US2005032860A1PendingUtilityA1
CBI analogs of CC-1065 and the duocarmycins
Est. expiryOct 3, 2015(expired)· nominal 20-yr term from priority
Inventors:Dale L. Boger
C07D 405/12C07C 281/02C07D 487/04C07D 409/12C07D 307/85C07D 409/14C07D 209/60C07D 405/14C07D 209/42A61P 35/00C07D 335/06C07D 209/96
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Claims
Abstract
Analogs of the antitumor antibiotics CC-1065 and the duocarmycins incorporate the 1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CBI) alkylation subunit. The CBI-based analogs have potent cytotoxic activity and are useful as efficacious antitumor compounds. A direct relationship between functional stability and in vitro cytotoxic potency is disclosed. The CBI-based analogs are easily synthesized and are 4× more stable and 4× more potent than the corresponding analogs containing the authentic CPI alkylation subunit of CC-1065 and comparable in potency to agents containing the authentic alkylation subunit of duocarmycin SA. Similarly, the CBI-based agents alkylate DNA with an unaltered sequence selectivity at an enhanced rate and with a greater efficiency than the corresponding CPI analog and were comparable to the corresponding analog incorporating the duocarmycin SA alkylation subunit. Systematic and extensive modifications and simplifications in the DNA binding subunits attached to CBI are also described.
Claims
exact text as granted — not AI-modified1 . A compound represented by the following structure:
wherein
R 1 is selected from the group consisting of —CH 2 CH 3 (alkyl), —NHCH 3 (—N-alkyl), —OCH 3 (O-alkyl), —NH 2 , —NHNH 2 , —NHNHCO 2 t Bu, and a radical represented by the following structure:
wherein:
A is selected from the group consisting of NH and O;
B is selected from the group consisting of C and N;
R 2 is selected from the group consisting of hydrogen, hydroxyl, O-alkyl (C1-C6), N-alkyl (C1-C6) 3 and a first N-substituted pyrrolidine ring;
R 3 is selected from the group consisting of hydrogen, hydroxyl, O-alkyl (C1-C6), N-alkyl (C1-C6) 3 , the first N-substituted pyrrolidine ring;
R 4 is selected from the group consisting of hydrogen, hydroxyl, O-alkyl (C1-C6), and N-alkyl (C1-C6) 3 ;
R 5 is selected from the group consisting of hydrogen, hydroxyl, O-alkyl (C1-C6), and N-alkyl (C1-C6) 3 ; and
V 1 represents a first vinylene group between R 2 and R 3 ;
with the following provisos:
if R 2 participates in the first N-substituted pyrrolidine ring, then R 3 also particlates in the first N-substituted pyrrolidine ring;
if R 3 participates in the first N-substituted pyrrolidine ring, then R 2 also particlates in the first N-substituted pyrrolidine ring;
if R 2 and R 3 participate in the first N-substituted pyrrolidine ring, then R 4 and R 5 are hydrogen;
if R 2 is hydrogen, then R 4 and R 5 are hydrogen and R 3 is N-alkyl (C1-C6) 3 ; and
wherein the first N-substituted pyrrolidine ring is fused to the first vinylene group between R 2 and R 3 and is represented by the following structure:
wherein:
V 1 represents the first vinylene group between R 2 and R 3 ;
R 6 is selected from the group consisting of —CH 2 CH 3 (alkyl), —NHCH 3 (—N-alkyl), —OCH 3 (O-alkyl), —NH 2 , —NHNH 2 , —NHNHCO 2 t Bu, and a radical represented by the following structure:
wherein:
C is selected from the group consisting of NE and O;
D is selected from the group consisting of C and N;
R 7 is selected from the group consisting of hydrogen, hydroxyl, O-alkyl (C1-C6), N-alkyl (C1-C6) 3 , and a second N-substituted pyrrolidine ring;
R 8 is selected from the group consisting of hydrogen, hydroxyl, O-alkyl (C1-C6), N-alkyl (C1-C6) 3 , the second N-substituted pyrrolidine ring;
V 2 represents the second vinylene group between R 7 and R 8 ;
with the following provisos:
if R 7 participates in the N-substituted pyrrolidine ring, then R 8 also particlates in the N-substituted pyrrolidine ring;
if R 8 participates in the N-substituted pyrrolidine ring only if R 7 also particlates in the N-substituted pyrrolidine ring; and
wherein the second N-substituted pyrrolidine ring is fused to the second vinylene group between R 7 and R 8 and is represented by the following structure:
wherein:
V 2 represents the second vinylene group between R 7 and R 8 ;
R 9 is selected from the group consisting of —CH 2 CH 3 (alkyl), —NHCH 3 (—N-alkyl), —OCH 3 (O-alkyl), —NH 2 , —NHNH 2 , and —NHNHCO 2 t Bu.
2 . A compound represented by the following structure:
wherein
X is selected from the group consisting of chlorine, bromine, iodine, and OTOS; and
R 1 is selected from the group consisting of —CH 2 CH 3 (alkyl), —NHCH 3 (—N-alkyl), —OCH 3 (O-alkyl), —NH 2 , —NHNH 2 , —NHNHCO 2 t Bu, and a radical represented by the following structure:
wherein:
A is selected from the group consisting of NH and O;
B is selected from the group consisting of C and N;
R 2 is selected from the group consisting of hydrogen, hydroxyl, O-alkyl (C1-C6), N-alkyl (C1-C6) 3 and a first N-substituted pyrrolidine ring;
R 3 is selected from the group consisting of hydrogen, hydroxyl, O-alkyl (C1-C6), N-alkyl (C1-C6) 3 , the first N-substituted pyrrolidine ring;
R 4 is selected from the group consisting of hydrogen, hydroxyl, O-alkyl (C1-C6), and N-alkyl (C1-C6) 3 ;
R 5 is selected from the group consisting of hydrogen, hydroxyl, O-alkyl (C1-C6), and N-alkyl (C1-C6) 3 ; and
V 1 represents a first vinylene group between R 2 and R 3 ;
with the following provisos:
if R 2 participates in the first N-substituted pyrrolidine ring, then R 3 also particlates in the first N-substituted pyrrolidine ring;
if R 3 participates in the first N-substituted pyrrolidine ring, then R 2 also particlates in the first N-substituted pyrrolidine ring;
if R 2 and R 3 participate in the first N-substituted pyrrolidine ring, then R 4 and R 5 are hydrogen;
if R 2 is hydrogen, then R 4 and R 5 are hydrogen and R 3 is N-alkyl (C1-C6) 3 ; and
wherein the first N-substituted pyrrolidine ring is fused to the first vinylene group between R 2 and R 3 and is represented by the following structure:
wherein:
V 1 represents the first vinylene group between R 2 and R 3 ;
R 6 is selected from the group consisting of —CH 2 CH 3 (alkyl), —NHCH 3 (—N-alkyl), —OCH 3 (O-alkyl), —NH 2 , —NHNH 2 , —NHNHCO 2 t Bu, and a radical represented by the following structure:
wherein:
C is selected from the group consisting of NH and O;
D is selected from the group consisting of C and N;
R 7 is selected from the group consisting of hydrogen, hydroxyl, O-alkyl (C1-C6), N-alkyl (C1-C6) 3 , and a second N-substituted pyrrolidine ring;
R 8 is selected from the group consisting of hydrogen, hydroxyl, O-alkyl (C1-C6), N-alkyl (C1-C6) 3 , the second N-substituted pyrrolidine ring;
V 2 represents the second vinylene group between R 7 and R 8 ;
with the following provisos:
if R 7 participates in the N-substituted pyrrolidine ring, then R 8 also particlates in the N-substituted pyrrolidine ring;
if R 8 participates in the N-substituted pyrrolidine ring only if R 7 also particlates in the N-substituted pyrrolidine ring; and
wherein the second N-substituted pyrrolidine ring is fused to the second vinylene group between R 7 and R 8 and is represented by the following structure:
wherein:
V 2 represents the second vinylene group between R 7 and R 8 ;
R 9 is selected from the group consisting of —CH 2 CH 3 (alkyl), —NHCH 3 (—N-alkyl), —OCH 3 (O-alkyl), —NH 2 , —NHNH 2 , and —NHNHCO 2 t Bu.
3 . A compound represented by the following structure:
wherein A is selected from the group consisting of NH and O and B is selected from the group consisting of NH, O, and S.
4 . A compound compound represented by the following structure:
5 . A compound compound represented by the following structures:
6 . A compound compound represented by the following structure:
7 . A compound compound represented by the following structure:
8 . A compound compound represented by the following structure:
where R is selected from the group comprising of: H, 5-NMe 3 + , 6-NMe 3 + , 7-NMe 3 + .
9 . A compound compound represented by the following structure:
where R is selected from the group comprising of: CO 2 t Bu, H—HCl.
10 . A compound compound represented by the following structure:
11 . A compound compound represented by the following structure:
12 . A compound compound represented by the following structure:
13 . A compound compound represented by the following structure:
14 . A compound compound represented by the following structure:
where R is selected from the group comprising of: H—HCl, CONHMe, CO 2 CH 3 , COEt.
15 . A compound compound represented by the following structure:
16 . A compound compound represented by the following structure:
wherein A is selected from the group consisting of O and R is selected from the group consisting of NO 2 and NH 2 .
17 . A compound compound represented by the following structure:
wherein B is selected from the group consisting of O and S.
18 . A compound compound represented by the following structure:
wherein A is selected from the group consisting of NH and O and B is selected from the group consisting of NH, O, and S and R is selected from the group consisting of H and CH 3 .
19 . A compound compound represented by the following structure:
wherein A is selected from the group consisting of NH and O and B is selected from the group consisting of NH, O, and S.
20 . A compound compound represented by the following structure:
21 . A compound compound represented by the following structure:
where R is selected from the group comprising of: CO 2 t Bu, H—HCl.
22 . A compound compound represented by the following structure:
where R is selected from the group comprising of: CO 2 t Bu, H.
23 . A compound compound represented by the following structure:
where R is selected from the group comprising of: O t Bu, NHNHCO 2 t Bu.
24 . A compound compound represented by the following structure:Join the waitlist — get patent alerts
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