A method of obtaining a 9-substituted guanine derivatives

 

(57) Abstract:

Usage: as antiviral agents and intermediates obtain drugs. Essence: 9-substituted derivatives of guanine General formula I:

< / BR>
where R is C1-C4-alkyl, benzyl or -(CH2)n-OR1where n = 0.2 and R1-CH2CH2OH. Reagent 1: 1-substituted 5-(thiocarbamoyl)amino-IH-imidazole-4-carboxamid General formula III:

< / BR>
where R has the above significance. Reagent 2: hydrogen peroxide in aqueous alkaline medium at a temperature of 0-30oC in the presence of ions produce by treatment with acid.

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

< / BR>
where R is C1-C4-alkyl, does not necessarily substituted by one or more groups, or R is:

< / BR>
a benzyl, robotjam, 2-deoxyribosyl or (CH2)n-OR1where n is 1 or 2, and R1is CH2CH2OH or

or their salts.

Connections of the specified type are therapeutically active compounds with antiviral activity, or they are intermediate compounds designed-1282), that guanosin can be obtained from 4-carboxamide-5-amino-1-ribofuranosylthiazole way, consisting of three stages, namely, the condensation derivative carbodiimide; cyclization in the presence of dO; processing using NH4OH. However, this method has several disadvantages, which include, for example, that this method requires the use of toxic compounds, phosgene to obtain a carbodiimide derivatives, and the subsequent stage of cyclization and treatment with NH4OH require 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 formula II:

< / BR>
first subjected to methylation with formation of the corresponding timetravel connection, which then cyclist in an alkaline environment (A. Yamzaki //Nuc1. Acids. Res. 1976, 3, 251-259). This method has the disadvantage that in its implementation 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 it is also reported that the cyclization of compounds II with salt heavy metal HgO I the N1-substituted derivatives of compounds of formula II may be effected without prior modeling and using peroxide compounds.

The method of the present invention differs in that 1-substituted 5-(thiocarbamoyl)amino-1H-imidazol-4-carboxamid General formula III:

< / BR>
where R has the same meaning as in formula I,

subjected to cyclization by treatment with peroksosoedinenii in aqueous alkaline medium at a temperature of about 0-30oC and in the presence of tungstate ions as a catalyst, after which the connection 1 produce by treatment with acid and, if necessary, turn into salt.

The parent compound of formula III:

< / BR>
where R is C1-C4-alkyl, does not necessarily substituted by one or more hydroxyl groups, or R is

< / BR>
a benzyl, ribosom, 2'-deoxyribosyl or (CH2)n-OR1where n is 1 or 2, and R1represents CH2CH2or

< / BR>
are new compounds, which implies that this connection includes these compounds as intermediates to obtain the 9-substituted derivatives of guanine of formula I.

Idov formula IV:

< / BR>
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 N-icalneu group and other acyl groups.

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

The method of the present invention is preferably carried out using as peroxidase hydrogen peroxide.

Obtaining raw materials

Getting 5-(N'-benzoylthiourea)amino-1-methyl-1H-imidazole-4-carboxamide

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 hours in the presence of N2. After cooling in an ice bath, the resulting product was filtered, washed with acetone and dried off. The result has allocated 13 g (95%) of target compound in the form of a white powder, so pl. 194-195oC.

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 square-178-180oC.

5-(N'-benzoyl similar way, so pl. 163-164oC.

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. 181-182,5oC.

1-[(2-hydroxyethoxy)methyl] -5-(thiocarbamoyl)amino-1H-imidazole-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 hour. To the resulting solution were added methanol (430 ml) and potassium carbonate (14.9 g, 108 mm) dissolved in water (45 mm), after which the mixture was heated in a vessel under reflux for 4 hours. After cooling to room temperature was added acetic acid to obtain a pH of 8. The resulting product was filtered at 0oC, washed and drained. The result provided is 39.2 g (83% ) of target compound in the form of a white powder, so square-181-182oC (decomp.). A sample, crystallized from water, had so pl. 182-183oC (decomp.).

13C-NMR DMCO-d6ppm: 183,9; 163,7; 134,9; 129,3; 127,9; 74,0; 70,4; 59,7.

Elemental analysis for C8H13N5O3S (%):

Calculated: 37,06; H of 5.05; N 27,01; S 12,37;

Found: C 36,92; H 5,07; N 27,30; S TO 12.28

1-[1,3-di is 5-amino-[1,3 - dihydroxy-(2-propyloxy)methyl]-1H-imidazole-4-carboxamide, so pl. 185oC (decomp.).

13C-NMR (DMCO-d6) d 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-[a/(2-hydroxyethoxy)methyl]-5-(thiocarbamoyl)amino-1H-imidazole-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 minutes at 25oC. After heating for 15 minutes in a flask under reflux, the solution was cooled to 20oC, and the resulting ammonium chloride was filtered and washed with acetone (20 ml).

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) dissolved 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 25oC. Then the solution is evaporated to obtain about 70 ml, and the pH value of the argument is Ali and drained. The result was isolated 8.0 g (77%) of target compound in the form of a white powder with so pl. 178-180oC (decomp.). Analysis by HPLC showed a purity of more than 96%

1-[(2-hydroxyethoxy)methyl] -5-(thiocarbamoyl)amino-1H-imidazole-4 - carboxamid

In the presence of N2at 25oC for 5 minutes to a solution of ammonium thiocyanate (1.6 g, 21 mm) in acetone (30 ml) was added drop acetylchloride (1.6 g, 21 ml). After heating for 15 minutes in a flask with reflux condenser and the mixture was cooled to 20oC, and the resulting ammonium chloride was filtered and washed with acetone (10 ml).

To the filtrate was added 5-amino-1[(2-(atomic charges)ethoxy)methyl]-1H-imidazol-4-carboxamid (4.8 g, 20 mm). The mixture was heated under reflux for 20 hours 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 25oC. Then the solution is evaporated to 30 ml, and the pH was brought to 7.0 with acetic acid. After cooling to 5oC the resulting product was filtered, washed with water and ASOSAI by HPLC showed a purity of more than 94%

1-methyl-5-(thiocarbamoyl)amino-1H-imidazole-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 hours, 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 (96%) of target compound in the form of a white powder with so pl. 270-274oC (decomp.) (conversion starts at about 220oC).

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

13C-NMR (DMCO-d6d ppm 184,0; 163,9; 134,8; 130,2; 127,3; 30,9

Calculated for C6H9N5OS (%): C 36,17;H 4,55; N 35,16;

Found: 36,06; H A 4.53; N 35,05.

1-ethyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide was obtained in a similar manner from 5-(N'-benzoylthiourea)amino-1-ethyl-1H-imidazole-4-carboxamide, so pl. is 265-268oC (decomp.).

13C-NMR (DMCO-d6d ppm: 183,8; 163,9; 133,8; 129,1; 127,8; 39,0; 15,2;

Calculated for C7Hthe evil-4-carboxamid received a similar manner from 5-(N'-benzoylthiourea)amino-1-(1-propyl)-1H-imidazole-4-carboxamide, so pl. 197-198oC (decomp.).

13C-NMR (DMCO-d6d ppm: 183,8; 163,9; 134,4; 129,2; 127,7; 45,7; 22,7; 10,8.

Calculated for C8H13N5OS (%): C 42,27; H 5,77; N 30,81;

Found: C 42,16; H, 5.84; N 30,86.

1-benzyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamide was obtained in a similar manner from 5-(N'-benzoylthiourea)amino-1-benzyl-1H-imidazole-4-carboxamide, so pl. is 264-266oC.(decomp.) (conversion starts at about 205oC).

13C-NMR (DMCO-d6d ppm: 183,8; 163,9; 136,5; 134,5; 129,6; 128,6; 127,7; 127,4; 47,6.

Calculated for C12H13N5OS (%) C 52,34; H AMOUNTS TO 4.76; N 25,44;

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

The following examples 1-7 illustrate a variant (a) of the method, and examples 8-12 illustrate the option () method.

Example 1. 9-(1-propyl)guanine

1-(1-propyl)-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamid (1,14 g, 5.0 mm) and sodium tungstate (0.2 g) was dissolved in 1 N. sodium hydroxide (50 ml) at 0oC. and Then for 30 minutes at 0 to 10oC drop) was added 35% hydrogen peroxide (1.8 ml, 20 mm) in water (5 ml). After stirring in an ice bath for 1 hour the pH was brought to 5.0 using acetic acid. The resulting product was filtered, washed with water and drained. In the received /P>13C-NMR (DMCO-d6d ppm: 156,8; 153,3; 151,0; 137,4; 116,5; 44,2; 22,7; 10,8

Calculated for C8H11N5O (PERCENT): C 49,73; H 5,74; N 36,25;

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

Example 2. 9-benzylguanine

1-benzyl-5-(thiocarbamoyl)amino-1H-imidazole-4-carboxamid (2,75 g, 10.0 mm) and sodium tungstate (0.1 g) suspended in 6 BC of sodium hydroxide (20 ml) at 5oC. and Then for 30 minutes at 5-15oC drop) was added 35% hydrogen peroxide (4.0 ml, 44 mm). To the obtained reaction mixture was added water (60 ml). After razryvanija for 1 hour in an ice bath, the pH was brought to 5.0 with hydrochloric acid. The resulting product was filtered, washed with water and drained. The result has been of 1.30 g (54%) of target compound in the form of a white powder. HPLC showed a purity of about 98% so pl. 305-308oC.

13C-NMR (DMCO-d6d ppm: 157,0; 153; 151,2; 137,6; 137,3; 128,7; 127,6; 127,2; 116,6; 45,9.

Calculated for C12H11N5O (PERCENT): C 59,74; H 4,59; N 29,03;

Found: 59,50; H To 4.52; N 28,91.

Example 3. 9-methylguanine

9-methylguanine was obtained in a similar manner from 1-methyl-5- (thiocarbamoyl)amino-1H-imidazole-4-carboxamide, so pl. >100oC.

13C-NMR (IH NOD) d ppm: 170,7; 163,6; 154,0; 141,4; 120,0; 32,2.

Calculated for C6H7 the n was obtained in a similar manner from 1-ethyl-5-(thiocarbamoyl)amino-1-imidazol-4-carboxamide, so pl. >300oC.

Calculated for C7H9N5O, I/4H2O (PERCENT): C 45,77; H TO 5.21; N 38,31;

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

Example 5. 9-[(2-hydroxyethoxy)methyl]guanine Allocvec

1-[(2-hydroxyethoxy)methyl] -5-(thiocarbamoyl)amino-1H-imidazole-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 5oC. Then at 5-15oC for 15 minutes drop was added 35% hydrogen peroxide (4.0 ml, 44 mm). After stirring for 15 minutes at 0-5oC was performed HPLC, 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% so about 250 squareoC (decomp.).

13C-NMR (DMCO-d6d ppm: 156,8; 153,8; 151,4; 137,8; 116,5; 72,1; 70,4; and 59,9.

Calculated for C8H11N5O33/4 H2O (PERCENT): C 40,25; H 5,28; N 29,34;

Found: 40,39; H 5,33; N 29,37.

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

< / BR>
where R1WITH4-alkyl, benzyl or -(CH2)the l)amino-1H-imidazol-4-carboxamid General formula II

< / BR>
where R has the above meaning,

subjected to cyclization by treatment with hydrogen peroxide in aqueous alkaline medium at a temperature of about 0 30oIn the presence of tungstate ions as a catalyst, after which the compound of formula I produce by treatment with acid.

 

Same patents:

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 CHor their salts

The invention relates to a method for producing derivatives of S-adenosylmethionine (HIMSELF), General formula

< / BR>
where R is benzene, p-toluensulfonyl or linear aliphatic acyl radical containing 2-6 carbon atoms; R1H or benzoyl or linear aliphatic acyl containing 2 to 6 carbon atoms; R and R1same or different when R1has a value other than hydrogen; n is 1-5; And is the equivalent of the acid with PKandless than 2.5

The invention relates to certain substituted purine to arabinoside and acceptable from the physiological standpoint derivatives, in particular esters and their use for the treatment of certain DNA-viral diseases

The invention relates to analogs of purine nucleosides containing unsaturated carbocyclic ring instead of the sugar residue, their pharmaceutically acceptable derivatives and to their use in medical therapy particularly for the treatment of certain viral diseases

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 CHor their salts

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 CHor their salts

The invention relates to new derivatives of pyridinemethanol formula RNI where R1represents a hydrogen atom, a C1-C3-alkyl; R2is1-C4-haloalkyl; R3represents a halogen atom, trifluoromethyl; R4is1-C3-haloalkyl, the method of obtaining these compounds and insecticides containing these compounds as active ingredients

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

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