Delivery of therapeutic alkaloid compounds
Disclosed are prodrug compounds that can be converted to mesembrine under biologically relevant conditions, such as hydrolysis in vivo; and related methods of preparing and using these compounds. Stable preparations of isolated mesembrine stereoisomers are also provided.
1. A compound of formula (I):
or a pharmaceutically acceptable salt thereof, wherein
R 1 is or C 1 -C 7 alkyl or H; and
ring A
wherein * denotes the attachment points of ring A to the compound of formula (I), and wherein
R 3 is —OSi(C 1 -C 6 alkyl) 3 , —OC(O)C 1 -C 6 alkyl, —OC(O)C 2 -C 6 alkenyl, —OC(O)C 3 -C 10 cycloalkyl, —OC(O)phenyl, —OC(O)-5- to 7-membered heteroaryl, wherein each hydrogen atom in C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 3 -C 10 cycloalkyl, phenyl, and 5- to 7-membered heteroaryl is optionally substituted by halogen, C 1 -C 6 alkyl, C 1 -C 3 alkoxy, nitro, —N(C 1 -C 3 alkyl) 2 , C 1 -C 3 haloalkyl, cyano, phenyl, phenoxy or —O(CH 2 ) p OCH 3 ; and
p is 2, 3, or 4.
2. The compound of claim 1 , wherein the compound is of formula (IIIb-1)
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein R 3 is —OC(O)C 1 -C 6 alkyl.
4. The compound of claim 1 , wherein R 3 is —OC(O)CH 3 .
5. The compound of claim 1 , wherein R 3 is
6. The compound of claim 1 , wherein R 3 is —OC(O)—C 2 -C 6 alkenyl; wherein the C 2 -C 6 alkenyl is isopropenyl or butenyl.
7. The compound of claim 1 , wherein the compound is a compound of formula (IIIb-1)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is methyl; and
R 3 is —OC(O)C 1 -C 6 alkyl, —OC(O)(cyclohexyl), —OC(O)phenyl, or —OC(O)-(6-membered heteroaryl), wherein each hydrogen atom in C 1 -C 6 alkyl, cyclohexyl, phenyl, and 6-membered heteroaryl is optionally substituted by C 1 -C 6 alkyl, C 1 -C 3 alkoxy, or —O(CH 2 ) p OCH 3 ; and
p is 2, 3, or 4.
8. The compound of claim 7 , wherein R 3 is —OC(O)C 1 -C 6 alkyl, and the C 1 -C 6 alkyl is unsubstituted.
9. The compound of claim 7 , wherein the C 1 -C 6 alkyl is substituted by methoxy.
10. A compound of formula (IIIb-1)
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is methyl; and
R 3 is —OC(O)C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is unsubstituted; or
R 3 is —OC(O)phenyl, wherein the phenyl is optionally monosubstituted with an unsubstituted C 1 -C 6 alkyl.
11. The compound of claim 10 , wherein R 3 is —OC(O)C 1 -C 6 alkyl.
12. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
13. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
14. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
16. The compound of claim 1 , wherein the compound is
or a pharmaceutically acceptable salt thereof.
17. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein R 3 is —OC(O)alkyl optionally substituted by alkoxy, —OH, halogen, or −O(CH 2 ) p CH 3 ; and p is 2, 3, or 4.
18. The compound of claim 17 , wherein R 3 is —OC(O)alkyl substituted by fluoro, —OH, methoxy or −O(CH 2 ) p OCH 3 ; and p is 2, 3, or 4.
19. The compound of claim 18 , wherein R 3 is —OC(O)alkyl substituted by fluoro, methoxy, or —O(CH 2 ) 2 OCH 3 .
20. The compound of claim 17 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
21. The compound of claim 17 , selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.