2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazine-7(4h)-one sodium salt dihydrate possessing antiviral activity

FIELD: organic chemistry, medicine, virology.

SUBSTANCE: invention relates to biologically active compounds and concerns the development of a novel substance - 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazine-7-(4H)-one sodium salt dihydrate of the formula: . This compound is designated for treatment and prophylaxis of diseases caused by viruses that are pathogenic form humans and animals. Proposed compound protects against infections caused by Rift Valley fever virus. Also, it shows activity against viruses of WEE(West Equine Encephalomyelitis), parainfluenza, respiratory-syncytium, Aujeszky's disease virus, avian infectious laryngotracheitis virus, avian influenza virus - totally against above 10 RNA- and DNA-containing viruses. The proposed compound is active in curative schedule of its using that is especially valuable.

EFFECT: valuable medicinal properties of compound.

1 cl, 6 tbl, 2 dwg, 7 ex

 

1. The technical field to which the invention relates.

The invention relates to the field of biologically active compounds and concerns of sodium salt of 2-methylthio-6-nitro-1,2,4-triazolo[5,1-C]-1,2,4-triazine-7(4H)-she dihydrate, which has antiviral action intended for the treatment and prevention of infectious diseases viral nature of humans and animals. The invention can be used in hospitals, research laboratories, as well as in livestock and poultry.

The urgency of the problem of antiviral therapy, especially in conditions of rapid mutation of the virus, detection of new pathogens dangerous and slow virus infections, causes a constant need for new tools that would possess high activity, prolonged action and low toxicity.

2. The prior art.

In a series of condensed isoloation there is evidence of antiviral activity of 6-nitro-4,7-dihydro-1,2,4-triazolo[5,1-C]-1,2,4-triazine-7-ones against the virus of Aujeszky's disease (BWA) [Rusinov V.L., Ulanski E.N., Chupakhin O.N. and other Chemical and pharmaceutical journal. 1990, No. 96, p.41-44]. It is also known antiviral activity 4 alkylthio-5,7-dihydro-7-oxo-1,2,4-triazolo[4,3-C1]-1,2,4-triazines [Cristesku S., Derivati de 5-oxo-5,6-dihidro-s-triazolo(4,3-d)-as-triazina si procedeu for prepararea lor. Pat. RAF, CL 12(C 07 d 55/10), the 56269, 13.03. 1974], and antitumor activity of imidazo[2,1-C]-1,2,3,5-tetrazine [Yongfeng W., M.F.G. Stevens Antitumor Imidazotetrasines. 35. New Synthetic Routesto to the Antitumor Drug Temozolomide. J. Org. Chem. 1997, vol. 62, No. 21, p.7288-7294]. As a prototype is the most appropriate connection - sodium salt of 6-nitro-4,7-dihydro-1,2,4-triazolo[5.1-C]-1,2,4-triazine-7-she - showed antiviral activity against against BWA [Rusinov V.L., Ulanski E.N., Chupakhin O.N. and other Chemical and pharmaceutical journal. 1990, No. 96, p.41-44].

3. Disclosure of the invention.

The technical result of the invention is to find new chemical compounds possessing a wide spectrum of antiviral action, effective against RNA and DNA viruses.

This technical result is achieved by the fact that according to the invention, the proposed new connection - sodium salt of 2-methylthio-6-nitro-1,2,4-triazolo[5,1-C]-1,2,4-triazine-7(4H)-it, dehydrate, possessing antiviral activity and having the formula 1

Sodium salt of 2-methylthio-6-nitro-1,2,4-triazolo [5,1-C]-1,2,4-triazine-7(4H)-she dihydrate (1) is obtained by condensation of the diazonium salts (3), obtained by diazotization of 3-amino-5-methylthio-1,2,4-triazole (2), with ethylnitrosourea in an alkaline environment.

The inventive compound is a yellow Cree is a metallic high-melting, soluble in water, methanol, acetone, dimethylformamide, dimethylsulfoxide, soluble in methanol, insoluble in benzene, chloroform and most aprotic solvents.

The data of elemental analysis and NMR spectroscopy are fully consistent attributed to the structure. The presence in the claimed connection between two water molecules is confirmed by the data of derivatographic (1, 2).

Figure 1. thermogram of the sodium salt of 2-methylthio-6-nitro-1,2,4-triazolo[5,1-C] -1,2,4-triazine-7(4H)-she dihydrate.

Figure 2. The loss of weight of sodium salt of 2-methylthio-6-nitro-1,2,4-triazolo[5,1-C]-1,2,4-triazine-7(4H)-she dihydrate by heating.

For the separation of the water from the sodium salt of 2-methylthio-6-nitro-1,2,4-triazolo[5,1-C]-1,2,4-triazine-7(4H)-she dihydrate substance takes a long time to heat at 150°in vacuum over P2O5. Anhydrous drug on the air instantly absorbs moisture and under normal conditions and for 2-3 h is fully converted to the dihydrate.

Example 1. Synthesis of sodium salt of 2-methylthio-6-nitro-1,2,4-triazolo [5,1-C]-1,2,4-triazine-7(4H)-she dihydrate (1)

To a cooled to 0°With a solution of 13 g (0.1 mol) 5-amino-3-methylthio-1,2,4-triazole in 16 ml of nitric acid (d=1,4) and 100 ml of water is added a solution of 8 g of sodium nitrite in 50 ml of water for 15 min, incubated 10 min and contribute portions of chilled mixture of 11 ml (0.1 mol) of ethylnitrosourea in 150 ml of 2 M is aStore sodium carbonate. Stirred for 2 hours at 0-5°C, the precipitate is filtered off, successively crystallized from 20%acetic acid, water and dried in air. Yield: 21.2 g (74%).

Sodium salt of 2-methylthio-6-nitro-1,2,4-triazolo [5,1-C]-1,2,4-triazine-7(4H)-she, the dihydrate has the following physicochemical characteristics: TPL>300°;1H NMR spectrum in DMSO-d6δ, ppm: 2,52 (3H, s, SCH3), was 4.76 (4H, USS, 2 H2O). Found: 20.83, N - 2.62, N - 29.21, S - 11.54%. Brutto-formula - C5H7N6NaO5S. Calculated: C - 20.98, N - 2.47, N - 29.36, S - 11.20%.

Example 2. Study of antiviral action against virus Venezuelan encephalomyelitis of horses (VAL) and Sindbis

Antiviral activity and cytotoxic activity of the claimed compounds were studied by micromethods in 96-well the micropanel in transplantable cell culture Vero against viruses VAL strain 230 and Sindbis strain EgA2-339 belonging to the genus of alpha viruses. The multiplicity of infection of viruses (M.I.) was 0,01 TCD50. The experience was taken into account in 72 hours until 100% cytopathic effect (the centre e) in the wells of virus control. The centre e was determined by 4-cross scheme; 4+-100% destruction of the cell monolayer, 3+-75%, 2+-26% degradation (table 1, 2).

Antiviral activity was studied by the reduction in infectious titer (IT) virus VAL-230 and virus Sindbis in the culture of Vero cells in 24 the Asa after infection with infective dose of the virus 0.01 PFU/cell. The results are shown in table 2. The inventive compound in a concentration of 200, 12.5 ág/ml reduced IT virus VAL-230 4.0, 1,9 DBE/ml, respectively, and IT virus Sindbis 3.9, 1,8 lg PFU/ml, respectively. Connection-prototype at a concentration of 125, and 6.25 μg/ml reduced I.R. virus Sindbis 3.0, and 1.0 lg PFU/ml, respectively, and IT virus VAL-230 3.3, and 1.5 lg PFU/ml, respectively. Rimantadine concentrations of 50, 25 MKT/ml reduced IT virus VAL-230 2.0, 1,4 lg PFU/ml, respectively. KTI (chemotherapeutic index) connections: describe - 20, prototype - 12, rimantadine - 2.

Example 3. The study of the antiviral activity against virus Western encephalomyelitis of horses (SEL)

The claimed compound was administered outbred mice weighing 10-12 g orally 2-m schemes: 1 - preventive - 24 hours, after 2, 24, 48, 72, 96 hours after infection 10 LD50virus II scheme - medical - virus was injected after 2, 24, 48, 72, 96 hours after exposure to the same infectious dose of virus.

A single dose of the compounds of 50 mg/kg, consistent with 1/32 LD50for these compounds. Heading dose of both compounds was 300-250 mg/kg of body weight depending on the applied scheme. The infectious dose of virus SEL 10 LD50in a volume of 0.1 ml intramuscularly. The method of using the compounds for oral administration. As can be seen from table 3, when medical scheme introduction (I) is described is imago connection protection amounted to 65%, the average life expectancy of animals extended to 10 days (table 3). The percentage protection in the application of therapeutic schemes amounted to 60%, and the average life expectancy has increased by 5.9 days. Connection-the prototype proved to be ineffective against SEL.

Example 4. Study of antiviral action against viruses, rift valley fever (LDR)

The claimed compound was administered outbred white mice weighing 6-8 g orally 2-schemes: scheme 1 - medical-prfilaktichesky (for 24 hours and through 1, 2, 3, 6, 7, 8, 9, 10 days after exposure to the same infectious dose of the virus). A single dose of the compounds of 50 mg/kg, which corresponds to 1/32 LD50these compounds. Heading dose of both compounds was 500-450 mg/kg of body weight depending on the applied scheme. The infective dose of the virus 10 LD50in a volume of 0.2 ml was injected subcutaneously. As can be seen from table 4, when medical scheme is the introduction of the claimed connection protection was 90%, the average life expectancy of treated animals increased by 12.2 per day. The percentage of protection when applying the treatment regimen was slightly higher and amounted to 80%and life expectancy increased by 13.4 days (table 4).

Example 5. Study of antiviral activity against parainfluenza virus and respiratory syncytial virus

Study of antiviral activity of the wearing of these viruses was carried out in experiments on tissue culture using parainfluenza virus type 3 (strain na-1) and respiratory syncytial virus (strain long).

In each experiment included 2 groups:

1) tube containing tissue culture, which was administered the test compound;

2) tubes with tissue culture, in which, instead of the test compound was administered to the growth medium.

It is established that the inhibition of parainfluenza virus has been observed in a dose of 500 μg/ml, whereas inhibition of respiratory syncytial virus was sufficient concentration of 60 µg/ml (table 5).

Example 6. Study of antiviral action against the virus of Aujeszky's disease, avian influenza and infectious laryngotracheitis birds

The tests were carried out with the virus of avian influenza (AIV) and infectious laryngotracheitis birds (TLI) on 10-day-old chick embryos (CE) and the virus of Aujeszky's disease (BWA) in cell cultures of chicken fibroblasts (KF).

When determining virostatics (inhibitory) action EC infected with a virus TLI at a dose of 50-100 FIGHT50and cell culture KF-BWA dose TCD50(tissue cytopathic doses). Through 1-1,5 hours after infection KE and KF contributed the test compound at doses of 50, 100, 250 μg/EC and incubated in a thermostat at 37,5°EC within 120 hours to 100% of plaque on the chorioallantoic membrane (HAO), and KF - up a clear cytopathic effect in control. At each dose of the studied compounds were taken at 10 KOE or 4 bottles with KF experiments p is bodily in 3 replications.

Virostatics action was determined by the difference between the titres in the experience and control CF and to suppress belascoaran in the experiment and the control experiment. The inhibitory activity is expressed in TCD50in KF and % rejection plaques with EC. The control were KE and KF, infected with a virus, as well as intact KE and KF.

When studying virucidal action (inactivating) the claimed compound was mixed with material containing AIV, and incubated at 37,5°within 24 hours, and then was titrated on EC in parallel with the control. Control served virusologii material, to which instead of the claimed compounds were added to saline (placebo) and intact KEV. Virucidal activity was determined as the difference of the titles in the experiment and the control and expressed in EDS50(embryonic lethal doses).

It is established that in experiments with TBE virus TLI the inventive compound in a dose of 500 µg/EC inhibited the development of plaques HAO 30% at 100%education control. In experiments on FE with the BWA the inventive compound in a dose of 100 μg/ml inhibited the reproduction of the virus, 2.75, and at a dose of 50 μg/ml to 1.5 TCD50. In experiments on FE with AIV inventive compound in a dose of 500 μg/ml and exposure 24 hours intentional AIV 3.6 EDS50.

Example 7. Determination of the toxicity of the claimed compounds

Determination of toxicity were carried out on outbred white mice what assay 7-8 g in a concentration range of 50-200 mg/kg (table 6). From table 7 it is seen that LD50sodium salt of 2-methylthio-1,2,4-triazolo[5,1-C]-1,2,4-triazine-7-she dihydrate is 1400 mg/kg

Study of antiviral action of the claimed compounds (sodium salts of 2-methylthio-1,2,4-triazolo[5,1-C]-1,2,4-triazine-7(4H)-she dihydrate) and comparing it with the prototype - sodium salt of 1,2,4-triazolo[5,1-C]-1,2,4-triazine-7-it is used in medical practice, the drug rimantadine has shown the following.

1. Against viruses VAL and Sindbis the claimed connection far exceeds rimantadine. In experiments on laboratory animals of the claimed compound has a stronger protective effect than the prototype.

2. The claimed compound has a broader spectrum of antiviral activity than the prototype. Sodium salt of 2-methylthio-1,2,4-triazolo[5,1-C]-1,2,4-triazine-7(4H)-she dehydrate protects animals against infections caused by viruses, rift valley fever. Especially valuable that the connection is active if the medical scheme is applied.

The claimed connection, unlike the compounds of the prototype and rimantadine, active against virus SEL, parainfluenza, respiratory syncytial virus, the virus of Aujeszky's disease, infectious laryngotracheitis birds, the virus of bird flu.

Thus the sodium salt of 2-methylthio-1,2,4-triazolo[5,1-C]-1,2,4-triazine-7(4H)-she, the dihydrate has a more pronounced is passed, than the prototype and remantadin antiviral effect. The claimed compound has a broad spectrum of biological activity than the compound-prototype and used in medical practice, drug rimantadine.

Table 1

Antiviral activity of the claimed compounds, prototype and rimantadine against viruses VAL and Sindbis
connectionIPC mg/mlVAL-230Sindbis
ED50µg/mlKTIED50; mcg/mlKTIP
Declare20010,02010,0200,01
the placeholder12510,01210,0120,01
rimantadine50252 2520,01
IPC - upper level concentration; ED50- the minimum concentration that inhibits the development of cytopathic effete (the centre e) 50%;

KTI - chemotherapeutic index (IPC/ ED50); P - level of confidence.
Table 2

Antiviral activity of the claimed compounds, prototype and rimantadine against viruses VAL and Sindbis
connectionIPC mg/mlconcentration, mg/mlVAL-230Sindbis
the titer of the virus, lg PFU/mlred eye reduction. title lg PFU/mlKTIthe titer of the virus, lg PFU/mlred eye reduction. title lg PFU/mlKTIP
2005,54,0±0,066,03,9±0,140,01
declare20012,57,61,9±0,08167, 1,8±0,11160,01
09,39,5
506,03,3±0,165,23,0±0,140,01
the placeholder1255,127,81,5±0,06128,01,0±0,08120,01
09,39,5
507,32,0±0,117,52,0±0,080,01
rimantadine 50257,91,4±0,1628,01,5±0,1420,01
09,39,5
IPC - upper level concentration; KTI - chemotherapeutic index (IPC/ED50); P - level of confidence.

Table 5

Antiviral activity of the claimed compounds against parainfluenza viruses and respiratory syncytial
virusthe dose of a compound, mg/mlthe dose of the virus, TCD50experiencecontrol
all tubesone of them contains a virusindex of protection %all tubesone of them contains a virus
paragra the p 5001-10204602019
10-1002016152013
respiratory-601-10103551010
intitially10-1001010101010
Table 6

The definition of LD50the claimed compounds by oral administration of his white mice weighing 7-8 g
the drug concentration, mg/kg5010020040080014002000
relative mortalityand0/6 0/60/60/60/63/64/6
and is expressed as the ratio of the number of dead white mice to the number of white mice in the experiment.

Sodium salt of 2-methylthio-6-nitro-1,2,4-triazolo[5,1-c]-1,2,4-triazine-7(4H)-it, dehydrate, possessing antiviral activity and having the formula



 

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19 cl, 21 tbl, 54 ex

FIELD: organic chemistry, herbicides.

SUBSTANCE: invention relates to a compound of the general formula [I]: wherein R1 and R2 can be similar or different and each represents (C1-C10)-alkyl group; each among R3 and R4 represents hydrogen atom; R5 and R6 can be similar or different and each represents hydrogen atom or (C1-C10)-alkyl group; Y represents 5-6-membered aromatic heterocyclic group or condensed aromatic heterocyclic group comprising one or some heteroatoms chosen from nitrogen atom, oxygen atom and sulfur atom wherein heterocyclic group can be substituted with 0-6 of similar or different groups chosen from the following group of substitutes α, and so on; n means whole values from 0 to 2; [Group of substitutes α]: hydroxyl group, halogen atoms, (C1-C10)-alkyl groups, (C1-C10)-alkyl groups wherein each group is monosubstituted with group chosen from the following group of substitutes β, (C1-C4)-halogenalkyl groups, (C3-C8)-cycloalkyl groups, (C1-C10)-alkoxy-groups, (C1-C10)-alkoxy-groups wherein each group is monosubstituted with group chosen from the following group of substitutes and so on; [Group of substitutes β]: hydroxyl group, (C3-C8)-cycloalkyl groups that can be substituted with halogen atom or alkyl group, (C1-C10)-alkoxy-group, (C1-C10)-alkylthio-groups, (C1-C10)-alkylsulfonyl groups, (C1-C10)-alkoxycarbonyl groups, amino-group, carbamoyl group (wherein its nitrogen atom can be substituted with similar or different (C1-C10)-alkyl groups), (C1-C6)-acyl groups, (C1-C10)-alkoxyimino-groups, cyano-group, optionally substituted phenyl group; [Group of substitutes γ]: optionally substituted phenyl group, optionally substituted aromatic heterocyclic groups, cyano-group. Also, invention relates to herbicide comprising derivative of isoxazoline of the formula [I] as an active component or its pharmaceutically acceptable salt. Invention provides the development of isoxazoline derivative possessing the herbicide activity with respect to resistant weeds, selectivity for cultural crop and weed.

EFFECT: valuable herbicide properties of substances.

18 cl, 24 tbl, 106 ex

FIELD: chemical industry; method of production of the fluorine-containing compounds.

SUBSTANCE: the invention is pertaining to the chemical industry, in particular, to the improved method of production of fluorine-containing compounds from the halogen-containing, compounds, preferably, from chlorine-containing compounds due to an exchange of halogen for fluorine at presence of the HF-additional compound of the mono- or bicyclic amine with at least two atoms of nitrogen. At that at least one atom of nitrogen is built in the cyclic system as the fluorating agent; or at presence of anhydrous hydrogen fluoride - as the fluorating agent and the indicated HF-additional compound of the mono- or bicyclic amine as the catalyst. At usage of the applicable solvents the reaction mixtures can be divided into two phases and thus to simplify the reprocessing of the products. The invention also is pertaining to the HF-additional compounds of 1.5-diazabicyclo[4.3.0]non-5-en and N,N-dialkylaminopiridin, where alkyl represents C1-C4alkyl and where the molar ratio of HF to amine makes 1:1, and to HF- additional compounds 1.8- diazabicyclo[5.4.0]undecyl-7-ene, where the molar ratio of HF to amine compounds more than 1:1.

EFFECT: the invention ensures at usage of the applicable solvents to divide the reaction mixture into two phases and thus to simplify reprocessing of the products.

17 cl, 13 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel derivative of 9-(2-diethylaminoethyl)-2-phenylimidazo[1,2-a]benzimidazole, namely its hydrobromide, eliciting properties of antagonist of serotonin 5-HT3-receptors that can be used in therapy of cytotoxic nausea and vomiting. New salt is low toxic and exceeds bemesetron by anti-serotonin activity that is a selective 5-HT3- antagonist.

EFFECT: improved and valuable medicinal properties of derivative.

2 cl, 2 ex

FIELD: chemical-pharmaceutical industry, biochemistry, medicine.

SUBSTANCE: invention relates to a liposome directly effecting on αvβ3-integrin receptors and comprising cationic amphiphilic substance including 1,2-dioleoyloxy-3-(N,N,N-trimethylammonium)propane chloride, neutral lipid, lipid with a direct effect having domain with a direct effect and hydrophobic domain bound with domain of a direct effect, and nucleic acid forming complex with cationic lipid. Cationic lipid presents in the amount from about 1 to about 50 molar % and indicated lipid with a direct effect presents in the amount from about 1 to about 20 molar % wherein molar percents are calculated as measured for the total number of lipid moles in liposome. Domain with a direct effect comprises a nonpeptide antagonist of αvβ3-integrin comprising 4-[2-(3,4,5,6-tetrahydropyrimidin-2-ylamino)ethyloxy]-benzoyl-2-(S)-aminoethylsulfonamino-β-alanine (compound 10) bound covalently with hydrophilic domain by amide bond. Also, invention relates to a method for inhibition of angiogenesis and involving administration to a patient needing in inhibition of angiogenesis a liposome in the therapeutically effective dose that directly effects on αvβ3-integrin receptors and comprising nucleic acid that is able to express a protein or peptide suppressing angiogenesis.

EFFECT: valuable properties of system.

27 cl, 2 tbl, 18 dwg, 8 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention elates to derivatives of benzothiazole of the general formula (I): wherein R means hydrogen atom, -(CH2)n-phenyl optionally substituted with a substitute chosen from the following group: halogen atom, (lower)-alkyl, (lower)-alkoxy-group, trifluoromethyl or -N(R')-C(O)-(lower)-alkyl, -(CH2)n-pyridinyl optionally substituted with (lower)-alkyl, -(CH2)n-(C3-C6)-cycloalkyl optionally substituted with hydroxy-group, -(CH2)n-benzo[1,3]dioxolyl, -(CR'2)-thiophenyl, -(CR'2)n-thiazolyl optionally substituted with (lower)-alkyl, -(CH2)n-C(O)-thiophenyl optionally substituted with halogen atom, -(CH2)-furanyl optionally substituted with (lower)-alkyl, -(CHR')n-benzofuran-1-yl, -(CH2)n-benzo[b]thiophenyl, -(CH2)n-N(R')-C(O)-phenyl optionally substituted with halogen atom or (lower)-alkoxy-group. -(CH2)n-C(O)-phenyl optionally substituted with (lower)-alkoxy-group, -(CH2)n-C(O)-2,3-dihydrobenzo[1,4]dioxine-6-yl, -(CH2)n-N(R')-C(O)-pyridinyl, -(CH2)n-tetrahydrofuranyl, -CH-biphenyl, -CH-(phenyl)pyridinyl, -(CH2)n-1-oxo-(CH2)n-CH-(phenyl)tetrahydropyranyl, -(CH2)n-1-oxo-1,2,3,4-tetrahydroquinoline-3-yl or -(CH2)n-S-[1,3,4]thiadiazol-2-yl optionally substituted with amino-group; R' means hydrogen atom or (lower)-alkyl and independently of one another in case R'2; n = 0, 1, 2, 3 or 4. Also, invention relates to a medicament possessing high affinity to adenosine A2A-receptors and high selectivity with respect to A1-receptors and comprising one or more derivatives of benzothiazole of the formula (I) and pharmaceutically acceptable excipients. Invention provides using derivatives of benzothiazole as ligands of adenosine receptors.

EFFECT: valuable medicinal properties of compounds and medicament.

13 cl, 2 tbl, 3 ex

FIELD: medical engineering.

SUBSTANCE: pill taken per os comprises pharmaceutically active agent selectable from (S,S)-Reboxetin or its salt and Pramipexol or its salt. The pharmaceutically active agent is taken in the amount of 0.01% by mass to 25% by mass of composition. It is dispersed in matrix composed of hydrophilic polymer and starch having rupture strength of at least approximately 0.15 kN·cm-2, at least approximately 0.175 kN·cm-2 or at least approximately 0.2 kN·cm-2, when having solid substance usable for producing pills where hydrophilic polymer takes approximately 20-70% by mass and starch is available in the amount of approximately 25-75% by mass. Method involves determining starch usability and composition applicability for treating the cases of disorders and states selected from depressive psychosis, neuropathic pains and Parkinson disease. Starch of specified rupture strength allows pill to withstand high speed pelletization operation and to provide prolonged drug release and to take a pill once a day.

EFFECT: controlled and prolonged drug action; enhanced effectiveness of treatment.

21 cl, 9 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel compound 4-(2-butylamino)-2,7-dimethyl-8-(2-methyl-6-methoxypyrid-3-yl)[1,5-a]-1,3,5-triazine of the formula (I):

, its steroisomeric forms or pharmaceutically acceptable salts, pharmaceutical composition comprising thereof and its using for preparing pharmaceutical composition used in treatment of anxiety in mammals.

EFFECT: valuable medicinal property of compound and pharmaceutical composition.

7 cl, 2 ex

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: medicine.

SUBSTANCE: compound is represented by structural formula

or its pharmaceutically permissible salts, where R1 is the hydrogen atom (1), C1-8acyl(2), hydroxyl (3), halogen atom (5), C2-8acyl (3), C1-8-alcocsy (4), substituted with phenyl or C2-8acyl, substituted with NR2R3; R2R3 independently represent hydrogen atom (1) or C1-8acyl(2), X and Y each independently representing C (1), CH (2) or N (3). is (1) single or (2) double bond. is 5-7-member carbocyclic group or 5-7-member partially or fully saturated heterocyclic group defined in claim 1 of invention. A is one of A1 to A5 groups defined by claim 1 of the invention. The compounds show inhibiting properties relative to poly(ADP-ribose)polymerase are usable as prophylactic and/or curative drugs for treating ischemic diseases (in brain, spinal cord, heart, digestive tract, skeletal muscle, eye retina, e.t.c.), inflammatory diseases (intestinal inflammation, disseminated sclerosis, arthritis, e.t.c.), neurodegenerative disorders (extrapyramidal disorder, Alzheimer disease, muscle dystrophy, cerebrospinal canal stenosis in lumbar segment of the vertebral column, e.t.c.), diabetes, stroke, cerebral injury, hepatic insufficiency, hyperalgesia, e.t.c. The compounds are also of use in struggling against retroviruses (HIV and others), as sensitizing agents for treating cancer cases and immunodepressant agents.

EFFECT: enhanced effectiveness of treatment.

19 cl, 90 tbl

FIELD: chemistry of metalloorganic compounds, medicine, oncology.

SUBSTANCE: invention relates to novel chemical compounds, namely, to complexes of palladium with heterocyclic ligands of the general formula (I): wherein R1 means-NH, oxygen atom (O), -CH2; R2 means two hydrogen atoms (2H), O; R3 means hydrogen atom H, CH3, CH2-CH2-NH2,-(CO)-CH3; X means chlorine (Cl), bromine (Br) atom; n = 1; m = 1 if R1 means -NH, O; R2 means 2H; R3 means H, CH3, CH2-CH2-NH2, -(CO)-CH3; n = 2; m = 1 if R1 means O, -CH2; R2 means O, 2H; R3 means H, CH3, -(CO)-CH3; n = 2; m = 3 if R1 means -NH; R2 means 2H; R3 means CH2-CH2-NH2 eliciting pharmacological, in particular, anti-tumor activity. Proposed compounds possess high activity and characterized by reduced toxicity as compared with anti-tumor preparations with platinum complexes.

EFFECT: valuable medicinal properties of complexes.

4 cl, 2 tbl, 10 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of (R)-2-arylpropionamide of the formula (I): , wherein Ar means aryl of the formula (IIIb): F-Arb wherein Arb means phenyl mono- or poly-substituted with the following groups: chlorine, fluorine atom; F means hydrogen atom, linear or branched (C1-C5)-alkyl residue, benzoyl, 2,6-dichlorophenylamino-, 2,6-dichloro-3-methylphenylamino-group; R means hydrogen atom, (C1-C4)-alkyl; X means linear or branched (C1-C6)-alkylene optionally substituted with the group -CO2R4 wherein R4 means hydrogen atom or linear or branched (C1-C6)-alkyl group, phenyl or phenylmethylene group; R1, R2 and R3 mean independently linear or branched (C1-C6)-alkyl, (C3-C7)-cycloalkyl, (C3-C6)-alkenyl, aryl, aryl-(C1-C3)-alkyl, or R1 and R2 in common with nitrogen atom (N) to which they are attached form nitrogen-containing 6-membered heterocyclic ring of the formula (II) , and R3 has values indicated above independently wherein in the formula (II) Y means a simple bond, methylene group, oxygen atom, nitrogen atom or sulfur atom; p means a whole number 2; Z- means a pharmaceutically acceptable counterion of quaternary ammonium salts. Also, invention relates to using compound of the formula (I) in treatment of psoriasis, pemphigus and pemphigoid, rheumatic arthritis, intestine chronic inflammatory pathology including ulcerous colitis, acute respiratory distress-syndrome, idiopathic fibrosis, mucoviscidosis, pulmonary chronic obstructive disease and glomerulonephritis, and also for prophylaxis and treatment of injure caused by ischemia and reprefusion. Also, invention relates to a pharmaceutical composition possessing the inhibitory activity with respect to chemotaxis of polymorphonuclear leukocytes and monocytes induced by complement C5a fractions and comprising compound of the formula (I) in mixture with a suitable carrier. Also, invention relates to a method for synthesis of compounds of (R)-2-arylpropionamide of the formula (I) that involves interaction of amides of the formula (IV) given in the invention description with compounds of the formula R3Zwherein Z means a leaving group, such as chloride, bromide, iodide, methanesulfonate, p-toluenesulfonate, sulfate. Invention provides synthesis of (R)-2-arylpropionic acid omega-aminoalkylamide quaternary ammonium salts used for inhibition of chemotaxis activation induced by the C5a complement component.

EFFECT: valuable properties of compounds and pharmaceutical compositions.

17 cl, 1 tbl, 6 ex

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention describes novel pyrimidotriazines of the general formula (I):

wherein each R1 and R2 is chosen from the group comprising hydrogen atom, or R1 and R2 form in common chemical bond, -CH2-Ar and Ar is chosen from the group comprising unsubstituted phenyl, unsubstituted naphthyl, phenyl, mono- or disubstituted with (lower)-alkoxy-group and naphthyl mono- or disubstituted with (lower)-alkyl, or their pharmaceutically acceptable salts. Also, invention relates to a method for synthesis of these compounds, pharmaceutical composition based on thereof and to using novel pyrimidotriazines for prophylaxis and/or treatment of diabetes mellitus as these compounds possess the strong expressed inhibitory effect on activity of protein tyrosine phosphatase PTP1B.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 27 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a novel solid formulation of anti-arrhythmic medicinal agents. Invention describes crystalline formulation of 4-({3-[7-(3,3-dimethyl-2-oxobutyl)-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl]propyl}amino)-benznitrile, tert.-butyl-2-{7-[3-(4-cyanoanilino)propyl]-9-oxa-3,7-dizabicyclo[3.3.1]non-3-yl}ethylcarbamate, tert.-butyl-2-{7-[4-(4-cyanophenyl)butyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate or tert.-butyl-2-{7-[(25)-3-(4-cyanophenoxy)-2-hydroxypropyl]-9-oxa-3,7-diazabicyclo[3.3.1]non-3-yl}ethylcarbamate and their pharmaceutically acceptable salts. Also, invention describes methods for their synthesis, a pharmaceutical preparation based on thereof, a method for prophylaxis or treatment of arrhythmia and their using.

EFFECT: valuable medicinal properties of compounds and pharmaceutical preparation.

73 cl, 22 dwg, 22 tbl, 23 ex

FIELD: organic chemistry, biochemistry, medicine.

SUBSTANCE: invention describes a method for prophylaxis or treatment of states wherein inhibition of enzyme activity is required wherein this enzyme catalyzes hydrolysis reaction of ester functional groups and wherein indicated disorder represents obesity or accompanying disease. Method involves prescribing compound of the formula (1):

or its pharmaceutically acceptable salt, ester, amide or precursor wherein in the formula (1) a means six-membered aromatic or heteroaromatic ring; R1 means a branched or unbranched alkyl (its carbon chain can be broken possibly by one or more oxygen atoms), alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, reduced arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, reduced aryl, reduced heteroaryl, reduced heteroarylalkyl or their substituted derivative wherein a substitute represents one or more group taken independently among the following group: halogen atom, alkyl, halogen-substituted alkyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, reduced heteroarylalkyl, arylalkoxy-, cyano-, -C(O)R4, -CO2R4, -SOR4, -SO2R4, -NR6R7, -OR6, -SR6, -C(O)CX1X2NR6R7, -C(O)NR4R5, -C(O)N(OR5)R6, -NR6C(O)R4, -CR6(NH2)CO2R6, -NCX1X2CO2R6, -N(OH)C(O)NR6R7, -N(OH)C(O)R4, -NHC(O)NR6R7, -C(O)NHNR6R7, -C(O)N(OR5)R6, or lipid or steroid (natural or synthetic one) under condition that any substituting heteroatom in R1 or R2 must be segregated from nitrogen exocyclic atom by at least two carbon atoms (preferably, saturated ones); R2 means hydrogen atom or group, such as determined for R1 and wherein R4 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl, OR6, NHCX1X2CO2R6 or NR6R7; R5 represents hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, reduced heteroaryl or reduced heteroarylalkyl; R6 and R7 are taken independently among hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylakyl, reduced heteroarylalkyl or -(CH2)n(OR5)m wherein n = from 1 to 12 but preferably from 2 to 10; m = from 1 to 3; for R5 (C2-C10)-alkyl is preferable; X1 and X2 represent independently hydrogen atom, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, reduced heteroaryl, heteroarylalkyl or reduced heteroarylalkyl. Also, invention describes compounds of formulas (II), (IIa), (IIb) given in the invention description, method for preparing compound of the formula (II), pharmaceutical composition used for prophylaxis or treatment of obesity or accompanying disorder, the nutrition foodstuff, method for prophylaxis or treatment of obesity or accompanying disorders, method for inhibition of enzymes activity, method for reducing the fat content in animals, cosmetic method for maintaining this weight of animals. Invention discloses the possibility for prophylaxis or treatment of obesity or accompanying disorders.

EFFECT: valuable medicinal properties of compounds.

30 cl, 1 dwg, 2 tbl, 5 ex

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