A method of obtaining a 9-substituted derivatives of guanine and 1 - substituted 5-(thiocarbamoyl)amino-1h-imidazol-4-carboxamide

 

(57) Abstract:

Usage: in medicine, in particular as antiviral drugs. The inventive product 9-substituted derivatives of guanine f ly R C1-C4-alkyl, perhaps with one or two HE, or R or R is benzyl, ribosyl, 2'-deoxyribosyl, or -(CH2)n-OR1when R1(CH2)2OH n is 1 or 2, or-CH(CH2OH)2. Reagent: R 1-substituted 5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide f-crystals II with R, see above. Reaction conditions: the cyclization of lead processing salt of heavy metal (Cu, Ag, Pb, Hg) in aqueous alkaline medium containing at least four equivalent hydroxyl ions, at a temperature from room temperature up to the boiling temperature under reflux and further selection of the target product by treatment with an acid. 2 S. and 1 C.p. f-crystals, 1 table.

The invention relates to a process for the preparation of 9-substituted derivatives of guanine General formula

(l) where R is a C1-C4-alkyl, optionally substituted by one or more hydroxyl groups, or R is

a benzyl, ribosom, 2-deoxyribosyl or (CH2)n-OR SIG1where n is 1 or 2, and R1is CH2CH2HE or the surrounding antiviral activity, either they are intermediate compounds designed to produce compounds of interest for genetic engineering.

It Is Known [T. Org.Chem.51, 1277-1282 (1986)] that guanosin can be obtained from 4-carboxamide-5-amino-1-ribofuranosyl - imidazole way, consisting of three stages, namely, the condensation derivative carbodiimide, cyclization in the presence of PdO and processing using NH4OH.

However, this method requires the use of toxic compounds, phosgene to obtain a carbodiimide derivatives, and the subsequent stage of cyclization and treatment with NH4IT requires too much time.

It is also known that the compound of the formula I, in which R is H, can be obtained by a method in which the compound of the formula

(ll) first subjected to methylation with formation of the corresponding timetravel connection, which then cyclist in an alkaline environment (A. Yamazaki, ci.Ac.Pe, 1976, 251-259).

When implementing this method as a by-product is toxic mercaptan with unwanted ability to swell. In addition, the performance of this method is extremely low. In this work also the S="ptx2">

The authors of the present invention, it was unexpectedly found that the cyclization of N1-substituted derivatives of compounds of formula 2 may be effected without prior methylation and using heavy metal in aqueous alkaline medium or by use of peroxide compounds.

The proposed method differs in that 1-substituted 5-(thiocarbamoyl)amino-1H-imidazol-4-carboxamid General formula

(III) where R has the same meaning as in formula I, is subjected to cyclization:

(a) by treating the salt of the heavy metal group: Cu, Ag, Pd and Hg in aqueous alkaline medium containing at least 4 equivalent of HE-ions, at a temperature of from about 0aboutWith temperatures of distillation, or

b) by treatment with peroksosoedinenii in aqueous alkaline medium at a temperature of about 0-30aboutWith and in the presence of tungstate ions as catalyst, after which the connection I produce by treatment with acid, and if necessary, turn into salt.

The initial compounds of the formula

where R is a C1-C4-alkyl optionally substituted by one or more hydroxyl groups, or R is

a benzyl, ribosom, 2CH2or

CH, or their salts are new compounds, which implies that the proposed compound includes the compounds as intermediates to obtain the 9-substituted derivatives of guanine of formula I

The initial compounds of formula III can be obtained by reaction of 1-substituted 5-amino-1H-imidazol-4-carboxamido formula

(lV) where R is defined in formula I and where the hydroxyl group in R, if they exist, can be etilirovany, with arylisocyanates with subsequent hydrolysis to remove the N-acyl group and any other amelnyk groups.

The compounds of formula IV can be obtained by alkylation of the known compound 5-amino-1H-imidazole-4-carboxamide in a standard way.

In variant (a) the proposed method is preferably carried out using as a heavy metal salt of copper. As a result, the method allows to obtain a high yield of a product using a cheap reagent.

In addition, option (a) method mainly carried out in a medium containing an alkali metal hydroxide, preferably potassium hydroxide or sodium.

In variant (b) of the method preferably orthocarbonic)amino-1-methyl-1H-imidazol-4-carboxy - Mead

5-Amino-1-methyl-1H-imidazol-4-carboxamid (6.5 g, 45 mm) and benzoylisothiocyanate (7.7 g, 47 mm) was heated in a flask under reflux in acetone (90 ml) for 4 h in the presence of N2. After cooling in an ice bath, the resulting product was filtered, washed with acetate and dried off. The result was isolated 13,0 g (95%) of target compound in the form of a white powder, so pl. 194-195aboutC.

5-(N'-benzoylthiourea)amino-1 - ethyl-1H-imidazol-4-carboxamide was obtained from 5-amino-1-ethyl-1H-imidazole-4-carboxamide in a similar manner, so pl. 178-180aboutC. 5-(N'-benzoylthiourea)amino-1-(1-propyl)-1H-imidazol-4-carboxamid received 5-amino-1-1-propyl-1H-imidazole-4-carboxamide in a similar way, so pl. 163-164aboutC.

5-(N'-benzoylthiourea)amino-1 - benzyl-1H-imidazol-4-carboxamide was obtained from 5-amino-1-benzyl-1H-imidazole-4-carboxamide in a similar way, so pl. 181-182,5aboutC. 1-[(2-Hydroxyethoxy)methyl]-5-(ticar-bemail)amino-1H-imidazol-4-carboxamid

5-amino-1-[2-atomic charges)ethoxy] methyl] --1H-imidazol-4-carboxamid (44,0 g, 182 mm) and benzoylisothiocyanate (29,7 g, 182 mm) was heated in a vessel under reflux in acetone (430 ml) for 1 h To the resulting solution were added methanol (430 ml) and potassium carbonate (14,9 After cooling to room temperature was added acetic acid to obtain a pH of 8. The resulting product was filtered at 0aboutC, washed and drained. The result provided is 39.2 g (83%) of target compound in the form of a white powder, so pl. 181-182aboutC (decomp.). A sample, crystallized from water, had so pl. 182-183aboutC (decomp.).

13C-NMR (D-d6) (ppm) 183,9; 163,7; 134,9; 129,3; 127,9; 74,0; 70,4; 59,7. Elemental analysis for C8H13N5ABOUT3S.

Calculated With 37,06; N. Of 5.05; N 27.01; S 12,37.

Found, With 36,92; N 5,07; N 27,30; S To 12.28.

1-[1,3-Dihydroxy-(2-propyloxy-methyl]-5-(thiocarbamoyl)amino-1H-imidazol-4-carboxamid received a similar manner from 5-amino-[1,3-dihydroxy-(2-propyloxy)methyl]-1H-imidazol-4-carboxy - Mead, so pl. 185aboutC (decomp.).

13C-NMR (DMSO-d6) ppm: 183,8; 163,9; 134,8; 129,2; 127,9; 80,2; 73,5; 60,7.

Elemental analysis for C9H15N5O4S.

Calculated C 37,36; H 5,23; N 24,21; S 11,08.

Found, 37,34; H 5,16; N 23,81; S 10,76. 1-[(2-Hydroxyethoxy)methyl] -5-(ticar-bemail)amino-1H-imidazol-4-carboxamid

The benzoyl chloride (5.9 g, 42 mm) in the presence of N2one drop was added to the solution amanitaceae (3.2 g, 42 mm) in acetone (80 ml) for 5 min at 25aboutC. After heating for 15 minutes in a flask with reflux condenser Rasta">

To the filtrate was added 5-amino-1-[(2-(atomic charges)ethoxy]methyl]-1H-imidazol-4-carboxamid (9.7 g, 40 mm). The mixture was heated in a flask under reflux for 90 minutes in the presence of N2. Then added methanol (80 ml) and potassium carbonate (5.8 g, 42 mm), soluble in water (12 ml) and the resulting mixture was heated in a flask under reflux in the presence of N2within 8 hours For hydrolysis mixture was added water, 70 ml, after which the mixture was treated with activated carbon at 25aboutC. Then the solution is evaporated to obtain about 70 ml, and the pH was brought to 7.0 with acetic acid. After cooling to 5aboutWith the obtained product was filtered, washed and dried. In the result of which was allocated 8.0 g (77%) of target compound in the form of a white powder with so pl. 178-180aboutC (decomp.). Analysis by HPLC showed a purity of more than 96% of 1-[(2-Hydroxyethoxy)methyl]-5-(ticar-bemail)amino)-1H-imida-4-carboxamid

In the presence of N2at 25aboutWith over 5 min to a solution of ammonium thiocyanate (1.6 g, 21 mm) in acetone (30 ml) was added drop acetylchloride (1.6 g, 21 mm). After heating for 15 min in a flask with reflux condenser and the mixture was cooled to 20aboutAnd the formed ammonium chloride was filtered the-4-carboxamid (4.8 g, 20 mm). The mixture was heated under reflux for 20 h in the presence of N2. Then added methanol (40 ml) and potassium carbonate (5.8 g, 42 mm) dissolved in water (12 ml) and the resulting mixture was heated under reflux in the presence of nitrogen. For hydrolysis mixture was added water (50 ml), after which the mixture was treated with activated carbon at 25aboutC. Then the solution is evaporated to 30 ml, and the pH was brought to 7.0 with acetic acid. After cooling to 5aboutWith the obtained product was filtered off, washed with water and drained.

The result was obtained 3.2 g (62%) of target compound in the form of a white powder with so pl. 175-177aboutC (decomp.). Analysis by HPLC showed a purity of more than 94%

1-Methyl-5-(thiocarbamoyl)amino-1H - imidazol-4-carboxamid

5-(N'-benzoylthiourea)amino-1 - methyl-1H-imidazol-4-carboxamid (12.1 g, 40 mm) was added to a mixture of acetone and methanol (1:1(200 ml). Then was added potassium carbonate (2.8 g, 20 mm) dissolved in water (12 ml). The reaction mixture was heated in a vessel under reflux in the presence of nitrogen for 6 h, after which was added acetic acid (2.9 g, 48 mm). After stirring in an ice bath, the product was filtered, washed and dried. The result has been to 7.7 g (oC).

A sample, crystallized from water, has a melting point 280-283aboutC (decomp.) (conversion starts at about 220aboutC).

13C-NMR (DMSO d6) ppm: 184,0; 163,9; 134,8; 130,2; 127,3; 30,9.

Analysis for C6H9N5OS

Calculated With 36,17; N 4,55; N 35,16.

Found, With 36,06; N A 4.53; N 35,05.

1-Ethyl-5-(thiocarbamoyl)amino-1H-them-Gasol-4-carboxamide was obtained in a similar manner from 5-(N'-benzoylthiourea)-amino-1-ethyl-1H-imidazol-4-carboxy - Mead, so pl. 265-268aboutC (decomp.).

13C-NMR (DMSO d6) ppm: 183,8; 163,9; 133,8; 129,1; 127,8; 39,0; 15,2.

Analysis for C7H11N5OS

Calculated With 39,42; N 5,20; N 32,84.

Found, With 39,37; N 5,19; N 32,71.

1-(1-propyl)-5-(thiocarbamoyl)amino - 1H-imidazol-4-carboxamid received a similar manner from 5-(N'-benzoylthiourea)-amino-1-(1-propyl)-1H-imidazole-4-carboxamide, so pl. 197-198aboutC (decomp.).

13C-NMR (DMSO d6) ppm: 183,8; 163,9; 134,4; 129,2; 127,7; 45,7; 22,7; 10,8.

Analysis for C8H13N5OS

Calculated, 42,27; N 5,77; N 30,81.

Found, 42,16; N. Of 5.84; N 30,86.

1-Benzyl-5-(thiocarbamoyl)amino-1H-imidazol-4-carboxamide was obtained in a similar manner from 5-(N'-beticola 205aboutC).

13C-NMR (DMSO-d6) ppm: 183,8; 163,9; 136,5; 134,5; 129,6; 128,5; 127,7; 127,4; 47,6.

Analysis for C12H13N5OS

Calculated With 52,34; N Was 4.76; N 25,44.

Found, 52,31; N To 4.73; N 25,52.

The following examples illustrate the proposed method.

Examples 1-7 illustrate a variant (a) of the method, examples 8-12 option (b).

P R I m e R 1. 9-methylguanine.

1-Methyl-5-(thiocarbamoyl)amino-1H - imidazol-4-carboxamid (3.98 g, 20 mm) was dissolved in 1 N. sodium hydroxide (160 ml). Then added copper acetate N2Of (4.6 g, 23 mm), after which the reaction mixture was heated in a flask under reflux for 1 h After cooling to 50aboutWith the formed copper sulfide was filtered. The filtrate was acidified with acetic acid to pH 5.0. The resulting product was filtered at 25aboutWith, washed with water and drained. The result is allocated to 3.16 (9%) of target compound in the form of a white powder, so more than 100 squareaboutC.

13C-NMR (1H. NaO) ppm: 170,7; 163,6; 154,0; 141,4; 120,0; 82,2.

Analysis for C6H7N5O.

Calculated With 43,63; N 4,27; N 42,41.

Found, With 43,05; N 4,20; N 41,95.

P R I m m e R 2. 9-Ethylguanine.

9-Ethylguanine received analog for C7H9N5ABOUT 1/4H2O

Calculated With 45,77; N To 5.21; N 38,13.

Found, 45,52; 5,00; N 38,04.

P R I m e R 3. 9-(1-Propyl)guanine

9-(1-propyl)guanine was obtained in a similar manner from 1-(1-propyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide, so pl. > 300aboutS.13C-NMR (DMSO d6) ppm: 156,8; 153,8; 151,0; 137,4; 116,5; 44,2; 22,7; 10,8.

Analysis for C8H11N5O

Calculated With 49,73; N 5,74; N 36,25.

Found, 49,50; N 5,76; N 36,30.

P R I m e R 4. 9-Benzylguanine.

9-Benzylguanine was obtained in a similar manner from 1-benzyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide, so pl. 305-308aboutC,13C-NMR (DMSO-d6) ppm: 157,0; 153; 151,2; 137; 137,3; 128,7; 127; 127,2; 116; 45,9.

Analysis for C12H11N5ABOUT

Calculated With 59,74; N 4,59; N 29,03.

Found, 59,50; N 4,51; N 28,91.

P R I m e R 5A. 9-[(2-Hydroxyethoxy)methyl]guanine(Acyclovir). 9-[(2-Hydroxyethoxy)methyl]-5-(ticar-bemail)amino-1H-Amidala-4-carboxamide (10.0 g, 38.6 mm) was added to a suspension of copper sulfate (7.0 g, 44 mm) in 6 n sodium hydroxide (80 ml) and the mixture stirred at room temperature for 4 hours Analysis by HPLC showed the output to 100% After filtration the filtrate was added 50% aqueous uksosnaboutC. the Product was filtered, was led out of the water and was treated with activated carbon. The result has been a 7.8 g(85%) 9-[(2-hydroxyethoxy)methyl]guanine, 3/4 H2On (Acyclovir) in the form of a white powder. Analysis by HPLC showed a purity of more than 99% of T. pl. 250aboutC (decomp.)13C-NMR (DMSO-d6) ppm: 156,8; 153,8; 151,4; 137,8; 116,5; 72,1; 70,4 and 59,9.

Analysis for C8H11N5O3, 3/4 H2O.

Calculated, 40,25; N 5,28, N 29,34.

Found, 40,39; N 5,22; N 29,37.

P R I m e R 5B. 9-(2-Hydroxyethoxy)methyl)guanine (Acyclovir). 1-[(2-Hydroxyethoxy)methyl]-5-(ticar-bemail)amino-1H-imidazol-4-carboxamid (of 1.30 g, 5.0 mm) was added to a suspension of copper acetate N2On (1,15 g of 5.75 mm) in 1 n sodium hydroxide (60 ml) and heated under reflux for 30 minutes Analysis by HPLC showed the output to 100% After filtration, to the filtrate was added acetic acid (5 ml) and then heated in the presence of activated charcoal. Then the charcoal was filtered, and the material was cooled to 5aboutC. the Precipitated product was filtered, washed with water and drained. The result has been 0,92 g(77%) 9-[(2-hydroxyethoxy)methyl]guanine, 3/4 H2About in the form of a white powder. HPLC showed a purity of more than 99% Usage is illustrated in the table.

P R I m e R 6. 9-[1,3-Dihydroxy-(2-propyloxy)methyl]guanine.

1-[1,3(-Dihydroxy-(2-propyloxy)IU - Tyl]-5-(thiocarbamoyl)-amino-1H-imidazol-4-carboxamid (of 0.58 g, 2.0 mm) was added to a suspension of copper sulfate (0.32 g, 2.3 mm) 3 N. of sodium hydroxide (8 ml) and heated under reflux for 1 h, HPLC showed the output to 100% After filtration, to the filtrate was added 33% acetic acid (6 ml), then was heated under reflux, while processing activated carbon. Then the charcoal was filtered, and the solution was cooled to 5aboutC. After filtration, washing with water and drying was obtained 0.33 g (61%) 9-1,3-dihydroxy-2-propylacetate guanine, 3/4 H2About in the form of a white powder, so pl. 245aboutC. (decomp.).13C-NMR (DMSO-d6) ppm: 157,0; 153,9; 151,8; 137,6; 116,3; 79,9; 71,9; 60,8.

Analysis for C9H13N5O4, 3/4H2ABOUT

Calculated WITH 40,22; N 5,43; N grade of 20.06

Found, 40,25; N 5,31; N 25,58.

P R I m e R 7. 9- -D-ribofuranosylpurine (guanosin)

5-Amino-1-( -D-ribofuranosyl)-1H-imidazol-4-carboxamide (5.0 g, 19,4 mm) and benzoylisothiocyanate (3.3 g, 20 mm) is stirred at room temperature in dimethylformamide (DMF) (40 ml) for 1 h, the Solvent is kept in the vacuum created waterjet nassauville under reflux for 2 hours After cooling to room temperature was added acetic acid to pH 6. Then the reaction mixture is evaporated in vacuum, the generated water pump and the residue was led from ethanol. The result was obtained 5.0 g of the crude 1-( -D-ribofuranosyl)-5-(thiocarbamoyl)amino-1H-them-Gasol-4-carboxamide. HPLC showed a purity of about 65% (the remaining 35% mainly constituted potassium acetate).

The crude product 1-( -D-ribofuranosyl)-5-(thiocarbamoyl)-amino-1H-them-Gasol-4-carboxamide (5.0 g) was added to a suspension of copper sulfate (2.9 g, 18 mm) 3 N. of sodium hydroxide (60 ml) and the mixture was heated under reflux for 1 h After filtration, to the filtrate was added a 33% aqueous acetic acid (30 ml) and again heated under reflux, while processing activated carbon. Then the charcoal was filtered, and the solution was cooled to room temperature over night. After filtration, washing with water and drying were obtained 2.0 g (65%) 9--D-ribofuranosyl-guanine, N2On (guanosin, N2O) in the form of a white powder, with so pl. 250aboutC (decomp.). The product had the same physical properties as the authentic sample of guanosine H2O.

P R I m e R 8. 9-(1-Propyl)guanine.

1-(1-Propyl)-5-(CTI is I (50 ml) at 0aboutC. and Then for 30 min at 0 to 10aboutWith one drop) was added 35% hydrogen peroxide (1.8 ml, 20 mm) in water (5 ml). After stirring in an ice bath for 1 h, the pH was brought to 5 with acetic acid. The resulting product was filtered, washed with water and drained. The result has been 0,41 g (42%) of target compound in the form of a white powder. HPLC showed a purity of more than 98% of the product Obtained had physical data similar to the data of the product of example 3.

P R I m e R 9. 9-benzylguanine.

1-Benzyl-5-(thiocarbamoyl)amino-1H-imidazol-4-carboxamid (2,75 g, 10.0 mm) and sodium tungstate (0.1 g) suspended in 6 BC of sodium hydroxide (20 ml) at 5aboutC. and Then for 30 min at 5-15aboutWith one drop) was added 35% hydrogen peroxide (4.0 ml, 44 mm). To the obtained reaction mixture was added water (60 ml). After stirring for 1 h in an ice bath, the pH is brought to 5 with hydrochloric acid. The resulting product was filtered, washed with water and drained. The result has been of 1.30 g, 54% of the target compound as a white powder. HPLC showed a purity of about 98% of the product Obtained had physical data similar to the data of the product of example 4.

P R I m e R 10. 9-Methylguanine.

9-Methylguanine who ate physical data similar to the product of example 1.

P R I m e R 11. 9-Ethylguanine.

9-Ethylguanine was obtained in a similar manner from 1-ethyl-5-(thiocarbamoyl)amino-1-imidazole-4-carboxamide. The resulting product had physical data similar to the data of the product of example 2.

P R I m e R 12. 9-[(2-Hydroxyethoxymethyl]guanine(Acyclovir). 1-[(2-Hydroxyethoxy)methyl] -5-(ticar-bemail)amino-1H-imidazol-4-carboxamid (2,59 g, 10.0 mm) and sodium tungstate (0.05 g) was dissolved in 6 BC of sodium hydroxide (20 ml) at 5aboutC. Then at 5-15aboutC for 15 min drop was added 35% hydrogen peroxide (4.0 ml, 44 mm). After stirring for 15 min at 0-5aboutC, HPLC was performed, which showed that the yield of the target compounds was 59%, the pH Value of the reaction mixture was brought to 5.5 with 25% aqueous acetic acid. The resulting product was filtered, washed with water, dried off and got 1.13 g (50%) of target compound in the form of a white powder. HPLC showed a purity of about 97% of the Product had physical data similar to the data of the product of example 5.

1. A method of obtaining a 9-substituted derivatives of guanine General formula I

< / BR>
where R1-C4-alkyl, possibly substituted by one or two of the>,

where n=1 or 2;

R1CH2CH2HE

< / BR>
wherein the 1-substituted 5-(thiocarbamoyl)amino-1H-imidazol-4-carboxamid General formula

< / BR>
where R has the above meaning,

subjected to cyclization by treating the salt of the heavy metal group Cu, Ag, Pb and Hg in aqueous alkaline medium containing at least four equivalent ions of HE-at a temperature of from room temperature up to the boiling temperature under reflux, after which the compound of formula I produce by treatment with acid.

2. The method according to p. 1, wherein the salt of a heavy metal is a copper salt.

3. 1-Substituted 5-(thiocarbamoyl)amino-1H-imidazol-4-carboxamide General formula II

< / BR>
where R1-C4-alkyl, possibly substituted by one or two hydroxy groups, or R residue

< / BR>
or benzyl, ribosyl, 2-deoxyribosyl, or

(CH2)n-OR1,

where n=1 or 2;

R1CH2CH2HE



 

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< / BR>
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FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to using phenylethenyl- or phenylethynyl-derivatives as antagonists of glutamates receptors. Invention describes using compound of the general formula (I):

wherein each among R1, R2, R3, R4 and R5 means independently of one another hydrogen atom, (C1-C6)-alkyl, -(CH2)n-halogen, (C1-C6)-alkoxy-group, -(CH2)n-NRR', -(CH2)n-N(R)-C(O)-C1-C6)-alkyl, phenyl or pyrrolyl that can be unsubstituted or substituted with one or more (C1-C6)-alkyl; each among R, R' and R'' means independently of one another hydrogen atom or (C1-C6)-alkyl; A means -CH=CH- or C≡C; B means ,, , , or wherein R6 means hydrogen atom, (C1-C)-alkyl, -(CH2)n-C(O)OR, or halogen atom; R7 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-C(O)OR', halogen atom, nitro-group or oxodiazolyl group that can be unsubstituted or substituted with (C1-C6)-alkyl or cycloalkyl; R8 means hydrogen atom, (C1-C6)-alkyl, -(CH2)n-OH, -(CH2)n-C(O)OR'' or phenyl; R9 means (C1-C6)-alkyl; R10 and R11 mean hydrogen atom; R12 means -(CH2)n-N(R)-C(O)-(C1-C6)-alkyl; R13 means hydrogen atom; each R14, R15, R16 and R17 independently of one another means hydrogen atom or (C1-C6)-alkoxy-group; each R18, R19 and R20 independently of one another means hydrogen atom; R21 means hydrogen atom or (C1-C6)-alkyl; R22 means hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkyl comprising one or more substitutes chosen from groups hydroxy- or halogen atom; R23 means hydrogen atom, (C1-C6)-alkanoyl or nitro-group; each among R24, R25 and R26 independently of one another means hydrogen atom or (C1-C6)-alkyl; n = 0, 1, 2, 3, 4, 5 or 6; X means -O- or -S-; Y means -CH= or -N=, and its pharmaceutically acceptable salts used in preparing medicinal agents designates for treatment or prophylaxis of disorders mediated by mGluR5-receptors. Also, invention describes compounds of the formula (I-A), compound of the formula (I-B-1) given in the invention description, and a medicinal agent used in treatment or prophylaxis of disorders mediated by mGluR5-receptors.

EFFECT: valuable medicinal properties of compounds.

44 cl, 1 tbl, 44 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes derivatives of 1H-imidazole-4-carboxamide of the formula (I): wherein R represents phenyl, 2-pyridinyl, 3-pyridinyl that can be substituted; R1 means phenyl, 5-membered aromatic heterocyclic ring comprising one nitrogen atom (N) as a heteroatom that can be substituted; R2 means hydrogen atom (H), (C1-C8)-alkyl; R3 represents (C2-C8)-alkyl, (C1-C8)-alkoxy-group, (C3-C8)-cycloalkyl, benzyl group, aromatic ring that can be substituted; R4 means hydrogen or halogen atom, cyano-group, sulfamoyl, methanesulfonyl, methylsulfanyl or (C1-C4)-alkyl. Also, invention describes methods for synthesis of these compounds and pharmaceutical compositions. Derivatives of 1H-imidazole-4-carboxamide are effective agonists, partial agonists or antagonists of cannabinoid CB1-receptors that can be useful in treatment of psychic and neurological diseases and other diseases with involving cannabinoid neurotransmission.

EFFECT: valuable biological and medicinal properties of compounds and pharmaceutical compositions.

11 cl, 1 tbl, 113 ex

FIELD: chemistry.

SUBSTANCE: in novel compounds of formula (I) X stands for C, N; R1 stands for H or (lower) alkyl, R2 stands for 9(lower) alkyl, -(CH2)n-R2a; R2a stands for C3-C8cycloalkyl, optionally and independently mono-, di-, tri- or tetrasubstituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent saturated heterocyclic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heterocyclic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy, 5- or 6-member single-valent heteroaromatic ring, containing from one to two heteroatoms, independently selected from nitrogen, oxygen and sulfur, said heteroaromatic ring being optionally and independently mono-, di- or tri-substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, C3-C6cycloalkyl; R3 stands for C3-C6cycloalkyl, being optionally and independently mono-, di- or tri- or tetra-substituted with groups: OH, (lower) alkyl, (lower)alkoxy, phenyl, which optionally and independently is mono-, di- or tri- or tetra-substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; R4 stands for 5- or 6-member single-valent heteroaromatic ring, containing from one to two nitrogen heteroatoms, said heteroaromatic ring being optionally and independently mono-, di- or tri- substituted with the following groups: OH, (lower) alkyl, (lower)alkoxy, halogen; naphtyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, (lower)alkylamino, halogenated (lower)alkyl, halogenated (lower)alkoxy, nitro; or phenyl, which optionally and independently is mono-, di- or tri- substituted with groups: OH, (lower)alkyl, (lower)alkoxy, halogen, nitro, halogenated (lower)alkyl, halogenated (lower)alkoxy, cyano, (lower)alkylsulfonyl, -NR7R8; or two neighbouring substituents in said phenyl residue together represent -O-(CH2)p-O-, -(CH2)2-C(O)NH-; R5 and R6 each independently represent H, (lower)alkyl; R7 and R8 each independently represent hydrogen, (lower)alkyl, or R7 and R8 together with nitrogen atom, to which they are bound, form 5- or 6- member saturated or aromatic heterocyclic ring, which optionally contain nitrogen as additional heteroatom; said saturated or aromatic heterocyclic ring, being optionally substituted with the following groups: OH, (lower)alkyl, (lower)alkoxy; m equals 1 or 2, n equals 0 or 1, p equals 1, 2 or 3; or their pharmaceutically acceptable salts.

EFFECT: increased antagonistic activity of compounds.

19 cl

FIELD: chemistry.

SUBSTANCE: invention refers to 1,2,4,5-tetrasubstituted imidazole derivatives of general formula (I) , where R1 represents chlorine, bromine, fluorine or hydrogen atom, R2 represents chlorine or bromine atom, A represents nitrogen atom or group CH, X represents sulphur atom or sulphoxide (S=O) group, or sulphonic (SO2) group, Y represents hydrogen atom or methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl group, Z represents CH group, n represents number 1,2 or 3, and pharmacologically acceptable salts of compounds. Besides, the invention concerns a pharmaceutical composition based on the compound of general formula (I), to the compounds of general formulas and and to application of compounds of general formula (I).

EFFECT: new imidazole derivatives being selective modulators of cannabinoid receptors CB1 with high selectivity.

12 cl, 1 tbl, 4 ex

FIELD: chemistry.

SUBSTANCE: invention refers to imidazoline derivatives having CB1-antagonist activity of general formula where: R1 and R2 independently stand for phenyl which can be substituted with 1-2 substitutes Y being identical and represent chlorine, bromine, fluorine, iodine, X stands for one subgroup or , where: R3 stands for hydrogen atom or linear C1-3 alkyl group, R4 stands for C3-8 cycloalkyl or C5-10, and said groups can contain one atom N, R7 represents benzyl or phenyl group, and specified groups can be substituted in aromatic ring by 1 substitute Y, where Y is evaluated as specified above being either identical, or different, or R7 stands for C1-8dialkylaminogroup, R8 represents hydrogen atom, R9 represents hydrogen atom and their salt. Additionally, the invention concerns a pharmaceutical composition based on compound of formula I, and to its application for therapy of diseases caused by canabiod neurotransmission.

EFFECT: new compounds possess useful biological activity.

9 cl, 1 tbl, 3 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to new imidazole derivatives of general formula I , where R1 is C1-C10alkyl or C3-C10cycloalkyl, each possibly and independently substituted with 1 substitute selected from C3-C10cycloalkyl or aryl or a heteroaryl group, possibly substituted with one or two halogens; aryl or heteroaryl; R2 is C1-C10alkoxy or C1-C10thioalkyl; R3 is C1-C10alkoxy, possibly substituted with one C1-C10alkoxy or nitrile, where the said alkoxy group can be cyclic or can contain one O heteroatom; R4 is C1-C10alkyl; C2-C10alkenyl; C1-C10alkoxy or C3-C10cycloalkyl, each possibly and independently substituted with 1 or 2 substitutes selected from C1-C10alkoxy, C3-C10cycloalkyl, carboxylic ester, or with one or two aryl or heteroaryl groups, possibly substituted with one substitute selected from C1-C10alkyl, C3-C10cycloalkyl, nitro or halogen; aryl or heteroaryl, each possibly and independently substituted with 1-3 substitutes selected from C1-C10alkyl, C3-C10cycloalkyl, C1-C10alkoxy, phenoxy, thiophenyl, halogen, nitro, nitrile or aryl group, possibly substituted with one halogen; where up to three hydrogen atoms of the alkyl group can be substituted with fluorine atoms; where the said cycloalkyl can independently have one or two carbon atoms substituted with O or N; where the said aryl denotes an aromatic ring having 6 to 10 carbon atoms, including mono- and bicyclic compounds; and where the said heteroaryl denotes an aromatic ring having 3 to 10 carbon atoms, including mono- and bicyclic compounds in which one to three ring atoms are oxygen, nitrogen or sulphur atoms; except compounds given in paragraph 1. The invention also pertains to use of the said compounds for making a medicinal agent, a treatment and prevention method, a compound of formula II (values of radicals are given in the formula of invention).

EFFECT: new imidazole derivatives having positive allosteric modulator effect on GABAB receptor are obtained.

30 cl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: there is described a compound of formula I: or its pharmaceutically acceptable salt, where R2 represents (CR3R4)n-NR5R6 and m, p, q, Ar, R1, R3, R4, R5 and R6 are those as specified in the patent claim and defined as selective 5-NT6 and/or 5-NT2A antagonists. There is also described a pharmaceutical composition containing this compound, and application thereof in preparing drugs for treating diseased conditions of central nervous system chosen from psychoses, schizophrenia, manic depressions, neural disorders, memory impairment, attention deficient syndrome, Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, malnutrition and Huntington's disease.

EFFECT: preparation of the compounds which can find application in treatment of a diseased condition of central nervous system.

27 cl, 1 tbl, 29 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel derivatives of 1H-imidazole of formula I, in which R1 represents hydrogen, halogen atom, C1-3-alkyl group, and said C1-3-alkyl groupcan include 1-3 fluorine atoms or R1 represents cyclopropyl, piano, or methylsulfanyl group, R2 represents phenyl group, which can be substituted with 1 substituent Y, selected from methoxy, chlorine, fluorine, trifluoromethyl and cyano, or R2 represents pyridyl group, on condition that R2 is not 6-methyl-2-pyridyl group, or R2 represents fully saturated 6-7-member monocyclic, condensed bicyclic ring system or benzothiazolyl, benzodioxane or thiazole group, and said groups can be substituted by 1 fluorine atom, or R2 represents group of general formula CH2-R5, in which R5 represents phenyl group or fully saturated 7-member condensed bicyclic carbocyclic ring system, or R5 represents piperidine or tetrahydrofuran ring system, which can be substituted by methyl, or R2 represents methylsulfonylamino(C3)alkyl group, R3 represents hydrogen, halogen atom, C1-6-alkylsulfonyl, cyanogroup, or R3 represents C1-8-alkyl group, and said C1-8-alkyl group can be substituted by 1-3 fluorine atoms, or R3 represents phenyl group, which is substituted by substituent Y, where Y has value, specified above, or R3 represents furanyl group, R4 represents one of subgroups (i) or (ii), where R6 represents C4-8-branched or linear alkyl group or naphtyl group, R7 represents hydrogen atom, linear C1-6-alkyl group, R8 represents C2-6-alkyl group, substituted by 1-3 fluorine atoms, or R8 represents C3-8-cycloalkyl group, piperidine group, C3-8-cycloalkyl- C1-2-alkyl group, tetrahydrofuranyl- C1-2-alkyl group, C5-10-bicycloalkyl group, C5-10-bicycloalkyl-C1-2-alkyl group, C6-10-tricycloalkyl group, C6-10-tricycloalkyl-C1-2-alkyl group, and said groups can be substituted by 1-3 substituents, selected from methyl or hydroxyl, or R8 represents phenyl group, substituted by 1-2 substituents Y, specified above, or R8 represents naphtyl, 1,2,3,4-tetrahydronaphtyl or indanyl group, and said groups can be substituted by 1 substituent Y, or R8 represents phenyl- C1-3-alkyl group, diphenyl- C1-3-alkyl group, and said groups can be substituted ob their phenyl ring by 1 substituent Y, where Y has value specified above, or R8 represents benzyl group, substituted by 2 substituents Y, or R8 represents quinilinyl, pyridinyl, benzimidazole or naphtylmethyl group which can be substituted by substituent Y, where Y has value, specified above, or R8 represents asabicyclo[3,3,0]octanyl group, on condition that R8 is neither 6-methoxybenzothiazole-2-yl group, nor [3-chlor-5-(trifluoromethyl)pyrid-2-yl]methyl group, or R7 and R8 together with nitrogen atom, to which they are bound, form saturated, non-aromatic, monocyclic or bicyclic heterocyclic group, including only one nitrogen atom, having 7-10 ring atoms, which can be subslituted by 3 C1-3-alkyl groups, or R7 and R8 together with nitrogen atom, to which they are bound, form saturated, monocyclic heterocyclic group, optionally including another N atom, having 6 ring atoms, and said heterocyclic group is substituted by C1-3-alkyl groups, on condition that R7 and R8 together with nitrogen atom, to which they are bound, do not form trimethylsubstituted asabicyclo[3,3,0]octanyl group, as well as their stereoisomers and pharmacologically acceptable salts of said formula (I) compounds and their stereoisomers Invention also relates to intermediate compounds of formula XIV, pharmaceutical composition based on formula I compound, method of obtaining such pharmaceutical composition and application of formula T compound.

EFFECT: obtained are novel derivatives of IH-imidazole, which are modulators of cannabinoid CB2-receptors.

8 cl, 1 tbl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to heterocyclylsubstituted imidazole derivatives of general formula or to its pharmaceutically acceptable salts wherein R1 stands for a group of formula where * stands for a position whereon a carbonyl group is bound, R4 stands for phenyl or pyridyl, and phenyl or pyridyl can be substituted by one substitute where the substitute is chosen from a group including haloid, nitrogroup, cyanogroup, trifluoromethyl, (C1-C6)alkyl and (C1-C6)alkoxygroup, R6 and R7 stands for hydrogen, R2 stands for (C1-C6)alkyl, and alkyl can be substituted by a substitute where the substitute is chosen from a group including (C3-C6)cycloalkyl and (C6)aryl where aryl can be substituted by a trifluoromethyl substitute, R3 stands for phenyl, and phenyl can be substituted by substitutes in number 1 to 2 independently chosen from a group including haloid, trifluoromethyl, trifluoromethoxygroup, difluoromethoxygroup, trifluoromethylthiogroup and (C1-C6)alkyl. Also, the invention refers to methods for producing compounds of formula I, to a drug prepared of the compound of formula I, to applying the compound of formula I for preparing the drug and to a method of controlling cytomegalovirus infection.

EFFECT: production of new imidazole derivatives exhibiting antiviral activity, particularly in relation to cytomegaloviruses.

10 cl, 4 tbl, 31 ex

FIELD: chemistry.

SUBSTANCE: invention describes N-cycloalkylbenzylamide derivatives of formula

, where A denotes a saturated 5-member heterocyclic group, Z1 denotes a substituted C3-C7-cycloalkyl; Z2 and Z3, which can be identical or different from each other, denote a hydrogen atom; C1-C8-alkyl; cyano; C1-C8-alkoxycarbonyl; a method of producing said compounds, use thereof as fungicidal active substances, particularly in form of fungicidal compositions, and method of controlling phytopathogenic fungi, mainly in plants, using said compounds or compositions.

EFFECT: higher activity, low amount of active substance while maintaining efficiency at least equivalent to that of existing compounds.

11 cl, 5 ex

FIELD: medicine, pharmacy.

SUBSTANCE: invention relates to new acid-additive nitrate salts of compounds taken among salbutamol, cetirizine, loratidine, terfenadine, emedastine, ketotifen, nedocromil, ambroxol, dextrometorphan, dextrorphan, isoniazide, erythromycin and pyrazinamide. Indicated salts can be used for treatment of pathology of respiratory system and elicit an anti-allergic, anti-asthmatic effect and can be used in ophthalmology also. Indicated salts have less adverse effect on cardiovascular and/or gastroenteric systems as compared with their non-salt analogues. Also, invention proposes pharmaceutical compositions for preparing medicinal agents for treatment of pathology of respiratory system and comprising above indicated salts or nitrate salts of metronidazol or aciclovir.

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: organic chemistry, chemical technology, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 8-phenyl-6,9-dihydro[1,2,4]-triazolo[3,4-I]purine-5-one of the general formula:

wherein R1 means hydrogen atom, group -CH2-R6 wherein R6 means phenyl; R2 means (C1-C5)-alkyl or group -(CH2)n-R6 wherein n= 1 or 2; R6 means (C1-C4)-alkoxy-group or pyridyl group; R3 means (C1-C6)-alkyl; R4 means hydrogen atom or (C1-C4)-alkyl; R5 means -(CH2)n-R7 wherein n = 0-4; R7 means 3-7-membered ring comprising 1-3 heteroatoms taken among nitrogen atom (N) and oxygen atom (O), (C3-C7)-cycloalkyl or phenyl wherein indicated groups can be substituted with different substitutes; or R4 and R5 mean independently hydrogen atom (H), (C2-C6)-alkynyl or (C1-C6)-alkyl that can be substituted possibly; or R4 and R5 in common with nitrogen atom (N) form 4-7-membered ring comprising 1-2 heteroatoms taken among N and O and substituted possibly. Also, invention relates to their pharmaceutically acceptable salts, methods for preparing these compounds, intermediate substances, pharmaceutical composition and a to a method for treatment of different diseases mediated by activity of phosphodiesterase-5 (PDE-5). Described compounds of the formula (I) are inhibitor of PDE-5.

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

20 cl, 5 tbl, 149 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel improved method of producing entecavir of formula (I) which has antiviral effect for possible use in a medicinal agent with low content of the active component, for example in treating hepatitis B. The invention also relates to novel intermediate products and their methods of production. The entecavir has general formula (I) . Its method of production involves subjecting a compound of formula 7c or its mixture with a compound of formula 8a, where Rb is C1-C4alkyl, to oxidation, mainly with a peroxidate, such as a sodium carbonate peroxidate, sodium pyrophosphate peroxidate etc. 7c + 8a. Compound of formula 7c or its mixture with a compound of formula 8a is obtained by bringing the compound of formula 7a into contact with at least one acid selected from halogenated methane-sulphonic acid and possibly methane-sulphonic acid, possibly in the presence of a compound of formula 8a, with subsequent treatment with at least one aqueous base. The invention also relates to production of compounds of formulae 7a and 8a.

EFFECT: increased antiviral effect of the compounds.

27 cl, 8 dwg, 19 ex

FIELD: chemistry.

SUBSTANCE: present invention relates to novel compounds - 9-substituted derivatives of 8-oxoadenine of general formula (I) and their pharmaceutically acceptable salts having interferon-inducing effect on viruses. In general formula (I): , ring A is phenyl; n equals 0; Z1 is a C1-C4alkylene group which is not substituted or substituted with a hydroxyl group; X2 is an oxygen atom, a sulphur atom, SO2, NR5, SO2NR5, NR5SO2 or NHCONH (in which R5 is a hydrogen atom, a substituted or unsubstituted C1-C6alkyl group, where the substitutes are selected from a hydroxyl group, C1-C6-alkoxy group, amino, C1-C6-alkylamino, di- C1-C6-alkylamino, 5-6-member saturated cycloamine group containing 1-2 nitrogen atoms, possibly containing an extra oxygen atom and possibly substituted with an oxo-group, and a tetrazolyl group); Y1, Y2 and Y3 each independently denotes a single bond or a C1-C4-alkylene group; X is an oxygen atom; R2 is a hydrogen atom, a C1-C4-alkyl group optionally substituted with an amino group, a C1-C6-alkylamino group or a di- C1-C6-alkylamino group and R1 is a hydrogen atom.

EFFECT: obtaining novel compounds which can be used as an antiviral or antiallergic agent.

14 cl, 32 tbl, 51 ex

FIELD: chemistry.

SUBSTANCE: nucleic base (e.g. uracil, cytosine, adenine, guanine, hypoxanthine, xanthine or similar) reacts with perfluoroalkyl halide in the presence of sulphoxide, peroxide and an iron compound to obtain a perfluoroalkyl-substituted nucleic base.

EFFECT: high cost effectiveness as an intermediate compound for producing medicinal agents.

15 cl, 6 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new purine derivatives of formula (I) and to their pharmaceutically acceptable salts exhibiting the properties of adenosine receptor A2A agonists. The compounds can find application for preparing a drug for treating an inflammatory or obstructive respiratory disease. In formula

,

R1, R2 and R3 are those as specified in the patent claim.

EFFECT: preparing new purine derivatives of formula (I) or their pharmaceutically acceptable salts showing the properties of adenosine receptor A2A agonists.

8 cl, 2 tbl, 264 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing acyclovir 2/3 hydrate, which involves mixing acyclovir with water in weight ratio of 1:5-50, dissolving at 50-100C, filtering, cooling the filtrate at 0-30 to deposit crystals, collecting crystals by filtering and drying the crystals at 0-150C for 0.5-24 hours to obtain acyclovir 2/3 hydrate having a stable crystalline structure.

EFFECT: preparation process is simple and suitable for industrial production.

10 cl, 4 dwg, 1 tbl, 15 ex

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