Derivatives of 1h-imidazole possessing cb1-agonistic, partial cb1-agonistic or cb1-antagonistic activity

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

 

The present invention relates to new derivatives of 1H-imidazole, to methods of producing such compounds and to pharmaceutical compositions containing one or more of such compounds as an active component.

Such derivatives of 1H-imidazole are effective agonists, partial agonists or antagonists of cannabinoid ST1receptors, which are useful in the treatment of mental and neurological diseases, and other diseases involving cannabinoid neurotransmission.

Cannabinoids are present in the Indian hempCannabis sativaand for centuries used as medicines (Mechoulam R., Feigenbaum J.J.,Prog. Med. Chem., 1987, 24, 159). However, only in the last ten years research in the field of cannabinoids revealed basic information on cannabinoid receptors and their endogenous) agonists and antagonists. The discovery and subsequent cloning of two different subtypes of cannabinoid receptors (CB1and ST2) stimulated the search for new antagonists of cannabinoid receptors (Munro, S., et al.Nature, 1993, 365, 61; Matsuda L.A, Bonner T.I.Cannabinoid chemistry Receptors, Pertwee, R.G., Ed., 1995, 117, Academic Press, London). In addition, pharmaceutical companies interested in the development of cannabinoid drugs for the treatment of diseases associated with impaired cannabinoid si theme (Consroe P. Neurobiology of Disease, 1998, 5, 534; Pop, E.Curr. Opin. In CPNS Investigational Drugs, 1999, 1, 587; Greenberg, D.A.Drug News Perspect., 1999, 12, 458; Pertwee R.G.Progress in Neurobiology, 2001, 63, 569). Currently, there are several antagonists ST1the receptors. Sanofi describes their diarylpyrazole analogues as selective antagonists ST1the receptors. A typical example is SR-A (Dutta A.K. et al.Med. Chem. Res., 1994, 5, 54; Lan R. et al.,J. Med. Chem., 1999, 42, 769; Nakamura-Palacios E.M et al.,CNS Drug Rev., 1999, 5, 43). CP-272871 is a derivative of pyrazole, similar to the SR-A, but less effective and less selective to ST1subtype receptor, SR-A (Meschler JP,et al.,Biochem. Pharmacol.2000, 60, 1315). As antagonists ST1receptors opened aminoalkylindole. A typical example is iodopovidone (AM-630), which is presented in 1995. AM-630 is moderately active antagonist SV1receptors, with some estimates as a weak partial agonist (Hosohata, K., et al.,Life Sc., 1997, 61, PL115). Scientists from Eli Lilly described aryl-arozamena benzofuran as selective antagonists ST1receptors (e.g., LY-320135) (Felder C.C., et al.,J. Pharmacol. Exp., Ther., 1998, 284, 291). 3-Alkyl-5,5'-diphenylimidazole-diones described as ligands of cannabinoid receptors, which, as indicated, are cannabinoid antagonists (Kanyonyo m, et al.,Biorg. Med. Chem. Lett., 1999, 9, 233). Aventis Pharma announced analogues of diarylpyrimidine as antagonists ST1receptors (Mignani, S., et al., French patent FR 2783246, 2000;Chem. Abstr., 2000, 132, 236982). Tricyclic pyrazoles declared by the company Sanofi-Synthelabo as antagonists ST1receptors (Barth F., et al., patent WO 0132663, 2001;Chem. Abstr., 2001, 134, 340504). Interestingly, many antagonists ST1receptors were reported to behave as reversible agonistsin vitro(Landsman, R.S., et al.,Eur. J. Pharmacol., 1997, 334, R1). Pyrazol cannabinoids also presented as partial agonists ST1receptors, showingin vivocannabimimetic effects (Willey J.L., et al.,J. Pharmacol. Exp. Ther., 2001, 296, 1013). A known number of classes agonists ST1receptors, such as, for example, classical cannabinoids (for example, Δ9-THC), non-classical cannabinoids, aminoalkylindoles and eicosanoids (e.g., anandamide). The reviews provide an excellent overview of research in the field of cannabinoids (Mechoulam R., et al.,Prog. Med. Chem., 1998, 35, 199; Lambert D.M.Curr. Med. Chem., 1999, 6, 635; Mechoulam R., et al.,Eur. J. Pharmacol., 1998, 359, 1; Williamson EM, Evans F. J.Drugs, 2000, 60, 1303; Pertwee, R., G.,Addiction Biology, 2000, 5, 37; Robson P.Br. J. Psychiatry, 2001, 178, 107; Pertwee R.G.Prog. Neurobiol., 2001, 63, 569; Goya, P. and N. JagerovicExp. Opin. Ther. Patents2000, 10, 1529; Pertwee R.G.,Gut, 2001, 48, 859).

Currently, it has been unexpectedly found that new derivatives of 1H-imidazole forms the crystals (I), their prodrugs and salts are effective agonists, partial agonists or antagonists at cannabinoid-ST1receptors:

where

-R represents phenyl, thienyl, 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, and these groups may be substituted by 1, 2, 3 or 4 substituents Y, which can be the same or different, from the group comprising From1-3-alkyl or alkoxygroup, the hydroxy-group, halogen atom, trifluoromethyl, triptoreline, triptoreline, nitro, amino, mono - or dialkyl-(C1-2)-amino, mono - or dialkyl-(C1-2)-aminogroup, (C1-3-alkoxycarbonyl, carboxyl, cyano, carbarnoyl, and acetyl, or R represents naphthyl, provided that when R is 4-pyridinyl, R4represents a halogen atom or a cyano, carbarnoyl, formyl, acetyl, TRIFLUOROACETYL, peracetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulfanyl or branched or unbranched1-4is an alkyl group, and With this1-4is an alkyl group may be substituted by 1-3 fluorine atoms or bromine atoms, chlorine, iodine, cyano, or hydroxyl group,

-R1represents phenyl or pyridinyl, and these groups may be substituted by 1-4 substituents Y, which can b the th same or different, where Y has the above meaning, or R1is pyrimidinyl, pyrazinyl, pyridazinyl or triazinyl, and these groups may be substituted by 1-2 substituents Y, which can be the same or different, or R1represents a five-membered aromatic heterocyclic ring containing one or two heteroatoms from the group N, O, S), and these heteroatoms may be the same or different and is a five-membered aromatic heterocyclic ring may be substituted by 1-2 substituents Y, which can be the same or different, or R1represents naphthyl;

-R2represents H, a branched or unbranched1-8-alkyl, C3-8-cycloalkyl,3-8alkenyl,5-8-cycloalkenyl, and these groups may contain an atom of sulphur, oxygen or nitrogen;

-R3is a branched or non-branched C2-8-alkyl, C1-8-alkoxy, C5-8-cycloalkylation, C3-8-cycloalkyl, C5-10-bicycloalkyl, C6-10-tricyclohexyl, C3-8alkenyl, C5-8-cycloalkenyl, and these groups may optionally contain one or more heteroatoms from the group (O, N, S), and these groups may be substituted by a hydroxyl group or 1-2 C1-3-alkyl groups or 1 to 3 fluorine atoms, or R3represents the gasoline is inuu or fenetylline group, aromatic ring which may be substituted by 1-5 substituents Z, which may be the same or different, from the group comprising C1-3-alkyl or alkoxygroup, the hydroxy-group, halogen atom, trifluoromethyl, triptoreline, triptoreline, nitro, amino, mono - or dialkyl-(C1-2)-amino group, mono - or dialkyl-(C1-2)-aminogroup, (C1-3)-alkylsulfonyl, dimethylsulfide, (C1-3-alkoxycarbonyl, carboxyl, trifloromethyl, cyano, carbarnoyl, sulfamoyl and acetyl, or R3represents phenyl or pyridinyl group, and these groups substituted by 1-4 substituents Z, where Z has the values listed above,

or R3represents pyridinyl group, or R3represents a phenyl group, provided that R4represents a halogen atom or a cyano, carbarnoyl, formyl, acetyl, TRIFLUOROACETYL, peracetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulfanyl or1-4is an alkyl group, and With this1-4is an alkyl group may be substituted by 1-3 fluorine atoms or bromine atoms, chlorine, iodine, cyano, or hydroxyl group,

or R3represents a group NR5R6provided that R2represents a hydrogen atom or methyl group, where

-R5and R6are odinakovymi different and are a branched or unbranched 1-4-alkyl, or R5and R6together with the nitrogen atom to which they are linked, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group containing from 4 to 10 atoms in the cycle, and this heterocyclic group containing one or two heteroatoms from the group N, O, S), and these heteroatoms may be the same or different, and these heterocyclic groups may be substituted With1-3is an alkyl group or a hydroxyl group, or R2and R3together with the nitrogen atom to which they are linked, form a saturated or unsaturated, heterocyclic group containing from 4 to 10 atoms in the cycle, and this heterocyclic group contains one or two heteroatoms from the group N, O, S), and these heteroatoms may be the same or different, and these heterocyclic groups may be substituted With1-3is an alkyl group or a hydroxyl group,

-R4represents a hydrogen atom or halogen, or cyano, carbarnoyl, formyl, acetyl, TRIFLUOROACETYL, peracetyl, propionyl, sulfamoyl, methanesulfonyl, methylsulfanyl or branched or unbranched1-4is an alkyl group, and With this1-4is an alkyl group may be substituted by 1-3 fluorine atoms or bromine atoms, chlorine, iodine, cyano or hydroxyl group.

Due to the high the th ST 1agonistic, partial agonistic or antagonistic activity of the compounds in accordance with the present invention can be used in the treatment of mental illness, such as psychosis, anxiety, depression, attention deficit disorder, memory disorders, disorders of cognitive abilities, impaired appetite, obesity, addiction, appetence, drug dependence and neurological disorders such as neurodegenerative diseases, soboma, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, Huntington's disease, Tourette syndrome, cerebral ischaemia, cerebral apoplexy, traumatic brain injury, spinal cord injury, neirolepticalkie diseases, thrombosis, viral encephalitis, disorders associated with demyelination, as well as for the treatment of painful disorders, including neuropathic painful disorders, and other diseases involving cannabinoid neurotransmission, including the treatment of septic shock, glaucoma, diabetes, cancer, vomiting, nausea, gastrointestinal disorders, stomach ulcers, diarrhoea and cardiovascular diseases.

The affinity of the compounds of the present invention to cannabinoid is In 1receptors determined using membrane preparations of cells Chinese hamster ovary (Chinese hamster ovary, Cho)stably transfected with human cannabinoid ST1receptor in conjugation with [3H]CP-55,940 as radioligand. After keeping just-cooked preparation of cell membranes with [3H]-ligand, with or without addition of compounds of the present invention carried out the separation of bound and free ligand by filtration through glass fiber filters. The radioactivity on the filter is measured by liquid scintillation counter.

Cannabinoid ST1antagonistic activity of the compounds of the present invention is determined by functional studies using Cho cells that stably expressed human cannabinoid ST1the receptors. Adenylylcyclase stimulate using Forskolin and determine the number of accumulated cyclic AMP. Concomitant activation of ST.1receptors with agonists ST1receptors (e.g., CP-55940, or (R)-WIN-55212-2) can weaken induced Forskolin accumulation of camp-dependent concentration. Such mediated ST1receptor reaction can be suppressed by using antagonists ST1 receptor, such as compounds of the present invention.

Cannabinoid agonist activity of the compounds of the present invention with partial agonistic activity can be determined in accordance with published methods, such as evaluation ofin vivocannabimimetic effects (Wiley J.L., et al.,J.Pharmacol. Exp. Ther.2001, 296, 1013).

The invention relates to racemates, mixtures of diastereoisomers and individual stereoisomers of the compounds having formula (I).

Compounds of the present invention can be converted into forms suitable for injection, using conventional processes using auxiliary substances and/or liquid or solid media.

Suitable schemes for the synthesis of compounds of the present invention are as follows.

The scheme of synthesis And

Stage 1: hydrolysis of ester compounds of the formula (II), where R7represents a branched or unbranched alkyl group (C1-4or benzyl group:

This reaction gives a compound having the formula (III):

where R, R1and R4have the meanings given above.

Intermediate compounds having the formula (II), where R7represents a branched or unbranched alkyl (C1-4 ) group or benzyl group, can be obtained in accordance with known methods, for example:

a) I.K. Khanna et al.,J. Med. Chem.2000, 43, 3168-3185;

b) N. Kudo et al.,Chem. Pharm. Bull. 1999, 47, 857-868;

c) K. Tsuji et al.,Chem. Pharm. Bull.1997, 45, 987-995;

d) I.K. Khanna et al.,J. Med. Chem.1997, 40, 1634-1647;

e) M. Guillemet et al.,Tetrahedron Lett. 1995, 36, 547-548.

Stage 2: the interaction of compounds having the formula (III)with a compound having the formula R2R3NH, where the substituents R2and R3have values that are presented above, through activation methods and combinations, such as the formation of the active complex ether, or in the presence of a combination of reagents, such as DCC, HBTU, BOP, or similar reagents. This reaction leads to the desired derivative 1H-imidazole of the formula (I).

(Information on methods of activation and combinations, see: M. Bodanszky and A. Bodanszky: The Practice of Peptide Synthesis, Springer-Verlag, New York, 1994; ISBN: 0-387-57505-7).

On the other hand, the compound having the formula (III)enter into reaction with a halogenation agent such as thionyl chloride (SO2Cl). This reaction leads to the corresponding carbonylchloride (IV).

The reaction of the compound having the formula (IV)with a compound having the formula R2R3NH, where the substituents R2and R3have the above specified values, gives the derivative 1H-imidazole, which has fo the formula (I). This reaction is preferably carried out in the presence of organic bases, such as, for example, diisopropylethylamine (DIPEA) or triethylamine.

On the other hand, the compound having the formula (II), interacts in terms of the amidation reaction with the compound of the formula R2R3NH, where the substituents R2and R3are as defined above, with the derivatization 1H-imidazole having the formula (I).

The scheme of synthesis In

The interaction of compounds having the formula (II), where the substituent R4represents a hydrogen atom and where the substituents R, R1and R7have the values defined above for compound (II)with a compound having the General formula R4'-X, where X is a leaving group, and R4' represents a C1-4is an alkyl group, this alkyl group may be substituted by 1-3 fluorine atoms, or where R4' represents a cyano, formyl, acetyl, trifluoracetyl, percetly, methylsulfanyl or probeonly residue, or a halogen atom. This reaction is carried out in the presence of strong nucleophilic bases, such as diisopropylamide lithium (LDA), preferably in anhydrous conditions in an inert organic solvent, for example tetrahydrofuran, and get a compound with formula (II):

where the substituents R, R1and R7have the meanings given above, and the substituent R4represents a C1-4is an alkyl group, this alkyl group may be substituted with 1-3 fluorine atoms, or the substituent R4represents a cyano, formyl, acetyl, trifluoracetyl, porazitelnuyu, methylsulfanyl or propionyloxy group, or halogen atom.

Compounds of General formula (II)obtained in accordance with the scheme of the synthesis, can be converted into compounds of General formula (I) is similar to the method described in the synthesis scheme A, step 1 of scheme a or stage 2 scheme A (see above).

The scheme of synthesis With

Compounds having the formula (II):

where substituent R4represents a branched or unbranched1-4is an alkyl group, and With this1-4is an alkyl group may be substituted by 1-3 fluorine atoms, and where the substituents R, R1have the meanings given above, and the substituent R7represents a branched or unbranched alkyl group (C1-4or benzyl group, can be synthesized in the interaction of compounds having the formula (V) or its tautomer:

where the substituents R and R1have the above specified value, the connection is using, having the formula (VI):

where substituent R4represents a branched or unbranched1-4is an alkyl group, and With this1-4is an alkyl group may be substituted by 1-3 fluorine atoms, and the substituent R8represents a leaving group, for example a bromine atom, and the substituent R7represents a branched or unbranched alkyl group (C1-4or benzyl group. The reaction is preferably carried out in an organic solvent, such as 2-propanol or N-methyl-2-pyrrolidinone (N). Adding acid type triperoxonane acid (TFUC) during the reaction can increase the formation of compounds having the formula (II).

(More detailed information of the leaving groups, see: M.B. Smith, J. March, Advanced organic Chemistry, p. 275, 5-th ed., (2001), John Wiley and Sons, New York. ISBN: 0-471-58589-0).

Compounds of General formula (II), which can be obtained in accordance with the scheme of the synthesis, can be converted into compounds of General formula (I) is similar to the method described in the synthesis scheme A, step 1 of scheme a or stage 2 scheme A (see above).

Compounds of the present invention having the formula (VI)can be obtained according to known methods, for example: P.Seifert et al.,Helv. Chem. Acta, 1950, 33, 725.

The scheme of synthesis D

The interaction of compounds having forms the Lu (II):

where substituent R4represents a methyl group and the substituents R, R1have the above specified values, and the substituent R7represents a branched or unbranched alkyl group (C1-4or benzyl group, with regioselective brainwashin compound, such as N-bromosuccinimide (NBS), in an organic solvent, such as CCl4in the presence of free-radical inhibitor type peroxide of Dibenzoyl, gives compound of formula (VII):

where the substituents R, R1and R7have the above specified values. The interaction of compounds having the formula (VII) (similar to the method described in Mathews, W.B., et al., J. Label. Compds. Radiopharm., 1999, 42, 589), for example, KCl, KI, KF or KCN gives compound of formula (VIII):

where the substituents R, R1and R7have the above specified values, and Nu represents the atoms of chlorine, iodine, fluorine or cyano. The reaction is preferably carried out in the presence of weak base type NaHCO3or in the presence of crown ether or cryptand(For more information on crown-ethers and cryptands see: M.B. Smith and J. March, Advanced organic Chemistry, p. 105, 5th ed. (2001), John Wiley & Sons, New York. ISBN: 0-471-58589-0).

Compounds of General formula (VII) or (VIII), which received the s in accordance with the scheme of the synthesis of D, can be converted into compounds of General formula (I) is similar to the method described in the synthesis scheme A, step 1 of scheme a or stage 2 scheme A (see above).

Example 1

Part a: To 1M solution of bis(trimethylsilyl)amide sodium in THF (70 ml) is added dropwise a solution of 4-Chloroaniline (8,86 g of 69.5 mmol) in anhydrous THF under nitrogen atmosphere. After stirring the mixture for 20 minutes, add a solution of 2,4-dichlorobenzonitrile (12 g, 70 mmol) in THF. The resulting mixture is stirred overnight, poured into a mixture of ice-water (400 ml) and extracted with dichloromethane, dried over Na2SO4and concentrated in vacuo. Receives a yellow oil (15.7 g). Crystallization from a mixture of dichloromethane/heptane and subsequent rinsing with methyl-tert.-butyl ether gives N-(4-chlorophenyl)-2,4-dichlorobenzophenone (8,66 g, yield 42%) as a yellow solid. The melting temperature (TPL): 93-95°C.

Similarly obtained:

N-(4-bromophenyl)-2,4-dichlorobenzophenone. TPL: 117-119°C.

Part b: A mixture of N-(4-chlorophenyl)-2,4-dichlorazodicarbonamidine (2.00 g, of 6.68 mmol), ethyl-3-bromo-2-oxopropanoic (2.65 g, to 13.6 mmol) and NaHCO3(1.12 g, 13.3 mmol) in 2-propanol is stirred at the boiling point under reflux for 20 hours After cooling to room temperature the mixture was concentrated in vacuo and the residue suspended in dichloromethane, washed with the water (3× 50 ml) and brine (3×50 ml). The aqueous layers extracted with dichloromethane. The combined organic layers dried over Na2SO4and concentrated in vacuo receive crude brown product (2.0 g). This product is optionally purified column chromatography (silica gel, heptane/EtOAc = 90/10 (vol./vol.), get ethyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (0,759 g, yield 29%) as a yellow small, which slowly solidifies upon standing. Melting point: 150-152°C; MS: 395 (MH+).1H-NMR (400 MHz, CDCl3): δ to $ 7.91 (s, 1H), 7,49 (DD, J=8 Hz, J=2 Hz, 1H), 7.29 trend was 7.36 (m, 4H), 7,07 (dt, J=8 Hz, J=2 Hz, 2H), of 4.44 (q, J=7 Hz, 2H), 1,42 (t, J=7 Hz, 3H).

PartEthyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (0.810 g, of 2.06 mmol) and LiOH (0,173 g, 7.20 mmol) dissolved in a mixture of N2O/THF (20 ml/20 ml) and stirred at 50°C for 16 hours the Mixture was concentrated in vacuo, get 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid. Add thionyl chloride (60 ml), the mixture is heated at the boil under reflux for 1 h and concentrated in vacuo receive crude 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazol-4-carbonylchloride.

Part DCrude 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazol-4-carbonylchloride (919 mg, ˜2,39 mmol), 1-aminopiperidine (0,469 g, 4,69 mmol) and triethylamine (0,363 g and 3.59 mmol) was dissolved in dichloromethane and displaced the more 1 h at room temperature. The mixture was washed with saturated aqueous NaHCO3(3×20 ml), dried over Na2SO4and concentrated in vacuo, optionally purified column chromatography (ethyl acetate, silica gel), receive 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid (356 mg, yield 26% based on ethyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate). Mass spectrum (MS): 449.

Similarly obtained:

2. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(pyrrolidin-1-yl)-1H-imidazol-4-carboxamid. MS: 435.

3. N-(tert.-butoxy)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazol-4-carboxamid. MS: 438.

4. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-phenyl-1H-imidazol-4-carboxamid. MS: 442.

5. 1-(4-chlorophenyl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-1H-imidazol-4-carboxamid. MS: 448.

6. N-(benzyl)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-1H-imidazol-4-carboxamid. MS: 470.

7. 1-[1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-4-(1H-imidazolyl)carbonyl]hexahydro-1H-azepin. MS: 448.

8. 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamide (obtained from 2,4-dichloraniline and 4-chlorobenzonitrile). MS: 449.

9. N-(tert.-butoxy)-2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-imidazol-4-carboxamide (obtained from 2,4-dichloraniline and 4-chlorobenzonitrile). MS: 438.

Example 10

Part a: Diisopropylamine (2.30 g, of 22.8 mmol) is added dropwise to anhydrous THF (100 ml) in an atmosphere of nitrogen is at 0° C. are added dropwise n-BuLi (7,34 ml, 2.5 M solution in hexane, 18.4 mmol). The resulting solution was cooled to -78°C. added dropwise a solution of ethyl-2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (6.0 g, of 15.2 mmol) in anhydrous THF. The color of the mixture changed from yellow to purple-brown. The mixture with stirring is heated to -40°and cooled to -78°leave for 30 minutes added dropwise methyliodide (6,44 g of 45.4 mmol) and the resulting solution was stirred for 30 min at -78°and then left to reach room temperature. The resulting solution was quenched with aqueous solution of NH4Cl add diethyl ether and the organic layer is dried over MgSO4, filtered and concentrated in vacuo, get an oil (6.4 g). The resulting oil is purified column chromatography (toluene/EtOAc = 10/2 (about./vol.), silica gel), pure ethyl-2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylate (5.3 g, yield 85%) as a yellow oil.

Part bEthyl-2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylate (0,250 g, 0.61 mmol) and LiOH (0,052 g, 2,17 mmol) dissolved in a mixture of N2O/THF (1:1 (vol./vol.); 50 ml) and stirred at 50°C for one hour. The mixture is concentrated and receive crude 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylic acid. To the resulting mixture are added SOCl2(50 ml) and obtained the offer is refluxed 1 h The mixture is concentrated and receive 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carbonylchloride.

Part: 2-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carbonylchloride (1.5 g, 3.75 mmol), 1-aminopiperidine (0,725 g of 7.25 mmol) and triethylamine (0,549, 5,44 mmol) is dissolved in dichloromethane and stirred for 1 h at room temperature. The mixture was washed with saturated aqueous NaHCO3, dried over Na2SO4and concentrated in vacuo, optionally purified column chromatography (heptane/ethyl acetate = 1/1 (vol./vol.), silica gel)will receive 2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid (0,220 g, yield 13%) as a white foam. MS: 463.

Similarly obtained:

11. N-(tert.-butoxy)-2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid. MS: 452.

12. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. MS: 463. Melting point: 165-167°C.

13. N-(tert.-butoxy)-2-(2,4-dichlorophenyl)-1-(4-chlorophenyl)-5-methyl-1H-imidazol-4-carboxamid. MS: 452.

14. N-(tert.-butoxy)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-1H-imidazol-4-carboxamid. Amorphous product. MS: 468.

15. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. MS: 477.

16. 1-(4-bromophenyl)-N-(tert.-butoxy)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid. Amorphous product.

17. 1-(4-br is fenil)-2-(2,4-dichlorophenyl)-5-methyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. TPL: >204°C; TLC (silica gel, EtOAc); Rf= 0,3.

18. 1-(4-bromophenyl)-N-(tert.-butoxy)-2-(2,4-dichlorophenyl)-5-ethyl-1H-imidazol-4-carboxamid. The amorphous product; TLC (silica gel, CH2Cl2/acetone = 9/1 (about./about.)): Rf= 0,45.

19. 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. TPL: >140°C; TLC (silica gel, EtOAc); Rf= 0,4.

20. 1-(4-bromophenyl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-5-ethyl-1H-imidazol-4-carboxamid. Melting point: >135-140°C.

21. 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(n-pentyl)-1H-imidazol-4-carboxamid. The syrup. TLC (silica gel, CH2Cl2/acetone = 19/1, (about./about.)); Rf= 0,4.

Example 22

Part a: To a solution of ethyl-1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (6,10 g, 0,0139 mol) in THF (70 ml) with stirring, add LiOH (0,67 g, 0,0278 mol) and water (70 ml). The resulting mixture was stirred for 16 h at 50°To get a clear solution. After cooling to room temperature, add HCl (1 n solution, 28 ml), get an oily residue, which is completely hardens after mixing and adding water (70 ml). The precipitate is filtered off, washed with water and dried in vacuum, to obtain 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid (4,92 g, yield 86%). Melting point: 138-142°C.

Part b: To a suspension of 1-(4-bromophenyl)-2(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid (1.23 g, to 2.99 mmol) in dry acetone (40 ml) under stirring consistently add diisopropylethylamine (DIPEA) (to 1.15 ml, 6.6 mmol), O-benzotriazol-1-yl-N,N,N',N'-tetramethylpropylenediamine (HBTU) (1,36 g, 3.6 mmol) and 1-aminopiperidine (of 0.39 ml, 3.6 mmol). After stirring for 16 h the mixture was concentrated in vacuo. The residue is dissolved in ethyl acetate and added dropwise an aqueous solution of NaHCO3. Collect an ethyl acetate layer was washed with water and brine, dried over Na2SO4, filtered and concentrated to obtain a crude solid. The obtained solid is recrystallized from acetonitrile, to obtain 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid (830 mg, yield 56%). Melting point: 219-221°C.

Similarly obtained:

23. N-(tert.-butoxy)-1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazol-4-carboxamid. Amorphous product. TLC (silica gel, Et2O); Rf= 0,3.

24. 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-N-(pyrrolidin-1-yl)-1H-imidazol-4-carboxamid. Melting point: 238-240°C.

25. N-(azepin-1-yl)-1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazol-4-carboxamid. Melting point: 201-204°C.

26. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(hexahydrotriazine[C]pyrrol-2(1H)-yl)-1H-imidazol-4-carboxamid. MS: 475.

27. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(4-terbisil)-1H-imidazol-4-carboxamid. MS: 44.

28. 1-(4-chlorophenyl)-2-(2-methoxy-4-chlorophenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. Melting point: 220°C.

29. 1-(4-chlorophenyl)-N-cyclohexyl-2-(2-methoxy-4-chlorophenyl)-1H-imidazol-4-carboxamid. Melting point: 177-179°C.

30. 1-(4-chlorophenyl)-2-(2-fluoro-4-chlorophenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. Melting point: 217-218°C.

31. 2-(2,4-dichlorophenyl)-1-(4-forfinal)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. Melting point: 175-176°C.

32. N-cyclohexyl-2-(2,4-dichlorophenyl)-1-(4-forfinal)-1H-imidazol-4-carboxamid. Melting point: 184-185°C.

33. N-cyclohexyl-2-(2-fluoro-4-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazol-4-carboxamid. Melting point: 157-159°C.

34. 1-(4-chlorophenyl)-2-(2-methoxy-4-chlorophenyl)-N-(n-pentyl)-1H-imidazol-4-carboxamid. Melting point: 115°C.

35. 2-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. Melting point: 178-179°C.

36. N-cyclohexyl-2-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-imidazol-4-carboxamid. Melting point: 175-176°C.

37. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N,N-diethyl-1H-imidazol-4-carboxamid. Melting point: 177-179°C.

38. 1-(4-chlorophenyl)-N-cyclohexyl-2-(2-trifluoromethyl-4-chlorophenyl)-1H-imidazol-4-carboxamid. Melting point: 172°C.

39. 1-(4-chlorophenyl)-N-(piperidine-1-yl)-2-(2-trifluoromethyl-chlorphenyl)-1H-imidazol-4-carboxamid. Melting point: 219°C.

40. N-(1-substituted)-1-(4-chlorophenyl)-2-(2-trifluoromethyl-4-chlorophenyl)-1H-imidazol-4-carboxamid. Melting point: 288°C.

41. 1-(4-chlorophenyl)-N-(2,2,2-triptorelin)-2-(2-trifluoromethyl-4-chlorophenyl)-1H-imidazol-4-carboxamid. Melting point: 149°C.

42. 2-(2,4-dichlorophenyl)-1-(pyridine-3-yl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. Melting point: 165-170°C.

43. N-cyclohexyl-2-(2,4-dichlorophenyl)-(1-pyridin-3-yl)-1H-imidazol-4-carboxamid. Melting point: 195°C.

44. 2-(2,4-dichlorophenyl)-(1-pyridin-3-yl)-N-(n-pentyl)-1H-imidazol-4-carboxamid. Melting point: 117°C.

Example 45

Part aDissolve 2,4-dichlorobenzophenone (40,0 g, to 0.19 mol) in tetrahydrofuran (1 l). Then, to the obtained solution under stirring consistently add diisopropylethylamine (DIPEA) (73,4 ml of 2.2 molar equivalents) and 4-(trifluoromethyl)phenylamine (30,7 g at 0.19 mol). After one hour the mixture was concentrated in vacuo, get the oil. The oil obtained is crystallized from ethanol, pure 2,4-dichloro-N-(4-(trifluoromethyl)phenyl)benzamide cases (53.2 g, yield 83%).1H-NMR (200 MHz, DMSO-d6): δ 10,90 (users, 1H), to $ 7.91 (userd, J=8 Hz, 2H), 7,63-to 7.77 (m, 4H), EUR 7.57 (dt, J=8 Hz, J=2 Hz, 1H).

Part bDissolve 2,4-dichloro-N-(4-(trifluoromethyl)phenyl)benzamide (19,0 g 0,057 mol) in benzene (150 ml) and add PCl5(13,0 g to 1.1 molar is quivalent). The resulting mixture is heated at boiling under reflux for two hours, allowed to reach room temperature and was concentrated in vacuo, receive the remainder. The resulting residue is dissolved in anhydrous THF, cooled to 0°and transferred to the autoclave. From laboratory flask quickly add an excess of NH3and the mixture is stirred at room temperature for 50 hours Add a mixture of ethyl acetate and aqueous NaHCO3. An ethyl acetate layer is collected, dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil is purified column chromatography (diethyl ether/petroleum ether = 1/1 (vol./vol.), silica gel), pure 2,4-dichloro-N-(4-trifluoromethyl)phenyl)benzoperoxide (16,9 g, yield 89%). Melting point: 108-109°C.

PartDissolve 2,4-dichloro-N-(4-trifluoromethyl)phenyl)benzoperoxide (15.0 g, 0,0450 mol) in 2-propanol and successively added ethyl-3-bromo-2-oxobutanoate (20,8 g, 2 molar equivalent) and NaHCO3. The resulting mixture is heated at boiling temperature under reflux for 40 h and allow to reach room temperature. Remove the 2-propanol in a vacuum, add ethyl acetate to the residue and the organic layer was washed with NaHCO3(5%aqueous solution). Collect an ethyl acetate layer is dried over Na2SO4, filtered and concentrated in vacuo. Received the aslo purified column chromatography (diethyl ether/petroleum ether = 1/3 (about./vol.), silica gel) and further purified by crystallization from cyclohexane, to obtain ethyl 2-(2,4-dichlorophenyl)-5-methyl-1-(4-trifluoromethyl)phenyl)-1H-imidazole-4-carboxylate (10,45 g, yield 52%) as a yellow solid. Melting point: 160-162°C.

Part D: Obtained ethyl 2-(2,4-dichlorophenyl)-5-methyl-1-(4-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxylate converted into 2-(2,4-dichlorophenyl)-5-methyl-1-(4-(trifluoromethyl)phenyl)-1H-imidazole-4-carboxylic acid (melting point: 224-226° (C), and the carboxylic acid is converted into 2-(2,4-dichlorophenyl)-5-methyl-N-(piperidine-1-yl)-1-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-carboxamide (melting point: 173-174° (C) by the procedure described above in example 22.

Similarly obtained:

46. 2-(2,4-dichlorophenyl)-N-(piperidine-1-yl)-1-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-carboxamid. Melting point: >200°C (decomposition).

47. N-cyclohexyl-2-(2,4-dichlorophenyl)-5-methyl-1-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-carboxamid. Melting point: 178-179°C.

48. N-cyclohexyl-2-(2,4-dichlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-imidazol-4-carboxamid. Melting point: 199-200°C.

Example 49

Part aDissolve N-(4-methoxyphenyl)-2,4-dichlorobenzophenone (15.0 g, 50.8 mmol) in 2-propanol and successively added ethyl 3-bromo-2-oxobutanoate (23,5 g, 2 molar equivalent) and NaHCO3(8.5 g 2 molar equivalent). The resulting mixture is heated at the boil under reflux for 40 h and allowed to reach room temperature. Remove the 2-propanol in a vacuum, to the residue is added ethyl acetate and the resulting organic layer was washed with NaHCO3(5%aqueous solution). Collect an ethyl acetate layer is dried over Na2SO4, filtered and concentrated in vacuo. The resulting oil is purified column chromatography (diethyl ether/petroleum ether = 1/3 (about./vol.), silica gel)to obtain ethyl 2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole-4-carboxylate (8,61 g, yield 42%) as a solid.1H-NMR (200 MHz, CDCl3): δ 7,33 (d, J=8 Hz, 1H), 7,27 (d, J=2 Hz, 1H), 7,18 (DD, J=8 Hz, J=2 Hz, 1H), 7,03(dt, J=8 Hz, J=2 Hz, 2H), 6,85 (dt, J=8 Hz, J=2 Hz, 2H), 4,42 (kV, J=7 Hz, 2H), 3,80 (s, 3H), 2,43 (s, 3H), 2,43 (s, 3H), USD 1.43 (t, J=7 Hz, 3H).

Part b: To a solution of ethyl 2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole-4-carboxylate (8.00 g, 0,0198 mol) in THF (80 ml) was added with stirring LiOH (0,59 g, 2 molar equivalents) and water (80 ml). The resulting mixture was stirred for 16 h at 80°C. After cooling to room temperature, add HCl (2 n solution of 12.3 ml), get an oily residue. After the addition of water and extraction with ethyl acetate, an ethyl acetate layer is collected, dried over Na2SO4, filtered and concentrated in vacuo. The residue is recrystallized from diisopropyl EPE is a and dried, get 2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole-4-carboxylic acid (Android 4.04 g, yield 87%) as a light grey solid. Melting point: 189-191°C.

Part: To 2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazole-4-carboxylic acid (1,00 g, to 2.65 mmol) in dry acetonitrile (25 ml) successively add diisopropylethylamine (DIPEA) (1,02 ml of 2.2 molar equivalent), O-benzotriazol-1-yl-N,N,N',N'-tetramethylpropylenediamine (HBTU) (1,21 g to 1.2 molar equivalent) and the resulting solution was stirred for 15 minutes Add cyclohexylamine (0,36 ml, to 1.2 molar equivalent). After stirring for 50 h, the mixture was concentrated in vacuo. The residue is dissolved in dichloromethane and added dropwise an aqueous solution of NaHCO3. The dichloromethane layer is collected, dried over Na2SO4, filtered and concentrated in vacuo. The residue is optionally purified column chromatography (gradient: dichloromethane⇒dichloromethane/methanol = 99/1 (about./vol.), silica gel), receive N-(1-cyclohexyl)-2-(2,4-dichlorophenyl)-5-methyl-1-(4-methoxyphenyl)-1H-imidazol-4-carboxamid (of 1.03 g, yield 85%). Melting point: 160-161°C.

Similarly obtained:

50. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N,N,5-trimethyl-1H-imidazol-4-carboxamid. Melting point: 101-104°C.

51. 1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-methyl-N-(piperidine-1-yl)-1H-they are the azole-4-carboxamide. MS: 464 (MN+).

52. 1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-methyl-N-(4-morpholinyl)-1H-imidazol-4-carboxamid. MS: 466 (MN+).

53. N-(1-azepane)-1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid. MS: 478 (MN+).

54. 1-(4-chloropyridin-2-yl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid. MS: 463.

55. 1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-methyl-N-(n-pentyl)-1H-imidazol-4-carboxamid. MS: 451.

56. 1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-N-(4-terbisil)-5-methyl-1H-imidazol-4-carboxamid. MS: 489. Melting point: 123-126°C.

57. 1-(4-chlorophenyl)-N-cyclohexyl-5-methyl-2-(2-trifluoromethyl-4-chlorophenyl)-1H-imidazol-4-carboxamid. Melting point: 212°C.

58. 1-(4-chlorophenyl)-5-methyl-N-(piperidine-1-yl)-2-(2-trifluoromethyl-4-chlorophenyl)-1H-imidazol-4-carboxamid. Melting point: 165°C.

59. 1-(4-chlorophenyl)-2-(2-methoxy-4-chlorophenyl)-5-methyl-N-(n-pentyl)-1H-imidazol-4-carboxamid. Melting point: 131°C.

60. 1-(4-chlorophenyl)-2-(2-methoxy-4-chlorophenyl)-5-methyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. Melting point: >256°C.

61. N-cyclohexyl-1-(4-chlorophenyl)-2-(2-methoxy-4-chlorophenyl)-5-methyl-1H-imidazol-4-carboxamid. Melting point: 201°C.

62. 2-(2,4-dichlorophenyl)-1-(4-forfinal)-5-methyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. Melting point: p.223-224°C.

63. 2-(2,4-di is lorgeril)-5-methyl-1-(4-methoxyphenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. Melting point: >90°C (decomposition).

64. N-cyclohexyl-1-(4-forfinal)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid. Melting point: 229-230°C.

65. 1-(4-chlorophenyl)-5-methyl-N-(n-pentyl)-2-(2-trifluoromethyl)-4-chlorophenyl)-1H-imidazol-4-carboxamid. Amorphous product.

66. 1-(4-chlorophenyl)-2-(2-fluoro-4-chlorophenyl)-5-methyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. Melting point: 195°C.

67. 1-(4-chlorophenyl)-2-(2-fluoro-4-chlorophenyl)-5-methyl-N-(n-pentyl)-1H-imidazol-4-carboxamid. Melting point: 115°C.

68. 1-(4-chlorophenyl)-N-(cyclohexyl)-2-(2-fluoro-4-chlorophenyl)-5-methyl-1H-imidazol-4-carboxamid. Melting point: 188°C.

69. 1-(4-chlorophenyl)-N-(cyclohexyl)-2-(1,5-dimethyl-1H-pyrrol-2-yl)-5-methyl-1H-imidazol-4-carboxamid. Melting point: 188-189°C.

70. 1-(4-chlorophenyl)-2-(1,5-dimethyl-1H-pyrrol-2-yl)-5-methyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. Melting point: 208-210°C.

71. 2-(2-chlorophenyl)-1-(3-forfinal)-5-methyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. Melting point: 236-238°C.

72. 2-(2-chlorophenyl)-1-(3-forfinal)-5-methyl-N-(n-pentyl)-1H-imidazol-4-carboxamid. Melting point: 97-102°C.

73. 2-(2-chlorophenyl)-N-cyclohexyl-1-(3-forfinal)-5-methyl-1H-imidazol-4-carboxamid. Melting point: 180-182,5°C.

74. 2-(2-chlorophenyl)-1-(3-forfinal)-N-(2-(4-forfinal)ethyl)-5-methyl-1H-imidazol--carboxamide. Melting point: 123,5-126°C.

75. 1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. Melting point: 146°C.

76. 1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(4-morpholinyl))-1H-imidazol-4-carboxamid. Melting point: 223°C.

77. N-(1-azepane)-1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-ethyl-1H-imidazol-4-carboxamid. Melting point: 177°C.

78. 1-(4-chloropyridin-2-yl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-5-ethyl-1H-imidazol-4-carboxamid. Melting point: 149°C.

79. 1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(n-pentyl)-1H-imidazol-4-carboxamid. Melting point: oil.

80. 1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(4-performer)-1H-imidazol-4-carboxamid. TPL: amorphous product.

81. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(hexahydrotriazine[c]pyrrol-2(1H)-yl)-5-methyl-1H-imidazol-4-carboxamid. So pl.: 143-146°C.

82. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-phenyl-1H-imidazol-4-carboxamid. Melting point: 91-95°C.

83. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(tetrahydro-2H-Piran-2-yloxy)-1H-imidazol-4-carboxamid. Melting point: 128-133°C.

84. N-(Exo-bicyclo[2.2.1]hept-2-yl)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid. Melting point: 194-195°C.

85. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(2-foradil)-5-IU the Il-1H-imidazol-4-carboxamid. Melting point: 128-133°C.

86. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(TRANS-4-hydroxycyclohexyl)-5-methyl-1H-imidazol-4-carboxamid. Melting point: 160°C (decomposition).

87. 1-{[1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-yl]carbonyl}-4-hydroxypiperidine. Melting point: amorphous product.

88. 1-{[1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline. Melting point: 143-146°C.

89. N-(Endo-bicyclo[2.2.1]hept-2-yl)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid. Melting point: 194-195°C.

90. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(4-terbisil)-5-methyl-1H-imidazol-4-carboxamid. Melting point: 165-166°C.

91. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(n-pentyl)-1H-imidazol-4-carboxamid. Butter.

92. N-(azepin-1-yl)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid. Melting point: 147-149°C.

93. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(pyrrolidin-1-yl)-1H-imidazol-4-carboxamid. Melting point: 205-206°C.

94. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(morpholine-4-yl)-1H-imidazol-4-carboxamid. Melting point: 225°C (decomposition).

95. 2-(2,5-dichlorophenyl)-5-methyl-1-phenyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. Melting point: 227°C.

96. N-cyclohexyl-2-(2,5-dichlorophen the l)-5-methyl-1-phenyl-1H-imidazol-4-carboxamid. Melting point: 236°C.

97. N-cyclohexyl-2-(2,4-dichlorophenyl)-1-(2,5-differenl)-5-ethyl-1H-imidazol-4-carboxamid. Melting point: 144-146°C.

98. N-cyclohexyl-2-(2,4-dichlorophenyl)-1-(2,5-differenl)-5-methyl-1H-imidazol-4-carboxamid. Melting point: 206-208°C.

99. N-cyclohexyl-2-(1,5-dimethyl-1H-pyrrol-2-yl)-5-ethyl-1-phenyl-1H-imidazol-4-carboxamid. Melting point: 195-196°C.

100. N-cyclohexyl-2-(2,5-dichlorophenyl)-5-ethyl-1-phenyl-1H-imidazol-4-carboxamid. Melting point: 198-199°C.

101. 2-(2,5-dichlorophenyl)-5-ethyl-1-phenyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. Melting point: 207-208°C.

102. 1-(4-chlorophenyl)-5-methyl-2-(3-methylpyridin-2-yl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. Melting point: 211-213°C.

103. 1-(4-chlorophenyl)-N-cyclohexyl-5-methyl-2-(3-methylpyridin-2-yl)-1H-imidazol-4-carboxamid. Melting point: 188-190°C.

104. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-1H-imidazol-4-carboxamid. Melting point: 177°C.

105. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-carboxamid. Melting point: 138-140°C.

106. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(4-(trifluoromethyl)benzyl)-1H-imidazol-4-carboxamid. Melting point: 232°C.

107. 1-(4-chlorophenyl)-N-cyclopentyl-2-(2,4-dichlorophenyl)-5-methyl-1H-they shall Gasol-4-carboxamide. Melting point: 172°C.

108. 1-(4-chlorophenyl)-N-cycloheptyl-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid. Melting point: 154-156°C.

Example 109

Part aEthyl 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate in turn ethyl 1-(4-bromophenyl)-5-chloro-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate similar to published methods (N.Kudo et al.,Chem. Pharm. Bull. 1999, 47, 857-868) using an excess of SO2Cl2in dichloroethane by boiling under reflux for 50 hours

Part bEthyl 1-(4-bromophenyl)-5-chloro-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate converted into 1-(4-bromophenyl)-5-chloro-2-(2,4-dichlorophenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamide (melting point: >150°S; Rf(silica gel, EtOAc) ˜0,35) similarly to the procedure described above in example 22.1H-NMR (400 MHz, CDCl3): δ a 7.85 (users, 1H), 7,52 (dt, J=8 Hz, J=2 Hz, 2H), 7,26 and 7.36 (m, 3H), 7,01 (dt, J=8 Hz, J=2 Hz, 2H), 2,85 of 2.92 (m, 4H), 1,72 and 1.80 (m, 4H), 1,40-of 1.44 (m, 2H).

Example 110

Part a: To a solution of 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid (18,38 g, 50 mmol) in toluene (200 ml) under nitrogen atmosphere with stirring, add di-tert.-butylacetyl N,N-dimethylformamide (50 ml)and the resulting mixture is heated at 80°C for 4 h After cooling to room temperature the reaction mixture was concentrated and DOB is given in diethyl ether. The resulting solution was washed twice with water, dried over MgSO4, filtered and concentrated in vacuo. The residue is crystallized from diisopropyl ether, pure tert.-butyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (10,35 g, yield 49%). Melting point: 179-181°C.

Part b: Diisopropylamide lithium (LDA) (a 5.25 ml, 2M solution in THF, 0,0105 mol) is added dropwise to a cooled solution (-70° (C) tert.-butyl-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (4,24 g 0,010 mol) in anhydrous THF (80 ml) under nitrogen atmosphere and the resulting mixture is stirred for one hour. Add dropwise a solution of p-toluensulfonate (1.88 g, to 0.011 mol) in anhydrous THF (20 ml) and the resulting red solution is stirred for one hour at -70°S, and then allowed to reach room temperature. Add diethyl ether, and the resulting solution was quenched with water and filtered through hyflo. The organic layer is collected and washed with water, dried over MgSO4, filtered and concentrated in vacuo, get the oil. The resulting oil is purified column chromatography (dichloromethane, silica gel), obtain 3.4 g of tert.-butyl 1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate. Recrystallization from diisopropyl ether gives crystalline tert.-butyl 1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (2.57 m) g, yield 57%). So the temperature value melting point: 210-212° C.

Similarly obtained:

tert.-butyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazole-4-carboxylate.1H-NMR (400 MHz, CDCl3): δ 7,38 (d, J=8 Hz, 1H), 7,34 (dt, J=8 Hz, J=2 Hz, 2H), 7,27 (d, J=2 Hz, 1H), 7,22 (DD, J=8 Hz, J=2 Hz, 1H), 7,03 (dt, J=8 Hz, J=2 Hz, 2H), 2.40 a (s, 3H), and 1.63 (s, N).

Part: To a solution of tert.-butyl 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-cyano-1H-imidazole-4-carboxylate (2.57 m) g, 5,73 mmol) in dichloromethane (40 ml) add triperoxonane acid, and the resulting solution was stirred at room temperature for 20 h and concentrated in vacuo. The residue is crystallized from diisopropyl ether, to obtain 1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid (1,95 g, yield 87%). Melting point: 200-202°C (decomposition).

Part D: 1-(4-Chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid is converted into 1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid with the release of 60% similar to the procedure described above in example 22, part C. melting point: 231-233,5°C.

Similarly obtained:

111. 1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-iodine-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid. Melting point: 196-201°C.

112. 1-(4-chlorophenyl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-5-iodine-1H-imidazol-4-carboxamid. Melting point: 226-230°C.

113. 1-(4-chlorophenyl)-5-cyano-N-cyclohexyl-2-(2,-dichlorophenyl)-1H-imidazol-4-carboxamid. Melting point: 157-158°C.

Pharmacological properties of the compounds of the invention

The following table 113 working examples PCT/ER/10434 (WO 03/027076, SPW0112) collected available pharmacological data. The table also contains some more examples.

Table
hCB1
Etc.RR1R2R3R4pKiRA2
96Phenyl2,5-Cl-phenylNCyclohexylCH38.2
100Phenyl2,5-Cl-phenylNCyclohexylEthyl
95Phenyl2,5-Cl-phenylNPiperidine-1-ylCH3 7.2
101Phenyl2,5-Cl-phenylNPiperidine-1-ylEthyl
99Phenyl1,5-dime-1H-pyrrol-2-ylNCyclohexylEthyl
733-Forfinal2-Cl-phenylNCyclohexylCH37.9
713-Forfinal2-Cl-phenylNPiperidine-2-ylCH37.4
743-Forfinal2-Cl-phenylN2-(4-F-phenyl)-ethylCH36.4
32Forfinal 2,4-dichlorophenylNCyclohexylN7.6
644-Forfinal2,4-dichlorophenylNCyclohexylCH3
314-Forfinal2,4-dichlorophenylNPiperidine-1-ylN6.7
624-Forfinal2,4-dichlorophenylNPiperidine-1-ylCH37.57.7
214-Bromophenyl2,4-dichlorophenylNn-pentylEthyl7.5>9.0
234-Bromophenyl2,4-dichlorophenylNO-tert.-butylN6.49.0
164-Bromophenyl2,4-dichlorophenylN O-tert.-butylCH36.27.8
184-Bromophenyl2,4-dichlorophenylNO-tert.-butylEthyl
204-Bromophenyl2,4-dichlorophenylNCyclohexylEthyl7.0>9.0
244-Bromophenyl2,4-dichlorophenylNPyrrolidin-1-ylN
224-Bromophenyl2,4-dichlorophenylNPiperidine-1-ylN6.48.0
1094-Bromophenyl2,4-dichlorophenylNPiperidine-1-ylCl6.68.8
174-Bromophenyl2,4-dichlorophenylNPiperidine-1-ylCH37.38.8
194-Bromophenyl2,4-dichlorophenylNPiperidine-1-ylE is Il 7.58.9
254-Bromophenyl2,4-dichlorophenylNAzepin-1-ylN6.98.0
694-Chlorophenyl1,5-dime-1H-pyrrol-2-ylNCyclohexylCH37.4
704-Chlorophenyl1,5-dime-1H-pyrrol-2-ylNPiperidine-1-ylCH38.3
1034-Chlorophenyl3-Me-pyridine-2-ylNCyclohexylCH3
1024-Chlorophenyl3-Me-pyridine-2-ylNPiperidine-1-ylCH3
334-Chlorophenyl2-fluoro-4-chlorophenylNCyclohexylN6.3
684-Chlorophenyl2-fluoro-4-chlorophenylNCyclohexylCH36.7
674-Chlorophenyl2-fluoro-4-chlorophenylNN-pentylCH36.4
304-Chlorophenyl2-fluoro-4-chlorophenylNPiperidine-1-ylN7.6
664-Chlorophenyl2-fluoro-4-chlorophenylNPiperidine-1-ylCH36.3
504-Chlorophenyl2,4-dichlorophenylCH3MethylCH38.3
374-Chlorophenyl2,4-dichlorophenylEthylEthylN
854-Chlorophenyl2,4-dichlorophenylN2-ForadilCH37.6 /td>
44-Chlorophenyl2,4-dichlorophenylNPhenylN6.9
824-Chlorophenyl2,4-dichlorophenylNPhenylCH38.6
1044-Chlorophenyl2,4-dichlorophenylN3-CF3-phenylCH38.2
64-Chlorophenyl2,4-dichlorophenylCH3BenzilN7.27.3
1054-Chlorophenyl2,4-dichlorophenylN3-CF3-phenylCH37.5
1064-Chlorophenyl2,4-dichlorophenylN4-CF3-phenylCH37.08.9
274-Chlorophenyl2,4-dichlorophenylN4-TerbisilN7.28.4
90 4-Chlorophenyl2,4-dichlorophenylN4-TerbisilCH38.0
1084-Chlorophenyl2,4-dichlorophenylNCycloheptylCH38.19.1
1074-Chlorophenyl2,4-dichlorophenylNCyclopentylCH36.88.9
New4-Chlorophenyl2,4-dichlorophenylNCyclohexylSO2CH37.2
New4-Chlorophenyl2,4-dichlorophenylNCyclohexylSCH37.2
54-Chlorophenyl2,4-dichlorophenylNCyclohexylN7.18.1
1134-Chlorophenyl2,4-dichlorophenylNCyclohexylCyan7.8
112 2,4-dichlorophenylNCyclohexylIodine8.2
864-Chlorophenyl2,4-dichlorophenylN4-HE-CyclohexylCH36.97.8
1084-Chlorophenyl2,4-dichlorophenylNCycloheptylCH38.19.1
924-Chlorophenyl2,4-dichlorophenylN1-azepaneCH37.28.8
894-Chlorophenyl2,4-dichlorophenylNAndbicycle[2. 2]hept-2-ylCH38.2
844-Chlorophenyl2,4-dichlorophenylNAltobello[2. 2]hept-2-ylCH37.88.9
944-Chlorophenyl2,4-dichlorophenylNMorpholine-4-ylCH37.07.5
914-lorgeril 2,4-dichlorophenylNn-pentylCH37.5
34-Chlorophenyl2,4-dichlorophenylNO-tert.-butylN6.87.5
134-Chlorophenyl2,4-dichlorophenylNO-tert.-butylCH37.18.5
144-Chlorophenyl2,4-dichlorophenylNO-tert.-butylEthyl7.09.9
14-Chlorophenyl2,4-dichlorophenylNPiperidine-1-ylN7.98.2
124-Chlorophenyl2,4-dichlorophenylNPiperidine-1-ylCH37.98.9
New4-Chlorophenyl2,4-dichlorophenylNPiperidine-1-ylCH2F7.2
New4-Chlorophenyl2,4-dichlor the Nile NPiperidine-1-ylCH2HE7.5
154-Chlorophenyl2,4-dichlorophenylNPiperidine-1-ylEthyl8.09.3
1104-Chlorophenyl2,4-dichlorophenylNPiperidine-1-ylCyan7.58.6
1114-Chlorophenyl2,4-dichlorophenylNPiperidine-1-ylIodine8.28.6
New4-Chlorophenyl2,4-dichlorophenylNPiperidine-1-ylBromine8.08.6
New4-Chlorophenyl2,4-dichlorophenylNPiperidine-1-ylSO2CH37.88.5
New4-Chlorophenyl2,4-dichlorophenylNPiperidine-1-ylSCH37.99.2
24-Chlorophenyl2,4-dichloropheny the NPiperidine-1-ylN7.07.6
934-Chlorophenyl2,4-dichlorophenylNPiperidine-1-ylCH37.78.2
834-Chlorophenyl2,4-dichlorophenylNTetrahydro-2-N-Piran-1 iloxi-CH38.4
264-Chlorophenyl2,4-dichlorophenylNN6.38.0
814-Chlorophenyl2,4-dichlorophenylNCH37.59.8
74-Chlorophenyl2,4-dichlorophenylHexahydroazepin-1-yl*N
874-Chlorophenyl2,4-dichlorophenyl4-Hydroxypiperidine-1-yl*CH36.8
884-Chlorophenyl2,4-dichlorophenyl1,2,3,4-re is rehydro-isoquinoline-1-yl* CH3
404-Chlorophenyl2-CF3-ChlorphenylN1-substitutedN
414-Chlorophenyl2-CF3-4-chlorophenylN2,2,2-Cryptor-N
Ethyl
654-Chlorophenyl2-CF3-4-chlorophenylNn-pentylCH3
384-Chlorophenyl2-CF3-4-chlorophenylNCyclohexylN6.77.7
574-Chlorophenyl2-CF3-4-chlorophenylNCyclohexylCH3
394-Chlorophenyl2-CF3-4-chlorophenylNPiperidine-1-yl N6.57.3
584-Chlorophenyl2-CF3-4-chlorophenylNPiperidine-1-ylCH36.7
294-Chlorophenyl2-och3-4-ClNCyclohexylN6.47.0
614-Chlorophenyl2-och3-4-ClNCyclohexylCH3
344-Chlorophenyl2-och3-4-ClNn-pentylN
594-Chlorophenyl2-och3-4-ClNn-pentylCH36.3
284-Chlorophenyl2-och3-4-ClNPiperidine-1-ylN7.2
604-Chlorophenyl2-och3-4-ClNPiperi is Jn-1-yl CH3
484-CF3-Phenyl2,4-dichlorophenylNCyclohexylN6,59.6
474-CF3-Phenyl2,4-dichlorophenylNCyclohexylCH36.8
464-CF3-Phenyl2,4-dichlorophenylNPiperidine-1-ylN7.38.2
454-CF3-Phenyl2,4-dichlorophenylNPiperidine-1-ylCH37.88.8
364-och3-Phenyl2,4-dichlorophenylNCyclohexylN6.8 8.2
494-och3-Phenyl2,4-dichlorophenylNCyclohexylCH36.9
354-och3-Phenyl2,4-dichlorophenylNPiperidine-1-ylN7.3
634-och3-Phenyl2,4-dichlorophenylNPiperidine-1-ylCH37.19.0
972,5-F-Phenyl2,4-dichlorophenylNCyclohexylCH37.3
982,5-F-Phenyl2,4-dichlorophenylNCyclohexylEthyl7.8
94-chlorophenylNO-tert.-butylN6.2
112,4-Cl-Phenyl4-chlorophenylNO-tert.-butylCH36.3
82,4-Cl-Phenyl4-chlorophenylNPiperidine-1-ylN
102,4-Cl-Phenyl4-chlorophenylNPiperidine-1-ylCH36.58.1
44Pyridine-3-yl2,4-dichlorophenylNn-pentylN
43Pyridine-3-yl2,4-dichlorophenylNCyclohexylN
42Pyridine-3-yl2,4-dichlorophenyl NPiperidine-1-ylN6.2
New4-Cl-pyridine-2-yl2,4-dichlorophenylNPiperidine-1-ylEthyl7.9
554-Cl-pyridine-2-yl2,4-dichlorophenylNn-pentylCH37.3
794-Cl-pyridine-2-yl2,4-dichlorophenylNN-pentylEthyl7.8
544-Cl-pyridine-2-yl2,4-dichlorophenylNCyclohexylCH37.0
784-Cl-pyridine-2-yl2,4-dichlorophenylNCyclohexylEthyl8.5
514-Cl-pyridine-2-yl2,4-dichlorophenylNPiperidin-Il CH37.38.7
754-Cl-pyridine-2-yl2,4-dichlorophenylNPiperidine-1-ylEthyl7.0
524-Cl-pyridine-2-yl2,4-dichlorophenylNMorpholine-1-ylCH36.38.6
764-Cl-pyridine-2-yl2,4-dichlorophenylNMorpholine-1-ylEthyl6.6
564-Cl-pyridine-2-yl2,4-dichlorophenylN4-TerbisilCH36.8
804-Cl-pyridine-2-yl2,4-dichlorophenylN2-(4-F-phenyl)ethylEthyl6.5
534-Cl-pyridine-2-yl2,4-dichlorophenylN1-AzepaneCH37.3
774-Cl-pyridine-2-yl2,4-dichlorophenylN1-ASEP the Nile Ethyl7.5
* including the nitrogen atom is attached to R2and R3in the General formula.

1. Derived 1H-imidazole-4-carboxamide of formula (1)

where R represents a phenyl, 2-pyridinyl, 3-pyridinyl, and these groups may be substituted by 1, 2 substituents Y, which can be the same or different and selected from the group comprising From1-3-alkoxygroup, halogen atom, trifluoromethyl;

R1represents phenyl, possibly substituted by 1, 2 substituents Y, which can be the same or different, where Y is selected from the group comprising From1-3alkoxygroup, halogen atom, trifluoromethyl, or R1represents a five-membered aromatic heterocyclic ring containing one heteroatom N, and it is five-membered aromatic heterocyclic ring may be substituted by 2 substituents Y, which can be the same or different, and denote With1-3alkyl;

R2represents H, a branched or unbranched C1-8-alkyl;

R3is a branched or non-branched C2-8-alkyl, C1-8-alkoxy, C3-8-cycloalkyl, and these groups may be substituted by a hydroxyl group or 1-3 the volumes of fluorine, or R3represents a benzyl group, an aromatic ring which may be substituted by the Deputy Z represents a halogen atom, or R3represents a phenyl group substituted by the Deputy Z represents a halogen atom;

or R3represents a group NR5R6provided that R2represents a hydrogen atom, where R5and R6together with the nitrogen atom to which they are linked, form a saturated or unsaturated, monocyclic or bicyclic heterocyclic group containing from 4 to 10 atoms in the cycle, and this heterocyclic group contains one or two heteroatoms from the group (N, O), and these heteroatoms may be the same or different, and these heterocyclic groups may be substituted With1-3is an alkyl group;

R4represents a hydrogen atom or halogen, or cyano, sulfamoyl, methanesulfonyl, methylsulfanyl or branched or unbranched1-4is an alkyl group, and this C1-4is an alkyl group may be substituted by 1-3 fluorine atoms or bromine atoms, chlorine, iodine or a hydroxyl group;

and its stereoisomers and salts.

2. The compound according to claim 1, which is a

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(pyrrolidin-1-yl)-1H-imida-evil-4-carboxamid

N-(tert.-butoxy)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-phenyl-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-1H-imidazol-4-carboxamid

N-(benzyl)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-methyl-1H-imidazol-4-carboxamid

1-[1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-4-(1H-imidazolyl)-carbonyl]hexahydro-1H-azepin

2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

N-(tert.-butoxy)-2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-1H-imidazol-4-carboxamid

2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

N-(tert.-butoxy)-2-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

N-(tert.-butoxy)-2-(2,4-dichlorophenyl)-1-(4-chlorophenyl)-5-methyl-1H-imidazol-4-carboxamid

N-(tert.-butoxy)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

1-(4-bromophenyl)-N-(tert.-butoxy)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid

1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(PIP who ridin-1-yl)-1H-imidazol-4-carboxamid

1-(4-bromophenyl)-N-(tert.-butoxy)-2-(2,4-dichlorophenyl)-5-ethyl-1H-imidazol-4-carboxamid

1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

1-(4-bromophenyl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-5-ethyl-1H-imidazol-4-carboxamid

1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(n-pentyl)-1H-imidazol-4-carboxamid

1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

N-(tert.-butoxy)-1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazol-4-carboxamid

1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-N-(pyrrolidin-1-yl)-1H-imidazol-4-carboxamid

N-(azepin-1-yl)-1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(hexahydrotriazine[C]pyrrol-2(1H)-yl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(4-terbisil)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2-methoxy-4-chlorophenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-N-cyclohexyl-2-(2-methoxy-4-chlorophenyl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2-fluoro-4-chlorophenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

2-(2,4-dichlorophenyl)-1-(4-forfinal)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

N-cyclohexyl-2-(2,4-dichlorophenyl)-1-(4-forfinal)-1H-imidazol-4-carboxamid

N-cyclohexyl-2-(2-fluoro-4-chlorphen the l)-1-(4-chlorophenyl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2-methoxy-4-chlorophenyl)-N-(n-pentyl)-1H-imidazol-4-carboxamid

2-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

N-cyclohexyl-2-(2,4-dichlorophenyl)-1-(4-methoxyphenyl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N,N-diethyl-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-N-cyclohexyl-2-(2-trifluoromethyl-4-chloro-phenyl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-N-(piperidine-1-yl)-2-(2-trifluoromethyl-4-chlorophenyl)-1H-imidazol-4-carboxamid

N-(1-substituted)-1-(4-chlorophenyl)-2-(2-trifluoromethyl-4-chlorophenyl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-N-(2,2,2-triptorelin)-2-(2-trifluoromethyl-4-chlorophenyl)-1H-imidazol-4-carboxamid

2-(2,4-dichlorophenyl)-1-(pyridine-3-yl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

N-cyclohexyl-2-(2,4-dichlorophenyl)-1-(pyridine-3-yl)-1H-imidazol-4-carboxamid

2-(2,4-dichlorophenyl)-1-(pyridine-3-yl)-N-(n-pentyl)-1H-imidazol-4-carboxamid

2-(2,4-dichlorophenyl)-5-methyl-N-(piperidine-1-yl)-1-(4-trifluoromethyl)phenyl)-1H-imidazol-4-carboxamid

2-(2,4-dichlorophenyl)-N-(piperidine-1-yl)-1-(4-trifluoromethyl)-phenyl)-1H-imidazol-4-carboxamid

N-cyclohexyl-2-(2,4-dichlorophenyl)-5-methyl-1-(4-(trifter-methyl)phenyl)-1H-imidazol-4-carboxamid

N-cyclohexyl-2-(2,4-dichlorophenyl)-1-(4-(trifluoromethyl)-phenyl)-1H-imidazol-4-carboxamid

p num="278"> N-(1-cyclohexyl)-2-(2,4-dichlorophenyl)-5-methyl-1-(4-(methoxyphenyl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N,N,5-trimethyl-1H-imidazol-4-carboxamid

1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-methyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-methyl-N-(4-morpholinyl)-1H-imidazol-4-carboxamid

N-(1-azepane)-1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid

1-(4-chloropyridin-2-yl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid

1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-methyl-N-(n-pentyl)-1H-imidazol-4-carboxamid

1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-N-(4-terbisil)-5-methyl-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-N-cyclohexyl-5-methyl-2-(2-trifluoromethyl-4-chlorophenyl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-5-methyl-N-(piperidine-1-yl)-2-(2-Cryptor-methyl-4-chlorophenyl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2-methoxy-4-chlorophenyl)-5-methyl-N-(n-pentyl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2-methoxy-4-chlorophenyl)-5-methyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

N-cyclohexyl-1-(4-chlorophenyl)-2-(2-methoxy-4-chlorophenyl)-5-methyl-1H-imidazol-4-carboxamid

2-(2,4-dichlorophenyl)-1-(4-forfinal)-5-methyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

2-(2,4-dichlorophenyl)-5-IU the Il-1-(4-methoxyphenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

N-cyclohexyl-1-(4-forfinal)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-5-methyl-N-(n-pentyl)-2-(2-trifluoromethyl-4-chlorophenyl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2-fluoro-4-chlorophenyl)-5-methyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2-fluoro-4-chlorophenyl)-5-methyl-N-(n-pentyl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-N-(cyclohexyl)-2-(2-fluoro-4-chlorophenyl)-5-methyl-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-N-(cyclohexyl)-2-(1,5-dimethyl-1H-pyrrol-2-yl)-5-methyl-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(1,5-dimethyl-1H-pyrrol-2-yl)-5-methyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

2-(2-chlorophenyl)-1-(3-forfinal)-5-methyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

2-(2-chlorophenyl)-1-(3-forfinal)-5-methyl-M-(n-pentyl)-1H-imidazol-4-carboxamid

2-(2-chlorophenyl)-N-cyclohexyl-1-(3-forfinal)-5-methyl-1H-imidazol-4-carboxamid

2-(2-chlorophenyl)-1-(3-forfinal)-N-(2-(4-forfinal)ethyl)-5-methyl-1H-imidazol-4-carboxamid

1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(4-morpholinyl)-1H-imidazol-4-carboxamid

N-(1-azepane)-1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-ethyl-1H-imidazol-4-carboxamid

1-(4-chloropyridin-2-yl)-N-cyclohexyl-2-(2,4-dichloro enyl)-5-ethyl-1H-imidazol-4-carboxamid

1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(n-pentyl)-1H-imidazol-4-carboxamid

1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-ethyl-N-(4-performer)-1H-imidazol-4-carboxamid

1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-N-(hexahydrotriazine[s]-2(1H)-yl)-5-methyl-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-phenyl-1H-imidazol-4-carboxamid

1-(4-chloropyridin-2-yl)-2-(2,4-dichlorophenyl)-5-methyl-N-(tetrahydro-2H-Piran-2-yloxy)-1H-imidazol-4-carboxamid

N-(Exo-bicyclo[2.2.1]hept-2-yl)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(2-foradil)-5-methyl-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(TRANS-4-hydroxy-cyclohexyl)-5-methyl-1H-imidazol-4-carboxamid

1-{[1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-yl]carbonyl}-4-hydroxypiperidine

1-{[1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-yl]carbonyl}-1,2,3,4-tetrahydroisoquinoline

N-(endo-bicyclo[2.2.1]hept-2-yl)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-N-(4-terbisil)-5-methyl-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(n-pentyl)-1H-imidazol-4-carboxamid

N-(azepin-1-yl)-1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazo the-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(pyrrolidin-1-yl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(morpholine-4-yl)-1H-imidazol-4-carboxamid

2-(2,5-dichlorophenyl)-5-methyl-1-phenyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

N-cyclohexyl-2-(2,5-dichlorophenyl)-5-methyl-1-phenyl-1H-imidazol-4-carboxamid

N-cyclohexyl-2-(2,4-dichlorophenyl)-1-(2,5-differenl)-5-ethyl-1H-imidazol-4-carboxamid

N-cyclohexyl-2-(2,4-dichlorophenyl)-1-(2,5-differenl)-5-methyl-1H-imidazol-4-carboxamid

N-cyclohexyl-2-(1,5-dimethyl-1H-pyrrol-2-yl)-5-ethyl-1-phenyl-1H-imidazol-4-carboxamid

N-cyclohexyl-2-(2,5-dichlorophenyl)-5-ethyl-1-phenyl-1H-imidazol-4-carboxamid

2-(2,5-dichlorophenyl)-5-ethyl-1-phenyl-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-5-methyl-2-(3-methylpyridin-2-yl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-N-cyclohexyl-5-methyl-2-(3-methylpyridin-2-yl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(3-(trifluoromethyl)phenyl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(3-(trifluoromethyl)benzyl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-methyl-N-(4-(trifluoromethyl)benzyl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-N-cyclopentyl-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-N-cyclopentyl-2-(2,4-dichlorophenyl)-5-methyl-1H-imidazol-4-carboxamid

1-(4-bromophenyl)-5-chloro-2-(2,4-dichlorophenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-5-cyano-2-(2,4-dichlorophenyl)-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-2-(2,4-dichlorophenyl)-5-iodine-N-(piperidine-1-yl)-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-N-cyclohexyl-2-(2,4-dichlorophenyl)-5-iodine-1H-imidazol-4-carboxamid

1-(4-chlorophenyl)-5-cyano-N-cyclohexyl-2-(2,4-dichlorophenyl)-1H-imidazol-4-carboxamid

3. The compound according to claim 1, which represents a 2-(2,4-dichlorophenyl)-N-(piperidine-1-yl)-1-(4-trifluoromethyl)phenyl)-1H-imidazol-4-carboxamid formula

and its salts.

4. Pharmaceutical composition having CB1-agonistic, partial CB1-agonistic or CB1-antagonistic activity, containing a pharmacologically active amount of at least one compound according to claim 1 as an active ingredient.

5. A method of obtaining a pharmaceutical composition according to claim 4, characterized in that the compound according to claim 1 translated into a form acceptable for injection.

6. The method of obtaining the compounds of formula (I), characterized in that the connection where the substituents R, R1-R3have the meanings given in claim 1, and the substituent R4 represents a hydrogen atom or halogen atom or a cyano, carbarnoyl, formyl, acetyl, TRIFLUOROACETYL, propionyl, sulfamoyl, methanesulfonyl, methylsulfanyl or1-4is an alkyl group, and With this1-4is an alkyl group may be substituted by 1-3 fluorine atoms, by reaction of the compound having the formula (II), (III) or (IV) with the compound of the formula R2R3NH.

7. Method of preparing compounds having the formula (II)

where substituent R4represents a C1-4is an alkyl group, and this C1-4is an alkyl group may be substituted by 1-3 fluorine atoms, or where R4represents a halogen atom or a cyano, formyl, acetyl, trifluoracetyl, porazitelnuyu, methylsulfanyl or propionyloxy group, wherein the substituents R and R1have the meanings defined in claim 1, and the substituent R7represents a branched or unbranched alkyl group (C1-4or benzyl group, the reaction of the compound having the formula (II), where the substituent R4represents a hydrogen atom, with a compound having the formula R4'-X, where X is a leaving group, and the substituent R4' represents a C1-4is an alkyl group, and With this1-4is an alkyl group may be substituted by 1-3 ATO the AMI fluorine, or where the substituent R4' represents a halogen atom or a cyano, formyl, acetyl, trifluoracetyl, porazitelnuyu, methylsulfanyl or propionyloxy group, in the presence of strong nucleophilic bases.

8. The method of obtaining compounds having the formula (II)

where substituent R4is a branched or non-branched C1-4is an alkyl group, and With this1-4is an alkyl group may be substituted by 1-3 fluorine atoms, characterized in that the compound, where R, R1have the meanings given in claim 1, and the substituent R7represents a branched or unbranched alkyl group (C1-4or benzyl group, the reaction of the compound having the formula (V)or its tautomer

where the substituents R and R1have the meanings given in claim 1, with a compound having the formula (VI)

where substituent R4is a branched or non-branched C1-4is an alkyl group, and With this1-4is an alkyl group may be substituted by 1-3 fluorine atoms, and the substituent R8represents a leaving group, and the substituent R7represents a branched or nerazvit the military alkyl (C 1-4or benzyl group.

9. The compounds of formula (IX)

where the substituents R and R4have the meanings given in claim 1, and where the substituent R1represents phenyl or pyridinyl group, and these groups substituted by 1-4 substituents Y, which can be the same or different and have the meanings given in claim 1, or a substituent R1represents pyrimidinyl, personilnya, pyridazinyl or triazinyl group, and these groups may be substituted by 1-2 substituents Y, which can be the same or different and have the meanings given in claim 1, or a substituent R1represents a five-membered aromatic heterocyclic residue containing one or two heteroatoms from the group N, O, S), and these heteroatoms may be the same or different, and five-membered aromatic heterocyclic residue may be substituted by 1-2 substituents and Y have the meanings given in claim 1, which may be the same or different, or the substituent R1represents naphthyl, and the substituent R9represents a hydroxyl group, a branched or unbranched alkoxy-(C1-4)-group, benzyloxy or a chlorine atom.

10. The compounds of formula (X)

where the Deputy R a 4-chloraniline group, 4-bromperidol group or 4-(trifluoromethyl)phenyl group.

11. The use of compounds according to claim 1 to obtain a pharmaceutical composition for treating diseases such as psychosis, anxiety, depression, attention deficit disorder, memory disorders, disorders of cognitive abilities, impaired appetite, obesity, addiction, appetence, drug dependence, neurodegenerative diseases, dementia, dystonia, muscle spasticity, tremor, epilepsy, multiple sclerosis, traumatic brain injury, stroke, Parkinson's disease, Alzheimer's disease, Huntington's disease, Tourette syndrome, cerebral ischaemia, cerebral apoplexy, craniocerebral trauma, spinal cord injury, neirolepticalkie diseases, thrombosis, viral encephalitis, disorders associated with demyelination, septic shock, glaucoma, cancer, diabetes, emesis, nausea, asthma, respiratory diseases, gastrointestinal disorders, stomach ulcers, diarrhoea and cardiovascular diseases.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 4-phenyltetrahydroisoquinoline of the general formula (I): wherein R1, R2, R3 and R4 mean independently of one another hydrogen (H), fluorine (F), chloride (Cl), bromine (Br) atoms, CaH2a+1 wherein one or more atoms H are substituted with F, -NR11R12 or -SOj-R15 wherein a = 1-8; R11 and R12 mean independently of one another H, CeH2e+1 or CrrH2rr-1 wherein e = 1-4; rr = 3, 4, or in common with nitrogen atom to which they are bound form a cycle chosen from group consisting of pyrrolidinyl, piperidinyl, N-methylpiperazinyl, piperazinyl or morpholine; j = 1 or 2; R15 means CkH2k+1 wherein k = 1-8; R5 means CpH2p+1 or CssH2ss-1; p = 1-8; ss = 3-8; R6 means H; R7, R8 and R9 mean independently of one another mean -SOwR23, -NR32COR30, NR32CSR30, -NR32SObbR30, H, F, Cl, Br, -OH, -NH2, CeeH2ee+1, -NR40R41, -CONR40R41 or -COOR42 wherein w = 0, 1 or 2; bb = 2 or 3; R23 means NR25R26 wherein R25 and R26 mean independently of one another H or CzH2z+1, CzzH2zz-1 wherein z = 1-8; zz = 3-8 wherein in CzH2z+1 and CzzH2zz-1 one or more H atoms are substituted with fluorine atom and one or more CH2-groups are substituted with -C(=O) or NR27 wherein R27 means H or CaaH2aa+1 wherein aa = 1-4; or R25 and R26 in common with nitrogen atom to which they are bound form 5-, 6- or 7-membered cycle; R30 means H, CccH2cc+1, CyyH2yy-1, pyrrolydinyl, piperidinyl wherein in their cycles CH2-group can be substituted with oxygen atom (O) or -NR33; R32 and R33 mean independently of one another H or ChH2h+1 wherein cc = 1-8; yy = 3-8; h = 1-8 wherein in the group ChH2h+1 one or more hydrogen atoms are substituted with fluorine atom, and in the groups CccH2cc+1 and CyyH2yy-1 one or more hydrogen atoms can be substituted with fluorine atom, and CH2-group can be substituted with O or -NR31 wherein NR31 means H, methyl, ethyl, acetyl or -SO2CH3; or R30 means 6-membered heteroaryl with 1-4 nitrogen atoms, 0 or 1, S-atoms or 0, or 1 O-atom that represents unsubstituted or substituted with up to three substitutes chosen from group consisting of F, Cl, Br, J, CooH2oo+1 wherein one or more hydrogen atoms can be substituted with fluorine atom, -NO2 or -NR70R71 wherein oo = 1-8; R70 and R71 mean independently of one another H, CuuH2uu+1 or -COR72 wherein uu = 1-8; R72 means H, CvvH2vv+1 wherein vv = 1-8; ee = 1-8; R40 and R41 mean independently of one another H, CttH2tt+1 or -C(NH)NH2 wherein tt = 1-8 and wherein in the group CttH2tt+1 one or more CH2-groups can be substituted with NR44 wherein R44 means CggH2gg+1 wherein gg = 1-8; R42 means H or ChhH2hh+1 wherein hh = 1-8 being, however, two substitutes from group R7, R8 and R9 can't mean -OH simultaneously, and at least one residue from R7, R8 and R9 must be chosen from group consisting of -CONR40R41, -OvSOwR23, -NR32COR30, -NR32CSR30 and -NR32SObbR30. Also, invention relates to using above given compounds for preparing a medicinal agent. Also, invention considers a medicinal agent representing inhibitor of sodium-proton exchange of subtype III (NHE3) based on proposed compounds. Invention provides synthesis of novel compounds, a medicinal agent based on thereof for aims of treatment of such diseases as nervous system ischemia, insult and brain edema, in treatment of snore, shock, impaired respiratory impulse, as purgative agents, as agents against extoparasites, for prophylaxis of gall stones formation, as anti-atherosclerotic agents, agents against diabetes mellitus later complications, cancer diseases, fibrous diseases, endothelial dysfunction, hypertrophies and hyperplasia of organs and others.

EFFECT: valuable medicinal properties of compounds and medicinal agents.

21 cl, 15 tbl, 221 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of quinoline of the formula (I): wherein R1 and R2 are chosen independently from hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, alkylcarbonyl, cycloalkylcarbonyl, phenyl, unsubstituted benzyl or benzyl substituted with halogen atom, cyano-group, trifluoromethyl, alkyl, alkoxy-group, benzylcarbonyl, pyridinyl, furyl, thiophenyl, indanyl, phenyl-SO2-, pyridinyl-SO2-, thiophenyl-SO2; or R1 and R2 in common with atom N to which they are added form piperidino-group, pyrrolidinyl, morpholinyl, azepanyl, 3,4-dihydro-1H-isoquinolinyl, and wherein heterocyclic ring is optionally substituted with one or some substitutes chosen independently from alkyl and alkoxy-group; R3 represents hydrogen atom, alkyl; R4 represents hydrogen atom; A in common with nitrogen atom that is added to quinoline ring represents pyrrolidinyl, azepanyl, and ring A is optionally substituted with one-three substitutes chosen independently from alkoxy-group, hydroxyalkyl, alkoxyalkyl. Also, invention describes methods of synthesis of quinoline derivatives of the formula (I). Proposed compounds can be used as components of pharmaceutical formulations in treatment or prophylaxis of arthritis, cardiovascular diseases, diabetes mellitus, renal insufficiency, disorders in food eating and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 122 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of quinazoline of the general formula (I): , wherein R1 represents -O-R4 or -N(R5)(R6); R2 represents alkyl; R3 represents hydrogen atom; R4 represents hydrogen atom, alkyl, alkoxyalkyl, hydroxyalkyl, aralkyl, pyridinylalkyl substituted with cyano-group or halogen atom, cycloalkylalkyl; R5 and R6 are chosen independently from hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, arylcarbonyl, alkoxyalkyl, hydroxyalkyl, pyridinyl, furanylcarbonyl, or R5 and R6 in common with nitrogen atom (N) to which they are added form a 5-10-membered heterocyclic ring that comprises optionally the second heteroatom chosen from nitrogen or oxygen atoms and wherein heterocyclic ring is substituted optionally with one or some substitutes chosen independently from alkyl or alkoxy-group; A represents 5-7-membered heterocyclic ring comprising nitrogen atom added to quinazoline ring, and optionally the second heteroatom that is chosen from oxygen, sulfur or nitrogen atoms and wherein ring A is substituted optionally with one or some substitutes chosen independently from alkoxy-, hydroxy-group, hydroxyalkyl, alkoxyalkyl, and their pharmaceutically acceptable salts and esters. Also, invention relates to a method for synthesis of compounds of the formula (I) and to pharmaceutical composition possessing antagonistic activity with respect to neuropeptide Y. Invention provides synthesis of novel biologically active compounds and pharmaceutical compositions based on thereof possessing antagonistic activity with respect to neuropeptide Y.

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

17 cl, 34 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for improved synthesis of pharmacologically active compound of the formula (A): Method involves the following steps: (a) interaction of compound of the formula (I): with alkaline metal nitrite in the presence of suitable acid to yield compound of the formula (VII): (b) coupling compound of the formula (VII) with compound of the formula (VI): to yield compound of the formula (V): and (c) removal of protection from compound of the formula (V) to yield compound of the formula (A). Compound of the formula (A) possesses property of antagonist of R2T receptors, high metabolic stability and bioavailability. Also, invention relates to a novel intermediate substance of the formula (I) and methods for its synthesis, and to novel intermediate substances used in its synthesis.

EFFECT: improved method of synthesis, valuable medicinal properties of compounds.

12 cl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

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

18 cl, 138 tbl, 527 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (U): or its pharmaceutically acceptable salt wherein X is chosen from -NR1, sulfur atom (S); Y1 and Y2 represent oxygen atom (O); Z represents O; m = 0 or 1; A is chosen from a direct bond, (C1-C6)-alkyl; R1 is chosen from hydrogen atom (H), alkyl; R3 and R6 are chosen independently from H, alkyl, halogenalkyl, heteroalkyl, cycloalkyl, aryl, cycloalkyl-alkyl, cycloalkyl-heteroalkyl, heterocycloalkyl-alkyl, alkylaryl, heteroaryl, arylalkyl, aryl-heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl or heterocycloalkyl; R4 is chosen from H, alkyl; R5 represents a bicyclic or tricyclic group comprising two or three ring structure wherein each of that comprises from 3 to 7 ring atoms chosen independently from cycloalkyl, aryl, heterocycloalkyl or heteroaryl wherein each ring structure is joined with the next ring structure through a direct bond, through -O-, through -S-, through (C1-C6)-alkyl, through (C1-C6)-heteroalkyl, through (C1-C6)-alkynyl, through carboxy-(C1-C6)-alkyl, or it is condensed with the next ring structure wherein heteroalkyl represents heteroatom-substituted alkyl comprising one heteroatom chosen from N, O and S. Also, invention describes compounds of formulae (Ib), (Ic) and (Id) given in the invention description, pharmaceutical composition and using these compounds in preparing a medicine for using in treatment of disease or state mediated by one or more enzymes representing metalloproteinase. Represented compounds are useful as inhibitors of metalloproteinases and especially as inhibitors of MMP12.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

17 cl, 3 tbl, 17 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I): wherein X represents -NR1; Y1 and Y2 represent oxygen atom (O); Z is chosen from -SO2N(R6), -N(R7)SO2; m = 1 or 2; A is chosen from a direct bond, (C1-C6)-alkyl; R1 represents hydrogen atom (H); each R2 and R3 is chosen independently from H, alkyl, aryl, alkylaryl, arylalkyl; each R4 is chosen independently from H, (C1-C3)-alkyl; R6 is chosen from H, alkyl, aryl, heteroaryl, alkylaryl, alkyl-heteroaryl, arylalkyl, heteroaryl-alkyl; R2 and R6 can join to form a ring comprising up to 7 ring atoms, or R3 and R6 can join to form a ring comprising up to 7 ring atoms, or R4 and R6 can join to form a ring comprising up to 7 ring atoms; R5 represents monocyclic, bicyclic or tricyclic group comprising one or two ring structures wherein each of that comprises up to 7 ring atoms chosen independently from cycloalkyl, aryl, heterocycloalkyl or heteroaryl and possibly substituted; when R5 represents bicyclic group then each ring structure is bound with the next ring structure through a direct bond, through -O-, through (C1-C6)-alkyl or condensed with this next ring structure; R7 is chosen from (C1-C6)-alkyl. Also, invention describes compound of the formula (II) given in the description, pharmaceutical compositions and using compound of the formula (I) or the formula (II) in preparing a medicine for using in treatment of disease or state mediated by one or more enzymes and representing metalloproteinase. Represented compounds are useful as inhibitors of metalloproteinases and especially as inhibitors of MMP12.

EFFECT: valuable medicinal and biochemical properties of inhibitors and pharmaceutical compositions.

20 cl, 3 tbl, 6 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel anthranilic acid amides with a by-side heteroarylsulfonyl chain. Invention describes compounds of the formula (I): wherein R1 means compounds of formulae: or wherein A means -CnH2n- wherein n = 0, 1, 2, 3, 4 or 5; D means a bond or -O-; E means -CmH2m- wherein m = 0, 1, 2, 3, 4 or 5; R8 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon atoms or -CpH2p-R14 wherein p = 1, 2, 3, 4 or 5; R14 means phenyl or heteroaryl wherein phenyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting fluorine (F), chlorine (Cl), bromine (Br) and iodine (J) atom, alkyl with 1, 2, 3 or 4 carbon atoms; R9 means hydrogen atom or alkyl with 1, 2, 3, 4, 5 or 6 carbon atoms; R10 means hydrogen atom, alkyl with 1, 2, 3 or 4 carbon toms, phenyl, naphthyl or heteroaryl wherein phenyl, naphthyl and heteroaryl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R11 means cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl, furyl, pyridyl, pyrazinyl wherein phenyl, furyl, pyridyl, pyrazinyl are unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms; R12 means alkyl with 1, 2, 3 or 4 carbon atoms, alkynyl with 1, 2, 3 or 4 carbon atoms, cycloalkyl with 3, 4, 5 or 6 carbon atoms, phenyl or heteroaryl; R13 means -CpH2p-R14 wherein p = 0, 1, 2, 3, 4 or 5; R15 means cycloalkyl with 3, 4, 5, 6, 7 or 8 carbon atoms; R2 means hydrogen atom; R3 means heteroaryl wherein heteroaryl is unsubstituted or substituted with 1, 2 or 3 substitutes chosen from group consisting of F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms; R4, R5, R6 and R7 mean independently of one another hydrogen atom, F, Cl, Br, J, alkyl with 1, 2, 3 or 4 carbon atoms, alkoxy-group with 1, 2, 3 or 4 carbon atoms, and their pharmaceutically acceptable salts also. Also, invention describes pharmaceutical composition containing compounds of the formula (I) possessing the effect blocking Kv1.5-channel. Proposed compounds can be used in treatment and prophylaxis of diseases mediated by K+-channel.

EFFECT: valuable medicinal property of compounds and pharmaceutical composition.

20 cl, 4 tbl, 70 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention describes a method for synthesis of novel R-methyl-derivatives of 3,5-diamino-1,2,4-triazole of the general formula (I):

wherein R means benzene ring possibly substituted with one or some substitutes, such as branched or linear (C1-C4)-alkyl, -O-(C1-C4)-alkyl, -N-[(C1-C4)-alkyl]2, halogen atom, nitro-group; or R means naphthalene or heterocycle of the order: thiophene, furan substituted possibly with methyl group. Method is carried out by successive interaction of 1-acetyl-3,5-diamino-1,2,4-triazole (II) with sodium hydroxide, acetic acid and aldehyde of the formula: R-C(=O)H (III) and sodium boron hydride in the mole ratio of reagents (II) : sodium hydroxide : (III) : sodium boron hydride = 1:(1.0-1.2):(0.9-1.0):(1.2-2.0), respectively. Method provides decreasing the cost of compounds of the formula (I) and enhancing safety of process in their synthesis. Synthesized compounds can be used in manufacture of medicaments and biologically active substances.

EFFECT: improved method of synthesis, valuable properties of compounds.

2 cl, 13 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to group of novel derivatives of 4,5-dihydro-1H-pyrazole and their stereoisomers that are strong antagonists of cannabinoid (CB1) receptors. These compounds are useful in treatment of some diseases associated with cannabinoid system disorders. Compounds have the general formula (I) wherein R represents phenyl or thienyl substituted with halogen atom, or R represents pyridyl; R1 represents phenyl that can be substituted with 1-2 substitutes chosen from halogen atom and trifluoromethyl group; R2 represents hydrogen atom; R3 represents hydrogen atom or branched or direct (C1-C4)-alkyl group; R4 represents branched or direct (C2-C4)-alkyl group that is substituted with hydroxy-, amino-, monoalkylamino-, dialkylamino-, methoxy-, acetoxy-, aminooxy-group or one fluorine atom, or R4 represents branched or direct (C1-C8)-alkoxy-group that can be substituted with amino-group, monoalkylamino-group or dialkylamino-group, or R4 represents (C4-C8)-nonaromatic heterocyclic or (C4-C8)-nonaromatic heterocycloalkyl-alkyl group that comprise 1-2 heteroatoms chosen from nitrogen (N) and oxygen (O) atom that can be substituted with (C1-C3)-alkyl group, or R4 represents hydroxy-group or imidazolylalkyl group or pyridylmethyl group; or if R represents hydrogen atom or methyl then R4 can represent group -NR6R7 wherein R6 represents hydrogen atom and R7 represents (C2-C4)-trifluoroalkyl; or R3 and R4 in common with nitrogen atom to which they are bound form saturated or unsaturated monocyclic or bicyclic heterocyclic group comprising 4-10 atoms in cycle that comprises 1-2 heteroatoms chosen from N and O, or group -SO2 wherein indicated group can be substituted with (C1-C4)-alkyl, hydroxy-group, hydroxyalkyl, pyridyl, amino-, monoalkylamino-, dialkylamino-group, monoalkylaminoalkyl, dialkylaminoalkyl or piperidyl group; R5 represents phenyl group substituted with 1-3 substitutes Y wherein Y represents halogen atom, trifluoromethyl group or (C1-C3)-alkyl, or R5 represents branched or direct (C1-C8)-alkyl. Also, invention relates to pharmaceutical compositions containing one or some these compounds as an active component.

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

5 cl, 4 tbl, 92 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel substituted derivatives of 4-phenyltetrahydroisoquinoline of the general formula (I): wherein R1, R2, R3 and R4 mean independently of one another hydrogen (H), fluorine (F), chloride (Cl), bromine (Br) atoms, CaH2a+1 wherein one or more atoms H are substituted with F, -NR11R12 or -SOj-R15 wherein a = 1-8; R11 and R12 mean independently of one another H, CeH2e+1 or CrrH2rr-1 wherein e = 1-4; rr = 3, 4, or in common with nitrogen atom to which they are bound form a cycle chosen from group consisting of pyrrolidinyl, piperidinyl, N-methylpiperazinyl, piperazinyl or morpholine; j = 1 or 2; R15 means CkH2k+1 wherein k = 1-8; R5 means CpH2p+1 or CssH2ss-1; p = 1-8; ss = 3-8; R6 means H; R7, R8 and R9 mean independently of one another mean -SOwR23, -NR32COR30, NR32CSR30, -NR32SObbR30, H, F, Cl, Br, -OH, -NH2, CeeH2ee+1, -NR40R41, -CONR40R41 or -COOR42 wherein w = 0, 1 or 2; bb = 2 or 3; R23 means NR25R26 wherein R25 and R26 mean independently of one another H or CzH2z+1, CzzH2zz-1 wherein z = 1-8; zz = 3-8 wherein in CzH2z+1 and CzzH2zz-1 one or more H atoms are substituted with fluorine atom and one or more CH2-groups are substituted with -C(=O) or NR27 wherein R27 means H or CaaH2aa+1 wherein aa = 1-4; or R25 and R26 in common with nitrogen atom to which they are bound form 5-, 6- or 7-membered cycle; R30 means H, CccH2cc+1, CyyH2yy-1, pyrrolydinyl, piperidinyl wherein in their cycles CH2-group can be substituted with oxygen atom (O) or -NR33; R32 and R33 mean independently of one another H or ChH2h+1 wherein cc = 1-8; yy = 3-8; h = 1-8 wherein in the group ChH2h+1 one or more hydrogen atoms are substituted with fluorine atom, and in the groups CccH2cc+1 and CyyH2yy-1 one or more hydrogen atoms can be substituted with fluorine atom, and CH2-group can be substituted with O or -NR31 wherein NR31 means H, methyl, ethyl, acetyl or -SO2CH3; or R30 means 6-membered heteroaryl with 1-4 nitrogen atoms, 0 or 1, S-atoms or 0, or 1 O-atom that represents unsubstituted or substituted with up to three substitutes chosen from group consisting of F, Cl, Br, J, CooH2oo+1 wherein one or more hydrogen atoms can be substituted with fluorine atom, -NO2 or -NR70R71 wherein oo = 1-8; R70 and R71 mean independently of one another H, CuuH2uu+1 or -COR72 wherein uu = 1-8; R72 means H, CvvH2vv+1 wherein vv = 1-8; ee = 1-8; R40 and R41 mean independently of one another H, CttH2tt+1 or -C(NH)NH2 wherein tt = 1-8 and wherein in the group CttH2tt+1 one or more CH2-groups can be substituted with NR44 wherein R44 means CggH2gg+1 wherein gg = 1-8; R42 means H or ChhH2hh+1 wherein hh = 1-8 being, however, two substitutes from group R7, R8 and R9 can't mean -OH simultaneously, and at least one residue from R7, R8 and R9 must be chosen from group consisting of -CONR40R41, -OvSOwR23, -NR32COR30, -NR32CSR30 and -NR32SObbR30. Also, invention relates to using above given compounds for preparing a medicinal agent. Also, invention considers a medicinal agent representing inhibitor of sodium-proton exchange of subtype III (NHE3) based on proposed compounds. Invention provides synthesis of novel compounds, a medicinal agent based on thereof for aims of treatment of such diseases as nervous system ischemia, insult and brain edema, in treatment of snore, shock, impaired respiratory impulse, as purgative agents, as agents against extoparasites, for prophylaxis of gall stones formation, as anti-atherosclerotic agents, agents against diabetes mellitus later complications, cancer diseases, fibrous diseases, endothelial dysfunction, hypertrophies and hyperplasia of organs and others.

EFFECT: valuable medicinal properties of compounds and medicinal agents.

21 cl, 15 tbl, 221 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of quinoline of the formula (I): wherein R1 and R2 are chosen independently from hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, alkylcarbonyl, cycloalkylcarbonyl, phenyl, unsubstituted benzyl or benzyl substituted with halogen atom, cyano-group, trifluoromethyl, alkyl, alkoxy-group, benzylcarbonyl, pyridinyl, furyl, thiophenyl, indanyl, phenyl-SO2-, pyridinyl-SO2-, thiophenyl-SO2; or R1 and R2 in common with atom N to which they are added form piperidino-group, pyrrolidinyl, morpholinyl, azepanyl, 3,4-dihydro-1H-isoquinolinyl, and wherein heterocyclic ring is optionally substituted with one or some substitutes chosen independently from alkyl and alkoxy-group; R3 represents hydrogen atom, alkyl; R4 represents hydrogen atom; A in common with nitrogen atom that is added to quinoline ring represents pyrrolidinyl, azepanyl, and ring A is optionally substituted with one-three substitutes chosen independently from alkoxy-group, hydroxyalkyl, alkoxyalkyl. Also, invention describes methods of synthesis of quinoline derivatives of the formula (I). Proposed compounds can be used as components of pharmaceutical formulations in treatment or prophylaxis of arthritis, cardiovascular diseases, diabetes mellitus, renal insufficiency, disorders in food eating and obesity.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

20 cl, 122 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to novel derivatives of 3-oxo-1-cyclobutene of the general formula (I): and their salts, solvates, hydrates and N-oxides wherein R1 represents group of the formula: Ar1L2Ar2Alk wherein Ar1 represents aromatic or heteroaromatic group; L2 represents a covalent bond or -O-, -NH- or -CONH-; Ar2 represents arylene or heteroarylene group; Alk represents chain -CH2CH(R) or -CH(CH2R)- wherein R represents -CO2H or -COOAlk7 wherein Alk7 represents (C1-C8)-alkyl, (C3-C8)-cycloalkyl, (C3-C8)-heterocycloalkyl group and others; X represents group -N(R2)- wherein R2 represents hydrogen atom or (C1-C6)-alkyl group; V represents oxygen atom; Rx, Ry and Rz represent atom or group -L1(Alk1)n(R3)v wherein L1 represents covalent bond or -O-, -S-, -Se-, -S(O)-, -NH- or -N(CH3)-; Alk1 represents aliphatic group; R3 represents hydrogen, halogen atom, group -OR3a, -SR3a and others wherein R3a represents hydrogen atom, (C1-C6)-alkyl and others; n = 0 or 1; v = 1, 2 or 3 under condition that if n = 0 and L1 represents covalent bond then v = 1; or Rz represents atom or group given above, and Rx and Ry taken together form spiro-bound cycloaliphatic or heterocycloaliphatic group. Compounds of the formula (I) possess inhibitory activity with respect to α4-integrin and can be used in medicine.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

26 cl, 216 ex

FIELD: organic chemistry, chemical technology, pharmacy.

SUBSTANCE: invention relates to novel derivatives of urea of the general formula (I): and their pharmaceutically acceptable salts wherein A represents -CH- or nitrogen atom; R1 represents (C3-C10)-alkyl, (C3-C10)-cycloalkyl, (C3-C10)-cycloalkyl-(C1-C10)-alkyl, 6-membered nitrogen-containing heterocycle, 6-membered nitrogen-containing heterocyclyl-(C1-C10)-alkyl, phenyl, phenyl-(C1-C10)-alkyl, 5-10-membered heteroaryl or 5-10-membered heteroaryl-(C1-C10)-alkyl, and others; R2 represents hydrogen atom, (C1-C6)-alkyl, (C0-C2)-alkyl-(C3-C10)-cycloalkyl, (C0-C2)-alkylphenyl, (C3-C10)-cycloalkyl-(C0-C2)-alkyl or phenyl-(C0-C2)-alkyl; R5 represents (C1-C6)-alkyl, (C3-C10)-cycloalkyl, 6-membered nitrogen-containing heterocyclyl, and others; L1 represents -S-, -S(O)-, -S(O2)-, -C(O)-, -N(Rc)-, -CH2-, and others; L2 represents a covalent bond, -O-, -C(O)-, -OC(O)-, -N(Rc)-, and others; W represents oxygen (O) or sulfur (S) atom; Z represents -C(O)ORd wherein Rc, Rd and Re represents hydrogen atom or alkyl; Rb represents -ORe, -NO2, halogen atom, -CN, -CF, (C1-C6)-alkyl; p represents a whole number from 0 to 4. Compounds of the formula (I) and their salts possess antagonistic activity with respect to α4-integrin and can be used in medicine for inhibition or prophylaxis of cellular adhesion in patient body mediated by α4β1- and/or α4β7-integrins.

EFFECT: improved methods of synthesis, valuable medicinal properties of compounds and pharmaceutical composition.

17 cl, 2 tbl, 180 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of piperidine of the general formula (I): or their pharmaceutically acceptable salts wherein rings A and B represent optionally substituted benzene rings; R1 represents alkyl, hydroxyl, thiol, carbonyl, sulfinyl, unsubstituted or substituted sulfonyl group and others; R2 represents hydrogen atom, hydroxyl, amino-group, alkyl, unsubstituted or substituted carbonyl group or halogen atom; Z represents oxygen atom or group -N(R3)- wherein R3 and R4 represent hydrogen atom or alkyl group under condition that N-acetyl-1-benzyloxycarbonyl-2-phenyl-4-piperidineamine is excluded. Compounds of the formula (I) or their salts possess antagonistic activity with respect to tachykinin NK1-receptors and can be used in medicine in treatment and prophylaxis of inflammatory, allergic diseases, pain, migraine, diseases of central nervous system, digestive organs and others.

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

18 cl, 138 tbl, 527 ex

FIELD: organic chemistry, medicine, cardiology.

SUBSTANCE: invention relates to (R)-2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylic acid 3-(1-diphenylmethylazethidin-3-yl) 5-isopropyldiester of the formula (I): or its pharmacologically acceptable salts. Indicated compounds possess antagonistic activity with respect to calcium channels and anti-hypertensive activity and can be used in medicine in treatment of diseases of cardiovascular system.

EFFECT: valuable medicinal properties of compound.

7 cl, 3 tbl, 5 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to novel derivatives of benzimidazole of the general formula (I): wherein A represents -CH2- or -C(O)-; Y represents -S- or -NH-; R1 and R2 represent independently hydrogen atom, (C1-C8)-alkyl, (C5-C9)-bicycloalkyl optionally substituted with one or some similar or different (C1-C6)-alkyl radicals, or radical of the formula -(CH2)n-X wherein X represents amino-group, (C3-C7)-cycloalkyl and other values of radicals also given in the invention claim; R3 represents -(CH2)p-W-(CH2)p'-Z3 wherein W3 represents a covalent bond, -CH(O)- or -C(O)-; Z3 represents (C1-C6)-alkyl, aryl radical, heteroaryl and other values of radical also; V3 represents -O-, -S-, -C(O)-, -C(O)-O-, -SO2- or a covalent bond; Y3 represents (C1-C6)-alkyl radical optionally substituted with one or some halogen-radicals, amino-group, di-((C1-C6)-alkyl)-amino-group, phenylcarbonylmethyl, heterocycloalkyl or aryl radicals; p, p' and p'' represent independently a whole number from 0 to 4; R4 represents radical of the formula: -(CH2)s-R''4 wherein R''4 represents heterocycle comprising at least one nitrogen atom and optionally substituted with (C1-C6)-alkyl or aralkyl, and other values of radicals given in the invention claim also. Also, invention relates to a pharmaceutical composition showing antagonistic property with respect to GnRH and based on these compounds. Also, using above proposed compounds for preparing a medicament is considered. Invention provides synthesis of novel compounds, preparing pharmaceutical composition and medicament based on thereof in aims for treatment of such diseases as endometriosis, fibroma, polycystic ovary, breast, ovary and endometrium cancer, gonadotropic hypophysis desensitization in medicinal stimulation of ovary in fertility treatment in females.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

18 cl, 2 tbl, 538 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (U): or its pharmaceutically acceptable salt wherein X is chosen from -NR1, sulfur atom (S); Y1 and Y2 represent oxygen atom (O); Z represents O; m = 0 or 1; A is chosen from a direct bond, (C1-C6)-alkyl; R1 is chosen from hydrogen atom (H), alkyl; R3 and R6 are chosen independently from H, alkyl, halogenalkyl, heteroalkyl, cycloalkyl, aryl, cycloalkyl-alkyl, cycloalkyl-heteroalkyl, heterocycloalkyl-alkyl, alkylaryl, heteroaryl, arylalkyl, aryl-heteroalkyl, heteroaryl-alkyl, heteroaryl-heteroalkyl or heterocycloalkyl; R4 is chosen from H, alkyl; R5 represents a bicyclic or tricyclic group comprising two or three ring structure wherein each of that comprises from 3 to 7 ring atoms chosen independently from cycloalkyl, aryl, heterocycloalkyl or heteroaryl wherein each ring structure is joined with the next ring structure through a direct bond, through -O-, through -S-, through (C1-C6)-alkyl, through (C1-C6)-heteroalkyl, through (C1-C6)-alkynyl, through carboxy-(C1-C6)-alkyl, or it is condensed with the next ring structure wherein heteroalkyl represents heteroatom-substituted alkyl comprising one heteroatom chosen from N, O and S. Also, invention describes compounds of formulae (Ib), (Ic) and (Id) given in the invention description, pharmaceutical composition and using these compounds in preparing a medicine for using in treatment of disease or state mediated by one or more enzymes representing metalloproteinase. Represented compounds are useful as inhibitors of metalloproteinases and especially as inhibitors of MMP12.

EFFECT: valuable medicinal and biochemical properties of compounds and pharmaceutical composition.

17 cl, 3 tbl, 17 ex

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I): wherein X represents -NR1; Y1 and Y2 represent oxygen atom (O); Z is chosen from -SO2N(R6), -N(R7)SO2; m = 1 or 2; A is chosen from a direct bond, (C1-C6)-alkyl; R1 represents hydrogen atom (H); each R2 and R3 is chosen independently from H, alkyl, aryl, alkylaryl, arylalkyl; each R4 is chosen independently from H, (C1-C3)-alkyl; R6 is chosen from H, alkyl, aryl, heteroaryl, alkylaryl, alkyl-heteroaryl, arylalkyl, heteroaryl-alkyl; R2 and R6 can join to form a ring comprising up to 7 ring atoms, or R3 and R6 can join to form a ring comprising up to 7 ring atoms, or R4 and R6 can join to form a ring comprising up to 7 ring atoms; R5 represents monocyclic, bicyclic or tricyclic group comprising one or two ring structures wherein each of that comprises up to 7 ring atoms chosen independently from cycloalkyl, aryl, heterocycloalkyl or heteroaryl and possibly substituted; when R5 represents bicyclic group then each ring structure is bound with the next ring structure through a direct bond, through -O-, through (C1-C6)-alkyl or condensed with this next ring structure; R7 is chosen from (C1-C6)-alkyl. Also, invention describes compound of the formula (II) given in the description, pharmaceutical compositions and using compound of the formula (I) or the formula (II) in preparing a medicine for using in treatment of disease or state mediated by one or more enzymes and representing metalloproteinase. Represented compounds are useful as inhibitors of metalloproteinases and especially as inhibitors of MMP12.

EFFECT: valuable medicinal and biochemical properties of inhibitors and pharmaceutical compositions.

20 cl, 3 tbl, 6 ex

The invention relates to an improved process for the preparation of 1-nitroso-4-methylpiperazine, which finds application in the chemistry of drugs as an intermediate product in the synthesis of 1-amino-4-methylpiperazine and 1-methylpiperazine used for modern drugs: rifampicin, azaleptinum, triftazin, pefloksatsina, tetrazine and other drugs
Up!