Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-11-06
1999-07-20
Owens, Amelia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549289, 435125, 4352525, A61K 3135, C07D31104, C12P 1706
Patent
active
059256710
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to isocoumarins having antitumor activity.
BACKGROUND OF THE INVENTION
Amicoumacin A is known from J. Antibiotics, 34(5): 611-613, 1981 and from Agric. Biol. Chem., 46(5): 1255-1259, 1982. It has the formula (II): ##STR2##
SUMMARY OF THE INVENTION
We have found antitumour activity in the compound amicoumacin A and in a new compound of related structure. The compounds inhibit protein synthesis.
The present invention provides antitumour isocoumarins of the general formula (III): ##STR3## where R is --CONH; or --C(CH.sub.3).sub.2, and pharmaceutically acceptable addition salts thereof.
The compound where R is --CONH.sub.2 is amicoumacin A of the formula (II).
The compound where R is --CH(CH.sub.3).sub.2 is a new compound is a new designated PM-94128, which was isolated from Bacillus sp. CECT 4546 deposited under the Budapest Treaty on Feb. 23, 1995. The compound PM-94128 is of formula (I): ##STR4##
BRIEF DESCRIPTION OF THE FIGURES
The compound PM-94128 was identified on the basis of detailed analysis of various spectral characteristics. See the data reproduced in FIGS. 1 to 5, wherein:
FIG. 1 is the IR absorption spectrum in KBr of PM-94128;
FIG. 2 is the UV spectrum of PM-94128;
FIG. 3 is the .sup.1 H NMR of PM-94128;
FIG. 4 is the .sup.13 C NMR of PM-94128; and
FIG. 5 is the mass spectrum of PM-94128.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides antitumor compositions containing the compounds of formula (III) methods of treating tumours using the compounds, processes for preparing the compositions, and a method for preparing the compound of formula (I), among other aspects.
The compounds of the present invention, amicoumacin A and PM-94128, exhibit antitumour activity against cell lines derived from human tumors, such as A-549 human lung carcinoma, HT-29 human colon carcinoma, and MEL-28 human melanoma. They can be employed in a method of treating any mammal affected by malignant tumor sensitive to amicoumacin A or PM-94128, which comprises administering to the affected individual a therapeutically effective amount of the compound or a pharmaceutical composition thereof.
The present invention also relates to pharmaceutical compositions, which contain amicoumacin A or PM-94128 as active ingredient, or a pharmaceutical acceptable acid addition salt thereof.
The pharmaceutical compositions of this invention can be made by admixing the active compound with a pharmaceutically acceptable carrier. Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions, or emulsions) with suitable composition of oral, topical or parenteral administration, and they may contain the pure compound or in combination with any carrier or other pharmacologically active compounds. These compounds may need to be sterile when administered parenterally.
The correct dosage of a pharmaceutical composition comprising amicoumacin A or PM-94128 will vary according to the pharmaceutical formulation, the mode of application, and the particular situs, host and bacteria or tumor being treated. Other factors like age, body weight, sex, diet, time of oral administration, rate of excretion, condition of the host, drug combinations, reaction sensitivities and severity of the disease shall be taken into account. Administration can be carried out continuously or periodically within the maximum tolerated dose.
Suitable pharmaceutically acceptable addition salts include salts with inorganic acids such as hydrochloric acid and organic acids such as oxalic or fumaric acid.
The invention also provides a process for obtaining PM-94128, which comprises cultivating a strain of a microorganism capable of producing PM-94128 in aqueous nutrient medium with assimilable carbon and nitrogen sources and salts, under controlled submerged aerobic conditions. The compound PM-94128 can be recovered and purified from the cultured broth.
The preferred microorganism is the Bacillus sp. strain designat
REFERENCES:
patent: 4393225 (1983-07-01), Hayashi
Inouye et al. 'Amicoumacin and SF-2370, Pharmacologically active agents of microbial origin CA 111:208552, 1989.
Itoh et al. 'Chemical structures of Amicoumacins produced by Bacillus pumilus, 1983.
Journal of Medicinal Chemistry, vol. 26, No.10, 1983, pp.1370-1374.
The Journal of Antibiotics, vol. XXXIV, No.5, May, 1981, pp.611-613.
Agric. Biol. Chem., 46(5), 1982, 1255-1259.
Garcia Gravalos Dolores
Hernandez Librada Canedo
Sarabia Cristina Acebal
Linek Ernest V.
Owens Amelia
Pharma Mar S.A.
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