Bis[2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidin-3-(5 - methyl-3 - tyuhexjl)-s]cis-dichloroplatinum showing immunotropic activity

 

(57) Abstract:

Usage: in medicine as a drug exhibiting immunotropic activity. The inventive PtCl with bis-[1(3)-isobutylthiazole-6-methyluracil] -CIS-configuration C22H36N4G2the output of 1.62 g (90%). Reagent 1: an aqueous solution of K2PtCl4. Reagent 2: acetone solution of 1(3)-isobutylthiazole-6-methyluracil. Conditions makes reactions: under stirring for 3 hours 3 table.

The invention relates to the field of organic chemistry, specifically to new chemical compound complex bis- [1(3)-isobutylthiazole-6-methyluracil] PtCl2formula

(X 989) showing immunotropic activity.

Similar in structure and purpose is a 6-methyluracil, synthesis and properties of which are described in the literature [1]

6-Methyluracil is obtained by mixing urea, acetoacetic ester, ethyl alcohol and concentrated hydrochloric acid, followed by separation-enaminoketones ester, which is treated with caustic soda solution, boiled for 2-3 h at 95aboutC, cooled and acidified with hydrochloric acid at 65aboutC, the precipitated crystals upon cooling is filtered off. The total yield of 6-methyluracil equal 50-55% [1]

The aim of the invention is the expansion of means of influence on a living organism characterized by pronounced immunotropic activity and development of method of obtaining.

This goal is achieved by the synthesis of new complex PtCl2with bis-[1(3)-isobutylthiazole-6-methyluracil] registration certificate Number 9991390 from 05.10.90. The method of producing complex lies in the interaction of K2PtCl4in aqueous acetone medium containing 1(3)-isobutylthiazole-6-methyluracil for 3 h at room temperature at a molar ratio of 1.2:2,0.

Investigations were carried out on outbred mice weighing 15,0-17,0 g, obtained from the nursery of laboratory animals "Rapolano of medical Sciences of the USSR.

Acute toxicity was determined on outbred mice of both sexes in a single intraperitoneal injection. Was administered a dose of from 5 to 1600 mg/kg After administration of toxic doses after 5-10 min the animals were observed depression, stretching limbs, reduced mobility. Death from respiratory arrest.

The toxicity parameters were determined by the method of Cerberus. Intraperitoneal injection LD50the connection was 400,036,2 mg/kg

On sitsa to low-toxic. The effect of compound X-989 on the immune system was studied on the model of delayed-type hypersensitivity (GST) and the antibody productions.

The delayed-type hypersensitivity to 2,4-dinitrofluorobenzene (DNFB) reproduced sensitization animal by applying to the skin of the abdomen 25 μl of a 0.5% aqueous solution DNFB in a mixture of acetone and olive oil (4:1). After 5 days after sensitization on previously measured with a micrometer ears was dropping 20 μl of 0.25% solution DNFB. The reaction was assessed by the increase in the thickness of the ears 24 h after application of the resolving dose DNFB. The compound was administered at a dose of 40 mg/kg (1/10 LD50within 4 days, starting from the first day after sensitization.

The influence of the connection and methyluracil reaction GST in mice is given in table. 1.

Thus, the thickness increase of the ears in the experimental group is significantly lower (P 0,006) than in the control, which suggests the presence of complex PtCl2with bis-[1(3)-isobutylthiazole-6-methyluracil] pronounced suppressive effect on cellular immunity, in contrast to structural analogue methyluracil, which significantly stimulates the reaction GST to DNFB.

The effect of compound X-989 on the formation of AFC in the spleen is the duty to regulate the formation of the KLA, without affecting the weight of the spleen, but increasing the number of splenocytes.

P R I m e R 1. In a flat-bottomed flask with a capacity of 50 ml asleep 1 g K2PtCl4, poured 10 ml of water, stirred until dissolved, and added dropwise with stirring on a magnetic stirrer 1,167 g (0,0048 mol) 1(3)-isobutylthiazole-6-methyluracil in 10 ml of acetone. The resulting reaction mixture is stirred for 3 h, the acetone is distilled off by evaporator IL-1M in water-jet vacuum pump, drained the water by decantation with fallen complex in water light yellow color in the form of ointments, washed with water to remove salts and extracted with chloroform, the chloroform is distilled off on a rotary evaporator IL-1M in water-jet vacuum pump and get 1,622 (90%) of the complex PtCl2c bis-[1(3)-isobutylthiazole-6-methyluracil]-CIS-configuration, soluble in acetone, chloroform.

Found, C 33,50; H 4,50; N 6,29; S 8,50; Cl 10, 0mm; Pt 25,7.

Calculated for C22H36N4O4S2With 35,20; H A 4.83; N 7,46; Cl 9,45; S 8,54; Pt 25,99; O 8,53.

IR spectrum (cm-1): 332,318 (stretching vibrations PtCl2), 307 (cur. rings, Pt-S).

Immunotropic activity of the compounds is illustrated by the following examples.

P R I m m e R 2. As a model cell GST reproduced in a known manner, sensibiliser mice applying mow the stomach 25 μl of a 0.5% aqueous solution of 2,4-dinitrofluorobenzene (DNFB) in a mixture of acetone and olive oil (4:1). The resolving dose (20 μl of a 0.25% solution DNFB) inflicted on the 4th day after sensitization on the ears with a pre-measured thickness. Compounds were administered intraperitoneally at a dose of 1/10 LD50with +1 to +4 day. Only 4 of the introduction. Structural analog of compound 6-methyluracil, taken as the standard, was introduced in the conventional dose (200 mg/kg) according to the same scheme.

P R I m e R 3. The effect of compounds on humoral immune response was determined by the method of N. K. Jerne, A. A. Nordin [2] in the modification A. Cunningham [3] Mice were immunized by intraperitoneal introduction norimono dose sheep red blood cells for 4 full days to experience. Suspension of sheep erythrocytes and complement the Guinea pig in the ratio of 1:1:2 was filled chamber. After incubation in a thermostat at a temperature of 37aboutC for 1.5 h was estimated visually the number of zones of hemolysis, corresponding to the amount of antibody productive cells (AFC). Have re-AOK 106the splenocytes. The compound was administered at +1 +4 days after immunization dose of 1/10 LD50, methyluracil at a dose of 200 mg/kg according to the same scheme.

The connection is the first number of splenocytes.

P R I m e R 4. Acute toxicity of complex PtCl2bis-1(3)-isobutylthiazole-6-methyluracil was determined on outbred mice of both sexes weighing 18-20 g at single intraperitoneal injection. Was administered a dose of from 50 to 1600 mg/kg After administration of toxic doses after 5-10 min the animals were observed depression, stretching limbs, reduced mobility. Death from respiratory arrest.

Elemental analysis of the target product is made again after drying in vacuum at 70aboutC.

Found, C 35,00; H Of 4.45; N 7,31; S 8,50; Cl 9,60; Pt 25,78.

Calculated for C22H36N4O4S2PtCl2C 35,20; H a 4.83; N 7,46; Cl 9,45; S 8,54; Pt 25,99; O 8,53; M. M. 750,6692, So pl. 204-205aboutC.

To establish the position of Deputy 1(3)-isobutylthiazole-6-methyluracil the study of the UV-spectrum at pH 1-12. pH 1min231,65max262,50 pH 7min231,85max262,50 pH 12min245,65max281,15

It is established that the maximum absorption of UV spectra with change in pH from 1 to 12 gives a bathochromic shift on 18,65.

The toxicity parameters were determined by the method of Cerberus. Intraperitoneal injection LD50the connection was 400,0 and 36.2 mg/kg based On the classification of the current of the ptx2">

Thus, low-toxic compound complex PtCl2bis-[1(3)-isobutylthiazole-6-methyluracil] characterized by pronounced immunotropic activity, suppressing cellular immunity and stimulating antitelomerase, which is typical for orallow, replaced by the third atom of the nitrogen cycle.

Therefore, the Deputy must be in the 3rd position, and to be called 3-isobutylthiazole-6-methyluracil or 2,4-dioxo-3-(5-methyl-3-tyuhexjl)-6-methyl-1,2,3,4-tetrahydropyrimidin.

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Since the complex PtCl2with the specified ligand is formed by communication with gray, the complex of the CIS-PtCl22L will be called by the Geneva nomenclature bis-[2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidin-3-(5-methyl-3 - tyuhexjl)-S] -CIS-dichloroethene or bis-[1-(2,6-dioxo-4-methyl - 1,2,3,6-tetrahydropyrimidin-1-yl)-5-methyl-3-tyuhexjl-S] CIS-dichloroethene.

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The structure of the target product is installed using IR, PMR-spectra, and also by analogy with known structural product.

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Known received complex compounds of Pt (II) and Pd (II) with 5-aminouracil and its methyl derivatives with monodentate coordination of the ligands only through the nitrogen atom ekzoticheskoy amino N3-platinum pyrimidine-2,4-dione and the second ligand through ekzoticeski oxygen atom CIS-Pt(NH3)2(1 MeU)2and CIS-Pt(NH3)2(1 MeT)2< / BR>
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Known series dual core complexes (X2)PtL2M(Y2Z n H2O L-1-metilurazilom (1-MeU, C5H5N2O2) or 1-methyl - diminnie (1-MeT, C6H7N2O2) link Pt N3position and a second metal via ON4position

X2and Y2(NH3)2, Ethylenediamine, EN; 2,2-bipyridine

P ZnH2O complexes are characterized by elemental analysis, spectroscopic methods.

In our case, the complex PtCl2formed through the connection with the grey

The IR spectrum of the complex there are two very strong bands in the region 318, 332 cm-1related to the stretching vibrations due PtCl and clearly indicate the formation of coordination compounds of the type CIS-PtCl22L (L monodentate ligand). Absorption bands in the region 305-310 cm-1belong to the stretching vibrations of communication Pt-S. absorption Bands in the region 3130 cm-1characteristic of stretching vibrations of (N-1)H absorption bands in the region 1660, 1720 characteristic ring of uracil (C2=02g), and 1.6 (m, 1H2); 2,046 (s, 3H3or6-CH3) 2,32 (m, 2Hin); of 2.58 (m, 2Hb), 3,88 (m, 2Hand), 5,475 (s, 1Hand), 10,729 (s, 1Hto).

The PMR spectrum of the complex bis-(3-isobutylether)-6-methyluracil-3) CIS-dichloroplatinum

the 1.04 (d, J 6,5, N4D); 2,08 (m 2N2G); to 2.18 (s, 6N, 2C6CH3); a 3.01 (m, 4H2B); or 3.28 (m, 4H2B), 4,36 (m, 4H2A); to 5.66 (s, 2H2); 10,45 (s, 2H2K).

That the complexation is carried out by forming a coordination Pt-S, shows an NMR spectrum1N. complex, in which, compared with the spectrum of the ligand, the greatest additional chemical shift is available for the signals of the protons of methylene groups at the sulfur atom in the region of weak fields (0,7 M. D.)

CH-SCH2_N

Studied immunotropic properties of the complex bis-[2,4-dioxo-3-(5-methyl-3-tyuhexjl)-6-methyl-1,2,3,4-tetrahydropyrimidin - S] CIS-dichloroplatinum dis PtCl2L2.

To study the biological activity of the complex as analogue was taken 6-methyluracil, as he has expressed immunotropic activity.

It is established that the complex CIS-PtClL2has a strong suppressive effect on cellular immunity is relevant effect on cellular immunity (on the model GST), conducted a series of experiments in comparison with hydrocortisone, which has immunosuppressant properties.

The reaction GST reproduced in the usual way, sensibiliser mice applying mow the stomach 25 μl of a 0.5% aqueous solution of 2,4-dinitrofluorobenzene (DNFB) in a mixture of acetone and olive oil (4:1). After 5 days after sensitization on previously measured with a micrometer ears was dropping 20 μl of 0.25% solution DNFB. The reaction was assessed by the increase in the thickness of the ears 24 h after application of the resolving dose DNFB. The compound was administered at a dose of 40 mg/kg (1/10 L50within 4 days, starting from the first day after sensitization.

The connections and influence of hydrocortisone on the reaction GST in mice is given in table. 3.

Structural analogue of hydrocortisone, taken as the standard, was introduced in the conventional dose of 50 mg/kg on a known schema.

Thus, the compound X-989 has a strong suppressive effect on cellular immunity (on the model GST), and its action is analogous) suppressive properties known immunosuppressant hydrocortisone.

The investigated compound X-989 may find practical application as a stimulator humoral immune si is ST.

Bis[2,4 dioxo-6-methyl-1,2,3,4 tetrahydropyrimidin-3 (5-methyl - 3 - tyuhexjl)-S Cys dichloroplatinum formula

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showing immunotropic activity.

 

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