SU687074A1 - 4-amino-4-diphenylsulfonammonium salt of 6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine possessing antileprotic and anticonvulsive activity - Google Patents

Description

(54) 4-AMINO-4-DIPHENYL SULPHONE-MONIUM SALT

6-METHYL-2,4-DIOXO-1,2,3,4-TETRAHYDROPYRIMIDINE, AND COATING ACTIVITY

OWNER OF THE ANTI-PRODOUS β-diphenylsulfonammonium salt of 6-methyl-2, 4-dirkso-1,2,3,4-tetrahydropyrimidine. Example 3. A mixture of 2.48 g (0.01 mol) of 4,4-diamikodiphenylsulfone 1.26 g (0.01 mol) of 6-methyluracil is heated in an oil bath for 10 minutes, shaken periodically. After cooling, I get crystals 4-amino-4-diphenylsulfonammonium salt of 6-methyluracil (quantitative yield). I In the experiment on male mice weighing 18-22 g and male rats 180200 g, the anticonvulsant and psychotropic properties of 4-amino-4-diphenylsulfonammonium salt of 6-methyl-2, 4-DIOXO-1,2,3,4-tetrahydropyr were studied. midina. The effect of the substance on the effect of convulsive agents, maximum electric shock (50 mA, 0.2 s, 50 Hz for mice and 150 mA, 0.2 s, 50 Hz for rats), corazol 110, mg / kg subcutaneously or 1% solution was studied. intravenously, strychnine (1.4 mg / kg), nicotine (7, mg / kg), arecoline (25 mg / kg), on the activity of the epileptic focus created by the application of penicillin on the sensyemotor cortex of rats (50 units in 0.001 ml a) through an implanted cannula, an EEG recording through, implanted into the cortex and a hippocampus. Comparison was performed with reference anticonvulsant phenobarbital and benzonal. The effect of the drug on the behavior of animals and the effects of interaction with stimulators and blockers of brain mediator structures: phenamine (6 mg / kg), apomorphine (10 mg / kg), L-DOPA (300 mg / kg), arecoline (25 mg / kg), reserpine (2.5 mg / kg). If a positive contra-convulsive effect was found, the average effective doses of ED50 were calculated (according to Litchfield and Wilcoxon, 1949). The drug has been found to have a pronounced anticonvulsant asset. ness. It shows especially clearly in tests with electroconvulsive seizures. In other tests, the drug effectively protects animals from the tonic phase of the seizure. In terms of latitude of therapeutic effect, it significantly exceeds the reference anticonvulsant drugs. The preyrat increases the threshold dose of corazol by 30-60%, and when its animals are administered at a dose of 110-80 mg / kg, the tonic-extensor phase does not develop at all. In the study of penicillin epileptic focus, it turned out that the drug does not prevent the development of the focus, but weakens its activity, reducing the number of attacks and interictal discharges on EEG by 40-60%. In this case, it is inferior to the action of VIS of diazepam and phenobarbital, which, at doses of 3 and 10 mg / kg, respectively, completely suppress the activity of the epileptic focus. The study drug has no effect on hyperkinesis caused by cholinomimetic nicotine and arecoline. In contrast to the anticonvulsant type of phenobarbital, benzonal, the drug does not have a sedative effect on animals, does not cause an incoordination of movements and muscular relaxation. In large doses (45.0-500 mg / kg), it gives a stimulating effect, enhances the motor activity of animals. In doses that exhibit anticonvulsant activity, the drug potentiates the effect of hypnotic drugs, prolongs the stereotepy caused by phenamine, apomorphine, L-DOPA, weakens ptosis and hypothermia caused by reserpine. This brings him closer to the group of activists. Thus, the effect of the proposed drug provides a combination of peculiar anticonvulsant and psychotropic properties, therefore, its use in the clinic for the treatment of patients with epilepsy with effective disorders is promising. Antiviral activity was monitored in mice with infected mycobacteria taken from human leprosy (strain 166). These complexes are tested on 40 mice infected with the mycobacteria of strain 166, isolated from patients, in the groin and stalk subcutaneously. Animals are treated with the 4-amino-4-diphenylsulfonammonium salt of 6-methyl-2,4-dioxo-1, 2,3,4-tetrahydropyrimidine orally, starting on the day of infection. In each series of 20 mice. As a control, take two groups of mice, 20 mice each, infected simultaneously with experienced mice with the same strain of mycobacteria, the same dose subcutaneously in the foot and in the groin. Control mice were kept under the same conditions as experienced mice, but did not receive any drugs. In the control group of animals infected in the groin, by the end of the third month of infection, subcutaneous lepromas measuring 0.5 X 1 cm were formed at the site of inoculation, animals infected subcutaneously in the foot, erythematous skin and swelling appeared. Bacterioscopic examination of the organs of animals in both control groups revealed an enormous number of mycobacteria. In the animal group that received the study drug, the development of lepromas and paw damage were not observed in one case. Bacterioscopic examination of tissue from sites of inoculation in some fields of view has isolated mycobacteria, which are apparently remnants of inoculated material. The results of the experiments showed that the 4-amino-4-diphenylsulfonammonium salt of 6-methyl-2,4-dioxo-1,2,3,4 tetrahydropyrimidine completely retards the reproduction of the introduced mycobacteria and the development of the clinical and bacterioscopic manifestations of the infectious process in humans. The obtained data allows recommending it for clinical trial. Acute toxicity is determined on white male myad weighing 18–20 g and on anesthetized cats when the drug is administered orally (by probe into the stomach) in the form of 10 and 20% aqueous suspension.

Toxicity of 4-amino-4-diphenylsulfonammonium salt of 6-methyl-2,4-DIOXO-1,2,3,4-tetrahydropyrimidine and DCS when administered orally to white mice. The preparation is administered to mice in doses of 500j 1000, 2000, 3000, 4000, 5000 mg / kg. Each dose was tested on 10 animals, the observation was carried out for 5 days. It was found that after 20-25 minutes after the administration of the drug, a mild, gradually intensifying agitation was observed in all animals, after 90-120 minutes the mice began to sweep the cage from side to side, jump on the hind legs, coordination of movements was disturbed, the animals were excited and the next day; on the third day, the animals gradually calm down. The results of studies of acute toxicity of drugs in mice are given in table. 1 (calculated according to Litchfield and Wilcoxon). Table 1

With a single dose inside the non-narcotized cat and the drug dose of 100 mg / kg, there is no visible change. the behavior and general condition of the animals is not observed. At a dose of 500 mg / kg of salt 30, 60, 90 minutes after administration, vomiting and mild anxiety are observed, then stereotypes develop in animals, which is also observed the next day after the administration of the drug; on the 3rd day, the stereotype gradually fades, on the 4th day, the condition of the animals is normalized. For white rats of both sexes weighing 160-180 g, the drug is administered orally (probes 1 into the stomach) as a water suspension for 3 months daily (except Saturday and Sunday) at the rate of 400 and 800 mg / kg and 150 and 300 mg / kg DCC (respectively 1/4 and 1/2 LD50 for mice). Each dose is examined in 20 animals (10 males and 10 females); 20 rats (10 males and 10 females) were left as control animals. During the experiment, we observe the weight, general state and behavior of animals, the pattern of peripheral blood (hemoglobin, red blood cells, leukocytes). Observations showed that the salt under study at a dose of 4–30 mg / kg did not cause significant changes in the behavior and general condition of the animals over the whole experiment. From a large dose (800 mg / kg) in rats

cyanosis of mucous membranes and skin of the paws. On the 3rd-3rd day of the introduction, one female fell, on the 4th day another 3 females fell, after the 8th and 9th day of the drug administration, 5 males fell, at autopsy they found a sharp increase in the adrenal glands and cachexia. On the effect of the studied

Effect of salt and DCC on the peripheral blood picture. As can be seen from the table. 2 animals, the salt received at a dose of 500 mg / kg, according to the weight gain, is not significantly different from the controls. The weight of the control animals differs from the weight gain of the rats, who received DCC in doses of 150 and 300 mg / kg. These animals lag behind the control more than 3 times. The pattern of peripheral blood with the administration of drugs did not change significantly only in females treated with DCS: there is a slight tendency to hypochromic anemia.

On the 12th day of the drug administration, the animals of this group became more mobile, their condition gradually improved, and further their behavior did not differ significantly from the behavior of 5 control animals (see Tables 2 and 3).

Table 2 salt and DCC on the weight gain of rats.

Table After the end of the administration of the preparations, the animals were scored by decapitation, part immediately, part after 2 weeks. Microscopic examination of rats treated orally with a salt of 800 mg / kg and diaminodiphenylsulfone at a dose of 300 mg / kg for three months did not reveal any changes. Microscopic examination of sections of the brain, pituitary, lungs, heart, kidneys, stomach, selenion, bone moeg., Gonads, adrenal glands stained with hematoxylin-eosin, pathological changes were not found. In the liver of animals of both groups, dystrophic changes are most pronounced in animals treated with diaminodiphenylsulfone.

Thus, the tests carried out show that 4-amino-4-diphenylsulfonammonium salt —b-methyl-2, 4-DIOXO-1,2,3,4-tetrahydrspirimidine is significantly (5–7 times) less toxic than diaminodiphenylsulfone at chronic administration in equitoxic doses, toxic compounds (weight loss and pathological changes in the liver) are more pronounced in animals treated with DCS.

Claims (2)

Claims. 4-AMINO-4-diphenylsulfonammonium salt of 6-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine:. It possesses excellent acne and anticonvulsant activity. Sources of information taken into account in the examination 1, Mashkovsky MD Medicines. M., Medicine, 1977, Part 2, p. 277. 2. Nesmenov A.N. and N. Nesmenov, Beginning of Organic Chemistry. M., Himn, 1970, p. 84.