4-oxa-1-azabicyclo [3,2,0] heptan-7-one derivatives as antitumor

Details 4-oxa-1-azabicyclo [3,2,0] heptan-7-one derivatives as antitumor 4-oxa-1-azabicyclo [3,2,0] heptan-7-one derivatives as antitumor

1995-03-16

1996-10-01

Goldberg, Jerome D.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

H61K 31395

Patent

active

055611265

DESCRIPTION:

BRIEF SUMMARY
The present invention relate to an antitumor composition comprising an effective amount of 4-oxo-1-azabicyclo[3,2,0] heptan-7-one derivatives and a pharmaceutically acceptable carrier.


BACKGROUND OF THE INVENTION

Since the isolation and structure elucidation of natural .beta.-lactamase inhibitor clavulanic acid, [Antimicrobial Agents and Chemotherapy, 11, 852 (1977)], as metabolized product of streptomyces clavuligerus, a number of exploratory efforts have been made to isolate another antibiotics. On the other hands, several synthetic studies also have been done for the .beta.-lactam compounds which have 4-oxa-1-azabicyclo[3,2,0] heptan-7-one (oxapenam) skeletons [DT2702091 A1, EP 0057664 A2, DT 2725690 A1, British Patent 1585661, J. Chem. Soc. Perkin Trans I, 2222 (1980), J. Antibiotics, 26, 217 (1983), J. Org. Chem. 50, 3457-3462 (1985), J. Antibiotics, 29, 510 (1986), ibid, 29, 516 (1987), Tetrahedron, 2467 (1987), Chem. Pharm. Bull., 39, 2813-2818 (1991)].
However, in most case, attention were paid to their strong antibacterial, antifungal and .beta.-lactamase inhibitory activities.
We paid attention to the cytotoxic activities of G0069A (JP 61-212587) and Tu1718 (DE 3727651 A1), produced by genus Streptomyces and have been trying to develop them as antitumor agents. However, there were lots of difficulties to obtain these compounds in large scale. For example, only 20 mg of G0069A was isolated from 10 L of fermentation broth even after under well controlled fermentation technique and suitable experimental conditions.
G0069A is chemically very unstable. Isolation process required very complex and special technique and should be done in dark at low temperature. In addition to the complexity in isolation of G0069A from fermentation broth, the synthetic approach is also seemed to be extremely difficult multistep process because they have 5 asymmetric centers and dipeptide side chain. Therefore, it is necessary to get compounds which are relatively easy to synthesis, have shorter chain than G0069A, chemically stable and have strong antitumor activity. ##STR2##


SUMMARY OF THE INVENTION

The present invention relates to an antitumor composition comprising an effective amount of the 4-oxa-1-azabicyclo [3,2,0]heptan-7-one derivative represented by the formula I or a pharmaceutically acceptable salt thereof ##STR3## and a pharmaceutically acceptable carrier.
Wherein R is
--OCOR.sub.1 wherein R.sub.1 is hydrogen atom, a C.sub.1-9 alkyl group which may be substituted by either one or two substitutents selected together from halogen atom, hydroxy, carboxy group or (3RS,5SR)-(4-oxa-1-azabicyclo[3,2,0]heptan-7-one-3-yl)methyl-oxycarbonyl, a C.sub.2-17 alkenyl group which may be substituted by carboxy group or (3RS,5SR)-(4oxa-1-azabicyclo[3,2,0] heptan-7-one-3-yl)methyloxycarbonyl, a C.sub.2-4 alkynyl group, a C.sub.3-6 cycloalkyl group which may be substituted by carboxy group or phenyl group which may have 1, 2 or 3 substituents selected from the group consisting of cyano group, halogen atom, carboxy group, C.sub.1-6 alkoxy group which may be substituted by carboxy group, C.sub.1-6 alkyl group, amino group or hydroxy group.
--OR.sub.2 wherein R.sub.2 is a hydrogen atom or benzyl group which may be substituted by 1 or 2 C.sub.1-6 alkoxy group.
--S(O).sub.n R.sub.3 wherein R.sub.3 is phenyl group or a benzyl group which may be substituted by C.sub.1-6 alkyl group, n is 0, 1 or 2;
or --CH.sub.2 OH
Examples of C.sub.1-9 alkyl group as the substituents in R.sub.1 are straight- or branched-chain alkyl groups having 1 to 9 carbon atoms such as methyl, ethyl, propyl, pentyl, hexyl, heptyl, octyl, nonyl, 2-methylpropyl, 3-methylbutyl, 4-methylpentyl, 5-methylhexyl, 6-methylheptyl, 7-methyloctyl, 1-methylpropyl, 1-methylbutyl, 1-methylpentyl, 1-methylhexyl, 1-methylheptyl, 1-methyloctyl and the like.
Examples of halogen atom as substituents in R.sub.1 are fluorine, chlorine, bromine or iodine atom.
Examples of C.sub.2-17 alkenyl group as the substituents in R.sub.1 are straight- or branched-chain alkenyl group having 2

REFERENCES:
patent: 4093626 (1978-06-01), Hunt
D. Hoppe et al, Tetrahedron, "Enantioselective Synthesis of the fungicide beta-lactam antibiotic . . . ", vol. 43, No. 11, 1987, pp. 2467-2474.
T. Konosu et al, Chem. Pharm. Bull., "Enantiocontrolled synthesis of the antifungal beta-lactam . . . ", vol. 39, No. 9, 1991, pp. 2212-2215.

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