Anti-liferative agents comprising substituted benzo[e]pyrido[1,2-a][1,4]diazepines
The invention relates to substituted pyrridinobenzodiazepines (PDDs) of formula (XVI) and pharmaceutically acceptable salts thereof, which are useful as medicaments, in particular as anti-proliferative agents.
1 . A compound of formula (XVI):
or a pharmaceutically acceptable salt thereof,
wherein:
(i) R 5 is H; and
R 6 is OH or OC 1-6 alkyl; or
(ii) R 5 and R 6 , taken together with the N atom and C atom to which they are attached, form N═C;
L is C 1-12 alkylene-;
Y 5 is CH or N;
q is 1;
Y 1 is CH or N;
Y 2 is CH or N;
R 19 is H or (CH 2 ) t NR 20 R 21 ;
t is 0, 1, 2, 3, 4, 5, or 6;
R 20 is H or C 1-6 alkyl;
R 21 is H or C 1-6 alkyl;
p is 1;
Z 1 is —NH—, —N(CH 3 )—, —O—, or —S—;
Z 2 is CH or N;
R 22 is (CH 2 ) j C(O)OH, (CH 2 ) j C(O)OC 1-6 alkyl, (CH 2 ) j NR 11 R 12 , or C(O)NHR 24 ;
R 24 is phenyl, wherein the phenyl is substituted with one (CH 2 ) j R 18 substituent;
j is 0, 1, 2, 3, 4, 5, or 6;
R 18 is H, C(O)OR 11 , or NR 11 R 12 ;
R 11 is H or C 1-6 alkyl; and
R 12 is H or C 1-6 alkyl;
with the proviso that at least one of Y 1 and Y 2 is CH.
2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 and R 6 , taken together with the N atom and C atom to which they are attached, form N═C.
3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Y 5 is CH.
4 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Y 1 is CH; and
Y 2 is CH.
5 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
Z 1 is —N(CH 3 )—; and
Z 2 is CH.
6 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 22 is C(O)NHR 24 ; and
R 24 is phenyl, wherein the phenyl is substituted with one (CH 2 ) j R 18 substituent.
7 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein j is 0.
8 . The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 18 is NR 11 R 12 .
9 . The compound of claim 8 , or a pharmaceutically acceptable salt thereof, wherein:
R 11 is H; and
R 12 is H.
10 . The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
11 . The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
12 . The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
13 . The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
14 . The compound of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
15 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient, carrier, or diluent and a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
16 . A method for inhibiting cancer cell proliferation in a patient in need thereof, wherein the method comprises administering to the patient a therapeutically effective amount of the pharmaceutical composition of claim 15 .
17 . The method of claim 16 , wherein the patient suffers from a cancer selected from the group consisting of breast cancer, cervical cancer, colorectal cancer, gastric cancer, leukemia, liver cancer, lung cancer, melanoma, pancreatic cancer, prostate cancer, rectal cancer, renal cancer, skin cancer, and stomach cancer.
18 . A compound of the following formula:
or a pharmaceutically acceptable salt thereof.