Water soluble bis-dioxopiperazine derivatives

Details Water soluble bis-dioxopiperazine derivatives Water soluble bis-dioxopiperazine derivatives

1992-03-02

1995-02-28

Bernhardt, Emily

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

Organic compounds

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

C07D24108, C07D40314, C07D41714

Patent

active

053938895

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

Compounds of the present invention are acid addition salts of bis-dioxopiperazine derivatives represented by the formula (I) ##STR4## wherein R.sup.1 represents a C.sub.1-6 alkyl group, R.sup.2 represents a hydrogen atom or a group of ##STR5## R.sup.3 represents a hydrogen atom, a C.sub.1-6 alkyl group or a group of --(CH.sub.2).sub.n --A mercapto group, an amino group, a benzyloxycarbonylamino group or a group of ##STR6## in which X represents a hydrogen atom, a trifluoromethyl group, a hydroxy group, an acetoxy group or a benzyloxy group, and 5-membered ring which may contain a sulfur atom.
Synthetic intermediates of the compounds of the present invention are water soluble bis-dioxopiperazine derivatives having antitumor activity represented by the formula (II) ##STR7## where in R.sup.1 is as defined above, R.sup.5 represents a hydrogen atom or a group of ##STR8## R.sup.6 represents a hydrogen atom, a C.sub.1-6 alkyl group or a group of --(CH.sub.2).sub.n --A' benzylthio group which may be substituted by a C.sub.1-6 alkoxy group, a benzyloxycarbonylamino group or a group of ##STR9## in which X represents a hydrogen atom, trifluoromethyl group, a hydroxyl group, an acetoxy group or benzyloxy group, and 5-membered ring which may contain a sulfur atom,


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 p441, 1981), d1-1,2-bis(4-morpholinomethyl-3,5-dioxopiperazin-1-yl)propane (see Japanese Patent Publication (Kokai) No. 190976/1984) and 1,2-bis(4-isobutoxycarbonyloxymethyl-3,5-dioxopiperazin-1-yl)ethane (see Abstract, 14th International Congress of Chemotherapy p324, 1985 and Japanese Patent Publication (Kokai) No. 97963/1985). Also known are the compounds described in the Japanese Patent Publication (Kokai) Nos. 152660/1986, 89668/1987, 281870/1987 and 279875/1989.
Though these compounds have excellent antitumor activity, water soluble salts thereof with retained activity cannot be formed so that route of administration and pharmaceutical form of the compounds are much limitative. Therefore, there has been a demand for a water soluble bis-dioxopiperazine derivative which may be expected to have wider clinical applicabilities.
Under these circumstances, we, the inventors carried out studies on novel bis-dioxopiperazine derivatives to find out that acid addition salts of the compounds represented by the formula (I) exhibit remarkably excellent antitumor activity, thus completing the present invention.
The terms used for definition of variables in the above-mentioned formulas (I) and (II) by which the compound of the present invention and synthetic intermediates thereof are respectively represented are defined and exemplified in the following.
The "C.sub.1-6 " refers to a group having 1 to 6 carbon atoms unless otherwise indicated.
The "C.sub.1-6 alkyl group" refers to a straight- or branched-chain alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, n-pentyl, n-hexyl or the like. Preferably, methyl is used for R.sup.1.
The "C.sub.1-6 alkoxy group" refers to a straight-or branched-chain alkoxy group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy, n-hexyloxy or the like.
The "protective group for amino group" may be tert-butoxycarbonyl, benzyloxycarbonyl or the like.
The compound of the present invention are for example as follows: tane tane ne ne piperazin-1-yl]butane n-1-yl]butane zin-1-yl]butane n-1-yl]butane 1-yl]butane e n-1-yl]butane 1-yl]butane tane 1-yl)butane azin-1-yl)butane in-1-yl)butane in-1-yl)butane xopiperazin-1-yl)butane l]-3-(3,5-dioxopiperazin-1-yl)butane dioxopiperazin-1-yl)butane in-1-yl]-3-(3,5-dioxopiperazin-1-yl)butane razin-1-yl)butane erazin-1-yl)butane
The compound (I) of the present invention has asymmetric carbon atoms in its molecules. It is to be understo

REFERENCES:
patent: 4650799 (1987-03-01), Cai et al.
patent: 4737497 (1988-04-01), Ren
patent: 4868303 (1989-09-01), Takase et al.
patent: 4877803 (1989-10-01), Cai et al.
Derwent Abstract for JP 62-135472 (Jun. 18, 1987).
Derwent Abstract for JP 61-152660 (Jul. 11, 1986).
Derwent Abstract for JP 1-279875 (Nov. 10, 1989).
Sai et al, Chemical Abstracts, vol. 106, No. 18614 (1987) (Abstract for JP 61-152660, Jul. 11, 1986).
14th International Congress of Chemotherapy, p. 324, Jun. 1985, Abstract p-18-34, Cai et al.
8th International Congress of Pharmacology, p. 441, Jul. 1981, Abstract 722, Zhang et al.

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