Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-05-24
1997-07-29
Bond, Robert T.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540460, A61K 31395, C07D24506
Patent
active
056522320
DESCRIPTION:
BRIEF SUMMARY
FIELD OF ART
The present invention relates to benzolactam derivatives. More specifically, the present invention relates to benzolactam derivatives having anti-human acquired immuno-deficiency syndrome virus activity and useful for the preventive and therapeutic treatment of AIDS.
BACKGROUND ART
AIDS (acquired immuno-deficiency syndrome) is a disease caused by an infection of one of retroviruses, human acquired immuno-deficiency virus (HIV). Any effective therapeutic method for treatment of the infection of the human acquired immuno-deficiency virus has not yet been developed, and the spread of AIDS has become a worldwide serious problem. Azidodeoxythymidine (AZT), dideoxyinosine (DDI), and dideoxycytosine (DDC) have been developed to date as anti-retroviral drugs having inhibitory activities against reverse transcriptions by retroviruses, which are used for the therapeutic treatment of AIDS. However, these drugs induce severe side effects such as cytotoxicities and their clinical applications are limited.
In addition, appearances of resistant strains having resistances against these drugs have also been problems. Therefore, developments of medicament having potent anti-retroviral activity and reduced side effects are much desired.
An object of the present invention is thus to provide novel substances which have excellent inhibitory activities against retroviruses and are useful as anti-retroviral drug with reduced side effects such as cytotoxicity.
DESCRIPTION OF THE INVENTION
The inventors of the present invention conducted various studies to achieve the foregoing object, and as a result, they found that the novel benzolactam derivatives according to the present invention had excellent inhibitory activities against retroviruses and reduced side effects such as cytotoxicity. They also found that the derivatives were useful for the treatment and prevention of AIDS. The present invention was achieved on the basis of these findings.
The present invention thus provides benzolactam derivatives represented by the following formula (I). ##STR2##
According to another aspect of the present invention, anti-retroviral drugs comprising the benzolactam derivative represented by the above formula (I) as an active ingredient are provided.
The benzolactam derivatives of the present invention have in their ring structures nitrogen atoms directly bound to the phenyl ring (nitrogen atom at the 1-position in the benzolactam ring), and in that regard they are structurally distinguishable from the compounds 4a-c and 14a disclosed in J. Am. Chem. Soc., 115, pp.3957-3965, 1993. In addition, the above-mentioned publication does not disclose that the compounds 4a-c and 14a have anti-retroviral activity.
BEST MODE FOR CARRYING OUT THE INVENTION
In the formula (I), n represents an integer of from 1 to 3, preferably an integer of 1 or 2. R.sup.1 represents a straight- or branched-chain alkyl group or an aralkyl group. Examples of the alkyl group include, for example, straight- or branched-chain alkyl groups containing 1 to 12 carbon atoms. For example, lower alkyl groups such as isopropyl group, isobutyl group, or t-butyl group, and alkyl groups containing 8 to 10 carbon atoms such as n-octyl group, n-nonyl group, or n-decanyl group may preferably be used. Examples of the aralkyl group include, for example, lower aralkyl groups such as benzyl group and phenethyl group. The carbon atom to which R.sup.1 binds (the carbon atom at the 2-position in the benzolactam ring) is an asymmetric carbon, on which two configurations are possible in respect of R.sup.1. Assuming that the 8- to 10-membered ring structure is a plane in the chemical structure represented by the above general formula (I), R.sup.1 may be either in the configuration being upward or downward from the plane. Both of these stereoisomers fall within the scope of the present invention. Similarly, the carbon atom which is adjacent to the nitrogen atom of the amide group (--NH--CO--) in the 8- to 10-membered ring and is substituted with the hydroxymethyl group (--CH.sub.
REFERENCES:
Kogan et al., "A Regio-and Stereocontrolled Total Synthesis of (-)-Indolactam-V", Tetrahedron, 46, pp. 6623-6632 (1990).
International Search Report (in Japanese and in English).
International Preliminary Examination Report (in Japanese and in English).
Kozikowski et al., "Synthesis, Molecular Modeling, 2-D NMR, and Biological Evaluation of ILV Mimics as Potential Modulators of Protein Kinase C", J. Am. Chem. Soc., 115, pp. 3957-3965 (1993).
Endo Yasuyuki
Fujiwara Tamio
Sato Akihiko
Shudo Koichi
Bond Robert T.
Shionogi & Co. Ltd.
Shudo Koichi
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