Symmetric diimines based on camphor - inhibitors of reproduction of influenza virus (strain a/california/07/09 (h1n1)pdm09)

FIELD: biotechnology.

SUBSTANCE: invention relates to new symmetrical diimines based on camphor of general formula 1a-f, which are inhibitors of influenza virus reproduction (strain A/California/07/09 (H1N1) pdm09). In the general formula 1a-f The compounds along with pronounced antiviral activity against the said influenza virus have low toxicity.

EFFECT: chemotherapeutic index exceeds that of the known reference preparations three or more times.

1 tbl, 8 ex

 

The invention relates to medicine and pharmaceuticals, specifically to biologically active substances, symmetric diimine based camphor of formula 1a-f, which can be used as inhibitors of reproduction of influenza virus (strain A/California/07/09 (H1N1)pdm09).

The development of new drugs for the treatment and prevention of viral infections is one of the topical problems of modern pharmacology and medicinal chemistry, as globalisation, population mobility and the transmission of viral infections contribute actively to spread throughout the world. The epidemic of avian influenza H5N1 (1997-2006) and then the flu pandemic of 2009, caused by a virus of swine origin A(H1N1)pdm09, made it necessary inspection of the problems with the development of antiviral drugs [Kiselev, I. Chemotherapy and chemotherapy flu. St. Petersburg, Rostock, 2012].

As shown, the most promising source for the development of antiviral drugs are natural compounds [Advances in Antiviral Drug Design. Vol.5. Ed. by E. De Clercq. Publ. by Elsever, 2007]. Among permitted in recent decades for clinical use in the United States of new drugs, about half are natural substances and their chemically modified derivatives. Antiviral agents for the treatment of rippa represent a very limited group of drugs, and for most of them are known drug resistance. The creation of antiviral drugs is the nearest-term development of medical science in the field of creation of means of treatment and prevention of viral infections [Petr M., Sarybaev CENTURIES of the Modern state of development of new antiviral drugs against influenza and ARVI // Pharmaceutical Bulletin, 2012. No. 1. - 68].

Due to the features of genome organization (the absence of a mechanism of correction of replication errors) and short life cycle of the influenza virus has a high rate of mutations. As a result, the antigenic structure of the virus is highly exposed to changes in the selective pressure of the immune system of the host body. In addition, the use of chemotherapy is perceived by the virus as a factor of selection, which also is the formation of resistant strains. These two processes lead to the emergence of variants of viruses that can escape as the activity of neutralizing antibodies, and thereby to escape from the immune response of the body, and to overcome the effect of chemotherapy, the source aimed at a certain stage of the virus reproduction. The complexity of the problem is that each type of virus has its own mechanism of adaptation to chemical drug [M.G. Ison Antivirals and resistance: influenza virus // Current Opinion i Virology. - 2011. - V.1. P. 563-573]. It is known that inhibit the reproduction of influenza virus can be at different stages of its life cycle.

The Foundation of the modern treatment of influenza is the use of several classes of compounds, which are aimed at inhibiting the replication of influenza virus (see figure 1). This neuraminidase inhibitors - Oseltamivir (Tamiflu) [Jong MD, Thanh TT, Khanh T.N., Hien V.M., Smith, G.J.D., Chau NV, Cam BV, Qui P.T., Ha with all your DQ, Malik Peiris J.S., Hien T.T., Farrar J. Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection // N. Engl. J. Med. -2005. - V 25. P.2667-72.] and Zanamivir (relenza) [Collins 1 P.J., Hairel L.F., Lin, Y.P., Liu J., Russell R.J., Walker, P.A., Skehel J.J., S.R. Martin, A.J. Hay S.J. Gamblin Crystal structures of oseltamivir-resistant influenza virus Hiking-aminidase mutants // Nature 2008. - V.453 - P.1258.], they are at the stage of budding newly synthesized virion influenza of sheath cells, blocking the removal of particles of viral progeny from the cell surface. The practice of neuraminidase inhibitors in the treatment of influenza have shown that the high efficiency of this group of drugs is limited to the early stage of infection. Ribavirin, an antiviral drug with a wide spectrum with high inhibitory activity against DNA and mainly of RNA viruses [P. Leyssen, Clercq E.D., Neyts J. The Anti-Yellow Fever Virus Activity of Ribavirin Is Independent of Error-Prone Replication // Mol. Pharmacol. - 2006. - V.69. - P.1461]. As an analogue of the nucleoside, ribavirin effective in subconsiously the concentration of the x system and its use causes adverse reactions, in particular anemia and teratogenic effect when used during pregnancy. In Russia in clinical practice in the treatment of influenza ribavirin not used.

The best known practical health antiviral drugs direct effect on the replication of influenza viruses are rimantadine (α-methyl-1-adamantanemethylamine hydrochloride) and amantadine (1-aminoadamantana) [Davies, W.L.; Grunert, R.R.; Haff, R.F.; McGahen, J.W.; Neumayer, E.M.; Paulshock, M.; Watts, J.C.; Wood, T.R.; Hermann, E.C.; Hoffmann, S.E. Antiviral Activity of 1-Adamantanamine (Amantadine) // Science. - 1964. - V.144. - P.862]. These compounds block the M2 protein of influenza virus, playing the role of ion channels in the viral membrane, thereby inhibiting the process of cleavage of hemagglutinin and fusion of the membranes of the virus and lysosomal vacuoles [Scholtissek C., Quack, G., Klenk H.D., Webster R.G. // Antiviral Res. 1998. - V.37. - P.83-95]. The mechanism of action of these drugs has been studied thoroughly enough [Cady S.D., Schmidt-Rohr, K., Wang J., Soto, C.S., W.F. DeGrado, Hong M.H. Structure of the amantadine binding site of influenza M2 proton channels in lipid bilayers // Nature. 2010. - Vol.463. - P.689-692].

Adamantanes as the class of caged compounds was the starting basis for the design of a large class of antiviral drugs [G. Zoidis, Kolocouris, N., Naesens L., Clercq E.D. Design and synthesis of 1,2-annulated adamantane piperidines with anti-influenza virus actvity // Bioorganic & Medicinal Chemistry - 2009. - N.17. P.1534]. The closest to classic adamantanes are frame connection - bonanini-replication inhibitors of the SARS coronavirus [Tanner J.A., B.J. Zheng, J. Zhou, R. Watt, J.Q. Jiang, Wong K.L., Lin, Y.P., Lu, L.Y., He, M.L., Kung H.F., Kesel A.J. The Adamantane-Derived Bananins Are Potent Inhibitors of the Helicase Activities and Replication of SARS Coronavirus // Chemistry & Biology, - 2005. - V.12. P.303]. Frame connections remain attractive as the basis for the design of antiviral drugs. So, catefory - (2-(G-amino-ethyl)bicyclo[2.2.1]heptane, is one of the most interesting products on the basis of natural bicyclic skeleton compounds Baranov [RF Patent №2448692. Kiselev, I., Tandoor, S.N., Deeva EG Pharmaceutical salt aminobutyl[2.2.1]heptanol as inhibitors of the transcription factor NF-KB with antiviral activity and their application]. It is important to emphasize that this compound actually has a natural origin, and borneol and isoborneol are widely known in folk medicine as anti-inflammatory agents.

Object of the invention is the expansion of the range of inhibitors reproduction of influenza virus.

The problem is solved by the new compounds of the formula la-f:

having the properties of inhibitors of reproduction of influenza virus.

Study of the biological activity of compounds 1a-f, carried out in relation to VIR the sa influenza (strain A/California/07/09 (H1N1)pdm09), showed their high efficiency as inhibitors of reproduction of the virus. The studies revealed that compounds 1a, b and 1d the most influence on the reproduction of influenza virus, which is confirmed by the following data (Example 8). Camphor is a bicyclic terpenoid with a rigid skeleton type, available in programada and levogyrate the enantiomers.

The obtained quantitative indicators of inhibition confirm the high degree of suppression of the replication of influenza virus in cell culture MDCK compounds 1a-f, exceeding the same indicator standards comparison of amantadine and rimantadine in 5 or more times. Use as Comparators adamantanone derivatives due to the presence of hard structural fragments as obtained compounds, and these drugs. The most active are symmetric diimine having aliphatic linker. It should be noted that the length of the aliphatic chain in the first place affect the toxicity of the compounds. So, is the least toxic compound 1d with skeleton-C12H24- the linker.

The claimed compounds was obtained as follows:

As starting compounds for the synthesis of target compounds using (+)-(1R)-camphor and diamines razlichnog the structure. The way of interaction camphor 1,2-diamination, leading to the formation of diastereomeric clean diimine, the recovery of which receive stereoselective Exo-Exo diamine, described in literature [Caselli, A., Giovenzanna, G.., Palmisano, G., Sisti, M., Pilati, .Synthesis of C2-syrnmetrical diamine based on (1R)-(+)-camphor and application to oxidative aryl coupling of naphthols // Tetrahedron:Asymmetry - 2003 - V.14 - P.1451-1454]. As a result of interaction of camphor with aliphatic diamines in one stage, get the claimed diimine 1a-d. The reaction is carried out in conditions of azeotropic distillation of water using as catalyst epirate boron TRIFLUORIDE. The degree of conversion is controlled by sampling and analysis by GC, HMS. Join le,f receive when interacting camphor with aromatic diamines in an environment of tetraethoxysilane used as a dehydrating agent, as described in the method [Love V.E., Ren J. J. Synthesis of Sterically Hidered Imines // Org. Chem. - 1993 - V.58 - P.5556-5557]. Compounds 1a-f purified column chromatography, all substances obtained previously in the literature were not described.

The invention is illustrated by the following examples.

Example 1.

Obtaining N1N6bis(1,7,7-trimethylbicyclo[2.2.1]heptane-2-ilidene)hexane-1,6-diamine (1A)

To a solution of 3 g of (1R)-(+) camphor (19.7 mmol) in toluene (30 ml) is added 1,6-diaminohexane (9.8 mmol), 0.14 ml BF3·Et2O in 5 ml of toluene. P the action is carried out at a constant boil for 28 h, through the nozzle Dean-stark azeotrope to remove water. The control reaction was carried out by GC and CMS. The reaction mixture is washed with saturated NaCl solution, extracted with CH2Cl2, dried Na2SO4remove the solvent. Diemen 1a cleanse method, column chromatography, eluent hexane/ethyl acetate(100:0→0:100)+methanol (1%), distributed with the release of 46%.

An NMR spectrum1H (CDCl3, δ, ppm): 0.70 s 0.87 s (8H3With8'H3and9H3With9'H3), 0.91 s (10H3With10'H3), 1.13 ddd (H4nH4n',2J 12.5, J4n,5n9.3, J4n 5k4.1 Hz), 1.24-1.32 (m 2N132N13H5nH5'n), 1.50-1.57 (m 2N122N12'), 1.60 ddd (H5kH5k',2J 13.0, J5k,4k12.2, J5k,4m4.1 Hz), 1.77 (d (H2nH2'n,2J 16.8 Hz), 1.75-1.83 m (H4kH4'k), 1.87 dd (H3H3'I , J3,2k=J3,4k=4.3 Hz), 2.27 ddd (H2kH2'k,2J 16.8, J2k,34.3, J2k,4k3.2 Hz), 3.08-3.2 m (2H11, 2H11'). An NMR spectrum13C (CDCl3), δ, ppm: 180.99 s (C1With1'), 35.211 (C2With2'), At 43.71 d (C3, C3'), 27.371 (4With4'), 32.09 t (s5With5'), 53.23 s (6With6'), At 46.66 s (7With7'), 19.40 k and 18.83 k (8With8'and9With9'), 11.31 k (10With10'), 52.191 ( 11With11'), 30.441 (12With12'), 27.311 (13With13').[α]D22=18(CHCl3with 1.0). Found: m/z 384.3499 [M]+C26H44N2. Calculated: M=384.3503.

Example 2.

Obtaining N1N7bis(1,7,7-trimethylbicyclo[2.2.1]heptane-2-ilidene)heptane-1,7-diamine (1b).

To a solution of 3 g of (1R)-(+) camphor (19.7 mmol) in toluene (30 ml) was added a 1.7-diaminoheptane (9.8 mmol), 0.14 ml BF3·Et2O in 5 ml of toluene. The reaction is carried out as described in example 1, maintaining the reaction mixture within 32 hours, produce the compound (1b) with a yield of 65%.

An NMR spectrum1H (CDCl3, δ, ppm): 0.70 s 0.87 s (C8H3C8'H3and C9H3C9'H3), 0.91 s (C10H3C10'H3), 1.13 m (H4nH4n'), 1.18-1.32 (m 2H13, 2H13H5nH5'n, 2H14), 1.50-1.57 (m 2H12, 2H12'), 1.60 m (H5kH5k'), 1.77 (d (H2nH2'n), 1.75-1.83 m (H4kH4'k), 1.87 m (H3H3'), 2.27 m (H2kH2'k), 3.08-3.2 m (2H11, 2H11'). An NMR spectrum13C (CDCl3), δ, ppm: 180.97 s (1With1'), 35.211 (2With2'), 43.73 d (3With3'), 27.381 (4With4'), 32.101 (C5With5' ), 53.23 s (6With6'), 46.67 s (7With7'), 18.83 k (8With8'), 19.40 k (9With9'), 11.32 k (10With10'), 52.26 t (s11With11'), 30.391 (12With12'), 27.401 (13With13'), 29.281 (14).[α]D25=20.7(SNS3c=0.66). Found: m/z 398.3656 [M]+C27H46N2. Calculated: M=398.3653.

Example 3

Obtaining N1N8bis(1,7,7-trimethylbicyclo[2.2.1]heptane-2-ilidene)octane-18-diamine (1c).

To a solution of 3 g of (1R)-(+) camphor (19.7 mmol) in toluene (30 ml) was added 1,8-diaminooctane (9.8 mmol), 0.14 ml BF3·Et2O in 5 ml of toluene. The reaction is carried out as described in example 1, maintaining the reaction mixture for 35 h, produce the compound (1c) with a yield of 67%.

An NMR spectrum1H (CDCl3, δ, ppm): 0.69 s and 0.86 s (9H3With9'H3and8H3With8'H3), 0.91 s (10H3With10'H3), 1.13 dia (H4nH4n',2J 12.3, J4n,5n9.3, J4n 5k4.2 Hz), 1.19-1.30 m (2N132N132N142N14), 1.29 ddd (N5hN5h',2J 13,J5h,4h9.3,J5h,4k4.4 Hz), 1.47-1.56 (m 2N122N12'), 1.59 DDD (H5kN5K'2J 13.0, J 5k,4k12.2, J5k,4h4.2 Hz), 1.77 (H2nH2'n,2J 16.7 Hz), 1.74-1.82 m (N4KN4 K), 1.86 DD (N3N3'J3,2k=J3,4k=4.4 Hz), 2.27 DDD (H2kH2'k,2J 16.7, J2k,34.4, J2k,4k3.2 Hz), 3.12 dt (H11aH11'a,2J 12.1, J11a,127.3 Hz), 3.16 dt (HllN11'e,2J 12.1, J11b,127.3 Hz) NMR Spectrum13C (CDCl3), δ, ppm: 180.00 s (1With1'), 35.191 (2With2'), At 43.71 d (3With3'), 27.35 t (s4With4'), 32.07 t (s5With5), 53.23 s (6With6'), At 46.66 s (7With7'), 19.38 k and 18.81 k (8With8'and9With9'), 11.29 k (10With10'), 52.22 t (s11With11'), 30.37 t (s12With12'), 27.33 t (s13With13'), 29.32 t (14With14').[α]D25=-32.0(CHCl3c=0.92). Found: m/z 412.3813 [M]+C28H48N2. Calculated: M=412.3812.

Example 4.

Obtaining N1N12bis(1,7,7-trimethylbicyclo[2.2.1]heptane-2-ilidene)dodecan-1,12-diamine (1d).

To a solution of 3 g of (1R)-(+) camphor (19.7 mmol) in toluene (30 ml) is added 1,12-diaminododecane (9.8 mmol), 0.14 ml BF3·Et2O in 5 ml of toluene. The reaction is carried out as described in example 1, maintaining reaction the second mixture for 48 h, highlight exit 41%.

An NMR spectrum1H (CDCl3, δ, ppm): 0.71 s and 0.88 s (C8H3C8'H3and C9H3C9'H3), 0.92 s (C10H3C10'H3), 1.15 ddd (H4nH4n',2J 12.2, J4n,5n9.3, J4n 5k4.2 Hz), 1.18-1.28 (m 2H13, 2H13', 2H142N14'2N152N15'2N162N16'), 1.30 ddd (N5hN5h',2J 12.8, J5k,4k9.3, J5h,4k4.3 Hz), 1.49-1.57 (m 2N122N12'), 1.61 ddd (H5kH5k',2J 12.8, J5k,4k12.2, J5m,4H4.1 Hz), 1.78 (d (H2nH2'n,2J 16.8 Hz), 1.76-1.84 m (H4kH4'k), 1.88 dd (H3H3'I , J3,2k=J3,4k=4.4 Hz), 2.28 ddd (H2kH2'k,2J 16.8, J2k,34.3, J2k,4k3.2 Hz), 3.13 dt (H11aH11'a2J 12.1, J11a,127.3 Hz), 3.17 dt (N11bHn,2J 12.1, JV7.3 Hz). An NMR spectrum13C (CDCl3), δ, ppm: 180.98 s (C1With1'), 35.23 t (s2With2'), 43.75 d (3C3'), 27.401 (4With4'), 32.11 t (s5C5'), 53.25 s (6With6'), 46.68 s (7With7'), 18.85 k (8With8') 19.41 k (9With9'), 11.33 k (10With10'), 52.261 (11With11'), 30.421 (12With12'), 27.411 (13With13'), 29.38 t (s14With14'), 29.46 t (s15With15'), 29.49 t (s16With16' [α]D25=-32.7(CHCl3with=0.8). Found: m/z 468.4435 [M]+C32H56N2. Calculated: M=468.4435.

Example 5.

Obtaining N,N'-4,4'-Methylenebis(N-(1,7,7-trimethylbicyclo[2.2.1]heptane-2-ilidene)aniline (1e).

To 3 g (19.8 mmol) of camphor added 1.95 g (9.9 mmol) of 4,4'-methylenedianiline and 0.1 ml conc. H2SO4, 4.1 ml (19.8 mmol) of Si(OEt)4, boiled for 10 h in an argon atmosphere. Remove any traces of alcohol, which was formed from tetraethoxysilane distillation on a rotary evaporator, add a saturated solution of NaHSO3, extracted with ether. The organic layer is dried with MgSO4remove the solvent. Later in the reaction mixture was added 4 ml of 1 M KOH and 20 ml EtOH. Stirred for 20 min, then filtered formed silicates, organic layer washed with saturated NaCl solution, extracted with ether, dried with Na2SO4. Remove sulfuric ether, obtain 3.8 g of the reaction mixture. Column chromatography on 40 g of SiO2, eluent hexane/ethyl acetate(100:0→0:100)+methanol(1%) secrete Diemen (1e) with a yield of 41%.

An NMR spectrum1H (CDCl3, δ, ppm): 0.83 s and 0.94 s (8H3With8'H3and9H3With9'H3), 1.06 s (0 H3With10'H3), 1.17-1.25 m (H4nN4 p) m 1.52-1.46 (H5nH5'n), m 1.70-1.77 (H2nH2'nH5kH5k') m 1.81-1.88 (H4kH4kN3), m 2.15-2.22 (H2kH2k'), s 3.87 (2H17), m 6.63 (n13,15,13',15'), m 7.04 (N12,16,12'16'). An NMR spectrum13C (CDCl3), δ, ppm: 184.43 s (C1With1'), 36.141 (2With2'), At 43.71 d (3With3'), 27.341 (C4With4'), 31.971 (5With5'), 53.81 s (6With6'), 46.99 s (7With7'), 18.93 k (8With8') 19.45 k (9With9'), 11.12 k (10With10'), 150.01 s (11With11'), 119.37 d (12With12'), 129.24 d (13With13'), 137.86 s(C14With14'), 129.24 d (15With15'), 119.37 d (16With16') At 40.58 t (s17),[α]D30=29(CHCl3, c=0.6). TPL=129-130°C. Found: m/z 466.3343 [M]+C33H42N2. Calculated: M=466.3347

Example 6.

Obtaining N-(1,7,7-trimethylbicyclo[2.2.1]heptane-2-ilidene)-4-(4-(1,7,7-trimethylbicyclo[2.2.1]heptane-2-ylideneamino)phenoxy)aniline (1f).

To 3 g (19.8 mmol) of camphor added 1.95 g (9.9 mmol) of 4,4'-occidentalia and 0.1 ml conc. H2SO4, 4.1 ml (19.8 mmol) of Si(OEt)4, boiled for 10 h in an argon atmosphere. Further processing the reaction is carried out, as described in example 5. The compound (1f) was isolated with a yield of 46%.

An NMR spectrum1H (CDCl3, δ, ppm): 0.83 s and 0.94 s (8H3With8'H3and9H3With9'H3), 1.07 s (10H3With10'H3), 1.19-1.26 m (H4nH4'n) m 1.53-1.46 (H5nH5'n), m 1.70-1.80 (H2nH2'nH5kH5k) m 1.81-1.92 (H4kH4kN3), m 2.18-2.25 (H2kH2k), m 6.68 (N13,15,13',15'), m 6.89 (N12,16,12',16'). An NMR spectrum13C (CDCl3), δ, ppm: 184.94 s (C1With1'), 36.141 (2With2'), 43.70 d (3With3'), 27.31 t (s4With4'), 31.93 t (s5With5'), 53.86 s (6With6'), 46.98 s (7, C'), 18.89 k (8With8'), 19.43 k (9With9'), 11.10 k (10With10'), 147.29 s (11With11'), 120.53 d (12With12'), 118.98 d (13With13'), 153.36 s (14With14'), 118.98 d (15With15'), 120.53 d (16With16').[α]D31=30,3(CHCl3c=0.56). Tthe Plava=S*. Found: m/z 468.3138 [M]+C32H40N2+. Vicis the network: M=468.3135.

Example 7.

The study of the toxicity of drugs.

Toxicity of the products was studied in relation to the MDCK cells. The MDCK cells were seeded in 96-well plates and cultured at 37°C in MEM medium with addition of 10% bovine serum in an atmosphere of 5% CO2(getprotocol incubator Sanyo-175) to the state of the monolayer. Of the study drug was prepared by the mother solution of concentration 10 mg/ml in dimethyl sulfoxide, and then prepared a series of twofold dilutions of the drugs in the environment MEM from 1000 up to 3.75 µg/ml Dissolved preparations were made in the wells of tablets and incubated for 2 days at 37°C. after this period, cells were washed 2 times for 5 min in phosphate-saline buffer, and the number of living cells was assessed using microtitration test (MTT). To this end, in the wells of tablets was added 100 μl of a solution (5 mg/ml 3-(4,5-dimethylthiazole-2)2,5-diphenyltetrazolium bromide (ICN Biochemicals Inc., Aurora, Ohio) in physiological solution. Cells were incubated at 37°C in an atmosphere of 5% CO2within 2 h and was washed for 5 min in phosphate-saline buffer. The precipitate was dissolved in 100 µl per well of DMSO, after which the optical density in the wells of the plates were measured on the multi-function reader Victor 1420 (Perkin Elmer, Finland) at a wavelength of 535 nm. The test results for each product was determined by the 50% cytotoxic dose (CTD50), i.e. the concentration of the drug is, causing the death of 50% of the cells in culture. The results are shown in the table.

Example 8.

Antiviral activity of drugs.

Determination of the antiviral activity of the drugs was performed on MDCK cells in 96-well tablets for cell cultures. Compounds were dissolved in a supportive environment for cells, was introduced into the wells of the panels with the cell monolayer and incubated for 1 h at 36°C in an atmosphere of 5% CO2.

From vaccinated liquid (strain A/California/07/09 (H1N1)pdm09) have prepared a series of ten-fold dilution from 10-1up to 10-7was added to the wells with drugs and incubated at 36°C for 48 h in an atmosphere of 5% CO2. At the end of the period of incubation, 100 μl of culture fluid was mixed with an equal volume of 1% chicken erythrocytes in a separate tablets with a round bottom. Analysis was performed after 60 min incubation at 20°C. the titer of the virus was taking the reciprocal of the decimal logarithm of the highest dilution of the initial virus that can cause a positive reaction of haemagglutination in the hole, and expressed in the amount of 50% infectious doses (ID50). Virusinghviru effect of the studied compounds was assessed by the reduction of the titer of virus in the experiment compared with the control. On the basis of the obtained data was calculated 50% inhibitory dose ED50, i.e. the concentration of the drug, snauwaert viral replication twice (0.3 lg ID 50), and chemotherapeutic index or index of selectivity (SI), representing the ratio of the CTD50to the ED50.

In the research process of inhibiting the reproduction of influenza virus compounds la-f and standards of comparison (amantadine and rimantadine) were obtained the results given in the table.

Thus, the claimed compounds exhibit pronounced antiviral activity in combination with low toxicity. Chemotherapeutic index of compounds (1a-d) exceeds that of the comparative drugs three or more times. The advantage of the above compounds is their activity against rimantadine-resistant influenza virus strain A/California/07/09 (HlNl)pdm09 that shows the viability of their application to the treatment of modern epidemically actual virus, the vast majority of which were resistant to rimantadine.

Table.
ConnectionFormulaCTD50µg/mlEC50µg/mlSI
1a5175,889
1b>5009,155
1c16110,016
1d103921,149
1e>5001643
1f>5001753
Amantadine42.99.74
Rimantadine60125

Symmetric diimine based camphor of formula 1a-f,

manifesting St is istwa inhibitors reproduction of influenza virus (strain A/California/07/09 (H1N1)pdm09).



 

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4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing 1,3-bis(3,4-diaminophenoxy)benzene hydrochloride. The method involves acylation of 2-nitro-5-chloroaniline with acetic anhydride at temperature 90°C for 0.5 hours and molar ratio 2-nitro-5-chloroaniline: acetic anhydride = 1:2, nucleophilic substitution of the chlorine atom with resorcin in dimethyl formamide in the presence of K2CO3 for 6 hours at temperature 110°C and molar ratio M-acetyl-5-chloro-2-nitroaniline: resorcin = 2:1, removing the acyl protection of the amino group as a result of acid hydrolysis for 1 hour at temperature 60°C in 25% aqueous H2SO4 solution. The nitro group in the aliphatic alcohol is then reduced under the effect of SnCl2·2H2O solution in concentrated hydrochloric acid at alcohol boiling point for 1 hour and molar ratio 1.3-bis(3-amino-4-nitrophenoxy)benzene: SnCl2·2H2O=1:6.7, with further extraction of the product with chloroform and transfer thereof into hydrochloride by treating concentrated hydrochloric acid with a chloroform extract and holding at temperature -10°C for 8 hours.

EFFECT: method enables to reduce the number of steps, optimise reaction conditions, ie cutting time and lower temperature of the process, increasing purity and output of the end product.

4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method for synthesis of 4-(3,4-diaminophenoxy)benzoic acid esters of general formula where R = CH3, CH(CH)3, which are used as an intermediate product in synthesis of thermally stable polymer materials. The desired compounds are obtained through acylation of 2-nitro-5-chloroaniline with acetic anhydride, nucleophilic substitution of the chlorine atom during reaction with 4-hydroxybenzoic acid in DMSO in the presence of K2CO3, removal the acyl protection of the amine group as a result alkaline hydrolysis, simultaneous reduction and formation of an ester bond of 4-(3-amino-4-nitrophenoxy)benzoic acid. Acylation of 2-nitro-5-chloroaniline is carried out at temperature 90°C for 1 hour and molar ratio of 2-nitro-5-chloroaniline: acetic anhydride = 1:2. Nucleophilic substitution of the chlorine atom is carried out in 8 hours at temperature 105°C and molar ratio of N-acetyl-5-chloro-2-nitrianiline: 4-hydroxybenzoic acid = 1:1.05. Removal of the acyl protection is carried out in 0.5 hours at temperature 60°C in 20% aqueous solution of KOH. Reduction with simultaneous formation of an ester bond is carried out in aliphatic alcohol using a solution of SnCl2·2H2O in concentrated hydrochloric acid at boiling point of the alcohol for 1 hour and molar ratio 4-(3-amino-4-nitrophenoxy)benzoic acid: SnCl2·2H2O = 1:3.35.

EFFECT: fewer steps, lower process temperature, high purity and output of the end products.

5 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method for synthesis of 4-(3,4-diaminophenoxy)benzoic acid, which is used as an intermediate product in synthesis of thermally stable polymer materials. The desired compound is obtained through acylation of 2-nitro-5-chloroaniline with acetic anhydride, nucleophilic substitution of the chlorine atom during reaction with 4-hydroxybenzoic acid in DMSO in the presence of K2CO3, removal the acyl protection of the amine group as a result alkaline hydrolysis, simultaneous reduction and formation of an ester bond of 4-(3-amino-4-nitrophenoxy)benzoic acid. Acylation of 2-nitro-5-chloroaniline is carried out at temperature 90°C for 1 hour and molar ratio of 2-nitro-5-chloroaniline: acetic anhydride = 1:2. Nucleophilic substitution of the chlorine atom is carried out in 8 hours at temperature 105°C and molar ratio of N-acetyl-5-chloro-2-nitrianiline: 4-hydroxybenzoic acid = 1:1.05.Removal of the acyl protection is carried out in 0.5 hours at temperature 60°C in 20% aqueous solution of KOH. Reduction is carried out using a solution of SnCl2·2H2O in concentrated hydrochloric acid at temperature 90°C for 1 hour and molar ratio 4-(3-amino-4-nitrophenoxy)benzoic acid: SnCl2·2H2O = 1:3.35.

EFFECT: possibility of obtaining acid in minimal time with high output and high degree of purity.

4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to method of obtaining 3,4'-diamino-4-R-benzhydrols of general formula . Where R1=Cl (1); R1=Br (2); R1= (3), which are used as semi- products in synthesis of nitrogen dyes, consisting in simultaneous reduction of nitro- and carbonyl groups of respective dinitrobenzophenons of general formula . Where: R1=Cl; R1=Br; , reduction system Zn-NaBH4 in alcohol with mole substratum ratio: zinc: sodium tetrahydroborate equals 1:6:0.5.

EFFECT: reduction of synthesis cost, reduction of time and temperature of process carrying out, increase of target product output.

1 cl, 2 tbl, 3 ex

FIELD: organic chemistry, polymers, chemical technology.

SUBSTANCE: invention elates to a method for preparing super-branched polyimides based on new 4,5-bis-(3-aminophenoxy)phthalic acid. Super-branched polyimides comprise the following statistically links distributed in macromolecule: dendrite structure of the formula (I):

; links with linear structure of the formula (II):

, and terminal links of structure of the formula (III):

. Polyimides are prepared by the polycondensation reaction with simultaneous or the following cyclization reaction of 4,5-bis-(3-aminophenoxy)phthalic acid of the structural formula:

in melt of at least one aromatic monocarboxylic acid at temperature 110-180°C. Proposed polyimides can be used for the development of new polymeric materials compromising thermal stability with possibility for processing and the presence of assigned amount of functional groups able to polymer-analogous transformation. Invention provides expanding assortment of super-branched polyimides and to use a single-stage method also.

EFFECT: improved preparing method, valuable properties of polyimides.

5 cl, 7 ex

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention relates to new derivatives of uracil of the formula [I] eliciting the herbicide effect, herbicide composition based on thereof and a method for suppression of weed growth. In the formula [I] W means oxygen (O), sulfur (S) atom or imino-group; Y means oxygen atom (O) or sulfur atom (S); R1 means (C1-C3)-alkyl or (C1-C3)-halogenalkyl; R2 means (C1-C3)-alkyl; R4 means hydrogen atom (H) or methyl; R5 means (C1-C6)-alkyl, (C1-C6)-halogenalkyl, (C3-C6)-alkenyl, (C3-C6)-halogenalkenyl, (C3-C6)-alkynyl or (C3-C6)-halogenalkynyl; X1 means halogen atom, cyano- or nitro-group; X2 means hydrogen atom (H) or halogen atom; each among X3 and X4 means independently hydrogen atom (H), halogen atom, (C1-C6)-alkyl, (C1-C6)-halogenalkyl, (C3-C6)-alkenyl, (C3-C6)-halogenalkenyl, (C3-C6)-alkynyl, (C3-C6)-halogenalkynyl, (C1-C6)-alkoxy-(C1-C6)-alkyl, (C1-C6)-alkoxy-, (C1-C6)-halogenalkoxy-, (C1-C6)-alkoxycarbonyl-(C1-C6)-alkoxy- or cyano-group. Also, invention relates to new intermediate substances used for preparing compounds of the formula [I] corresponding to formulae [VII] , [XXXIV] and [XXXIII] wherein in compound of the formula [VII] W means oxygen (O), sulfur (S) atom or imino-group; Y means oxygen (O) or sulfur atom (S); in compounds of formulae [XXXIV] and [XXXIII] W means oxygen atom (O); R17 means oxygen atom (O); R4 means hydrogen atom (H) or methyl. Also, invention relates to methyl- or ethyl-[2-(5-amino-2-chloro-4-fluorophenoxy)phenoxy]acetate not early described in the literature.

EFFECT: valuable herbicide properties of compounds.

23 cl, 17 sch, 9 tbl, 11 ex

The invention relates to new tricyclic derivative of the formula (I), (Ia'), (Ib'), (Ig'), (If'), their salts and hydrates, which have immunosuppressive or anti-allergic activity, pharmaceutical compositions based on these compounds and to a method of suppressing immune response or treatment and/or prevention of allergic diseases

The invention relates to new substituted bicyclic compounds of General formula I: R1-A-D-E-G-L-R2(I) where R1means naphthyl or a residue of formula:

< / BR>
< / BR>
< / BR>
< / BR>
where a = 1 or 2, R3means H, C2-C6alkenyl, C1-C6alkyl or C1-C6acyl and all of the above ring systems and the remains unsubstituted or substituted optionally gemenele, one or more, same or different substituents selected from the group: halogen, carboxyl, hydroxy, phenyl, C1-C6alkoxy, a group of the formula -(CO)b-NR4R5where b = 0 or 1, R4and R5the same or different and independently of one another denote hydrogen, phenyl, C1-C6acyl, C4-C7cyclacel, benzene C1-C6alkyl and the other dialkylamino, where alkyl with 1-6 carbon atoms, a and E are the same and different and mean a connection or C1-C4alkylene, D is-O - or a residue of formula-S(O)c- or-N(R9)- , THE 2-5T.GIF" ALIGN="ABSMIDDLE">< / BR>
and the other, G means double-linked aryl with 6-10 carbon atoms, or double-linked 5-7 membered aromatic heterocycle containing up to 3 heteroatoms from the series of sulfur, nitrogen and/or oxygen, which may be substituted by one or more identical or different substituents, R2means6-C10aryl or a 5-7 membered saturated or aromatic heterocycle containing up to 3 heteroatoms from the series of sulfur, nitrogen and/or oxygen, unsubstituted or substituted by one or more identical or different substituents with the exception of compounds of the formula I, where R1means of naphthas-1-yl, unsubstituted or substituted in position 3 C1, C1-C4the alkyl and in position 4 chlorine or phenyl; a and E indicate the relationship, D is-O-; G means 1,4-phenyl, unsubstituted or substituted C1-C4by alkyl; L is-O-; R2means of CH3and except for the connection m-bis-(1-naphthyloxy)benzene

Chemical plant // 2508287

FIELD: chemistry.

SUBSTANCE: chemical plant includes a first process unit, having a reactor for producing nitrobenzene via nitration of benzene to produce a first waste water stream containing nitrobenzene; at least a second process unit, having a reactor for producing aniline by reducing nitrobenzene with hydrogen to provide a second waste water stream containing aniline; an aniline purification apparatus for removing nitrobenzene from aniline, a stripping column for separating aniline from the waste water stream. The first waste water stream is fed into the stripping column below the point of input of the second waste water stream, where said stripping column separates aniline and nitrobenzene from said first and second waste water streams, and the separated aniline and nitrobenzene are fed into said aniline purification apparatus. The stripping column normally used for the plant has n theoretical trays denoted by symbols A1 through An, wherein A1 corresponds to the top tray and An corresponds to the bottom tray; said second waste water stream is fed into the stripping column at theoretical tray Ax, where x is not less than 1, and said first stream is fed into the stripping column at theoretical tray A[y], where [y] is the integer part of the value y, and the value y itself satisfies the equation 0.5*(n+1)+0.5*x<y<0.85*(n+1)+0.15*x. The plant can further include a reactor for producing diaminodiphenylmethane (DADPM) for converting said aniline of said aniline stream into DADPM.

EFFECT: invention enables to obtain products of high quality with a considerable economic effect by avoiding the need to treat each stream separately.

18 cl, 2 dwg, 2 tbl

FIELD: chemistry.

SUBSTANCE: method of producing polyphenyl polyamines comprises steps of producing an aqueous stream containing polyphenyl polyamines and removing the polyphenyl polyamines from the aqueous stream. The method of removing polyphenyl polyamines involves preparing pertraction equipment, having a membrane which has a first side and a second side opposite the first side. The membrane is then soaked with a liquid characterised by surface tension of less than 40 mN/m. Further, the aqueous stream containing polyphenyl polyamines linked by bridge methylene groups is brought into contact with the first side fo the membrane and the second side of the membrane is brought into contact with an organic stream. During this process, there is transfer of polyphenyl polyamines from the aqueous stream through the membrane into the organic stream.

EFFECT: invention reduces the number of steps of the method, makes the extraction step more robust when operating in varying process conditions.

14 cl, 4 dwg

FIELD: chemistry.

SUBSTANCE: method involves reacting aniline and formaldehyde in the presence of an acid catalyst, wherein the aniline used contains 0.0001-0.25 wt %, with respect to the weight of the used aniline, of compounds having at least one carbonyl group or which are products of reaction of such carbonyl compounds with aniline. The invention also relates to a method of producing di- and polyisocyanates of the diphenylmethane series, wherein di- and polyamines of the diphenylmethane series obtained using the disclosed method react with phosgene.

EFFECT: method considerably improves the colour of the obtained product.

6 cl, 1 tbl, 9 ex

Antioxidants // 2496768

FIELD: chemistry.

SUBSTANCE: invention relates to novel dialkylaniline cyclohexane derivatives which can be used as antioxidants. In formulae and , Ar1 and Ar2 can be identical or each represents a C1-30alkylC6aromatic group; each of R1, R2, R3, R4, R5 and R6 is hydrogen.

EFFECT: invention also relates to a method of producing said compounds and lubricating oil compositions containing said compounds.

8 cl, 2 dwg, 2 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing alkylated 1,3-benzenediamine compounds of structural formula II. The alkylated 1,3-benzenediamine compound is used as a deposit growth inhibiting additive for lubricating oil for organic materials containing lubricating oil, gasoline and diesel fuel. The method of alkylating a 1,3-benzenediamine compound involves reacting a first carbonyl compound with a 1,3-benzediamine compound to form an intermediate compound, where the first carbonyl compound is substituted on the corresponding nitrogen atoms of 1,3-benzenediamine, and reacting a second carbonyl compound with said intermediate compound in the presence of hydrogen and a hydrogenation catalyst to form alkylated 1,3-benzenediamine, where the second carbonyl compound is substituted on the central aromatic ring of the alkylated 1,3-benzenediamine. The alkylated 1,3-benzenediamine has the structure (II) of general formula: (I), in which R1 and R2 are independently selected from a group consisting of hydrogen, C1-C20 alkyl, 2-methylpropenyl, benzyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl; R3 and R4 are independently selected from a group consisting of C1-C20 alkyl, 2-methylpropenyl, benzyl, cyclopentyl, cyclohexyl, cycloheptyl and cycloocty; and R5 and R6 are independently selected from a group consisting of n-propyl, 1-methylethyl, n-butyl, isobutyl, sec-butyl, 1,3-dimethylbutyl, 1,4-dimethylpentyl, n-pentyl, isopentyl, 1,5-dimethylhexyl, hexyl, 2-methylpropenyl, benzyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and hydrogen, under the condition that at least one of R5 and R6 is not hydrogen.

EFFECT: method increases selectivity of alkylation on amino groups and the benzene ring; obtained compounds improve oxidation resistance of lubricant substances and fuel.

5 cl, 5 tbl, 21 ex

FIELD: chemistry.

SUBSTANCE: invention relates to an improved method of producing 4-(1-adamantyl)-1,2-diaminobenzene, which exhibits various types of biological activity. The method involves reaction of 1-bromoadamantane and o-phenylenediamine at temperature 180°C for 8 hours in molar ratio -bromoadamantane: o-phenylenediamine equal to 1:2-3.

EFFECT: method enables to obtain 4-(1-adamantyl)-1,2-diaminobenzene in a single step from readily available reactants without using highly toxic solvent with high output (55-76%).

1 dwg, 2 ex

FIELD: chemistry.

SUBSTANCE: according to the disclosed method, a) dinitrotoluene undergoes hydrogenation in the presence of a catalyst and the obtained reaction mixture is separated from the catalyst, water and optionally solvent to obtain crude toluylenediamine, and b) crude toluylene undergoes distillation separation in a column with a partition in the middle part of the column, having a condenser, an evaporator and separating segments, to obtain at least four product streams P1-P4, wherein stream P1 contains low-boiling products, stream P2 contains o-toluylenediamine, stream P3 contains m-toluylenediamine, streap P4 contains high-boiling products and m-toluylenediamine.

EFFECT: method enables easy and efficient extraction of m-toluylenediamine from crude toluylenediamine obtained through hydrogenation of dintritoluene.

11 cl, 5 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to organic chemistry and particularly to a combined method of obtaining 4-amino-2,6-dinitro- and 2,4,6-triaminotoluenes, which involves reacting a solution of 2,4,6-triaminotoluene in aliphatic alcohol with titanium trichloride in aqueous solution of hydrochloric acid in molar ratio of 2,4,6-triaminotoluene to titanium trichloride equal to 1:(8-9), with subsequent removal of aliphatic alcohol in a vacuum and extraction of the obtained 4-amino-2,6-dinitrotoluene in form of its hydrochloride through filtration. The filtrate undergoes electrochemical reduction in a diaphragm cell, which has a cathode and an anode. The catholyte is subsequently evaporated in a vacuum at temperature 50-60°C and the formed 2,4,6-triaminotoluene is extracted in form of its trihydrochloride through filtration with subsequent return of the obtained filtrate to the reaction.

EFFECT: proposed method is not explosive and virtually produces no wastes.

2 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention pertains to new derivatives of the row N-(2-aminophenyl)-N-(9-anthrylmethyl)amine, and particularly 1-[2-(9-anthrylmethylamino)phenyliminomethyl]-2-naphthol with formula I: , which in a neutral medium, has highly effective properties of selective fluorescent chemosensor on Hg2+ cations.

EFFECT: obtaining of new derivatives with highly effective properties.

1 dwg, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to the method of obtaining diaminephenylmethane and its highest homologues by the condensation of aniline and formaldehyde in the presence of heterogeneous solid acid catalysts, which are characterised by the fact that the utilised catalysts are catalysts selected from (a) split zeolites and/or (b) alumo-silicate catalysts, which have the regulated hexagonal mesoporous structure with the size of 3-10nm.

EFFECT: it makes it possible to get diaminephenylmethane with the increased contents of primary amines.

4 cl, 4 ex

FIELD: chemistry.

SUBSTANCE: in adamantane amino-derivatives of general formula (1), R=OH, R1=R2=R3=H, R4=C2H5, X=Cl, n=1 (I); R=Br, R1=R2=R3=H, R4=C2H5, X=Br, n=1 (II); R=OH, R1=R2=H, R3+R4=-CH2CH2CH2CH2-, X=Cl, n=1 (III); R=Br, R1=R2=H, R3+R4=-CH2CH2CH2CH2-, X=Br, n=1 (IV); R=OH, R1=R2=CH3, R3=R4=H, X=CI, n=1 (V); R=CH3, R1=-CH2OH, R2=R3=R4=H, X=Cl, n=1 (VI).

EFFECT: higher antiviral activity of derivatives towards influenza virus.

1 cl, 1 tbl, 9 ex

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