Cyclic
A group of cyclic N-acyl O-amino phenol CBI derivatives were synthesized and shown to be pro-drugs, subject to reductive activation by cleavage of a N-0 bond, effectively releasing the free drug in functional in vitro cellular assays for cytotoxic activity approaching the activity of the free drug, yet remain essentially stable to ex vivo DNA alkylation conditions. Assessment of the in vivo antitumor activity of a representative pro-drug indicates that a contemplated pro-drug approaches the potency and exceeds the efficacy of the free drug itself (CBI-indole 2 ), indicating that the inactive pro-drugs not only effectively release the free drug in vivo, but that they offer additional advantages related to a controlled or targeted release in vivo.
1. A cyclic N-acyl O-amino phenol CBI derivative represented by Formula I:
wherein:
R is hydrido or a C 1 -C 6 hydrocarbyl; and
R 3 is selected from group consisting of radicals represented as follows:
wherein:
R 4 is selected from group consisting of radicals represented as follows:
R 5 , R 6 , R 7 and R 8 are each independently selected from the group of radicals consisting of —H, —OH, —O(C 1 -C 6 hydrocarbyl), C 1 -C 6 hydrocarbyl and halogen; and
R 9 is selected from the group of radicals consisting of —H, —C(O)O′(C 1 -C 6 hydrocarbyl), —C(O)(C 1 -C 6 hydrocarbyl), —C(O)NH 2 , —C(O)NHNH 2 , and —C(O)NHNHC(O)O(C 1 -C 6 hydrocarbyl).
2. The cyclic N-acyl O-amino phenol CBI derivative according to claim 1 , wherein R is hydrido or methyl.
3. The cyclic N-acyl O-amino phenol CBI derivative according to claim 1 , wherein R 3 is one or the other of the following radicals:
R 4 is one or the other of the following radicals
4. The cyclic N-acyl O-amino phenol CBI derivative according to claim 1 that is represented by the formula
5. The cyclic N-acyl O-amino phenol CBI derivative according to claim 1 that is represented by the formula
6. The cyclic N-acyl O-amino phenol CBI derivative according to claim 1 that is represented by a formula selected from the group consisting of one or more of
wherein R, R 4 , R 5 and R 6 are as defined in claim 1 .
7. A pharmaceutical composition comprising a proliferative disease-inhibiting amount of a compound of claim 1 dissolved or dispersed in a pharmaceutically acceptable diluent.
8. The composition according to claim 7 , wherein said compound is one or the other or both of
9. A process for treating a cancer or leukemia disease in a mammal comprising the step of administering an effective amount of a compound of claim 1 to said mammal in need thereof.
10. The process according to claim 9 , wherein said disease is leukemia.
11. The process according to claim 9 , wherein said compound is one or the other or both of