Bis-dioxopiperazine derivatives

Details Bis-dioxopiperazine derivatives Bis-dioxopiperazine derivatives

1987-09-25

1989-09-19

Daus, Donald G.

Organic compounds -- part of the class 532-570 series

Organic compounds

Nitrogen attached directly or indirectly to the purine ring...

C07D40306, A61K 31495

Patent

active

048683035

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

The present invention relates to bis-dioxopiperazine derivatives having antitumor activity and pharmaceutically acceptable salts thereof.


BACKGROUND ART

Several kinds of bis-dioxopiperazine derivatives have been already reported. Among them, especially known as compounds having antitumor activity are 1,2-bis(4-morpholinomethyl-3,5-dioxopiperazin-1-yl)ethane (see Abstract, 8th International Congress of Pharmacology p 441, 1981), dl-1,2-bis(4-morpholinomethyl-3,5-dioxopiperazin-1-yl)propane (see Japanese Patent Provisional Publication No. 59-190976 and European Patent Publication No. 0125475A1) and 1,2-bis(4-isobutoxycarbonyloxymethyl-3,5-dioxopiperazin-1-yl)ethane (see Abstract, 14th International Congress of Chemotherapy p 324, 1985, Japanese Patent Provisional Publication No. 60-97963 and European Patent Publication No. 0140327A2).
Still, there has been a demand for a bis-dioxopiperazine derivative having more excellent antitumor activity than those known compounds.


DISCLOSURE OF THE INVENTION

Under such circumstances, we, the inventors further carried out studies on novel bis-dioxopiperazine derivatives. As a result, we found that the below-mentioned bis-dioxopiperazine derivatives of formula (I) exhibit remarkably excellent antitumor activity.
A compound of the present invention is represented by the formula (I): ##STR4## wherein R.sup.1 represents a lower alkyl group; ##STR5## and R.sup.3 represents a lower alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted furyl group, a substituted or unsubstituted styryl group or a group of --(CH.sub.2).sub.n --R.sup.4, ##STR6## or --OR.sup.7 in which group or a substituted or unsubstituted phenoxy group, group for amino group, benzyl group, and being selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group and a cyano group, being selected from the group consisting of a halogen atom, a lower alkyl group, a lower alkoxy group, a nitro group, an amino group and a cyano group.
Terms used for definition of letters in this formula are defined and exemplified in the following.
The term "lower" refers to from 1 to 6 carbon atoms unless otherwise indicated.
The "lower alkyl group" may be selected from the group having a normal or branched carbon chain such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. Preferably, methyl is used for R.sup.1.
The "protective group for amino group" may be acetyl, tert-butoxycarbonyl or benzyloxycarbonyl.
When the benzene ring such as the phenyl group, the styryl group, the benzyl group or the phenoxy group or the furyl group has a substituent, such substituent may be a halogen atom such as fluorine, chlorine or bromine, a lower alkyl group such as methyl or ethyl, a lower alkoxy group such as methoxy or ethoxy, a nitro group, an amino group or a cyano group. The benzene ring or the furyl group may have two substituents.
The compound of the present invention is for example as follows: utane erazin-1-yl]butane trifluoroacetate ne piperazin-1-yl)butane erazin-1-yl)butane xopiperazin-1-yl)butane razin-1-yl)butane n-1-yl]-3-(3,5-dioxopiperazin-1-yl)butane iperazin-1-yl)butane trifluoroacetate utane l)butane tane n-1-yl)butane zin-1-yl)butane zin-1-yl)butane oxopiperazin-1-yl)butane
The compound (I) of the present invention has asymmetric carbon atoms in its molecules. It is to be understood that isomers due to such asymmetric carbon atom or combination of any of the isomers are included in the category of the compound (I). Especially, meso- or erythro-form is preferred.
The compound (I) of the present invention may be in the form of pharmaceutically acceptable salt such as hydrochloride, oxalate, p-toluenesulfonate, acetate or trifluoroacetate.
The compound (I) of the present invention may be prepared by reacting a compound represented by the formula (II): ##STR7## wherein R.sup.1 is as defined above, with formaldehyde and then reacting the resultant compound with a compoun

REFERENCES:
patent: 4404381 (1983-09-01), Woo
patent: 4536564 (1985-08-01), Woo
patent: 4650799 (1987-03-01), Cai
patent: 4737497 (1988-04-01), Ren
patent: 4764614 (1988-08-01), Miller
Cai, Chemical Abstract, 106:293e.

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