초록 ▼

Provided herein are novel iso-ergoline derivatives and 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 ot

Provided herein are novel iso-ergoline derivatives and 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 the 5-HT1B receptor, without agonizing the 5-HT2B 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 adrenergic alpha2A and/or the alpha2B receptors using the compounds and compositions disclosed herein.

대표청구항 ▼

1. A compound of Formula (I) or (II): or ion pairs, salts, hydrates or solvates thereof, wherein:R1 is hydrogen, (C1-C4) alkyl, substituted (C1-C4) alkyl or (C1-C4) alkyl substituted with one or more fluorine atoms;R2 is alkyl, substituted alkyl, acyl, substituted acyl, halo, heteroalkyl, substitute

1. A compound of Formula (I) or (II): or ion pairs, salts, hydrates or solvates thereof, wherein:R1 is hydrogen, (C1-C4) alkyl, substituted (C1-C4) alkyl or (C1-C4) alkyl substituted with one or more fluorine atoms;R2 is alkyl, substituted alkyl, acyl, substituted acyl, halo, heteroalkyl, substituted heteroalkyl, —NO2, —N3, —OH, —S(O)kR100, —OR101, —NR102R103, —CONR104R105, —CO2R106 or —O2CR107;R3 is hydrogen, (C1-C3) alkyl, (C1-C3) substituted alkyl or (C1-C3) alkyl substituted with one or more fluorine atoms;R4 is hydrogen, methyl, ethyl, substituted aryl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl, —OR108, —NR109R110, R5 is (C1-C4) alkyl or (C1-C4) substituted alkyl;R6 is hydrogen, (C1-C4) alkyl, substituted (C1-C4) alkyl, benzyl or substituted benzyl;R7 is (C1-C4) alkyl, substituted (C1-C4) alkyl, benzyl or substituted benzyl;R8 is hydrogen, OH, ═O, (C1-C4) alkyl, (C1-C4) substituted alkyl, —CO2R114 or —CONR115R116;R9 is hydrogen, OH, ═O, (C1-C4) alkyl, (C1-C4) substituted alkyl, —CO2R117 or —CONR118R119;R10 is hydrogen, OH, ═O, (C1-C4) alkyl, (C1-C4) substituted alkyl, —CO2R120 or —CONR121R122;R11 is hydrogen, (C1-C3) alkyl or (C1-C3) alkyl substituted with one or more fluorine atoms;R12 is hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —S(O)mR111 or —CONR112R113;R100-R122 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;m and k are independently 0, 1 or 2;n is 0, 1, 2 or 3; andprovided that when R11 is hydrogen or (C1-C3) alkyl, R1 is (C1-C4) alkyl substituted with one or more fluorine atoms; and R109 and R110 are not substituted with fluorine unless R12 is acyl or substituted acyl. 2. The compound of claim 1, wherein R1 is hydrogen or (C1-C4) alkyl substituted with one or more fluorine atoms, n is 0, R3 is hydrogen or (C1-C3) alkyl, R4 is —NR109R110, R11 is methyl substituted with one or more fluorine atoms and R12 is hydrogen, substituted alkyl, substituted acyl or —CONR112R113. 3. The compound of claim 1, wherein R1 is hydrogen, methyl or methyl substituted with one or more fluorine atoms, R2 is alkyl, halo, —OR101, n is 1, R3 is hydrogen, methyl or allyl, R4 is —NR109R110, R11 is methyl substituted with one or more fluorine atoms and R12 is hydrogen, substituted alkyl, substituted acyl or —CONR112R113. 4. The compound of claim 1, wherein R1 is hydrogen, methyl or methyl substituted with one or more fluorine atoms, n is 0, R3 is hydrogen, methyl or allyl, R4 is —NR109R110, R11 is methyl substituted with one or more fluorine atoms and R12 is hydrogen, substituted alkyl, substituted acyl or —CONR112R113. 5. The compound of claim 1, wherein R1 is hydrogen or (C1-C4) alkyl substituted with one or more fluorine atoms, n is 0,R3 is hydrogen or (C1-C3) alkyl, R4 is R8, R9 and R10 are hydrogen, R11 is methyl substituted with one or more fluorine atoms and R12 is hydrogen, substituted alkyl, substituted acyl or —CONR112R113. 6. The compound of claim 1, wherein R1 is hydrogen, methyl or methyl substituted with one or more fluorine atoms, R2 is alkyl, halo, —OR101, n is 1,R3 is hydrogen, methyl or allyl, R4 is R8, R9 and R10 are hydrogen, R11 is methyl substituted with one or more fluorine atoms and R12 is hydrogen, substituted alkyl, substituted acyl or —CONR112R113. 7. The compound of claim 1, wherein R1 is hydrogen, methyl or methyl substituted with one or more fluorine atoms, n is 0, R3 is hydrogen, methyl or allyl, R4 is R8, R9 and R10 are hydrogen, R11 is methyl substituted with one or more fluorine atoms and R12 is hydrogen, substituted alkyl, substituted acyl or —CONR112R113. 8. The compound of claim 1, wherein R1 is hydrogen, methyl or methyl substituted with one or more fluorine atoms, R2 is alkyl, acyl, halo, —NO2, —OH, —S(O)kR100, —OR101, —NR102R103, —CONR104R105, —CO2R106 or —O2CR107, n is 1,R3 is hydrogen, methyl or allyl, R4 is R8, R9 and R10 are hydrogen, R11 is methyl substituted with one or more fluorine atoms and R12 is hydrogen, substituted alkyl, substituted acyl or —CONR112R113. 9. The compound of claim 1, wherein R1 is hydrogen, n is 0, R3 is allyl, R4 is —NR109R110, R11 is methyl substituted with one or more fluorine atoms and R12 is hydrogen, substituted alkyl, substituted acyl or —CONR112R113. 10. The compound of claim 1, wherein R1 is hydrogen, n is 0, R3 is methyl, R4 is —NR109R110, R11 is methyl substituted with one or more fluorine atoms and R12 is hydrogen. 11. The compound of claim 1, wherein R1 is hydrogen, n is 0, R3 is methyl, R4 is R8, R9 and R10 are hydrogen, R11 is methyl substituted with one or more fluorine atoms and R12 is hydrogen. 12. The compound of claim 1, wherein R1 is hydrogen, n is 0, R3 is allyl, R4 is —NR109R110, R11 is methyl substituted with one or more fluorine atoms and R12 is substituted alkyl. 13. The compound of claim 1, wherein R1 is hydrogen, n is 0, R3 is allyl, R4 is —NR109R110, R11 is methyl substituted with one or more fluorine atoms and R12 is hydrogen. 14. The compound of claim 1, wherein R1 is hydrogen, n is 0, R3 is allyl, R4 is —NR109R110, and R12 is substituted acyl. 15. The compound of claim 1, wherein R1 is hydrogen, n is 0,R3 is allyl, R4 is —NR109R110, and R12 is —CONR112R113. 16. The compound of claim 1, wherein R1 is hydrogen, n is 0, R3 is methyl, R4 is —NR109R110, R11 is methyl substituted with one or more fluorine atoms and R12 is substituted alkyl. 17. The compound of claim 1, wherein R1 is hydrogen, n is 0, R3 is methyl, R4 is —NR109R110, R11 is methyl substituted with one or more fluorine atoms and R12 is hydrogen. 18. The compound of claim 1, wherein R1 is hydrogen, n is 0, R3 is methyl, R4 is —NR109R110, and R12 is substituted acyl. 19. The compound of claim 1, wherein R1 is hydrogen, n is 0,R3 is methyl, R4 is —NR109R110, and R12 is —CONR112R113. 20. The compound of claim 1, wherein R1 is hydrogen or (C1-C4) alkyl substituted with one or more fluorine atoms, n is 0, R3 is hydrogen or (C1-C3) alkyl, R4 is —NR109R110 or substituted alkyl, and R12 is hydrogen, substituted alkyl, substituted acyl or —CONR112R113. 21. The compound of claim 1, wherein R1 is hydrogen, methyl or methyl substituted with one or more fluorine atoms, R2 is alkyl, halo, —OR101, n is 1, R3 is hydrogen, methyl or allyl, R4 is —NR109R110, and R12 is hydrogen, substituted alkyl, substituted acyl or —CONR112R113. 22. The compound of claim 1, wherein R1 is hydrogen, methyl or methyl substituted with one or more fluorine atoms, n is 0,R3 is hydrogen, methyl or allyl, R4 is —NR109R110, R12 is hydrogen, substituted alkyl, substituted acyl or —CONR112R113. 23. The compound of claim 1, wherein R1 is hydrogen, methyl or methyl substituted with one or more fluorine atoms, R2 is alkyl, acyl, halo, —NO2, —OH, —S(O)kR100, —R101, —NR102R103, —CONR104R105, —CO2R106 or —O2CR107, n is 1, R3 is hydrogen, methyl or allyl, R4 is —NR109R110 or substituted alkyl, R8, R9 and R10 are hydrogen, R11 is methyl substituted with one or more fluorine atoms and R12 is hydrogen, substituted alkyl, substituted acyl or —CONR112R113. 24. The compound of claim 1, wherein R1 is hydrogen, n is 0, R3 is allyl, R4 is —NR109R110, R11 is methyl substituted with one or more fluorine atoms and R12 is —CONR112R113. 25. The compound of claim 1, wherein R1 is hydrogen, n is 0, R3 is methyl, R4 is —NR109R110, R11 is methyl substituted with one or more fluorine atoms and R12 is hydrogen. 26. The compound of claim 1, wherein R1 is hydrogen, n is 0, R3 is methyl, R4 is —NR109R110, R11 is methyl substituted with one or more fluorine atoms and R12 is substituted alkyl. 27. The compound of claim 1, wherein R1 is hydrogen, n is 0, R3 is allyl, R4 is —NR109R110, R11 is methyl substituted with one or more fluorine atoms and R12 is substituted alkyl. 28. The compound of claim 1, wherein R1 is hydrogen, n is 0, R3 is allyl, R4 is —NR109R110, R11 is methyl substituted with one or more fluorine atoms and R12 is hydrogen. 29. The compound of claim 1, wherein R1 is hydrogen, n is 0, R3 is methyl, R4 is —NR109R110, R11 is methyl substituted with one or more fluorine atoms and R12 is substituted acyl. 30. The compound of claim 1, wherein R1 is hydrogen, n is 0, R3 is methyl, R4 is —NR109R110, R11 is methyl substituted with one or more fluorine atoms and R12 is —CONR112R113.