Azaindenoisoquinoline topoisomerase I inhibitors
The invention described herein pertains to substituted azaindenoisoquinoline compounds, in particular 7-, 8-, 9-, and 10-azaindenoisoquinoline compounds, which are inhibitors of topoisomerase I, processes and intermediates for their syntheses, pharmaceutical compositions of the compounds, and methods of using them in the treatment of cancer.
1. A compound of the formula
or a pharmaceutically acceptable salt thereof, wherein:
each of R A , R B , R C and R D is independently hydrogen, hydroxy, acyloxy, halo, cyano, nitro, optionally substituted (1-6C) alkyl or optionally substituted (1-6C) alkoxy; or two adjacent R A , R B , R C and R D radicals form a methylenedioxy or ethylenedioxy group and each of the others is defined as above;
R E is —(CH 2 ) n R N ;
n is 2, 3 or 4;
R N is 1-imidazolyl or 1,2,4-triazol-2-yl; or R N is —NR 1 R 2 ; in which each of R 1 and R 2 is independently hydrogen or (1-3C) alkyl or in which one of R 1 and R 2 is hydrogen and the other of R 1 and R 2 is 2-hydroxyethyl; or —NR 1 R 2 forms a pyrrolidino, piperidino, piperazino, morpholino or thiomorpholino group, each of which may bear one or more methyl substituents; in which a pyrrolidino or piperidino may bear a hydroxy substituent on a carbon not bound to nitrogen; and in which a pyrrolidino or piperidino may be a 3,4-didehydro moiety;
W is N or CR W ; X is N or CR X ; Y is N or CR Y ; Z is N or CR Z ;
one of W, X, Y and Z is N, and each of the others of W, X, Y and Z is CR W , CR X , CR Y or CR Z , respectively; and
each of R W , R X , R Y and R Z , is independently hydrogen, (1-3C) alkyl, (1-3C) alkoxy, or acyloxy.
2. The compound of claim 1 wherein each of R A and R D is hydrogen.
3. The compound of claim 2 wherein each of R B and R C is methoxy, or R B is hydrogen and R C is nitro.
4. The compound of claim 1 wherein n is 3 and R N is dimethylamino or morpholino.
5. The compound of claim 1 wherein each of R W , R X and R Z is hydrogen; and R Y is hydrogen or methoxy.
6. The compound of claim 1 wherein W is N.
7. The compound of claim 2 wherein W is N.
8. The compound of claim 3 wherein W is N.
9. The compound of claim 4 wherein W is N.
10. The compound of claim 5 wherein W is N.
11. The compound of claim 1 wherein X is N.
12. The compound of claim 1 wherein Y is N.
13. The compound of claim 1 wherein Z is N.
14. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, together with a diluent, excipient or carrier.
15. A method of treatment of cancer comprising administering a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, to a patient in need thereof.
16. The method of claim 15 wherein the cancer is ovarian cancer, small-cell lung cancer, cervical cancer, colon cancer or rectal cancer.
17. A process for the preparation of a compound as described in claim 1 , or a pharmaceutically acceptable salt thereof, comprising one or more of the steps of the group consisting of:
a. treating a homophthalic anhydride of the formula (A)
with a cyanopyridine of formula (B)
to form a compound of formula (C)
b. oxidizing a compound of formula (C), to afford a compound of formula (D)
c. alkylating a compound of formula (D) with a compound of formula R E -L 2 ; to afford a compound of claim 1 ; and
d. alkylating a compound of formula H—R N with a compound of formula (E)
to afford a compound of claim 1 ; wherein
each of n, W, X, Y, Z, R A , R B , R C , R D , R E and R N is defined as in claim 1 ;
W P is N or CR WP ; X P is N or CR XP ; Y P is N or CR YP ; Z P is N or CR ZP ;
one of W P , X P , Y P and Z P is N, and each of the others of W P , X P , Y P and Z P is CR WP , CR XP , CR YP or CR ZP , respectively; and
each R WP , R XP , R YP and R ZP is independently hydrogen, (1-3C) alkyl or (1-3C) alkoxy, or is a precursor or protected derivative thereof; and
each of L 1 , L 2 and L 3 is a leaving group.
18. A compound, or salt thereof, selected from the group consisting of
a compound of formula (C)
a compound of formula (D)
a compound of formula (E)
wherein
L 3 is a leaving group;
each of n, W, X, Y, Z, R A , R B , R C and R D is defined as in claim 1 ;
W P is N or CR WP ; X P is N or CR XP ; Y P is N or CR YP ; Z P is N or CR ZP ;
one of W P , X P , Y P and Z P is N, and each of the others of W P , X P , Y P and Z P is CR WP , CR XP , CR YP or CR ZP , respectively; and
each R WP , R XP , R YP and R ZP is independently hydrogen, (1-3C) alkyl or (1-3C) alkoxy, or is a precursor or protected derivative thereof.