PRODRUGS OF CC-1065 ANALOGS
Prodrugs of analogs of the anti-tumor antibiotic CC-1065 having a cleavable protective group such as a piperazino carbamate, a 4-piperidino-piperidino carbamate or a phosphate, in which the protecting group confers enhanced water solubility and stability upon the prodrug, and in which the prodrug also has a moiety, such as a disulfide, that can conjugate to a cell binding reagent such as an antibody. The therapeutic use of such prodrug conjugates is also described; such prodrugs of cytotoxic agents have therapeutic use because they can deliver cytotoxic prodrugs to a specific cell population for enzymatic conversion to cytoxic drugs in a targeted fashion.
1 . A prodrug comprising an analog of CC-1065 in which the phenolic group of the alkylating portion of the molecule is protected and wherein said prodrug further comprises a linker capable of conjugating said prodrug to a cell binding agent.
2 . The prodrug of claim 1 wherein said linker comprises a thiol or a disulfide bond.
3 . The prodrug of claim 1 wherein said protecting group increases water-solubility of said prodrug.
4 . The prodrug of claim 3 wherein said protecting group is selected from the group consisting of a piperazino carbamate, a 4-piperidino-piperidino carbamate and a phosphate.
5 . The prodrug of claim 1 wherein said linker comprises a polyethylene glycol of the formula—(—O(CH2)2) n− , wherein n is an integer from 2 to 1000.
6 . A composition comprising the prodrug of claim 1 and a pharmaceutically acceptable carrier.
7 . A prodrug comprising an analog of a seco-cyclopropabenzindole-containing cytotoxic drug selected from the group consisting of analogs formed from a first subunit of formula (I) covalently linked to a second subunit of the formula (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX) via an amide bond from the secondary amino group of the pyrrole moiety of the first subunit to the C-2 carboxyl of the second subunit,
wherein the formula (I) is as follows:
wherein the formulae (II)-(IX) are as follows:
wherein R represents a moiety that enables linkage of said prodrug to a cell binding agent; wherein R 1 -R 6 are each independently hydrogen, C 1 -C 3 linear alkyl, methoxy, hydroxyl, primary amino, secondary amino, tertiary amino, or amido;
and wherein R 7 is an enzyme-cleavable protecting group.
8 . The prodrug of claim 7 , wherein R comprises a thiol or a disulfide bond.
9 . The prodrug of claim 7 , wherein R 1 -R 6 are hydrogen.
10 . The prodrug of claim 7 , wherein R 7 is selected from the group consisting of a piperazino carbamate, a 4-piperidino-piperidino carbamate and a phosphate.
11 . The prodrug of claim 10 , wherein R represents a moiety that enables linkage of the prodrug to a cell binding agent via a disulfide bond.
12 . The prodrug of claim 10 , wherein said second subunit is represented by formula (II) and wherein R 1 -R 6 are hydrogen.
13 . The prodrug of claim 12 which is (S)-N-[2-{(1-chloromethyl)-1,2-dihydro-5-[(4-methylpiperazino)carbonyloxy]-3H-benz(e)indol-3-yl}carbonyl]-1H-indol-5-yl]-5-[(3-methyldithio-1-oxopropyl)-amino]-1H-indole-2-carboxamide, or a salt or an isomer thereof.
14 . The prodrug of claim 12 which is (S)-N-[2-{(1-chloromethyl)-1,2-dihydro-5-[(4-methylpiperazino)carbonyloxy]-3H-benz(e)indol-3-yl}carbonyl]-1H-indol-5-yl]-5-[(3-mercapto-1-oxopropyl)-amino]-1H-indole-2-carboxamide, or a salt or an isomer thereof.
15 . The prodrug of claim 12 which is (S)-N-[2-{(1-chloromethyl)-1,2-dihydro-5-[(4-piperidino-piperidino)carbonyloxy]-3H-benz(e)indol-3-yl}carbonyl]-1H-indol-5-yl]-5-[(3-methydithio-1-oxopropyl)-amino]-1H-indole-2-carboxamide, or a salt or an isomer thereof
16 . The prodrug of claim 12 which is (S)-N-2-{(1-chloromethyl)-1,2-dihydro-5-[(4-piperidino-piperidino)carbonyloxy]-3H-benz(e)indol-3--yl}carbonyl]-1H-indol-5-yl]-5-[(3-mercapto-1-oxopropyl)-amino]-1H-indole-2-carboxamide, or a salt or an isomer thereof.
17 . The prodrug of claim 12 which is (S)-N-2-{(1-chloromethyl)-1,2-dihydro-5-(phosphonoxy)-3H-benz(e)indol-3-yl}carbonyl]-1H-indol-5-yl]-5-[(3-methyldithio-1-oxopropyl)-amino]-1H-indole-2-carboxamide, or a salt or an isomer thereof.
18 . The prodrug of claim 12 which is (S)-N-2-{(1-chloromethyl)-1,2-dihydro-5-(phosphonoxy)-3H-benz(e)indol-3-yl}carbonyl]-1H-indol-5-yl]-5-(3-mercapto-1-oxopropyl)-amino]-1H-indole-2-carboxamide, or a salt or an isomer thereof.
19 . The prodrug of claim 12 which is (S)-N-2-{(1-chloromethyl)-1,2-dihydro-5-(dibenzylphosphonoxy)-3H-benz(e)indol-3-yl}carbonyl]-1H-indol-5-yl]-5-[(3-methyldithio-1-oxopropyl)-amino]-1H-indole-2-carboxamide, or a salt or an isomer thereof.
20 . The prodrug of claim 12 which is (S)-N-2-{(1-chloromethyl)-1,2-dihydro-5-hydroxy-3H-benz(e)indol-3-yl}carbonyl]-1H-indol-5-yl]-5-nitro-1H-indole-2-carboxamide, or a salt or an isomer thereof.
21 . The prodrug of claim 12 which is (S)-N-[2-{(1-chloromethyl)-1,2-dihydro-5-hydroxy-3H-benz(e)indol-3-yl}carbonyl]-1H-indol-5-yl]-5-[(3-methyldithio-1-oxopropyl)-amino]-1H-indole-2-carboxamide, or a salt or an isomer thereof.
22 . The prodrug of claim 12 which is (S)-N-[2-{(1-chloromethyl)-1,2-dihydro-5-hydroxy-3H-benz(e)indol-3-yl}carbonyl]-1H-indol-5-yl]-5-[(15″-methyldithio-4″,7″,10″,13″-tetraoxapentadecyl-1-oxopropyl)-amino]-1H-indole-2-carboxamide, or a salt or an isomer thereof.
23 . A prodrug conjugate comprising a cell binding agent linked to one or more of the prodrugs of claim 1 or claim 7 .
24 . The prodrug conjugate of claim 23 wherein said cell binding agent is an antibody or a fragment thereof.
25 . A composition comprising the prodrug of claim 7 and a pharmaceutically acceptable carrier.
26 . A method for treating a subject, comprising administering to a subject in need thereof an effective amount of the composition of claim 6 or 25 .
27 . A method for treating a subject, comprising administering to a subject in need thereof an effective amount of the prodrug conjugate of claim 24 .
28 . The prodrug of claim 7 wherein said linker comprises polyethylene glycol of the formula—(—O(CH 2 ) 2 ) n− , wherein n is an integer from 2 to 1000.