Nitroxyl derivatives of 3'-azido-2'3'-dideoxythymidine having antiviral activity

 

(57) Abstract:

The invention relates to new biologically active compounds-nitroxyl derivatives of azidothymidine General formula

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where R1radical containing nitroxyl group >N O, and R2=R1or H, which possess antiviral activity against RNA-containing viruses (human immunodeficiency virus and vesicular stomatitis virus) and DNA-containing virus (CMV). 5 table.

The invention relates to new biologically active compounds-nitroxyl derivatives of azidothymidine (AZT) (3'-azido-2',3'-dideoxythymidine, 1-(3'-azido-2',3'-dideoxy-- pentofuranose)thymine) of General formula (I)

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where R1radical containing nitroxyl group > N O;

R2=R1or H, which possess antiviral activity.

Nitroxyl derivatives of AZT are not described in literature. The closest analogue of the claimed substances is AZT, which is among the well-known modified nucleosides has the greatest activity against human immunodeficiency virus (HIV).

Synthesis of AZT carried out in 1964 r.(J. P. Horwitz, J. Chu, M. Noel, J. Org. Chem. , 1964, 29, 2076-2080), and its activity against HIV in the cult of ticheskih tests showed that AZT prolongs the life of patients with acquired immunodeficiency syndrome (AIDS) (M. J. Jotnston. D. F. Hoth. Science, 1993, 260, 1286-1293). Currently, AZT is the main drug for the treatment of AIDS and prevention of potential patients are infected with HIV.

However, recent studies have shown that AZT causes only a temporary improvement of the patients and 3 years after onset of the disease, no differences in survival of patients treated and not treated with AZT. The inefficiency of this drug with prolonged courses of treatment is associated with development of drug resistance. The use of AZT causes severe side effects. In 50% of patients taking AZT, anemia, caused by suppression of bone marrow hematopoiesis. In addition, AZT causes paralysis of the peripheral endings of the nervous system. AZT weakly affects associated with AIDS virus infection (primarily, the cytomegalovirus (CMV)), which is the main cause of death of AIDS patients.

Another close analogue of the claimed compounds - dihydropyridine ester azidothymidine (1, R1=1,4-dihydro-1-methylpyridin-C-ylcarbonyl, R2=H) was synthesized with the aim of improving drug delivery to the brain. Anti - not reported (P. F. Torrence, J. Kinjo, K. Lesiak, J. Balzarini. E.De Clercq, FEBS Letters, 1988, 234, 135-140).

Also known a few modified nucleosides (oxyanion and its derivatives) with moderate activity against a broad spectrum of viruses, including HIV (AA. Krayevsky, K. A. Watanabe. Modified nucleosides as anti-AIDS drugs: current status and perspectives. - Bioinform, Moscow, 1993, pp. 48, 209). However, information about clinical trials of such drugs in the available literature is not found.

Recently found that nitroxyl radicals significantly reduce the cytopathic activity of the herpes simplex virus HSV-1 as in experiments on cell cultures, and in experiments with animals (Gorbunov N. In. and other bull. exp. Biol., 1992, 113(6), 604-606).

Received evidence that the development of AIDS causes in the body of the patient oxidative stress by reducing levels of natural antioxidants and signs of lipid peroxidation ( W. Droge, H. P. Esk, S. Mihm. lmmunol. Today, 1992, 13, 211-214). Thanks to the introduction of nitroxyl radicals, which have the properties of specific antioxidants, the claimed derivatives (I) unlike these counterparts may have regulatory effects on cellular redox processes, as shown, is honey. chemistry, 1993, 39, 16-20).

The purpose of the invention is the obtaining of new hybrid drugs with a broad spectrum of antiviral activity, acting simultaneously on HIV and related viral infections,

This goal is achieved by the proposed nitroxyl derivatives of AZT General formula (I) have activity against both RNA-containing viruses (HIV and vesicular stomatitis virus (WWC)), and against DNA-containing virus (CMV).

Nitroxyl derivatives of azidothymidine obtained by condensation of azidothymidine, for example, anhydrides nitrosylcobalamin acid (2A, b), and (3).

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The reaction is carried out in an inert solvent, for example acetonitrile, or in the environment of pyridine. As a catalyst and acceptor released hydrogen chloride using pyridine or other tertiary amine.

In the course of the reaction is consistent with the substitution of hydrogen atoms in the 5'-hydroxyl group of the sugar residue and 3-aminogroup thymine on nitroquinazoline group. The selectivity of substitution depends on alleluya activity of acid chlorides nitrosylcobalamin acid (2), (3) and the reaction conditions. Slow addition of equimolar to adnie of azidothymidine on oxygen 5'- hydroxyl group. The substitution of a hydrogen atom of aminogroup on nitroquinazoline group is significantly slower and to obtain dinitroaniline derivatives of azidothymidine necessary excess acid chloride and great response time.

Nitroxyl derivatives of azidothymidine - solid yellow color. They can be in two States, crystalline and amorphous (glassy). The crystalline state has a clear melting point, and amorphous when heated gradually moving into a liquid state. Amorphous and crystalline States also differ in the IR spectra. The IR spectra of the amorphous state is close to the spectra of the solutions.

The structure of the obtained nitroxyl derivatives confirmed by elemental analysis and methods of EPR, IR, UV and mass spectroscopy. EPR spectra of dilute solutions (C10-3mol/l) mononitrosyl derivatives of azidothymidine consist of three lines, characteristic of manordeilo. EPR spectra dinitroaniline derivatives of azidothymidine in addition to the three lines contain additional components, characteristic of nitroxyl diradicals. Mass spectra of nitroxyl derivatives of azidothymidine contain peaks of the molecular ion is P> In the IR spectra of nitroxyl derivatives of azidothymidine there are bands of stretching vibrations of sidegroup about 2100 cm-1and bands of the carbonyl groups tiaminovogo and acyl fragments in the field 1670-1730 cm-1. In the IR spectra mononitrosyl derivatives of azidothymidine there are bands oscillation band of N-H at 3180 cm-1and no bands of hydroxyl groups of about 3460 cm-1. In the spectra dinitroaniline derivatives bars are missing as imino and hydroxyl groups, as they are replaced by nitroquinazoline group.

Electronic spectra of nitroxyl derivatives of azidothymidine due to overlapping absorption bands tiaminovogo and nitrocellulose chromophores. Timinova fragment belong to two intense bands in the UV region withmaxabout 215 and 265 nm. The yellow color obtained in the connection due to a weak absorption nitroxyl group in the field 320-430 nm. The second band nitroxyl groups with a maximum of about 240 nm is blocked stripes tiaminovogo chromophore.

Below are examples of obtaining nitroxyl derivatives of azidothymidine (1A-d), where a - R1=R3, R2=H; b - R1=R2-R3; R1=R4, R,5,5-tetramethyl-1-oxyl-3-pyrrolin-3-ylcarbonyl)-3'-azido-2', 3'-dideoxythymidine (1a). To a solution of 1.34 g (5 mmol) of azidothymidine in 10 ml of pyridine added for 1 h under stirring of 1.02 g (of 5.05 mmol) of the acid chloride of 2.2.5.5-tetramethyl-1-oxyl--pyrrolin-3-icarbonell acid (2A). The reaction mixture is left at room temperature. After 3 hours, add 10 ml of toluene. The precipitation of pyridinylamino filtered off and the solution evaporated in vacuo. To the residue three times, add 10 ml of toluene and evaporated in vacuum. Obtain 2.1 g of solid yellow substance, which is cleaned by chromatography on a column of h mm silica gel 30-40 μm, eluent CHCl3-MeCN (20: 1). Obtain 1.70 g of chromatographic clean (1A) as a vitreous yellow powder. The substance has no definite melting temperature and liquefies when temperature above 70oC.

Found, %: C 52,4; H Of 5.92; N 19,27.

C19H25N6O6.

Calculated, %: C 52,65; H Of 5.81; N 19,39.

M 433,45.

IR-spectrum (in vaseline oil,maxcm-1): 3165 (N-H), 2097 (N3), 1717 (C= O acyl), 1685 (C=O thymine). UV spectrum (EtOH, cm-1(3, l/malism)): 30700 PL (74), 37700 (9600) and 46750 (22560). The EPR spectrum (PhMe, 510-4mol/l, 20oC): line 3, with the ratio of the amplitudes of 100:100:87, andN1,49 UB>14NO3]+(9), 136 [M-297]+(39), 81 [M-352]+(100).

Example 2. Getting 3,5'-O-bis(of 2.2.5.5-tetramethyl-1-oxyl-3- pyrrolin-3-ylcarbonyl)-3'-azido-2', 3'-dideoxythymidine (1B). To a solution of 1.34 g (5.0 mmol) of azidothymidine in 10 ml of pyridine are added during the mixing of 2.40 g (to 11.8 mmol) of the acid chloride of 2.2.5.5-tetramethyl-1-oxyl--pyrrolin-3-icarbonell acid (2A). The reaction mixture is left at room temperature. After 20 h, add 10 ml of toluene, precipitated sludge, pyridinylamino filtered off and the solution evaporated in vacuo. The yellow solid residue chromatographic on column 30 x 200 mm silica gel 30-40 μm. Elute with a mixture of CHCl3-MeCN (20:1). Compound (1B) is the first yellow area, which is translated in the eluate. After evaporation of the eluate obtain 0.6 g (1B) in the form of a yellow powder with no clear melting point and razzhizhayuschiesya with over 70oC.

Found, %: C 56,2; H 6,25; N 16,5.

C28H37N7O8.

Calculated, %: C 56,08; H 6,22; N 16,35.

M 599,65.

IR-spectrum (in vaseline oil,maxcm-1): 2097 (N3), 1740 (C=O acyl), 1718, 1700, 1660 (C=O thymine), 1622 (C=C). UV spectrum (EtOH, , cm-1, (3, l/malism)): 28000 square (107), 38300 PL (11200) and 45150 (35400). Range of EPR (PhMe, 510-SUB>Rel, %): 433 [M-C9H13NO2+1]+(1.4), 403 [M-196]+(1.2), 292 [M 307]+(2.9), 262 [M-337]+(4.7), 184 [C9H14NO3]+(14), 136 [M-463]+(93), 41 [M-558]+(100).

Example 3. Obtaining 5'-O-(4-bromo-of 2.2.5.5-tetramethyl-1-oxyl-3-pyrrolin-Z-ylcarbonyl)-3'-azido-2', 3'-dideoxythymidine (1B). To a solution of 2.67 g (10 mmol) of azidothymidine in 20 ml of pyridine for 1.5 h added at 20oC and stirring 2.85 g (10.1 mmol) of acid chloride of 4-bromo-of 2.2.5.5-tetramethyl-1-oxyl--pyrrolin-3-icarbonell acid 26. The reaction mixture was stirred for further 1 h at 20oC, then add 20 ml of toluene. The precipitation of pyridinylamino filtered off, the filtrate evaporated in vacuum. To remove traces of pyridine remaining orange oil is dissolved in three times with fresh portions of toluene (10ml) and evaporated in vacuo. Finally, the oil is dissolved in 10 ml of acetone and after evaporation in vacuo get 5,0-5,2 g of amorphous solid product, which according to HPLC contains about 4% of the impurities of the original GTA. The substance is purified by chromatography on a column of silica gel, eluent CHCl3-MeCN (9: 1) and crystallization from acetone. From acetone (1B) crystallizes in the presence of a seed in the form of a yellow plate crystals with so pl. 167oC.

M 512,36.

IR-spectrum (in mineral oil , cm-1): 3191 (N-H), 2091 (N3), 1731 (C-C); (CHCl3): 3386 (N-H free), 3181 (N-H related), 2104 290(max290 l/malism) (N3), 1719 (C-O acyl), 1711, 1701, 1691 and 1680 (C=O thymine), 1609 (C=C). UV spectrum (EtOH, , cm-1, (3l/mol cm)):30000 (623), 38200 (1235020), 4190 (1535070) and 47200 (1757070). The EPR spectrum (PhMe, 510-4mol/l, 20oC): line 3, with the ratio of the amplitudes of 100:100:96, andN1,45 MT, g 2,0057. Mass spectrum (ES, 70 eV), m/z (IRel,%): 513 [M]+(2.1), 511 [M]+(2.1), 483 [M-110]+(0.3), 481 [M-110]+(0.4), 264 [C9H13BrNO3(1.1), 262 [C9H13BrNO3]+(0.9), 81 [M-431]+(100).

Example 4. Getting 3,5'-O-bis-(4-bromo-of 2.2.5.5-tetramethyl-1-oxyl--pyrrolin-Z-ylcarbonyl)-3'-azido-2', 3'-dideoxythymidine (1G). To a solution of 1.0 g (3.7 mmol) of azidothymidine in 8 ml of pyridine added over 10 min with stirring, 2.4 g (8.5 mmol) of acid chloride of 4-bromo-of 2.2.5.5-tetramethyl-1-oxyl--pyrrolin-3-icarbonell acid (2B). The reaction mixture is left for 6 h at 20oC, then add 10 ml of toluene. Yellow pyridine-toluene solution is separated from the precipitated resin and evaporated in vacuum. To the residue three times add toluene and evaporated in vacuum. The remaining yellow oil with rubbing with heptane and the reaction product contains biradical (1G) (Rf0,75), MOMORDICA (1B) (Rf0,30) and other impurities. Biradical (1 g) was isolated by chromatography on a column (30 x 250 mm) with silica gel (30-40 μm), eluent CHCl3-MeCN (20:1). After evaporation of the eluates, containing pure (1G), get 460 mg (16%) of the desired product as a yellow amorphous powder. (1G) does not have a clear melting temperature and liquefies when over 80oC

Found, %: C 44,27; H Amounts To 4.76; N 12,85.

C28H35Br2N7O8.

Calculated, %: C 44,40; H 4,46; N 12,94.

M 757,44.

IR spectrum (CHCl3, , cm-1): 2105 (max490 l/malism) (N3), 1739 (C=O acyl), 1705 and 1669 (C=O thymine), 1602 (C=C). UV-spectrum (MeCN, , cm-1,(, l/malism)): 26700 PL(893), 41000 (22800400), 46300 (20400600). The EPR spectrum (PhMe, 510-4mol/l, 20oC): 7 lines with a ratio of amplitudes 100:2:4: 99:3:4:92, andNthe 1.44 MT, g 2,0058. Mass spectrum (ES, 70 eV), m/z (IRel,%): (757 [M]+(2), 513 [M-245]+(27), 371 [M-386]+(79), 264 [C9H13BrNO3]+(26), 262 [C9H13BrNO3]+(24), 153 [M-604]+(100).

Example 5. Obtaining 5'-O-(of 2.2.5.5-tetramethyl-1-oxypyridine-3-ylcarbonyl)-3'-azido-2',3'-dideoxythymidine 1D.

To a solution of 1.34 g (5.0 mmol) of azidothymidine in 10 ml of pyridine added over 5 min with stirring rests-icarbonell acid and 0.36 ml SOCl2. The reaction mixture is left at room temperature. After 1.5 h to it was added 20 ml of water and acidified with diluted HCl to pH 3. The benzene layer is separated and the aqueous phase is then treated with twice extracted with ethyl acetate (15 ml). After evaporation in vacuum benzene-an ethyl acetate solution remains 1.5 g of yellow solid substance consisting mainly of mononitrosyl derived 1D. For purification the product chromatografic on column h mm, filled with silica gel, 30-40 μm. Elute with a mixture of CHCl3-MeCN (9:1). Substance 1D is in the yellow zone, which is translated in the eluate. After evaporation of the solvents to obtain 1.1 g of chromatographic pure 1D as a yellow powder, no clear melting point and gradually razzhizhayuschiesya above 60oC.

Found,%: C Of 52.1; H, 6.42 Per; N 19,2.

C19H27N6O6.

Calculated% C 52,41; H 6,25; N 19,30.

M 435,46.

IR spectrum (CHCl3, , cm-1): 3390 (N-H free), 3182 (N-H related), 2107 (max560 l/malism), (N3), 1740 (C=O acyl), 1685 (C=O thymine). UV-spectrum (MeCN, , cm-1, ( , l/malism)): 23000 (6,5); 37800 (10500) and 47800 (11600). The EPR spectrum (PhMe, 510-4mol/l, 20oC): line 3, with the ratio of the amplitudes of 100:98:91 andN1,41 MT, g 2,0058. M IS UP>+
(30), 81 [M-354]+(100).

Biological testing of the proposed nitroxoline derivatives of azidothymidine. The breadth of the spectrum antiviral activity of drugs is determined by their ability to inhibit both RNA-and DNA-containing viruses.

As RNA-containing viruses used the human immunodeficiency virus (HIV-1) and vesicular stomatitis virus (air force), and as a DNA containing the cytomegalovirus (CMV).

Example 6. Activity nitroxyl derivatives of azidothymidine against human immunodeficiency virus HIV-1. Antiviral activity of the proposed compounds were determined by the inhibitory action of drugs on the development of HIV-1 in cells of the human lymphocyte MT-4 (MPC. Britain). Cells MT-4 suspended in RPMI medium LMO (Rosewell Park Memorial Institute) containing 10% fetal calf serum. A suspension of cells containing 2105cells/ml, were distributed in 24 hole fee of 0.5 ml After a short period of sedimentation of the cells in the bottom wells were made of 0.25 ml of the virus suspension obtained from HIV-infected cells MTHIV (strain obtained in scientific research Institute of epidemiology and Microbiology. H. F. Gamaleya RAMS) with a multiplicity of infection of 100. Then the cells were cultured at 37o

From the obtained measurement results were calculated the proportion of virus-infected cells, which in control experiments was 70%, while in the experiments with the addition of the studied drugs were in the range 0-70%. The dependencies of the protective effect of the drugs on their concentration to find the minimum concentration of drugs EU100that protects 100% of the cells MT-4 from the cytopathic effect of HIV-1. Value EC100are given in table. 1, which shows antiviral activity against HIV-1 of azidothymidine and offer nitroxyl derivatives of AZT.

From these results, it follows that h is and nitroxides groups. We offer nitroxyl derivatives 1A-d antiviral activity is markedly reduced in comparison with azidothymidine, however, in the case of compounds 1A, 1B and 1D, it remains at a sufficiently high for the drug.

Example 7. Determination of the toxicity of nitroxyl derivatives of azidothymidine on diploid cells M-19. Determination of the toxicity of nitroxyl derivatives of AZT were performed on the culture of diploid cells of a human embryo (strain M-19, registered in the International collection of cell cultures of the world health organization). Used a suspension of cells containing 2105cells/ml, which was dispersed in 1 ml in 24-hole Board. Cultural environment the Needle-MEM (from the Institute of poliomyelitis and viral encephalitides RAMP) with 10% bovine serum. Fee thermostatically at 37oC in an atmosphere of air with 5% CO2. After 3 days. at the bottom of the hole was formed layer of fibroblasts. The fibroblasts were added to 1 ml of the drugs in the culture medium with a concentration of 1 mg/ml in 2 days. temperature control Board viewed with a microscope. The presence or absence of toxic effect was determined by the concentration of drug that causes full, and the maximum concentration of drugs not toxic to cells NTD. The results of toxicity derivatives of AZT given in table. 2. The results imply that AZT and its nitroxyl derivatives have comparable toxicity. The least toxic drugs 1A, 1B and 1D.

Example 8. Anticytomegalovirus activity nitroxyl derivatives of azidothymidine. Evaluation of the action of drugs on the CVM conducted in the culture of diploid human cells M-19. Used a standard strain of CMV AD 169, obtained in 1992 from the Institute of hygiene, Warsaw. The titer of virus (titer cytopathic dose TCPD50/ml) was taken back breeding uterine sample, causing the defeat of 50% of the cells M-19, i.e., the number of cytopathic virus doses (JRC50) in 1 ml of the fallopian image. As the culture medium used Wednesday Needle MEME (from the Institute of poliomyelitis and viral encephalitides RAMS) with 10% bovine serum.

Definition anticytomegalovirus activity conducted by two tests: - the effect of drugs on the cytopathic effect of CMV and the effect of drugs on reproduction CMV.

Test A. a Suspension of cells M-19, containing 2105cells/ml, were scattered 0.2 ml in 96-well card and cultivated Edam added environment support (Needle-MEM without serum) 0.1 ml, contains different breeding uterine material CMV (10-1up to 10-8). The first two bands (1 and 2), the fee was left as a control and thereto was added 0.1 ml of medium. In the other lane (3-12) was added to 0.1 ml of medium containing various concentrations (ranging from non-toxic or less) AZT and its derivatives. After 3 days. cultivation was determined in the microscope the presence of cytopathic effect at different dilutions of the virus, i.e., the titer of the cytopathic activity TCP50in control and when exposed to AZT and its nitroxyl derivatives. By the difference between the titres in the control and experience to calculate the index of inhibition (AI) cytomegalovirus. The effects of nitroxyl derivatives of AZT on the cytopathic activity of CMV are given in table. 3. The results imply that anticytomegalovirus activity nitroxyl derivatives of AZT is determined by the structure and number nitroxidergic fragments. So, azidothymidine and nitroxyl derivative 1B, 1C, 1D, taken at the maximum non-toxic doses, have virtually no effect on the cytopathic activity of the CMV. In contrast, compound 1A on the order reduces the activity of this virus. The most effective formula 1G, which lowers AK the Wali in 24 hole card 1 ml in each well and cultured at 37oC in an atmosphere of air with 5% CO2within three days. Then the culture medium was decanted and cells were filled with 0.5 ml medium Needle-MEM with different concentrations of virus (104JRS50/ml, 103JRS50/ml, 102JRS50/ml), to obtain different multiplicity of infection. The latter was calculated from the ratio of the number JRS50104cells M-19. After that in the control well) was added to 0.5 ml of eagle medium, and experienced well) was added to 0.5 ml of this medium containing non-toxic concentrations of the studied drugs. All charges were cultured at 37oC in an atmosphere of air with 5% CO2for three days, then the fee was frozen, thawed, and in each well was determined the titer of the newly formed virus TCPD. According to the difference of CMV titers in control and experience to calculate the index of inhibition (AI).

In table. 4 traced the influence of AZT and its derivatives on the reproduction of the CVM. The results imply that in spite of different multiplicity of infection, resulting in different intensities of infection (see inspection results) all nitroxyl derivatives of AZT have a significant inhibitory effect on the reproduction of CMV. More pronounced protivovirusnym of the proposed nitroxyl derivatives was the preparation 1G, which almost completely blocks the reproduction of CMV regardless of the multiplicity of infection.

Example 9. Activity nitroxyl derivatives of azidothymidine against vesicular stomatitis virus. Assessment of effects on the reproduction of the air force conducted in the culture of diploid cells of a human embryo M-19. Used laboratory model strain air force Indiana Institute of Virology. Ivanovo RAMS. The titer of the virus TCPD50/ml was taken back breeding uterine sample, causing the death of 50% of the cells M-19 and equal to the number of cytopathic doses JRS50virus in a 1 ml sample. To determine the anti-air force active suspension cells M-19, containing 2105cells/ml in medium Needle-MEM with 10% bovine serum, subcultured in 24 hole card 1 ml in each well and cultured at 37oC in an atmosphere of air with 5% CO2within three days. Then the culture medium was decanted and poured in 0.5 ml medium Needle-MEM containing air at a concentration of 103TCPD50/ml. While the multiplicity of infection TCPD50/CL=0,1. Then in the control wells were added to 0.5 ml of eagle medium, and experienced well) was added to 0.5 ml of this medium containing non-toxic concentratie in each well was determined the titer of the newly formed virus. For this same suspension cells M-19 was poured into 96-well card to 0.2 ml in each well were cultured 3 days. at 37oC in an atmosphere of air with 5% CO2and for the grown monolayer was performed titration newly acquired virus by infecting tenfold dilutions. Then the cells were again cultured for 2 days. at 37oC and using an optical microscope in them took into account the presence or absence of cytopathic effect. The last breeding veronicadelgado material that causes the death of 50% of the cells were taken for the titer of the virus. By the difference between the titles of the air force in the control and experience determined the index of inhibition of AI. The results of the study for the two compounds are presented in table. 5, where we tracked the effect of nitroxyl derivatives of AZT on the reproduction of the air force.

The results imply that anti-air force activity depends on the number of nitroxyl groups in the connection. So, migracyjny monoracial 1A 1000 times reduces the yield of infectious virus, and similar in structure to biradical 1B does not affect the reproduction of the air force.

The totality of the results obtained on biological activity is indicative of the broad spectrum of activity nitroxyl derivatives of azidothymidine in relation to what Nisha activity against HIV-1, however, in the case of compounds 1A, 1B and 1D, it remains fairly high for drugs. Unlike AZT, which has a low anti-CMV activity, nitroxyl derivatives 1B and 1G effectively inhibit the reproduction of this DNA-containing virus. Check two nitroxyl derivatives 1A and 1B for anti-air force activity showed that compound 1A effectively inhibits reproduction of the virus. Toxicity nitroxyl derivatives of AZT is comparable to the toxicity of azidothymidine. Due to the promising applications of drugs acting simultaneously on HIV and related viral infections, nitroxyl derivatives of azidothymidine 1A, 1 b and 1 g are promising drugs for the treatment of AIDS patients.

An important advantage of this drugs is their paramagnetism. The electron paramagnetic resonance method, you can determine the localization of paramagnetic drugs in the body at the level of the cell and its organelles and to obtain data on the mechanism of their biological action.

Nitroxyl derivatives of 3'-azido-2',3'-dideoxythymidine General formula

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where R1nitrogen-containing heterocycle having a nitroxyl

 

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FIELD: organic chemistry, pharmaceutical industry.

SUBSTANCE: invention relates to clathrate of azithromycin hydrate with 1,2-propyleneglycol of formula I , wherein m =1-2 and n = 0.20-0.40. Method for production of target compound includes azithromycin dissolution in acetone followed by addition of 1,2-propyleneglycol and water in solution, formed crystal filtering, washing with water and drying. Also disclosed is pharmaceutical composition for microbial infection treatment based on clathrate of formula I.

EFFECT: azithromycin with reduced hygroscopicity and increased storage stability.

7 cl, 7 dwg, 2 tbl, 4 ex

FIELD: organic chemistry, medicine, oncology.

SUBSTANCE: invention relates to new glycosides of indolo[2,3-a]-pyrrolo[3,4-c]carbazol-5,7-diones of the general formula (1)

wherein: -R1 means residue of mono- or disaccharide in pyranose form taken among the group: D-Rib, L-Ara, D-Xyl, D-Gal, D-Glc, D-Lac; -R2 means hydrogen atom, methyl group or residue of mono- or disaccharide; -R3 means hydrogen atom, hydroxyl group, amino-group or formamido-group; each -X1 and -X2 means independently of one another hydrogen atom or bromine atom under condition that they can't mean hydrogen atom simultaneously and under condition also that if R1 means disaccharide residue then R2 differs from hydrogen atom. Prepared derivatives show, in particular, cytotoxic and antitumor activity against melanoma B16 and Ehrlich tumor.

EFFECT: valuable medicinal properties of derivatives.

3 cl, 3 tbl, 2 dwg, 8 ex

FIELD: medicine.

SUBSTANCE: method involves treating hepatitis C virus infection or hepatitis B virus infection by introducing carboxamidine of formula 1 or its pharmaceutically permissible salt at a dose of 0.1-40.0 mg/kg of body mass. Α-interferon is also introduced. Compound of formula 1 is in D-configuration.

EFFECT: enhanced effectiveness of treatment.

7 cl, 5 dwg

FIELD: veterinary science.

SUBSTANCE: as biologically active substances one should apply succinic acid 4-6 mg%, riboxin 4-6 mg%, vitamin B12 0.8-1.0 mcg%, silver 2 x 10-7 M - 2 x 10-9 M; moreover, the mentioned biologically active substances should be applied in balanced soluble form at applying drinking water purified with a filters system: mechanical, ion-exchange, coal and antibacterial Millipore 0.22 μ that contains no foreign admixtures. The present innovation enables to restore hepatic function, normalize urinary pH, restore renal filtration capacity and this, in its turn, enables to prevent renal lithogenesis, restore intestinal microflora, restore animal hairy integument and prolong their active life period.

EFFECT: higher efficiency of normalization.

1 cl, 3 ex

FIELD: organic chemistry, antibiotics, pharmacy.

SUBSTANCE: invention relates to 9a-N-[N'-(phenylsulfonyl)carbamoyl]-derivatives of 9-deoxo-9-dihydro-9a-aza-9a-homoerythromycin A and 5-O-desosaminyl-9-deoxo-9-dihydro-9a-aza-9a-homoerythronolide A that are new semisynthetic macrolide antibiotics relating to class of azalides showing antibacterial effect and describing by the general formula (1):

wherein R1 means hydrogen atom (H), (C1-C4)-alkyl or halogen atom; R means H or cladinosyl radical, and to their pharmaceutically acceptable salts. Also, invention relates to a method for their preparing and a pharmaceutical composition based on thereof.

EFFECT: improved preparing method, valuable medicinal properties of derivatives.

16 cl, 2 tbl, 14 ex

FIELD: medicine.

SUBSTANCE: composition comprises Clindamycin phosphate and water-soluble zinc salt taken in molar proportion of 1.2:1 to 1:2. Arising polymer gel is applicable in local treatment of acne vulgaris and acne rosacea under very low systemic Clindamycin level being retained. Aqueous nature of the drug prevents skin from drying. The drug exerts both immediate and prolonged action allowing its application once a day.

EFFECT: enhanced effectiveness of treatment.

39 cl, 5 dwg, 6 tbl

FIELD: medicine, in particular dry azithromicine mixtures to produce azithromicine pellets by direct pressing.

SUBSTANCE: claimed formulation contains non-dehydrated azithromicine selected from group containing B, D, E, F, G, H, J, M, N, O, P, Q, R forms or mixtures thereof, and at least one pharmaceutically acceptable carrier. Pellet containing non-dehydrated azithromicine mixture and at least one pharmaceutically acceptable carrier, as well as azithromicine pellet obtained by providing of dry mixture containing non-granulated azithromicine A and at least one pharmaceutically acceptable carrier, followed by direct pressing said mixture also are disclosed.

EFFECT: direct pressable azithromicine-containing formulations; azithromicine pellets having acceptable hardness and frangibility.

14 cl, 6 ex, 1 dwg, 6 tbl

FIELD: medicine.

SUBSTANCE: method involves administering pyrimidine nucleotide precursors at a daily dose of 0.05-0.3 g/kg of body weight. The method is applicable under condition that cytotoxic chemotherapy agent does not belong to pyrimidine nucleoside analogs.

EFFECT: enhanced effectiveness in eliminating mitochondrial respiration chain dysfunction.

2 cl

FIELD: pharmaceutical industry.

SUBSTANCE: method for granulation of non-dehydrated azitromicine includes mixing of non-dehydrated azitromicine particles with granulating amount of non-aqueous granulating liquid followed by drying of wet granules to remove non-aqueous granulating liquid. Non-dehydrated azitromicine is selected from group containing from hemi-ethanol solvate of azitromicine monohydrate, hemi-n-propanol solvate of azitromicine monohydrate, azitromicine sesquihydrate, and hemi-isopropanol solvate of azitromicine monohydrate. Also disclosed are pharmaceutical compositions containing granules of non-dehydrated azitromicine and method for treatment of protosoal or bacterial infections in mammalian by administration of said pharmaceutical composition.

EFFECT: granules of non-dehydrated azitromicine with improved quality.

10 cl, 8 tbl, 9 ex

FIELD: medicine.

SUBSTANCE: method involves making patient contact with effective quantity of one or several compounds. Pharmaceutical composition comprises one or several compounds applicable in absence of exogenous antigen for treating or alleviating the cases of infectious, autoimmune diseases and allergy.

EFFECT: enhanced effectiveness of treatment or prophylaxis.

52 cl

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