NOVEL SUBSTITUTED INDOLO 4,3 FG QUINOLINES USEFUL FOR TREATING MIGRAINE

摘要

Provided herein are novel ergoline derivatives and pharmaceutical compositions thereof. In other embodiments, provided herein are methods of treatment, prevention, or amelioration of a variety of medical disorders such as, for example, migraine using the compounds and compositions disclosed herein. In still 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.

主权项

1. A method of treating or preventing migraine in a patient comprising administering to the patient in need thereof 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; R7 is (C1-C4) alkyl; R8 is hydrogen, (C1-C4) alkyl, substituted (C1-C4) alkyl, benzyl or substituted benzyl; R9 is (C1-C4) alkyl; 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, 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; and k is 0, 1 or 2; n is 0, 1, 2 or 3; provided that when R1 and R5 are methyl, R2, R3, R4, R10, R11, R12 and R13 are hydrogen and R6 isthat:
R7 is not methyl, R8 is not hydrogen and R9 is not sec-butyl; R7 is not methyl, R8 is not hydrogen and R9 is not benzyl; R7 is not n-butyl, R8 is not methyl and R9 is not methyl; R7 is not isopropyl, R8 is not methyl and R9 is not benzyl; R7 is not isopropyl, R8 is not hydrogen and R9 is not n-propyl; R7 is not isopropyl, R8 is not hydrogen and R9 is not isobutyl; R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl; R7 is not ethyl, R8 is not hydrogen and R9 is not isobutyl; provided that when R1 and R5 are methyl, R3 is —OH, R2, R4, R10, R11, R12 and R13 are hydrogen and R6 isthat:
R7 is not methyl, R8 is not hydrogen and R9 is not sec-butyl; provided that when R1 and R5 are methyl, R3 is —OCH3, R2, R4, R10, R11, R12 and R13 are hydrogen and R6 isthat:
R7 is not methyl, R8 is not hydrogen and R9 is not sec-butyl; R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl; R7 is not isopropyl, R8 is not hydrogen and R9 is not benzyl; 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; provided that when R1 and R5 are methyl, R2, R3, R4, R10, R11 and R12 are hydrogen, R13 is bromine and R6 isthat:
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 isopropyl; R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl; R7 is not isopropyl, R8 is not hydrogen and R9 is not isobutyl; provided that when R1 is n-propyl, R5 is methyl, R2, R3, R4, R10, R11 and R12 are hydrogen, R13 is bromine and R6 isthat:
R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl; provided that when R1 and R5 are methyl, R2, R3, R4, R10, R11 and R12 are hydrogen, R13 is iodine and R6 isthat:
R7 is not methyl, R8 is not hydrogen and R9 is not benzyl; provided that when R1 is methyl, R5 is n-propyl, R2, R3, R4, R10, R11, R12 and R13 are hydrogen and R6 isthat:
R7 is not isopropyl, R8 is not hydrogen and R9 is not benzyl; R7 is not methyl, R8 is not hydrogen and R9 is not benzyl; provided that when R2, R3, R4, R10, R11, R12 and R13 are hydrogen and R6 isthat:
R1 is not allyl; provided that when R1 is ethyl, R5 is methyl, R2, R3, R4, R10, R11, R12 and R13 are hydrogen and R6 isthat:
R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl; provided that when R1 is n-propyl, R5 is methyl, R2, R3, R4, R10, R11, R12 and R13 is hydrogen and R6 isthat:
R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl 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 is CH2NHMe2, R5 is methyl, R2, R3, R4, R10, R11, R12 and R13 are hydrogen and R6 isthat:
R7 is not methyl, R8 is not hydrogen and R9 is not benzyl; R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl; R7 is not isopropyl, R8 is not hydrogen and R9 is not benzyl; R7 is not isopropyl, R8 is not hydrogen and R9 is not isobutyl; provided that when R1 is CH2OCOCH3, R5 is methyl, R2, R3, R4, R10, R11, R12 and R13 are hydrogen and R6 isthat:
R7 is not isopropyl, R8 is not hydrogen and R9 is not isobutyl; R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl; R7 is not isopropyl, R8 is not hydrogen and R9 is not benzyl; provided that when R1 is CH2OH, R5 is methyl, R2, R3, R4, R10, R11, R12 and R13 are hydrogen and R6 isthat:
R7 is not isopropyl, R8 is not hydrogen and R9 is not isobutyl; R7 is not isopropyl, R8 is not hydrogen and R9 is not isopropyl; R7 is not isopropyl, R8 is not hydrogen and R9 is not benzyl; R7 is not methyl, R8 is not hydrogen and R9 is not benzyl; 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 notprovided that when R1 and R5 are methyl and R2, R3 and R4 are hydrogen that: R6 is not