2-cycloalkylimino-5-(4-nitrophenyl)-1,3,4-thiadiazines possessing biological activity against smallpox virus

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to novel 2-cycloalkylimino-5-(4-nitrophenyl)-1,3,4-thiadiazines of the general formula (I): wherein the group represents: piperidino-, pyrrolidino-, methylpiperazino-, hexamethyleneimino-group that possess the biological activity against smallpox virus. Invention provides preparing novel biological active compounds possessing an antiviral effect, in particular, against smallpox virus.

EFFECT: valuable biological and medicinal properties of compounds.

1 cl, 1 tbl, 4 ex

 

The invention relates to the field of biologically active compounds concerns the development of new derivatives of 1,3,4-thiadiazines, and is intended for the treatment and prevention of diseases caused by pathogenic for human and animal viruses and virus osamaksena (treatment of post-vaccination complications).

The problem of development of antiviral drugs is valid for the entire period of existence of mankind. Among viral infections are the causative agents of especially dangerous viral infections, as the variola virus that causes severe disease in humans with a mortality of up to 60%. The most effective way to prevent smallpox is vaccination with the use of vaccinia virus, however, mass vaccination may cause a significant amount of post-vaccination complications. In addition, the nature of the smallpox virus exists in cows, which is able to cause disease in humans. In Equatorial Africa in recent years, there are Monkeypox outbreak with mortality up to 10-20%. Thus, you must have highly effective antiviral drugs that would be possessed high activity, moderate toxicity and prolonged activity against pox viruses pathogenic for humans and animals.

Viruses are Nutrilite the major parasites, which have no independent metabolism and can multiply only in living cells of the body. As the processes of viral replication are closely associated with the metabolism of the cells of the body, we can understand how difficult it is to create medicines, providing selective antiviral effect.

The course of action of antiviral drugs may be different and relate to different stages of the interaction of the virus with the cell.

These drugs mainly act as follows:

- inhibit the adsorption of the virus on the cell or its penetration into the cell, and the process of release of the viral genome;

- inhibit the synthesis of early viral proteins-enzymes (guanidine);

- inhibit the synthesis of nucleic acids (idoxuridine - inhibitor of DNA synthesis, actinomycin D, an inhibitor of RNA synthesis);

- inhibit Assembly of virions by inhibiting the synthesis of viral structural proteins;

- increase the resistance of cells to the virus (interferons).

One of the mechanisms of action of previously known 2-cyclooctylamino-5-aryl-1,3,4-thiadiazines is associating them with the active groups of the macromolecules substrates receptors [2]. These compounds, found a rare combination of serotonin-, adrenergic and holinoblokirutm properties. Such extensive blockade of receptor cells suggests as the most probable in the second direction of action for alleged drugs - inhibition of viral penetration into the cell.

Prior art

In the pharmaceutical market at present, virtually no drugs, active against viruses group smallpox; in this regard, the development of such substances can be an important step in pharmacological safety of people's lives.

Existing drug methisazone (Marboran®) has only a preventive but not curative activity against variola virus. The drug cidofovir (Vistide®) is currently under investigation as a preventive or therapeutic drug, but his research is not finished.

In a series of 2-cyclooctylamino-5-aryl-1,3,4-thiadiazine, belong to declare new connection, the relationship "structure - property" very sensitive: there are a number of their derivatives, with small differences in the structure of other substituents in the phenyl ring and various cyclooctylamine in position-2 1,3,4-thiadiazines rings, which have cardiovascular and reduce the metabolism of animals activity [1]. Known also evidence of biological activity, similar in structure to the claimed patent compounds: 2-morpholino-5-phenyl-1,3,4-thiadiazin, hydrochloride and even more close - 2-pyrrolidino-5-(4-chlorophenyl)-1,3,4-thiadiazin, hydrobromide, which have a neuro whom sauropol activity [2]:

This compound differs in structure from the claimed fact that as a substituent in the phenyl ring contains chlorine and not the nitrogroup. All the above compounds do not possess antiviral activity and antiviral activity against pox viruses pathogenic for humans and animals.

Disclosure of inventions

The technical result of the invention is to find new chemical compounds - derivatives of 1,3,4-thiadiazine having antiviral activity, in particular against pox viruses pathogenic for humans.

This technical result is achieved by the fact that according to the invention proposed new 2-cyclooctylamino-5-(4-nitrophenyl)-1,3,4-thiadiazine possess biological activity against poxviruses and having the General formula 1.

wherepiperidino; pyrrolidino; methylpiperazine; hexamethylenimine.

Examples of the synthesis and physico-chemical characteristics of the claimed compounds

All connections obtained with a yield of 60-80% by condensation α-bromo-4-nitroacetophenone with the corresponding 4,4-cycloalkylcarbonyl [3], flowing smoothly when heated in ethanol. The structure of compounds proven spectral data1N THE MP. The purity of the compounds is confirmed by elemental analysis.

Example 1.

2-Piperidino-5-(4-nitrophenyl)-1,3,4-thiadiazin, hydrobromide (1).

Compound 1 obtained by heating on a water bath for 20 minutes in 50 ml of absolute ethanol 2.5 g (0.01 mol) α-bromo-4-nitroacetophenone with 1.6 g (0.01 mol) 4,4-pentamethylenetetrazol and 1.4 ml of concentrated HBr.

The mixture is cooled with ice to obtain a yellow precipitate. The product is crystallized from ethanol with the addition of a few drops of HBr (conc.). Yield 68%.

TPL 214-215°C. Found, %: 44.1; H 4.7; N, 14.3. With14H17BrN4O2S. Calculated, %: 43.8; N, 4.4; N, 14.5.1H NMR in DMSO-d6that δ, ppm: 1.5-1.8 [6N, m, (CH2)3, piperidino]; 3.6-3.8 [4H, m, N(CH2)2, piperidino]; 3.27 (2H, s, CH2S); 8.1, 8.3 (4H, dd,6H4).

Example 2

2-Pyrrolidino-5-(4-nitrophenyl)-1,3,4-thiadiazin, hydrobromide (2).

Compound 2 is obtained similarly 1 heating 2.5 g (0.01 mol) α-bromo-4-nitroacetophenone with 1.45 g (0.01 mol) 4,4-tetraethylorthosilicate.

Yield 54%. TPL 211-212°Found, %: 41.7; N, 4.0; N, 5.3. C13H15BrN4O2S. Calculated, %: 42.05; N, 4.07; N, 15.1.1H NMR in DMSO-d6that δ, ppm: 2,1 [4H, m, (CH2)2, pyrrolidino]; 3.7 [4H, m, N(CH2)2, pyrrolidino]; of 4.45 (2H, s, CH2S); 7.7, 7.8 (4H, dd,6H4).

Example 3

2-(N-methylpiperazine)-5-(4-nitrophenyl)-1,3,4-ideasin, dihydrobromide (3).

Compound 3 obtained similarly 1 heating 2.5 g (0.01 mol) α-bromo-4-nitroacetophenone with 1.74 g (0.01 mol) of N-methylpiperazine thiocarbanilide acid. Yield 82%. TPL p.223-224°C. Found, %: 34.5; N, 4.2; N, 14.3. C14H19Br2N5O2S. Calculated, %: 34.7; N, 4.0; N, 14.5.1H NMR in DMSO-d6that δ, ppm: 3,6 [8 H, m, methylpiperazine]; 4,4 (2H, s, CH2S); 7.4, 7.8 (4H, dd,6H4).

Example 4

2 Hexamethyleneimino-5-(4-nitrophenyl)-1,3,4-thiadiazin, hydrobromide (4).

Compound 4 is obtained analogously to 1 by heating 2.5 g (0.01 mol) α-bromo-4-nitroacetophenone with 1.73 g (0.01 mol) 4,4-hexamethylenebiguanide. A yield of 75%. TPL 220-221°C. Found, %: C 45,3; N Is 4.9; N 13,8. C15H19BrN4O2S. Calculated, %: 45,1; N 4,8; N 14,0.1H NMR in DMSO-d6that δ, ppm: 1.7-1.9 [8H, m, (CH2)4hexamethylenimine]; 3.95 [4H, m, N(CH2)2hexamethylenimine]; 4,5 (2H, s, CH2S); 8.2, 8.4 (4H, dd,6H4).

The antiviral activity of the claimed compounds

Evaluation of the antiviral action of the claimed compounds 1-4 were conducted at the State research center of Virology and biotechnology "Vector". For the evaluation used the following method.

The culture of Vero cells or MK-2 were grown in the wells of flat-bottomed 96-well plates. In culture medium were added in serial dilution is issleduemykh compounds and the corresponding virus. After incubation for 3-5 days monolayer cells were progressively the vital dye neutral red, after removal of the dye and washing his surplus contributed lyse solution and the amount of dye included in the monolayer of cells was taken into account on the spectrophotometer at a wavelength of 490 nm. As controls were used wells, in which the virus did not (the control cell culture). This methodology is based on the ability of test compounds to prevent the reproduction of the virus and its spread from cell to cell, and therefore the cells do not die and retain the ability to englobe neutral red.

As the study of viruses used the virus VV - ospowiki (strain LIPV)used for vaccination, CPV - smallpox cows (strain, Grisak), MPV - Monkeypox virus (strain Zair 599). In addition to orthopoxviruses pathogenic for humans to assess antiviral activity used virus ectromelia virus of mice (strain MC-2).

The results of the study of the antiviral activities of the compounds are given in the table.

High performance index (IS=1527,8) was determined for compound 1: 2-piperidino-5-(4-nitrophenyl)-1,3,4-thiadiazine, hydrobromide as viruses osamaksena and viruses smallpox of the cow.

For compound 2: 2-pyrrolidino-5-(4-nitrophenyl)-1,3,4-thiadiazine, hydrobro the IDA high performance index (IS=814,3) was found only on viruses ospowiki, and the connection 3-2-methylpiperazine-5-(4-nitrophenyl)-1,3,4-thiadiazine, hydrobromide antiviral efficacy (IS=413.5) was found only on the viruses of smallpox mice. Compound 4: 2-cyclohexylethylamine-5-(4-nitrophenyl)-1,3,4-thiadiazin, hydrobromide was toxic, but showed high activity on viruses ospowiki (IC50=of 0.182 mg/ml).

Industrial applicability.

These compounds may be used as a potential pharmacologically active substances for the production of drugs, which allows to treat smallpox or postvaccinal complications after vaccination with the use of vaccinia virus in humans and animals. The invention can be used in medicine and veterinary, medical institutions, research laboratories.

Sources of scientific and technical information

1. O.N. Chupakhin, L.P. Sidorova and other PCT Patent of Russian Federation №2157210 (2000).

2. IF Lavretsky, O.N. Chupakhin, L.P. Sidorova and others, ed. mon. No. 1475126 (1988).

3. VIA Cossacks, IA Postovsky, DAN SSSR, V. 4, s-827 (1960).

2 Cyclooctylamino-5-(4-nitrophenyl)-1,3,4-thiadiazine possess biological activity against poxviruses and having the General formula

wherepiperidino; piroli the Ino; methylpiperazine; hexamethylenimine.



 

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29 cl, 12 tbl, 587 ex

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3 cl, 1 dwg, 2 tbl, 1 sch, 8 ex

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4 cl, 2 tbl, 7 dwg, 33 ex

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EFFECT: valuable medicinal properties of compounds.

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10 cl, 1 tbl, 173 ex

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26 cl, 2 tbl, 253 ex

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EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 5 tbl, 8 ex

The invention relates to arylalkylamines formula (I)

< / BR>
where R1and R2each, independently of one another, denotes H or A;

R3and R4each independently of one another, denotes-OH, -OR10, -S-R10, -SO-R10, -SO2-R10, Gal, methylendioxy-group-NO2- NH2, HHR10or-NR10R11;

R5denotes unsubstituted or mono - or twice substituted with R6and/or R7phenyl residue;

Q is absent or denotes alkylene with 1-6 C-atoms;

R6and R7each, independently of one another, denotes-NH2, -NR8R9-THE OTHER10, -NR10R11, -NO2, Gal, -CN, -OA, -COOH or COOA;

R8and R9each, independently of one another, denotes H; acyl with 1 to 8 C-atoms which may be substituted by 1 to 5 fluorine atoms and/or chlorine; -COOA, -S,-A, -SO-A, -SO2A, -CONH2, -CONHA, -CONA2, -CO-COOH, -CO-COOA, -CO-CONH2, -CO-CONHA or-CO-CONA2;

A denotes alkyl with 1-6 C-atoms which may be substituted by 1 to 5 fluorine atoms and/or chlorine;

R10and R11each, independently of one another, denotes a, cycloalkyl with 3-7 C-atoms, methylanrylate logicheskie acceptable salts

The invention relates to a method for the preparation of 3-isopropyl(1H)benzo-2,1,3-thiadiazine-4-dioxide-2,2 used in agriculture as a herbicide to control weeds in crops of cereals, soybeans, corn, rice and other crops

FIELD: medicine, in particular surgery, oncology.

SUBSTANCE: claimed method includes immunotherapy, namely on day before operation reaferonum-EC-lipint in dose of 1000-15000 U/kg is perorally administrated to patient. Then in postoperative period blood sampling, extracorporal incubation of leucocytes with imunofan, and intravenous drop administration are carried out. Further for 5 days after operation reaferonum-EC-lipint is perorally administrated to patient dose of 1000-15000 U/kg one time per day. Method of present invention may be used in treatment of patients after radiotherapy in postoperative period. Furthermore method makes it possible to decrease of therapy time by 1.6 times, to reduce total accident number by 2.3 times and decrease of mortality by 2 times.

EFFECT: improved method for rectal cancer treatment.

3 ex, 1 tbl

FIELD: medicine, in particular agent for treatment of hepatitis, toxoplasmosis, cytomegaloviral infection and influenza.

SUBSTANCE: claimed agent contains physiological saline for intravenous administration, comprising hydrogen peroxide, 0.2 % riboxine solution and decoction of liquorice roots in specific ratio.

EFFECT: non-toxic and effective agent for treatment of abovementioned diseases.

7 ex

FIELD: medicine, biotechnology, healthy medical and veterinary preparations.

SUBSTANCE: claimed method includes exposing of aqueous isotonic solution of sugar-containing raw materials such as mixture of glucose and fructose in mass ratio of 1:1 with gamma-irradiation in absorbed dose of 25-40 kGy.

EFFECT: agent of standard composition with high antiviral and hepatoprotective action.

2 tbl, 2 ex

FIELD: medicine, neurology, virology.

SUBSTANCE: invention relates to treatment of neurological diseases caused by herpes virus, such as Bell's paralysis, Hunt's disease, herpetic encephalitis accompanying with damage of cerebral nerves. Invention involves using 1,4-dihydropyridine blockers of calcium channels, such as felodipine, nifedipine, nimodipine, nisodipine being taken preferably in combination with herpes virus antagonist. Invention provides repairing damaged cerebral nerves by topical expanding arteriols and recovery of local microcirculation based on specific competitive interaction of definite groups of calcium blockers of 1,4-dihydropyridine type with vasoconstrictor endothelin.

EFFECT: enhanced effectiveness of treatment.

47 cl, 2 dwg, 1 ex

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