N-hetaryl-substituted 4-hydroxy-1-methyl-2,2-dioxo-1h-2λ6,1-benzothiazine-3-carboxamides, exhibiting analgesic activity

FIELD: chemistry.

SUBSTANCE: invention relates to N-hetaryl-substituted 4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamides of general formula: , where R=5-methyl-1,3-thiazol-2-yl, or 4-ethoxycarbonylmethyl-1,3-thiazol-2-yl, or 6-methylpyridin-2-yl, or 5-chloropyridin-2-yl, or pyrimidin-2-yl. Novel N-hetaryl-substituted 4-hydroxy-1-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxamide derivatives which exhibit analgesic activity are obtained.

EFFECT: high activity of derivatives.

2 tbl, 7 ex

 

The invention relates to medicinal chemistry and relates to biologically active substances, in particular N-retailsalescome 4-hydroxy-1-methyl-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxamido exhibiting analgesic activity, due to which it can be used in chemical and pharmaceutical industry and medicine.

Among the famous drugs used in modern medicine to combat pain and pain syndromes of different origin, prominently NSAIDs excambio number: N-hetaryl-4-hydroxy-2-methyl-1,1-diokso-2H-1λ6,2-benzothiazin-3-carboxamide - piroxicam and meloxicam [1]. Unfortunately, with all its positive sides of these drugs are not without various kinds of deficiencies that caused numerous contraindications and limitations in their practical application. The main of them is quite high toxicity [2, 3] and the need to achieve the analgesic effect of taking large doses of the drug [4].

The present invention is the obtaining of new less toxic narcotic analgesics, manifesting a high analgesic effect at relatively low doses.

The task is achieved due to the fact that the obtained N-retailsalescome 4-hydroxy-1-methyl�-2,2-diokso-1H-2λ 6,1-benzothiazin-3-carboxamide of the General formula (1):

where R=5-methyl-1,3-thiazol-2-yl (1a), or 4-ethoxycarbonylmethyl-1,3-thiazol-2-yl (1B), or 6-methylpyridine-2-yl (1B), or 5-chloropyridin-2-yl (1G), or pyrimidine-2-yl (1D) exhibiting analgesic activity.

In accordance with the present claimed invention 5 individual chemical compounds presented in table 1.

The claimed compounds are synthesized by the interaction of methyl ester of 4-hydroxy-1-methyl-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxylic acid with the appropriate getrolename that deliver the claimed structures 1A-1D, at a temperature of 150°C in xylene and in an argon atmosphere, followed by separation of the resulting precipitate.

Table 1
VariantRThe claimed connection
1A4-Hydroxy-1-methyl-N-(5-methyl-1,3-thiazol-2-yl)-2,2-diokso-1H-2λ2,1-benzothiazin-3-carboxamide
1B4-Hydroxy-1-methyl-N-(4-ethoxycarbonyl�yl-1,3-thiazol-2-yl)-2,2-diokso-1H-2λ 6,1-benzothiazin-3-carboxamide
1B4-Hydroxy-1-methyl-N-(6-methylpyridine-2-yl)-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxamide
1G4-Hydroxy-1-methyl-N-(5-chloropyridin-2-yl)-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxamide
1D4-Hydroxy-1-methyl-N-(pyrimidine-2-yl)-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxamide

The invention is illustrated by the following examples.

Example 1. Getting a 4-hydroxy-1-methyl-N-(5-methyl-1,3-thiazol-2-yl)-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxamide (1a). A mixture of 2.69 g (0.01 mol) of methyl ester of 4-hydroxy-1-methyl-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxylic acid, 1.14 g (0.01 mol) of 2-amino-5-thiazole, and 5 ml of xylene stand on a metal bath at 150°C in argon atmosphere for 1 hour. The reaction mixture was cooled, add 5 ml of ethanol and allowed to stand for several hours at room temperature. The crystals formed amide 1A is filtered off, washed with cold ethyl alcohol and dried. The yield of 3.12 g (89%). So a MP 277-279°C decomp. (DMFA-which contains chamazulene�, 1:5). The NMR spectrum1H, δ, M. D. (J, Hz): 15.09 (1H, s, 4-OH); 8.82 (1H, s, NH); 8.00 (1H, d, J=7.7, H-5); 7.50 (1H, t, J=7.6, H-7); 7.18-7.11 (2H, m, H-6+H-8); 6.93 (1H, s, H-4' of the thiazole); 3.27 (3H, s, NCH3); 2.37 (3H, s, 5'-CH3). The NMR spectrum13C, δ, M. D.: 169.9 (4-OH), 162.3 (C=O), 159.9 (C-2' of thiazole), 141.1 (C-8a), 133.1 (C-5), 128.9 (C-4' of thiazole), 127.7 (C-5' of thiazole), 125.5 (C-7), 123.5 (C-6), Beijing 122.8 (C-8), 117.2 (C-4A), 104.4 (C-3), 30.5 (NCH3), 12.1 (C-5'-CH3). The mass spectrum (EI, 70 eV), m/z (IRel, %): 351 [M]+(8.2), 237 (1.6), 211 (100), 147 (2.9), 140 (76.2), 114 (73.7), 105 (35.2), 91 (53.1), 72 (50.2). Found, %: C, 47.76; H, 3.65; N, 12.03; S 18.11. C14H13N3O4S2. Calculated, %: C 47.85; N, 3.73; N, 11.96; S 18.25.

Example 2. Getting a 4-hydroxy-1-methyl-N-(4-ethoxycarbonylmethyl-1,3-thiazol-2-yl)-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxamide (1B). A mixture of 2.69 g (0.01 mol) of methyl ester of 4-hydroxy-1-methyl-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxylic acid, 1.86 g (0.01 mol) of 2-amino-4-ethoxy-carbonyldiimidazole and 5 ml of xylene stand on a metal bath at 150°C in argon atmosphere for 1 hour. The reaction mixture was cooled, add 5 ml of ethanol and allowed to stand for several hours at room temperature. The crystals formed amide 1B is filtered off, washed with cold ethyl alcohol and dried. The yield of 3.51 g (83%). So a MP 144-146°C (DMF-ethanol, 1:8). The NMR spectrum1N, δ, M. D. (J, Hz): 16.08 (1H, s, 4-OH); 9.67 (1H, s, NH); 8.01 (1H, d, J=7.8, H-5); 7.58 (1H, t, J=7.8, H-7); 7.25-7.18 (2H, m, H-6+H-8); 7.04 (1H, s, H-5' TIA�Ola); 4.17 (2H, K, J=7.2, och2); 3.79 (2H, s, CH2COOEt); 3.32 (3H, s, NCH3); 1.29 (3H, t, J=7.2, OCH2CH3). The NMR spectrum13C, δ, M. D.: 172.6 (COOEt), 169.6 (4-OH), 162.8 (C=O), 162.6 (C-2' of thiazole), 141.2 (C-8a), 135.0 (C-4' of thiazole), 133.7 (C-5), Beijing 127.6 (C-7), 123.3 (C-6), 123.1 (C-8), 117.5 (C-4A), 111.5 (C-5' of thiazole), 105.0 (C-3), 61.6 (OCH2), 34.3 (CH2COOEt), 30.7 (NCH3), 14.7 (OCH2CH3). The mass spectrum (EI, 70 eV), m/z (IRel, %): 423 [M]+(14.0), 237 (1.9), 212 (47.0), 211 (88.8), 186 (58.0), 147 (5.4), 139 (100), 118 (20.9), 105 (35.1), 91 (53.9), 71 (30.7). Found, %: 48.15; N, 3.96; N, 9.98; S 15.02. C17H17N3O6S2. Calculated, %: 48.22; H 4.05; N, 9.92; S 15.14.

Example 3. Getting a 4-hydroxy-1-methyl-N-(6-methylpyridine-2-yl)-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxamide (1B). A mixture of 2.69 g (0.01 mol) of methyl ester of 4-hydroxy-1-methyl-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxylic acid, 1.08 g (0.01 mol) of 2-amino-6-methylpyridine and 5 ml of xylene stand on a metal bath at 150°C in argon atmosphere for 1 hour. The reaction mixture was cooled, add 5 ml of ethanol and allowed to stand for several hours at room temperature. The crystals formed amide 1B is filtered off, washed with cold ethyl alcohol and dried. The yield of 3.17 g (92%). So a MP 234-236°C (DMF-ethanol, 1:3). The NMR spectrum1H, δ, M. D. (J, Hz): 15.16 (1H, ush. C, 4 HE); 14.55 (1H, s, CONH); 8.07-8.01 (2H, m, H-5+H-4'); 7.89 (1H, d, J=7.5, H-3'); 7.58 (1H, t, J=7.4, H-7); 7.27-7.20 (2H, m, H-6+H-8); 7.16 (1H, d, J=7.1, H-5'); 3.32 (3H, s, NCH3/sub> ); 2.62 (3H, s, 6'-CH3). The NMR spectrum13C, δ, M. D.: 174.5 (C=O), 164.1 (4-OH), 150.5 (C-6'), 149.7 (C-4'), 146.0 (C-2'), 141.3 Mm (C-8a), 133.3 (C-4A), Beijing 127.8 (C-7), 125.0 (C-5'), 122.9 (C-5), 118.9 (C-8), 117.4 (C-3'), 113.8 (C-6), 104.8 (C-3), 30.7 (NCH3), 20.3 (C-6'-CH3). The mass spectrum (EI, 70 eV), m/z (IRel, %): 345 [M]+(8.5), 281 (13.9), 280 (19.8), 237 (52.0), 211 (100), 173 (9.7), 147 (12.1), 146 (23.5), 134 (47.2), 118 (15.2), 108 (75.6), 91 (58.0), 77 (30.9). Found, %: 55.73; H 4.41; N, 12.20; S 9.36. C16H15N3O4S. Calculated, %: 55.64; H 4.38; N, 12.17; S 9.28.

Example 4. Getting a 4-hydroxy-1-methyl-N-(5-chloropyridin-2-yl)-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxamide (1G). A mixture of 2.69 g (0.01 mol) of methyl ester of 4-hydroxy-1-methyl-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxylic acid, 1.29 g (0.01 mol) of 2-amino-5-chloropyridine and 5 ml of xylene stand on a metal bath at 150°C in argon atmosphere for 1 hour. The reaction mixture was cooled, add 5 ml of ethanol and allowed to stand for several hours at room temperature. The crystals formed amide 1 g was filtered, washed with cold ethyl alcohol and dried. The yield 3.44 g (94%). So a MP 230-232°C (DMF-ethanol, 1:3). The NMR spectrum1H, δ, M. D. (J, Hz): 15.09 (1H, ush. C, 4 HE); 14.32 (1H, s, CONH); 8.35 (1H, d, J=1.4, H-6'); 8.15 (1H, d, J=8.1, H-4'); 8.08 (1H, d, J=7.9, H-5); 7.91 (1H, d, J=8.0, H-3'); 7.77 (1H, t, J=7.6, H-7); 7.48 (1H, d, J=8.4, H-8); 7.37 (1H, t, J=7.1, H-6); 3.49 (3H, s, NCH3). The NMR spectrum13C, δ, M. D.: 171.0 (C=O), 163.9 (4-OH), 150.0 (C-6'), 145.6 (C-4'), 144.6 (C-2'), 137.3 (C-8a), 134.5 (C-4A) Beijing 127.6 (C-7), 126.1 (C-5'), 124.2 (C-5), 123.9 (C-8), 118.4 (C-3'), 116.2 (C-6), 104.9 (C-3), 31.9 (NCH3). The mass spectrum (EI, 70 eV), m/z (IRel, %): 365/367 [M]+(2.5/3.1), 301/303 (40.4/13.4), 300/302 (30.9/16.4), 237 (6.7), 211 (6.2), 173 (24.6), 154/156 (6.5/3.2), 147 (24.2), 146 (69.5), 128/130 (100/49.4), 118 (9.5), 91 (24.1), 77 (27.2). Found, %: 49.20; H, 3.25; N, 11.42; S 8.84. C15H12ClN3O4S. Calculated, %: 49.25; N, 3.31; N, 11.49; S 8.77.

Example 5. Getting a 4-hydroxy-1-methyl-N-(pyrimidine-2-yl)-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxamide (1D). A mixture of 2.69 g (0.01 mol) of methyl ester of 4-hydroxy-1-methyl-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxylic acid, 0.95 g (0.01 mol) of 2-aminopyrimidine and 5 ml of xylene stand on a metal bath at 150°C in argon atmosphere for 1 hour. The reaction mixture was cooled, add 5 ml of ethanol and allowed to stand for several hours at room temperature. The crystals formed amide 1D filtered off, washed with cold ethyl alcohol and dried. The yield 2.72 g (82%). T. PL 213 to 215°C (DMF-ethanol, 1:3). The NMR spectrum1H, δ, M. D. (J, Hz): 14.38 (2H, ush. C, 4 HE+CONH); 8.83 (2H, d, J=5.4, H-4'+H-6'); 8.03 (1H, d, J=8.0, H-5); 7.53 (1H, t, J=7.7, H-7); 7.36 (1H, t, J=5.2, H-5'); 7.22-7.15 (2H, m, H-6+H-8); 3.29 (3H, c, NCH3). The NMR spectrum13C, δ, M. D.: 175.2 (C=O), 163.9 (4-P-HE), 158.3 (C-2'), 154.5 (C-6'), 141.3 MM (C-4'), 133.4 (C-8a), 128.1 (C-4a), 125.3 (C-7), 123.1 (C-5), 117.6 (C-5'), 116.3 (C-8), 110.6 (C-6), 104.7 (C-3), 30.9 (NCH3). The mass spectrum (EI, 70 eV), m/z (IRel, %): 268 (9.1), 237 (7.6), 211 (26.8), 173 (8.1), 147 (6.5), 146 (18.4), 121 (29.0), 118 (15.8), 95 (100), 91 (41.8), 7 (33.2). Found, %: 50.66; N, 3.71; N 16.93; S 9.72. C14H12N4O4S. Calculated, %: 50.60; N, 3.64; N, 16.86; S 9.65.

The NMR spectra1H and13C claimed compounds recorded on the instrument Varian Mercury-400 (400 and 100 MHz, respectively) in a solution of DMSO-d6, internal standard TMS. Mass-spectra were registered on the instrument Varian 1200L in the full scan mode in the range of 35...700 m/z, ionization by electron impact 70 eV by direct input of the sample. Elemental analysis performed on the microprobe Euro Vector EA-3000. The melting temperature determined in a capillary on the digital analyzer SMP10 melting point Stuart.

Example 6. Acute toxicity of N-hetaryl-4-hydroxy-1-methyl-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxamide 1A-d were studied in intact white mice weighing 18-22 g of 6 animals in series with each dose. The test substance was administered in the form of a thin aqueous suspension, stabilized by tween-80, oral (with high doses 2-3 times with an interval of 10 minutes). The number of surviving animals was recorded every 24 hours for 14 days. Srednetemperaturnyi dose (LD50) was calculated according to the method of Kerber [5]. Given the data in table 2 indicate that all of the claimed substances according to the classification K. K. Sidorov [6], at least, are less toxic. Piroxicam and meloxicam significantly inferior to them on this indicator, since p� reported in literature [2, 3] their srednetemperaturnyi doses to the mice orally are only 250 and 470 mg/kg, respectively.

Example 7. The analgesic activity of the claimed N-hetaryl-4-hydroxy-1-methyl-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxamide 1A-d were studied on the model of thermal irritation of the tip of the tail white rats (tail-flick) [7]. The tip of the tail of the animal is immersed in heated to 54°C water bath. Determine the initial length of the latent period of immersion (withdrawal) of the tail, expressed in seconds. Analgesic effect ( % ) estimated by changing the duration of the latent period after 1 h after injection of the compounds under investigation. To obtain statistically reliable results (adopted level of significance confidence interval p≤0.05) in testing each of the claimed amides 1A-d, the comparison drugs and in control were involved in 7 experimental animals. All of the test substances and preparations (piroxicam and meloxicam) is administered orally in the form of stabilized with Tween-80 thin aqueous suspensions or solutions at a dose of 20 mg/kg. Animals in the control group received an equivalent amount of water and tween-80.

Table 2
ConnectionLD50 mg/kgThe latent period after 1 h after injection of connectionsIncreasing the duration of the latent period compared with the control, %
1A>30006.29±0.20+61.5
1B>30007.27±0.22+86.4
1B>30006.87±0.21+76.2
1G>30007.67±0.24+96.7
1D>30007.73±0.22+98.1
Piroxicam250 [7]4.87±0.17+24.9
Meloxicam470 [8]5.78±0.15+48.2
Control-3.90±0.18-

Presented in table.2 experimental �data indicate, all the claimed compounds are able to inhibit irritation caused by thermal pain response is much more efficient than known drugs meloxicam and piroxicam in equal doses with them.

Thus, the inventive N-hetaryl-4-hydroxy-1-methyl-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxamide in the analgesic properties in several times more active than the comparison drugs at a much lower toxicity. All compounds synthesized from available reagents and by simple methods, which can be reproduced in terms of chemical and pharmaceutical companies or laboratories using standard equipment.

N-Retailsalescome 4-hydroxy-1-methyl-2,2-diokso-1H-2λ6,1-benzo-thiazin-3-carboxamide can be used as a substance in the creation of analgesics in different dosage forms.

Sources of information

1. M. D. Mashkovsky Medicines. - M.: RIA "New wave": the Publisher Merenkov, 2009. - P. 176-178.

2. Kleemann, A., Engel J. / Pharmaceutical substances. Synthesis, patents, applications. - Multimedia Viewer, Version 2.00. - Stuttgart: Georg Thime Verlag. 2001.

3. The Merck Index on CD-ROM. - Version 12:3, Merck & Co Inc, Whitehouse station, NJ, USA, 2000. - Published on CD-ROM by Chapman & Hall/CRC.

4. Sigidin J. A., Schwartz, G. J., A. Arzamastsev P., S. S. Lieberman/ Drug therapy of inflammatory process (experimental and clinical pharmacology �protivovospolitelnyh drugs). - M.: Medicine, 1988. - Page 62-63.

5. Sarnow L. N., Hazura Vladimir Elements of experimental pharmacology. - M.: PPP "Typography "Science". - 2000. - P. 318.

6. Sidorov, K. K. On the classification of the toxicity of poisons in parenteral routes of administration // In the book. Toxicology of new industrial chemical substances. - M.: Medicine, 1973. - Vol.13. - P. 50.

7. Drug Discovery and Evaluation: Pharmacological Assays / H. G. Vogel (Ed.), 3rd ed. - Berlin: Springer. - 2008. - P. 1011.

N-Retailsalescome 4-hydroxy-1-methyl-2,2-diokso-1H-2λ6,1-benzothiazin-3-carboxamide the General formula:

where R=5-methyl-1,3-thiazol-2-yl, or 4-ethoxycarbonylmethyl-1,3-thiazol-2-yl, or 6-methylpyridine-2-yl, or 5-chloropyridin-2-yl, or pyrimidine-2-yl exhibiting analgesic activity.



 

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FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I, such as below, or its pharmaceutically acceptable salts. What is described is a method for preparing them.

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FIELD: chemistry.

SUBSTANCE: invention relates to field of organic chemistry, namely to heterocyclic compounds of formula I

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17 cl, 2 tbl, 89 ex

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16 cl, 1 tbl, 46 ex

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1 tbl, 1 ex

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1 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to 6-substituted isoquinoline and isoquinolinone derivatives of formula or to its stereoisomer and/or tautomer forms and/or a pharmaceutically acceptable salt, wherein R1 represents H, OH or NH2; R3 represents H; R4 represents H, a halogen atom, CN or (C1-C6)alkylene-(C6-C10)aryl; R5 represents H, a halogen atom, (C1-C6)alkyl; R7 represents H, a halogen atom, (C1-C6)alkyl, O-(C1-C6)alkyl; R8 represents H; R9 and R6 are absent; R10 represents (C1-C6)alkyl, (C1-C8)heteroalkyl, (C3-C8)cycloalkyl, (C6)hetrocycloalkyl, (C1-C6)alkylene-(C3-C8)cycloalkyl, (C1-C6)alkylene-(C6-C10)aryl, (C1-C6)alkylene-(C6)heterocycloalkyl; R11 represents H; R12 represents (C1-C6)alkyl, (C3-C8)cycloalkyl, (C5)heteroaryl or (C6-C10)aryl; R13 and R14 independently represent H, (C1-C6)alkyl, (C1-C6)alkylene-R'; n is equal to 0; m is equal to 2 or 3; s is equal to 1 or 2; r is equal to 1; L represents O or NH; R' represents (C3-C8)cycloalkyl, (C6-C10)aryl; wherein in the rests, R10, R12-R14 alkyl or alkylene are unsubstituted or optionally substituted by one or more OCH3; wherein in the rests, R10, R12-R14 alkyl or alkylene are unsubstituted or optionally substituted by one or more halogen atoms; wherein (C1-C8)heteroaryl group means (C1-C8)alkyl groups, wherein at least one carbon atom is substituted by O;. (C6)heterocycloalkyl group means a monocyclic carbon ring system containing 6 ring atoms wherein one carbon atom can be substituted by 1 oxygen atom or 1 sulphur atom which can be optionally oxidated; (C5)heteroaryl means a monoring system wherein one or more carbon atoms can be substituted by 1 nitrogen atom or 1 sulphur atom or a combination of various heteroatoms. Also, the invention refers to using the compound of formula (I) and to a therapeutic agent based on the compound of formula (I).

EFFECT: there are prepared new compounds effective for treating and/or preventing diseases associated with Rho-kinase and/or mediated by Rho-kinase by phosphorylation of myosin light chain phosphatase, and the compositions containing these compounds.

32 cl, 111 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to novel chromenone derivatives of formula II or its pharmaceutically acceptable salts, where each R20 is hydrogen; R11 is selected from phenyl and 5-6 member saturated or aromatic heterocycle, including one or two heteroatoms, selected from N, O or S, where R11 is optionally substituted with one-two substituents, independently selected from C1-C4alkyl, =O, -O-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13), where each R13 is independently selected from hydrogen and -C1-C4alkyl; or two R13 together with nitrogen atom, to which they are bound, form 5-6-member saturated heterocycle, optionally including one additional O, where, when R13 is alkyl, alkyl is optionally substituted with one or more substituents, selected from -OH, fluorine, and, when two R13 together with nitrogen atom, to which they are bound, form 6-member saturated heterocycle, saturated heterocycle is optionally substituted on each carbon atom with -C1-C4alkyl; R12 is selected from phenyl and pyridyl, where R12 is optionally substituted with one or more substituents, independently selected from halogen, C1-C4alkyl, C1-C2 fluorine-substituted alkyl, -O-R13, -S(O)2-R13, -(C1-C4alkyl)-N(R13)(R13), -N(R13)(R13); R14 is selected from hydrogen; and X1 is selected from -NH-C(=O)-†, -C(=O)-NH-†, - -S(=O)2-NH-†, where † stands for place, where X1 is bound with R11; and, when R14 is H; R12is phenyl; and X1 is - C(=O)-NH-†, then R11 is not 1H-pyrazol-3-yl, possessing stimulating activity.

EFFECT: invention relates to pharmaceutical composition based on said compounds, method of treating subject, suffering from or having resistance to insulin, metabolic syndrome or diabetes, as well as to method of increasing sensitivity to insulin.

16 cl, 1 tbl, 24 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: compounds can find application for preventing or treating cancer, lung cancer, non-small cells lung cancer, small-cell lung cancer, EML4-ALK hybrid polynucleotide-positive cancer, EML4-ALK hybrid polynucleotide-positive lung cancer or EML4-ALK hybrid polynucleotide-positive non-small cells lung cancer. In formula (I) -X-: group of formula , A represents chlorine, ethyl or isopropyl; R1 represents phenyl wherein carbon in the 4th position is substituted by the group -W-Y-Z, and carbon in the 3rd position can be substituted by a group specified in a group consisting of halogen, R00 and -O-R00; R00: lower alkyl which can be substituted by one or more halogen atoms; -W-: a bond, piperidine-1,4-diyl or piperazine-1,4-diyl; -Y- represents a bond; Z represents a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more substitutes R00; R2 represents (i) an optionally bridged saturated C3-10cycloalkyl which can be substituted by one or more groups specified in -N(lower alkyl)2, lower alkyl, -COO-lower alkyl, -OH, -COOH, -CONH-RZB and morpholinyl, or (ii) a monovalent 3-10-membered monocyclic non-aromatic heterocyclic ring which contains 1 to 4 heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, which can be substituted by one or more groups specified in a group consisting of lower alkyl, -CO-lower alkyl, oxo, -CO-RZB and benzene; and RZB: phenyl which can be substituted by a group consisting of halogen and -O-lower alkyl; R3 represents -H.

EFFECT: invention refers to new compounds of formula or their pharmaceutically acceptable salts possessing the properties of a selective inhibitor of EML4-ALK hybrid protein kinase activity.

16 cl, 201 tbl, 582 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine, and consists in using compounds that are sigma-1 receptor antagonists.

EFFECT: preparing the compounds for treating or preventing neuropathic pain caused by the chemotherapy with taxane preparations with the neuropathic pain representing allodynia or hyperalgesia.

8 cl, 2 tbl, 7 dwg

FIELD: biotechnologies.

SUBSTANCE: invention refers to a biotechnology industry, and namely to synthetic peptides having a non-narcotic type of analgetic action of a general formula: 1 H - XDL - L-Leu - D-His - L-Lys - L-Leu - L-Gln - L-Thr - R2 (I), where: H - hydrogen, XDL - absence of amino acid or L-Tyr, R2 - OMe or NH2, as well as peptides - retroinversions of formula (I), which have reverse sequence of amino acids with replacement of L-shape of amino acids with D-shape and D-shape of amino acids with L-shape, with the following general formula: 2 H - D-Thr - D-Gln - D-Leu - D-Lys - L-His - D-Leu - XDL1 - R2 (II), where: H - hydrogen, XDL1 - absence of amino acid or D-Tyr, R2 - OMe or NH2.

EFFECT: invention allows producing safe analgetic medical preparations with a non-narcotic type of analgetic action.

5 tbl, 2 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to chemical-pharmaceutical industry and represents a method for direct transmucosal buprenorphine delivery into an individual's body as an analgesic, involving coating an individual's oral mucosa with a biodegradable drug delivery agent containing buprenorphine in a buffer mucoadhesive polymer diffuse medium characterised by a pH value within the range of 4 to 6 and related to a barrier medium to form a one-direction gradient when coating the mucosa with the delivery agent and delivering buprenorphine into the individual body.

EFFECT: invention provides the improved delivery profile and more effective drug delivery.

47 cl, 4 ex, 4 tbl, 6 dwg

FIELD: chemistry.

SUBSTANCE: amino acid derivatives form new compounds of a common formula (I) with radicals values indicated in description. Amino acid derivatives disclosed herein are novel compounds which demonstrate excellent analgesic activity not only with respect to nociceptive pain model animals, but also with respect to neuropathic pain model animals.

EFFECT: amino acid derivatives medical are very effective as medicinal agents for treatment of various diseases accompanied by pain.

19 cl, 175 ex, 15 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to cyclohexane derivatives presented by general formula wherein the substitute A is a group of general formula or wherein the radicals and symbols are presented in the patent claim. The compounds of formula (I) possess strong analgesic action both on nociceptive pain, and on neuropathic pain, and to a lesser degree side effects. Their pharmaceutical use is also described.

EFFECT: cyclohexane derivative and its pharmaceutical use is presented.

17 cl, 42 tbl, 7 dwg, 177 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is peroral pharmaceutical composition for treatment of urinary retention, caused by opioids, which includes, at least, one opioid antagonist naloxone or its pharmaceutically acceptable salt (versions).

EFFECT: disclosed is achievement of claimed intention, with naloxone possessing very low peroral bioavailability, and does not prevent (does not reverse) pain-killing action of opioid agonist.

17 cl, 19 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed is application of tapentadol for manufacturing medication for treatment of pain caused by osteoarthrosis, in which at the beginning of treatment amount of taken in tapentadol is gradually increased in order to avoid side effects (titration from 25 mg two times per day to 200 mg two times per day).

EFFECT: reduction of prevalence of treatment side effects: day drowsiness, nausea, vomiting, dizziness and dry mouth.

13 cl, 4 dwg, 4 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel imidazole derivatives of formula where A is pyridinyl; and B is a condensed ring system consisting of: a. a phenyl ring bonded to a molecular residue, b. a second heterocyclic 5- or 6-member ring which is condensed with the phenyl ring, and has one nitrogen or oxygen atom, and to tautomeric forms thereof.

EFFECT: obtaining novel imidazole derivatives which are antagonists of adrenergic receptors.

6 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: galenic form for transmucosal introduction contains as an active substance paracetamol completely and stably dissolved in an aqueous-alcoholic solution containing 40 to 55% of ethanol and 45 to 60% of water by volume to ensure fast absorption of paracetamol through the oral and/or oropharyngeal mucosa. The galenic form under the invention contains 25 to 250 mg of paracetamol per volume of the aqueous-alcoholic solution 0.5 to 2.5 ml. The invention also refers to a method for preparing and applying the galenic form.

EFFECT: galenic form under the invention enables the introduction of paracetamol in the amount which becomes bioavailable immediately with paracetamol quickly and effectively showing its therapeutic action, particularly analgesic and antipyretic action.

15 cl, 6 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of general formula

(where values of radicals are given in the claim), as well as salts of such compounds and pharmaceutical compositions based on such compounds. The described compounds exhibit type 1 channel antagonists with transient receptor potential (TRPV1).

EFFECT: compounds can be used to treat diseases and conditions causing pain.

30 cl, 255 ex, 40 tbl

FIELD: medicine.

SUBSTANCE: carious cavity is prepared. Then it is treated instrumentally and antiseptically. A hole of an apical canal of a causative tooth is expanded. Methylene blue is introduced into the cyst through a root canal at a depth of 7-10 min. The cyst envelope is exposed to a laser light generated by a diode laser through the root canal for 30-60 s by means of a needle light guide. The exposure is continued from the vestibular or oral surface for 60.0-120.0 s by means of a plate light guide of intensity 0.5-1 W, wave length 625-630 nm in a pulse mode. Before the root canals of the causative tooth is hermetically sealed, Collap-An gel with metrogil 1.0-1.5 ml is introduced into the cyst.

EFFECT: method enables provides increasing clinical effectiveness, avoiding the complications by removing the cyst envelope completely that enables restoring the bone defect structure completely.

2 ex

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