Ergoline compounds and uses thereof
Provided herein are ergoline compounds and pharmaceutical compositions thereof. In some 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-HT 1A , 5-HT 1B and 5-HT 1D receptors without agonizing the 5-HT 2B receptor using the compounds and pharmaceutical compositions disclosed herein. In still other embodiments, provided herein are methods of antagonizing the 5-HT 2B adrenergic alpha 2A and/or the alpha 2B 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.
1. A compound of structural Formula (I):
or salts thereof, wherein:
R 1 is hydrogen, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, halo, haloalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —S(O) j R 101 , —C(O)NR 102 R 103 or —CO 2 R 104 ;
R 2 is alkyl, substituted alkyl, acyl, substituted acyl, halo, haloalkyl, heteroalkyl, substituted heteroalkyl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, —NO 2 , —N 3 , —S(O) k R 110 , —OR 111 , —NR 112 R 113 , —C(O)NR 114 R 115 , —OC(O)NR 116 R 117 , —CO 2 R 118 or —OC(O)R 119 ;
j and k are independently 0, 1 or 2;
n is 0, 1, 2 or 3;
R 3 is hydrogen, alkyl, substituted alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
R 4 and R 5 are independently hydrogen, alkyl, substituted alkyl, halo, haloalkyl, —OR 120 , —OC(O)NR 121 R 122 , —OC(O)R 123 or together with the atoms to which they are attached form a double bond;
R 6 is hydrogen;
R 7 is alkyl or substituted alkyl comprising at least one fluorine atom;
X is NR 8 —;
Z is —CH 2 — or —NR 9 —;
a is 0;
R 8 is hydrogen;
R 9 , R 102 -R 104 and R 111 -R 123 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; and
R 101 and R 110 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 of structural formula (XIII):
wherein R 7 is
R 10 is substituted alkyl comprising at least one fluorine atom;
Y is —S(O) k R 117 —OR 12 or —NR 13 R 14 ;
k is 0, 1 or 2;
b is 1, 2, 3 or 4
R 11 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; and
R 12 -R 14 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.
3. The compound of claim 2 , wherein:
R 1 is hydrogen, alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl;
R 2 is alkyl, substituted alkyl, acyl, halo, —OR 111 , —C(O)NR 114 R 115 or —CO 2 R 118 ;
n is 0 or 1;
R 3 is hydrogen, alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl;
R 4 and R 5 are independently hydrogen, alkyl, substituted alkyl, —OR 120 or together with the atoms to which they are attached form a double bond;
b is 1 or 2;
Y is —OR 12 or —NR 13 R 14 ; and
R 9 , R 12 -R 14 , R 102 -R 104 and R 111 -R 123 are independently hydrogen, alkyl, substituted alkyl, arylalkyl or substituted arylalkyl.
4. The compound of claim 2 , wherein:
R 1 is hydrogen, alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl;
R 2 is alkyl, substituted alkyl, acyl, halo, —OR 111 , —C(O)NR 114 R 115 or —CO 2 R 118 ;
n is 0 or 1;
R 3 is hydrogen, alkyl, substituted alkyl, heteroalkyl or substituted heteroalkyl;
R 4 and R 5 are independently hydrogen, alkyl, substituted alkyl, —OR 120 or together with the atoms to which they are attached form a double bond;
b is 1 or 2;
Y is —OR 12 or —NR 13 R 14 ; and
R 9 , R 12 -R 14 , R 102 -R 104 and R 111 -R 123 are independently hydrogen, alkyl or arylalkyl.
5. The compound of claim 2 wherein:
R 1 is hydrogen, halo, alkyl or substituted alkyl;
R 3 is alkyl; and
Y is —OR 12 .
6. The compound of claim 1 of structural Formula (VIII):
wherein:
R 1 is alkyl or halo;
R 3 is hydrogen, alkyl;
R 4 and R 5 are independently hydrogen, halo, —OR 120 , —OC(O)NR 121 R 122 , —OC(O)R 123 or together with the atoms to which they are attached form a double bond;
R 120 is hydrogen, methyl or alkyl;
R 121 and R 122 are independently hydrogen or alkyl; and
R 123 is alkyl.
7. A composition comprising the compound of claim 1 and a vehicle.
8. The compound of claim 1 , wherein R 1 is (C 1 -C 4 ) alkyl or (C 1 -C 4 ) substituted alkyl.
9. The compound of claim 1 , wherein R 1 is cyclopropyl, substituted cyclopropyl cyclobutyl or substituted cyclobutyl.
10. The compound of claim 1 having the structure:
11. The compound of claim 1 having the structure:
12. The compound of claim 1 having the structure:
13. The compound of claim 1 having the structure:
14. The compound of claim 1 having the structure:
15. The compound of claim 1 having the structure:
16. The compound of claim 1 having the structure:
17. The compound of claim 1 having the structure:
18. The compound of claim 1 having the structure:
19. The compound of claim 1 having the structure:
20. The compound of claim 1 having the structure:
21. The compound of claim 1 having the structure:
22. The compound of claim 1 having the structure:
23. The compound of claim 1 having the structure:
24. The compound of claim 1 having the structure:
25. The compound of claim 1 having the structure:
26. The compound of claim 1 having the structure:
27. A compound having the structure:
28. A compound selected from the following:
29. A compound of structural formula (VIII):
or salts thereof, wherein:
R 1 C 3 -C 6 cycloalkyl or substituted C 3 -C 6 cycloalkyl;
R 3 is hydrogen, alkyl, substituted alkyl, haloalkyl, heteroalkyl, substituted heteroalkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heteroaryl, substituted heteroaryl, heteroarylalkyl or substituted heteroarylalkyl;
R 4 and R 5 are independently hydrogen, alkyl, substituted alkyl, halo, haloalkyl, —OR 120 , —OC(O)NR 121 R 122 , —OC(O)R 123 or together with the atoms to which they are attached form a double bond;
R 6 is hydrogen;
R 7 is alkyl or substituted alkyl;
R 8 is hydrogen; and
R 120 -R 123 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.
30. The compound of claim 29 , wherein the C 3 -C 6 cycloalkyl is selected from cyclopropyl, cyclobutyl, or cyclopentyl.
31. The compound of claim 30 , wherein the C 3 -C 6 cycloalkyl is cyclopropyl.
32. The compound of claim 29 having the structure:
33. The compound of claim 29 having the structure:
34. The compound of claim 29 having the structure: