Aspartyl derivatives of histamine, method for their preparing, pharmaceutical composition and their using as modulators of enzyme activity of antioxidant protection

FIELD: bioorganic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to novel aspartyl derivatives of histamine of the general formula (I): , wherein R means hydrogen atom (H), or , or that are able to modulate activity of enzymes of antioxidant protection - superoxide dismutase (SOD) and catalase. Also, invention relates to using the known compounds of the general formula (I) for the same designation wherein at the same values of X the value R represents acetyl group, and to their pharmaceutically acceptable salts. Also, invention relates to a pharmaceutical composition possessing capacity to modulate activity of SOD and catalase and comprising the effective amount of compound of the general formula (I), and to a method for synthesis of compounds of the general formula (I). Method involves interaction of pentafluorophenyl ester Nα-Z-, β- or α-benzyl ester of aspartic acid with histamine followed by hydrogenolysis without isolation of intermediated protected derivatives of aspartyl histamine.

EFFECT: improved method of synthesis, valuable biochemical properties of derivatives.

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

 

The present invention relates to the field of Bioorganic chemistry and relates to new compounds, N-aspartyl derivatives of biogenic amine histamine, and a method for the synthesis of novel and known compounds and their biomedical applications in biology and medicine as modulators of the activity of enzymes of antioxidant protection.

PRIOR art

It is known that the violation of oxidative and energy processes in the body leads to the emergence and development of some diseases. The degree of disturbance of these processes correlates with the depth of the pathology, and their normalization with the development of the restorative functions in tissues and improving the condition of patients.

In regulation of functioning of organs and tissues is an important role of active forms of oxygen, peroxide compounds, and antioxidant substances of several, in particular the antioxidant enzymes - superoxide dismutase (SOD) and catalase. These enzymes in the body are as balanced and coordinated system in which the functioning of the enzyme correlates with the action of another [Halliwell C. Gutteridge J. // Free radicals in biology and medicine. / 1999. University Press. Oxford. 963 p. P.171] When changing the activity and balance of these enzymes may increase the number of active forms of oxygen and peroxides, which, in turn, can call the performance degradation of proteins, nucleic acids and lipids and the stability of cell membranes [Halliwell C. Gutteridge J. // Free radicals in biology and medicine. / 1999. University Press. Oxford. 963 p.; Boldyrev A.A. // Carnosine. Biological significance and possible applications in medicine. / M: Publishing house of Moscow state University. 1998. 320 S.; Guilivi C., Cadenas E. The role of mitochondrial glutatione in DNA base oxidation. //Biochim. Biophys. Acta. 1998. V.1366. No. 3. P.265-274].

It is known that moderately increased expression of SOD in normal neuronal cells increases the lifespan of mice, and inhibition of SOD leads to apoptosis of neurons [Halliwell C. Gutteridge J. // Free radicals in biology and medicine. / 1999. University Press. Oxford. 963 p. P.751]. At the same time, overexpression of Zn/Cu SOD is one of the reasons cell death, increasing the FLOOR, the destruction of neurons in the brain [Y.C., Hyeok Y.Kwon, O.B.Kwon, J.H.Kang. Hydrogen peroxide-mediated Cu, Zn-superoxide dismutase fragmentation: protection by carnosine, homocarnosine and anserine. // Biochem. Biophys. Acta. 1999. V.1472. P.651-657; Halliwell C. Gutteridge J. // Free radicals in biology and medicine. / 1999. University Press. Oxford. 963 p.].

The accumulation of H2O2in the cell can be observed in the activation of SOD and reduction of catalase activity.

The result of this imbalance may be the disruption of the functioning of cells, apoptosis, and even death, which is unacceptable for healthy cells, but is the target of anticancer therapy. Thus, elevated levels of SOD in the cell can have on them cytotoxic effect caused by the fragmentation of the nucleic acid is t under the action of HEformed by the reaction of Fenton decomposition of H2O2catalyzed by Zn,Cu-SOD [Dowja W., Kharatishvili M., Costa, M. DNA and RNA strand scission by cooper, zinc and manganese superoxide dismutases. // Biometals. 1996. V.9. P.327-335].

It is known that inhibitors of SOD can, increasing the number of O2-•to cause apoptosis of tumor cells [Huang P., Feng L, Oldham E.A. et al. Superoxide dismutase as a target for the selective killing of cancer cells. // Nature. 2000. V.407. No. 6802. R-395]. In this case, the mechanism of apoptosis is also associated with the formation of HEof O2-•with the subsequent destruction of them of nucleic acids.

In connection with the above, the enzymes SOD and catalase are attractive targets for pharmacological effects and modulators of their activity as activators and inhibitors, can find use as therapeutic agents for the treatment of diseases accompanied by increased levels of reactive oxygen species, such as diabetes, myocardial infarction, cerebral ischemia, inflammatory and autoimmune diseases, etc. in Addition, regulation of the activity of antioxidant enzymes using biocompatible low molecular weight compounds represents a new strategy in the treatment of neoplastic diseases.

Biosynthesis of N-aspartyl derivatives of histamine (II, III, IV) was observed in the rat brain, and the biological function of these compounds is unclear [.Kvamme, .L.Reichelt, P.D.Edminson. Proceedings of the tenth FEBS meeting. // 1975. P.127]. Compounds II, III, IV were isolated from the homogenate of the brain. For espartignac proizvodnyh histamine there are no published data on their chemical synthesis, physico-chemical constants and biological activity.

It is known the use of inorganic compounds, mainly salts, such as sulfides, cyanides, azides, HOCI and others [Halliwell C. Gutteridge J. // Free radicals in biology and medicine. / 1999. University Press. Oxford. 963 p.] as inhibitors of SOD and catalase.

In addition, for this purpose are organic compounds. So, a well-known aminotriazol as an inhibitor of catalase used in vitro and in vivo [Halliwell C. Gutteridge J. // Free radicals in biology and medicine. / 1999. University Press. Oxford, p.138, 381].

The most commonly used inhibitor of SOD is diethyldithiocarbamic acid (DETCA)acting at a concentration of 10-3M [N. Kanie, K. Kamata Contractile responses in spontaneously diabetic mice. I. Involvement of superoxide anion in enhanced contractile response of aorta to norepinephrine in C57BL/ KSJ (db/db) mice. // General Pharmacology. 2000. V.35. No. 6. P311-318]; Triethylenetetramine (THETA) with the same current concentration [Weissmann N., Winterhalder, S., M. Nollen et al. NO and reactive oxygen species are involved in biphasic hypoxic vasoconstriction of isolated rabbit lungs. // American J. Discrimination. 2001. V.280. No. 4. P.638-645].; hydroxyl and hydroxymethylene estrogen derivatives [P. Huang, Feng L, Oldham E.A. et al. Superoxide dismutase as a target for the selective killing of cancer cells. // Nature. 2000. V.407. No. 6802. P.390-395]; EDTA [Somani B.L, V. Ambade, Bulak. P.M., Y.V. Sharma Elimination of superoxide dismutase interference in fructosamine assay. // Clinical biochemistry. 1999. V.32. No. 3. R-188]; diethylcarbamazine [X. Chen, J.D. Catravas Release of a leukocyte activation inhibitor by staurosporine-treated pulmonary artery endothelial cells. // Amer. J. Discrimination. 1999. V.275. P.184-192].

The main disadvantages of the known inhibitors are their toxicity, unnatural or endogene origin and high current concentration, which limits the possibilities for further study for biomedical applications.

The aim of the invention is a method for the synthesis of novel and known aspartyl derivatives of histamine General formula I and their use as effective modulators of the activity of antioxidant enzymes SOD and catalase.

BRIEF description of the INVENTION

The present invention relates to new aspartyl derived histamine General formula I:

where R is hydrogen, and X is

and their pharmaceutically acceptable salts, having the ability to modulate the activity of antioxidant enzymes - superoxide dismutase (SOD) and catalase.

The present invention relates also to the use of compounds of General formula I:

where R represents acetyl group, and represent

and their pharmaceutically acceptable salts, having the ability to modulate the activity of the enzymes superoxide dismutase (SOD) and catalase.

Further, the present invention relates to a pharmaceutical composition having the ability to modulate the activity of SOD and catalase containing an effective amount of the compounds of General formula I or its pharmaceutically acceptable salts, and, if necessary, pharmaceutically acceptable carrier.

The present invention relates also to method of obtaining compounds of General formula I.

A DETAILED DESCRIPTION of the INVENTION

New preferred compounds (II, III, IV), known preferred connection (V, VI, VII) of the General formula I shown in table 1.

Table 1

No. Conn.X, the connection nameR
IIH
α-sportinguistas
IIIH
β-sportinguistas
IVH
aminobenzylpenicillin
VCH3-CO-
N-acetyl-β-sportinguistas
VICH3-CO-
N-acetyl-β-sportinguistas
VIICH3-CO-
N-acetylaminofluorene

Synthesis of new (II, III, IV) and known (V, VI, VII) compounds of General formula I can be carried out using methods of peptide chemistry in solution [herskowitz A.A., Kibirev VK // Chemical synthesis of peptides / Kiev. Naukova Dumka. 1992. 360 C.]. It is known that the synthesis of peptides comprising the amino acid sequence Asp-His, may be the reaction of the formation of cyclic operations derived under the action of acids and bases [M.A. Ondetti, Deer, A., J.T. Sheehan, Pluscec J., Braid Acting Side reaction in the synthesis of peptides containing the aspartylglycyi sequence. // J. Biochemistry. 1968. V.7. No. 11. P.4069-4075]. To avoid such effects in the course of the synthesis of new compounds of General formula I, which represents the derivative decarboxylating of the dipeptide AspHis, for the protection of the NH2 - and a - or R-COOH groups of aspartic acid is used for the NGOs benzyloxycarbonyl (Z) and benzyl (Bzl-) protective group, removed by hydrogenolysis. Amide link creating method activated pentafluorophenyl esters as the most active of the known. Reaction activation free αor β-carboxyl group is protected aspartic acid is carried out in ethyl acetate by the action of N,N'-dicyclohexylcarbodiimide in the presence of pentafluorophenol when cooled. Pentafluorophenyl esters corresponding αor β-protected derivatives of aspartic acid is introduced into the reaction peptideprophet with an equivalent amount of histamine in anhydrous dimethylformamide. Histamine is derived from histamine dihydrochloride by the action of sodium methylate in methanol. According to the analysis of the reaction mixture by TLC and mass spectrometry, the reaction proceeds with high yield, but with education at this stage two connections: the target linear reaction product (Z-II(OBzl) or Z-III-OBzl) and ˜30% by-product, which represents the cyclic operations of the derived Z-IV (m/z 450.8 and 342.7, respectively).

To exclude any impacts on protected derivative, mixture of Z-II(OBzl) or Z-III-OBzl and Z-IV without separation is subjected to further catalytic hydrogenolysis. The branch target products II or III impurities from the cyclic derivative IV is conducted at the final stage, using poor solubility of the synthesized linear connection of the clusters II or III in isopropanol, unlike soluble cyclic derivative IV. The use of such a scheme (scheme 1) outputs α-AspHA and β-AspHA, counting on the original Z-Asp(OBzl)-HE or Z-Asp(OH)-OBzl, is about 40%. This output is high enough, given the unusually easy cyclization of Z-II(OBzl) or Z-III-OBzl in the Z-IV, which takes place even during storage and during purification column chromatography.

For the synthesis of known acetyl derivative sportinguista as starting compounds we used βor α-benzyl ester of aspartic acid (scheme 2). Nα-acetylation was carried out by the action of acetic anhydride on the suspension of the relevant aminoboronic benzyl esters of aspartic acid in water at a ratio of AU2O: H2O (4:1). The reaction of activated carboxyl group and create a peptide bond is carried out in the conditions described above for the Z-protected derivative (Z-Asp(OBzl)-HE or Z-Asp(OH)-OBzl). In the synthesis of Nα-AC-derivatives of Asp-HA also observed the formation of cyclic derivative VII. Analysis of the mass and NMR spectra confirmed the absence of benzyl protection from compounds VII and presence in its FTIR spectrum, a strong absorption band at 1700 cm-1and weak - at 1779 cm-1corresponding to the stretching vibrations of the carbonyl groups of succin midnig derivatives [M.A. Ondetti, Deer A., J.T. Sheehan, Pluscec J., Braid Acting Side reaction in the synthesis of peptides containing the aspartylglycyi sequence. // J. Biochemistry. 1968. V.7. No. 11. P.4069-4075].

Due to the increased propensity for cyclization of N-Ac-Asp(OBzl) αand β-structure occurring both at short storage and during hydrogenation on a palladium catalyst, the hydrogenation mixture is subjected to αor β-benzylamine peptides V(OBzl) or VI-OBzl with cyclic derived VII without selection. Department dibenzylamine linear peptides V or VI from the cyclic derivative VII is carried out by the resultant deposition rates of organic solvents, preferably a mixture of methanol with acetone. The scheme of synthesis allows to obtain compound V or VI with a yield of about 50%, considering the source αor β-benzyl ester of aspartic acid.

Targeted synthesis of cyclic compounds IV and VII may be carried out by treating the reaction mixtures obtained after the formation of the peptide bond in the compounds Z-II(OBzl) or V(OBzl) - triethylamine (pH 8), followed by drying in vacuum, with access from 37 to 41%. The cyclic structure thus obtained substance was confirmed by FTIR and1H-NMR spectroscopy and mass spectrometry.

Thus, the method of synthesis of a new family (II, III, IV) and known (V, VI, VII) aspartyl derivatives of gitam is on the basis of Z-Asp(OBzl)HE or Z-Asp(OH)-OBzl and Ac-Asp(OBzl)HE or Ac-Asp(OH)OBzl.

Compounds of General formula I can also be obtained in the form of pharmaceutical acceptable salts with non-toxic acids such as fumaric acid, maleic acid, succinic acid, acetic acid, citric acid, tartaric acid and the like, bases such as sodium hydroxide, potassium hydroxide, sodium carbonate and the like.

Compounds of General formula I possess the ability to modulate the activity of the enzymes SOD and catalase, and can be used for the treatment of diseases associated with impaired oxidative processes and changes in the level of reactive oxygen species.

The pharmaceutical compositions contain a compound of the present invention in amounts effective to achieve the desired result, and can be entered as standard medicinal forms (for example, in solid, semisolid, or liquid form), containing compounds of the present invention as an active ingredient in a mixture with a carrier or excipient suitable for intramuscular, intravenous, oral, sublingual, inhalation, and intrarectal administration. The active ingredient can be included in a composition together with commonly used non-toxic pharmaceutically acceptable carriers suitable for the manufacture of solutions, tablets, pills, capsules, pills, suppose the oriyiv, emulsions, suspensions, ointments, gels or any other medicines.

As fillers can be used in a variety of substances such as sugars, for example glucose, lactose or sucrose, lures or sorbitol, cellulose derivatives and/or calcium phosphates, for example tricalcium phosphate or acid phosphate of calcium, as a binder component can be used such as starch paste, for example corn, wheat, rice, potato starch, gelatin, methylcellulose, hypromellose, sodium carboxymethylcellulose and/or polyvinylpyrrolidone. If necessary, can be used loosening agents, such as the abovementioned starches and carboximetilkrahmal, transversely crosslinked polyvinylpyrrolidone, agar or alginic acid or its salt, such as sodium alginate.

The core tablets generally covered with a layer, which is resistant to gastric juice. For this purpose, can be used in concentrated solutions of sugars, which may not necessarily contain the Arabian gum, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, and suitable organic solvents or mixtures thereof.

The additives can also be used stabilizers, thickeners, dyes and fragrances.

As ointment bases can be used is in turn supported by hydrocarbon ointment bases, such as vaseline white and yellow (Vaselinum album, Vaselinum flavum), vaseline oil (Oleum Vaselini), white ointment and liquid (Unguentum album, Unguentum flavum), and as additives to give a more solid consistency of solid paraffin and wax; absorptive ointment bases - hydrophilic petrolatum (Vaselinum hydrophylicum), lanolin (Lanolinum), cold cream (Unguentum leniens); ointment bases, washable water - hydrophilic ointment (Unguentum hydrophylum); water-soluble ointment bases polietilenglikolja ointment (Unguentum Glycolis Polyethyleni). bentonite foundations and others.

As the basis for gels can be used methyl cellulose, sodium carboxymethyl cellulose, oxypropylation, polyethylene glycol or polyethylene oxide, carbopol, tylose.

As the basis for the suppository can be used basis, not soluble in water, cocoa butter, principles, soluble in water or miscible with water, gelatin-glycerin or polietilenoksidnoy; combined basics - soap-glycerin.

In the preparation of standard dosage forms, the amount of active ingredient used in combination with a carrier, may vary depending on the recipient treated, the specific method of administration of the drug.

For example, when using the compounds of the present invention in the form of solutions for injection, the content of the active agent is from 0.01 to 100 mg, preferably 1-10 mg as diluents can be used with 0.9%sodium chloride solution, distilled water, a solution of novocaine injection, ringer's solution, glucose solution. When introduced into the body of the compounds of the present invention in the form of tablets and suppositories, their number is 1.0-100 mg standard dosage form.

Dosage forms of the present invention receive by standard techniques, such as, for example, the processes of mixing, granulating, the formation of drops, dissolution and lyophilization.

It should be noted that the compounds of the present invention are modulating activity at concentrations orders of magnitude lower compared with the known compounds. When toxicity study with the introduction of the animals studied compounds at a dose of 1000 mg/kg orally was not observed death of experimental animals.

Detailed description of the compounds of the present invention, their preparation and study of pharmacological activity are presented in the following examples are intended to illustrate the preferred variants of the invention, and not limiting its scope.

EXAMPLES of SYNTHESIS of COMPOUNDS of the PRESENT INVENTION

As starting compounds in the synthesis used: Z-L-Asp(OBzl), Z-L-Asp-OBzl, L-Asp(OBzl)-L-Asp(OH)-OBzl produced by "Bachem" (Seam is Icaria).

The identity of the compounds was checked by TLC on plates plates Kieselgel 60 F254(company Merck, Germany) in the system chloroform-methanol 9:1 (1), isopropanol-water-ammonia 6:1:3 (2).

Electrophoresis on paper (paper electrophoresis Kondopoga pulp and paper mill, 120×320 mm) is carried out in a buffer with pH 5.1 composition pyridine-methanol-water 12:10:1000 in camera (150×320×150 mm) with a gradient of 15 V/cm for 2 hours.

The chromatogram showed chlorthalidone reagent, reagent Pauli, ninhydrin and glow in UV light.

The angles of the optical rotation was measured on a polarimeter "Perkin Elmer 341 (USA).

1H-NMR were recorded on a device "AMX-400 Bruker (Germany).

FTIR spectra were taken in tablets CVG on device "Mada 750" ("Nicolet" the U.S.).

The melting point was determined on the device "Boetius (Germany).

Mass high resolution spectra were obtained on a time-of-flight mass spectrometer by the method of matrix laser desorption ionization, as the matrix 2,5-dihydroxybenzoic acid, on the device and REFLEX™ III (Bruker, Germany).

Analytical reversed-phase HPLC was carried out on the devices:

chromatograph "Breeze"detector "Waters" (USA), detection at 214 nm, the rate of elution 1 ml/min, under the conditions (1): column Symmetry 300 C18, 3,9×150 mm, 5 μm, elution of 0.1%aqueous TFA with a gradient of acetonitrile from 0% to 60% for 18 mi is.

EXAMPLE 1

α-Bartelheimer (II)

To a solution of 2.0 g (5.6 mmol) of Z-Asp(OBzl)-HE is in 20 ml of ethyl acetate with vigorous stirring was added 1.10 g (5.9 mmol) of pentafluorophenol, the solution was cooled to 0° and was added 1.22 g (5.9 mmol) of DCC. Was stirred 2 hours at 0° and left for 12 hours at +4°. The precipitated DCU was filtered.

The solvent was removed in vacuum. The oily residue triturated with hexane. The resulting white solid precipitate was filtered, washed with hexane and dried in vacuum over CaCl2. Received 2.87 g (98%) of Z-Asp(OBzl)-OPfp. Rf0.59 (1). TPL94-96°. Lit.[Grosz, E., Meienhofer And. // Peptides. The main methods of formation of the peptide bond. M: Peace. 1983 s.] 95.5-96°.

A solution of 0.25 g (10.96 mmol) of metallic sodium in 4 ml of anhydrous methanol under cooling was added to a solution of 1.0 g (5.48 mmol) AT·2hcl in 11.5 ml of anhydrous methanol and stirred 20 min at 0° and 20 minutes at +22°. Precipitated NaCl was filtered, washed with methanol. The solvent of the filtrate was removed in vacuum. The oily residue was dissolved in 16 ml of DMF. To the obtained solution under vigorous stirring was added 2.87 g (5.48 mmol) of Z-Asp (OBzl)-OPfp. Was stirred 2 h at +20° and left for 12 h at +4°. The solvent was removed in vacuo, the residue triturated with anhydrous ether. Kept under ether at +4° within 12 hours, Dropped ocado is separated by filtration and dried in vacuum over CaCl 2. Received 1.13 g (46%) of a mixture of substances with Rf10.36 (1) Z-Asp (OBzl)-(Z-II(OBzl)); Rf20.2 (1) Nα-benzyloxycarbonylglycine (Z-IV). Mass spectrum, m/z: [M+1]+451.2 Z-II(OBzl); [M+1]+343.1 (Z-IV). To a solution of 1.13 g of a mixture of products in 12 ml of methanol under vigorous stirring was added 0.80 g of 10%palladium on coal and was first made in a stream of hydrogen for 1.5 hours, the Catalyst was filtered. The solvent of the filtrate was removed in vacuum. The obtained white crystalline substance is triturated with isopropanol, filtered and dried in vacuum over CaCl2. Was obtained 0.22 g (90%). Exit 40% in the calculation of the original Z-Asp(OBzl)-HE. Rf0.71 (2). EHA-0.37. TPL207-209°. Mass spectrum, m/z: [M+1]+227.0.- 7,47 (0.35; Meon-N2O (1:1)).1H-NMR, D2O δ. ppm: 2.20-2.35 (m, 2H, αCH2-ON), 2.5 (t, J 6 Hz, 2H, βCH2-Asp), 3.0-3.15; 3.2-3.35 (m, 2H, βCH2-ON), 3.65 (t, J 6 Hz, N., α-CH-Asp), 6.7 (s, 1H, 4-CH-lm), 7.6 (s, 1H, 2-CH-lm). FTIR, δcm-1: 1669 (amide I); 1570 (amide II); 1081 (amide III). HPLC under the conditions (1): individual peak, the retention time of 1.68 min Found, %: C 47.50; H 6.20; N at 24.32. With9H14N4O3. Calculated, %: 47.78; N, 6.24; N 24.76. HPLC under conditions 8: individual peak, retention time 2.00 min

EXAMPLE 2

β-Bartelheimer (III)

To a solution of 1.5 g (4.2 mmol who) Z-Asp (OH) -OBzl in 8.5 ml of ethyl acetate with vigorous stirring was added 0.83 g (4.5 mmol) of pentafluorophenol, then the solution was cooled to 0° and added 0.927 g (4.5 mmol) of DCC. Was stirred 3 hours at 0° and left for 48 hours at +4°. The precipitated DCU was filtered. The solvent was removed in vacuum. The oily residue triturated with hexane. The resulting white solid precipitate was filtered and dried in vacuum over CaCl2. Received 2.12 g (96.5%) of Z-Asp(OPfp)-OBzl. Rf0.93 (1). A solution of 0.176 g (7.64 mmol) of Na in 3 ml of anhydrous methanol under cooling was added to the solution 0.704 g (3.82 mmol) AT·2hcl in anhydrous methanol and stirred 20 min at 0° and 20 min at +25°. Precipitated NaCl was filtered, washed with methanol. The solvent of the filtrate was removed in vacuum. The oily residue was dissolved in 20 ml of DMF. To the obtained solution under vigorous stirring was added 2.0 g (3.82 mmol) of Z-Asp(OBzl)-OPfp. Was stirred 2 h at 20° and left for 20 h at 4°. The solvent was removed in vacuum, the residue is rubbed clean with a dry ether. Kept at +4° within 3 days. The precipitation was separated by filtration and dried in vacuum over CaCl2and P2O5. Got a white crystalline substance. Yield 0.86 g (50%). Rf10.54 (11) Z-Asp(HA)-OBzl (Z-III-OBzl); Rf20.2 (11) (Z-IV). Mass spectrum, m/z: [M+1]+451.2 (Z-III-OBzl); [M+1]+343.1 (Z-IV). To a solution of 0.86 g of a mixture of products in 11 ml of methanol under vigorous stirring was added 0.40 g of 10%palladiana coal was first made in a stream of hydrogen for 3 hours The catalyst was filtered. The solvent of the filtrate was removed in vacuum. The resulting white crystalline substance is triturated with isopropanol, filtered and dried in vacuum over CaCl2. Yield 0.20 g (90%). The overall yield of the synthesis of 41%. Rf0.67 (2). EHA-0.34. TPL196-198°. Mass spectrum, m/z: [M+H]+227.1., - 10,52 (0.29; Meon-N2About (1:1)).1H-NMR, δ, ppm, D2O: 2.20-2.35 (m, 4H, β-CH2-Asp, α-CH2-HA), 3.12 (t, J 5 Hz, 2H, βCH2-ON), 3.61 (DD, J 4 Hz, J 6 Hz, 1H, α-CH-Asp), 6.65 (s, H, 4-CH-lm), 7.45 (s, N, 2-CH-lm). FTIR, δcm-1: 1641 (amide I); 1528 (amide II); 1087 (amide III). HPLC under the conditions (I): individual peak, the retention time of 1.90 minutes Found, %: C 47.78; N, 6.35; N 24.83. C9H14N4O3. Calculated, %: 47.78; N, 6.24; N 24.76.

EXAMPLE 3

N-Aminobenzylpenicillin (IV)

To a solution of 0.40 g of a mixture of Z-III-OBzl (Rf0.54 (1)) and Z-IV (Rf0.2 (1)) (see methods synthesis β-sportinguista) in 5 ml of chloroform-methanol 8:2 was added triethylamine to pH 8, the solvent was removed in vacuum and dried in vacuum over anhydrous CaCl2within 2 hours. Received cyclic Z-IV with Rf 0.76 (2). EHA-0.60. FTIR, δcm-1: 1700, 1779 (the shaft. C=O in cyclic imide); 1250 (amide III). To a solution of 0.20 g (0.56 mmol) of the cyclic Z-Asp(ON) in 7 ml of anhydrous methanol, was added 0.14 g of 10%palladiana angle with vigorous stirring was first made in a stream of hydrogen for 1.5 hours The catalyst was filtered. The solvent of the filtrate was removed in vacuum. The resulting oily residue is triturated with ether. The solid white precipitate was filtered and dried in vacuum over CaCl2. Received 0.056 g (41%). Rf0.76 (2). TPL150-152°- 42.72 (0.32; Meon-N2O (1:1)).1H-NMR, CD3OD, δ, ppm: 1.26 (DD, J=5 Hz, N., β-CH2-Asp), 1.85 (t, J=5 Hz, 2H, αCH2-ON), 2.0 (DD, J=10 Hz, J=20 Hz, N., βCH2-ON), 3.0 (t, J=5 Hz, N., α-CH-Asp), 7.21 (s, H, CH-4-Jm), 8.14 (s, H, CH-2-Jm). FTIR, δcm-1: FTIR, δcm-1: 3449, 3338 (the shaft. NH2); 1781, 1701 (the shaft. C=O in cyclic imide); 1250 (amide III). Found, %: C 51.05; H 5.67; N 26.00. C9H12N4O2. Calculated. %51,92; H 5.81; N 26,91.

EXAMPLE 4

N-Acetyl-α-bartelheimer (V)

To a suspension of 2.4 g (10.75 mmol) of L-Asp (OBzl) -HE's in 3 ml of water with vigorous stirring and heated to 40° was added 10 ml of acetic anhydride. After 30 min to the reaction mass was added 5 ml of water, the solvent was removed in vacuum, the oily residue was dried in vacuum over NaOH, recrystallize from a mixture of 5 ml ethanol and 0.5 ml of water, dried over CaCl2. Yield 2.24 g (80%). Next, the synthesis was performed on the basis of 1.0 g (3.77 mmol) of Ac-L-Asp(OBzl)-in accordance with the methodology described for compound II. Yield 0.54 g (54%) in the calculation of L-Asp(OBzl)-HE. Rf0.65 (2). EHA -0.08. TPL112-114°(1; N2O).1H-NMR (CD3OD) δ: 1.75 (s, 3H, AC), 2.40 (d, J 8 Hz, 2H, βCH2-Asp), 2.6 (t, J 8 Hz, 2H, αCH2-ON), 3.10-3.20 (m, 2H, βCH2-ON), 4.31 (t, J 8 Hz, 1H, α-CH-Asp), 6.9 (s, 1H, 4-CH-lm), with 8.05 (s, 1H, 2-CH-lm). FTIR, νcm-1(in the film): 3319 (the shaft. NH); 1662 (amide I); 1570 (amide II). Found, %: 49.29; H 6.32; N 23.80. C11H16N4O4. Calculated, %: 49.25; N, 6.01; N 23.86. HPLC under the conditions (1): retention time 3.35 min

EXAMPLE 5

N-Acetyl-β-bartelheimer (VI)

Acetylation was carried out in accordance with the methodology described for compound VII, then the synthesis was carried out on the basis of 0.24 g (0.9 mmol) of Ac-L-Asp(OH)-OBzl according to the method for compound III. Yield 0.12 g (54%) in the calculation of L-Asp(OBzl)-OH. Rf0.65 (2). EHA-0.10. Hygroscopic,(0.27; Meon-N2O (1:1)). Mass spectrum, m/z: [M+H]+269.0.1H-NMR (CD3OD) δ: 1.90 (s, 3H, Ac), 2.45-2.70 (m, 2H, β-CH2-Asp), 2.85 (t, J 6 Hz, 2H, α-CH2-HA), 3.36-3.48 (m, 2H, βCH2-ON), 4.38-4.42 (m, 1H, α-CH-Asp), 7.20 (s, 1H, 4-CH-lm), and 8.50 (s, 1H, 2-CH-lm). FTIR, ν/cm-1: 3271 (the shaft. NH), 1654 (amide I), 1551 (amide II). Found, %: 46.48; H 6.37; N 19.64. C11H16N4O4-H2O. Calculated, %: 46.15; N, 6.34; N, 19.57. HPLC under the conditions (I): retention time 4.00 minutes

EXAMPLE 6

N-Acetylaminofluorene (VIII)

intes conducted on the basis of 1.0 g (3.77 mmol) of Ac-L-Asp(OBzl)-IT is in accordance with the methodology provided for connection IV. Yield 0.32 g (37%) in the calculation of L-Asp (OBzl)-HE. Rf0.80 (2). EHA-0.40. TPL226-228°.(0.41; Meon-N2O (1:1)). Mass spectrum, m/z: [M+H]+251.0.1H-NMR (CD3OD+DMSO-d6) δ: 2.20 (s, 3H, AC), 2.80-2.95 (m, 1H, β-CH2-Asp), 3.08 (t, J 9 Hz, 2H, α-CH2-HA), 3.25 (DD, J 10 Hz, J 22.5 Hz, 1H, β-CH2-Asp), 3.95 (t, J 9 Hz, 2H, β-CH2-HA), 4.65-4.75 (m, 1H, α-CH2-Asp) 7.15 (s, 1H, 4-CH-lm), 7.90 (s, 1H, 2-CH-lm). FTIR, ν/cm-1: 3266 (the shaft. NH); 1779, 1700 (the shaft. C=O in cyclic imide); 1659 (C=O, acetyl); 1584 (Def. NH). Found, %: C 52.67; H 5.45; N 22.40. With11H14O3. Calculated, %: 52.79; H 5.64; N 22.39. HPLC under the conditions (I): retention time 4.30 minutes

TESTS FOR BIOLOGICAL ACTIVITY

Set the modulating effect obtained by the claimed method compounds derived sportinguista corresponding to General formula I, on the activity of antioxidant enzymes, which have been studied by known methods (1, 2, 2, 3).

EXAMPLE 7

The effect of compounds of General formula 1 on the activity of Zn/Cu SOD

To assess the impact on the activity of Cu/Zn-SOD compounds in vitro used commercial preparation of the enzyme (Sigma, USA), Cu/Zn-SOD (from bovine erythrocytes). SOD activity was measured spectrophotometrically at 550 nm for the inhibition of recovery of oxidized cytochrome is with in the course of generation of superoxide anion radical in the system of xanthine oxidase - xanthine (50 mm KN2PO4buffer, pH 7.8, 10 mm EDTA, 0.01 mm Fe3+-Tits, 0.05 mm xanthine). The number entered in the system xanthoceras should cause the rate of cytochrome C reduction 0.025 oped/min. Per unit of SOD activity is activity is the amount of enzyme, the content of which causes a decrease by 50% the rate of cytochrome C reduction under these conditions. The impact modifier was evaluated after pre-incubation for 15 min at 25° [McCord J.M., Fridovich I. Superoxide Dismutase. // J.Biol.Chem. 1969. V.244. P.6049-6053].

EXAMPLES OF DOSAGE FORMS.

EXAMPLE 8

A. Preformed shape

Tablet form is received, using the following ingredients:

The compound corresponding to General formula (I)0.5-500 mg
Potato starch20-50 mg
Magnesium stearate3 mg
Aerosil1 mg
Lactoseup to 300 mg

The components are mixed and pressed to form tablets weighing 300 mg each.

B. Suppositories

An example of the composition of the suppository:

The compound corresponding to General formula (I)0.5-500 mg
Cocoa butter the number needed to obtain
the suppository.

If necessary, it is possible to manufacture rectal, vaginal and urethral suppositories with appropriate fillers.

Century Ointment

An example of the composition of the ointment:

The compound corresponding to General formula (I)of 0.05-0.5 g
Vaseline10 g

Ointments are made by well-known technology.

, Gels

An example of the structure of the gel:

The compound corresponding to General formula (I)5-500 mg
Tolosa200 mg
benzyl alcohol : 0.3 mg
ethanol300 mg
waterto 10 g

RESULTS

Introduction to the incubation medium containing Cu, Zn-SOD, effector compounds V corresponding to General formula I, causes a highly reliable inhibition of enzyme activity (50÷90%) in the concentration range of effector 10-5-10-7M and 10-13-10-14M Related compound VI with a different type of amide bond, on the contrary, significantly increases the activity of Cu, Zn-SOD - 50÷70%, in the concentration range of effector 10 -10-14M

Cyclic operations derived VII has little effect on the activity of Cu, Zn-SOD, but significantly activates catalase (60%) in a wide concentration range 10-12-10-4M-effector.

Dezazetilirovanie compounds corresponding to General formula 1 (R=H), significantly less influence on the activity of Cu, Zn SOD and catalase effects do not exceed 30%. For these compounds is also observed multidirectional effect on catalase: compound II weakly inhibits catalase in a wide range of concentrations (10-4-10-12M), and the compound III - activates it, and SOD at a concentration of effector 10-8-104M

CONCLUSION

New and known compounds corresponding to the General formula I have a modulating effect on the antioxidant enzymes Cu, Zn SOD and catalase, and achieved the highest percentage of inhibition (or activation), including at very low concentrations and/or in a wide range of concentrations of the effector.

These properties offer a range of new and known compounds corresponding to General formula I, can be widely used, including in Oncology (antitumor activity), immunology (modulation of immune responses, radioprotective effect), cardiology (anti-ischemic and antihypoxic action is), in ophthalmology (cataract treatment), to correct the effects of diabetes, disorders of the Central nervous system, as well as antihypoxants including the use of hyperbaric oxygen therapy, wound healing agents; in cosmetology as additives to prevent degradation and aging of skin cells.

Thus, the proposed effective modulators of the activity of antioxidant enzymes Cu, Zn SOD and catalase corresponding to General formula I, including new and known derivatives of sportinguista, including in the form of pharmaceutically acceptable salts, as well as an easy way of obtaining them.

Table 2

The effect of compound VI on SOD activity in vitro (basic activity of SOD 7.8±0.14 U/mg)
The drug concentration (M)The activity of SOD, U/mg protein
12
10-46.8±0.10
10-55.8±0.16
10-67.8±0.12
10-77.8±0.14
10-88.8±0.10
10-97.8±0.11
10-1013.6±0.12
10-11 11.7±0.12
10-1211.7±0.10
10-1311.7±0.10
10-1411.7±0.10
10-158.8±0.12
10-1610.7±0.10
10-1712.8±0.12

Table 3

The effect of compound VII on catalase activity in vitro (basic activity of catalase 262±11 U/mg)
The drug concentration (M)Catalase activity, Units/mg protein
10-3304±11
10-4399±11
10-5420±14
10-6451±13
10-7441±12
10-8430±10
10-9430±11
10-10315±10
10-11462±11
10-12283±12
10-13304±11
10-14252±14
10-15220±10
1016 367±11
10-17304±10

Scheme 1

The synthesis of compounds II, III, IV

Scheme 2

The synthesis of compounds V, VI, VII

1. Aspartamine derivatives of histamine General formula I

where R=H,

oror

and their pharmaceutically acceptable salts.

2. Compounds according to claim 1, having the ability to modulate the activity of antioxidant enzymes - superoxide dismutase and catalase.

3. The compound according to claim 2, where R=H,

having the ability to inhibit catalase, including in the concentration range from 10-12M to 10-4M

4. The compound according to claim 1, where R=H,

having the ability to activate superoxide dismutase, including in the concentration range from 10-14M to 10-10M, and catalase, including in the concentration range from 10-8M to 10-4M

5. Pharmaceutical composition having the ability to modulate the activity of superoxide dismutase and catalase, comprising as active agent an effective amount is about compounds of General formula I

where R represents hydrogen or acetyl group, X represents

oror

and their pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.

6. The use of compounds of General formula I

where R represents an acetyl group, X represents

oror

and farmatsevticheskii acceptable salts for the modulation of the activity of the enzymes superoxide dismutase and catalase.

7. The use of compounds according to claim 6, where

for inhibiting the activity of superoxide dismutase, including

in the concentration range from 10-6M to 10-7M and from 10-13M to 10-14M

8. The use of compounds according to claim 6, where

for activation of superoxide dismutase, including in the concentration range from 10-10M to 10-14M

9. The use of compounds according to claim 6, where

for activation of catalase, including in the concentration range from 10-12M to 10-4M

10. The method of obtaining N-asparty is lnyh derivatives of histamine General formula (I), namely, that activated pentafluorophenyl ester of Nα-protected derivative αor β-benzyl ester of aspartic acid is injected into the interaction with histamine in an organic solvent, and the resulting products - N-protected derivative αor β- ethers of sportinguista without separation of N-protected cyclic operations derived sportinguista subjected to hydrogenolysis in the presence of a catalyst of palladium on charcoal for removal of protection, followed by the separation of target products H-Asp(HA)-OH or H-Asp(OH)-HA

by crystallization from an organic solvent.

11. The method according to claim 10, where the Nα-protection use benzyloxycarbonyloxy or acetyl group.

12. The method according to claim 10, where the reaction of the amide bond formation is carried out in dimethylformamide, and the crystallization line products H-Asp(HA)-OH or H-Asp(OH)-HA exercise of isopropanol.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of adamantine of the formula (I): wherein D represents -CH2 or -CH2-CH2; E represents -C(O)NH or -NHC(O); each R1 and R2 represents independently hydrogen atom or halogen atom but R1 and R2 can't mean hydrogen atom simultaneously; R3 represents group of the formula: -R4-X-R5 (II) wherein R4 represents (C1-C6)-alkyl group; X represents oxygen or sulfur atom or the group NR13; R5 represents (C1-C6)-alkyl or (C2-C6)-alkenyl and each of them can be optionally substituted with at least one substitute taken among halogen atom, hydroxyl, di-(C1-C6)-alkylamino-group, -Y-R6, , and 5- or 6-membered heteroaromatic ring comprising 1-4 heteroatoms taken independently among nitrogen atom wherein heteroaromatic ring can be optionally substituted with at least one (C1-C6)-alkyl; Y represents oxygen or sulfur atom or the group -NH; R6 represents the group -R7Z wherein R7 represents (C2-C6)-alkyl group and Z represents -OH; when Y represents oxygen or sulfur atom or the group -NH then R6 represents additionally hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkylcarbonyl; R13 represents hydrogen atom, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkylmethyl; or R13 represents (C1-C6)-alkyl group optionally substituted with at least one hydroxyl, or to its pharmaceutically acceptable salts or solvates. These compounds are effective antagonists of P2X7 receptors and can be used in treatment of rheumatic arthritis or lung chronic obstructive disease. Also, invention describes methods for preparing these compounds, pharmaceutical composition comprising indicated compounds, method for preparing pharmaceutical composition and their using in therapy.

EFFECT: improved preparing and treatment methods, valuable medicinal properties of compounds and composition.

19 cl, 1 tbl, 77 ex

FIELD: organic chemistry, medicine, cardiology, biochemistry.

SUBSTANCE: invention relates to benzoyl guanidines of the formula (I): wherein R1 means -CF3; R2 means -Y-para-(C6H4)-R11, -Y-meta-(C6H4)-R11 or -Y-ortho-(C6H4)-R11 wherein R11 means (C1-C9)-heteroaryl comprising two or more nitrogen atoms adjoining across nitrogen (N) atom; Y means oxygen atom; R3 means hydrogen atom; R4 means (C1-C4)-alkyl, and to their pharmaceutically acceptable salts. Indicated compounds elicit very high activity with respect to inhibition of Na+/H+ exchange and improved water solubility and therefore they can be used as anti-arrhythmic medicinal agents with cardioprotective component for prophylaxis of infarction and treatment of infarction and for treatment of stenocardia. Also, proposed compounds inhibit pathophysiological processes in arising disorders induced by ischemia, in particular, in treatment of cardiac arrhythmia induced by ischemia.

EFFECT: improved preparing method, improved treatment and prophylaxis, valuable medicinal properties of compounds.

17 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of imidazole of the formula (I):

or its pharmaceutically acceptable salts wherein X represents -CH2-(CH2)p-, -O-; R1 represents phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl wherein indicated phenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, (C3-C7)-cycloalkyl are substituted optionally with 1-3 substitutes taken independently among halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group and OH-(C1-C6)-alkyl; R2 represents hydrogen atom (H) or (C1-C6)-alkyl; R3 represents H or (C1-C6)-alkyl; R4 represents H or (C1-C6)-alkyl; R5 represents H, or R5 and R7 form in common a bond; each R6 represents independently halogen atom, -OH, halogen-(C1-C6)-alkyl, (C1-C6)-alkyl, (C1-C6)-alkoxy group or OH-(C1-C6)-alkyl; R7 represents H, or R7 and R5 form in common a bond; each R8 represents independently -OH, (C1-C6)-alkyl, halogen-(C1-C6)-alkyl or (C1-C6)-alkoxy group; m = 0, 1, 2 or 3; n = 0 or 1; p = 0 or 1; r = 0 or 1; t = 0. Also, invention relates to a method for preparing compounds of the formula (I) and to a pharmaceutical composition showing affinity to alpha-2-adrenoceptors based on these compounds. Invention provides preparing new compounds and pharmaceutical composition based on thereof used in aims for treatment of neurological disturbances, psychiatric disorders or disturbances in cognitive ability, diabetes mellitus, lipolytic diseases, orthostatic hypotension or sexual dysfunction.

EFFECT: improved preparing method, valuable medicinal properties of compounds and compositions.

25 cl, 1 tbl, 14 ex

FIELD: organic chemistry, medicine, hormones.

SUBSTANCE: invention describes imidazole derivatives of the formula (I) , racemic-diastereomeric mixtures and optical isomers, pharmaceutical salts wherein ---- represents an optional bond; R1 represents hydrogen atom (H), -(CH2)m-C(O)-(CH2)m-Z1, -(CH2)m-Z1; R2 represents hydrogen atom (H), or R1 and R2 are joined with nitrogen atoms to which they are bound forming compounds represented by formulae (Ia), (Ib) or (Ic) wherein R3 represents -(CH2)m-E-(CH2)m-Z2; R4 represents hydrogen atom (H) or -(CH2)m-A1; R5 represents (C1-C12)-alkyl, (C0-C6)-alkyl-C(O)-NH-(CH2)m-Z3 and optionally substituted phenyl; R6 represents hydrogen atom (H); R7 represents (C1-C12)-alkyl or -(CH2)m-Z4; m = 0 or a whole number from 1 to 6; n is a whole number from 1 to 5. Proposed compounds bind with subtypes of somatostatin receptors selectively.

EFFECT: valuable properties of compounds.

20 cl, 13776 ex

The invention relates to new imidazole derivative of the formula (I):where R1represents phenyl or pyridinyl, substituted by substituents selected from the group comprising (1) phenyl, (2) furyl, thienyl, (3) halogen, (4) halogen(lower)alkyl, (5) lower alkylthio, (6) nitro, (7) lower alkenyl, optionally substituted phenyl, (8) lower quinil, optionally substituted phenyl, (9) lower alkoxy, optionally substituted cyclo(lower)alkyl or phenyl, (10) lower alkyl, optionally substituted, phenyloxy or (11) amino, optionally substituted protected carboxyla; R2represents lower alkyl; R3represents halogen or lower alkyl; R4represents (1) lower alkenyl, optionally substituted phenyl, (2) phenyl, optionally substituted lower alkyl or lower alkenyl, (3) lower alkyl or (4) thienyl, optionally substituted with halogen; a represents a lower alkylene and L represents a simple bond, a lower albaniles or lower alkylene, optionally substituted phenyl or pyridinyl, or-X-CH2- where X represents O or NR5where R5represents hydrogen or n is

New drug substances // 2237657
The invention relates to organic chemistry and can find application in medicine

New drugs // 2237057
The invention relates to organic chemistry and can find application in medicine

The invention relates to new and nitrate salts of heterocyclic compounds of formulas (a) and (b), where R is hydrogen, alkoxyl, R1- alkyl, alkoxyl, R2is hydrogen, alkyl, R3- alkyl, alkoxyl, X denotes N-R11or oxygen, R11means the free valence, Y represents N-R16, sulfur or alkyl, R16means hydrogen; other values radicals presented in the description of the invention

The invention relates to new derivatives of phenyl - and aminobenzenesulfonamide formula

< / BR>
where a denotes (R1SO2NR2-), (R3R60NSO2NR2-); X represents-NH-, -CH2- or-OCH2-; Y represents 2-imidazoline, 2-oxazoline or 4-imidazole; R1means (NISS

The invention relates to the derivatives of dihydronaphthalene formula I, where R1represents hydrogen, hydroxyl or alkyloxy, R2represents hydrogen, lower alkyl, aralkyl or phenyl, and R3represents pyridyl or imidazolyl

FIELD: organic chemistry, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to benzamide derivatives possessing with inhibitory activity with respect to tyrosine kinase Flt-1-receptors VEGF that can be used in treatment of neoplastic disease. Invention describes a pharmaceutical substance comprising compounds of the group 2-[(4-pyridyl)methyl]-amino-N-[R1]-benzamide wherein R1 means 4-chlorophenyl, 4-methylphenyl, 4-chloro-3-(trifluoromethyl)phenyl or 3-(trifluoromethyl)phenyl possessing with the inhibitory activity with respect to tyrosine kinase Flt5-2-receptors VEGF associated with neoplastic disease and angiogenesis. Also, invention describes novel compounds of the group 2-[(nitrogen-containing heterocycle)methyl]-amino-N-[R1]-benzamide wherein nitrogen-containing heterocycle is represented by 4-pyrodyl, 4- or 5-quinolinyl, 2-imidazolyl, and a method for their synthesis. Also, invention describes a pharmaceutical composition comprising abovementioned compounds possessing the inhibitory activity with respect to tyrosine kinase VEGF receptors used in treatment of neoplastic disease.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 74 ex

Ionic liquids ii // 2272043

FIELD: organic chemistry.

SUBSTANCE: invention relates to new ionic liquids designated for using in electrochemical cells and in organic synthesis. Invention describes ionic liquids of the general formula: K+A- (I) wherein K+ represents one of cations of the group consisting of the following formulae: wherein R1-R5 can be similar or different and can be bound to one another by a simple or double bond also, and each of them separately or in common can represent the following values: hydrogen atom (H), halogen atom, (C1-C8)-alkyl radical that can be partially or completely substituted with the following groups but preferably with fluorine atom (F), chlorine atom (Cl), N-[CnF(2n+1-x)Hx]2, O-[CnF(2n+1-x)Hx], SO2-[CnF(2n+1-x)Hx] or CnF(2n+1-x)Hx wherein 1 < n < 6 and 0 < x < 2n+1; A- means anion taken among the group consisting of [PFx(CyF(2y+1-z)Hz)6-x]- wherein 1 ≤ x ≤ 6, 1 ≤ y ≤ 8 and 0 ≤ z ≤ 2y+1. Invention provides the development of ionic liquids showing broad range of liquid state, high thermal resistance and low corrosive activity.

EFFECT: improved and valuable properties of ionic liquids.

3 ex

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to compounds of formula I ,

where R(1), R(2), R(3), R(4), R(5), R(6), R(7), R(8), R(30), and R(31) are disclosed in claims. Compound of present invention are particularly useful as new antiarrythmia bioactive substances, in particular for treatment and prophylaxis of atrial arrhythmia (e.g., atrial fibrillation or auricular flutter).

EFFECT: higher efficiency.

13 cl, 18 ex, 1 tbl

The invention relates to imidazole derivative of formula (1), where X, Y, R, R2, R3and R4such as defined in the claims

The invention relates to means for inhibiting the adhesion or migration of cells, or inhibition of VLA-4 receptor, representing the heterocycles of General formula (I), where W means R1-A-C (R13), Y represents carbonyl, Z denotes N(R0), And means a divalent residue of phenylene, divalent (C1-C6)-alkalinity balance, means the divalent (C1-C6)-alkalinity residue which may be substituted (C1-C8)-alkyl, D is C(R2) (R3), E mean R10CO., R and R0independently of one another denote hydrogen, if necessary substituted (C6-C14)-aryl, if necessary substituted heteroaryl, if necessary substituted in the aryl residue (C6-C14)-aryl-(C1-C6)-alkyl or, if necessary, substituted in the heteroaryl residue heteroaryl-(C1-C6)-alkyl, R1means hydrogen, Gets the remainder R28N (R21)-C(O)-, R2means hydrogen, R3means CONHR4, R11NH, R4means (C1-C28)-alkyl, which optionally may be single - or multi-substituted by identical or different residues selected from the range hydroxy (C6-C14)-aryl, R10means hydroxyl or (C1-C6)-alkoxy, R11means R12CO., R12means R15-O-, R13means (C1-C6)-alkyl, R15means R16-(C1-C6)-alkyl, R16means 7-12-membered bicyclic or tricyclic residue, a saturated or partially unsaturated and which may be substituted by one or more identical or different (C1-C4)-alkyl residues, R21means hydrogen, R28means R21, Het denotes a mono - or polycyclic, 4-14-membered, aromatic or non-aromatic cycle, which may contain 1, 2, 3 or 4 nitrogen atom, b, C, d and f independently of one another denote 0 or 1, but at the same time may not mean zero, e, g and h independently of one another denote 0, 1, 2, 3, 4, 5 or 6, in all their stereoisomeric forms and mixtures thereof in any ratio, and their physiologically acceptable salts

The invention relates to new derivatives of phenyl - and aminobenzenesulfonamide formula

< / BR>
where a denotes (R1SO2NR2-), (R3R60NSO2NR2-); X represents-NH-, -CH2- or-OCH2-; Y represents 2-imidazoline, 2-oxazoline or 4-imidazole; R1means (NISS

The invention relates to heterocyclic compounds of the formula I, values radicals cm

The invention relates to imidazole derivative of General formula I, where n=0 or 1, R1is hydrogen, alkyl, R2is hydrogen or R2and R3form a double bond, R3is hydrogen, alkyl, R4is hydrogen, alkyl, hydroxy-group, alkoxy, R5is hydrogen or alkyl, or R4and R5form a carboxyl group, R6, R7, R8is hydrogen, alkyl, hydroxy-group, alkoxy, hydroxyalkyl, halogen, X-CHR9-(CHR10)m-, m = 0 or 1, R9and R10is hydrogen or alkyl

The invention relates to products derived from histamine and, in particular, the condensation products of histamine or methylsiloxanes histamine and amino acids, the method of their preparation and use as active principle in areas such as therapy and cosmetology, as well as the factor (agent), improving the stability of compositions used in therapy, cosmetology, agriculture and food industry (region)

FIELD: medicine.

SUBSTANCE: method involves introducing anti-staphylococcus-proteus-blu-pus-bacillus vaccine twice: once before and once after an operation with 7-10 days long interval. Antibiotic and vaccination therapy is administered in combination with immunomodulator introduced. The immunomodulator is selected from a group composed of immunomodulator of microbial origin, synthetic chemical substance immunomodulator, immunomodulator obtained from marrow and nucleic acid-based immunomodulator. The treatment is continued by administering probiotics combined with biologically active nutrient additive selected from a group composed of blackberry syrup with Echinacea, Echinacea with vitamin C added and Immunostat E, given beginning from 5th-10th day.

EFFECT: enhanced effectiveness in restoring soft tissue structure in postoperative wound region.

6 cl

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