6-[4- (4-alkylpiperazine-1) phenylamino] -1,2,5 - thiadiazolo [3,4-h] quinoline with anthelminthic activity in alveolar echinococcosis and gimenolepidoze

 

(57) Abstract:

Scope: the compounds obtained have anthelminthic activity. The essence of Oia: product 6-[4-(4 - methylpiperazine-1) phenylamino] -1,2,5 - thiadiazolo [3,4-h] quinoline, BF C20H20H6S , yield 90%, so pl. 293 - 295C, 6-[4-(4 - ethylpiperazine-1) phenylamino] -1,2,5-thiadiazolo [3,4-h] quinoline, BF C21H22N6S , I. pl. 275 - 277C. Compounds produced by interaction of 6-chloro-1,2,5 - thiadiazolo [3,4-h]quinoline with 4-(4 - alkylpiperazine -1) aniline boiling in hydrochloric acid. 3 table.

The invention relates to the first new derivatives of 1,2,5-thiadiazolo[3,4-h] quinoline General formula 1

NNAlK where Alk is methyl or ethyl, with improved anthelminthic activity.

The purpose of the invention is a new heterocyclic compounds with higher anthelminthic activity in experimental larval alveolar echinococcosis (cotton rats) and spontaneous gimenolepidoze white mice.

Research anthelminthic activity of the new compounds of formula 1 are shown in comparison with known drugs mebendazole and fenasalom.

The prototype structure to the claimed compounds avla (U.S. Pat.USSR N 1072809, CL 07 D 513/ 04, publ. 1980, "Rhone Poulenc, Industry").

P R I m e R 1. Obtain 6-[4-(4-methylpiperazine-1(phenylamino]- 1,2,5-thiadiazolo[3,4-h]quinoline (preparation G-1574).

A mixture of 2.8 g (0,0126 mol) 6-chloro-1,2,5-thiazolo[3,4-h]quinoline (obtained as described in CHC, N 1, pp. 61-64, 1976), 2.7 g (of 0.014 mol) of 4-(4-methylpiperazine-1)of aniline, 30 ml of 7% hydrochloric acid is boiled with vigorous stirring to form solution (about 2 hours). The resulting solution is cooled to 20aboutWith, filter and add conc. aqueous ammonia to pH 9. The residue is a yellow filtered off, washed with water and dried. Get 4.3 g )91%) substances with so pl. 293-295aboutC (from DMF).

Found, %: C To 63.8; H 5,5; 23,0 N; S 8,1.

WITH20H20N6S.

Calculated, %: C To 63.8; H 5,4; 22,6 N; S 8,5.

IR-spectrum (device "SPECORD 1R 75, tablets with KBR).

P R I m m e R 2. Obtain 6-[4-(4-ethylpiperazine-1)phenylamino]-1,2,5-thiadiazolo[3,4-h]quinoline (preparation G-1569).

Analogously to example 1, replacing 4-((4-methylpiperazin-1)aniline with equimolar amounts of 4-(4-ethylpiperazine-1)aniline (obtained as described in the author's certificate of the USSR N 1643539; bull. Fig. N 15, 1991) receive the drug G-1569 in the form of yellow crystals with so pl. 275->Calculated,%: C 64,6; H 5,7; 21,5 N; S 8,2.

P R I m e R 3. The study of the acute toxicity Mr. 1569 and Mr. 1574.

Study of acute toxicity of compounds G-1569 and G-1574 conducted on white mice weighing 12-15, Compounds were administered orally as a suspension in a starch paste. Found that animals carry the drug G-1569 dose of 3.15 g/kg, and the drug G-1574 dose 0,63 g/kg, i.e., both compounds have low toxicity.

P R I m e R 4. Study of the efficacy of G-1569 and G-1574 in experimental larval alveolar echinococcosis cotton rats.

In experiments were used in cotton rats of both sexes, infected at the age of 1 month intraperitoneally protocolectomy and cefaloridine larval alveolar Echinococcus (alveoli). The duration of the experimental invasion to the beginning of treatment was 2 weeks, and the original mass developed in the abdominal cavity darvocet alveolate - 0,96+0.28 g (determined according to the autopsy 6 animals). In the first experiment, the drugs were injected into the stomach B1% starch paste 2 times a day in a daily dose of 0.1 g/kg for 12 days in a row (dose rate of 1.2 g kg).

In the second experiment the drugs were injected intraperitoneally in a sterile physiological solution is ka, Belgium) in similar experimental conditions. The dissection of animals in both experiments were performed in 37 days after infection, we determined the presence and mass of the identified darvocet alveoli; Average mass darvocet in treated animals compared with those in rats of the control group. About the effectiveness of the tested compounds was assessed by the index of inhibition of growth darvocet (ITL), which was calculated by the formula

ITRL = (Mto- Mabout/Mto- Mand)100 where Mto, Maboutand Mand- weight darvocet alveoli respectively in control treated animals and the source.

The results of drug trials G-1569 and G-1574, introduced into the stomach infested alveococcosis cotton rats are presented in table.1, which shows that protivokarakurtovaya activity of the tested compounds did not yield any of mebendazole and even slightly exceeded last. Among darvocet alveoli isolated from the abdominal cavity of rats after treatment with drugs G-1569 and G-1574, met the dead (about 25% darvocet from all identified), whereas in rats treated with mebendazole, all servocity were alive.

The results of drug trials G-1569 and G-1574 entered vnutribruchinnom the introduction of the compound was more effective, than when introduced into the stomach. All animals that received these drugs, revealed servicesto discovered the destruction of all germinal elements (protoscoleces and acetalized), indicating that parasite death. The effectiveness of mebendazole was similar. All control animals exposed to the same date as the treatment, all identified servocity contained a lot of live embryonic elements.

The results of comparative trials G-1569, 1574 and mebendazole showed that the effectiveness of drugs G-1569 and G-1574 when larval alveococcosis cotton rats similar and significantly higher than that of mebendazole in equal experimental conditions in the case of the introduction of drugs into the stomach, as evidenced by indicators ITRL and microscopy data content darvocet alveoli in treated animals.

P R I m e R 5. The effectiveness of the drug G-1574 in gimenolepidoze mice.

The effectiveness of the drug G-1574 studied in spontaneous invasion dwarf tapeworm Hymenolepis nana) nonlinear mice. In the experience of animals were used in the feces which prior to treatment by the method of Kato revealed eggs of the tapeworm. The drug was administered to mice in the stomach in 1% cu is the first single effective when gimenolepidoze mice at a dose of 1.0 g/kg The mice were dissected after 3 days after injection and determine the presence and quantity of specimens of parasites in the small intestine of animals. The test results are given in table.3, which shows that the drug G-1574 after a single dose in the stomach in the studied doses caused cure all experimental animals. In only one case in the intestines of the mice received the drug at a dose of 0.2 g/kg revealed one killed but not destroyed juvenile N. nana. The data obtained showed that the drug G-1574 was better fenasala and ensured 100% treated experimental animals at doses which are 2.5-5 times lower than the effective dose fenasala.

Thus, the tests give grounds to conclude that the drugs Mr. 1569 and G-1574 have high antiparasitic activity against larval stages of alveolar Echinococcus and imaginal stages of the dwarf tapeworm. The investigated compounds are more effective than mebendazole and fenasal, currently used for the treatment accordingly larval of hydatid cysts and geminilepidos.

6 [4-(4-Alkylpiperazine-1)phenylamino]-1,2,5-thiadiazolo[3,4-h]quinoline General formula

NNAlk

where Alk is methyl or ethyl,

with the

 

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