Provided herein are isoergoline compounds 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 pharmaceutical compositions disclose
Provided herein are isoergoline compounds 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 pharmaceutical compositions disclosed herein. In still other embodiments, provided herein are methods of agonizing receptors such as, for example, the 5-HT1A, 5-HT1B and 5-HT1D receptors without agonizing the 5-HT2B receptor using the compounds and pharmaceutical compositions disclosed herein. In still other embodiments, provided herein are methods of antagonizing the 5-HT2B adrenergic alpha2A and/or the alpha2B receptors using the compounds and pharmaceutical compositions disclosed herein. In still other embodiments, provided herein are methods of antagonizing the D2 and D3 receptor using the compounds and pharmaceutical compositions disclosed herein.
대표청구항▼
1. A compound of structural Formula (II): or salts thereof, wherein: R1 is hydrogen, haloalkyl, cycloalkyl or substituted cycloalkyl, -heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo, heteroaryl, substituted heteroaryl, heteroarylalkyl, substitut
1. A compound of structural Formula (II): or salts thereof, wherein: R1 is hydrogen, haloalkyl, cycloalkyl or substituted cycloalkyl, -heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —S(O)jR101, —C(O)NR102R103 or —CO2R104;R2 is alkyl, substituted alkyl, acyl, substituted acyl, halo, haloalkyl, heteroalkyl, substituted heteroalkyl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —NO2, —N3, —S(O)kR110, —OR111, —NR112R113, —C(O)NR114R115, —OC(O)NR116R117, —CO2R118 or —OC(O)R119;n is 0, 1, 2 or 3;j and k are independently 0, 1 or 2;R3 is hydrogen, alkyl, substituted alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;R4 and R5 are independently hydrogen, alkyl, substituted alkyl, halo, haloalkyl, —OR120, —OC(O)NR121R122, —OC(O)R123 or together with the atoms to which they are attached form a double bond;R7 is R10 is alkyl, substituted alkyl, haloalkyl, heteroalkyl, or substituted heteroalkyl;Y is —S(O)lR11, —OR12 or —NR13R14;l is 0, 1 or 2;b is 1, 2, 3 or 4;R11 is alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo, haloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; andR12-R14 are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;X is —NR8—;R8 is hydrogen;R102-R104 and R111-R123 are independently hydrogen, alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl; andR101 and R110 are independently alkyl, substituted alkyl, acyl, substituted acyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo, haloalkyl, heteroalkyl, substituted heteroalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl. 2. The compound of claim 1, wherein: R1 is hydrogen, haloalkyl, cycloalkyl or substituted cycloalkyl, heteroalkyl or substituted heteroalkyl;R2 is alkyl, substituted alkyl, acyl, halo, —OR111, —C(O)NR114R115 or —CO2R118;n is 0 or 1;R3 is hydrogen, alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl;R4 and R5 are independently hydrogen, alkyl, substituted alkyl, —OR120 or together with the atoms to which they are attached form a double bond;R10 is alkyl or substituted alkyl;b is 1 or 2;Y is —OR12 or —NR13R14; andR12-R14, R102-R104 and R111-R123 are independently hydrogen, alkyl, substituted alkyl, arylalkyl or substituted arylalkyl. 3. The compound of claim 1, wherein: R1 is hydrogen, haloalkyl, cycloalkyl or substituted cycloalkyl, heteroalkyl or substituted heteroalkyl;R2 is alkyl, substituted alkyl, acyl, halo, —OR111, —C(O)NR114R115 or —CO2R118;n is 0 or 1;R3 is hydrogen, alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl;R4 and R5 are independently hydrogen, alkyl, substituted alkyl, —OR120 or together with the atoms to which they are attached form a double bond;R10 is alkyl or substituted alkyl;b is 1 or 2;Y is —OR12 or —NR13R14; andR12-R14, R102-R104 and R111-R123 are independently hydrogen, alkyl or arylalkyl. 4. The compound of claim 1, wherein: R1 is hydrogen, haloalkyl, cycloalkyl or substituted cycloalkyl, heteroalkyl or substituted heteroalkyl;R2 is alkyl, substituted alkyl, acyl, halo, —OR111, —C(O)NR114R115 or —CO2R118,n is 0 or 1;R3 is hydrogen, alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl;R4 and R5 are independently hydrogen, alkyl, substituted alkyl, —OR120 or together with the atoms to which they are attached form a double bond;R10 is alkyl or substituted alkyl;b is 1 or 2;Y is —OR12 or —NR13R14,R12-R14, R102-R104 and R111-R123 are hydrogen, alkyl or arylalkyl. 5. The compound of claim 1, wherein: R1 is hydrogen, haloalkyl, cycloalkyl or substituted cycloalkyl;R2 is alkyl, substituted alkyl, acyl, halo, —OR111, —C(O)NR114R115 or —CO2R118;R3 is hydrogen, alkyl or alkyl substituted with one or more fluorine atoms;R4 and R5 are independently hydrogen, —OR120 or together with the atoms to which they are attached form a double bond;R10 is alkyl or alkyl substituted with one or more fluorine atoms;b is 1;Y is —OR12 or —NR13R14; andR12-R14, R102-R104 and R111-R123 are independently hydrogen, alkyl, substituted alkyl, arylalkyl or substituted arylalkyl. 6. The compound of claim 1, wherein: R1 is hydrogen, haloalkyl, cycloalkyl or substituted cycloalkyl;R2 is alkyl, substituted alkyl, acyl, halo, —OR111, —C(O)NR114R115 or —CO2R118;R3 is hydrogen or alkyl;R4 and R5 are independently hydrogen, —OR120 or together with the atoms to which they are attached form a double bond;R10 is alkyl or alkyl substituted with one or more fluorine atoms;b is 1;Y is —OR12; andR13, R102-R104 and R111-R123 are hydrogen, alkyl or arylalkyl. 7. The compound of claim 1, wherein: R1 is hydrogen, halo, haloalkyl, cycloalkyl or substituted cycloalkyl;R3 is alkyl or alkyl substituted with one or more fluorine atoms;R10 is alkyl or substituted alkyl; andY is —OR12. 8. The compound of claim 1 of structural formula (III): wherein R7 is and R10 is methyl, b is 1 and Y is OH. 9. The compound of claim 1 of structural Formula (IV): wherein: R1 is hydrogen, halo haloalkyl, cycloalkyl or substituted cycloalkyl;R3 is alkyl;R7 is; R10 is alkyl or substituted alkyl; andY is —OR12. 10. A composition comprising the compound of claim 1 and a vehicle. 11. The compound of claim 9, wherein X is —NH—, R1 is —CF3 or Br, R3 is methyl, R4 and R5 are a double bond, R10 is —CF3, —CH2CF3, —C2H5 or —C2F5 and Y is —OH. 12. The compound of claim 11, wherein R1 is —Br. 13. The compound of claim 12 having the structure: 14. The compound of claim 12 having the structure: 15. The compound of claim 12 having the structure: 16. The compound of claim 12 having the structure: 17. The compound of claim 11, wherein R1 is —CF3. 18. The compound of claim 17 having the structure: 19. The compound of claim 17 having the structure: 20. The compound of claim 17 having the structure: 21. The compound of claim 17 having the structure: 22. The compound of claim 9 having the structure: 23. The compound of claim 9 having the structure: 24. The compound of claim 9, wherein X is —NH—, R1 is —CF3 or Br, R3 is methyl, R4 and R5 are hydrogen, R10 is —CF3, —CH2CF3, —C2H5 or —C2F5 and Y is —OH. 25. The compound of claim 24, wherein R1 is —Br. 26. The compound of claim 25 having the structure: 27. The compound of claim 25 having the structure: 28. The compound of claim 25 having the structure: 29. The compound of claim 25 having the structure: 30. The compound of claim 24, wherein R1 is —CF3. 31. The compound of claim 30 having the structure: 32. The compound of claim 30 having the structure: 33. The compound of claim 30 having the structure: 34. The compound of claim 30 having the structure: 35. The compound of claim 9 having the structure: 36. The compound of claim 9 having the structure: 37. The compound of claim 1, selected from the following:
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