(O)Rb, —NRbC(S)Rb, —NRbC(O)O−, —NRbC(O)ORb, —NRbC(S)ORb, —NRbC(O)NRcRc, —NRbC(NRb)Rb and —NRbC(NRb)NRcRc, where Ra is selected from the group consisting of alkyl, cycloalkyl, heteroalkyl, cycloheteroalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl; each Rb is independently hydrogen or Ra; and each Rc is independently Rb or alternatively, the two Rcs are taken together with the nitrogen atom to which they are bonded form a 4-, 5-, 6- or 7-membered cycloheteroalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S; and substituted with reference to an unsaturated carbon atom or an nitrogen atom in a heteroalkyl group is limited to —Ra, halo, —O−, —ORb, —SRb, —S−, —NRcRc, trihalomethyl, —CF3, —CN, —OCN, —SCN, —NO, —NO2, —N3, —S(O)2Rb, —S(O)2O−, —S(O)2ORb, —OS(O)2Rb, —OS(O)2O−, —OS(O)2ORb, —P(O)(O−)2, —P(O)(ORb)(O−), —P(O)(ORb)(ORb), —C(O)Rb, —C(S)Rb, —C(NRb)Rb, —C(O)O−, —C(O)ORb, —C(S)ORb, —C(O)NRcRc, —C(NRb)NRcRc, —OC(O)Rb, —OC(S)Rb, —OC(O)O−, —OC(O)ORb, —OC(S)ORb, —NRbC(O)Rb, —NRbC(S)Rb, —NRbC(O)O−, —NRbC(O)ORb, —NRbC(S)ORb, —NRbC(O)NRcRc, —NRbC(NRb)Rb and —NRbC(NRb)NRcRc where Ra, Rb and Rc are as defined above;provided that when R1 and R5 are methyl, R2, R10, R11, R12 and R13 are hydrogen and R6 is that: R7 is not methyl, R8 is not hydrogen and R9 is not benzyl;R7 is not methyl, R8 is not hydrogen and R9 is not sec-butyl;R7 is not ethyl, R8 is not hydrogen and R9 is not isopropyl;R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl;provided that when R1 is CH2OH, R5 is methyl, R2, R10, R11, and R12 are hydrogen, R13 is bromine and R6 is that: R7 is not isopropyl, R8 is not hydrogen and R9 is not sec-butyl. 9. The compound of claim 8, wherein R6 is R7 is methyl, ethyl or isopropyl, R8 is hydrogen, R9 is n-propyl, isopropyl or sec-butyl and R10, R11 and R12 are hydrogen. 10. The compound of claim 8, wherein R1 is (C1-C4) alkyl or (C1-C4) perfluoroalkyl and R6 is 11. The compound of claim 8, wherein R1 is —CH3, —C2H5, —C3H7, i-C3H7, —CF3, —C2F5, —C3F7 or i-C3F7 and R6 is 12. The compound of claim 8, wherein R1 is —CH3, —C2H5, —C3H7, i-C3H7, —CF3, —C2F5, —C3F7 or i-C3F7, R2 is (C1-C4) alkyl, (C1-C4) substituted alkyl, (C1-C4) acyl, (C1-C4) substituted acyl, halo, —NO2, —OR101, —NR102R103, —CONR104R105, —CO2R106 or —OC(O)R107, n is 0 or 1, R5 is —CH3, —C2H5, —C3H7, —CF3, C2F5 or —C3F7, R6 is R10, R11 and R12 are independently hydrogen, OH or (C1-C4) alkyl; and R13 is hydrogen or bromine. 13. The compound of claim 8, wherein R1 is —CH3, —C2H5, -n-C3H7, —CF3, —C2F5 or -n-C3F7, R2 is (C1-C2) alkyl, (C1-C2) substituted alkyl, halo, —NO2, —OR101, —NR102R103, —CONR104R105, —CO2R106 or —OC(O)R107, n is 0, R5 is —CH3 or —CF3, R6 is R7 is methyl, ethyl or isopropyl, R8 is hydrogen, R9 is n-propyl, isopropyl, sec-butyl, or benzyl, R10, R11 and R12 are hydrogen; and R13 is hydrogen. 14. The compound of claim 8, having the structure: 15. The compound of claim 8, having structure: 16. The compound of claim 8 having the structure: 17. The compound of claim 8, having the structure: wherein z is 5 or 8. 18. A pharmaceutical composition comprising the compound of claim 8 and a pharmaceutically acceptable vehicle. 19. The compound having the structure:
※ AI-Helper는 부적절한 답변을 할 수 있습니다.