Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-01-19
1998-12-22
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142345, 514255, 514323, 514338, 514394, 544134, 544138, 544139, 544140, 544141, 544 62, 544367, 544372, 544374, 546199, 5462734, 5483047, 5483061, C07D40304, C07D40904, A61K 3144, A61K 31415
Patent
active
058520112
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel benzimidazole derivatives bondable to DNAs to inhibit proliferation of cells, and also to pharmaceutical compositions containing same, especially their use as anticancer agents, antiviral agents, antimicrobial agents or the like.
2. Description of the Related Art
DNA-acting compounds include those useful as anticancer agents. For example, adriamycin is useful as an anticancer agent which intercalates into DNA. Further, DNA-reacting compounds such as cisplatin and mitomycin are also employed widely. Anticancer effects which are derived from such action on DNA are considered to have been ascertained although their mechanisms have not been fully elucidated. In the meantime, it has come to be known that distamycin and netropsin are substances bondable to DNA and having anti-tumor activities (Nature, 203, 1064-65(1964)). These substances have attracted attention as groove binders which are different in their manner of bonding with DNA compared to conventional anticancer agents.
According to the conventional knowledge of anticancer agents, it is presently by no means possible to foresee which structural part of a compound is really needed for interaction with DNA or what other structures can substitute for the part of the compound. It is however meaningful to predict the presence of other compounds having a desired structure and to make a search for them. A strong demand is therefore believed to exist for the search of such a new structure so that a novel anticancer agent can be created.
Also known are compounds in which the structure of an alkylating agent has been bonded to distamycin derivatives. Typical examples are found inter alia in J. Am. Chem. Soc., 107, 8266(1985), EP 246868, WO 93-13739, J. Med. Chem., 32, 774(1989). Compounds in each of which the structure of an alkylating agent has been bound to a compound similar to distamycin by bonding N-methyl-imidazole as a partial structure via an amide bond are also known (U.S. Pat. No. 5,273,991). These compounds include those making use of a bis(2-chloroethyl)amino residual group as an alkylating agent. This residual group is already known to be a structural part of anticancer agents. For example, chlorambucil is known as an anticancer agent which contains a bis(2-chloroethyl)amino residual group in its molecule. The anticancer activities of this compound are presumed to result from alkylation of DNA, enzymes or the like. However the value of addition of the structure of an alkylating agent, for example, the structure of chloroethylamine, as a part of the structure of a DNA-bonding anticancer agent is still hardly considered to have been ascertained.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a novel compound which acts on DNA or contains a structural part capable of acting on DNA and which is useful as an anticancer agent, an antiviral agent, an antimicrobial agent or the like.
The above-described distamycin is a typical example of compounds which bind to DNA. Distamycin is characterized in that a pyrrole ring is bonded via an amide bond. As DNA-binding compounds include several other types of compounds, the present inventors made a search for a new structure under the assumption of existence of compounds which have a structure different from the known compounds and exhibit anticancer action. As a result, novel compounds having the structure created from the direct bonding of a 5-membered aromatic ring with benzimidazole have been chosen as compounds useful as anticancer agents. Preferred examples include derivatives, derivatives and These compounds have novel structures and are not known at all as useful anticancer agents. These compounds, for example, rboxamide have been found to bind to DNA, indicated by the measurement of an increased Tm value (Tm: the melting temperature of double-stranded DNA) and, when tested in vitro, showed a similar degree of proliferation-inhibiting activity against tumor cells as distamycin.
Compounds in whic
REFERENCES:
patent: 4053472 (1977-10-01), Ruter et al.
Rufer et al., Chem. Abstract 75:140764, 1971.
Journal of Medicinal Chemistry, vol. 33, No. 2, 1990, Washington, U.S., pp. 814-819, XP002007402, W.A. Denny et al., "Potential Antitumor Agents . . . ".
Journal of Medicinal Chemistry, vol. 36, No. 2, 1993, Washington, U.S., pp. 1746-1753, XP002007403, T.A. Fairley et al, "Structure, DNA Minor Groove Binding, and . . . ".
Edatsugi Hajime
Iwata Daiji
Kohno Hiroshi
Komatsu Hironori
Matsunaga Akio
Mitsui Chemicals Inc.
Rao Deepak R.
Shah Mukund J.
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