Organic compounds -- part of the class 532-570 series – Organic compounds – Nitrogen attached directly or indirectly to the purine ring...
Patent
1984-10-17
1985-12-10
Daus, Donald G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Nitrogen attached directly or indirectly to the purine ring...
548530, C07D23910, C07D20720
Patent
active
045581274
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to novel biologically acitve compounds, viz. uracyl derivatives possessing antitumor activity.
BACKGROUND OF THE INVENTION
Known in the art is 5-fluorouracyl which is currently employed in oncology for non-operable forms of gastro-intestinal carcinoma, lung cancer and ovary carcinoma. (J. Amer. Chem. Soc. vol. 79, No. 16, published 1957; R. Dushinsky, E. Pleven, C. Heidelberg "The synthesis of 5-Fluoropyrimidines".
This compound, however, is highly toxic, it strongly affects the function of bone marrow and gastro-intestinal tract.
Another analog of the compound according to the present invention is 1-(.alpha.-furanidyl)-5-fluorouracyl (Ftorafur) (cf. British Pat. No. 1,168,391, Cl. C 07 d 51/30 1969). This is a low-toxic (LD.sub.50 for mice is 750 mg/kg) compound having rather high activity in respect of solid experimental tumors: sarcoma 180, Harding-Passey melanoma, Walker carcinosarcoma, alveolar carcinoma of liver. In clinics the preparation based on Ftorafur is employed for treating mammal carcinoma, rectum carcinoma, large intestine and stomach cancer. This preparation, however, inhibits hemopoiesis and causes complications on the side of the gastro-intestinal tract. Furthermore, Ftorafur, likewise fluorouracyl, lacks paramagnetic properties.
DISCLOSURE OF THE INVENTION
The present invention is directed to the provision of novel compounds possessing an antitumor activity, a low toxicity and having paramagnetic properties.
This object is accomplished by nitroxyl derivatives of 5-fluorouracyl of the general formula: ##STR3## wherein
R.sub.1 =R.sub.2 =X, R1 ? ##STR4##
or R.sub.1 =X, R.sub.2 =H
or R.sub.1 =H, R.sub.2 =X,
or R.sub.1 =Na, R.sub.2 =X, possessing antitumor activity.
These compounds feature a high antitumor activity which is by 2-4 times superior to that of Ftorafur and is comparable with the antitumor activity of 5-fluorouracyl.
The compounds according to the present invention are distinguished by their low toxicity, thus making it possible to minimize the undesirable side effects, enhance the effectiveness of inhibition of malignant neoplasms in the organism and to considerably enlarge the therapeutic scope of their action.
The availability of paramagnetic properties in the compounds according to the present invention enable a simplified control of the treatment process. The possibility of determination of paramagnetic preparations in the tumor tissues and spots of their localization up to the cellular level makes these compounds indispensible in the investigation of tumor processes and finding-out the mechanism of action of antitumor compounds.
BRIEF DESCRIPTION OF DRAWINGS
The present invention is further illustrated by specific embodiments thereof with reference to the accompanying drawings wherein:
FIG. 1 shows kinetic curves of variation of mass of mice spleen in the case of La-leukemia in the control and upon administration of equimolar doses of Ftorafur, 5-fluorouracyl and a nitroxyl derivative of 5-fluorouracyl (R.sub.1 =Na, R.sub.2 =X) plotted in coordinates M- .tau., where M is mass of mice spleen in g, .tau.-time, days;
FIG. 2 shows kinetic curves of a tumor volume gain in the case of adenocarcinoma 755 in mice in the control and upon the administration of equimolar doses of Ftorafur and a nitroxyl derivative of 5-fluorouracyl (R.sub.1 =Na, R.sub.2 =X), plotted in coordinates V- .tau., where V is volume of adenocarcinoma 755 tumor, in cm.sup.3, .tau.-time, days.
BEST MODE OF CARRYING-OUT THE INVENTION
The nitroxyl derivatives of 5-fluorouracyl according to the present invention corresponding to the above general formula, wherein R.sub.1 =R.sub.2 =X or R.sub.1 =X, R.sub.2 =H are prepared by condensation of bis-(trimethylsilyl)-5-fluorouracyl (A) with 2,2,5,5-tetramethyl-1-oxyl-.DELTA..sup.3 -pyrrolin-3-carboxylic acid chloride (B) in a medium of an inert solvent such as benzene or without solvent at room temperature or upon a mild heating. At a molar ratio of compound (A) to compound (B) equal to 1:2-3 respectively
REFERENCES:
patent: 3971784 (1976-07-01), Tada
patent: 4130648 (1978-12-01), Kijima et al.
patent: 4169201 (1979-09-01), Kiss
patent: 4399140 (1983-08-01), Gacek et al.
patent: 4415573 (1983-11-01), Ochi et al.
Donze et al., Chemical Abstracts 92: 43272g, (1980).
Bogdanov Gennady N.
Emanuel Nikolai M.
Golubev Valery A.
Konovalova Nina P.
Rozenberg Albina N.
Daus Donald G.
Kapner Stephen M.
LandOfFree
5-Fluorouracil nitroxyl derivatives possessing antitumor activit does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 5-Fluorouracil nitroxyl derivatives possessing antitumor activit, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 5-Fluorouracil nitroxyl derivatives possessing antitumor activit will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-59609