The orotate n,n'-diaminodiphenylsulfone showing antileprosy and immunotropic activity


(57) Abstract:

The invention relates to new biologically active chemical compounds, derived diaminodiphenylsulfone General formula;

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which is obtained by the interaction equimolecular amounts of diaminodiphenylsulfone and orotovoy acid in water. Allatoxin (LD50in the acute experience of 950 mg/kg). Actively in the experiment against Mycobacterium leprosy, has a pronounced immunomodulating effect and can be used as a treatment for leprosy.

The invention relates to new biologically active chemical compound derived diaminodiphenylsulfone General formula I:

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showing leprosy and immunotropic activity, which can find application in medicine.

Currently the main leprosy drugs are diaminodiphenylsulfone (p,p'-diaminodiphenylsulfone, DDS), demoliton and diazepan (p, p'-(2,4-dioxo-6-pyrimidinyl-5-sulphonamido)-diphenylsulfone, however, they have insufficient activity, in addition DDS has a number of disadvantages: immunosuppressive action, a fast-growing patients resistente>/BR>The aim of the invention is the synthesis of new derivatives diaminodiphenylsulfone less toxic and exhibiting higher leprosy and immunotropic activity and does not have an immunosuppressive effect.

This goal is achieved by the invention orotata p,p'-diaminodiphenylsulfone General formula I, manifesting leprosy and immunotropic activity.

The specified connection is produced by boiling equimolecular amounts of diaminodiphenylsulfone and orotovoy acid in aqueous solution.

The toxicity of this substance was determined in the acute experience in outbred mice of both sexes (weight 18-20 g) by the method of Litchfield and Wilcoxon signed and amounted to 950 mg/kg

The invention is illustrated by the following examples:

Example 1. The orotate p,p'-diaminodiphenylsulfone.

A mixture of 3.12 g (0.02 mol) orotovoy acid and 2.48 g (0.01 mol) of diaminodiphenylsulfone in 250 ml of water is boiled for 3 hours. Filter the hot solution is cooled. Obtain 4.4 g (78%) of white needles with so pl. 293-294oC (from water). Found, From 46.8; H 3,9; S 5,6. C12H14N2O2S C10H6N4O8. Calculated 47,3; H 3,6; S 5,7. IR-spectrum (vaseline) 1105 cm-1, 1140 cm-1, Example 2. The definition of leprosy activity.

Leprosy activity of the compounds was studied by the method of Shepard in mice (female) lines IAS infected with Mycobacterium strain K-1 in the amount of 4000 microbial bodies (op. 1), and mice (F1(CBA C57BI), infected with Mycobacterium leprosy, taken from the patient lepromatous type of leprosy in the amount of 5000 microbial bodies (op.2). Mycobacteria were introduced intraplantar in the ball of the foot mouse. Animals were treated 5-8 months from the date of infection. The drugs were injected 5 times a week in the form of starch suspension (0.5 ml) inside the probe. Leprosy activity orotata was determined in comparison with diaminodiphenylsulfone, deuteronom and dimocifonum. The control group of mice the same lines, infected at the same time the same quantity of the pathogen, were kept in the same conditions with an experienced and got inside through the probe only starch suspension.

After the end of the experiment, all animals were killed and held microscopy counting of Mycobacterium leprosy in each foot mouse in all groups of animals.

The results obtained are presented in table. 1.

The table presents the results of steps minimum is referred as 1, and in 2 experiments was significantly lower than in animals treated with Comparators. Thus, the claimed compound exhibits pronounced Antileprosy effect even at a dose of 25 μg/mouse unlike other drugs, which begin to act in a dose of 50 µg/m Therapeutic index of the compound 1 in the treatment of leprosy is higher than that applied leprosy drugs.

Example 3. Influence orotata p,p'-diaminodiphenylsulfone on the immune response of mice.

Immunotropic activity was determined in comparison with Deuteronomy in mice lines F.1(CBA C57BI). All mice in 7 goals in the group were immunized intraperitoneally 5 106sheep erythrocytes. The above compound 1 was injected once at doses of 25, 50, 100, 500 μg/mouse in 0.5 ml of starch suspension. A control group of mice was given 0.5 ml of starch suspension. On the fifth day after immunization was determined by the number antitelomerase cells (AFC) in the spleens using local hemolysis in gel.

The results of the experiment are presented in table.2.

As can be seen from the table. 2, connection 1 in all studied cases has immunotropic activity, which increases with decreasing dose. In the inquiry or new different from control, as evidenced by the low (600) in comparison with the described connection (1100) therapeutic index.

The tests have shown that this compound has a higher Antileprosy immunotropic activity and, at the same time it can be classified as low-toxic compounds.

The orotate N,N'-diaminodiphenylsulfone General formula

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showing Antileprosy and immunotropic activity.


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SUBSTANCE: invention relates to an intermediate compound, i. e. tert.-butyl-(E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-yl}-(4R,6S)-2,2-dimethyl[1,3]dioxane-4-yl]acetate that can be used in synthesis of compound of the formula (IV)

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wherein each P1 and P2 represents independently (C1-C4)-alkyl or group:

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EFFECT: improved preparing methods.

9 cl, 1 tbl, 8 ex