Synthetic salicylihalamides, apicularens and derivatives thereof
View Patent ↗The present invention provides compounds having improved stability over that of natural benzolactones, and a process for synthesizing these compounds. These compounds exhibit anti-cancer activity and inhibit V-ATPase activity.
1. A compound of formula:
wherein E is selected from the group consisting of:
X=O, S, NR 2 ;
Y=CH 2 , O, S, NR 2 ;
Q=O, NH;
F=ortho, meta, para substituents such as halogen, CN, OR 2 , OC(O)R 3 , NO 2 , OSO 2 R 3 , NR 2 R 2 , NR 2 C(O)R 3 , NR 2 SO 2 R 3 , R 3 ;
R 1 =H, Me;
R 2 =R 1 , straight chain saturated alkyl, straight chain unsaturated alkyl, branched chain alkyl, branched chain unsaturated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, CH 2 aryl, CH 2 heteroaryl, CH 2 heterocycle, CHR 1 CHR 1 aryl, CHR 1 CHR 1 heteroaryl, CHR 1 CHR 1 heterocycle;
R 3 =R 2 or CR 1 ═CR 1 aryl, CR 1 ═CR 1 heteroaryl, CR 1 ═CR 1 heterocycle, C≡Caryl, C≡Cheteroaryl, C≡Cheterocycle; and
Z is a contiguous linker whose presence completes an 11 to 15 membered ring.
2. The compound of claim 1 wherein E is selected from the group consisting of:
X=O, S, NR 2 ;
Y=CH 2 , O, S, NR 2 ;
F=ortho, meta, para substituents such as halogen, CN, OR 2 , OC(O)R 3 , NO 2 , OSO 2 R 3 , NR 2 R 2 , NR 2 C(O)R 3 , NR 2 SO 2 R 3 , R 3 ;
R 1 =H, Me;
R 2 =R 1 , straight chain saturated alkyl, straight chain unsaturated alkyl, branched chain alkyl, branched chain unsaturated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, CH 2 aryl, CH 2 heteroaryl, CH 2 heterocycle, CHR 1 CHR 1 aryl, CHR 1 CHR 1 heteroaryl, CHR 1 CHR 1 heterocycle;
R 3 =R 2 or CR 1 ═CR 1 aryl, CR 1 ═CR 1 heteroaryl, CR 1 ═CR 1 heterocycle, C≡Caryl, C≡Cheteroaryl, C≡Cheterocycle; and
Z is a contiguous linker whose presence completes an 11 to 15 membered ring.
3. A compound of formula:
wherein E is selected from the group consisting of:
X=O, S, NR 2 ;
Y=CH 2 , O, S, NR 2 ;
Q=O, NH;
F=ortho, meta, para substituents such as halogen, CN, OR 2 , OC(O)R 3 , NO 2 , OSO 2 R 1 , NR 2 R 2 , NR 2 C(O)R 3 , NR 2 SO 2 R 3 , R 3 ;
R 1 H, Me;
R 2 =R 1 , straight chain saturated alkyl, straight chain unsaturated alkyl, branched chain alkyl, branched chain unsaturated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, CH 2 aryl, CH 2 heteroaryl, CH 2 heterocycle, CHR 1 CHR 1 aryl, CHR 1 CHR 1 heteroaryl, CHR 1 CHR 1 heterocycle;
R 3 =R 2 or CR 1 ═CR 1 aryl, CR 1 ═CR 1 heteroaryl, CR 1 ═CR 1 heterocycle, C≡Caryl, C≡Cheteroaryl, C≡Cheterocycle; and
R 4 =R 1 , C(O)R 3 , SO 2 R 3 , R 2 .
4. The compound of claim 3 wherein E is selected from the group consisting of:
X=O, S,NR 2 ;
Y=CH 2 , O, S, NR 2 ;
F=ortho, meta, para substituents such as halogen, CN, OR 2 , OC(O)R 3 , NO 2 , OSO 2 R 3 , NR 2 R 2 , NR 2 C(O)R 3 , NR 2 SO 2 R 3 , R 3 ;
R 1 =H, Me;
R 2 =R 1 , straight chain saturated alkyl, straight chain unsaturated alkyl, branched chain alkyl, branched chain unsaturated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, CH 2 aryl, CH 2 heteroaryl, CH 2 heterocycle, CHR 1 CHR 1 aryl, CHR 1 CHR 1 heteroaryl, CHR 1 CHR 1 heterocycle;
R 3 =R 2 or CR 1 ═CR 1 aryl, CR 1 ═CR 1 heteroaryl, CR 1 ═CR 1 heterocycle, C≡Caryl, C≡Cheteroaryl, C≡Cheterocycle; and
R 4 =R 1 , C(O)R 3 , SO 2 R 3 , R 2 .
5. A compound of formula:
wherein R 1 =H, Me, Ac; and
R 2 =straight chain saturated alkyl, straight chain unsaturated alkyl, branched chain alkyl, branched chain unsaturated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, CH 2 aryl.
6. A compound of formula:
wherein R 1 =H, Me, Ac; and
R 2 =straight chain saturated alkyl, straight chain unsaturated alkyl, branched chain alkyl, branched chain unsaturated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, CH 2 aryl.
7. A compound of formula:
8. A compound of formula:
9. A compound of formula:
wherein R 1 =H, Me, Ac; and
R 2 =straight chain saturated alkyl, straight chain unsaturated alkyl, branched chain alkyl, branched chain unsaturated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, CH 2 aryl.
10. A compound of formula:
11. A compound of formula:
12. A compound of formula:
wherein E is selected from the group consisting of:
X=O, S, NR 2 ;
Y=CH 2 , O, S, NR 2 ;
Q=O, NH;
F=ortho, meta, para substituents such as halogen, CN, OR 2 , OC(O)R 3 , NO 2 , OSO 2 R 3 , NR 2 R 2 , NR 2 C(O)R 3 , NR 2 SO 2 R 3 , R 3 ;
R 1 =H, Me;
R 2 =R 1 , straight chain saturated alkyl, straight chain unsaturated alkyl, branched chain alkyl, branched chain unsaturated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, CH 2 aryl, CH 2 heteroaryl, CH 2 heterocycle, CHR 1 CHR 1 aryl, CHR 1 CHR 1 heteroaryl, CHR 1 CHR 1 heterocycle;
R 3 =R 2 or CR 1 ═CR 1 aryl, CR 1 ═CR 1 heteroaryl, CR 1 ═CR 1 heterocycle, C≡Caryl, C≡Cheteroaryl, C≡Cheterocycle; and
R 4 =R 1 , C(O)R 3 , SO 2 R 3 , R 2 .
13. The compound of claim 12 wherein E is selected from the group consisting of:
X=O, S, NR 2 ;
Y=CH 2 , O, S, NR 2 ;
F=ortho, meta, para substituents such as halogen, CN, OR 2 , OC(O)R 3 , NO 2 , OSO 2 R 3 , NR 2 R 2 , NR 2 C(O)R 3 , NR 2 SO 2 R 3 , R 3 ;
R 1 =H, Me;
R 2 =R 1 , straight chain saturated alkyl, straight chain unsaturated alkyl, branched chain alkyl, branched chain unsaturated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, CH 2 aryl, CH 2 heteroaryl, CH 2 heterocycle, CHR 1 CHR 1 aryl, CHR 1 CHR 1 heteroaryl, CHR 1 CHR 1 heterocycle;
R 3 =R 2 or CR 1 ═CR 1 aryl, CR 1 ═CR 1 heteroaryl, CR 1 ═CR 1 heterocycle, C≡Caryl, C≡Cheteroaryl, C≡Cheterocycle; and
R 4 =R 1 , C(O)R 3 , SO 2 R 3 , R 2 .
14. A compound of formula:
wherein R 1 =H, Me, Ac; and
R 2 =straight chain saturated alkyl, straight chain unsaturated alkyl, branched chain alkyl, branched chain unsaturated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, CH 2 aryl.
15. A compound of formula:
wherein R 1 =H, Me, Ac; and
R 2 =straight chain saturated alkyl, straight chain unsaturated alkyl, branched chain alkyl, branched chain unsaturated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, CH 2 aryl.
16. A compound of formula:
wherein R 1 =H, Me, Ac; and
R 2 =straight chain saturated alkyl, straight chain unsaturated alkyl, branched chain alkyl, branched chain unsaturated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, CH 2 aryl.
17. A compound of formula:
wherein R 1 =H, Me, Ac; and
R 2 =straight chain saturated alkyl, straight chain unsaturated alkyl, branched chain alkyl, branched chain unsaturated alkyl, cycloalkyl, aryl, heteroaryl, heterocycle, CH 2 aryl.