Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-05-22
1998-03-17
Ford, John M.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
544385, C07D24108, C07D28515
Patent
active
057288305
DESCRIPTION:
BRIEF SUMMARY
This application is a national stage application under 35 U.S.C. .sctn.371 of PCT/JP94/01543, filed Sep. 20, 1994, published as WO95/08542 Mar. 30, 1995.
TECHNICAL FIELD
The present invention relates to a farnesyltransferase inhibitor comprising a piperazinedione derivative as an active ingredient, which has antitumor activity and is useful as an antitumor agent.
BACKGROUND ART
The ras oncogene undergoes point mutation in various tumor tissues in humans and is detected as an activated form capable of transforming normal cells. It is essential for the exhibition of transforming activity by the ras oncogene product that the 12th, 13th, or 61st amino acid should undergo mutation and also the cysteine residue at the C terminal region should be farnesylated for the membrane association of the ras oncogene product. This reaction is catalyzed by farnesyltransferase. Accordingly, a farnesyltransferase inhibitor is expected to inhibit the function of the ras oncogene product and thereby to possess antitumor activity.
Known farnesyltransferase inhibitors having a piperazinedione skeleton
Some of the piperazinedione derivatives according to the present invention are known to have activities such as antagonistic activity against platelet activating factors (Japanese Published Unexamined Patent Application No. 233675/86) and antibacterial activity (Get. Offen. 2029306). However, there has been no report on their farnesyltransferase inhibitory activity or antitumor activity.
DISCLOSURE OF THE INVENTION
The present invention relates to a farnesyltransferase inhibitor and an antitumor agent containing, as an active ingredient, a piperazinedione derivative represented by formula (I): ##STR2## wherein R.sup.1 and R.sup.2 independently represent lower alkyl, lower alkoxyalkyl, substituted or unsubstituted aryl, or aralkyl; R.sup.3 and R.sup.4 independently represent mercapto, lower alkanoylthio, aroylthio, lower alkoxycarbonylthio, or aryloxycarbonylthio, or alternatively R.sup.3 and R.sup.4 are combined together to form disulfide; and R.sup.5 and R.sup.6 independently represent hydrogen, lower alkyl, lower alkoxyalkyl, hydroxyalkyl, lower alkanoyloxyalkyl, aroyloxyalkyl, aralkyloxyalkyl, or aralkyl.
The present invention also relates to a method for the prevention or treatment of diseases caused by the action of farnesyltransferase and a method for the prevention or treatment of tumors, Which comprise administering an effective amount of a piperazinedione derivative represented by formula (I).
The present invention further relates to the use of a piperazinedione derivative represented by formula (I) for the preparation of a pharmaceutical composition which is useful for the prevention or treatment of diseases caused by the action of farnesyltransferase and the prevention or treatment of tumors.
The present invention furthermore provides piperazinedione derivatives represented by formula (I-A), formula (I-B), and formula (I-C) shown below which exhibit farnesyltransferase inhibitory activity, antibacterial activity, and antitumor activity: ##STR3## wherein R.sup.1a represents substituted or unsubstituted aryl; R.sup.2a represents lower alkyl; R.sup.6a represents lower alkyl, lower alkoxyalkyl, hydroxyalkyl, lower alkanoyloxyalkyl, aroyloxyalkyl, aralkyloxyalkyl, or aralkyl; and R.sup.3, R.sup.4, and R.sup.5 have the same meanings as defined above; ##STR4## wherein R.sup.1b and R.sup.2b independently represent aralkyl; and R.sup.3 and R.sup.4 have the same meanings as defined above; ##STR5## wherein R.sup.3c and R.sup.4c independently represent aroylthio, lower alkoxycarbonylthio, or aryloxycarbonylthio; and R.sup.1 and R.sup.2 have the same meanings as defined above.
The compounds represented by formula (I), formula (I-A), formula (I-B), and formula (I-C) are hereinafter referred to as Compounds I, Compounds I-A, Compounds I-B, and Compounds I-C, respectively. The same applies to the compounds of other formula numbers.
In the definitions of the groups in formula (I), formula (I-A), formula (I-B), and formula (I-C),
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Akasaka Kazuhito
Kanda Yutaka
Mizukami Tamio
Nakano Hirofumi
Saitoh Yutaka
Ford John M.
Kyowa Hakko Kogyo Co. Ltd.
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