5-aryl-1h-1,2,4-triazole derivatives and pharmaceutical composition containing the same

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I

, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

 

The present invention relates to compounds 5-aryl-1H-1,2,4-triazole, to the way they are received and containing pharmaceutical compositions.

Nonsteroidal anti-inflammatory drugs (NSAIDs) often appear to act through inhibition of prostaglandin-H-synthase (PGHS), which mediates the conversion of arachidonic acid to prostaglandins. The first stage of this process is the oxidative cyclization of arachidonic acid to PGE2followed by peroxide recovery to PGH2according to the second specific binding site. PGHS, commonly known as cyclooxygenase or SOH, exist in two isoforms, each plays a distinct physiological role (Hia, T et al, Proc. Natl. Acad. Sci. USA. 1992, 89, 7384; Holtzman H.J. et al, J. Biol. Chem. 1992, 267, 21438; H.R. Herschman, Cancer Metastasis Rev. 1994, 13, 241). One of the isoforms, MOR-1, constitutively produced in various tissues and, apparently, important for maintaining normal physiological functions, including blood flow through the kidneys and cytotoxic stomach. The second isoform, SOH-2, is induced by various inflammatory stimuli and, apparently, largely responsible for the high level production of prostaglandins, which leads to inflammatory processes (Masferrer J.L. et al., Proc. Natl. Acad. Sci. USA. 1994, 91, 3228; Vane J. et al. Proc. Natl. Acad. Sci. USA. 1994, 91, 2046).

In applications WO 95/15318, WO 95/15316, p the tents USA US 5434178, US 5466823, US 5504215, US 5508426 and US 5510496 disclosed 1,5-diarylpyrazole, with activity in vitro and in vivo.

Some of 1,5-diphenyl-1H-1,2,4-triazole, such as the compound (a)having moderate SOH-2 inhibitory activity and anti-inflammatory potential, which do not exceed the properties of a known anti-inflammatory agents have been disclosed in Monatshefte fur Chemie 119, 349-353 (1998).

3-cyano-1,5-diphenyl-1H-1,2,4-triazole, such as the compound (b), reported in Chem. Pharm. Bull. 45(6), 987-995 (1997), are weak and nonselective inhibitors of cyclooxygenase-1 and cyclooxygenase-2.

Unexpectedly, it was found that some compounds 5-aryl-1H-1,2,4-triazole are particularly selective and potent inhibitors of cyclooxygenase-2.

Accordingly, one objective of the present invention to provide compounds 5-aryl-1H-1,2,4-triazole, which would be effective and selective inhibition ability SOH-2.

Connection 5-phenyl-1H-1,2,4-triazole of the present invention represented by the following General formula:

where R1is hydrogen; (C1-C6)alkyl; halo (C1-C6) alkyl; or phenyl, optionally substituted by one or more substituents selected from the group consisting of the C (C 1-C4)alkyl, halogen, halo(C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, mono - or di-(C1-C4)alkylamino, (C1-C4)alkylcarboxylic, (C1-C4)alkyldiethanolamine, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxycyanobiphenyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylsulfonyl, methylenedioxy, nitro and cyano;

R2is (C1-C4)alkyl, (C3-C8)cycloalkyl; phenyl or phenyl (C1-C4)alkyl, where phenyl optionally substituted by one or more substituents selected from the group consisting of (C1-C4)alkyl, halogen, halo(C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, mono - or di-(C1-C4)alkylamino, (C1-C4)alkylcarboxylic, (C1-C4)alkyldiethanolamine, (C1-C4)alkoxycarbonyl, (C1-C4)alkoxycyanobiphenyl, (C1-C4)alkylsulfonyl, (C1-C4)alkylsulfonyl, methylenedioxy, nitro and cyano; or a heteroaromatic radical;

R3represents hydrogen; halogen; hydroxy; (C1-C6)alkoxy; amino; mono - or di-(C1-C6)alkylamino; (C1-C6)alkylcarboxylic; (C1-C6)alkyldiethanolamine (C 1-C6)alkoxycarbonyl; (C1-C6)alkoxycyanobiphenyl; nitro or cyano;

R4is (C1-C6)alkyl; amino; mono - or di-(C1-C6)-alkylamino; (C1-C6)alkylcarboxylic; (C1-C6)alkyldiethanolamine; (C1-C6)alkoxycarbonyl; or (C1-C6)alkoxycyanobiphenyl; and its pharmaceutically acceptable salts.

The term "(C1-C4)alkyl or(C1-C6)alkyl" means linear or branched hydrocarbon chain containing from 1 to 4 (or 6) carbon atoms, such as, for example, methyl, ethyl, sawn, ISO-propyl, boutigny, isobutylene, tert-boutigny, pentelenyi, isopentenyl or sexily radical.

The term "(C1-C4)alkoxy or(C1-C6)alkoxy" means the group OR in which R represents a C1-C4)alkyl or (C1-C6)alkyl as indicated above.

The term "halo (C1-C4) or (C1-C6)alkyl" means a (C1-C4) or (C1-C6)alkyl radical in which 1 to 7 hydrogen atoms substituted by 1 to 7 halogen atoms, such as, for example, triptorelin, 2,2,2-triptoreline, panafcortelone, CHLOROTHALONIL or brometalia radical.

The term "halogen" means chlorine atom, bromine, iodine or fluorine

The term "(C3-C8)cycloalkyl" means a saturated monocyclic hydrocarbon containing from 3 to 8 carbon atoms, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo, cycloheptenyl or cyclooctyl radical.

The term "heteroaromatic radical" means a 5-or 6-membered monocyclic or 9-or 10-membered bicyclic aromatic heterocycle containing one or two heteroatoms selected from N, S and O, such as, for example, pyridinoline, pyridazinyl, personilnya, pyrimidinyl, personilnya, finalininkiu, izohinolinove, benzimidazolinyl, benzoxazolyl, indaily or indaily radical.

Preferred compounds of formula (I) are compounds in which:

- R1represents hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl or phenyl;

- R2is (C3-C8)cycloalkyl; phenyl, optionally substituted by one or more substituents selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy, nitro, di(C1-C4)alkylamino, (C1-C4)alkylsulfonyl, (C1-C4)alkylsulfonyl, methylendioxy; phenyl(C1-C4)-alkyl, where phenyl is substituted by one or more substituents you the security of a group, consisting of hydroxy, (C1-C4)alkyl and (C1-C4)alkoxy; or a 5 - or 6-membered monocyclic aromatic heterocycle containing one or two atoms of nitrogen, sulfur and/or oxygen;

- R3represents hydrogen or halogen;

- R4is (C1-C6)alkyl, (C1-C4)alkylcarboxylic or amino. Especially preferred compounds of formula (I)in which R1is (C1-C4)alkyl or halo (C1-C4)alkyl, such as trifluoromethyl.

Moreover, especially preferred compounds of formula (I)in which R2represents phenyl, optionally substituted by one or more substituents selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy, nitro, di(C1-C4)alkylamino, (C1-C4)alkylsulfonyl, (C1-C4)alkylsulfonyl, methylendioxy.

Especially preferred are also the compounds of formula (I)in which R3is hydrogen, and those in which R4is (C1-C6)alkyl or amino.

Especially valuable are the following connections:

-1-(4-methoxyphenyl)-3-methyl-5-(4-methylsulfinylphenyl)-1H-1,2,4-triazole;

-1-(4-methoxyphenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole;

-1-(4-bromophenyl)-5-(4-methyl shall wltnylfj)-3-trifluoromethyl-1H-1,2,4-triazole;

-1-(4-methylsulfonylamino)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole;

-1-(4-methoxyphenyl)-5-(4-aminosulphonylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole.

Pharmaceutically acceptable salts of compounds of formula (I) are non-toxic salts, including (i) a salt formed by the compounds of formula (I)containing acidic groups, for example, alkali metal salts or salts of alkaline earth metals such as sodium, potassium salts, magnesium salts and calcium salts, and also salts of pharmaceutically acceptable Quaternary ammonium ions or organic amines, such as triethylamine or Tris(2-hydroxyethyl)amine and the like, and (ii) a salt formed by the compounds of formula (I)containing a basic group, for example, salts of inorganic acids, such as hydrochloric acid, Hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid, phosphoric acid, etc. or salts of organic carboxylic acids, such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonate acid, etc.

Soedineniya formula (I) can be used for pain relief, treatment of colds and inflammations in various from the tijaniyah, including rheumatic fever, symptoms associated with influenza or other viral infections, colds, pain in the back and neck, dysmenorrhea, headache, toothache, sprain and strain, myositis, neuralgia, synovitis, arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylose the spondylitis, tendency, bursitis, burns, injuries and wounds, especially following surgical and dental procedures. In addition, such compounds may inhibit cellular neoplastic transformations and growth of tumor metastases, and therefore they can be used for the treatment of hereditary polyps and cancer (cancer of the colon, lung, esophagus and stomach). The compounds of formula (I) can also be used for the treatment of dementia, including Predtechensky and senile dementia, especially dementia associated with Alzheimer's disease (dementia of Alzheimer's). The compounds of formula (I) also inhibit the contraction of smooth muscles induced prostanoids, by preventing synthesis contractile of prostanoids and hence they can be used for the treatment of dysmenorrhea, premature birth, and asthma.

Due to the high inhibitory activity against cyclooxygenase-2 (SOH-2) and/or high selectivity of inhibition of the cycle is oxygenase-2 compared with inhibition of cyclooxygenase-1, the compounds of formula (I) are useful as an alternative to conventional non-steroidal anti-inflammatory drugs (NSAIDs), especially in those cases where such non-steroidal antiinflammatory drugs may be contra-indicated such as in cases where patients present a peptic ulcer, gastritis, regional enteritis, ulcerative colitis, diverticulitis, or in patients with recurrent lesions of the gastrointestinal tract; bleeding of the gastrointestinal tract; coagulation disorders including anemia such as hypoprothrombinemia, hemophilia, or other problems with bleeding (including those associated weakened or impaired platelet function); kidney disease (e.g., impaired renal function); those patients undergoing surgery or those who are taking anticoagulants; and those who are predisposed to asthma caused by NSAID.

Accordingly, another aim of the present invention related to the use of compounds of formula (I) or their pharmaceutically acceptable salts to obtain drugs that can be used for the treatment of diseases mediated by cyclooxygenase, particularly those diseases that are treatable using NSAIDs, and which is convenient to treat the agent that selectively inhibits SOH-2 compared to MOR-1.

This is General the invention relates also to a method of treatment of the above diseases, mediated by cyclooxygenase, including the introduction in need of such treatment to the subject a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt.

To treat any of the diseases mediated by cyclooxygenase, the compounds of formula (I) can be entered, for example, orally, locally, parenterally, by inhalation spray, or rectally in a standard dosage forms, containing a non-toxic pharmaceutically acceptable carriers, adjuvants and delivery vehicles. Such dosage forms are given only as examples, but the specialists-pharmacists can develop other pharmaceutical forms for administration of the compounds of formula (I). The term “parenteral” in the sense as it is used herein, includes subcutaneous injections, intravenous, intramuscular injection, injection into the brain stem or infusion. In addition to treating people the compounds of formula (I) can be used for the treatment of warm-blooded animals, such as mice, rats, horses, sheep, dogs, cats, etc.

So the next target of the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt as an active ingredient.

Pharmaceutical compositions comprising the act is wny ingredient, can be in a form suitable for oral administration, for example, in the form of tablets, pellets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft gelatin capsules, syrups or elixirs. Compositions intended for oral use can be obtained by any known in the art methods, pharmaceutical compositions, and such compositions may include one or more agents selected from the group consisting of sweetening agents, corrigentov, dyes and preservatives to make preparations elegant, with a pharmaceutical point of view, kind and pleasant taste. The tablets include the active ingredient in a mixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and loosening agents, for example corn starch or alginic acid; binding agents, for example starch, gelatin or the Arabian gum, and lubricating agents, e.g. magnesium stearate, stearic acid or talc. Tablets can be without the shell, or are known methods can be applied on the shell, to delay disintegration and absorption in the gastrointestinal tract and thereby provide a prolonged action over a long period of time. For example, you could use this extending the duration of the material, such as glycerol monostearate or distearate glycerin. The coating can also be applied in the manner disclosed in U.S. patent 4256108, 4166452 and 4265874 to obtain the osmotic therapeutic tablets for controlled selection.

Compositions for oral administration can be in the form of hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium carbonate, calcium phosphate or kaolin, or in the form of soft gelatin capsules where the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions comprise the active ingredient in a mixture with excipients suitable for the preparation of aqueous suspensions. Such excipients are suspendresume agents, such as sodium carboxymethyl cellulose, methylcellulose, hypromellose, sodium alginate, polyvinylpyrrolidone, resin tragakant and the Arabian gum; dispersing or wetting agents such as natural phosphatides, for example lecithin, or products condense the AI alkalinized with fatty acids, for example polyoxyethylenated, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecafluorooctane, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol, such as polyethyleneterphthalate, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides hexitol, such as polyethyleneterphthalate. Aqueous suspensions may also include one or more preservatives, for example ethyl or n-propyl-para-hydroxybenzoate, one or more dyes, one or more corrigentov and one or more sweetening agents such as sucrose, saccharin or aspartame. Oil suspensions can be prepared by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. Oil suspensions can include a thickening agent, for example beeswax, liquid paraffin or cetyl alcohol. You can add sweetening agents such as those mentioned above, and corrigentov to impart a pleasant taste to the preparations for oral administration. These compositions can be maintained by adding antioxidants such as serbinova acid.

Dispersible powders and granules suitable for preparation of an aqueous suspension by adding water, contain the active ingredient mixed with dispersing or wetting agent, suspenders agent and one or more preservatives. Examples of suitable suspendida or wetting agents are already above agents. May also contain additional excipients, for example sweetening agents, corrigentov and dyes.

The pharmaceutical compositions of the present invention may also be in the form of emulsions of the type oil-in-water. The oil phase can serve as a vegetable oil, such as olive oil, or peanut oil, or mineral oil, for example, liquid paraffin, or mixtures thereof. Suitable emulsifying agents may be natural phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and anhydrides hexitol, such as servicemanual, and condensation products of these partial esters and ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsion may also include sweeteners and corrigentov.

Syrups and elixirs may contain sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such compositions may also contain painkillers, conserve the s and corrigentov and dyes.

Pharmaceutical compositions may also be in the form of a sterile aqueous or oily suspensions for injection. Such suspensions can be prepared by known methods, using suitable dispersing or wetting agents and suspendresume agents that have been described above. Sterile injectable preparations may also be in the form of sterile solutions or suspensions for injection in a non-toxic parenterally acceptable diluents or solvents, for example, in the form of a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used, you can specify the water, ringer's solution and isotonic sodium chloride solution. In addition, as a solvent or suspendida environment typically use sterile, non-volatile oils. For this purpose you can use any mixture of soft fixed oils, including synthetic mono - or diglycerides. In addition, in preparations for injection are used in fatty acids such as oleic acid.

The compounds of formula (I) can also be entered in the form of suppositories for rectal injection of the active ingredient. Such compositions can be prepared by mixing the active ingredient with a suitable not irritating excipient, which is solid at normal temperature but becomes liquid at rectal temp is Torah and therefore melt in rectum, highlighting the active ingredient. Such materials are, for example, cocoa butter and polyethylene glycols.

For local applications use creams, ointments, jellies, solutions or suspensions and the like, comprising a compound of formula (I) for purposes of applying such forms for local application must include a gargle for mouth and elixirs).

For treatment of the above conditions applicable dose levels of the order from about 0.01 mg to about 140 mg/kg of body weight per day, or in another embodiment from about 0.5 mg to about 1 g for the patient per day. For example, inflammation can be treated effectively by introducing from about 0.01 to 50 mg of compound per kilogram of body weight per day, or in another embodiment from about 0.5 mg to about 3.5 g to the patient per day, preferably from about 2.5 mg to 1 g for the patient per day.

The amount of active ingredient which can be combined with the material of the media to produce a single dosage form will vary depending on subject to treatment of the subject and the particular route of administration. For example, a form intended for oral administration to humans may contain from 0.5 mg to 5 g of the active ingredient, combined with an appropriate and convenient amount of carrier, which may vary from about 5 to about 95 wt.% from the whole composition. Standard dosage form typically contains from about mg to about 1000 mg of the active ingredient, usually 25, 50, 100, 200, 300, 400, 500, 600, 800 or 1000 mg

Note, however, that a particular level of dosage for any particular patient will depend upon a variety of factors, including age, body weight, General health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of a particular subject to treatment of disease.

The present invention relates further to methods for producing compounds of formula (I). These compounds can be obtained in accordance with the sequences shown below in schemes of reactions I, II and III.

In accordance with scheme I, the starting materials can be derived amides of formula (1). They can be obtained from the corresponding carboxylic acids described in the literature (see, for example, Org. Synth. col 1,153). Their condensation with dimethylacetal N,N-dimethylamino as described in Synthesis, 119 (1980), leads to N2-acyl-N1N1dimethylamide 5. Condensation derivatives of 5 with hydrazine in a polar solvent (e.g. methanol, ethanol or the like) results of 1H-1,2,4-triazole compounds 9. If you use cleaners containing hydrochloride salt of hydrazine, add one equivalent of an organic base. Hydrazines are mostly available from commercial sources, or p is to obtain from the appropriate amines known in the art methods (Advanced organic chemistry. Jerry March, Wiley, 1985). Then the oxidation of two equivalents of meta-chloroperbenzoic acid (MSRA) in an inert solvent (e.g. chloroform) gives 1H-1,2,4-triazole compounds Ia.

In accordance with scheme II, the starting materials can be alkilinity 2 or their salts. The reaction of alkylamide with benzoyl chloride 4 in the presence of organic bases such as triethylamine, results in N-allmydata 6. This method disclosed in Synthesis, 483 (1983). The reaction is carried out at room temperature in a nonpolar solvent such as methylene chloride, chloroform or toluene. Cyclization of N-allmydata 6 with hydrazine to obtain IH-1,2,4-triazole compounds 9 takes place at room temperature without a catalyst in a non-polar solvent such as methylene chloride. If you use cleaners containing hydrochloride salt of hydrazine, add one equivalent of an organic base (such as triethylamine). Stage oxidation, similar to the one shown in scheme I, leads to the production of 1H-1,2,4-triazole compounds 1A.

In accordance with scheme III source materials can serve derivative of amidine 3 or their salts. They are commercially available, or they can be obtained are described in the literature (G.V.BOYD. The chemistry of amidines and imidates, Wiley, vol. 2, chapter 7, 339, 1991). The reaction of the hydrazine derivative of amidine 3 is carried out at room temperature in polar the solvent (for example, in methanol or ethanol), receiving amerzone 7. Condensation of amerzone 7 with benzoyl chloride 4 in the presence of organic bases such as pyridine, yields a 1H-1,2,4-triazole compounds 9. This reaction proceeds preferably at the boiling point under reflux nonpolar solvent such as dioxane. Stage oxidation, similar to the one shown in scheme I, leads to the production of 1H-1,2,4-triazole compounds Ia.

Processing of arylmethylidene Ia base and triethylborane gives the corresponding rearranged sulfonic acid, which is converted into arylsulfonamides Ib in the process of oxidative amination. This method is described H.Chuang, E.J.Reinhard and D.B.Reitz in Tetrahedron letters, 35 (39), 7201-7204, (1994). Arylmethylidene Ia deprotonized slight excess of base, such ethylaniline, at low temperature (for example, when 0° (C) in an inert solvent like THF and then treated with triethylborane at the boiling point under reflux for several hours. As a result of processing hydroxyamine-O-sulfonic acid at room temperature get arylsulfonamides Ib.

Sulfonamides Ib is treated with acetylchloride in acetic acid, receiving sulfonamides IC.

Hereinafter the present invention will be illustrated in the following examples the AMI and tests.

EXAMPLE 1

1-((3-chloro-4-methyl)phenyl)-3-methyl-5-(4-methylsulfinylphenyl)-1H-1,2,4-triazole

a) Ethyl N-(4-methylthiophenyl)acetamide

To a cooled ice stirred suspension of the hydrochloride of ethylacetamide (80 g, of 0.65 mol) and triethylamine (175 ml of 1.24 mol) in CH2Cl2(1000 ml) is added dropwise a solution of 4-methyl-dibenzoylperoxide (110 g, 0,591 mol) (obtained in situ from 4-methylthiazole acid) in CH2Cl2. Then the reaction mixture was stirred over night at room temperature. The organic layer is washed with water, dried over sodium sulfate and evaporated in vacuum. The resulting residue is treated chromatography on silica gel using a mixture 8/2 heptane/ethyl acetate as eluent, to obtain an amorphous solid (92 g, 65%). The connection used in the next stage without additional purification.

1H-NMR(DMSO-d6): 1.30 (t, J=7.2 Hz, 3H), 1.98 (s, 3H), 2.5 (s, 3H), 4.25 (q, J=7.2 Hz, 2H), 7.35 (DD, J=8.2 Hz, 2H), 7.85 (d, J=8.2 Hz, 2H)

b) 1-((3-chloro-4-methyl)phenyl)-3-methyl-5-(4-methylthiophenyl)-1H-1,2,4-triazole

A solution of ethyl N-(4-methylthiophenyl)acetamide (5 g, 21,09 mmol), (3-chloro-4-methyl)phenyl hydrazine hydrochloride (4.5 g, 23,20 mmol) and triethylamine (3.5 ml, 25,31 mmol) in CH2Cl2(25 ml) is stirred for 1.5 hours at room temperature. The organic layer is washed with water, dried over sodium sulfate and pariva the t in vacuum. The resulting residue is treated chromatography on silica gel using a mixture 8/2 toluene/ethyl acetate as eluent, and get a brown oil (6.4 g), which crystallized from diisopropyl ether, receiving a yellow-orange powder (3.6 g, 52%).

So melting 100°C.

1H-NMR (l3): 2.4 (s, 3H), 2.48 (s, 3H), 2.50 (s, 3H), 7.0-7.5 (m, 7H).

C) 1-((3-chloro-4-methyl)phenyl)-3-methyl-5-(4-methylsulfinylphenyl)-1H-1,2,4-triazole

To a solution of 1-((3-chloro-4-methyl)phenyl)-3-methyl-5-(4-methylthiophenyl)-1H-1,2,4-triazole (3.6 g, 10.9 mmol) in l3(40 ml) is added 2 equivalents MSRV (6.3 g, 21,85 mmol). The reaction mixture is stirred for 0.5 hour at room temperature, then add hydrosulfite sodium and the mixture is neutralized with NaOH. The organic phase is allocated, washed with saturated sodium bicarbonate solution and dried over sodium sulfate. As the result of evaporation under reduced pressure to get the oil light yellow (3.5 g). As a result of crystallization from ethanol, the solid white (2.2 g, 56%). So melting 156°C.

1H-NMR (l3): 2.45 (s, 3H), 2.55 (s, 3H), 3.1 (s, 3H), 7.0 (DD, 1H), 7.3 (DD, 1H), 7.45 (d, 1H), 7.7 and 7.9 (AB, 4H).

The following connections will be received, using the method of example 1, but replacing (3-chloro-4-methyl)phenylhydrazine on:

- 4-forfamilies

- 4-chloranilide is n

- 4-methylphenylhydrazine

phenylhydrazine

- 2-chlorophenylhydrazone

- 3-chlorophenylhydrazone

- 4-tert-butylphenylmethyl

- 4-bromophenylacetate

- 4-methoxyphenylhydrazine

- 2,4-dipohenhydramine

- 4-nitrophenylhydrazine

3,4 - dipohenhydramine

3,4 - dimethoxyphenylacetic and

- 4-dimethylaminobenzylidene respectively.

EXAMPLE 2

1-(4-forfinal)-3-methyl-5-(4-methylsulfinylphenyl)-1H-1,2,4-triazole

So melting 180°

1H-NMR(l3): 2.50 (s, 3H), 3.1 (s, 3H), 7.05-7.4 (m, 4H), 7.7 and 7.95 (AB, 4H)

MN+=332.

EXAMPLE 3

1-(4-chlorophenyl)-3-methyl-5-(4-methylsulfinylphenyl)-1H-1,2,4-triazole

So melting 186°

1H-NMR (l3): 2.50 (s, 3H), 3.1 (s, 3H), 7.30 and 7.45 (AB, 4H), 7.7 and 7.95 (AB, 4H).

MN+=348.

EXAMPLE 4

3-methyl-1-(4-were)-5-(4-methylsulfinylphenyl)-1H-1,2,4-triaal

So melting 176°C.

1H-NMR (Cl3): 2.4 (s, 3H), 2.48 (s, 3H), 3.05 (s, 3H), 7.2 (m, 4H), 7.7 and 7.9 (AB, 4H).

EXAMPLE 5

3-methyl-5-(4-methylsulfinylphenyl)-1-phenyl-1H-1,2,4-triaal

So melting 146°C.

1H-NMR (CCl3): 2.5 (s, 3H), 3.05 (s, 3H), 7.25-7.5 (m, 5H), 7.7 and 7.9 (AB, 4H).

EXAMPLE 6

1-(2-chlorophenyl)-3-methyl-5-(4-methylsulfinylphenyl)-1H-1,2,4-triazole

So melting 170°

1H-NMR (CCl3): 2.5 (s, 3H), 3.05 (s, 3H), 7.4-7.6 (m, 4H), 7.7 and 7.9 (AB, 4H).

EXAMPLE 7

1-(3-chlorophenyl)-3-methyl-5-(4-metalsalt ylphenyl)-1H-1,2,4-triazole

So melting 130°

1H-NMR (l3): 2.5 (s, 3H), 3.05 (s, 3H), 7.15 (d, 1H), 7.25-7.50 (m, 2H), 7.7 and 7.95 (AB, 2H).

EXAMPLE 8

1-(4-tert-butylphenyl)-3-methyl-5-(4-methylsulfinylphenyl)-1H-1,2,4-triazole

So melting 142°

1H-NMR(L3): 1.35 (s, N), 2.55 (s, 3H), 3.1 (s, 3H), 7.25 and 7.45 (AB, 4H), 7.75 and 7.95 (AB, 4H).

EXAMPLE 9

1-(4-bromophenyl)-3-methyl-5-(4-methylsulfinylphenyl)-1H-1,2,4-triazole

So melting 188°

1H-NMR(l3): 2.5 (s, 3H), 3.05 (s, 3H), 7.20 and 7.60 (AB, 4H), 7.70 and 7.95 (AB, 4H).

EXAMPLE 10

1-(4-methoxyphenyl)-3-methyl-5-(4-methylsulfinylphenyl)-1H-1,2,4-triazole

So melting 128°

1H-NMR(Cl3): 2.5 (s, 3H), 3.05 (s, 3H), 3.85 (s, 3H), 6.95 and 7.25 (AB, 4H),7.7 and 7.9 (AB, 4H).

EXAMPLE 11

1-(2,4-differenl)-3-methyl-5-(4-methylsulfinylphenyl)-1H-1,2,4-triazole

So melting 160°

1H-NMR(CCl3): 2.5 (s, 3H), 3.05 (s, 3H), 6.9-7.15 (m, 2H), 7.45-7.60 (m, 1H), 7.7 and 7.9 (AB, 4H).

EXAMPLE 12

3-methyl-5-(4-methylsulfinylphenyl)-1-(4-nitrophenyl)-1H-1,2,4-triazole

So melting 180°

1H-NMR (l3): 2.55 (s, 3H), 3.1 (s, 3H), 7.55 (d, 2H), 7.7 (d, 2H), 7.95 (d, 2H), 8.30 (d, 2H).

EXAMPLE 13

1-(3,4-differenl)-3-methyl-5-(4-methylsulfinylphenyl)-1H-1,2,4-triazole

So melting 194°

1H-NMR(l3): 2.5 (s, 3H), 3.1 (s, 3H), 7.0-7.35 (m, 3H), 7.7 and 7.95 (AB, 4H).

EXAMPLE 14

1-(3,4-acid)-3-methyl-5-(4-methylsulfinylphenyl)-1H-,2,4-triazole

So melting 186°

1H-NMR (DMSO d6): 2.40 (s, 3H), 3.25 (s, 3H), 3.7 (s, 3H), 3.8 (s, 3H), 6.85 (DD, 1H), 7 (d, 1H), 7.1 (d, 1H), 7.7 and 7.95 (AB, 4H).

EXAMPLE 15

1-(4-dimethylaminophenyl)-3-methyl-5-(4-methylsulfinylphenyl)-1H-1,2,4-triazole

So melting 200°

1H-NMR(CCl3): 2.45 (s, 3H), 2.50 (s, 3H), 3.0 (s, 6N), 6.65 (d, 2H), 7.15 (2D, 4H), 7.45 (d, 2H).

EXAMPLE 16

1-(4-chlorophenyl)-5-(4-methylsulfinylphenyl)-3-phenyl-1H-1,2,4-triazole

a) Methyl N-(4-methylthiophenyl)benzamide

To a cooled ice stirred suspension of methylbenzamide hydrochloride (5.8 g, 33.8 mmol) and triethylamine (9 ml, of 62.4 mmol) in CH2Cl2(60 ml) was added dropwise a solution of 4-methyldibenzothiophene (5.8 g, 30.7 mmol) (obtained in situ from 4-methylthiazole acid) in CH2Cl2(5.8 ml). Then the reaction mixture was stirred at room temperature. The organic layer is washed with water, dried over sodium sulfate and evaporated in vacuum. The resulting residue is treated chromatography on silica gel using toluene as eluent, and receive an amorphous solid (500 mg, 5%). The connection used in the next stage without additional purification.

1H-NMR(DMSO d6): 2.5 (s, 3H), 4 (s, 3H), 7.3-7.6 (m, 7H), 7.9 (d, 2H).

b) 1-(4-chlorophenyl)-5-(4-methylthiophenyl)-3-phenyl-1H-1,2,4-triazole

A solution of methyl N-(4-methylthiophenyl)benzamide (500 mg, about 1.75 mmol), is hydrochloride (4-chloro)phenyl (345 mg, 1.92 mmol) and triethylamine (0.3 ml, 2.1 mmol) in CH2Cl2(2.5 ml) is stirred for 1.5 hours at room temperature. The organic layer was diluted with dichloromethane, washed with water, dried over sodium sulfate and evaporated in vacuum. The obtained solid yellow triturated with toluene, getting solid white (130 mg, 20%).

1H-NMR(Cl3): 2.5 (s, 3H), 7.15-7.65 (m, 11N), 8.25 (DD, 2H).

c) 1-(4-chlorophenyl)-5-(4-methylsulfinylphenyl)-3-phenyl-1H-1,2,4-triazole

To a solution of 1-(4-chlorophenyl)-5-(4-methylthiophenyl)-3-phenyl-1H-1,2,4-triazole (130 mg, 0.34 mmol) in l3(5 ml) is added 2 equivalents MSRV (200 mg, to 6.88 mmol). The reaction mixture is stirred for two days at room temperature, then add hydrosulfite sodium and the mixture is neutralized with concentrated NaOH. After extraction with chloroform, the organic phase is washed with water and dried over sodium sulfate. As the result of evaporation under reduced pressure and crystallization from ethanol, the solid white (50 mg, 36%).

So melting 170°

1H-NMR(Cl3): 3.1 (s, 3H), 7.3-7.55 (m, 7H), 7.8 and 8.0 (AB, 4H), 8.15-8.30 (m, 2H).

EXAMPLE 17

1-(4-methoxyphenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

a) N-(4-methoxyphenyl)-triftoratsetatov

A mixture of the hydrochloride of 4-methoxyphenol is drazine (of 27.84 g, 159,4 mmol), triptorelin (25 g, 223,2 mmol), triethylamine (22,12 ml, 159,4 mmol) and methanol (100 ml) is stirred under nitrogen atmosphere at room temperature for 6 hours. The reaction mixture was diluted with water (100 ml), extracted with ethyl acetate (3×100 ml) and the combined organic layers washed with water, saturated brine, and dried over Na2SO4. In the flash-chromatography on silica gel (CH2Cl2as eluent) to obtain a brown oil (35 g, 94%), which is used in the next stage without additional purification.

1H-NMR(Cl3): 3.75 (s, 3H), 4.35 (CL, 2H), 6.1 (SHS, 1H), 6.7 and 7.0 (AB, 4H).

b) 1-(4-methoxyphenyl)-5-(4-methylthiophenyl)-3-trifluoromethyl-1H-1,2,4-triazole

To a solution of N-(4-methoxyphenyl)triftoratsetata (35 g, 0.15 mol) and pyridine (of 11.6 ml) in dioxane (360 ml) add a solution of 4-methylsulfonylbenzoyl (26,6 g, 0,142 mol) (obtained in situ from 4-methylthiazole acid) in dioxane (120 ml). Then the reaction mixture is heated at boiling under reflux overnight. After evaporation of the dioxane, the residue is placed in dichloromethane, the organic layer washed with water, 0.1 N. Hcl, saturated brine, dried over sodium sulfate and evaporated in vacuum. The resulting residue is treated chromatography on silica gel (CH2CL2as eluent)to give colorless the oil (30,9 g, 65%).

1H-NMR(DMSO d6): 2.5 (s, 3H), 3.35 (s, 3H), 7.1 and 7.5 (AB, 4H), 7.3 and 7.4 (AB, 4H).

C) 1-(4-methoxyphenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

To a solution of 1-(4-methoxyphenyl)-5-(4-methylthiophenyl)-3-trifluoromethyl-1H-1,2,4-triazole (30 g, 0.08 mol) in CH2CL2(320 ml) was added in several portions MSRV (47,2 g, 0.16 mol). The reaction mixture was stirred at room temperature for 1.5 hours, then cooled to 0-5°and carefully add the Hydrosulphite solution of sodium (500 ml) maintaining the temperature below 18-20°C. the pH is brought to 8 by adding 30% NaOH. This mixture is extracted with dichloromethane, the organic phase is washed with saturated brine, dried over sodium sulfate and evaporated. As a result of processing using flash chromatography on silica gel (toluene/ethyl acetate: 8/2 as eluent) and recrystallization from ethanol, the solid white (29,42 g, 90%).

So melting 156°C.

1H-NMR(DMSO d6): 3.29 (s, 3H), 3.83 (s, 3H), 7.1 and 7.5 (AB, 4H), 7.75 and 8.0 (AB, 4H).

MN+=398.

EXAMPLE 18

1-(4-bromophenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

a) N-(4-bromophenyl)triftoratsetatov

A mixture of 4-bromophenylacetonitrile (7,1 g of 31.8 mmol), triptorelin (5 g, to 44.6 mmol), triethylamine (4.5 ml, of 31.8 mmol) and methanol (20 ml) is stirred overnight at room temperature. Re Klenow mixture is diluted with water, extracted with ethyl acetate, the organic layer washed with water, saturated brine, dried over Na2SO4. In the flash-chromatography on silica gel (CH2Cl2as eluent) to get an orange oil (6.7 g, 53%), which is used in the next stage without additional purification.

1H-NMR(l3): 4.45 (CL, 2H), 6.25 (SHS, 1H), 6.9 and 7.35-7.55 (AB, 4H).

b) 1-(4-bromophenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

To a solution of N-(4-bromophenyl)triftoratsetata (6.7 g, with 23.7 mmol) and pyridine (2.1 ml) and 26.1 mmol) in dioxane (40 ml) add a solution of 4-methylsulfonylbenzoyl (5,96 g and 27.3 mmol) (obtained in situ from 4-methylsulfonylbenzoyl acid) in dioxane (40 ml). Then the reaction mixture is heated at the boil under reflux for 5 hours. After evaporation of the dioxane, the residue is placed in dichloromethane, the organic layer washed with water, 0.1 N. Hcl, saturated brine, dried over sodium sulfate and evaporated in vacuum. The resulting residue is treated chromatography on silica gel using a mixture of 95/5 toluene/dioxane as eluent, and then recrystallized from ethanol, getting a solid white color (2.8 g, 26%).

So melting 198°

1H-NMR(DMSO d6): 3.29 (s, 3H), 7.55 (d, 2H), 7.76 (d, 2H), 7.8 (DD, 2H), 8.02 (DD, 2H).

MN+=446

The following compounds is Oia get using the method of example 18, but substituting 4-bromophenylacetonitrile on:

- 4-nitrophenylhydrazine

- 4-forfamilies

- 4-chlorophenylhydrazone

- cyclohexylpiperazine (obtained by the method NI. Ghali, J.Org.Chem.,1981, 46, 5413) and

- 4-methoxyphenylhydrazine respectively.

EXAMPLE 19

1-(4-nitrophenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

1H-NMR(DMSO d6): 3.30 (s, 3H), 7.85 (t, 4H), 8.05 (d, 2H), 8.45 (d, 2H).

EXAMPLE 20

1-(4-forfinal)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

So melting point 230-232°

1H-NMR(DMSO d6): 3.27 (s, 3H), 7.4 (t, 2H), 7.6-7.8 (m, 2H), 7.8 and 8.0 (AB, 4H).

EXAMPLE 21

1-(4-chlorophenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

So melting point 190-192°

1H-NMR(DMSO d6): 3.3 (s, 3H), 7.2 (m, 4H), 7.8 and 8.05 (AB, 4H).

EXAMPLE 22

1-(cyclohexyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

So melting 136°

1H-NMR(DMSO d6): 1.15-2.5 (m, 10H), 3.3 (s, 3H), 4.3-4.4 (m, 1H), 8 and 8.15 (AB, 4H).

EXAMPLE 23

1-(4-methoxyphenethyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-thiazole

So melting 142°

1H-NMR(DSMO d6): 3.3 (s, 3H), 3.7 (s, 3H), 5.5 (s, 2H), 6.9 and 7.1 (AB, 4H), 8 and 8.1 (LW, 4H).

The following connections will be received, using the method of example 18, but substituting 4-methylsulfonylbenzoyl 2-chloro-4-IU is resultoriented and 4-bromophenylacetate 4-methoxyphenylhydrazine.

EXAMPLE 24

5-(2-chloro-4-methylsulfinylphenyl)-1-(4-methoxyphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

So melting 148°

1H-NMR(DMSO d6): 3.35 (s, 3H), 3.80 (s, 3H), 7 and 7.4 (AB, 4H), 8-8 .2 (m, 3H).

EXAMPLE 25

1-(4-methylsulfonylamino)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

a) 1-(4-AMINOPHENYL)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

A mixture of 1-(4-nitrophenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole (1.2 g, only 2.91 mmol), iron powder (0.8 g, 14,27 mmol), ammonium chloride (0,80 g, 1,45 mmol), ethanol (25 ml) and water (13 ml) is heated at boiling under reflux for 1 hour, then cooled and filtered. The resulting filtrate was poured into water, extracted with ethyl acetate and a solution of dichloromethane/methanol. The organic extracts washed with saturated brine, dried over Na2SO4and evaporated, receiving a yellow powder (1 g, 91%), which is used in the next stage without additional purification.

1H-NMR(DMSO d6): 3.30 (s, 3H), 5.7 (CL, 2H), 6,65 and 7.18 (AB, 4H), 7.75 and 8 (AB, 4H).

b) 1-(4-methylsulfonylamino)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

To a cooled ice stirred suspension of 1-(4-AMINOPHENYL)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole (1 g, 2,61 mmol) and triethylamine (0.4 ml, 2,87 mmol) in CH2Cl2(20 ml) added dropwise met sulphonylchloride (0.2 ml, 2,87 mmol). Then the reaction mixture was stirred at room temperature for 2 hours. The results obtained by TLC showed the presence of starting material. Then add 0.4 ml of methanesulfonanilide and 10 mg dimethylaminopyridine (D) and the reaction mixture is heated at the boil under reflux for 2 hours. Again, add 0.4 ml of methanesulfonanilide and 10 mg of DMAP and the mixture is stirred over night at room temperature. The reaction mixture is diluted with water, extracted with CH2Cl2combined organic layers washed with water, dried over Na2SO4and evaporated, obtaining a light yellow colour powder (1.1 g). The crude product is triturated with a mixture of dichloromethane/isopropyl ether, receiving solid beige color (0.65 g). Then a solution of this solid in 60 ml Meon/THF (2/1) and 1 N. NaOH (3.6 ml) was stirred at room temperature for 0.25 hour. After evaporation of the solvent, addition of ethyl acetate and neutralized using 1 N. Hcl the organic layer washed with water, dried over sodium sulfate and evaporated. As a result of crystallization from pentane and recrystallized from a mixture of isopropyl ether/ethanol, the solid light pink color (0.3 g, 25%).

So melting 188°

1H-NMR(DMSO d6): 3.15 (s, 3H), 3.0 (s, 3H), 7.35 and 7.55 (AB, 4H), 7.75 and 8.05 (AB, 4H).

MN+=461

EXAMPLE 26

1,5-di-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

a) N-(4-methylsulfinylphenyl)triftoratsetatov

A mixture of 4-(methylsulphonyl)phenylhydrazine (10,1 g and 44.6 mmol), triethylamine (6.2 ml and 44.6 mmol), triptorelin (2.5 g, of 22.3 mmol), THF (40 ml) and methanol (40 ml) is stirred overnight at room temperature. The reaction mixture is diluted with water, extracted with ethyl acetate, the organic layer washed with water, saturated brine and dried over Na2SO4. In the flash-chromatography on silica gel (cyclohexane/ethyl acetate: 8/2 as eluent) and a thorough trituration with isopropyl ether to obtain a solid (2.9 g, 46%).

So melting 164°C.

1H-NMR (DMSO d6): 3.1 (s, 3H), 6.7 (CL, 2H), 7.05 and 7.7 (AB, 4H), 9.25 (s, 1H).

(b) 1,5-di-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

To a solution of N-(4-methylsulfinylphenyl)triftoratsetata (4.3 g, 15,28 mmol) and pyridine (1.4 ml, is 16.8 mmol) in dioxane (30 ml) add a solution of 4-methylsulfonylbenzoyl (4.3 g, a 19.5 mmol) (obtained in situ from 4-methylsulfonylbenzoyl acid) in dioxane (10 ml). Then the reaction mixture is heated at boiling under reflux for 6 hours, then stirred overnight at room temperature. The reaction mixture is shown that the comfort, concentrate to dryness, split between methylene chloride and water, the residue is extracted with methylene chloride, the organic layer was washed with Hcl 0.1 N., saturated brine, dried over sodium sulfate and evaporated in vacuum. The resulting residue is treated chromatography on silica gel using a mixture 8/2 toluene/dioxane as eluent, and then recrystallized from ethanol, getting a solid white color (1.1 g, 26%).

So melting 214°C.

1H-NMR (DMSO d6): 3.29 (s, 3H), 3.32 (s, 3H), 7.8 (d, 2H), 7.9 (d, 2H), 8.03 (DD, 2H), 8.12 (DD, 2H).

MN+=446.

The following connections will be received, using the method of example 26, but substituting 4-methylsulfonylmethan on:

3,4 - dimethoxyphenylacetic and

3,4 - methylenedioxyphenylacetic respectively.

EXAMPLE 27

1-(3,4-acid)-5-(4-methylsulfinylphenyl)-3-Cryptor-methyl-1H-1,2,4-triazole

So melting 140°

1H-NMR(DMSO d6): 3.25 (s, 3H), 3.7 (s, 3H), 3.8 (s, 3H), 7.1 (s, 2H), 7.28 (s, 1H), 7.8 and 8 (AB, 4H).

EXAMPLE 28

1-(3,4-methylenedioxyphenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

So melting 185°

1H-NMR(DMSO d6): 3.30 (s, 3H), 6.2 (s, 2H), 7.1 (s, 2H), 7.28 (s, 1H), 7.8 and 8.05 (AB, 4H).

EXAMPLE 29

1-(4-hydroxyphenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

A mixture of 1-(4-methoxyphenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-t is Isola (10 g, of 25.2 mmol), 48% aqueous HBr (70 ml) and acetic acid (70 ml) is heated at 120°C for 5.5 hours. Then added 48% HBr (20 ml) and Asón (20 ml) and the mixture is again heated at 120°C for 2 hours. After cooling, the solution was poured into water (2 l), the precipitate is filtered off, washed several times with water and dried. As a result of recrystallization from ethanol, the solid white (7.5 g, 78%).

So melting 246°

1H-NMR(DMSO d6): 3.25 (s, 3H), 6.9 and 7.35 (AB, 4H), 7.75 and 8 (AB, 4H), 10.2 (SHS, 1H).

EXAMPLE 30

1-(4-ethoxyphenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

A mixture of 1-(4-hydroxyphenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole (4 g, 10.4 mmol), KOH (1.5 g, 26.8 mmol) and DMF (40 ml) was stirred at room temperature for 1 hour. Then add diethylsulfate (1.6 ml, 12.2 mmol), the reaction mixture was stirred at room temperature for 1.5 hours, add NH4OH (20 ml) and the mixture was poured into water (1 liter). The precipitate is filtered off, washed several times with water and dried. As a result of recrystallization from ethanol, the solid white color (3.7 g, 88%).

So melting 112°C.

1H-NMR(DMSO d6): 1.35 (t, 3H), 3.3 (s, 3H), 4.10 (q, 2H), 7.1 and 7.5 (AB, 4H), 7.75 and 8 (AB, 4H).

EXAMPLE 31

1-(2-pyridinyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole hydrochloride

a)N-(2-pyridinyl)triftoratsetatov

A mixture of 2-hydrazinopyridazine (5 g, with 45.8 mmol), triptorelin (3.4 g, 30,5 mmol) and methanol (50 ml) is stirred overnight at room temperature. The reaction mixture is evaporated to dryness. In the flash-chromatography on silica gel (toluene/ethyl acetate: 65/35 as eluent) to obtain an amorphous solid light orange color (3.1 g, 50%), which is used in the next stage without additional purification.

1H-NMR(DMSO d6): 6.65 (CL, 3H), 7 (d, 1H), 7.1 (t, 1H), 8.05 (d,1H), 9.2 (s, 1H).

b) 1-(2-pyridinyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazolinone

To a solution of N-(2-pyridinyl)triftoratsetata (3.1 g, 15.1 mmol) in dioxane (15 ml) add a solution of 4-methyl-sulfonylmethane (3.6 g, and 16.7 mmol) (obtained in situ from 4-methylsulfonylbenzoyl acid) in dioxane (15 ml). Then the reaction mixture is refluxed for 2 hours. After cooling, the reaction mixture is filtered and concentrated to dryness. The residue is treated chromatography on silica gel using a mixture 85/15 toluene/dioxane as eluent, and then recrystallized from ethanol, getting a solid white color (0,94 g, 15%).

So melting 144°

1H-NMR (DMSO d6): 3.27 (s, 3H), 7.6 (t, 1H), 7.8 and 8 (AB, 4H), 7.9 (d, 1H), 8.16 (t, 1H), 8.46 (d, 1H).

The following connections will be received, using the method of the example 31, but replacing 2-hydrazinopyridazine on:

- 3-hydrazinopyridazine (obtained according to the method of WO 97/10243) and

- 3-fluoro-4-methoxyphenylhydrazine respectively.

EXAMPLE 32

1-(3-pyridinyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole hydrochloride

So melting 180°

1H-NMR (DMSO d6): 3.27 (s, 3H), 7.6 (m, 1H), 7.77 (d, 2H) 7.99-8.09 (m, 3H), 8.77 (s, 2H).

EXAMPLE 33

1-(3-fluoro-4-methoxyphenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

So melting 180°

1H-NMR (DMSO d6): 3.30 (s, 3H), 3. 95 (s, 3H), 7.35-7.5 (m, 2H), 7.65 (DD, 1H), 7.8 and 8.05 (AB,4H).

EXAMPLE 34

1-(4-methoxyphenyl)-5-(4-aminosulphonylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole

To a cooled with ice to a solution of 1-(4-methoxyphenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole (10 g, 25/19 mmol) in THF (100 ml) added dropwise a 2 M solution of n-butylacrylamide in THF (21 ml, 42 mmol). Then the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was cooled to 0°With added dropwise a 1 M solution of triethylborane in THF (70 ml, 70 mmol) and the reaction mixture is refluxed for 18 hours. After cooling, added dropwise a solution of hydroxylamine-O-sulfonic acid (12 g, 106 mmol) and sodium acetate (17,38 g, 210 mmol) in H2O (140 ml), while maintaining the temperature below 15°C. Then the reaction is mesh stirred at room temperature for 2 hours, the residue is extracted with ethyl acetate (2×100 ml), the organic layer was washed with saturated brine, dried over sodium sulfate and evaporated in vacuum. The resulting residue is treated chromatography on silica gel, using as eluent a mixture of methylene chloride/methanol 99/1, then 98/2, then recrystallized from ethanol, getting solid beige (2.5 g, 25%).

So melting 228°C.

1H-NMR (DMSO d6): 3.9 (s, 3H), 7.15 (d, 2H), 7.5-7.6 (m, 4H), 7.75 and 7.95 (AB, 4H).

EXAMPLE 35

1-(4-methoxyphenyl)-5-[(4-(acetylamino)sulfonyl)phenyl]-3-trifluoromethyl-1H-1,2,4-triazole

To a suspension of 1-(4-methoxyphenyl)-5-(4-(aminosulfonyl)phenyl)-3-trifluoromethyl-1H-1,2,4-triazole (2 g, 5 mmol) in acetic acid (10 ml) added dropwise acetylchloride (10 ml). Then the reaction mixture is heated at 80°C for 5 hours, concentrated to dryness and the residue is treated chromatography on silica gel using a mixture 98/2 dichloromethane; methylene chloride/methanol as the eluent, and then recrystallized from a mixture of pentane/methanol, getting a solid white color (1.6 g, 72%).

So melting 85°

1H-NMR (l3): 2.05 (s, 3H), 3.9 (s, 3H),7 and 7.3 (AB, 4H), 7.75 and 8.05 (AB, 4H).

EXAMPLE 36

1-(4-methoxyphenyl)-5-(4-methylsulfinylphenyl)-1H-1,2,4-triazole

a) N-(dimethylaminomethylene)-4-(methylsulphonyl)benzamid

A suspension of 4-methylsulfonyl samida (8 g, 40,2 mmol) in dimethylformamide-dimethylacetal (16 ml, 120 mmol) was stirred at 120°C for 1.75 hours, and at this time the formed methanol is collected using a reverse refrigerator. After cooling, the solid orange color is filtered off and dried (8,92 g, 87%).

So melting 130°

1H-NMR (DMSO d6): 3.16 (s, 3H), 3.22 (s, 3H), 3.27 (s, 3H), 8 and 8.35 (AB, 4H), 8.67 (s, 1H).

b) 1-(4-methoxyphenyl)-5-(4-methylsulfinylphenyl)-1H-1,2,4-triazole

A mixture of N-(dimethylaminomethylene)-4-(methylsulphonyl)benzamide (4 g, 15.7 mmol), 4-methoxyphenylacetonitrile (2,75 g, 15.7 mmol), triethylamine (2.2 ml, 15.7 mmol) in ethanol (20 ml) is heated at the boil under reflux for 2.5 hours. After cooling, the reaction mixture is concentrated to dryness, then diluted with ethyl acetate. The organic phase is washed with water and saturated brine and dried over sodium sulfate. The residue is treated chromatography on silica gel using a mixture of 70/30 toluene/dioxane as eluent, and then recrystallized from ethanol, getting a solid light orange (0.4 g, 15%).

So melting 182°

1H-NMR (DMSO d6): 3.26 (s, 3H), 3.82 (s, 3H), 7.05 and 7.35 (AB, 4H), 7.7 and 8 (AB,4H), 8.3 (s, 1H).

The results of biological tests

Connection examples of the present invention are tested for their ability inhibi the SQL SOH-1 and/or MOR-2 activity in vitro. Peeled MOR-1 from sheep seminal vesicles and purified SOH-2 from the placenta of sheep (both company Cayman Chemicals) and incubated for 10 minutes at 25°in the presence of their substrate arachidonic acid (5 μm), with a test compound or without test compounds or in the presence or in the absence of standard inhibitors. The reaction product is prostaglandin E2 is determined using an enzyme immunoassay (R&D Systems). Each value is the result of two definitions. The target value of the inhibition is average±standard error from at least 3 independent experiments performed on different days.

In this test system diclofenac, which is the standard non-selective inhibitor of both MOR-1 and MOR-2, reproducibly demonstrates its inherent dose-dependent inhibition of the activity of MOR-1 and MOR-2 IR50equal 0/54±0.13 (17) and 0.97±0,14 µm (18), respectively. Standard selective inhibitor SOH-2 nimesulide tested as comparative compounds in the concentration range from 0.1 to 10 μm. At intermediate concentrations of 1 μm, is used for comparison, the compounds of examples 3, 10, 15, 17, 18, 25 and 34 did not show any significant inhibition of MOR-1, but was able to selectively inhibit MOR-2 (table 1).

Table 1
Inhibition of MOR-1 and MOR-2 activities
Compound (concentration)% inhibition of MOR-1 (n)% inhibition of MOR-2 (n)
Nimesulide(0.1 ám)+ 7±6,6 (9)- 23±5,4 (9)
 (1 μm)+ 16±12,2 (26)- 30±3,2 (23)
 (10 μm)+ 13±8,3 (9)- 50±5,4 (12)
EXAMPLE 3(1 μm)- 2±5,7 (6)- 19±2,6 (3)
EXAMPLE 10(1 μm)- 4±14,6 (4)- 32±4,5 (3)
EXAMPLE 15(1 μm)+ 2±7,0 (3)- 18±7 (3)
EXAMPLE 17(1 μm)+ 8±2,7 (6)- 44±6,8 (6)
EXAMPLE 18(1 μm)- 5±12 (3)- 53±11 (3)
EXAMPLE 25(1 μm)- 5±9 (3)- 31±10 (3)
EXAMPLE 34(1 μm)- 16±10 (3)- 78±2 (3)
(n) number of experiments

The compounds of examples 10 and 25 about adut similar nimesulide efficiency in the same concentration, and the compounds of examples 17, 18 and 34 are even more effective. The compound of example 18, one of the most effective compounds in the series, demonstrates the effectiveness, about 10 times the efficiency of nimesulide, as it causes the same inhibition (-53%)and nimesulide (-50%), but at concentrations 10 times lower: 1 μm vs. 10 μm, respectively.

1. Derivatives of 5-aryl-1H-1,2,4-triazole of the General formula (I)

where R1is hydrogen; (C1-C6)alkyl; halo(C1-C6) alkyl; or phenyl;

R2is (C3-C8) cycloalkyl; phenyl, optionally substituted by one or more substituents selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy, nitro, di-(C1-C4)alkylamino, (C1-C4)alkylsulfonyl, (C1-C4)alkylsulfonyl, methylendioxy; phenyl (C1-C4)-alkyl, where phenyl is substituted by (C1-C4)alkoxy; or pyridyl;

R3represents hydrogen or halogen;

R4is (C1-C6)alkyl, amino, or (C1-C4)alkylcarboxylic;

or its pharmaceutically acceptable salt.

2. The derivative according to claim 1, where R1is ( 1-C4)alkyl or halo(C1-C4)alkyl, or its pharmaceutically acceptable salt.

3. The derivative according to claim 2, where R1represents trifluoromethyl, or its pharmaceutically acceptable salt.

4. The derivative according to claims 1-3, where R2represents phenyl, optionally substituted by one or more substituents selected from the group consisting of halogen, (C1-C4)alkyl, (C1-C4)-alkoxy, hydroxy, nitro, di(C1-C4)alkylamino, (C1-C4)alkylsulfonyl, (C1-C4)alkylsulfonyl, methylendioxy; or its pharmaceutically acceptable salt.

5. Derivative according to any one of claims 1 to 4, where R3represents hydrogen, or its pharmaceutically acceptable salt.

6. Derivative according to any one of claims 1 to 5, where R4is (C1-C6)alkyl or amino, or its pharmaceutically acceptable salt.

7. The derivative according to claim 1 or its pharmaceutically acceptable salt, which is selected from the group consisting of

1-(4-methoxyphenyl)-3-methyl-5-(4-methylsulfinylphenyl)-1H-1,2,4-triazole;

1-(4-methoxyphenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole;

1-(4-bromophenyl)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole;

1-(4-methylsulfonylamino)-5-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole;

1-(4-methodology Setenil)-5-(4-aminosulphonylphenyl)-3-trifluoromethyl-1H-1,2,4-triazole.

8. The pharmaceutical composition inhibiting cyclooxygenase-2 comprising a therapeutically effective amount of a compound according to any one of claims 1 to 7 or its pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8 for the treatment of inflammatory diseases.

10. The pharmaceutical composition of claim 8 or 9, comprising from 1 to 1000 mg of the compounds.



 

Same patents:

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: color-forming compositions and recording material.

SUBSTANCE: claimed composition includes developer containing urea-urethane compound and colorless or light colored leuco dye. Recording material based on this composition also is proposed.

EFFECT: color-forming compositions with improved image conservation ability and increased image intensity.

21 cl, 14 tbl, 153 ex

The invention relates to a method for producing a condensed 2-getreleasedate General formula

using the diamine of General formula

where A=

R=2-furyl, 2-thienyl, 2-(1-methyl)pyrrolyl, 3-(1-methyl)indolyl, and aldehydes in the presence of acetate or copper sulfate, characterized in that the interaction takes place by boiling in 50% acetic acid, followed by decomposition of the copper salt, the effect on its suspension in 50% acetic acid sodium thiosulfate in 100With

The invention relates to derivatives of 6-sulfamoylbenzoic-4-carboxylic acid of formula (1), where R1, R2, R3and R4such as defined in the claims

The invention relates to 1-methyl-5-alkylsulfonyl-, 1-methyl-5-alkylsulfonyl - 1-methyl-5-alkylthiomethyl pyrazolylborate and herbicide tool based on them

The invention relates to tricyclic condensed heterocyclic compounds of the formula I, X is, for example, CH, CH2, СНR (where R means a lower alkyl group or a substituted lower alkyl group) or CRR' (where R and R' have the values specified above for R); Y means, for example, CH, CH2or C=O; z means, for example, S, S=O=; U denotes C; R1-R4independent means, for example, a hydrogen atom, SR (where R has the above values), phenyl group, substituted phenyl group, follow group, thienyl group, benzofuran or benzothiazyl at least one element of R5and R8means, for example, HE and the rest of the elements of R5and R8independent means, for example, a hydrogen atom; and their optical isomers, conjugates, and pharmaceutically acceptable salts

The invention relates to a new crystalline modification of 5-fluoro-1-(tetrahydro-2-furyl)uracil, as well as complex compounds of this form with 2,4-dioxo-6-methyl-1,2,3,4-tetrahydropyrimidine or licorice root extract (Radices Glycyrrhzae)

FIELD: organic chemistry.

SUBSTANCE: invention relates to new antibacterial agents. Invention describes cycloalkyl-substituted derivatives of aminomethylpyrrolidine represented by the general formula (I): wherein each among R1 and R2 represents hydrogen atom; n represents a whole number from 1 to 4; Q represents structural moiety represented by the following formula (Ia): wherein R3 represents cyclic alkyl group comprising from 3 to 6 carbon atoms that can be substituted; R4 represents hydrogen atom; R5 represents hydrogen atom or amino-group; X1 represents halogen or hydrogen atom; A1 represents nitrogen atom or structural moiety represented by the formula (II): wherein X2 represents hydrogen, halogen atom or alkyl group comprising from 1 to 6 carbon atoms, or alkoxyl group comprising from 1 to 6 carbon atoms; X2 and R3 can form a ring structure in common with part of the parent skeleton optionally comprising oxygen, nitrogen or sulfur atom as a ring-forming atoms and optionally comprising alkyl group comprising from 1 to 6 carbon atoms as a substitute; Y represents hydrogen atom. Also, invention describes an antibacterial an agent containing compound by cl. 1. Invention provides preparing new compounds eliciting valuable biological properties.

EFFECT: valuable properties of compounds and agent.

15 cl, 1 tbl, 10 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of 1-arenesulfonyl-2-arylpyrrolidine and piperidine of the formula (I):

wherein R1 means hydrogen atom (H), (C1-C7)-alkyl; R2 means furyl, thienyl, pyridyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, cyano-group, CF3 or -N(R4)2; R3 means naphthyl or phenyl optionally substituted with 1-3 substitutes taken among (C1-C7)-alkyl, (C1-C7)-alkoxy-group, halogen atom, acetyl, cyano-group, hydroxy-(C1-C7)-alkyl, -CH2-morpholine-4-yl, (C1-C7)-alkyloxy-(C1-C7)-alkyl, (C1-C7)-alkyl-N(R4)2 or CF3; R4 means independently of one another hydrogen atom (H), (C1-C7)-alkyl with exception for (RS)-2-phenyl-1-(toluene-4-sulfonyl)pyrrolidine, (RS)-1-(toluene-4-sulfonyl)-2-p-tolylpyrrolidine, N-tosyl-cis-3-methyl-2-phenylpyrrolidine, 3-[1-(toluene-4-sulfonyl)pyrrolidine-2-yl]pyridine and N-tosyl-2-(3,4-dimethoxyphenyl)pyrrolidine, and their pharmaceutically acceptable salts also. Compounds of the formula (I) elicit the effect of agonists or antagonists of metabotropic glutamate receptors that allows their using in pharmaceutical agent useful for treatment or prophylaxis of acute and/or chronic neurological disturbances.

EFFECT: valuable medicinal properties of compounds.

9 cl, 1 tbl, 3 sch, 94 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of dihydropyrimidine of the general formula (I):

or its isomeric form of the formula (Ia):

that can be used, for example, for treatment and prophylaxis of hepatitis B. In indicated formulas R1 means unsubstituted phenyl or phenyl substituted once or many times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, nitro-, amino-group, hydroxyl and alkyl with 1-6 carbon atoms, or residues of formulas:

, or ; R2 means residue of the formula -XR5 wherein X means a bond or oxygen atom; R5 means alkenyl with 2-4 carbon atoms or alkyl with 1-4 carbon atoms that can be unsubstituted or substituted with phenoxy-group; R3 means amino-group, alkyl with 1-4 carbon atoms or cyclopropyl; R4 means pyridyl that is substituted with up to three times with similar or different substitutes taken among the group including halogen atom, trifluoromethyl group, alkoxy-group with 1-6 carbon atoms and alkyl with 1-6 carbon atoms, and their salts. Also, invention relates to 3,5-difluoro-2-pyridincarboxyimidamide and 3,5-difluoro-2-pyridincarbonitrile that can be sued as intermediates products for preparing compounds of the formula (I) or (Ia) and to a medicinal gent.

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

10 cl, 2 sch, 4 tbl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of 5-phenylpyrimidine or their pharmaceutically acceptable acid-additive salts that elicit properties of antagonists of neuropeptide receptor neurokinin-1 (NK-1). This allows their applying for treatment of such diseases as Alzheimer's disease, cerebrospinal sclerosis, attenuating syndrome in morphine withdrawal, cardiovascular alterations and so on. Compounds of invention correspond to the general formula (I):

wherein R1 means hydrogen or halogen; R2 means hydrogen, halogen atom, (lower)-alkyl or (lower)-alkoxy-group; R3 means halogen atom, trifluoromethyl group, (lower)-alkoxy-group or (lower)-alkyl; R4/R4' mean independently hydrogen atom or (lower)-alkyl; R5 means (lower)-alkyl, (lower)-alkoxy-group, amino-group, hydroxyl group, hydroxy-(lower)-alkyl, -(CH2)n-piperazinyl substituted optionally with lower alkyl, -(CH)n-morpholinyl, -(CH2)n+1-imidazolyl, -O-(CH2)n+1-morpholinyl, -O-(CH2)n+1-piperidinyl, (lower)-alkylsulfanyl, (lower)-alkylsulfonyl, benzylamino-group, -NH-(CH2)n+1N(R4'')2, -(CH2)n-NH-(CH2)n+1N(R4'')2, -(CH2)n+1N(R4'')2 or -O-(CH2)n+1N(R4'')2 wherein R4'' means hydrogen atom or (lower)-alkyl; R6 means hydrogen atom; R2 and R6 or R1 and R6 in common with two ring carbon atoms can represent -CH=CH-CH=CH- under condition that n for R1 is 1; n means independently 0-2; X means -C(O)N(R4'')- or -N(R4'')C(O)-. Also, invention relates to a pharmaceutical composition.

EFFECT: valuable medicinal properties of compounds.

15 cl, 4 sch, 86 ex

The invention relates to new derivatives of 4-phenylpyrimidine and their pharmaceutically acceptable acid additive salts, which possess the properties of receptor antagonists neirokinina(NK-1), and can be used to treat diseases, oposredstvovanii NK-1 receptor, for example, headache, Alzheimer's disease, multiple sclerosis, cardiovascular changes, oedema, chronic inflammatory diseases and so on

The invention relates to new monoethanol and hemiethanolate N-(5-cyclopropyl-1-quinoline-5-yl-1H-pyrazole-4-carbonyl)guanidine, to crystalline forms of these Atanasov, methods for producing Atanasov, methods of treatment using Atanassov and mutilates salts obtained using Atanassov

The invention relates to organic chemistry and can find application in medicine

The invention relates to the chemistry of heterocyclic compounds, namely to substituted 1-(pyridinyl-3)-2-azolylmethyl General formula I

where R means a hydrogen atom, an unbranched or branched alkyl with a number of carbon atoms of from one to eight, cycloalkyl with the number of carbon atoms from three to eight, cycloalkenyl with the total number of atoms from four to ten, alkylsilanes with the total number of atoms from four to ten, X denotes a nitrogen atom or CH group, which possess fungicidal activity and can be used as agricultural, industrial, medical or veterinary fungicides

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