3-(substituted methyl)-4-oxa-1-azabicyclo[3.2.0]heptan-7-one der

Details 3-(substituted methyl)-4-oxa-1-azabicyclo[3.2.0]heptan-7-one der 3-(substituted methyl)-4-oxa-1-azabicyclo[3.2.0]heptan-7-one der

1997-04-04

1999-11-30

Shah, Mukund J.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

540347, C07D50300, A61K 3142

Patent

active

059943424

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to novel 3-(substituted methyl)-4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivatives, and to the preparation of such compounds, and to their incorporation in pharmaceutical compositions, and to their use as pharmacological agents, in particular for use in anti-cancer treatment.


BACKGROUND OF THE INVENTION

Since the invention of G0069A (JP 61-212587) and Tu 1718 (DE 3727651), we paid attention to develop .beta.-lactam class of compounds as antitumor agents. However, there were a lot of difficulties to obtain these compounds in large scales. For example, only 20 mg of G0069A was isolated from 10 L fermentation broth even after under well controlled fermentation techniques and suitable experimental conditions. On the other hand, another .beta.-lactam compound having the same stereochemistry at C.sub.5, (3R,5S)-3-hydroxymethyl-4-oxa-1-azabicyclo[3.2.0]heptan-7-one (clavam 1, G0069B) was isolated by Brown and Evans (J. Chem. Soc. Chem. Comm. 1979, 282) from the culture of Streptomyces clavuligerus, which is reported to exhibit antifungal activity. We have synthesized clavam 1 and have done extensive biological evaluation. We found that clavam 1 exhibit excellent antitumor activity both in vitro and in vivo but is chemically unstable. ##STR2##
The chemical unstability may be due to the intermolecular interaction of --OH to the .beta.-lactam ring which results in the decomposition of product.
As a part of the program directed toward the development of .beta.-lactam class of compounds as novel antitumor agents, it is necessary to get compounds which are relatively easy to synthesize, chemically stable and have strong antitumor activity.


SUMMARY OF THE INVENTION

The present invention is based on the discovery that certain 3-(substituted methyl)-4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivatives exhibit excellent activity against sensitive and resistant tumor cells.
In accordance to the present invention, there is provided a 3-(substituted methyl)-4-oxa-1-azabicyclo[3.2.0]heptan-7-one derivative of general formula I or pharmaceutically acceptable salt thereof, ##STR3## wherein X is NH or O, when X is NH, group which may be substituted by 1-3 substituents selected from halogen, hydroxy, formyloxy, azido, carboxyl, heteroaryl or acetamide, (ii) a C.sub.2 -C.sub.4 alkenyl group, (iii) a C.sub.2 -C.sub.4 alkynyl group, (iv) a C.sub.3 -C.sub.6 cycloalkyl group, (v) a phenyl group which may be substituted by 1-3 substituents selected from hydroxy, halogen, C.sub.1 -C.sub.6 alkoxy group or cyano, (vi) a C.sub.5 -C.sub.6 heteroaryl group, (vii) a NR.sub.2 R.sub.3 wherein R.sub.2 and R.sub.3 are the same or different and each is a hydrogen, C.sub.1 -C.sub.6 alkyl group or (7-oxo-1-aza-4-oxabicyclo[3.2.0]hept-3-yl)methyl group or (viii) benzyloxy group; phenyl group which may be substituted by 1-3 substituents selected from C.sub.1 -C.sub.6 alkyl group, halogen or C.sub.1 -C.sub.6 alkoxy group; sodium, potassium, magnesium, calcium, hydrogen chloride, tartaric acid, succinic acid, fumaric acid or p-toluenesulfonic acid.
Examples of C.sub.1 -C.sub.6 alkyl group as substitutents in R.sub.1, R.sub.2, R.sub.3 or R.sub.4 are straight or branched chain alkyl group having 1-6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 3-methylbutyl, hexyl and the like.
Examples of halogen atoms as substituents in R.sub.1 or R.sub.4 are fluorine, chlorine, bromine or iodine.
Examples of heteroaryl group in R.sub.1 are 1,2,3-triazole, 1,2,4-triazole, thiophene, pyridine and the like.
Examples of C.sub.2 -C.sub.4 alkenyl group as defined in R.sub.1 are alkenyl groups having 2-4 carbon atoms such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 3-butenyl and the like.
Examples of C.sub.2 -C.sub.4 alkynyl group as defined in R.sub.1 are ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-butynyl and the like.
Examples of C.sub.3 -C.sub.6 cycloalkyl group as defined in R.sub.1 are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
Examples of heteroaryl group o

REFERENCES:
patent: 4202819 (1980-05-01), Kellett et al.
International Publication No. WO 94/01109 published Jan. 20, 1994.

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