Phenyl-containing n-acylamine derivatives, method for production thereof, pharmaceutical composition and uses thereof as anti-inflammatory and analgesic agents

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to amine derivatives of general formula I , wherein R1 is hydrogen or hydroxyl; R2 is hydrogen, -COOH, -COOR4 (R4 is C1-C6-alkyl); R3 is hydrogen or hydroxyl; or pharmaceutically acceptable salts thereof. Also disclosed is method for production of said compounds (wherein n = 1 or 2) including activation of carboxyl group of p-hydroxyphenylacetic acid or phenylacetic acid by interaction of with diphenylphosphorylazide and triethylamine in organic solvent under cooling followed by interaction with amine compound. Method for production of said compounds (wherein n = 1) includes converting of p-hydroxyphenylacetic acid or phenylacetic acid to activated N-oxysuccinimide ester by N'dicyclohexylcarbodiimide method followed by interaction of N-succinimide ester with amine derivative. Disclosed are pharmaceutical composition and agent having cyclooxygenase inhibitor activity, containing effective amount of claimed compound (wherein n = 1 or 2) as active ingredient. Also disclosed is method for cyclooxygenase inhibition by administering to mammalian of effective amount of claimed compound (wherein n = 1 or 2) or pharmaceutically acceptable salt thereof.

EFFECT: phenyl-containing N-acylamine derivatives having cyclooxygenase inhibitor activity and useful in treatment pain, inflammation and other disorders of joints and connective tissues.

19 cl, 9 tbl, 19 ex

 

The present invention relates to the field of Bioorganic chemistry and relates to new compounds - forsteriana N-acyl derivatives of biogenic amines, as well as method for the synthesis of novel and known compounds, their use in medicine as a potential analgesic and anti-inflammatory drugs.

Prior art

In the published international application WO 97/23202 disclosed phenylaziridine N-acyl derivatives of amines of General formula (XV)

including, among others, 3-(p-hydroxyphenyl) propionitrile, 3-(p-hydroxyphenyl)propionitrile and 3-phenylpropionitrile (compounds IX, X, XI of the present invention, respectively), as intermediate compounds, their synthesis and use as selective ligands of the subtypes of NMDA receptors used to treat chronic pain, migraineous headache, and anesthetics. However, neither in the description nor in the claims specified publication is not described not described specific structures that correspond to the compounds X and XI of the present invention, and there are no data confirming the declared type of activity, and the connection IX as an intermediate compound and its synthesis are disclosed only in the way of getting other derivatives of amines.

is soedineniya IX, X and XI of the present invention are also described in earlier publications, which became public before the priority date of the above-mentioned international application WO 97/23202, for use for any other purpose.

3-(p-Hydroxyphenyl)propionitrile (IX) disclosed in Jacobson, K.A., Kirk, K.L. New high-performance liguid chromatographic procedure for the detection and quantification of β-phenyletylamine. // J. Chromatography. 1987. V.415. P. 124 to 128); (3-(p-hydroxyphenyl)propionitrile (X) - R.B. Herbert, A.E.Kattah. The biosynthesis ofSceletiumalkaloids inSceletiumsubvelutinumL. Bolus. // Tetrahedron. 1990. V.46. No. 20. P.7105-7118 and (3-phenylpropionitrile (XI) - Maldonado E., Hernandez E., Ortega A. Amides, coumarine and other constituents fromsimsia cronquistii. // Phytochem. 1992. P. 1413-1414.

In the published international application WO 97/23202 the possibility of using the compounds of General formula (XV) to prevent only certain specific types of pain, such as migrainea headache, chronic pain, and their use for anesthesia, due to the ability of these compounds to show the effect of selective ligands subtypes of NMDA receptors. However, it should be noted that in the description of WO 97/23202 there is no evidence of inventive activity and, consequently, the possibility of applying connections to a specified destination, in particular models with animalsin vivoand, thus, conclusions about the possible pharmacological effects based solely on the assertion that everything stated in the patent compounds are selective ligands of the subtypes of the NMDA receptor.

In the published international application WO 97/23202 described method of synthesis of 3-(p-hydroxyphenyl)propionitrile (IX) using 1-hydroxybenzotriazole in the presence of N,N'- dicyclohexylcarbodiimide (DCC). Not described the isolation and purification of this compound, the physico-chemical constants are given melting point and data1H-NMR spectroscopy.

In article Jacobson, K.A., Kirk, K.L. New high-performance liguid chromatographic procedure for the detection and quantification of β-phenyletylamine. // J. Chromatography. 1987. V.415. P.124-128 disclosed the synthesis of 3-(p-hydroxyphenyl)propionitrile (IX) with a modified N-oxysuccinimide ester 3-(p-hydroxyphenyl)propionic acid. The reaction is carried out in a mixture of methanol - 1M Na2HPO4, pH 8 (1:1), using sulfosuccinimidyl-3-(p-hydroxyphenyl)propionate (sulfated reagent Bolton-Hunte). The resulting product is characterized only by the melting point. In accordance with this article, the obtained 3-(p-hydroxyphenyl)propionitrile used as an internal standard in an electrochemical detector in the quantitative determination of the level of endogenous phenethylamine in biological fluids by HPLC method.

In article R.B. Herbert, Kattah A.E. The biosynthesis ofSceletiumalkaloids inSceletiumsubvelutinumL. Bolus. // Tetrahedron. 1990. V.46. No. 20. P.7105-7118 described the use of 3-(p-hydroxyphenyl)propionitrile (X) as the e of the intermediate product in the synthesis of alkaloids Sceletium subvelutinumand its method of synthesis method DCC. The disadvantage of this method is the necessity of applying for purification of the target product column chromatography, its relatively low yield of about 48%.

In article Maldonado E., Hernandez E., Ortega A. Amides, coumarine and other constituents fromsimsia cronquistii. // Phytochem. 1992. P.1413-1414 described selection 3-phenylpropionitrile (XI) of terrestrial plantsSimsia cronquistiiand presents the data of mass spectrometry,1H-NMR spectroscopy, melting point. Data on the biological activity not listed.

Synthesis of compound XI using condensing agent 4-(4,6-dimethoxy-1,3,5-triazine-2-yl)-4-methylmorpholinium chloride (DMT-MM) described in Kunishima, M., Kawachi C., Hioki K. et al. Formation of carboxamides by direct condensation of carboxylic acids and amines in alcohols using a new alcohol - and water-soluble condensing agent: DMT-MM. // Tetrahedron. 2001. V.57. No. 8. P.1551-1558. The disadvantage of this method of synthesis is the formation of by-product and the necessity of using preparative thin-layer chromatography for the purification of the target product, which complicates the process and must inevitably lead to reduced output. Despite this, indicates a high product output (XI)of 98%. Compound XI was synthesized to study the applicability of the new condensing agent DMT-MM.

Synthesis of amino acid derivatives of tyrosine and phenylalanine 3-(p-g is PROXIFIER)propionitrile, phenylpropionitrile, phenylacetylamino, phenylpropionylamino and phenylpropionitrile methyl ester (compound XIV, XV, XVI, XVIII and XXI of the present invention, respectively) and study their inhibitory effect on the neuron TAN identified in the ganglia of the snailAchatina fulica ferussacdescribed in articles Takeuchi H., Ariyoshi y, Effects of N-beta-phenylpropionyl-L-tyrosine and its derivatives on the excitability of an identifiable giant neuron ofAchatina fulica ferussac. // Comparative biochemistry and discrimination. C: Comparative pharmacology. 1982. V.72. No. 2. P. 225-229 and Y.Ariyoshi. H. Takeuchi. Structure-activity relationships of N-β-phenylpropionyl-L-tyrosine and its derivatives on the inhibition of an identifiable giant neurone of an identifiable giant neurone of an African giant snail. // Br. J. Pharmacol. 1982. V.77. P.631-639. In article Y.Ariyoshi. H. Takeuchi. Structure-activity relationships of N-β-phenylpropionyl-L-tyrosine and its derivatives on the inhibition of an identifiable giant neurone of an identifiable giant neurone of an African giant snail. // Br. J. Pharmacol. 1982. V.77. P.631-639. Describes a typical method of synthesis of compounds XIV, XV, XVI, XVIII, XXI method of activated N-oxysuccinimide esters using as amino methyl ester of tyrosine, with its subsequent saponification (for compounds XIV, XV, XVI, XVIII), but the physico-chemical constants and outputs are not shown. In addition, the synthesis of phenylacetylcarbinol (XV) with high yield (94%) using 1-hydroxybenzotriazole and ethyl-3(3-dimethylamino)propylbromide, using as starting compounds ethyl ester of tyrosine and phenylpropyl the howling acid, with subsequent saponification of the ethyl ester described in Tangpasuthadol V., Pendharkar S.M., Kohn J. Hydrolytic degradation of tyrosine-derived polycarbonates, a class of new biomaterials. Part I: Study of model compounds. // Biomaterials. 2000. V. 21. No. 23. P. 2371-2378. The data1H-NMR spectroscopy and melting point.

Synthesis of phenylpropionylamino (XVIII) chloranhydride method in the presence of KOH disclosed in N. Lustig, Spiegelstein-Klarfeld H., Schneider E., N. Lichtenstein Phenylacetyl and phenylpropionyl amino acids. Their inhibitory effect on glutamine synthetase and their resistance to acylase. I. // Israel Journal of Chemistry. 1974. V.12. No. 3. P.757-763. Given melting point and elemental analysis. The synthesis was conducted to study the extent of inhibition by this compound XVIII of glutamine synthase.

Phenylpropionitrile methyl ester (XXI) is referred to as intermediate compounds in the Japan patent JP 57193437, where its synthesis is carried out by the method of the activated N-oxysuccinimide esters.

SNES of phenylazodiphenylamine (XIX), a similar synthesis of compound XVIII, using the acid chloride phenylacetic acid disclosed in Chen H.M., M.S. Hsu, Huang, L.J., et al. Effect of N-phenylacetyl-L-amino acids on the differentiation of HL-60 cells // Chinese Pharmaceutical Journal. 2001. V.53. No. 3. R-167. The physical-chemical characteristics of the target compounds: melting point data1H-NMR and IR spectroscopy, mass spectrometry. It was found that phenylazodiphenylamine (XIX) is an inducer of cell differentiation.

3-(p-Hydroxyphenyl)propionitrile methyl ester (XX) is mentioned in a publication of the international application WO 99/52962, however, the methods of synthesis and physico-chemical characteristics not shown. The compound (XX) was synthesized with a view to its use as a monomer for obtaining biodegradable polymers that are compatible with the tissues.

Natural compound isolated from symbiotic bacteria Xenorhabdus nematophilus, phenylacetylglutamine (XXIII) was synthesized chloranhydride method and were characterized by physico-chemical data1H-NMR,13C-NMR and IR spectroscopy, mass spectrometry, melting point Park S.H., Paik S.U., Suh, S.I. et al. Novel aliphatic amide having anticancer property. Int pat. WO 01/49656 (PCT). SS 255/60. 2001; Paik S.U., Park Y.H., Suh, S.I. et al. Unusual cytotoxic phenethylamides from Xenorhabdus nematophilus. // Bulletin of the Korean Chemical Society. 2001. V.22. No. 4. R-374. The results of the study compounds corresponding to the structure XXIII, on the antitumor activity in vitro.

The General formula of the compounds disclosed in published international application WO 01/49656 fall and other compounds of the present invention: p-hydroxyphenylethylamine, p-hydroxyphenylacetonitrile and phenylacetylglutamine (compounds VII, VIII and VI of the present invention, respectively. However, neither of the formulas of these compounds or methods of synthesis or physico-chemical constants, nor dannijo biological activity for them is not given.

Phenylpropionitrile (XII) referred to in article Takeuchi Hiroshi; Tamura Hiroko. The effects of aromatic amino acid derivatives on the excitability of an identifiable giant neuron of the African giant snail (Achatina fulica Ferussac). // British Journal of Pharmacology. 1980. V.69. No. 1. R.29-34, but without a description of its synthesis, physico-chemical characteristics and destination.

Article by Garrett C.E., Jiang X., Prasad K., O. Repic New observations on peptide bond formation using CDMT. // Tetrahedron Letters. 2002. V.43. No. 23. R-4165 revealed phenylpropionylamino methyl ester (XXIV) and the method of its synthesis with the use of the condensing agent 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) in the presence of N-methylmorpholine. Specific methods of synthesis and physico-chemical characteristics of the compound XXIV is not given, but it is reported that this method of synthesis has advantages: the one-stage synthesis and isolation of the product by planting water lead to chromatographically pure product with a high yield of 90%. The compound corresponding to the structure XXIV, was synthesized in order to study the applicability of the new condensing agent CDMT.

In article Peric M., Vercek Century, Petric A. ω-Diazoacetophenones as reagents for a mild and selective protection of an amino group. // Acta Chimica Slovenica. 1996. V.43. No. 2. R-173 describes the synthesis of phenylacetylcarbinol methyl ester (XXII), intermediate compounds for the synthesis of peptides, condensation of phenylacetic acid with methyl ether of tyrosine through the formation of diazoketone. For cleaning compound XXII obligations is Ino used column chromatography. Given the melting point data1H-NMR spectroscopy and elemental analysis.

Phenylazodiphenylamine methyl ester (XXV), in accordance with Votano J. R., J. Altman, M. Wilchek, Potential use of biaromatic L-phenylalanyl derivatives as therapeutic agents in the treatment of sickle cell disease. // Proceedings of the National Academy of Sciences of the United States of America. 1984. V.81, No. 10. P. 3190-3194, was synthesized by the method of the activated N-oxysuccinimide esters, followed by purification column chromatography. Physico-chemical constants for him, not shown. In this article the compound XXV is an intermediate in the synthesis of compound XIX, which is investigated as a potential tool for the treatment of sickle cell disease.

Also known enzymatic method for the synthesis of compound XXV [Didziapetris, R., Drabnig Century, V. Schellenberger, Jakubke H.D., Svedas V. Penicillin acylase-catalyzed protection and deprotection of amino groups as a promising approach in enzymic peptide synthesis. // FEBS Letters. 1991. V.287. No. 1-2. R. 31-33].

In article Bok, S., Lee, S., Jeong So, Phenolic acid derivatives and composition for preventing or treating blood lipid level-related diseases comprising the same. Pat. US. US 2003199566 describes the synthesis of 3-(p-hydroxyphenyl)propionitrile (XVII) and 3-(p-hydroxyphenyl)propionitrile methyl ester (XIII) using 1-hydroxybenzotriazole and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride in the presence of triethylamine. In the case of 3-(p-hydroxyphenyl)propionitrile (XVII) further conducted saponification with what hodom 78%. For both compounds are given data1H-NMR and13C-NMR spectroscopy. Compounds XVII and XIII proposed to be used for the prevention and treatment of diseases associated with lipid levels in the blood.

It is known that the analgesic action may be carried out in accordance with the various mechanisms, in particular by inhibition of the cyclooxygenase enzyme in the arachidonic acid cascade [Mashkovsky PPM Medicines. / M, Medicine, 1993, Vol.2].

The most pronounced analgesic effect among drugs that reduce the synthesis of algogenic have non-narcotic analgesics and non-steroidal anti-inflammatory drugs. Non-narcotic analgesics represented by salicylates (aspirin), derivatives of pyrazolone (amidopirina, analgin) and para-aminophenol (paracetamol). To NSAIDs are derivatives of salicylic, acetic, propionic and Anthranilic acid. Non-narcotic analgesics and non-steroidal anti-inflammatory drugs, along with an analgesic effect, anti-inflammatory and antipyretic activity [Kukushkin M., Khitrov NICHOLAS General pathology pain. / Moscow, Medicine, 2004, 142 S.]. The main side effect of NSAIDs is ulcerogenesis.

The aim of the present invention which is the synthesis and application of new and known forsteriana N-acyl derivatives of biogenic amines and amino acids as non-toxic, more effective analgesics and protivovospolitelnyh funds, without side effects, in particular ulcerogenesis.

Brief description of the invention

The present invention relates to new generaterandom N-acyl derivatives of amines of General formula I:

where R1represents hydrogen or a hydroxy-group;

R2represents hydrogen, -COOH, -COOR4where R4is1-C6alkyl;

R3represents hydrogen, a hydroxy-group;

n is 1 or 2;

provided that

when n is 1, R1is hydrogen and R2represents-COOH, -COOR4where R4is methyl, R3is not a hydroxy-group;

when n is 1, R1and R3simultaneously represent hydrogen, R2is not-COOH, -COOR4where R4is methyl; and

n is not equal to 2,

and their pharmaceutically acceptable salts, possessing inhibiting cyclooxygenase activity, anti-inflammatory and analgesic action, does not exhibit side ulcerogenic effect.

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

where R1represents hydrogen or a hydroxy-group;

R2represents hydrogen, -COOH, -COOR where R4represents C1-C6alkyl;

R3represents hydrogen, a hydroxy-group;

n is 1 or 2;

and their pharmaceutically acceptable salts as inhibitors of cyclooxygenase, analgesic and anti-inflammatory drugs.

Further, the present invention relates to a pharmaceutical composition or means of having inhibiting cyclooxygenase activity, anti-inflammatory and analgesic action, not shown ulcerogenic side effect, containing an effective amount of the compounds of General formula I or its pharmaceutically acceptable salts, and also, if you want pharmaceutically acceptable carrier.

Another object of the invention is a method of treating pain of various origins, as well as inflammatory diseases, including the introduction of an effective amount of compounds of General formula I or its pharmaceutically acceptable salt.

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

A detailed description of the invention

Preferred compounds of formula I are compounds in which R2represents-COOH, -COON3.

New preferred compounds of General formula I are presented in Table 1.

Table 1
Connectionno connect.R1nR2R3
II-HE1-COOH-HE
III-HE1-COOHN
IV-HE1SOON3-HE
V-HE1SOON3N
VII-HE1N-HE
VIII-HE1NN

Known preferred compounds of General formula I are presented in Table 2.

Table 2
ConnectionNo. Conn.R1nR2R3
VIN1N-HE
IX-HE2NN
X-HE2N-HE
XIN2NN
XIIN2N-HE
XIII-HE2SOON3N
XIV-HE2-COOH-HE
XVN2-COOH-HE
XVIN1-COOH-HE
XVII-HE2-COOHN
XIXN1-COOHN
XX-HE2SOON3-HE
XXIN2SOON3-HE
XXIIN1SOON3-HE
XXIIIN1NN
XXIVN2SOON3N
XXVN1SOON3N
XVIIIN2-COOHN

Compounds of General formula I is produced by activation of the carboxyl group of p-hydroxyphenylarsonic acid or phenylacetic acid interaction with diphenylphosphorylacetate (DPPA) and triethylamine (TEA) in an organic solvent under cooling, with the further implementation of interaction with amino derivatives. Preferably the activation of the carboxyl groups are using 1-1,2 equivalents of DPPA and TEA. As amino derivatives can be used esters of tyrosine and phenylalanine. To obtain the compounds II and III, as the original use of amino benzyl esters of tyrosine and phenylalanine, respectively, with subsequent removal of the benzyl group by catalytic hydrogenolysis. In contrast to previously used methods for the synthesis of known compounds of General formula I, the use of diphenylphosphinite method made it possible to reduce the number of stages, namely, to exclude the extraction of the activated derivative of the carboxylic component, limited extraction for the separation of target substances and increase yields (≥90%).

The General scheme of synthesis diphenylphosphoryl method presented in Scheme 1.

Scheme 1

New compounds II, III, IV, V, VII, VIII, including, containing a phenolic hydroxyl group, can be obtained by the method of the activated N-oxysuccinimide esters, advantage of which is the availability of the reagents, the water-solubility of the released N-hydroxysuccinimide, the speed of flow as the reaction obtain the N-oxysuccinimide esters of carboxylic components and the formation of the amide bond and the possibility of achieving high yields of the target products (70-80%), despite the presence of phenolic hydroxyl. In accordance with the proposed method of synthesis of N-oxysuccinimide esters of carboxylic component is the conversion of p-hydroxyphenylarsonic acid or phenylacetic acid in the activated N-oxysuccinimide ether N,N'-dicyclohexylcarbodiimide method, DCC method) with high yield (about 90%), followed by the formation of amide linkages by the reaction of N-oxysuccinimide esters with amino derivatives with high yields (70-80%), for a short time (1-2 hours) and without the use of chromatographic purification. As amino derivatives can be used esters of tyrosine and phenylalanine. Similarly can be obtained from known compounds X, XI, XII, XIII, XV, XVII, XIX, XX, XXII, XXIII, XXIV, which synthesis method of activated N-oxysuccinimide esters have not been described in the literature.

The General scheme for the synthesis of compounds of General formula I by the method of the activated N-oxysuccinimide esters is presented in Scheme 2.

Scheme 2

Synthesis of hydroxyphenylpropionic (XIV) can be carried out also by the method of the activated N-oxysuccinimide esters, with the aim of reducing the number of stages can be used unprotected on the C-end of tyrosine. In addition, it avoids long in the action of alkali, which would be required for the saponification of methyl ester of tyrosine and could adversely affect the optical purity of the obtained compounds [Schroeder, E., lyubts K. // Peptides. / M, Mir, 1967, 2 T.; gross, E., Meienhofer And.// Peptides. The main methods of formation of the peptide bond / Moscow, Mir, 1983, s]. The problem of very low solubility unprotected tyrosine as in organic solvents and in water solved by transitioning the soluble Na salt by adding to the suspension of tyrosine in DMF 2 equivalents of 1N NaOH solution, resulting in the observed complete dissolution of amino acids. The reaction of the thus obtained solution of amine derivatives with N-oxysuccinimide ether 3-(p-hydroxyphenyl)propionic acid is almost completely and quickly (within 2 hours). After extraction extraction without the use of chromatographic purification, the yield of the target (XIV) of the product was about 63%.

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

Compounds of General f is rmula I have inhibiting cyclooxygenase activity and can be used for the treatment of pain of various Genesis, inflammatory and inflammatory-degenerative diseases of joints and connective tissue and of the musculoskeletal system, other diseases involving inflammation.

In particular, the compounds of the present invention can be used to treat post-operative pain, post traumatic pain, and pain syndromes gynecological, neurological, Oncology, dental, nature, rheumatoid arthritis, arthropathy, ankylosing spondylitis, nonspecific spondyloarthropathies, gouty arthritis, osteoarthritis, non-articular rheumatism and thrombophlebitis.

Compounds of the present invention are introduced in an effective amount that provides the desired therapeutic result.

For the treatment of pain syndromes of different origin, such as post-operative pain, post traumatic pain, and pain syndromes gynecological, neurological, Oncology, dental, nature, inflammatory and inflammatory-degenerative diseases of joints and connective tissue and of the musculoskeletal system, such as rheumatoid arthritis, arthropathy, ankylosing spondylitis, nonspecific spondyloarthropathies, gouty arthritis, osteoarthritis, extra-articular rheumatism and thrombophlebitis, other diseases involving inflammation, joint the formula (I) can be administered orally, topically, parenterally, by inhalation and rectally in the form of standard dosage forms containing non-toxic pharmaceutically acceptable carriers. Used in the present description, the term "parenteral" refers to subcutaneous, intravenous, intramuscular or intrathoracic injection or infusion.

Compounds of the present invention can be administered to the patient in doses, comprising from 0.1 to 10 mg/kg of body weight per day, preferably in doses from 0.5 to 5 mg/kg once or more than once a day.

It should be noted that the specific dose for each particular patient will depend on many factors, including the activity of this used compound, the age, body weight, sex, General health and diet of the patient, time and route of administration of drugs, the rate of its excretion from the body, specifically used a combination of drugs and the severity of the disease under treatment.

The pharmaceutical compositions of the present invention 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 the active ingredient is mixed 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, suppositories, 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, tragakant, 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.

Can be used optional additives, such as agents that regulate fluidity, and lubricating agents, such as diacs the d silicon, talc, stearic acid and its salts, such as magnesium stearate or calcium stearate and/or propylene glycol.

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 may be used hydrocarbon ointment bases such as petrolatum, 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, such as paraffin wax and wax; absorptive ointment bases such as hydrophilic petrolatum (Vaselinum hydrophylicum), lanolin (Lanolinum), cold cream (Unguentum leniens); ointment bases, water washable, such as hydrophilic ointment (Unguentum hydrophylum); water-soluble ointment bases, such as polietilenglikolja ointment (Unguentum Glycolis Polyaethyleni), bentonite foundations and others.

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

As the basis for the suppository can be used bases, insoluble in water, such as cocoa butter;

bases that are soluble in water or miscible with water, such as 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 concentration of active agent is from 0.01 to 5%. As diluents can be used with 0.9% sodium chloride solution, distilled water, a solution of novocaine injection, ringer's solution, glucose solution, specific additives to dissolve. When introduced into the body of the compounds of the present invention in the form of tablets and suppositories, their number is 5.0-500 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 nastojasih the invention show a biological activity in doses of two to three orders of magnitude lower in comparison with the known compounds, used for comparison, with almost the same efficiency, and there are no identified negative side effects and no contraindications. However, in the study of toxicity of the compounds of the present invention at a dose of 1000 mg/kg, oral, has not registered the 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 are not limiting its scope.

Examples of synthesis of compounds of the present invention

As starting compounds in the synthesis usedp-hydroxyphenylarsonic acid, 3-(p-hydroxyphenyl)propionic acid, 3-phenylpropionate acid (Sigma, USA), phenylethylamine, tyramine ("Fluka, Switzerland).

The identity of the compounds was checked by TLC on plates "Kieselgel 60 F254" (Merck, Germany) in the solvent system: chloroform - methanol 9:1 (1).

The chromatogram showed a chlorine-toleenum the reagentwith ninhydrin, iodine and glow in UV light.

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

FTIR spectra were taken in KBr pellets on the device "Magna 750" ("Nicolet" the U.S.).

The temperature has been melted down what I 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 usernamescorpionbay ionization, using as the matrix 2,5-dihydroxybenzoic acid, devices 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, 4,6×250 mm, 20 mm, elution with 0.1%TFA with a gradient of 0.09% TFA in a mixture of 60:40 acetonitrile : water from 0% to 100% over 15 min; (2): 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% over 18 min;

- chromatographs "System Gold" ("Beckman, USA), the rate of elution of 0.25 ml/min, detection at 220 nm, under conditions (3): column Phenomenex (USA) C18, 2×250 mm, 5 μm, elution with 0.1%TFA with a gradient of 0.08% TFA in 100% MeCN from 0% to 100% for 50 minutes

Example 1

p-Hydroxyphenylethylamine (VII)

Methodology A.

With stirring to a solution of 0.40 g (2,63 mmol) p-hydroxyphenylarsonic acid in 3.5 ml of DMF was added 0.35 g (2,63 mmol) tiramina. The solution was cooled to -10°and was added 0.68 ml (3,16 mmol) diphenylphosphinite and 0.44 ml (3,16 mmol) of triethylamine. Was stirred 2 h at -10°and left at 20°With 15 hours To the reaction mass was added 35 ml of water, was extracted with 20 ml ethyl acetate. telecity layer was washed with 10 ml of 5% solution of Na 2CO3and with water to pH 7, 10 ml of 5% HCl solution, with water to pH 7. An ethyl acetate layer was dried over Na2SO4that was filtered Na2SO4the ethyl acetate was removed in vacuum. The oily residue triturated with a mixture of ether-hexane (1:1). The resulting white precipitate was filtered and dried in vacuum over CaCl2. The yield of 0.68 g (95%).

Rf0,7 (1).

TPL= 147-149°C.

[M]+271,6.

1H-NMR, CD3OD, δ, ppm: to 2.65 (t,J=7 Hz, 2H, α-CH2-TA), 3,29-of 3.32 (m, 4H, β-CH2-TA, CH2(OH-PhAc)), 6,63 to 6.75 (m, 4H,o-CH-arene.), 6,90-7,06 (m, 4H,m-CH-arene.).

FTIR, cm-1: 3276 (the shaft. OH); 3108 (Val., =C-H arene.); 1612 (amide I); 1591 (amide II); 1515 (arene. -C-C-); 1226 (Val., -C-O phenol).

Found, %: C 70,57; H to 6.43; N 5,50 C16H17NO3.

Calculated, %: C 70,83; H 6,32; N 5,16.

HPLC under the conditions (2): individual peak, retention time 8,71 minutes

Method B

To a solution 0,70 g (4,60 mmol) p-hydroxyphenylarsonic acid in 17 ml of ethyl acetate under stirring was added 0,53 g (4,60 mmol) of N-hydroxysuccinimide, the solution was cooled to 0°and was added 0.95 g (4,60 mmol) N,N'- dicyclohexylcarbodiimide (DCC). Was stirred 2 hours at 0°and left for 20 hours at 4°C. the precipitated N,N'- dicyclohexylmethane (DCU) was filtered. The solvent was removed in vacuum. The oily residue triturated with hexane. The resulting white solid sieges which it was filtered, washed with hexane and dried in vacuum over CaCl2. Got 1,08 g (94,6%). Rf0,58 (1).

With stirring to a solution of 0.30 g (1.2 mmol) of N-oxysuccinimide etherp-hydroxyphenylarsonic acid in 8 ml of N,N-dimethylformamide (DMF) was added 0.16 g (1.2 mmol) of tiramina. The reaction mixture was stirred 2 hours at 20°C, left at 4°With 20 hours. DMF was removed in vacuum. The oily residue triturated with water. The resulting white precipitate was filtered, washed with water. Yield 0.26 g (80%).

Rf0,68 (1).

TPL= 146-148°C.

[M+H]+272,3.

Found, %: C 71,05; H 6,10; N 5,25 C16H17NO3.

Calculated, %: C 70,83; H 6,32; N 5,16.

Example 2

p-Hydroxyphenylacetonitrile (VIII)

The synthesis was carried out in accordance with methods As described for compound VII.

The output of 0.57 g (90,5%).

Rf0,82 (1).

TPL= 69-70°C.

[M]+255,5.

1H-NMR, DMSO-d6that δ, ppm: 2,68 (t,J=8gts, 2H, β-CH2-PEA), 3,22-3,26 (m, α-CH2- PEA), to 3.36 (s, 2H, CH2(OH-PhAc)), 6,66 (l,J=4 Hz, 2H,m-CH-arene. OH-PhAc), 7,00 (l,J=4 Hz, 2H,m-CH-arene. OH-PhAc), 7,14-7,28 (m, 5H, arene.-CH-PEA), 8,0 (ush C., 1H, NH-PEA), to 9.20 (s, 1H, OH-OH-PhAc)).

FTIR, cm-1: 3332 (the shaft. OH); 3087 (Val., =C-H arene.); 1626 (amide I); 1558 (amide II); 1515 (arene. -C-C-); 1249 (Val., -C-O phenol).

Found, %: C 75,57; H to 6.80; N 5,77 C16H17NO2.

Vechicle is about, %: 75,27; H OF 6.71; N 5,49.

HPLC under the conditions (2): individual peak, retention time 11,17 minutes

The synthesis was carried out according to method B described for compound VII.

Yield 0.50 g (79.4 per cent).

Rf0,85 (1).

TPL= 68-70°C.

[M]+255,7.

Found, %: C 75,17; H 6,87; N 5,75 C16H17NO2.

Calculated, %: C 75,27; H Of 6.71; N 5,49.

Example 3

3-(p-Hydroxyphenyl)propionitrile (X)

The synthesis was carried out in accordance with methods As described for compound VII.

The yield of 0.41 g (95%).

Rf0,38 (1).

TPL174-176°C.

1H-NMR, DMSO-d6that δ, ppm: 2.26 and (t,J=8 Hz, 2H, α-CH2-(HO-PhPr)), 2,53 (t,J=6 Hz, 2H, β-CH2-Tyra), to 2.67 (t,J=8 Hz, 2H, β-CH2-(HO-PhPr)), and 3.16 (t,J=6 Hz, 2H, α-CH2-Tyra), 6,62 (l,J=7 Hz, 2H,m-CH-Bzl-Tyra), of 6.65 (d,J=7 Hz, 2H,m-CH-Bzl-(HO-PhPr)), 6,92 - of 6.96 (m, 4H,o-CH-Bzl-Tyra ando-CH-Bzl-(HO-PhPr)), 7,79 (c, 1H, NH-Tyra), which is 9.09 (ush. c, 2H, OH-Tyra and OH-(HO-PhPr)).

FTIR, cm-1: 3249 (the shaft. OH), 1621 (amide I), 1515 (arene.), 1541 (amide II).

Found %: 71,56; H Is 6.78; N Equal To 4.97.

Calculated %: 71,56; H of 6.71; N 4,91, C17H19NO3.

HPLC under the conditions (3): individual peak, retention time 25,62 minutes

The synthesis was carried out according to method B described for compound VII.

The yield of 0.37 g (85%).

Rf0,35 (1).

TPL172-174°C.

[M]+285,3.

Example 4

3-Phenylprop difenilalkilamina (XI)

The synthesis was carried out in accordance with methods As described for compound VII.

Yield 0.26 g (97%).

Rf0,78 (1).

TPL94-96°C.

1H-NMR, DMSO-d6that δ, ppm: 2,34 (t,J=8 Hz, 2H, α-CH2-PhPro), 2,66 (t,J=6 Hz, 2H, β-CH2-PEA), and 2.79 (t,J=8 Hz, 2H, β-CH2-PhPro), 3,24 (t,J=6 Hz, 2H, α-CH2-PEA), 7,25-7,30 (m, 10H, CH-arene.), 7,89 (ush. c,1H, NH-PEA).

FTIR, cm-1: 1637 (amide I), 1546 (amide II).

Found %: C Of 80.24; H To 7.61; N, 5,54.

Calculated %: 80,60; H 7,56; N Of 5.53. C17H19NO3.

HPLC under the conditions(3): individual peak, retention time 37,86 minutes

The synthesis was carried out according to method B described for compound VII.

Yield 0.20 g (77%).

Rf0,80 (1).

Found %: C 80,39; H 7,53; N 5,30.

Calculated %: 80,60; H 7,56; N Of 5.53. C17H19NO3.

Example 5

3-(p-hydroxyphenyl)propionitrile (IX)

The synthesis was carried out in accordance with methods As described for compound VII.

Yield 0.20 g (90%).

Rf(11) 0,4.

TPL= 102-104°C. Lit. [84] 102-104°

[M]+269,6.

1H-NMR, CDCl3that δ, ppm: 2,39 (t,J=7 Hz, 2H, α-CH2-(HO-PhPr)), by 2.73 (m, 2H, β-CH2-PEA), 2,86 (t,J=7 Hz, 2H, β-CH2-(HO-PhPr)), of 3.48 (m, 2H, α-CH2-PEA), to 6.75 (m, 2H,m-CH-arene. HO-PhPr), 7,03 (m, 2H,o-CH-arene. HO-PhPr), to 7.09 (m, 2H,o-CH-arene. PEA), and 7.3 (m, 3H,m,n-CH-arene. PEA).

IR For is, cm-1: 3263 (the shaft. OH); 1618 (amide I); 1537 (amide II).

Found %: C 75,57; H 6,93; N 5,09. C17H19NO2.

Calculated %: 75,81; H 7,11; N 5,20.

HPLC under the conditions (1): individual peak, retention time 14,77 minutes

Tests for biological activity

Example 6

Investigation of the effect of compounds of General formula I on metabolism [14C]arachidonic acid in cell-free homogenate of lung tissue of the mousein vitro

Studies of the metabolism of arachidonic acid were performed on mice-female line FGPs were on a standard diet of the vivarium. Animals (mice) were scored, drew the lungs, homogenized in a glass homogenizer firm Wheaton (USA) at 40With 10 volumes of 0.05 M Tris-HCl buffer. Aliquots (0.5 ml) of the supernatant were incubated with 0.5 mccu [1-14]-arachidonic acid ([C14]-AA), Amersham, England; specific activity 50-60 ICJ/mmol) at 370C for 30 min Extraction nematerializiranih [C14]-AK and products of its metabolism was carried out in 20 volumes of a mixture of chloroform and methanol (1:1), extraction efficiency not less than 90%, estimated using [C14]-PG f. Separation and identification [C14]-AA and its metabolites was carried out using TLC (Kieselgel plate 60 by Merck, Germany), using as the organic phase solvent system (ethyl shall zett, the isooctane, acetic acid, water - 110:50:20:100) and labeled standards. Autoradiographically obtained on x-ray film X-Omat AR (Kodak, USA) and HS 11 ("ORWO", Germany), was densitometrically on dancescene KS 3 ("Kipp and Zonnen, the Netherlands). Quantitative analysis of individual eicosanoids conducted using radiometry fractions obtained by high-performance liquid chromatography (HPLC-system firm "Gilson, France; column C8 BOND company Du Pont, USA) and elution of the spots on the TLC plates. The test compounds were injected at a concentration of 10-4M

The obtained data are presented in Table 3.

Table 3

The effect of compounds of General formula I (at a concentration of 10-4M) on the metabolism of [14C]arachidonic acid in cell-free homogenate of lung tissue of the mousein vitro
No. Conn.6-keto-PG fPG fTXB2PGE2AKProstanoids
IX-30-27-40-38+47-33
X-9-15-42-38+27-22
XIV-24-2 -49-54+84-35
XII-42-47+42-44
VII-45-32+22-40
VIII-45-33+40-40

PG- prostaglandins
TX- thromboxane
AK- arachidonic acid

The obtained data on the profile of eicosanoids demonstrate the ability of compounds of General formulaIto inhibit cyclooxygenase on 22-44% and testify about their viability as potential analgesic and anti-inflammatory drugs.

Example 7

Analgesic and anti-inflammatory activity of the compounds corresponding to General formula (I)

Study of analgesic activity on the model of acetic cramps"

The tests were carried out on outbred mice-males weighing 22-24, Specific pain reaction ("cramps") caused by intraperitoneal administration to mice of a 0.75% solution of acetic acid. Take into account the number of apnoea is okraseni abdominal muscles, accompanied by a stretching of the hind limbs and the bowing of the back. Analgesic activity was assessed by the decrease in the number of writhing animals in % of control within 15 min after the injection of acetic acid. The methodology of the tests described in R. Koster, M. Anderson, de Beer E. // Fed. Proc. 1959. V.18. P.412. The compounds were administered intragastrically (using probe) at a dose of 10 mg/kg 60 min before the injection of the acid. As the comparison drug used diclofenac (10 mg/kg). Analgesic effect was calculated by the formula:

where Ctothe number of writhing in the control group,

Withaboutthe number of writhing in the experimental group.

The obtained data are presented in Table 4.

Table 4

Analgesic activity of the studied compounds of General formula I at a dose of 10 mg/kg in test acetic cramps" (the number of writhing for 15 min)
ConnectionThe number of miceWith±mC, % of controlAnalgesic effect (%)
IX811,8±2,93268
control 1836,8±3,5100-
X811,0± 2,4*46,054
diclofenac

10 mg/kg
812,9±3,13*50,849,2
control 2825,4 ± 2,41000
XI1021,2±2,5**61,838,2
XII1020,1±2,1**58,641,4
control 3934,3±3,0100-
VIII816,0±4,543,556,5
control 4836,8±3,5100-
V1016,2±2,6*60,739,3
control 51026,7±0,79100-

* P < 0,05 relative to the control group

** P < 0,01 relative to the control group

Compounds corresponding to General formula I, in the test of "cramps" show analgesic activity similar to diclofenac - drug comparison (table 4), with analgesic effect of most compounds is from 38 to 68 %.

Example 8

Investigated the e analgesic activity on the model of "hot plate"

Analgesic effect of the compounds corresponding to General formulaI,studied on the model of "hot plate" method presented in Woolfe, G., McDonald A.D. //The evaluation of the analgesic action of pethidine hydrochloride (Demerol). // J.Pharmacol. Exp. Ther. 1944. V.80. P. 300-307. The tests were carried out on outbred mice-males weighing 22-24, Animals are individually placed on a hot plate (firm Ugo Basile"), whose temperature remains constant and equal to 55° C. Registered the first manifestations of painful reaction: licking feet, jumping up to the introduction of substances (background levels) and after 0.5, 1, 2, 3 and 4 hours after administration of the substance. The substance was administered intragastrically (using a probe). A portion of the substance is thoroughly stirred in 0.1 ml of tween 80 to obtain a solution, then added with saline to a volume of 0.5 ml was Calculated the average latency time pain threshold (PBC, s) in each group. The results were expressed in % of the background values. Analgesic effect (%) was calculated by the formula:

A-100% = XwhereAnd- background value;X- analgesic effect (%)

And= (time out 0.5-4 hours ×100%): background time

As Comparators used: dipyrone (150mg/kg), paracetamol (200 mg/kg), ketorol (10 mg/kg).

The obtained data are presented in Table 5.

Table 5

Comparative evaluation of analgesic action of compounds of General formulaIin the dose of 10 mg/kg and reference preparations of aspirin and paracetamol in the test "hot plate" in mice largest latent period pain threshold (PBC, sec)
N=10Time after injection connection, min
0 (background)3060120180240
ConnectionVII
M±m5,1±0,496,9±0,728,2±0,94*
Latency time PBC (%)100134,5158,9
Analgesia (%)34,5of 58.9
ConnectionVIII
M±m5,1±0,498,5±0,27*6,5±1,16
Latency time PBC (%)100159,6 123,3
Analgesia (%)to 59.623,3
ConnectionX
M±m4,3±0,257,54±0,78*5,75±0,838,50±1,03*8,84±0,925*
Latency time PBC (%)100175,3133,7197,7200,6
Analgesia (%)75,3to 33.897,7100,6
ConnectionXI
M±mto 3.73±0,195,35±0,98of 6.49±1,1*6,27±0,334,07±0,26
Latency time PBC (%)100143,4174,0141,3135,9
Analgesia (%)43,474,041,335,9
ConnectionIX
M±m4,14±0,258,4±1,23*of 7.36±1,04* 9,83±2,52*7,72±0,24*
Latency time PBC (%)100202,9of 177.8237,0186,5
Analgesia (%)102,977,8137,086,5
ConnectionXIV
M±m3,72±0,425,59±1,124,7±0,517,3±1,09*6,78±0,504*
Latency time PBC (%)100150,3126,3196,2182,3
Analgesia (%)50,326,396,282,3
Analgin, 150 mg/kg
M±m4,85±0,447,44±1,22*7,29±0,71*6,25±0,755,35±0,38
Latency time PBC (%)100153,4150,3128,9110,3
Analgesia (%)53,450,328,9 10,3
Paracetamol 200 mg/kg
M±m3,95±0,219,44±1,3*6,24±0,82*7,6±1,15*
Latency time PBC (%)100238,9158192,0
Analgesia (%)138,958,092,0

* P<0,01 relative to background values

The data obtained show that the compounds of General formula I in the test "hot plate" also demonstrate significant activity, significantly increasing the pain threshold. It is important to emphasize, which is comparable with the standard drugs analgesic effect is achieved with doses of 0.1-10 mg/kg, mainly 1-10 mg/kg, which is one to two orders of magnitude below the dose of the comparator drug - paracetamol has analgesic and antipyretic action. The data presented in table 5 also show that the analgesic effect of the compounds of General formula I is on average from 50 and up to a maximum of 140%, can be regarded as prolonged as it lasts for a long time - more than 4 hours.

Therefore clicks the zoom, by the severity of analgesic effect of the compounds of General formula I is comparable with the known non-narcotic analgesics (aspirin, paracetamol), and duration of analgesic action exceed the Comparators, and the effective dose was found to be significantly lower than that of the reference non-narcotic analgesics.

Example 9

Study of the effect of substances on carrageenophyte swelling of the paws of rats

The tests were carried out on outbred white male rats weighing 250-270 g were Used model carrageenin induced edema according to the method described in Winter et al. In: De Rosa M., Giroud J.P., D.A. Willoughby Studies of the mediators of the acute inflammatory response induced in rats in different sites by carrageenan and turpentine. // J.Phamacol. 1971. V.104. P.15-29.

In the right paw of the rat subplantar has introduced a 1% solution carragenin (SERVA) of 0.1 ml. Animals were seated in individual cameras. 1% Ointment was applied to the paw immediately after injection carragenin, after 1 and 2 hours. The measurement of the volume of the paw was performed using plethysmometer (Ugo Basile) at 4 hours after injection carragenin. The effect of therapeutic effects of the ointment was evaluated by the degree of inhibition of the inflammatory response in comparison with the intact left paw of this animal and the reaction of the paw of the rats of the control (untreated) group. Inhibition of the inflammatory response, expressed in percent, was calculated by the formula:

Increase =the difference × 100--------------the amount of the lion. feet

Inhibition of edema = 100 -(increase(experience)× 100)
----------------------
increase(control)

The obtained data are presented in Table 6.

Table 6

The effect of compound IX (1% ointment) on the development of carragenine swelling of the paws of rats (M ± m)
Group

N=8
The increase in paw (%)Inhibition of edema (%)
Controlto 70.2-
ConnectionIX(1% ointment)32,953,1
Indomethacin (10% ointment)45,050,0

The results presented in table 6, show a pronounced local anti-inflammatory activity of the compounds of General formula I that is comparable to the activity of the reference drug from the group of NSAIDs - indometacin, with the current dose of a compound is lower than the comparison drug.

Example 10

The study ulice ogandaga actions

The tests were performed on white outbred rats female weighing 300-320, Test compounds were administered at a dose of 30 µg/kg, once, intragastrically to rats deprived of food for 24 hours before the experiment. Animals in the control group was administered distilled water in the same volume. After 24 hours the animals were scored, drew stomachs. In an empty stomach was administered 2% aq formalin and put it in a glass of formalin. After 30 minutes dissected the stomach along the greater curvature, spread out on the stage, fixed and washed with distilled water. With the help of a magnifying glass MBS-9 (8-cu. HC.) we measured the length and width of the defects of the gastric mucosa and counted the total area in mm2(1 division line magnifier = 0.1 mm). Ulcerogenic effect of the substances was evaluated by square ulcerative lesions of the gastric mucosa according to methods described in the Manual on experimental (preclinical) study of new pharmacological substances. / Moscow, Remedium, 2000, 398 S.

The obtained data are presented in table 7.

Table 7

A comparative study of the effect of compounds of General formula I and indomethacin in a dose of 30 mg/kg in the gastric mucosa of rats (M±m)
Group, n=5The area of ulcerative lesions, mm2
Control 0
ConnectionIX0
Indometacin7,3±1,75

The data obtained show that after intragastric administration of compounds of General formulaIat a dose of 30 mg/kg, ulcerative lesions of the gastric mucosa of rats is missing.

EXAMPLES of STANDARD DOSAGE FORMS

EXAMPLE 11

A. Preformed shape

Tablet form is received, using the following ingredients:

The compound corresponding to

of General formula (I)

Potato starch

Magnesium stearate

Aerosil

Lactose


5-100 mg

20-50 mg

3 mg

1 mg

up 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)

Cocoa butter


5-100 mg

the amount needed to obtain 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)

Vaseline
of 0.05-0.5 g

10 g

Ointments are made by well-known technology.

, Gels

An example of the structure of the gel:

The compound corresponding to General formula (I)

the carbopol

benzyl alcohol

ethyl alcohol

water


100 mg

200 mg

20 mg

300 mg

to 10 g

Thus, the present invention relates to new compounds of General formulaIsimple and preparative methods for the synthesis of novel and known compounds and their use as non-steroidal anti-inflammatory drugs, cyclo-oxygenase inhibitors with anti-inflammatory and pre-emptive analgesic effect, not shown ulcerogenic side effect.

Additional data

Examples of synthesis of compounds of the present invention

As starting compounds in the synthesis used p-hydroxyphenylarsonic acid (Sigma), methyl and benzyl esters of L-tyrosine, as well as methyl and benzyl esters of L-phenylalanine ("Bachem, Germany), tyramine and 3-(p-hydroxyphenyl)propionic acid ("Fluka"). All amino acids L-series.

The identity of the compounds was checked by TLC on plates"Kieselgel 60 F 254" (Merck, Germany) in the solvent system: chloroform - methanol - ethyl acetate 6:1:3 (1), chloroform - methanol - ammonia 6:3:0.5 in (2). The chromatogram showed a chlorine-toleenum reagent, ninhydrin and glow in UV light.

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

Analytical reversed-phase HPLC was carried out on the chromatograph "Breeze"detector "Waters" (USA) under the conditions:

detection at 214 nm, the rate of elution 1 ml/min, 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 15 min (1);

in the conditions specified above with a gradient of acetonitrile from 0% to 60% over 18 min (2).

Example 12

Benzyl ester p-hydroxyphenyltriazine

The synthesis was carried out in accordance with methods As described for compound VII.

Yield 0.59 g (55.7%). Rf0.57 (1). [M+1]+406.0. [α]D20-9.18 (0.20, Meon). FTIR, δcm-1: 1649 (amide I); 1515 (amide II); 1737 (Val C=O sloep). Found, %: C at 71.05; H 5.70; N, 3.43. Calculated, %: C 71.10; H 5.72; N, 3.45.

p-Hydroxyphenylacetate (II)

To a solution of 0.59 g (1.47 mmol) of benzyl ester p-hydroxyphenyltriazine in 10 ml of methanol was added 0.20 g of 10%palladium on coal and 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 HAC is the mind. The oily residue triturated with a mixture of ether-hexane (1:1). The resulting white precipitate was filtered and dried in vacuum over CaCl2and R2O5. Was obtained 0.32 g (68%).

Yield 37%. Rf0.28 (2). [M+1]+316.07. [α]D20+28.03 (0.31, Meon).1H-NMR, DMSO-d6, δ, ppm: 2.75 (DD, 1H, CH2-Tyr), 2.9 (DD, 1H, CH2-Tyr), 3.2-3.4 (m, 2H, CH2-HOPhAc), 4.3-4.4 (m, 1H, α-CH-Tyr), 6.55-7.1 (m, 8H, arene. H), 8.05 (d, 1H, NH-Tyr). FTIR, δcm-1: 1614 (amide I); 1516 (amide II); 1254 (amide III). Found, %: C 64.65; N, 5.41; N, 4.37. C17H17NO5Calculated, %: C 64.75; N, 5.43; N, 4.44. HPLC under the conditions (2), an individual peak, the retention time of 6.33 minutes

Example 13

Benzyl ester p-hydroxyphenylethylamine

The synthesis was carried out in accordance with methods As described for compound VII.

Yield 0.76 g (74%). Rf0.87 (1). [M+1]+390.1. [α]D20-19.47 (0.19, Meon). FTIR, δcm-1: 1649 (amide I); 1515 (amide II); 1740 (Val C=O sloep). Found, %: C 74.12; H 5.92; N, 3.57. Calculated, %: C 74.02; N, 5.95; N, 3.60.

p-Hydroxyphenylacetonitrile (III)

To a solution of 0.65 g (1.67 mmol) of benzyl ester p-hydroxyphenylethylamine in 10 ml of methanol was added 0.30 g of 10%palladium on coal and 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. Macloops the initial residue triturated with hexane. The resulting white precipitate was filtered and dried in vacuum over CaCl2and R2O5. Was obtained 0.27 g (53%).

The output of 39.2%. Rf0.42 (2). [M+1]+300.09. [α]D25+18.57 (0.44; Meon).1H-NMR, DMSO-d6, δ, ppm: 2.85 (DD, 1H, CH2-Phe), 3.1 (DD, 1H, CH2-Phe), 3.2-3.35 (m, 2H, CH2-HOPhAc), 4.4-4.5 (m, 1H, α-CH-Phe), 6.55-6.95 (m, 4H, arene. N HOPhAc), 7.1-7.3 (m, 5H, arene. N Phe), 8.15 (d, 1H, NH-Phe). FTIR, δcm-1: 1611 (amide I); 1512 (amide II). Found, %: C 68.30; H 5.68; N, 4.65. Calculated, %: C 68.21; H 5.72; N, 4.68. HPLC under the conditions (1), individual peak, the retention time of 7.59 minutes

Example 14

p-Hydroxyphenyltriazine methyl ether (IV)

The synthesis was carried out in accordance with methods As described for compound VII.

Yield 0.17 g (39%). Rf0.56 (1). [M]+329.85. [α]D25+12.22 (0.36; Meon).1H-NMR, DMSO-d6, δ, ppm: 2.78 (DD, 1H, CH2-Tyr), 2.9 (DD, 1H, CH2-Tyr), 3.25-3.45 (m, 2H, CH2-HOPhAc), 4.3-4.4 (m, 1H, α-CH-Tyr), 3.6 (s, 3H, och3Tight), 6.55-7.1 (m, 8H, arene. H), 8.25 (d, 1H, NH-Tyr). FTIR, δcm-1: 1649 (amide I); 1515 (amide II); 1263 (amide III). Found, %: C 65.75; H 5.75; N, 4.23. Calculated, %: C at 65.64; H 5.81; N, 4.25. HPLC under the conditions (1), individual peak, the retention time of 7.25 minutes

Example 15

p-Hydroxyphenylethylamine methyl ester (V)

The synthesis was carried out in accordance with methods As described for compound VII.

Yield 0.40 g (39%), oil. Rf 0.70 (1). [M] +313.83. [α]D20+35.05 (0.19, ethyl acetate).1H-NMR, DMSO-d6, δ, ppm: 2.9 (DD, 1H, CH2-Phe), 3.05 (DD, 1H, CH2-Phe), 3.25-3.4 (m, 2H, CH2-HOPhAc), 3.6 (s, 3H, och3Phe), 4.4-4.5 (m, 1H, α-CH-Phe), 6.55-6.95 (m, 4H, arene. N HOPhAc), 7.1-7.3 (m, 5H, arene. N Phe), 8.3 (d, 1H, NH-Phe), 9.2 (s, 1H, HE-Ar HOPhAc). FTIR, δcm-1: 1663 (amide I); 1515 (amide II); 1263 (amide III). Found, %: C 69.08; H 6.05; N, 4.45. Calculated, %: C 68.99; H 6.11; N, 4.47. HPLC under the conditions (1), individual peak, retention time to 8.57 minutes

Example 16

3-(p-Hydroxyphenyl)propionitrile methyl ester (XIII)

The synthesis was carried out in accordance with methods As described for compound VII.

Yield 0.37 g (38%), oil. Rf0.73 (1). [M+1]+328.21. [α]D25-6.95 (0.46; Meon).1H-NMR, DMSO-d6, δ, ppm: 2.3 (t, 2H, 1-CH2HOPhPr), 2.6 (t, 2H, 2-CH2HOPhPr), 2.85 (DD, 1H, CH2-Phe), 3.0 (DD, 1H, CH2-Phe), 3.6 (s, 3H, och3Phe), 4.4-4.5 (m, 1H, α-CH-Phe), 6.6-6.95 (m, 4H, arene. N HOPhPr), 7.15-7.3 (m, 5H, arene. N Phe), 8.22 (d, 1H, NH-Phe), 9.1 (s, 1H, HE-Ar HOPhAc). FTIR, δcm-1: 1651 (amide I); 1516 (amide II); 1266 (amide III). Found, %: C at 69.61; N, 6.49; N, 4.29. Calculated, %: C 69.71; H 6.47; N, 4.28. HPLC under the conditions (1), individual peak, retention time of 8.9 minutes

Example 17

Phenylacetylamino (VI)

The synthesis was carried out in accordance with methods As described for compound VII.

Yield 0.35 g (37.6%). Rf0.85 (1). TPL105-108°C. [M+1]+256.2.1H-NMR, DMSO-d6, δ, ppm: 2.6 (t, 2H, α-CH2-TA), 3.2 (q, 2H, βCH2-TA), 3.4 (s, 2H, CH2-PhAc), 6.6-7.0 (m, 4H, arene. N t), 7.15-7.3 (m, 5H, arene. N PhAc), 8.0 (t, 1H, NH-TA), 9.1 (s, 1H, HE IS that). FTIR, δcm-1: 1646 (amide I); 1516 (amide II); 1264 (amide III). Found, %: C 75.37; N, 6.69; N, 5.45. Calculated, %: C 75.27; H 6.71; N, 5.49. HPLC under the conditions (1), individual peak, retention time 8.06 minutes

Tests for biological activity

Example 18

Analgesic and anti-inflammatory activity of compounds

corresponding to General formula (I)

Study of analgesic activity on the model of acetic cramps" (see table 8).

Table 8
Analgesic activity of the studied compounds of General formula I at a dose of 10 mg/kg in test acetic cramps" (the number of writhing for 15 min)
ConnectionThe number of miceC±mC, % of controlAnalgesic effect (%)
II1024,2±1,9*to 75.224,8
III819,4±3,3*60,239,9
control 11032,2±1,6100-
IV1020,8±1,9* 77,922,1
V1016,2±2,6*60,739,3
control 21026,7±0,79100-
VI821,1±1,8*74,525,5
XIII814,6±1,8**51,648,4
Voltaren 8 mg/kg815,8±2,6*55,544,5
control 3828,4±2,5100-
*- P<0,05, **- P<0,01 - statistically significant relative to the control group

Example 19

Study of analgesic activity on the model of "hot plate" (see table).

Table 9

Comparative evaluation of analgesic action of compounds of General formula I at a dose of 10 mg/kg and reference preparations of aspirin and paracetamol in the test "hot plate" in mice largest latent period pain threshold (PBC, sec)
N=10Time after injection connection, min
0 (background)30 60120
Compound II
M±m3,4±0,36,0±0,6*6,1±0,8*7,3±0,6**
Latency time PBC (%)100176,5179,4214,7
Analgesia (%)76,579,4to 114.7
Compound III
M±m3,7±0,36,7±0,9*5,9±0,8*7,0±0,6**
Latency time PBC (%)100181,0159,5189,2
Analgesia (%)81,059,589,2
Compound IV
M±m5,03±0,165,24±0,885,54±0,325,93±0,59
Latency time PBC (%)100104,2110,1117, 9
Analgesia (%)4,2the 10.117,9
Connection V
M±m3,74±0,164,85±0,39*5,9±0,81*6,58±0,72*
Latency time PBC (%)100129,7157,8175,9
Analgesia (%)29,757,875,9
Compound VI
M±m5,9±0,47,8±0,8*8,3±1,0*6,8±0,5
Latency time PBC (%)100132,2140,7115,3
Analgesia (%)32,240,715,3
Compound XIII
M±m5,5±0,45,9±0,36,7±0,76,8±0,3*
Latency time PBC (%)100107,3the level of 121.8123,6
Analgesia (%)7,321,823,6
* -P<0,05; ** -P<0,01 - relative to background values

1. Phenylaziridine N-acyl derivatives of amines of General formula I

where R1represents hydrogen or a hydroxy-group;

R2represents hydrogen, -COOH, -COOR4where R4represents C1-C6alkyl;

R3represents hydrogen, a hydroxy-group;

n = 1;

provided that

1) when p is 1, R1is hydrogen and R2represents-COOH, -COOR4where R4represents methyl or ethyl, R3is not a hydroxy-group;

2) when n is 1, R1and R3simultaneously represent hydrogen, R2is not-COOH, -COOR4where R4represents methyl or ethyl;

3) when p is 1, R2is hydrogen, R1and R3at the same time are not hydrogen;

4) when p is 1, R1and R2simultaneously represent hydrogen, R3is not a hydroxy-group;

and their pharmaceutically acceptable salts.

2. The compound according to claim 1, in which R2represents-COOH, -COON3.

3. The compound according to claim 1, selected from

p-hydroxyphenylacetonitrile,

p-hydroxyphenylethylamine,

p-hydroxyphenyltriazine methyl ester,

p-hydroxyphenylethylamine methyl ester,

p-hydroxyphenylethylamine,

p-hydroxyphenylacetonitrile,

and their pharmaceutically acceptable salts.

4. The compound according to any one of claims 1 to 3, with inhibiting cyclooxygenase activity.

5. The compound according to claim 4, possessing the E. analgesic and anti-inflammatory action.

6. The method of obtaining compounds of General formula I

where R1represents hydrogen or a hydroxy-group;

R2represents hydrogen, -COOH, -COOR4where R4represents C1-C6alkyl;

R3represents hydrogen, a hydroxy-group;

n is 1 or 2; or pharmaceutically acceptable salts, including the activation of the carboxyl group of p-hydroxyphenylarsonic acid or phenylacetic acid of General formula

interaction with diphenylphosphorylacetate and triethylamine in an organic solvent under cooling with subsequent interaction with aminoguanidinium General formula

where R1-R3take the values defined for compounds of General formula I.

7. The method according to claim 6, in which the use of 1-1 .2 equivalents diphenylphosphinite and triethylamine.

8. The method according to claim 6 or 7, in which the use of amino esters of tyrosine or phenylalanine.

9. Method of preparing compounds according to claim 1, or pharmaceutically acceptable salts, including the conversion of p-hydroxyphenylarsonic acid or phenylacetic acid of General formula

in activated N ether of General formula

N'-dicyclohexylcarbodiimide method, followed by interaction of activated N-operations ether derivatives of General formula

where R1-R3take the values defined for compounds of General formula I in claim 1.

10. The method according to claim 9, in which the use of amino esters of tyrosine or phenylalanine.

11. Pharmaceutical composition having inhibitory cyclooxygenase activity comprising as an active agent an effective amount of the compounds of General formula (I)

where R1represents hydrogen or a hydroxy-group;

R2represents hydrogen, -COOH, -COOR4where R4represents C1-C6alkyl;

R3represents hydrogen, a hydroxy-group;

n is 1 or 2; or pharmaceutically acceptable salts, and pharmaceutically acceptable carrier.

12. The pharmaceutical composition according to claim 11, having analgesic and anti-inflammatory properties.

13. A means of having inhibiting cyclooxygenase activity, comprising a compound of General formula (I)

where R1represents hydrogen or GI is oxygraph;

R2represents hydrogen, -COOH, -COOR4where R4represents C1-C6alkyl;

R3represents hydrogen, a hydroxy-group;

n is 1 or 2; or its pharmaceutically acceptable salt.

14. The means indicated in paragraph 13, with analgesic and anti-inflammatory action.

15. The use of compounds of General formula (I)

where R1represents hydrogen or a hydroxy-group;

R2represents hydrogen, -COOH, -COOR4where R4represents C1-C6alkyl;

R3represents hydrogen, a hydroxy-group;

n is 1 or 2; or their pharmaceutically acceptable salts as inhibitors of cyclooxygenase.

16. The use of compounds according to § 15, as analgesic and anti-inflammatory drugs.

17. A method of inhibiting cyclooxygenase, including introduction to the mammal an effective amount of compounds of General formula (I)

where R1represents hydrogen or a hydroxy-group;

R2represents hydrogen, -COOH, -COOR4where R4represents C1-C6alkyl;

R3represents hydrogen, a hydroxy-group;

n is 1 or 2; or pharmaceutically acceptable with the I.

18. The method according to 17, for the treatment of pain syndromes, inflammatory and inflammatory-degerativnye diseases of joints and connective tissue and of the musculoskeletal system, other diseases involving inflammation.

19. The method according to p, for the treatment of post-operative pain, post traumatic pain, and pain syndromes gynecological, neurological, Oncology, dental, nature, rheumatoid arthritis, arthropathy, ankylosing spondylitis, nonspecific spondyloarthropathies, gouty arthritis, osteoarthritis, non-articular rheumatism and thrombophlebitis.



 

Same patents:

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to (R)-enantiomers of 2-arylpropionamides of the formula (Ia): and their pharmaceutically acceptable salts wherein Aryl represents phenyl group substituted with a group chosen from isopropyl, acetyl, (2'',6''-dichlorophenyl)amino-group, α-hydroxyisopropyl, (R,S)-α-hydroxybenzyl and its individual R-isomers, (R,S)-(α-methylbenzyl) and its individual R-isomer and (R,S)-α-hydroxy-α-methylbenzyl and its individual R-isomer; R represents hydrogen atom (H) or (C1-C4)-alkyl; R' represents the following groups: -amino acid residue consisting of linear or branched (C1-C6)-alkyl substituted with carboxy-group -CO2H; -residue of the formula: -CH2-CH2X-(CH2-CH2O)nR wherein R has abovementioned values; n means a whole number from 0 to 1 while X represents oxygen atom; -heteroaryl chosen from the group consisting of 2-pyrimidinyl or 4-pyrimidinyl. Also, invention proposes a pharmaceutical composition inhibiting of interleukin-8-induced chemotaxis of neutrophiles and comprising as an active components (R)-enantiomers of 2-arylpropionamides of the formula (I) and their pharmaceutically acceptable salts in mixture with a suitable carrier. Also, invention proposes a method for preparing compounds of the formula (Ia). Also, invention proposes (R)-enantiomers of 2-arylpropionic acids of the formula (Va) given in the invention description and their pharmaceutically acceptable salts. Proposed (R)-2-arylpropionamides are useful in prophylaxis and treatment of tissue damage caused by enhanced accumulation of polymorphonuclear neutrophiles in the inflammation sites.

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

13 cl, 6 tbl, 24 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to compounds of the formula (I): wherein Ar represents phenyl substituted with a group taken among isobutyl, benzoyl, isopropyl, styryl, pentyl, (2,6-dichlorophenyl)-amino-group, α-hydroxyethyl, α-hydroxybenzyl, α-methylbenzyl and α-hydroxy-α-methylbenzyl; R represents hydrogen atom; X means linear (C1-C6)-alkylene, (C4-C6)-alkenylene, (C4-C6)-alkynylene optionally substituted with group -CO2R3 wherein R3 means hydrogen atom, group (CH2)m-B-(CH2)n wherein B means oxygen atom; m = 0; n means a whole number 2; or B means group -CONH; m means a whole number 1; n means a whole number 2 and so on; R1 and R2 are taken independently among group comprising hydrogen atom, linear (C1-C4)-alkyl, hydroxy-(C2-C3)-alkyl and so on. Invention proposes a method for preparing compounds of the formula (I). Invention proposes inhibitors of C5-induced hemotaxis of polymorphonuclear leukocytes and monocytes representing (R)-2-arylpropionic acid omega-aminoalkylamides of the formula (I). Also, invention relates to a pharmaceutical composition possessing inhibitory activity with respect to hemotaxis of polymorphonuclear leukocytes and monocytes and comprising compounds of the formula (I) in mixture with suitable carrier. Proposes (R)-2-arylpropionic acid omega-alkylamides are useful for inhibition of hemotaxic activation induced C5a and other hemotaxic proteins.

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

18 cl, 3 tbl, 23 ex

FIELD: medicine, chemical-pharmaceutical industry.

SUBSTANCE: agent possessing antioxidant, antitumor, anti-inflammatory, antibacterial, hypotensive, immunomodulating and adaptogenic effect comprises complex of active substances isolated from aqueous extract of peach leaves and involving flavonoids, tannic substances, coumarins, phenylcarboxylic acids, phenolglycosides, saponins, complex of active substances isolated from plant eyebright (Euphrasia) aqueous extract and involving flavonoids, phenolcarboxylic acids, steroid saponins, glycosides, carotinoids wherein the ratio of complexes is 1:1 or 1;2, or 2;1, and also biologically active components chosen from group: glucose, lactose, ascorbic acid, vitamins A and B, vegetable cellulose and accessory substance taken in the definite ratio. Agent is designated for oral using as drops, powders, tablets, lozenges and capsules. Agent doesn't possess toxicity, mutagenic, embryotoxic and teratogenic effects. Invention can be used in treatment and prophylaxis of inflammatory diseases being among them eyes, tumor processes, cardiovascular system diseases, secondary immunodeficient states and as a general tonic agent. Invention expands spectrum of effect the preparation, provides the development of a novel medicinal preparation based on substances of vegetable origin and possessing antioxidant, antitumor, anti-inflammatory, hypotensive, immunomodulating and adaptogenic effect by combination of two aqueous purified concentrated extracts from peach leaves and plant eyebright (Euphrasia).

EFFECT: improved, enhanced and valuable medicinal effects of agent.

3 cl, 5 tbl, 4 ex

FIELD: biotechnology, medicine.

SUBSTANCE: strain Bifidobacterium longum infantis NCIMB 41003 is isolated from dissecated and washed human gastrointestinal tract and has immunomodulating action after peroral administering. Said strain is useful in production of probiotic, anti-microbial agent and preparation with immunomodulating properties. Preparation is used for prophylaxis and/or treatment of undesired inflammation activity such as inflammatory bowel disease, irritable bowel syndrome, or inflammation caused by cancer.

EFFECT: new pharmaceutical agents.

46 cl, 25 dwg, 9 tbl, 9 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to new compounds of general formula I , wherein one from V or X is N and another is CRa or both V and X are CRa (each CRa is independently hydrogen atom); Y is O, S; Z is N(R2)(R3); R1 is hydrogen, C1-C10-alkyl, C3-C7-cycloalkyl, etc.; R4 is hydrogen, C1-C6-alkyl, C3-C7-cycloalkyl, etc.; A is hydrogen, C1-C10-alkyl, halo-C1-C6-alkyl, etc.; B is optionally substituted 5-membered aromatic ring containing at least one nitrogen atom and 0-3 additional heteroatoms; U is -NR5; meanings of the rest substituents are as defined in specification, and pharmaceutically acceptable salts thereof. Also disclosed are pharmaceutical composition and intermediates of formula I.

EFFECT: new biologically active compounds and pharmaceutical compositions based on the same having inhibition activity in relates to IKK-β enzyme.

26 cl, 13 ex

FIELD: medicine, chemical and pharmaceutical industry.

SUBSTANCE: claimed composition contains as active ingredient 11-beta, 16-alpha, 17-alpha, 21-tetrahydroxy-9-alpha-fluoro-1,4-pregnadiene03,20-dione or pharmaceutically acceptable salt thereof as well as 1-(para-chlorophenyl)-1-(2-pyridyl)-3-N,N-dimethylpropylamine or pharmaceutically acceptable salt thereof. As target additives composition contains lactose, microcrystalline cellulose, crospovidone and magnesium stearate.

EFFECT: composition of prolonged action and high effectiveness useful in treatment of both allergic and inflammation diseases.

4 cl, 10 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to compounds of formula I , wherein G is carbon or nitrogen atom; A is i) phenyl substituted with any from -COOH, -CONH2, COOCH3, -CN, -NH2 or -COCH3; ii) naphthyl, benzophuranyl, and quinolinyl; and iii) formulae , , .

Compounds of present invention are useful in particular in pain treatment.

EFFECT: new agents for pain treatment.

58 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: Described are derivatives of general formula I (all symbols are as described in specification), pharmaceutically acceptable salts thereof or cyclodextrin clathrates. Such compounds hardly bind of EP2 subtype of PGE receptor and are useful in prophylaxis of immune diseases, allergy, death of neuronal cells, liver or kidney insufficiency, etc.

EFFECT: new agent for prophylaxis of various diseases.

18 cl, 388 ex, 68 tbl, 3 dwg

FIELD: medicine, anesthesiology, resuscitation, field surgery, medicine of catastrophes.

SUBSTANCE: it is necessary to carry out combined intramuscular injection of toradol and dalargin, moreover, toradol should be injected every 4-6 h, and dalargin should be injected per 1 mg every 2-3 h. The innovation suggested enables to achieve quick adequate anesthesia under any conditions due to optimally matched combination of preparations and, also, the modes and techniques of their injection.

EFFECT: higher efficiency.

8 dwg, 2 ex, 5 tbl

FIELD: seafood-based biologically active agents of anti-inflammation and immunomodulating action.

SUBSTANCE: claimed agent contains "Eiconol" preparation and biologically active substance such as copper/chlorophyll complexes in amount of 5-15 mass %. Method for disease prophylaxis and treatment includes dosed therapy with abovementioned agent, wherein for topical administration agent containing 5-15 mass % of copper/chlorophyll complexes is used, and for internal administration agent containing 5-10 mass % copper/chlorophyll complexes, and dosing therapy at internal administration is carried out in dose 1.2-2.5 g/day for 7-90 days.

EFFECT: new agent for prophylaxis and therapy of diseases associated with lipid transport system disturbances.

7 cl, 2 ex

FIELD: medicine, oncology.

SUBSTANCE: it is necessary to fulfill the puncture of posterior section of iliac ala to sample 150 ml medullary suspension into the vial with 50 ml hemoconservant. The vial's content should be supplemented with 40 mg/sq. m doxorubicin, 600 mg/sq. m cyclophosphan and 1.4 mg/sq.m vincristine. The mixture obtained should be incubated at 37°C for 40 min. Then this mixture should be injected for a patient intravenously by drops. Then it is important to conduct infusion of 375 mg/sq.m dacarbazine on the 1st d of therapy. Since the 1st to the 10th d they prescribe per 40 mg/sq. m prednisolone. On the 8th d of therapy one should intravenously inject 10 mg/sq. m bleomycin. The course should be repeated in 14 d. The innovation enables to apply automyelochemotherapy on the 3d-4th stage of systemic malignant disease as the main type of therapy by preventing the increased rate of aseptic necroses of capuit femoris in this category of patients due to the matched injection scheme.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: medicine, pulmonology, pediatrics.

SUBSTANCE: the present innovation deals with treating relapsing nonobstructive bronchitis in children. Due to inhalations it is necessary to introduce Aldecin into bronchi at the dosage of 200-300 mcg/d. The dosage should be decreased by 50 mcg weekly. The period for dosage decrease corresponds to about 3-5 wk. Total duration of therapy course corresponds to about 2-3 mo. The innovation provides efficient removal of bronchial hyperactivity and allergic predisposition of respiratory tract and leads to no relapses during prolonged period of time and proves the necessity to apply glucocorticoids for this category of patients.

EFFECT: higher efficiency of therapy.

3 ex

FIELD: medicine.

SUBSTANCE: the suggested transdermal therapeutic system (TTS) includes adhesive matrix that contains biologically active substance - rotigotin. The adhesive matrix contains thermofusible contact glue, the latter consists of contact glue, the mixture of different contact glues or contact glue with a plastifier and at 160°C is of dynamic viscosity being 100 Pa·sec, not more. TTS has been obtained due to hot fusion technique: before stratifying the adhesive matrix its components should be fused and homogenized without usage of solvents at 70-200°C. According to the present innovation TTS has got high degree of filling with rotigotin which is released out of thermofusible matrices constantly and at therapeutically desirable rate. Rotigotin in case of carrying out the technique of hot fusion keeps its stability at heating up to 160°C. There is no necessity in applying, removing, regenerating or burning up organic solvents and providing corresponding safety measures during TTS manufacturing.

EFFECT: higher efficiency.

24 cl, 10 dwg, 10 ex, 4 tbl

FIELD: medicine.

SUBSTANCE: the present innovation deals with obtaining a biologically active peptide fraction out of poultry blood serum being useful at some human and animal diseases and disorders. It is necessary to carry out electrostimulation of a bird's head at the mode of about 70-80 V for about 2-3 sec to sample blood and incubate it at 4-8°C for about 18-24 h, then the serum sampled should be irradiated with C0 60 at the mode of 25±5.0 kGy and extracted after irradiation with 0.5 mM solution of phenylmethane sulfonyl fluoride in distilled water at the ratio of 1:10 to be mixed at 5°C for 1 h and centrifuged at 12000 rot./min for 30 min, then the residue should be repeatedly centrifuged under the same conditions, supernatant should be filtered successively through the membrane at pore's diameter being 0.45 mcm and 10 kDa, and a target product being a peptide fraction at molecular weight up to 10 kDa should be lyophilized and kept at about 4-8°C. The suggested pharmaceutical composition is characterized by the fact that as an active substance it contains efficient quantity of peptides of molecular weight up to 10 kDa obtained to a certain technique and a pharmaceutically acceptable carrier or filler. The innovation enables to obtain new biologically active peptide fraction up to 10 kDa and develop its medicinal form.

EFFECT: higher efficiency.

2 cl, 2 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes a novel derivative of 5-methoxy-8-aryl[1,2,4]-triazole[1,5-a]pyridine of the general formula (I): wherein R1 means hydrogen, halogen atom or lower alkoxy-group; R2 means -C(O)-phenyl wherein ring can be unsubstituted or substituted with one or two substitutes chosen from group consisting of halogen atom, lower alkyl, lower alkoxy-group or trifluoromethyl, or it means -C(O)-furanyl or -C(O)-thiophenyl wherein rings are not substituted or substituted with halogen atom, and its pharmaceutically acceptable salts. Proposed compounds can be used in treatment of diseases associated with adenosine A2 receptors. Also, invention describes a medicinal agent used in treatment of diseases associated with adenosine A2A receptors containing compound of the formula (I) and pharmaceutically acceptable excipients.

EFFECT: valuable medicinal properties of agent.

8 cl, 1 tbl, 1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes using the compound (R/S)-(-/+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman or their salts for preparing a medicinal agent. This agent is used in treatment of extrapyramidal motor disorders, in particular, in treatment of unfavorable effects of anti-parkinsonic preparations and using (S)-(+)-2-[5-(4-fluorophenyl)-3-pyridylmethylaminomethyl]-chroman in combination with an anti-parkinsonic preparation for preparing the combined medicinal agent. Also, invention relates to a pharmaceutical composition for treatment of extrapyramidal disorders and a set of the same designation. Proposed compounds are able to prevent catalepsy caused by usual anti-dopaminergic preparations and they are strong agonists of 5-HT1A-receptors in combination with antagonism to dopamine D2-receptors and interaction with D3-receptors that provides positive effects on extrapyramidal system in treatment of dyskinesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzothiazole of the general formula (I): and their pharmaceutically acceptable acid-additive salts used as ligands of adenosine receptors and to a medicinal agent based on thereof. In compound of the general formula (I) R means phenyl, pyridine-2-yl, -C(O)-O-(lower)-alkyl, -C(O)-(lower)-alkyl, -C(O)-morpholinyl, -C(O)-NR'2, -(CH2)n-NR'2 or -(CH2)n-O-(lower)-alkyl; R' means hydrogen atom or (lower)-alkyl. Compounds can be used in treatment and prophylaxis of diseases mediated by adenosine receptors A2A and A1, for example, in Alzheimer's disease, some depressive states, toxicomania, Parkinson's disease.

EFFECT: valuable medicinal properties of compounds.

15 cl, 3 sch, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nicotine- or isonicotine-benzothiazole of general formulas (IA) and (IB) their pharmaceutically acceptable acid-additive salts and a medicinal agent based on thereof. In compounds of general formula (IA) and (IB) R1 means phenyl, piperidine-1-yl or morpholine; A means -O-; R means -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-O-lower alkyl, -(CH2)n-O-(CH2)n-O-lower alkyl, lower alkyl, -(CH2)n-morpholinyl, -(CH2)n-phenyl, -(CH2)n-N(R''), -(CH2)n-pyridinyl, -(CH2)n-CF3, -(CH2)n-2-oxopyrrolidinyl or (C4-C6)-cycloalkyl; R'' mean(s) independently of one another hydrogen atom or lower alkyl; n= 1 or 2; A means -N(R')-; R means lower alkyl, (C4-C6)-cycloalkyl, -(CH2)n-O-lower alkyl, -(CH2)n-pyridinyl, -(CH2)n-piperidinyl, -(CH2)n-phenyl, -(CH2)n-N(R'')-C(O)-lower alkyl, -(CH2)n-morpholinyl or -(CH2)n-N(R'')2; R' and R'' mean independently of one another hydrogen atom or lower alkyl; n = 1 or 2; or A means -CH2-; R means -N(R'')-(CH2)m-O-lower alkyl, -N(R'')2, S-lower alkyl, or R means azethidinyl, pyrrolidinyl or piperidinyl that are substituted optionally with hydroxy-group or lower alkoxy-group; or R means morpholinyl, -N(R'')-(CH2)m-(C4-C6)-cycloalkyl, -N(R'')-(CH2)m-C(O)-O-lower alkyl, -O-(CH2)m-O-lower alkyl or alkoxy-group; R'' mean(s) independently of one another hydrogen atom or lower alkyl; m = 1, 2 or 3; or A means -S-; R means lower alkyl, or A-R mean in common piperazinyl substituted with alkyl, -C(O)-lower alkyl or oxo-group, or group A-R means piperidinyl substituted with lower alkoxy-group or hydroxy-group, or group A-R means morpholinyl substituted with lower alkyl, or group A-R means (C4-C6)-cycloalkyl, azethidine-1-yl optionally substituted with hydroxy-group or lower alkoxy-group, or group A-R means thiomorpholinyl-1,1-dioxo-group, tetrahydropyrane or 2-oxa-5-azabicyclo[2.2.1]hept-5-yl. Proposed compounds can be used in treatment of diseases mediated by adenosine A2A-receptors, for example, Alzheimer disease, some depressive states, toxicomania and Parkinson's disease.

EFFECT: valuable medicinal properties of compounds and agent.

37 cl, 10 sch, 109 ex

Fumaric acid amides // 2290946

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to medicinal agents, namely, to using fumaric acid amides of the formula (I): These compounds are used in preparing a medicinal agent designated for treatment of autoimmune diseases, response reactions "transplant against host", treatment of diseases mediated by NfkappaB, and to fumaric acid amides of the formula (I) and to a medicinal agent comprising fumaric acid amide of the formula (I) taken in the dose corresponding to 1-500 mg of fumaric acid as measured for a single dose and designated for treatment abovementioned diseases. Fumaric acid amides and a medicinal agent comprising thereof are characterized by absence of systemic adverse effect of body and resistance against hydrolysis that allows avoiding their multiply dosing.

EFFECT: valuable medicinal properties of agents.

19 cl, 2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of pyrimidine of the general formula (I) that possess properties of antagonists to adenosine A2-receptors and can be effective in relieve, for example, of defecation. In compound of the general formula (I) each R1 and R2 represents hydrogen atom; R3 represents hydrogen atom, halogen atom, amino-group, cyano-group, alkyl group comprising 1-6 carbon atoms, alkoxy-group comprising 1-6 carbon atoms, alkenyloxy-group comprising 2-6 carbon atoms, phenyl group that can be substituted with halogen atom, pyridyl group, furyl group or thienyl group; R4 represents pyridyl that can be substituted with a substitute chosen from the group comprising: hydrogen atom, halogen atom, amino-group, mono- or dialkylamino-group, aminoalkylamino-group wherein each has in alkyl residue from 1 to 6 carbon atoms, alkyl group comprising from 1 to 6 carbon atoms that can be substituted with halogen atom, hydroxy-group, amino-group, mono- or dialkylamino-group, alkoxycarbonyl wherein each has in alkyl residue from 1 to 6 carbon atoms, alkoxy-group comprising in alkyl group from 1 to 6 carbon atoms substituted with phenyl or pyridyl, hydroxyalkoxy-group comprising in alkyl residue from 1 to 6 carbon atoms, hydroxycarbonyl, alkoxycarbonyl comprising from 1 to 6 carbon atoms in alkyl residue, alkenyl group comprising from 2 to 6 carbon atoms, alkynyl group comprising from 2 to 6 carbon atoms, piperidinyl group that can be substituted with hydroxyl group, or represents group of the formula (IV): R5 represents phenyl that can be substituted with halogen atom, pyridyl group, thienyl or furyl group.

EFFECT: valuable biological properties of derivatives.

16 cl, 2 tbl, 185 ex

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