Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-02-19
1999-10-19
Dees, Jose' G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514255, 514326, 514451, 514459, 544106, 544111, 544 56, 544 59, 544358, 544359, 544366, 544370, 548414, 548419, 548146, 548148, 5483017, 5483027, C07D23514, C07D40314, C07D40306
Patent
active
059689331
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a novel class of DNA-targeted alkylating agents, to methods of preparing the novel compounds, and to the use of these compounds in the treatment of neoplastic disease. In particular, the invention relates to novel bisbenzimidazole compounds which in addition to having the ability to bind to the minor groove of deoxyribonucleic acid (DNA) have the ability to alkylate DNA.
BACKGROUND OF THE INVENTION
Alkylating agents are an important class of anticancer drugs, which express their cytotoxic and antitumour effects by forming adducts with cellular DNA. The bisbenzimidazole moiety itself has been reported in the literature as an efficient DNA minor groove binding agent, and a number of compounds of this general structure have been reported to have DNA binding and cytotoxic properties. In particular, the compound pibenzimol (Hoechst 33258), which binds to regions of the minor groove rich in adenine and thymine bases, and its analogues, have been intensively investigated. See for example: 2,6-Bis-benzimidazolederivate, eine neue chemotherapeutisch aktive Korperklass" Arz.-Forschung, 1974 24 1927-1933. benzimidazoles and imdazolo[4,5-b]pyridines using nitrobenzene as oxidant" Synth. Comm., 1990 20 955-963. Bathini, Y. "Effects of analogs of the DNA minor groove binder Hoechst 33258 on topoisomerase II and I mediated activities" Biochim. Biophys. Acta., 1992 1131 53-61. Whittaker, A. R. D. "DNA binding compounds. V. Synthesis and characterisation of boron-containing bisbenzimidazoles related to the DNA minor groove binder Hoechst 33258" Aus. J. Chem., 1994 47 247-262. preference and biological evaluation of minor groove selective N1-alkoxyalkyl bisbenzimidazoles" Anti-Cancer Drug Design, 1994 9 153-180.
A recent publication [Lee, M., Walker, C. D., Eckert, J. M., Bowers, S. K., Montague, D., McAdams, S. and Hartley, J. A., "DNA sequence selective alkylation and cytotoxicity of monoheterocyclic analogues of Hoechst 33258", Med. Chem. Res., 1993 3 79-86] describes three monobenzimidazole mustard compounds. Subsequent to the priority date of this application, a further publication [Gupta, R., Wang, H., Huang, L. And Lown, J. W. "Design, synthesis, DNA sequence preferential alkylation and biological evaluation of N-mustard derivatives of Hoechst 33258 analogues", Anti-Cancer Drug Design, 1995 10 25-41] has described four mixed benzimidazole/benzoxazole mustard analogues of Hoechst 33258.
We have now developed a novel class of bisbenzimidazole compounds which have not only the ability to bind to DNA in the minor groove, but also to alkylate DNA. These compounds show good anti-tumour activity both in vitro and in vivo.
SUMMARY OF THE INVENTION
According to a first aspect, the invention provides compounds of General Formula I ##STR1## wherein A represents CN, NHR or any one of the tormulae IIa-IId; ##STR2## B represents CH or N; D represents NH, NR, O or S; NHCO(CH.sub.2).sub.n, CONH, or CONH(CH.sub.2).sub.n ; ##STR3## m is 1 or 2, n is from 0 to 6, and functions, (CH.sub.2).sub.n, n is 0, m is 1 and E is IIIa, then Y in IIIa is not 4-N(CH.sub.2 CH.sub.2 Cl).sub.2, 2-OMe, 3-OMe, 4-OMe, 3-Me, 4-Me, 2-Cl, 3-Cl, 4-Cl, 2-NO.sub.2, 3-NO.sub.2, 4-NO.sub.2 or 4-NMe.sub.2.
In formula IIa, R is a lower alkyl group optionally substituted with amine and/or hydroxyl functions.
In formula IIIa, Y is one of N(CH.sub.2 CH.sub.2 Q).sub.2, N(Me)CH.sub.2 CH.sub.2 Q or N(Et)CH.sub.2 CH.sub.2 Q, together with up to one of NO.sub.2, Cl, Br, F, OMe, Me or CONH.sub.2 at positions 2 to 6, and Q is Cl, Br, I, OH or OSO.sub.2 Me.
In formula IIIb, G is up to two of COOR, CH.sub.2 OCONHR, CH.sub.2 Q, where R is a lower alkyl group optionally substituted with amine and/or hydroxyl functions, and Q is Cl, Br, I, OH or OSO.sub.2 Me, and Z is .dbd.N-- or --CH.dbd..
In formula IIIc, G is up to two of COOR, CH.sub.2 OCONHR, or CH.sub.2 Q, where R is a lower alkyl group optionally substituted with amine and/or hydroxyl functions, and Q is Cl, Br, I, OH or OSO.sub.2 Me, and the K groups are separately H, Me, or together form
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Denny William A.
Smaill Jeffrey B.
Auckland Division Cancer Society of New Zealand Inc.
Circadian Pharmaceuticals (Australia) Pty. Ltd.
Dees Jos,e G.
Qazi Sabiha N.
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