Use of 5-Thia-1,4-diazabicyclo [4.2.0] octane-3,8-dioxo compounds in antitumor therapy

Abstract: The present invention relates to the use of 5-thia-1,4-diazabicyclo[4.2.0]octane-3,8-dioxo compounds of the general formula I, wherein the radicals have the following meanings: R¹ is hydrogen, halogen, R² is hydrogen, halogen, amino, PhCH₂CONH, PhOCH₂CONH, phthalimido, o-MeNHCOC₆H₄CONH, 3-o-chlorophenyl-5-methyl-isoxazolyl-4-carbonyl amino, R³ is hydrogen, alkyl, benzyl, a heterocyclic ring e.g. isoxazole, pyrazole, n is 1 or 2. In the application examples of the suppression of uterine cervix carcinoma cells (HeLa) by the use of various substituted 5-thia-1,4-diazabicyclo[4.2.0]octane-3,8-dioxo derivatives are disclosed.

Description: EP 0 598 375 A2 of 25 May 1994 discloses 5-thia-1,4-diazabicyclo[4.2.0]octane-3,8-dioxo compounds of the general formula I, wherein the radicals have the following meanings: R 1 is hydrogen, halogen, R 2 is hydrogen, halogen, amino, PhCH 2 CONH, PhOCH 2 CONH, phthalimido, o-MeNHCOC 6 H 4 CONH, 3-o-chlorophenyl-5-methylisoxazolyl-4-carbonyl amino, R 3 is hydrogen, alkyl, benzyl, a heterocyclic ring e.g. isoxazole, pyrazole, n is 1 or 2, as well as their usefulness as active components of medicaments in antibacterial therapy. The present invention refers to the use of compounds of the general formula I, wherein the radicals have the afore-mentioned meanings, for the preparation of a pharmaceutical for antitumor therapy. It has not been known to use compounds of similar structures nor of any other β-lactam structures in antitumor therapy. It was found that 5-thia-1,4-diazabicyclo[4.2.0]octane-3,8-dioxo analogs of the general formula I, wherein the radicals have the afore-mentioned meanings, strongly suppress the growth of the uterine cervix carcinoma cells (HeLa). By the use of compounds of formula I in concentrations from 10 -3 to 10 -6 M, a tumor-cell suppressive effect from 25 % to 65 % was established after 72 hours. The best effects were achieved at the concentration 5 x 10 -4 M. The following examples of the suppressive effect of the compounds of the general formula I upon the uterine cervix carcinoma indicate the possibility of the said compounds being also efficient in the suppression of other tumor cells. Testing process Cells were cultured within a period of 12 hours in the growth medium DMEM (Dulbecco's Modified Eagle's Medium) supplemented with foetal calf serum (FCS) (10%), glutamine (2 mM), penicillin (100 U/ml), streptomycin (100 µg/ml) and Hepes (1 mM) at pH 7 at a temperature of 37°C under the flow of a mixture consisting of air and of 5% CO 2 . The cells were seeded at a concentration of 10 4 cells/ml on 24- or 96-well cell culture plates. After a period of 12 hours, solutions of compounds I in concentrations from 10 -3 to 10 -6 M were added. At the beginning all substances were prepared as 10 -1 M solutions in dimethylformamide and then the desired concentrations were obtained by diluting with the cell growth medium. 72 hours after the addition of the active substance the cells were counted by using an electronic counter and the suppressive effects of compounds I were determined as indicated in the following examples:

Claims: The use of a 5-thia-1,4-diazabicyclo[4.2.0]octane-3,8-dioxo compound of the general formula I, wherein the radicals have the following meanings: R 1 is hydrogen, halogen, R 2 is hydrogen, halogen, amino, PhCH 2 CONH, PhOCH 2 CONH, phthalimido, o-MeNHCOC 6 H 4 CONH, 3-o-chlorophenyl-5-methylisoxazolyl-4-carbonyl amino, R 3 is hydrogen, alkyl, benzyl, a heterocyclic ring e.g. isoxazole, pyrazole, n is 1 or 2, for the preparation of a pharmaceutical for antitumor therapy.

Inventors: GRDISA MIRA D SC, HERAK JURE J D SC, HORVATIC MARJETA M SC, KOVACEVIC MICE D SC, LUKIC IRENA M SC, MANDIC ZORA M SC, PAVELIC KRESIMIR D SC, TOMIC MIRJANA M SC, GRDISA, MIRA, D. SC., HERAK, JURE J., D. SC., HORVATIC, MARJETA, M. SC., KOVACEVIC, MICE, D. SC., LUKIC, IRENA, M. SC., MANDIC, ZORA M. SC., PAVELIC, KRESIMIR, D. SC., TOMIC, MIRJANA M. SC.
Applicants: PLIVA PHARM & CHEM WORKS, PLIVA, FARMACEUTSKA, KEMIJSKA, PREHRAMBENA I KOZMETICKA INDUSTRIJA DIONICKO DRUSTVO
Application year: 1995
Main classification: A61K31
IPC codes: A61P35, A61K31, C07D513