CONVERGENT AND ENANTIOSELECTIVE TOTAL SYNTHESIS OF COMMUNESIN ANALOGS

• US 20170333405A1
• Filed: 05/10/2017
• Published: 11/23/2017
• Est. Priority Date: 05/11/2016
• Status: Active Grant

• Current Assignee: Massachusetts Institute of Technology
• Original Assignee: Mohammad Movassaghi
• Inventors: MOVASSAGHI, Mohammad, LATHROP, Stephen Paul, POMPEO, Matthew W., CHANG, Wen-Tau Timothy
• Granted Patent: US 10,918,627 B2
• Time in Patent Office: Days
• CPC Class Codes: A61K 31/407 condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/55 having seven-membered rings, e.g. azelastine, pentylenetetrazole
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: C07D 487/22 in which the condensed system contains four or more hetero rings
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

A highly convergent biomimetic synthesis of a complex polycyclic scaffold has been successfully implemented. From these efforts, compounds having a structure of Formula (I):

or a pharmaceutically acceptable salt, tautomer or stereoisomer thereof, wherein R¹-R⁸ and m, n, r, s, t, and u are as defined herein, is provided. Methods of making such compounds are also disclosed as are methods for the treatment of cancer, various infectious diseases, and abnormal cardiovascular function.

Claims

1. A compound of Formula (I):

2. The compound of claim 1, wherein R⁶ is H, C₁-C₁₂ alkyl, C₁-C₁₂ alkenyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl.

3. The compound of claim 1, wherein R⁴ is H, —

C(═

O)R⁹, C₁-C₁₂ alkyl, aryl or heteroaryl.

4. The compound of claim 1, wherein R³ is H, C₁-C₁₂ alkyl, or —

S(═

O)_uR¹².

5. The compound of claim 1, wherein R² and R⁵ are each independently F, Br, Cl, I, C₁-C₁₂ alkyl, aryl or heteroaryl.

6. The compound of claim 1, wherein R⁶ is

7. The compound of claim 6, wherein R¹ is —

C(═

O)R⁹.

8. The compound of claim 7, wherein R⁹ is Me, Et, n-Pr,

9. The compound of claim 8, wherein R⁶ is

11. A method of treating a disease or condition treatable with a compound of Formula (I), comprising administering an effective amount of a compound of claim 1 to a subject in need thereof.

12. The method of claim 11, wherein the disease or condition is cancer.

13. The method of claim 12, wherein the cancer is a cancer of the blood.

14. The method of claim 13, wherein the cancer of the blood is histiocytic leukemia, monocytic leukemia, Burkitt'"'"'s lymphoma, Hodgkin'"'"'s′

lymphoma, T-cell leukemia, or B-cell leukemia.

15. The method of claim 11, wherein the disease or condition is a bacterial infection.

16. The method of claim 15, wherein the bacterial infection is an infection of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumanii, Neisseria gonorrhoeae, or Bacillus subtilis.

17. The method of claim 11, wherein the disease or condition is a fungal infection.

18. The method of claim 17, wherein the fungal infection is an infection of Candida albicans, Trichophyton mentagrophytes, or Amorphotheca resinae.

19. The method of claim 11, wherein the disease or condition is a viral infection.

20. The method of claim 19, wherein the viral infection is and infection of Herpes simplex type 1.

21. The method of claim 11, wherein the disease or condition is abnormal cardiovascular function.

22. The method of claim 21, wherein the abnormal cardiovascular function is bradycardia.

23. A method of treating an insect infestation, comprising contacting the insect with a compound of claim 1.

24. The method of claim 23, where in the insect infestation is caused by silkworms at the third instar larval stage.

25. A method of making a compound of claim 1, comprising rearranging a compound of Formula (V):

26. The method of claim 25, wherein the compound of Formula (V) is prepared by a radical recombination reaction of a compound of Formula (VI):

27. The method of claim 26, wherein the compound of Formula (VI) is prepared by the extrusion of sulfur dioxide from a compound of Formula (VII):

28. The method of claim 27, wherein the compound of Formula (VII) is prepared by reacting a compound of Formula (III) and a compound of Formula (VIII):

10. A pharmaceutical composition comprising a compound of Formula (I) and a pharmaceutically acceptable excipient.