Tricyclic-bis-enone derivatives and methods of use thereof
Novel tricyclic-bis-enone derivatives (TBEs) as well as the process for the preparation of such TBEs are provided. Also provided are methods for prevention and/or treatment of cancer, Alzheimer's disease, Parkinson's disease, multiple sclerosis, amyotropic lateral sclerosis, rheumatoid arthritis, inflammatory bowel disease, and all other diseases whose pathogenesis is believed to involve excessive production of either nitric oxide (NO) or prostaglandins or the overexpression of iNOS or COX-2 genes or gene products. Further, methods for the synthesis of the TBE compounds of the invention utilize cheap commercially available reagents and are highly cost effective and amenable to scale-up. Additional high efficiency synthetic methods that utilize novel intermediates as well as the synthesis of these intermediates are also provided. Furthermore, the invention also provides methods for designing novel and water-soluble TBEs.
1. A compound having the formula:
wherein R 1 is CN, or CO 2 H;
R 2 is ═O;
R 3 is H, CH 3 , CO 2 H, CO 2 Me, CONH 2 , CN, or (CH 2 ) n —R 10 ;
R 4 is H, OH, OAc, CH 3 , CO 2 H, CO 2 Me, CONH 2 , CN, or (CH 2 ) n —R 10 ;
R 5 is H, CH 2 , CH 2 CH 3 , or part of a double-bond A;
R 6 is H, CH 3 , CO 2 H, CO 2 Me, CONH 2 , CN, CH 2 X, CH 2 OAc, CH 2 OH, CHO, CH 2 NH 2 , (CH 2 ) n —R 10 , CO 2 R, CH 2 OR, CH 2 OSiMe 2 (t-Bu), CONR 1 R 2 , CH 2 NHCOOR, or CH 2 NHCOO(t-Bu);
R 7 is H, ═O;
R 8 is H, OH, forms an epoxide with R 9 ; or forms part of double-bond B;
R 9 is H, forms an epoxide with R 8 , or forms part of double-bond B;
R 10 is CH 3 , CO 2 H, CO 2 CH 3 , CO 2 CH 2 CH 3 , CONH 2 , CN, NH 2 , CH(CH 3 ) 2 , NR 11 R 12 , pyrrolidine, piperidine, pyrazine, imidazole, pyrazole, triazole, tetrazole, substituted at N with R 13 , or 1,4-oxazine, where R 11 , R 12 , and R 13 are alkyl;
X is F, Cl, or Br;
n is 0–20; and
A & B independently signifies a single- or double-bond;
or an optically active form (−)-, (+)-, thereof, or a (±) racemic form thereof;
or a pharmaceutically acceptable salt or formulation thereof.
2. The compound of claim 1 , wherein said compound is (±)-TBE-1 which has the formula:
or a pharmaceutically acceptable salt or formulation thereof.
3. The compound of claim 1 , wherein said compound is (±)-TBE-2 which has the formula:
or a pharmaceutically acceptable salt or formulation thereof.
4. The compound of claim 1 , wherein said compound is (±)-TBE-3 which has the formula:
or a pharmaceutically acceptable salt or formulation thereof.
5. The compound of claim 1 , wherein said compound is (±)-TBE-4 which has the formula:
or a pharmaceutically acceptable salt or formulation thereof.
6. The compound of claim 1 , wherein said compound is (±)-TBE-5 which has the formula:
or a pharmaceutically acceptable salt or formulation thereof.
7. The compound of claim 1 , wherein said compound is (+)-TBE-5 which has the formula:
or a pharmaceutically acceptable salt or formulation thereof.
8. The compound of claim 1 , wherein said compound is (±)-TBE-6 which has the formula:
or a pharmaceutically acceptable salt or formulation thereof.
9. The compound of claim 1 , wherein said compound is (±)-TBE-7 which has the formula:
or a pharmaceutical salt or formulation thereof.
10. The compound of claim 1 , wherein said compound is (±)-TBE-8 which has the formula:
or a pharmaceutically acceptable salt or formulation thereof.
11. The compound of claim 1 , wherein said compound is (±)-TBE-9 which has the formula:
or a pharmaceutically acceptable salt or formulation thereof.
12. The compound of claim 1 , wherein said compound is (±)-TBE-10 which has the formula:
or a pharmaceutically acceptable salt or formulation thereof.
13. The compound of claim 1 , wherein said compound is (±) TBE-12 which has the formula:
or a pharmaceutically acceptable salt or formulation thereof.
14. The compound of claim 1 , wherein said compound is (±)-TBE-13 which has the formula:
wherein R═CH 2 OH,
or a pharmaceutically acceptable salt or formulation thereof.
15. The compound of claim 1 , wherein said compound is (±)-TBE-14 which has the formula:
wherein R═CN
or a pharmaceutically acceptable salt or formulation thereof.
16. The compound of claim 1 , wherein said compound is (±)-TBE-15 which has the formula:
wherein R═CH 2 OSiMe 2 (t-Bu),
or a pharmaceutically acceptable salt or formulation thereof.
17. The compound of claim 1 , wherein said compound is (±)-TBE-16 which has the formula:
wherein R═CH 2 NHCOO(t-Bu),
or a pharmaceutically acceptable salt or formulation thereof.
18. The compound of claim 1 , wherein said compound is (±)-TBE-17 which has the formula:
wherein R═CH 2 NH 2 ,
or a pharmaceutically acceptable salt or formulation thereof.
19. The compound of claim 18 , wherein said pharmaceutically acceptable salt is (±)-TBE-18 which has the formula:
wherein R═CH 2 NH 2 .HCl,
or a pharmaceutically acceptable formulation thereof.
20. The compound of claim 1 , wherein said compound is (±)-TBE-19 which has the formula:
wherein R═CO 2 H,
or a pharmaceutically acceptable salt or formulation thereof.