Synthesis of polycyclic alkaloids
View Patent ↗Disclosed embodiments concern polycyclic alkaloid compounds and methods for their use and synthesis. Particular embodiments concern polycyclic alkaloids having a fused, six-membered ring, while other embodiments concern polycyclic alkaloids having a fused, five-membered ring. Methods for making the polycyclic alkaloids are disclosed, as well as methods for their use as prophylactics or treatments for certain diseases. Also disclosed are pharmaceutical compositions comprising the polycyclic alkaloids and their use.
1. A compound having a formula
wherein
R 14 and R 15 are selected to form, together with the atom to which each is attached, a six-membered aromatic ring;
R 16 is selected from hydrogen, lower alkyl, or sulfonyl;
R 20 is lower alkyl; and
R 21 is selected from lower alkyl, amine, or nitro.
2. The compound according to claim 1 wherein R 16 is sulfonyl.
3. The compound according to claim 1 wherein R 21 is nitro.
4. The compound according to claim 1 wherein the compound has a formula
5. The compound according to claim 1 wherein the compound is selected from
6. The compound according to claim 1 having the structure
7. The compound according to claim 6 wherein the compound has a formula
8. A method for making a polycyclic alkaloid, comprising:
providing an aromatic amine compound having a formula
and a carboxylic acid intermediate having a formula
exposing the aromatic amine compound and the carboxylic acid compound to reaction conditions sufficient to form a hemiaminal intermediate having a formula
exposing the hemiaminal intermediate to an acid to form a polycyclic alkaloid having a formula
wherein
R 1 is bound to either R 2 or R 3 to form a five-membered cyclic lower alkyl;
R 2 and R 3 independently are selected from hydrogen or lower alkyl and bound to R 1 ;
R 14 and R 15 are selected to form, together with the atom to which each is attached, a six-membered aromatic ring;
R 16 is selected from hydrogen, lower alkyl, or sulfonyl;
R 20 is lower alkyl;
R 21 is selected from lower alkyl, amine, or nitro; and
V is N.
9. The method according to claim 8 wherein the aromatic amine compound is
10. The method according to claim 8 wherein the carboxylic acid compound is
11. The method according to claim 8 wherein the conditions sufficient to form the hemiaminal intermediate comprise one or more activating reagent, a base, and a solvent.
12. The method according to claim 11 wherein the one or more activating reagents are selected from N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, dicyclohexylcarbodiimide, carbonyl diimidazole, 1-hydroxybenzotriazole, 1-hydroxy-7-aza-benzotriazole, and o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate, and any combination thereof, the base is selected from triethylamine, 1,8-diazabicycloundec-7-ene, 1,4-diazabicyclo[2.2.2]octane, and diisopropylethylamine, and the solvent is dichloromethane.
13. The method according to claim 8 wherein the hemiaminal intermediate is
14. The method according to claim 8 wherein the acid is selected from para-toluenesulfonic acid, trifluoroacetic acid, and camphorsulfonic acid.
15. The method according to claim 8 wherein the polycyclic alkaloid is selected from
16. A pharmaceutical composition, comprising an effective amount of a compound of formula I according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
17. A compound selected from