Synthesis of polycyclic alkaloids

Patent metadata

Field	Value
Publication number	US-8927564-B2
Application number	US-201313789289-A
Country	US
Kind code	B2
Filing date	Mar 7, 2013
Priority date	Mar 7, 2012
Publication date	Jan 6, 2015
Grant date	Jan 6, 2015

Abstract

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.

First claim

We claim:

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

Assignees

• Rigel Pharmaceuticals Inc

Inventors

• Goff Dane
• Payan Donald G
• Braselmann Sylvia

Classifications

• A61P3/00

  Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00) · CPC title

• C07D487/16

  Peri-condensed systems · CPC title

• C07D471/14

  Ortho-condensed systems · CPC title

• C07D495/14

  Ortho-condensed systems · CPC title

• C07D491/22

  in which the condensed system contains four or more hetero rings · CPC title