Triazolo- and tetrazolopyridazine derivatives and their hypotension and heart rate activity.

6-Chloro-, 6-morpholino- and 6-N-methylpiperazino-1,2,4-triazolo[4,3-b]- or 1,2,3,4-tetrazolo[1,5-b]pyridazines [II-VII] were synthesized from 3-chloro-6-hydrazinopyridazine [I]. Positive effect of a series of tetra- and triazolopyridazines for lowering blood-pressure without affecting the heart rate was found in tests on rats. Their lipophilicity and other properties are discussed.

Experimental antitumor activity of new azathioprine analogues.

Two newly synthesized azathioprine (AZA) analogues, 6-(1,2-dimethyl-4-nitro-5-imidazolyl)thiopurine (Met-AZA) and 6-(2-methyl-5-nitro-4-imidazolyl)thiopurine (IZO-AZA), were investigated against KB human tumor cells. In 5 transplantable murine tumor models, including sc Sa180, sc Ca755, ip LL and ip leukemias; L1210 and P388 both drugs were found to be antitumor active in all the experiments carried out regardless of dosing regimen or the route of administration. Similar good activity was shown in the KB, ip Sa180, and Ca755 systems and partly against LL as compared to AZA. However, Met-AZA against ip P388 demonstrated therapeutic advantage following qd 1-9 daily dosing, 0.33 log10 tumor cell kill; therapeutic index (TI = ILSmax/ILS 25) = 2, and ILS = 69% in comparison to AZA and IZO-AZA, TI = 1.3, 1.2, and ILS = 31%, 40%, respectively. Met-AZA is comparable to AZA, while seeming to display greater antileukemic activity than AZA.

Cytostatic activity of pyridazinee derivatives. Part III. Cytotoxic studies on some pyridazine-3,6-diones and pyridazin-6-ones using a particle counter and a proliferation inhibition test.

The cytoxicity of 10 pyridazine-3,6-dione and 11 pyridazine-6-one derivatives was studied on L-1210 cells using the proliferation inhibition (PI) test and particle counter (PC) test. Eight compounds with ED50 value below 1 microgram/ml in the PI system and with minimal effective concentration (MEC) below 0.2 mg/ml in the PC system, were qualified for further in vivo investigation. A good solubility-activity relationship depending on bromine substituents at C-4 and C-5 in the pyridazine-3, 6-dione group was observed. The activity of soluble, pyridazine-3,6-diones depended proportionally on the number of bromine substituents at C-4 and C-5 -contrary to solubility inversely proportional to the number of bromine atoms. The moderately soluble and moderately active compounds appear to have the highest efficiency. Activity of pyridazine-6-ones seems also to be related to the number of chlorine atoms substituted at those positions. The preliminary information about the cellular mechanism and quantitative differences in the action of model analogues in correlation to structure-solubility was obtained. A new cytotoxic particle counter index (CPCI) was helpful for differentiation of activity of pyridazine analogues.

Cytostatic activity of pyridazine derivatives. Part II. In vitro studies on halogen derivatives of 6-pyridazinone and 3,6-pyridazinedione.

Cytotoxicity f 22 halogen derivatives of 6-pyridazinone (6-PD-ones) and 2-methyl-3,6-pyridazinedione (3,6-PD-diones) was studied on KB and HeLa human tumor tissue cultures. 15 compounds with ED50 activity values ranging between 0.043-2.8 micrograms/ml (9.7 x 10(-8)-9.9 x 19(-6)M) on the base of DR and D, NCI, NIH Bethesda criterium were qualified for further in vivo investigation. The presence of halogen at C-5 position determines the cytotoxic activity of 6-PD-ones and 3,6-PD-diones. Additional halogen introduction into heterocyclic ring C-4 increases the activity both meta and para bromophenyl derivatives of 6-PD-ones and, proportionally to the number of bromines, of 3,6-PD-diones. The acceptable activity demonstrated also the halogen unsubstituted 3,6-PD-diones. The 3,6-PD-dione activity seems to depend in small degree on the kind of substituent in benzene ring.

Cytostatic activity of pyridazine derivatives. I. In vitro studies on 1-methoxyphenylpyridazine-6-ones.

Cytotoxicity of 15 pyridazine derivatives was studied by tissue method on human KB and HeLA cell lines. Six compounds with ED50 activity values between 0.025 and 1.1 micrograms/ml/5.7 X 10(8) - 3.2 X 10(-6) M/were classified for further in vivo investigations. It seems that the halogen in C-5 position plays the main role in the cytotoxic activity of pyridazine-6-ones. The para position of methoxy C-4 group in the lateral benzene ring may be assumed as the next determinant of activity. On the basis of theoretical possibilities a hypothetical model of the role of C-5 halogen substituent in complementary hydrogen bonds with the purines of DNA has been proposed.