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Some 3-alkylthio- derivatives of 7-chloroisothiazolothieno-1,2,3-triazine and of isothiazolothieno-1,2,3-triazin-7(4H)one were prepared. The synthesized compounds were subjected to pharmacological screening for antiallergic, antiinflammatory and analgesic activity as well as to a microbiological test in order to evaluate potential antifungal activity.
Thirteen amidoderivatives of 3-methyl-3,4-dihydro-6-R-benzo-1,2,4-triazin-3-yl-acetic acids and of 3-methyl-3,4-dihydro-pyrido [3,2-e]/[3,4-e]-1,2,4-triazin- 3-yl-acetic acids were prepared and submitted to a wide pharmacological screening. The dihydrobenzotriazine and dihydropyridotriazine moieties were endowed with a wide pharmacogenic capacity; in fact, several compounds exhibited high antiinflammatory [(I c), (I d), (II d), (V f), (VI f)], diuretic [(I f), (I g), (I h)] and antihypertensive activities [(I d), (III d)], as well as minor effects on the C.N.S.
A method for measuring the triamino-s-triazine content in various fertilizer mixes has been developed and collaboratively studied. Samples are dissolved in deionized water and analyzed using liquid chromatographic separation on a RP-18 LiChrosorb column. Collaborators analyzed 5 sets of blind duplicates, comparing peak heights to an external standard to quantitate the triamino-s-triazine content. Coefficients of variation ranged from 0.8 to 2.2%. The method has been adopted official first action.
The nucleophilic substitution of one chlorine atom in 2,4-dichloro-6-(dihexylamino)-1,3,5-triazine (1) by primary (2a-b) or secondary (2c) amines leads to the aliphatically substituted chloro-dihexylamino-1,3,5-triazines (3a-c) Structures of type 3 may be characterized by the spectroscopic data. In the mass spectra, the complete degradation of the alkyl groupings is striking and manifested in a series of consecutive peaks with differences of 14 between each other. Antiviral activity is exhibited by 3a through an inhibitory effect towards vaccinia virus and by 3b as interferon inductor towards encephalomyocarditis virus. Moreover, 3a and 3b exhibit a strong activity towards Trichomonas vaginalis. Additionally, 3a is capable of exerting temperature lowering and anthelminthic effects.
Triazine chloro derivatives: atrazine, simazine manifest no mutagenic and recombinogenic properties in yeasts; triazine methylthio derivatives: prometryne, semeron (desmetryne) generate both genetic events with low concentrations of 0.5 and 5 mg/l. It is found that prometryne is more able to generate point mutations, while semeron--to generate mitotic recombinations. In this case frequency of experimental prototrophs is twice higher than the control level.
The metabolism of the anticoccidial 2-[3-chloro-4-(4-chlorobenzoyl)phenyl]-as-triazine-3,-5(2H,4H)-dione (CP-25,415) was investigated in the chicken. It was shown that the predominant residue present in the chicken was 2-[3-chloro-4-(alpha-hydroxy-4-chlorobenzoyl)phenyl]-as-triazine-3,5(2H,4H)-dione (CP-25,641). A gas-liquid chromatographic assay for the analysis of CP-25,641 in biological fluids and tissues was developed which was rapid, accurate, and reproducible. Results of the analytical method correlated well with radiochemical measurements and were indicative of the total drug-related residues. The half-life of CP-25,641 in tissues was approximately 32 hr except in the kidney, where the half-life was approximately 40 hr due to urine retention by the kidneys. CP-25,641 was excreted without further change.
The nucleophilic substitution of one chlorine atom in cyanuric chloride (1) by piperidine derivatives (2a-c) leads to the 6-substituted 2,4-dichloro-1,3,5-triazines (3a-c). Reaction of 1 with piperazine derivatives (4a-c) yields the substituted 2,4-dichloro-6-(1-piperazinyl)-1,3,5-triazines (5a-c). Structures of type 3 and 5 may be characterized by the spectroscopic data. In the mass spectra, the degradation of 3c leading to the base peak comprises the cleavage into a 2,4-dichlorotriazinyl radical and a 3,4-dihydroquinolinium ion m/e 132. Strong activity is exhibited by 5a and 5b towards Trichomonas vaginalis. Moreover, 5a displays strong antimycotic activity towards Trichophyton mentagrophytes, Trichophyton rubrum, and Microsporum canis. Additionally, 5a and 5b are capable of exerting very strong anthelminthic activity towards Caenorhabditis elegans.
The metabolism of 2,4-diamino-6-(2,5-dichlorophenyl)-s-triazine maleate (MN-1695) was studied in rats, guinea pigs, dogs and monkeys. MN-1695 was metabolized to more than 8 metabolites after oral administration in a dose of 3.1 mg/kg in rats. These metabolites were isolated from the urine and characterized by cochromatography with reference compounds, mass spectrometry and other instrumental analysis. The main metabolite in the urine was MN-1695 X m-OH, which was excreted as a conjugate, in rats and guinea pigs, and MN-1695 X N-oxide in dogs. In monkeys, MN-1695 X m-OH (free and conjugate) and MN-1695 X N-oxide predominated in the urine, although MN-1695 was not extensively metabolized. In rats, over 90% of the radioactivity excreted into the bile consisted of the polar metabolites. The major metabolic pathways of MN-1695 found in various animal species involved the hydroxylation at the positions of 3 and 4 of the aromatic ring and the N-oxidation at the position of 3 of the s-triazine ring. In addition, the sulfur-containing metabolites were detected in all species examined.
In insects it is known that the chemosterilant treatment induces dominant lethal mutations which bring about embryonic death. The possibility of delayed expression of the chemosterilant-induced dominant lethals in F(1) progeny of the tropical house mosquito, Culex pipiens fatigans Wiedemann has been investigated. The chemosterilants employed were 8 aziridinyl compounds, 3 phosphoramides, and 4 s-triazines. In general, all the chemosterilants tested were found to cause different degrees of mortality at different life stages of the F(1) progeny. In this respect the aziridinyl compounds were more effective than the phosphoramides and s-triazines. This effect of the chemosterilants may be useful in the sterile-male technique.
The experiments on rats have shown that there is a linear dependence of the logarithms of reciprocal molar toxic (LD50) and therapeutic (ED50) for sarcoma 45 doses of 6-oxyalkyl-amino-2,4-bis(I-aziridinyl)-sym-triazines and 6-(5-substituted-2,2-dimethyl-1,3-dioxan-5-yl)-amino-2,4-bis(I-aziridinyl)-sym-triazines upon the induction constants of substituents at tertiary carbon, the antitumor activity being more sensitive to the substituent effect compared with the toxicity. The dependence of the logarithms of reciprocal molar therapeutic (ED50 for sarcoma 45 and ED95 for Walker sarcoma) and toxic (LD50 and LD100) doses of the compounds, both synthesized by us and taken from the literature, upon the logarithms of their distribution coefficients in the octanol-water system (IgP) shows a parabolic character with the maximum effect at the extreme point of the parabola. The antitumor activity was more sensitive to a changed IgP than the toxicity.
Cyanuric acid was not toxic for soil microorganisms examined and was even observed to stimulate the growth of Azotobacter in chernozem. Some isolated fungi were capable of cleaving the ring of cyanuric acid. With the use of 15N-labeled cyanuric acid it was found that the nitrogen taken from this compound by Aspergillus minutus and Pseudogymnoascus sp. was incorporated into their proteins. About 70-90% of 15N derived from cyanuric acid was detected in the biomass of the examined fungi. The ability of soil microorganisms to cleave the triazine ring is of importance in the detoxication of soils treated with triazine herbicides.
A new triazine folate antagonist, 3-chloro-4-((4-(2-chloro-4-[4,6-diamino-2,2-dimethyl-s-triazin-1(2H)-yl]phenyl)butyl)) benzenesulfonyl fluoride compounded with ethanesulfonic acid (1:1) (NSC 127755), was highly active against four transplantable colon adenocarcinomas (36, 38, 10/A, 12/A) and the Dunning murine ovarian tumor M5076. Treatment schedule studies indicated that a prolonged time of exposure provided optimum antitumor activity for the compound. The combination of NSC 127755 plus 4-amino-1-[5-O-(1-oxohexadecyl)-beta-D-arabinofuranosyl]-2(1H)-pyrimidinone (palmO-ara-C, NSC 135962) was found to have therapeutic synergism against grossly evident colon adenocarcinoma 36.
In an attempt to improve upon the 43%-48% regression rates noted for various CAP regimens consisting of cyclophosphamide, doxorubicin (Adriamycin), and cis-diamminedichloroplatinum(II) in various doses and schedules, triazinate was added to that three-drug combination, and the new combination (T-CAP) was evaluated in patients with advanced adenocarcinoma of the lung. T-CAP produced a regression rate of 57% with a 7-week increase in overall median time to progression and a 4-week increase in overall median survival compared to the best of the CAP schedules. More stomatitis and dermatitis were noted with the new combination, but myelosuppression was similar to that of the CAP regimens. These data suggest that further studies with triazinate should be conducted in patients with adenocarcinoma of the lung.
Several new 3-thio-1,2,4-triazine derivatives were synthesized and investigated for antimicrobial and antitumor activity in in vitro and in vivo systems. Some of the investigated compounds inhibited growth of gram-positive bacteria and fungi at the concentration of 5-20 microgram/ml. Two methyl-nitro-imidazole-triazine derivatives (XI and XIII) inhibited the development of chicken fibroblast at 0.1 microgram/ml. Three out of fourteen compounds tested (V, XII and XIII) inhibited by 75% growth of sarcoma 180 when injected s.c. for 14 consecutive days in the doses of 50 and 100 mg/kg. At the same doses no effect was noted on leukemia L 1210 and P 388. Correlation between chemical structure, cytotoxic activity, antitumor effect and antimicrobial activity is discussed.
Twenty-four patients with advanced metastatic colorectal cancer with measurable sites of disease were treated with a combination of 5-FU, methyl-CCNU, ICRF-159, and triazinate. Only two had objective regression of disease. Two patients died of complications from drug-induced myelosuppression. Toxic effects were moderate in the remaining patients. Attempts to escalate doses were limited by myelosuppression. The regimen used has no advantage over 5-FU alone. It is unlikely that triazinate and ICRF-159 will add substantially to the efficacy of chemotherapy for colorectal cancer.
Polarization fluoroimmunoassay for s-triazine herbicides was developed. The sensitive of assay is higher with using shortest chemical "bridge" length between the molecule of antigen and fluorescent label. The detection limit of atrazine in 50 microL sample was 6 ng/ml. The total time required for an assay of 10 samples was 6 ng/ml. The total time required for an assay of 10 samples is approximately 7 min. The method may be used for environmental monitoring of s-triazine herbicides in water samples.
Only few data have been published on the environmental impact of pesticide degradation products on soil and groundwater. It is known that some of the degradation products of triazines, particularly those formed from N-dealkylation reactions, can be phytotoxic and more mobile than their parent compounds. In some cases it has been shown that they are present at even higher concentrations than the latter. Yet, their impact on groundwater quality is unknown since information on both environmental levels and chemiodynamic parameters are generally lacking. The conclusions of this work are that many triazine degradation products may pose a significant hazard to the quality of groundwater and that there is a need to promote and extend the production of experimental data on this topic.
Some new pyrido[3',2':4,5]thieno[3,2-d]1,2,3-triazine-4(3H)-ones (C) were synthesized from 2-thioxo-1,2-dihydro-3-carbonitriles (A) via the 3-amino-thieno[2,3-b]pyridine-2-carboxamides (B). Substances of structure A were converted to 3-amino-thieno[2,3-b]pyridine-2-carbonitriles (G) which yielded the desired 4-amino substituted compounds I via the tricyclic 4-chloro-pyrido[3',2':4:5]thieno[3,2-d]1,2,3-triazines (H) by the reaction with N-nucleophiles. Some of the investigated compounds showed a respectable antianaphylactic activity.