Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-10-06
1997-07-29
Goldberg, Jerome D.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
A61K 31395
Patent
active
056522347
DESCRIPTION:
BRIEF SUMMARY
This invention relates to the use of 3-(7-oxo-1-aza-4-oxabicyclo[3.2.0]hept-3-yl) alanine derivatives as antitumor agents.
BACKGROUND OF INVENTION
Since the isolation and structural elucidation of natural .beta.-lactamase inhibitor clavulanic acid, a number of naturally occurring metabolites, G0069A (JP 61-212587), Tu 1718 (DE 3727651 A1), Clavamycin (J. of Antibiotic 39, 510 (1986)), Ibid 39, 516 (1986)), Ro 22-5417 (J. of Antibiotic 36, 217 (1983)) have been isolated from the culture of genius streptomyces. None of the above metabolites exhibited .beta.-lactamase inhibitory properties. However, in most cases, attention was paid to their antibacterial and antifungal activity.
We paid attention to develop G0069A (JP 61-212587) as antitumor agent. However, there were a lot of difficulties in obtaining this compound in large scale. For example, only 20 mg of G0069A was isolated from 10L of fermentation broth even after being under well controlled fermentation technique and suitable experimental conditions.
G0069A is a chemicalyl unstable isolation process and required very complex and special techniques. This should be done in the dark at low temperatures. In addition to the above complexity in isolation of G0069A from fermentation broth, the synthetic approach also seemed to be an extremely difficult multi-step process because they have 5-asymmetric carbon centres and dipeptide side chain. Therefore, it is necessary to get compounds which are relatively easy to synthesize, have shorter chains than G0069A, chemically stable and have stronger antitumor activity.
SUMMARY OF THE INVENTION
The present invention relates to an antitumor composition comprising of an effective amount of the 3-(7-oxo-1-aza-4-oxabicyclo[3.2.0]hept-3-yl)alanine derivative represented by the formula (I) or a pharmaceutically acceptable salt thereof ##STR2## and a pharmaceutically acceptable carrier, wherein R is: which may be substituted with 1-3 aryl groups; aryl groups.
Example of C.sub.1 -C.sub.3 alkyl group as substituent in R.sub.1 and R.sub.2 are methyl, ethyl, propyl or isopropyl.
More specifically, R in general formula (I) is selected from hydrogen, methoxycarbonyl, ethoxycarbonyl or benzyloxycarbonyl, and R.sub.1 is selected from hydrogen, methyl, benzyl, diphenylmethyl or triphenylmethyl.
Examples of pharmaceutically acceptable salts are sodium, potassium, calcium, magnesium, hydrogen chloride, tartaric, fumaric, maleic, acetic, trifluoroacetic, citric, methanesufonic, trifluoromethanesulfonic, p-toluenesulfonic and so on.
The present invention provides a method of treating tumors in mammalian animals which comprises of administering to mammalian animals having tumors with an effective amount of the derivative of formula (I).
Furthermore, the present invention provides use of the derivative of formula (I) for the preparation of a pharmacological composition for treatment of tumors.
The bicyclic nucleus carries two asymmetric carbon atoms at position 3 and 5 and can exist as 4-diastereoisomers. In general, the preferred isomer is (3R,5S) and (3S,5R) or mixture of them for superior toxicity against different malignant cells such as P388, KB, NUGC4, WI38, L-1210, sarcoma 180 and colon 26. Such diastereoisomers and their mixtures are also included within the use of oxapenam derivatives as antitumor agents.
The chain alanine at C.sub.3 of bicyclic nucleus carries one asymmetric carbon atom having D and L isomers. Both of the isomers (D and L) are included within the use of oxapenam derivatives as antitumor agents.
Antitumor activity of the compounds described above is expected against some solid cancers such as gastrointestinal tract, lung, breast, liver, uterus and leukemia and so on.
DESCRIPTION OF PREFERRED EMBODIMENTS
The present invention relates to the use of oxapenam derivatives having excellent antitumor activity. The compounds of this invention are characterized by the general formula (I) ##STR3## The synthesis of the compound of general formula (I) was done by following the synthetic scheme as shown below using D
REFERENCES:
Database WPI Week 8644, Derwent Publications Ltd., Londgon, GB; AN 86-289067 (1986).
Chinese J. Antibiot., vol. 16, No. 1, 1991, pp. 1-13, "A study of new clavam antibiotics G0069." pp. 8-13 only.
Fiakpui Charles
Ha Chan
Matsumoto Hiroshi
Micetich Ronald
Oie Shinji
Goldberg Jerome D.
SynPhar Laboratories, Inc.
Taiho Pharmaceutical Co., Limited
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