Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1987-02-24
1989-10-31
Raymond, Richard L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142322, 514255, 544 60, 544121, 544359, 544360, 544364, A61K 31435, C07D41314
Patent
active
048778036
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to novel bis-dioxopiperazine derivatives having an antitumor activity and pharmaceutical compositions containing the same.
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 (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 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 these circumstances, we, the inventors carried out studies for new bis-dioxopiperazines derivatives and found that the below-mentioned bis-dioxopiperazine derivatives of formula (I) exhibit remarkably excellent antitumor activity, thus completing the present invention.
A compound according to the present invention is represented bythe formula (I): ##STR3## wherein R.sup.1 represents a lower alkyl group; A represents an oxygen atom, a sulfur atom or a group of ##STR4## wherein R.sup.2 represents a hydrogen atom, a lower alkyl group or phenyl; R.sup.3 represents a lower alkyl group, phenyl or benzyl; and X and Y, which are respectively independent and are the same or different, represent a hydrogen atom or a lower alkyl group. The meaning and examples of terms used in this formula will be described.
The wording "lower" refers to a group having 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-prrophyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl and n-hexyl. Preferably, methyl is used as the lower alkyl group for R.sup.1.
The compound according to the present invention is for example as follows:
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) of the present invention.
The compound (I) of the present invention may be prepared by reacting a compound represented by the formula (II): ##STR5## wherein R.sup.1 is as defined above, with formaldehyde and a compound represented by the formula (III): ##STR6## wherein A, X and Y are as defined above.
In this reaction, at least two equivalent molar amounts of the compound of the formula (III) and formaldehyde, respectively, should be used to one molar amount of the compound of the formula (II).
The reaction temperature may range from 25.degree. to 200.degree. C., preferably from 75.degree. to 160.degree. C. and the reaction time may range from 0.5 to 12 hours which depends on reaction temperature.
As for the reaction solvent, polar solvent such as N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), acetonitrile, ethyl acetate, methanol, ethanol, butanol or their mixture may be used.
The compound of the formula (II) which is the starting material in the above-mentioned process is a known compound and can be prepared according to a process described in British Patent Specification No. 1234935.
The antitumor activity of the compound of the formula (I) according to the present invention, which is prepared by the above-mentioned process, was verified by the below-mentioned tests. The test compounds in these tests were as follows: meso-2,3-bis[4-(N-phenylpiperazinomethyl)-3,5-dioxopiperazin-1-yl]butane meso-2,3-bis[4-(3,5-dimethylpiperidinomethyl)-3,5-dioxopiperazin-1-yl]buta ne
Comparative Compounds
(I) Growth Inhibition of Tumor Cells in Vitro:
Tumor cells were collected aseptically with capillary tube from ascites in CDF.sub.1 m
REFERENCES:
patent: 4737497 (1988-04-01), Ren
Chemical Abstract, vol. 103, #31960n, Herman, 1985, "Comparison of the Protective Effect of ICRF-187 and Structurally Related Analogs . . . ".
Cai Jun-Chao
Takase Muneaki
Covington Raymond
Raymond Richard L.
Zenyaku Kogyo Kabushiki Kaisha
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