1,2,4-triazole derivative, methods for its preparing, pharmaceutical composition, intermediate compound and method for its preparing

FIELD: organic chemistry, medicine.

SUBSTANCE: invention describes a novel triazole derivative of the general formula (I): wherein R1 represents phenyl group optionally substituted with one or two groups chosen from (C1-C6)-alkyl group, (C1-C6)-halogenalkyl group, (C1-C6)-alkoxy-group, (C1-C6)-halogenalkoxy-group, halogen atom, nitro-group or cyano-group, styrenyl group, (C1-C6)-alkoxystyrenyl-group or pyridyl group; R2 represents methyl or amino-group; A and B are carbon atoms; C and D represent independently carbon or nitrogen atom, and its nontoxic salt and pharmaceutical composition based on thereof. Also, invention relates to methods for synthesis of novel compounds, novel intermediate substances of the formula: wherein R2, A, B, C and D have above given values; n means a whole number from 0 to 2, and to a method for their synthesis. Compounds of the formula (I) possess anti-inflammatory activity and can be used potentially in treatment of fever, pain and inflammation.

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

9 cl, 2 tbl, 50 ex

 

The technical field to which the invention relates.

The present invention relates to 1,2,4 triazole derivative or its non-toxic salts, method of its production and pharmaceutical composition containing a specified derivative as an active ingredient.

The level of technology

Most non-steroidal anti-inflammatory agents responsible for blocking the enzyme cyclooxygenase (SOH) or prostaglandin G/H synthase, thereby reducing inflammation, pain or fever. In addition, they inhibit uterine contractions caused by hormones, as well as inhibit the development of certain types of cancer. The cyclooxygenase-1 (MOR-1) was first discovered in bulls. MOR-1 is expressed in various cell types. In contrast to MOR-1, cyclooxygenase 2 (SOH-2) is a recently discovered isoform of cyclooxygenase, which is easily induced by the mitogen, toxin, hormone, growth factor or cytokine.

Prostaglandin is a powerful mediator of various pathological and physiological processes. MOR-1 plays an important physiological role, such as the release of endogenous prostaglandin, physical form, the functioning of the stomach and the renal circulation. On the other hand, MOR-2 is induced by inflammatory factor, hormone,growth factor or cytokine. Therefore, SOH-2 involved with pathological processes of prostaglandin, in contrast to the main MOR-1. In this regard, selectively acting inhibitors SOH-2 produce rare and not severe side effects from the point of view of the mechanism of action compared to conventional non-steroidal anti-inflammatory agents. In addition, they reduce inflammation, pain and fever, and inhibit uterine contractions caused by hormones, and growth of some types of tumors. In particular, they are effective in reducing the side-effects, such as gastrointestinal and renal toxicity. In addition, they inhibit the synthesis contractile of prostanoid, thus, leading to the suppression of the reduction of smooth muscles. Therefore, they can prevent premature birth, irregular menstrually, asthma and eosinophilic disease.

Recently it was reported that non-steroidal anti-inflammatory agents are effective in the treatment of colon cancer [European Journal of Cancer, Vol.37, p.2302, 2001], prostate cancer [Urology, Vol.58, p.127, 2001] and dementia [Exp. Opin. Invest. Drugs, Vol.9, p.671, 2000].

In addition, it is expected that selective inhibitors SOH-2 can be effective in the treatment of osteoporosis and glaucoma. The usefulness of selective MOR-2 inhibitor described John Vane, "Towards a Better Aspirin" in Nature, Vol.367, p.215-216, 1994; Bruno Battistini, Regina Botting and Y.S. Bakhle, "COX-1 and SOH-2: Toward the Development of More Selectve NSAIDs" in Drug News and Perspectives, Vol.7, p.501-512, 1994; David B. Reitz and Karen Seibert, "Selective Ciclooxygenase Inhibitors" in Annual Reports in Medicinal Chemistry, James A. Bristol, Editor, Vol.30, p.179-188, 1995.

Have been known various selective inhibitors SOH-2, with different patterns. Among them, selective MOR-2 inhibitor, has dilloway heterocyclic structure, i.e. tricyclic structure has been extensively studied as a potential candidate. Derilova heterocyclic structure has a Central ring and sulfonamidnuyu or methylsulfonyl group attached to one of the aryl rings. The original connection with such dilloway heterocyclic structure is a Dup697 [Bioorganic & Medicinal Chemistry Letters, Vol.5, p.2123, 1995]. SC-58635, having a pyrazol ring (Journal of Medicinal Chemistry, Vol.40, p.1347, 1997) and MK-966, having furanone ring (WO 95/00501), were identified as derivatives of Dup697.

One of the selective MOR-2 inhibitors, Celecoxib (Celecoxib) formula 58 is disclosed in U.S. 5466823. Celecoxib is a substituted pirazolilzameshchennogo derived.

Formula 58

Another selective MOR-2 inhibitor, Rofecoksib (Rofecoxib) formula 59 is disclosed in WO 95/00501. Rofecoksib has diarylethylene structure with a Central furninova ring.

Formula 59

Valdecoxib (Valdecoxib) formula 60 as another selektivnogo-2 inhibitor disclosed in U.S. 5633272. Valdecoxib has phenylsulfonyl balance Central isoxazoline ring.

Formula 60

Selective MOR-2 inhibitors, are described by formulas 58 through 60, are effective anti-inflammatory therapeutic agents with less and less common side effects compared to conventional non-steroidal anti-inflammatory agents.

The invention

The present invention is the provision of 1,2,4-triazole derivative of formula 1 or its non-toxic salt.

Another objective of the present invention is the provision of a method of obtaining a 1,2,4-triazole derivative or a nontoxic salt.

Another objective of the present invention is to provide pharmaceutical compositions containing the 1,2,4-triazole derivative or its non-toxic salts as the active ingredient in the treatment of fever, pain and inflammation

Still another objective of the present invention is to provide pharmaceutical compositions containing the 1,2,4-triazole derivative or its non-toxic salts as the active ingredient in the treatment of cancer and dementia.

The preferred method of carrying out the invention

According to one aspect of the present invention provides the 1,2,4-resoling derivative of formula 1:

Formula 1

where R1represents a C3-C6cycloalkyl group; C3-C6cycloalkenyl group; phenyl group; a phenyl group substituted by one or more groups selected from the group consisting of C1-C6alkyl group, a C1-C6halogenoalkanes group, C1-C6alkoxygroup, C1-C6halogenlampe, halogen group, amino group, monoalkylamines, dialkylamines, nitro and cyanopropyl; steinley group; C1-C6alkoxystyrene group; or peredelnoj group;

R2represents a methyl or amino group; and

A, b, C and D independently represent carbon or nitrogen;

or their non-toxic salt.

1,2,4-Triazole derivative of formula 1 may be in the form of a non-toxic salt. The term "non-toxic salt", as used in the present description, refers to pharmaceutically acceptable, non-toxic salts, including organic salt and inorganic salt.

Inorganic salt of 1,2,4-triazole derivative of formula 1 includes an inorganic salt of aluminum, ammonium, calcium, copper, iron, lithium, magnesium, manganese, potassium, sodium or zinc without restrictions. Inorganic salt ammonium, calcium, potassium or sodium is predpochtitel is Oh.

Organic salt of 1,2,4-triazole derivative of formula 1 includes an organic salt of a primary, secondary or tertiary amine, substituted amine, which is present in nature or cyclic amine, or salt of a basic ion-exchange resin without restrictions. Examples of salts of a basic ion-exchange resins include, without limitation salt of arginine, betaine, caffeine, choline, N,N-dibenziletilendiaminom, diethylamine, 2-Diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, Ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, N-methylglucamine, glucamine, glucosamine, histidine, N-(2-hydroxyethyl)piperidine, N-(2-hydroxyethyl)pyrrolidine, Isopropylamine, lysine, methylglucamine, research, piperazine, piperidine, resin polyamine, procaine, purine, triethylamine, trimethylamine and Tripropylamine.

1,2,4-Triazole derivative of formula 1 may be in the form of a salt of an organic acid salt or inorganic acid.

Examples of salts of organic acid salt or inorganic acid 1,2,4-triazole derivative of formula 1 include, without limitation, a salt of acetic acid, adipic acid, aspartic acid, 1,5-naphthalenedisulfonic acid, benzosulfimide acid, benzoic acid, camphorsulfonic acid, citric acid, 1,2-ethicolegal acid, econsultancy acid, atlantium votetrustusa acid, fumaric acid, glucoheptonate acid, gluconic acid, glutamic acid, iodine-hydrogen acid, Hydrobromic acid, hydrochloric acid, isetionate acid, lactic acid, maleic acid, malic acid, almond acid, methanesulfonic acid, mucinosa (mucus) acid, 2-naphthalenedisulfonic acid, nitric acid, oxalic acid, pantotenovoi acid, phosphoric acid, pavlikova acid, propionic acid, salicylic acid, stearic acid, succinic acid, sulfuric acid, tartaric acid, p-toluensulfonate acid, undecanoic acid and 10-undecenoic acid. Salt of succinic acid, Hydrobromic acid, hydrochloric acid, maleic acid, methanesulfonic acid, phosphoric acid, sulfuric acid or tartaric acid is preferred.

A preferred group of the 1,2,4-triazole derivative of the present invention is as follows:

1-(4-methanesulfonyl)-5-phenyl-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(4-bromophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3-bromophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(4-forfinal)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3,5-dichloro-4-methoxyphenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

-(4-chlorophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3,4-dichlorophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3,4-acid)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3,4-differenl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

1-(4-methanesulfonyl)-5-(4-methoxyphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3,4-acid)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

1-(4-methanesulfonyl)-5-p-tolyl-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3,4-dimetilfenil)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3-chloro-4-were)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(4-chloro-3-were)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3-chloro-4-methoxyphenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(4-chloro-3-methoxyphenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3-fluoro-4-were)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(4-fluoro-3-were)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3-fluoro-4-methoxyphenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

1-(4-methanesulfonyl)-3-trifluoromethyl-5-(4-(trifluoromethyl)-1H-[1,2,4]triazole;

5-(4-ethoxyphenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

1-(4-methanesulfonyl)-5-(4-trifloromethyl)-3-trifluoromethyl-1H-[1,24]triazole;

5-(4-tert-butylphenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(4-cyanophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-[4-(N-methylamino)-phenyl]-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-[4-(N,N-dimethylamino)-phenyl]-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(4-AMINOPHENYL)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3-triptoreline)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3-methoxyphenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

1-(4-methanesulfonyl)-5-m-tolyl-3-trifluoromethyl-1H-[1,2,4]triazole;

1-(4-methanesulfonyl)-5-o-tolyl-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(2-bromophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(2-methoxyphenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(2,4-differenl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(2,5-differenl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(2,4,5-tryptophanyl)-1-(4-methanesulfonyl-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(2,3-dichlorophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(2,4-dichlorophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3,5-differenl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3,5-acid)-1-(4-shall ethanolgasoline)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(2,4-acid)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3,4,5-trimethoxyphenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(2-fluoro-4-triptoreline)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(2-chloro-4-nitrophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(2,4-dichloro-5-forfinal)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3-fluoro-4-were)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-benzo[1,3]dioxol-5-yl-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(triptoreline)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(4-ethoxyphenyl)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(4-trifloromethyl)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(4-tert-butylphenyl)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(4-cyanophenyl)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(4-AMINOPHENYL)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(4-N-methylaminophenol)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(4-N,N-dimethylaminophenyl)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(3-were)-[1,2,4]triazole-1-yl]pyridine;

5-means lpanel-2-[3-trifluoromethyl-5-(3-triptoreline)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(3-methoxyphenyl)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(2,4-differenl)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(2,5-differenl)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(2,4,5-tryptophanyl)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(2,3-dichlorophenyl)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(2,4-dichlorophenyl)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(3,5-differenl)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(3,5-acid)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(2,4-acid)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(3,4,5-tryptophanyl)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(2-fluoro-4-triptoreline)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(2-chloro-4-nitrophenyl)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(2,4-dichloro-5-forfinal)-[1,2,4]triazole-1-yl]pyridine;

5-methanesulfonyl-2-[3-trifluoromethyl-5-(3-fluoro-4-were)-[1,2,4]triazole-1-yl]pyridine;

2-(5-benzo[1,3]dioxol-5-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)-5-methanesulfonamide;

3-[2-(4-methanesulfonyl)-5-trifluoromethyl-2H-[1,2,4]triazole-3-yl]pyridine;

4-[2-(4-m is consultonline)-5-trifluoromethyl-2H-[1,2,4]triazole-3-yl]pyridine;

5-cyclohexyl-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-cyclohexen-1-yl-1-(4-methanesulfonyl)-3-Cryptor-1H-[1,2,4]triazole;

4-(5-phenyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)benzosulfimide;

4-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl)benzosulfimide;

4-[5-(4-forfinal)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide;

4-[5-(3,4-differenl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide;

4-[5-(4-chlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide;

4-[5-(3,4-dichlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide;

4-[5-(4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide;

4-[5-(3,4-acid)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide;

4-(5-p-tolyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)benzosulfimide;

4-[5-(3,4-dimetilfenil)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide;

4-[5-(3-chloro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide;

4-[5-(4-chloro-3-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide;

4-[5-(3-chloro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide;

4-[5-(4-chloro-3-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide;

4-[5-(3-fluoro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide;

4-[5-(4-fluoro-3-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]bensalah named;

4-[5-(3-fluoro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide;

4-[5-(3,5-dichloro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(4-triptoreline)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(4-ethoxyphenyl)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(4-trifloromethyl)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(4-tert-butylphenyl)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(4-cyanophenyl)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(4-AMINOPHENYL)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(4-N-methylaminophenol)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(4-N,N-dimethylaminophenyl)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-m-tolyl-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(3-triptoreline)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(3-methoxyphenyl)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(2-bromophenyl)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(2-methoxyphenyl)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(2,4-differenl)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(2,5-differenl)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(2,4,5-cryptorf the Nile)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(2,3-dichlorophenyl)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(2,4-dichlorophenyl)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(3,5-acid)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(2,4-acid)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(3,4,5-tryptophanyl)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(2-fluoro-4-triptoreline)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(2-chloro-4-nitrophenyl)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(2,4-dichloro-5-forfinal)-[1,2,4]triazole-1-yl]benzosulfimide;

4-[3-trifluoromethyl-5-(3-fluoro-4-were)-[1,2,4]triazole-1-yl]benzosulfimide;

4-(5-benzo[1,3]dioxol-5-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)benzosulfimide;

4-(5-pyridin-3-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)benzosulfimide;

4-(5-pyridin-4-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)benzosulfimide;

4-(5-cyclohexyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)benzosulfimide;

4-(5-cyclohexen-1-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)benzosulfimide;

5-methanesulfonyl-2-(5-phenyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine;

2-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(4-forfinal)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(3,4-differenl)-3-cryptomate the-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(4-chlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(3,4-dichlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

5-methanesulfonyl-2-[5-(4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine;

2-[5-(3,4-acid)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

5-methanesulfonyl-2-(5-p-tolyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine;

2-[5-(3,4-dimetilfenil)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(3-chloro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(4-chloro-3-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

6-[5-(3-chloro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[5-(4-chloro-3-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[5-(3-fluoro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(4-triptoreline)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(4-ethoxyphenyl)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(4-trifloromethyl)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(4-tert-butylphenyl)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(-cyanophenyl)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(4-AMINOPHENYL)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(4-N-methylaminophenol)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(4-N,N-dimethylaminophenyl)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-m-tolyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(3-methoxyphenyl)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(3-triptoreline)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(2-bromophenyl)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(2-methoxyphenyl)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(2,4-differenl)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(2,5-differenl)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(3,5-differenl)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(2,4,5-tryptophanyl)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(2-fluoro-4-triptoreline)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(2,4-acid)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(3,4,5-trimethoxyphenyl)-1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(2-chloro-4-nitrophenyl)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(2,4-debtor-5-forfinal)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[3-trifluoromethyl-5-(3-fluoro-4-were)-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

2-[5-(4-fluoro-3-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(3-fluoro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(3,5-dichloro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

5-methanesulfonyl-2-((3-pyridinyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine;

5-methanesulfonyl-2-((4-pyridinyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine;

2-(5-cyclohexyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)-5-methanesulfonamide;

2-(5-cyclohexen-1-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)-5-methanesulfonamide;

6-(5-phenyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine-3-sulfonic acid amide;

6-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[5-(4-forfinal)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[5-(3,4-differenl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[5-(4-chlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[5-(3,4-dichlorophenyl)-3-trifluoromethyl-[1,2,triazol-1-yl]pyridine-3-sulfonic acid amide;

6-[5-(4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[5-(3,4-acid)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-(5-p-tolyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine-3-sulfonic acid amide;

6-[5-(3,4-dimetilfenil)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[5-(3-chloro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[5-(4-chloro-3-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[5-(3-chloro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[5-(4-chloro-3-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[5-(3-fluoro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[5-(4-fluoro-3-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[5-(3-fluoro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-[5-(3,5-dichloro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-3-sulfonic acid amide;

6-(5-pyridin-3-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine-3-sulfonic acid amide;

6-(5-pyridin-4-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine-3-sulfonic acid amide;

6-(5-cyclohexyl-3-cryptomate the-[1,2,4]triazole-1-yl)pyridine-3-sulfonic acid amide;

6-(5-cyclohexen-1-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine-3-sulfonic acid amide;

2-methanesulfonyl-5-(5-phenyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine;

5-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-2-methanesulfonamide;

5-[5-(4-forfinal)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-2-methanesulfonamide;

5-[5-(3,4-differenl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-2-methanesulfonamide;

5-[5-(4-chlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-2-methanesulfonamide;

5-[5-(3,4-dichlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-2-methanesulfonamide;

2-methanesulfonyl-5-[5-(4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine;

5-[5-(3,4-acid)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-2-methanesulfonamide;

2-methanesulfonyl-5-(5-p-tolyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine;

5-[5-(3,4-dimetilfenil)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-2-methanesulfonamide;

5-[5-(3-chloro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-2-methanesulfonamide;

5-[5-(4-chloro-3-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-2-methanesulfonamide;

5-[5-(3-chloro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-2-pyridine-2-sulfonic acid amide;

5-[5-(4-chloro-3-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-[5-(3-fluoro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-[5-(4-fluoro-3-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-2-methanesulfonamide;

5-[5-(3-fluoro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-2-methanesulfonamide;

5-[5-(3,5-dichloro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-2-methanesulfonamide;

5-(5-cyclohexyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)-2-methanesulfonamide;

5-(5-cyclohexen-1-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)-2-methanesulfonamide;

5-(5-phenyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine-2-sulfonic acid amide;

5-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-[5-(4-forfinal)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-[5-(3,4-differenl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-[5-(4-chlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-[5-(3,4-dichlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-[5-(4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-[5-(3,4-acid)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-(5-p-tolyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine-2-sulfonic acid amide;

5-[5-(3,4-dimetilfenil)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-[5-(3-chloro-4-were)-3-trifter ethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-[5-(4-chloro-3-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-[5-(3-chloro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-[5-(4-chloro-3-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-pyridine-2-sulfonic acid amide;

5-[5-(3-fluoro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-[5-(4-fluoro-3-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-[5-(3-fluoro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-[5-(3,5-dichloro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine-2-sulfonic acid amide;

5-(5-pyridin-3-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine-2-sulfonic acid amide;

5-(5-pyridin-4-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine-2-sulfonic acid amide;

5-(5-cyclohexyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine-2-sulfonic acid amide;

5-(5-cyclohexen-1-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridine-2-sulfonic acid amide;

3-methanesulfonyl-6-(5-phenyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridazin;

3-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methanesulfonamido;

3-[5-(4-forfinal)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methanesulfonamido;

3-[5-(3,4-differenl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methanesulfonyl dasin;

3-[5-(4-chlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methanesulfonamido;

3-[5-(3,4-dichlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methanesulfonamido;

3-methanesulfonyl-6-[5-(4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazin;

3-[5-(3,4-acid)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methanesulfonamido;

3-methanesulfonyl-6-(5-p-tolyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridazin;

3-[5-(3,4-dimetilfenil)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methanesulfonamido;

3-[5-(3-chloro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methanesulfonamido;

3-[5-(4-chloro-3-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methanesulfonamido;

3-[5-(3-chloro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methanesulfonamido;

3-[5-(4-chloro-3-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methanesulfonamido;

3-[5-(3-fluoro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methanesulfonamido;

3-[5-(4-fluoro-3-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methanesulfonamido;

3-[5-(3-fluoro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methanesulfonamido;

3-[5-(3,5-dichloro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methanesulfonamido;

3-methanesulfonyl-6-(5-pyridin-3-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridazin;

3-methanesulfonyl-6-(5-pyridin-4-yl-3-trifluoromethyl-[1,2,4]three the evils-1-yl)pyridazin;

3-(5-cyclohexyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)-6-methanesulfonamide;

3-(5-cyclohexen-1-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)-6-methanesulfonamide;

6-(5-phenyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridazin-3-sulfonic acid amide;

6-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazin-3-sulfonic acid amide;

6-[5-(4-forfinal)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazin-3-sulfonic acid amide;

6-[5-(3,4-differenl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazin-3-sulfonic acid amide;

6-[5-(4-chlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazin-3-sulfonic acid amide;

6-[5-(3,4-dichlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazin-3-sulfonic acid amide;

6-[5-(4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazin-3-sulfonic acid amide;

6-[5-(3,4-acid)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazin-3-sulfonic acid amide;

6-(5-p-tolyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridazin-3-sulfonic acid amide;

6-[5-(3,4-dimetilfenil)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazin-3-sulfonic acid amide;

6-[5-(3-chloro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazin-3-sulfonic acid amide;

6-[5-(4-chloro-3-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazin-3-sulfonic acid amide;

6-[5-(3-chloro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazin-3-the foreign Ministry sulfonic acid;

6-[5-(4-chloro-3-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazin-3-sulfonic acid amide;

6-[5-(3-fluoro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazine-3-sulfonic acid amide;

6-[5-(4-fluoro-3-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazine-3-sulfonic acid amide;

6-[5-(3-fluoro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazin-3-sulfonic acid amide;

6-[5-(3,5-dichloro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridazin-3-sulfonic acid amide;

6-(5-pyridin-3-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridazin-3-sulfonic acid amide;

6-(5-pyridin-4-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridazin-3-sulfonic acid amide;

6-(5-cyclohexyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridazin-3-sulfonic acid amide;

6-(5-cyclohexen-1-yl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyridazin-3-sulfonic acid amide;

5-methanesulfonyl-2-(5-phenyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyrimidine;

2-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(4-forfinal)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(3,4-differenl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(4-chlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(3,4-dichlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonyl the Dean;

5-methanesulfonyl-2-[5-(4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyrimidine;

2-[5-(3,4-acid)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

5-methanesulfonyl-2-(5-p-tolyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyrimidine;

2-[5-(3,4-dimetilfenil)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(3-chloro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(4-chloro-3-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(3-chloro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(4-chloro-3-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(3-fluoro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-(5-phenyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyrimidine-5-sulfonic acid amide;

2-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyrimidine-5-sulfonic acid amide;

2-[5-(4-forfinal)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyrimidine-5-sulfonic acid amide;

2-[5-(3,4-differenl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyrimidine-5-sulfonic acid amide;

2-[5-(4-chlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyrimidine-5-sulfonic acid amide;

2-[5-(3,4-dichlorophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyrimidine-5-sulfonic acid amide;

2-[5-(4-methoxyphenyl is)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyrimidine-5-sulfonic acid amide;

2-[5-(3,4-acid)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyrimidine-5-sulfonic acid amide;

2-(5-p-tolyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)pyrimidine-5-sulfonic acid amide;

2-[5-(3,4-dimetilfenil)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyrimidine-5-sulfonic acid amide;

2-[5-(3-chloro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyrimidine-5-sulfonic acid amide;

2-[5-(4-chloro-3-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyrimidine-5-sulfonic acid amide;

2-[5-(3-chloro-4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyrimidine-5-sulfonic acid amide;

2-[5-(4-chloro-3-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyrimidine-5-sulfonic acid amide;

2-[5-(3-fluoro-4-were)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyrimidine-5-sulfonic acid amide;

5-styryl-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole; or

5-[2-(4-methoxyphenyl)-vinyl]-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole.

In accordance with another aspect of the present invention is provided Amerasinghe derived as an intermediate compound of formula 4 for the synthesis of 1,2,4-triazole derivative of formula 1:

Formula 4

where R2, A, B1, C and D have the meanings as defined in formula 1, and n is an integer from 0 to 2.

In accordance with another aspect of this is part II of the invention provides a method of obtaining a 1,2,4-triazole derivative of formula 1 or its non-toxic salts, including interaction emersonvega derivative of formula 4A with acylchlorides formula 5 in the presence of a base.

Formula 4A

Formula 5

where R1, R2, A, b, C and D have the meanings as defined in formula 1.

In accordance with another aspect of the present invention provides a method of obtaining a 1,2,4-triazole derivative of formula 1 or its non-toxic salts, including interaction emersonvega derivative of formula 4b with acylchlorides formula 5 in the presence of a base and oxidation of the obtained compound oxidizing agent selected from the group consisting of uranyl monoperoxyphthalate magnesium (MMR), m-chloroperoxybenzoic acid (MSRA) and peroxymonosulfate potassium.

Formula 4b

where R2, A, b, C and D have the meanings as defined in formula 1 and m is 0 or 1.

The above reaction is preferably carried out in polar solvent. Examples of the polar solvent include, without limitation dimethylformamide, 1,4-dioxane, dimethylsulfoxide, N-methylpyrrolidinone or m-xylene.

The reaction is preferably carried out in the temperature range from -10 to 110°C. the reaction Time is determined depending on the reagents. Generally requires a reaction time of 10 min is t to 36 hours.

When the reaction is complete, the products obtained is extracted with water and an organic solvent, such as ethyl acetate, dichloromethane, tetrahydrofuran, and others, to remove the salt. Crude extracts purified using chromatography on a column of silica gel, to obtain the final products.

The base used in the present description, are organic bases or inorganic bases. Preferred organic bases are triethylamine, trimethylamine, Tripropylamine, pyridine or imidazole. Preferred inorganic bases are sodium acetate, sodium hydroxide, sodium hydride, potassium hydroxide, sodium carbonate or potassium carbonate. Pyridine is preferred.

The oxidation reaction is preferably carried out in dichloromethane in the presence of an oxidant. The preferred oxidants are MMRR, MSRWA or peroxymonosulfate potassium.

In accordance with another aspect of the present invention provides a method of obtaining the compounds of formula 1b, including the interaction of the compounds of formula 1A with hydroxylamine or its salt in the presence of a strong base and a Lewis acid.

Formula 1A

Formula 1b

where R1, A, b, C and D have the meanings as defined is prohibited in the formula 1.

In accordance with another aspect of the present invention provides a method of obtaining a 1,2,4-triazole derivative of formula 1b or its non-toxic salts, including interaction of the compounds of formula 6A with hydroxylamine or its salt in the presence of a strong base and Lewis acid and oxidation of the resulting product, using an oxidant selected from the group consisting of MMR, MSRV and peroxymonosulfate potassium.

Formula 6A

where R1, A, b, C and D have the meanings as defined in formula 1 and k has a value of 1 or 0.

The preferred salt of hydroxylamine is hydroxylamine sulfate, hydroxylamine hydrochloride, hydroxylamine phosphate, nitrate, hydroxylamine or hydroxylamine sulfonate.

In order to obtain the compound in which R2represents the amino group in the formula 1, the first compound of the formula 1A or a compound of formula 6A digitalout in tertrahydrofuran ring solvent or ether at a temperature in the range from -78 to 80°in the presence of a strong base, such as alkylate, argillite, chloraniline or chlorosilane. Then, the compound obtained is subjected to interaction with a Lewis acid, such as boralkar, barrel, alkylamine and arylamine in the temperature range from -78 to 80°With subsequent aminer the cation, using hydroxylamine sulphate. Preferably, use sulfate hydroxylamine, because when using an excess of hydroxylamine sulphate, side effects are minimal and the remainder hydroxylamine sulfate and the by-products are easily removed by extraction. After extraction of the crude extract purified using chromatography on a column that produces a product having desirable sulfonamidnuyu group.

In accordance with another aspect of the present invention provides a method of obtaining the compounds of formula 4, which includes the interaction of hydrazine powered derivative of the formula 2 with cryptorchidism formula 3 in the presence of a base.

Formula 2

Formula 3

where R2, A, b, C, D and n have the meanings as defined in formula 4.

The reaction is carried out in a solvent. The preferred solvent is methanol or a mixture solvent of methanol and tetrahydrofuran. The reaction is preferably carried out in the temperature range from -10 to 66°C. the reaction Time is determined depending on the reagents. Preferably the reaction time is from 10 minutes to 48 hours.

When the reaction is fully completed, the reaction mixture is extracted with water and an organic solvent, such as ethyl is Etat, dichloromethane, tetrahydrofuran, and others, to remove the salt. The crude extract was purified using chromatography on a column of silica gel that gives compound of formula 4.

The base used in the present invention is an organic base or inorganic base. Preferably, the organic base is a triethylamine, trimethylamine, Tripropylamine, pyridine, or imidazole. Preferably, the inorganic base is a sodium acetate, sodium hydroxide, sodium hydride, potassium hydroxide, sodium carbonate or potassium carbonate. More preferably using triethylamine.

All crude products obtained by the above reaction, purified using conventional subsequent processing, for example, by chromatography and recrystallization, thus, gives the final products.

The method of obtaining the compounds of formula 1 is expressed by the following scheme 1:

Scheme 1

where R1, R2, A, B, C, D and n have the meanings as defined above.

As hydrazine powered derivative used in scheme 1, apply hydrochloride 4-hydrazinonicotinamide, which can be obtained from the company Maybridge (United Kingdom). Other hydrazine derivatives can be synthesized by themselves or in the form of their hydrochloride is in accordance with known methods [Tetrahedron Letters, vol.28, No42, p.4933, 1987; U.S. Patent No. 4204870; The Journal of Organic Chemistry, vol.56, No. 16, p.4974, 1991; EP 1104759; and Tetrahedron, vol.48, No21, p.6791, 1989]. Methods of synthesis of the main hydrazine derivatives represented on figures 2 through 5.

Scheme 2

In the diagram 2,4-bromothioanisole treated with magnesium to provide the connection of the Grignard reagent. The coupling of the Grignard reagent interacts with diazoketones, and then with hydrogen chloride, to thereby obtain cleaners containing hydrochloride salt of a derivative of hydrazine.

Scheme 3

Figure 3 pyridine derivative interacts with hydrazine monohydrate to provide 2-hydrazinopyridazine derived.

Scheme 4

Figure 4 nitrosamine pyridine derivative restore to aminosilanes pyridine derivative. Then hydrazine powered group is introduced into aminosilane pyridine derivative, resulting in the formation of 3-hydrazinopyridazine derived.

Scheme 5

Figure 5 2-hydrazinopyridazine derived derived from 2,5-dichloropyridine in accordance with the same method presented in scheme 3.

In methods of producing compounds of the present invention the reaction conditions, such as the types and amounts of the solution of the body, bases and reagents are without limitation, those as mentioned above. It is clear that the average person skilled in the art can easily obtain the compounds of the present invention using any combination of methods of synthesis, as described in the description or disclosed in the prior art.

In accordance with another aspect of the present invention is provided a pharmaceutical composition comprising a therapeutically effective amount of 1,2,4-triazole derivative or a nontoxic salt as an active ingredient and a pharmaceutically acceptable carrier for the treatment of fever, pain and inflammation.

The pharmaceutical composition contains a compound of formula 1 or its non-toxic salt when it is a selective inhibitor of cyclooxygenase-2. Therefore, the pharmaceutical composition can be used as antipyretic, analgesic and anti-inflammatory agent with minimal side effects.

Conventional nonsteroidal anti-inflammatory agents selectivity inhibit enzymes of the synthesis of prostaglandins, cyclooxygenase-1 and cyclooxygenase-2. Therefore, there can be many side effects.

On the other hand, the compound of formula 1 and its non-toxic salt selectively inhibit cyclooxygenase-2. Therefore, the usual side effects of nonsteroidal Jarupong is affected, painkillers and anti-inflammatory agents may be reduced.

The pharmaceutical composition of the present invention includes a compound of formula 1 and/or its non-toxic salt, and a pharmaceutically acceptable carrier or excipient. Therefore, the pharmaceutical composition can be used as a substitute to conventional non-steroidal anti-inflammatory agents. In particular, due to the decrease side effects of conventional non-steroidal antipyretic, analgesic and anti-inflammatory agents, the pharmaceutical composition of the present invention, useful for the treatment of patients with peptic ulcer disease, gastritis, regional enteritis, ulcerative colitis, diverticulitis, gastrorrhagia or gipoprotrombinemiey.

The pharmaceutical composition of the present invention can be used for the treatment of all inflammatory diseases associated with pathological prostaglandin, and it is especially useful in the treatment of osteoarthritis and rheumatoid arthritis, which require large doses of non-steroidal anti-inflammatory agents.

The pharmaceutical composition of the present invention can be applied in the form of the adult dosage of 1 mg/day to 1000 mg/day of the compounds of formula 1. Adequate dose is determined depending on the severity of the disease.

In soo is according to another aspect of the present invention provides the pharmaceutical composition, comprising a therapeutically effective amount of 1,2,4-triazole derivative of formula 1 or its non-toxic salts and pharmaceutically acceptable carrier for the treatment of cancer and dementia.

Recently it was reported that non-steroidal anti-inflammatory agents are effective in the treatment of colon cancer [European Journal of Cancer, Vol.37, p.2302, 2001], prostate cancer [Urology, Vol.58, p.127, 2001] and dementia [Exp.Opin. Invest. Drugs, Vol.9, p.671, 2000]. Therefore, it is clear that the pharmaceutical composition of the present invention as non-steroidal anti-inflammatory agent, can also be used in the treatment of these diseases.

The pharmaceutical composition of the present invention can be applied in the form of the adult dosage of 1 mg/day to 1000 mg/day of the compounds of formula 1 or its non-toxic salts. Adequate dosage is determined depending on the severity of the disease.

The pharmaceutical composition of the present invention may be in the form of tablets, effervescent tablets, capsules, granules, powder, tablets with prolonged action, delayed release capsules (single unit or a multiple unit composition), intravenous and intramuscular injection solution, solution injection, suspensions or suppositories, or in other suitable dosage forms.

Forms of pharmaceutical doses of sustained-release soda is RATM active ingredients with or without the initial boot doses. They are fully or partially form of pharmaceutical doses of sustained-release, controlled-input active ingredients.

Preferably, the pharmaceutical composition is for oral administration.

The pharmaceutical composition also includes a pharmaceutically acceptable excipient and/or diluent and/or adjuvant in a pharmaceutically effective amounts.

Examples of excipient and adjuvant include gelatin, natural sugars such as sucrose and lactose, lecithin, pectin, starch such as corn starch and amylose, cyclodextrin and a derivative of cyclodextrin, dextran, polyvinylpyrrolidone, polyvinyl acetate, gum Arabic, arginine acid, xylose, talc, salicylic acid, calcium phosphate, cellulose, cellulose derivative such as methylcellulose, methoxypropylacetate, hypromellose and phthalate of hydroxypropylmethylcellulose, fatty acids having from 12 to 22 carbon atoms, emulsifying agent, oil and grease, in particular, vegetable ester of glycerol and polyglycerol ester of saturated fatty acids, monohydroxy alcohol, a polyhydric alcohol, polyglycol, such as polyethylene glycol, aliphatic alcohol having from 1 to 20 carbon atoms or alifaticheskii saturated or ester of unsaturated fatty is islote, having from 2 to 22 carbon atoms with polyhydric alcohols, such as glycol, glycerol, diethylene glycol, 1,2 propylene glycol, sorbitol and mannitol.

Other suitable adjuvants include baking powder. Examples of disintegrating agents include cross-linked polyvinylpyrrolidone, carboxymethyl sodium starch, sodium carboxymethyl cellulose and microcrystalline cellulose. Can also be used agent for coating tablets, which is traditionally used in this area. Examples of the agent for coating tablets include acrylic acid and/or methacrylic acid and/or ether polymer or copolymer, Zein, ethylcellulose, succinate ethyl cellulose and shellac.

Plasticizers suitable for agent coating the tablets represent the ester of citric acid and the ester of tartaric acid, glycerol and ester of glycerin, or polyethylene glycol with different lengths of chain.

Liquid composition, such as the solution and the suspension is prepared in water or a physiologically acceptable organic solvent, such as ethyl alcohol and an aliphatic alcohol.

Liquid pharmaceutical composition can also include a preservative, such as MES potassium, methyl-4-hydroxybenzoate and propyl-4-hydroxybenzoate, antioxidant, such as ascorbic acid and flavoring, such as peppermint oil.

Chrome is also when the composition of the liquid pharmaceutical compositions can be used conventional solubilizers agent or emulsifier, such as polyvinylpyrrolidone and Polysorbate 80.

Other examples of suitable inert fillers and adjuvants disclosed in Dr.H.P. Fielder, "Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete [encyclopedia of auxiliaries for pharmacy, cosmetics and related fields].

Further, the present invention will be described more specifically by examples. However, the following examples are presented only for illustration and, thus, the present invention is not limited to these examples.

Example 1

N-(4-Methylsulfinylphenyl)triftoratsetatov

Formula 8

Hydrochloride 4-methylsulfonylmethane (1.0 g (5,24 mmol)) dissolved in 40 ml of a solvent mixture of 1:1 methanol and tetrahydrofuran and added dropwise to 0.80 ml (USD 5.76 mmol) of triethylamine. The reaction mixture was stirred at room temperature for 30 minutes and added dropwise to 0.90 g (for 6.81 mmol) 85% of the TRIFLUORIDE acetamidine. The reaction mixture was stirred at room temperature for 24 hours. When the reaction completed, the reaction mixture was added water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer once washed on Ishenim solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered under reduced pressure. The resulting crude product was then purified using flash chromatography on a column (or a mixture of ethyl acetate/n-hexane = 2/8)that give 0.88 g of the above compound in the form of liquid (yield 67%).

1H-NMR (400 MHz, CDCl3): δ to 2.55 (s, 3H), of 5.45 (s, 2H, extended), 7,40 (d, 2H, J=8.0 Hz), 7,60 (d, 2H, J=8.0 Hz), to 9.70 (s, 1H).

Example 2

N-(5-Methanesulfonamido-2-yl)triftoratsetatov

Formula 9

205 mg (yield 54%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds of example 1, except that use of 300 mg (of 1.34 mmol) of the hydrochloride of 5-methanesulfonamido-2-yl hydrazine, instead of hydrochloride of methylsulfonylmethane.

1H-NMR (400 MHz, CDCl3): δ 2,90 (s, 3H), 5,65 (s, 2H, extended), to 6.95 (DD, 1H, J1=9,0 Hz, J2=2,8 Hz), 7,80 (DD, 1H, J1=9,0 Hz, J2=2.0 Hz), to 9.70 (d, 1H, J=2,8 Hz), of 9.75 (s, 1H).

Example 3

N-(2-Methanesulfonamido-5-yl)triftoratsetatov

Formula 10

194 mg (yield 51%) of the titled compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds of example 1, except that use of 300 mg (of 1.34 mmol) of the hydrochloride of 2-metasolv espiridion-5-yl hydrazine, instead of the hydrochloride of 4-methylsulfonylmethane.

1H-NMR (400 MHz, CDCl3): δ at 3.35 (s, 3H), 5,65 (s, 2H, extended), to 6.95 (DD, 1H, J1=9,0 Hz, J2=2,8 Hz), 7,80 (DD, 1H, J1=9,0 Hz, J2=2.0 Hz), to 9.70 (d, 1H, J=2,8 Hz), of 9.75 (s, 1H).

Example 4

N-(6-Methanesulfonamido-3-yl)triftoratsetatov

Formula 11

0.8 g (yield 64%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds of example 1, except using 1.0 g (of 4.45 mmol) of the hydrochloride of 6-methanesulfonamido-3-yl-hydrazine, instead of the hydrochloride of 4-methylsulfonylmethane.

1H-NMR (400 MHz, CDCl3): δ of 3.45 (s, 3H), 7,15 (s, 2H, extended), was 7.45 (d, 1H, J=9.5 Hz), 8,00 (D. 1H, J=9.5 Hz), 10,80 (s, 1H).

Example 5

N-(4-Sulfonatophenyl)triftoratsetatov

Formula 12

0.9 g (yield 68%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds of example 1, except using 1.0 g (4,47 mmol) of the hydrochloride of 4-hydrazinonicotinamide, instead of the hydrochloride of 4-methylsulfonylmethane.

1H-NMR (400 MHz, CDCl3): δ the 5.45 (s, 2H, extended), 7,31 (s, 2H), 7,40 (d, 2H, J=8.0 Hz), 7,60 (d, 2H, J=8.0 Hz), to 9.70 (s, 1H).

Example 6

p> 1-(4-Methylsulfinylphenyl)-5-p-tolyl-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 13

220 mg (0.88 mmol) of N-(4-methylsulfinylphenyl)triftoratsetata dissolved in 5 ml of 1,4-dioxane and added dropwise to 0.08 ml (0.97 mmol) of pyridine. The reaction mixture was stirred at room temperature for 10 minutes and added dropwise to 150 mg (0.97 mmol) of p-trouillard. The reaction mixture is stirred at the boiling temperature under reflux for 24 hours. When the reaction completed, the reaction mixture is cooled to room temperature and there is added water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer once washed with a saturated solution of sodium chloride and dried over anhydrous magnesium sulfate and filtered under reduced pressure. The resulting crude product was then purified using flash chromatography on a column (or a mixture of ethyl acetate/n-hexane = 2:8), which gives 210 mg of the titled compound as oil (yield 65%).

1H-NMR (400 MHz, CDCl3): δ to 2.35 (s, 3H), by 2.55 (s, 3H), 7,15 (d, 2H, J=8.0 Hz), 7,20-7,30 (m, 4H), was 7.45 (d, 2H, J=8.0 Hz).

Example 7

1-(4-Methylsulfinylphenyl)-5-phenyl-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 14

210 mg (71%yield) of the named compound in the form of oil are in accordance with the methodology, Ana is ulichney method for obtaining compounds of example 6, except that using 140 mg (0.97 mmol) of benzoyl chloride instead of p-trouillard. The named compound is used in the next stage without further purification.

Example 8

5-(4-Chlorophenyl)-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 15

210 mg (yield 65%) of the named compound in the form of oil are in accordance with the method similar to the method for obtaining compounds of example 6, except that using 170 mg (0.97 mmol) of 4-chlorobenzylchloride, instead of p-trouillard. The named compound is used in the next stage without further purification or identification.

Example 9

5-(4-Bromophenyl)-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 16

280 mg (yield 76%) of the named compound in the form of oil are in accordance with the method similar to the method for obtaining compounds of example 6, except that the use of 213 mg (0.97 mmol) of 4-bromobenzonitrile, instead of p-trouillard. The named compound is used in the next stage without further purification or identification.

Example 10

1-(4-Methylsulfinylphenyl)-5-(4-methoxyphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 17

203 mg (yield 69%) of the named compound in the form of oil p is to obtain in accordance with the methodology analogous to the methods for obtaining compounds of example 6, except that the use of 165 mg (0.97 mmol) of p-Antillid, instead of p-trouillard. The named compound is used in the next stage without further purification or identification.

Example 11

5-(3-Bromophenyl)-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 18

280 mg (yield 76%) of the named compound in the form of oil are in accordance with the method similar to the method for obtaining compounds of example 6, except that the use of 213 mg (0.97 mmol) of 3-bromobenzonitrile, instead of p-trouillard. The named compound is used in the next stage without further purification or identification.

Example 12

5-(3-Chlorophenyl)-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H- [1,2,4]triazole

Formula 19

182 mg (yield 72%) of the named compound in the form of oil are in accordance with the method similar to the method for obtaining compounds of example 6, except that using 170 mg (0.97 mmol) of 3-chlorobenzylchloride, instead of p-trouillard. The named compound is used in the next stage without further purification or identification.

Example 13

5-(3-Triptoreline)-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 20

209 mg (yield 64%) of the named compound in the form of oil are in accordance with the method similar to the method for obtaining compounds of example 6, except that the use of 202 mg (0.97 mmol) of 3-triftormetilfullerenov, instead of p-trouillard. The named compound is used in the next stage without further purification or identification.

Example 14

5-(2,4-Acid)-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 21

188 mg (yield 54%) of the named compound in the form of oil are in accordance with the method similar to the method for obtaining compounds of example 6, except that the use of 195 mg (0.97 mmol) of 2,4-dimethoxybenzonitrile, instead of p-trouillard. The named compound is used in the next stage without further purification or identification.

Example 15

5-Styryl-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 22

232 mg (yield 73%) of the named compound in the form of oil are in accordance with the method similar to the method for obtaining compounds of example 6, except that the use of 161 mg (0.97 mmol) of cinnamoylcocaine, instead of p-trouillard. The named compound is used in the next stage without further purification or identification.

the example 16

5-[2-(4-Methoxyphenyl)vinyl]-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 23

189 mg (yield 55%) of the named compound in the form of oil are in accordance with the method similar to the method for obtaining compounds of example 6, except that the use of 191 mg (0.97 mmol) of 4-methoxycinnamaldehyde, instead of p-trouillard. The named compound is used in the next stage without further purification or identification.

Example 17

5-(4-Ethoxyphenyl)-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 24

243 mg (yield 73%) of the named compound in the form of oil are in accordance with the method similar to the method for obtaining compounds of example 6, except that the use of 181 mg (0.97 mmol) of 4-ethoxybenzaldehyde, instead of p-trouillard. The named compound is used in the next stage without further purification or identification.

Example 18

5-(4-Tert-butylphenyl)-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 25

282 mg (yield 82%) of the named compound in the form of oil are in accordance with the method similar to the method for obtaining compounds of example 6, except that the use of 193 mg (0.97 mmol) of 4-tert-butylbenzoyl lorida, instead of p-trouillard. The named compound is used in the next stage without further purification or identification.

Example 19

5-(4-Cyanophenyl)-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 26

165 mg (yield 52%) of the named compound in the form of oil are in accordance with the method similar to the method for obtaining compounds of example 6, except that the use of 163 mg (0.97 mmol) of 4-cyanobenzaldehyde, instead of p-trouillard. The named compound is used in the next stage without further purification or identification.

Example 20

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

Formula 27

248 mg (yield 68%) of the named compound in the form of oil are in accordance with the method similar to the method for obtaining compounds of example 6, except that the use of 213 mg (0.97 mmol) of 4-nitro-2-chlorobenzylchloride, instead of p-trouillard. The named compound is used in the next stage without further purification or identification.

Example 21

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

Formula 28

215 mg (yield 61%) of the named compound in the form of oil are in accordance with what logikoi, analogous to the methods for obtaining compounds of example 6, except that the use of 200 mg (0.97 mmol) of 3-chloro-4-methoxybenzylamine, instead of p-trouillard. The named compound is used in the next stage without further purification or identification.

Example 22

5-Benzo[1,3]dioxol-5-yl-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 29

206 mg (yield 59%) of the named compound in the form of oil are in accordance with the method similar to the method for obtaining compounds of example 6, except that use 180 mg (0.97 mmol) of benzo[1,3]dioxol-5-yl of carbonylchloride, instead of p-trouillard. The named compound is used in the next stage without further purification or identification.

Example 23

4-[2-(4-Methylsulfinylphenyl)-5-trifluoromethyl-2H-[1,2,4]triazole-3-yl]pyridine

Formula 30

121 mg (yield 41%) of the named compound in the form of oil are in accordance with the method similar to the method for obtaining compounds of example 6, except that the use of 138 mg (0.97 mmol) of isonicotinamide, instead of p-trouillard. The named compound is used in the next stage without further purification or identification.

Example 24

1-(4-Methanesulfonyl)-5-p-tolyl-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 31

310 mg (0.89 mmol) of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole dissolved in a mixture solvent of dichloromethane (10 ml) and methanol (2 ml) and slowly added dropwise 710 mg (1,16 mmol) of 80% MRR. The reaction mixture was stirred at room temperature for 8 hours. When the reaction completed, the reaction mixture is filtered. The filtrate is washed with sodium bicarbonate and saturated sodium chloride solution (1x each), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting crude product was then purified using flash chromatography on a column (or a mixture of ethyl acetate/n-hexane = 7:3)that give 308 mg (yield 91%) of the named compound as a solid substance.

1H-NMR (400 MHz, CDCl3): δ of 2.45 (s, 3H), 3.15 in (s, 3H), of 7.23 (d, 2H, J=8,2 Hz), 7,38 (d, 2H, J=8,2 Hz), 7,63 (d, 2H, J=8.7 Hz), 8,03 (d, 2H, J=8.7 Hz).

Melting point: 176-178°C.

Example 25

1-(4-Methanesulfonyl)-5-phenyl-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 32

283 mg (yield 86%) of the titled compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds in example 24, except that the use of 300 mg (0.89 mmol) of 1-(4-methylsulfinylphenyl)-5-phenyl-3-Cryptor-1H-[1,2,4]triazole instead of 1-(methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ 3,15 (s, 3H), 7,42-of 7.48 (m, 2H), 7,50-of 7.55 (m, 3H), 7,63 (d, 2H, J=8.6 Hz), 8,03 (d, 2H, J=8.6 Hz).

Melting point: 153-154°C.

Example 26

5-(4-Chlorophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 33

294 mg (yield 82%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds in example 24, except using 330 mg (0.89 mmol) of 5-(4-chlorophenyl)-1-(4-methylsulfinylphenyl)-3-Cryptor-1H-[1,2,4]triazole instead of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ 3,15 (s, 3H), 7,40-to 7.50 (m, 4H), 7,60 (d, 2H, J=6,7 Hz), 8,03 (d, 2H, J=6,7 Hz).

Melting point: 190-192°C.

Example 27

5-(4-Bromophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H- [1,2,4]triazole

Formula 34

365 mg (yield 92%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds in example 24, except that they use 370 mg (0.89 mmol) of 5-(4-bromophenyl)-1-(4-methylsulfinylphenyl)-3-Cryptor-1H-[1,2,4]triazole instead of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ 3,15 (s, 3H), 7,35 (d, 2H, J=8.5 Hz), 7,50-of 7.60 (m, 4H), 8,03 (d, 2H, J=6.3 Hz).

Melting point: 198-199°C.

Example 28

1-(4-Methanesulfonyl)-5-(4-methoxyphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 35

300 mg (yield 85%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds in example 24, except that the use of 325 mg (0.89 mmol) of 1-(4-methylsulfinylphenyl)-5-(4-methoxyphenyl)-3-Cryptor-1H-[1,2,4]triazole instead of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1 H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ 3,15 (s, 3H), 3,90 (s, 3H), 6.90 to (d, 2H, J=6.9 Hz), 7,35 (d, 2H, J=6.9 Hz), the 7.65 (d, 2H, J=8.7 Hz), 8,03 (d, 2H, J=8.7 Hz).

Melting point: 155-156°C.

Example 29

5-(3-Bromophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole.

Formula 36

365 mg (yield 92%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds in example 24, except that they use 370 mg (0.89 mmol) of 5-(3-bromophenyl)-1-(4-methylsulfinylphenyl)-3-Cryptor-1H-[1,2,4]triazole instead of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ 3,15 (s, 3H), 7,35-7,72 (m, 6N), 7,92 (d, 2H, J=8.7 Hz).

Melting point: 195-196°C.

Example 30

5-(3-Chlorophenyl)-1-(4-metasolv ylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 37

326 mg (yield 91%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds in example 24, except using 330 mg (0.89 mmol) of 5-(3-chlorophenyl)-1-(4-methylsulfinylphenyl)-3-Cryptor-1H-[1,2,4]triazole instead of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ the 3.11 (s, 3H), of 7.00 (d, 1H, J=9.0 Hz), 7,28 (m, 1H), 7,35 (d, 1H, J=9.0 Hz), a 7.62 (s, 1H), to 7.64 (d, 2H, J=9,2 Hz), of 8.09 (d, 2H, J=9,2 Hz).

Melting point: 188-190°C.

Example 31

5-(3-Triptoreline)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 38

340 mg (yield 88%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds in example 24, except that the use of 360 mg (0.89 mmol) of 5-(3-triptoreline)-1-(4-methylsulfinylphenyl)-3-Cryptor-1H-[1,2,4]triazole instead of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ 3,10 (s, 3H), 7,56 (m, 1H), to 7.61-to 7.64 (m, 3H), 7,79 (d, 1H, J=4.0 Hz), 7,86 (s, 1H), 8,09 (d, 2H, J=8,8 Hz).

Melting point: 135-137°C.

Example 32

5-(2,4-Acid)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 39

357 mg (yield 94%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds in example 24, except that they use 350 mg (0.89 mmol) of 5-(2,4-acid)-1-(4-methylsulfinylphenyl)-3-Cryptor-1H-[1,2,4]triazole instead of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ the 3.11 (s, 3H), 3,26 (s, 3H), of 3.84 (s, 3H), 6,34 (d, 1H, J=2.4 Hz), of 6.66 (DD, 1H, J=8,4 Hz, J=2.4 Hz), 7,58 (d, 1H, J=8,4 Hz), 7,69 (d, 2H, J=8,8 Hz), 7,98 (d, 2H, J=8,8 Hz).

Melting point: 110-112°C.

Example 33

5-Styryl-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 40

287 mg (yield 82%) of the named compound as a solid gain in accordance with a technique similar to the method for obtaining compounds in example 24, except that the use of 320 mg (0.89 mmol) of 5-styryl-1-(4-methylsulfinylphenyl)-3-Cryptor-1H-[1,2,4]triazole instead of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ 3,15 (s, 3H), 6,83 (d, 1H, J=15,9 Hz), 7,39-7,41 (m, 3H), 7,52-rate of 7.54 (m, 2H), 7,82 (d, 2H, J=8.6 Hz), 8,01 d, 1H, J=15,9 Hz), 8,21 (d, 2H, J=8.6 Hz).

Melting point: 168-170°C.

Example 34

5-[2-(4-Methoxyphenyl)vinyl]-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 41

340 mg (yield 91%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds in example 24, except that they use 378 mg (0.89 mmol) of 5-[2-(4-methoxyphenyl)vinyl]-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole instead of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ 3,17 (s, 3H), 3,85 (s, 3H), 6.75 in (d, 1H, J=15,9 Hz), of 6.96 (d, 2H, J=8.7 Hz), 7,50 (d, 2H, J=8.7 Hz), 7,82 (d, 2H, J=8.6 Hz), 7,95 (d, 1H, J=15,9 Hz), 8,21 (d, 2H, J=8.6 Hz).

Example 35

5-(4-Ethoxyphenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 42

300 mg (yield 82%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds in example 24, except that the use of 337 mg (0.89 mmol) of 5-(4-ethoxyphenyl)-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole instead of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ a 1.45 (t, 3H, J=7,0 Hz)and 3.15 (s, 3H), 4,10 (d, 2H, J=7,0 Hz)6,91 (d, 2H, J=8,9 Hz), was 7.45 (d, 2H, J=8,9 Hz), the 7.65 (d, 2H, J=8.7 Hz), with 8.05 (d, 2H, J=8.7 Hz).

Melting point: 152-154°C.

Example 36

5-(4-tert-Butylphenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1 H-[1,2,4]triazole

Formula 43

343 mg (yield 91%) of the named compound in the form of a solid gain in accordance with the methodology analogous to the methods for obtaining compounds in example 24, except that the use of 348 mg (0.89 mmol) of 5-(4-tert-butylphenyl)-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole instead of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ of 1.30 (s, N)and 3.15 (s, 3H), 7,40-to 7.50 (m, 4H), to 7.68 (d, 2H, J=9.0 Hz), 8,08 (d, 2H, J=9.0 Hz).

Melting point: 81-82°C.

Example 37

5-(4-Cyanophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 44

320 mg (yield 92%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds in example 24, except that the use of 320 mg (0.89 mmol) of 5-(4-cyanophenyl)-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole instead of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ 3,15 (s, 3H), of 7.64 (d, 2H, J=8,8 Hz), to 7.68 (d, 2H, J=8,8 Hz), of 7.75 (d, 2H, J=8.7 Hz), 8,13 (d, 2H, J=8.7 Hz).

Melting point: 109-111°C.

Example 38

5-(4-Nitro-2-chlorophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 45

314 mg (yield 79%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds in the ore 24, except that the use of 369 mg (0.89 mmol) of 5-(4-nitro-2-chlorophenyl)-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole instead of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ 3,15 (s, 3H), 7,51 (d, 2H, J=8.6 Hz), 7,83 (d, 1H, J=9.0 Hz), of 7.97 (d, 2H, J=8.6 Hz), 8,29 (d, 1H, J=9.0 Hz), 8,32 (c, 1H).

Melting point: 110-111°C.

Example 39

5-(3-Chloro-4-methoxyphenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 46

319 mg (yield 83%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds in example 24, except that the use of 356 mg (0.89 mmol) of 5-(3-chloro-4-methoxyphenyl)-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole instead of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ 3,15 (s, 3H), of 3.95 (s, 3H), 6.90 to (d, 1H, J=8.6 Hz), 7,25 (DD, 1H, J1=8.6 Hz, J2=2,5 Hz), of 7.75 (DD, 2H, J1=6,8 Hz, J2=2.0 Hz), 7,76 (d, 1H, J=2.5 Hz), 8,08 (DD, 2H, J1=8.6 Hz, J2=2,0 Hz).

Example 40

5-Benzo[1,3]dioxol-5-yl-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole

Formula 47

322 mg (yield 88%) of the named compound in the form of a solid gain in accordance with a technique similar to m is todoke obtain compound in example 24, except that they use 337 mg (0.89 mmol) of 5-benzo[1,3]dioxol-5-yl-1-(4-methylsulfinylphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole instead of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ 3,15 (s, 3H), equal to 6.05 (s, 2H), PC 6.82 (d, 1H, J=7.5 Hz), 6,97-7,02 (m, 2H), 7,65 (d, 2H, J=8.6 Hz), with 8.05 (d, 2H, J=8.6 Hz).

Example 41

4-[2-(4-Methanesulfonyl)-5-trifluoromethyl-2H-[1,2,4]triazole-3-yl]pyridine

Formula 48

244 mg (yield 72%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds in example 24, except that the use of 299 mg (0.89 mmol) of 4-[2-(4-methylsulfinylphenyl)-5-trifluoromethyl-2H-[1,2,4]triazole-3-yl]pyridine instead of 1-(4-methylsulfinylphenyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, CDCl3): δ 3,15 (s, 3H), 7,45 (d, 2H, J=6.0 Hz), the 7.65 (d, 2H, J=8.0 Hz), 8,10 (d, 2H, J=8.0 Hz), the rate of 8.75 (d, 2H, J=6.0 Hz).

Melting point: 180-182°C.

Example 42

4-(5-p-Tolyl-3-trifluoromethyl-[1,2,4]triazole-1-yl)benzosulfimide

Formula 49

120 mg (0.32 mmol) of 1-(4-Methanesulfonyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole dissolved in 2 ml of anhydrous tetrahydrofuran and the reaction temperature is brought to 0°C. are added dropwise to 0.18 ml (0.54 mmol) of 3 M solution Metalmania chloride tetrahydro the uranium and the reaction temperature was raised to room temperature. The reaction mixture was stirred at the same temperature for 3 hours. Added dropwise 0.9 ml (0.90 mmol) of 1 M solution of tributylamine in tetrahydrofuran and heated to the boiling temperature under reflux for 18 hours. The reaction temperature was lowered to 0°C. Then slowly add a solution in which 150 mg (1,34 mmol) of hydroxylamine-O-sulfonic acid and of 2.56 mg (3,20 mmol) of sodium salt of acetic acid dissolved in 2 ml of water, and the reaction mixture was stirred at room temperature for 3 hours. When the reaction is completed, water is added and the ethyl acetate and then stirred. Then the resulting solution was extracted three times with ethyl acetate. The combined organic layer once washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate, filtered under reduced pressure and concentrated under reduced pressure. The resulting crude product was then purified using flash chromatography on a column (or a mixture of ethyl acetate/n-hexane = 7/3)that give 63 mg (yield 52%) of the named compound as a solid substance.

1H-NMR (400 MHz, DMSO-d6): δ of 2.45 (s, 3H), 7,20 (d, 2H, J=8,2 Hz), 7,35 (d, 2H, J=8,2 Hz), 7,52 (s, 2H), of 7.70 (d, 2H, J=6.6 Hz), 7,98 (d, 2H, J=6.6 Hz).

Melting point: 245-247°C.

Example 43

4-[5-(4-Methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide

Formula 50

img src="https://img.russianpatents.com/836/8368394-s.jpg" height="50" width="66" >

68 mg (yield 53%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds of example 42, except that the use of 127 mg (0.32 mmol) of 1-(4-methylsulfinylphenyl)-5-(4-methoxyphenyl)-3-Cryptor-1H-[1,2,4]triazole instead of 1-(4-methanesulfonyl)-5-p-tolyl-3-Cryptor-1H-[1,2,4]triazole.

1H-NMR (400 MHz, DMSO-d6): δ 3,85 (s, 3H), of 6.96 (d, 2H, J=6.9 Hz), was 7.45 (d, 2H, J=6.9 Hz), 7,55 (s, 2H), of 7.75 (d, 2H, J=8.6 Hz), 7,95 (d, 2H, J=8.6 Hz).

Melting point: 251-253°C.

Example 44

4-[5-(4-Bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide

Formula 51

250 mg (0.88 mmol) of N-(4-sulfonatophenyl)triftoratsetata dissolved in 5 ml of 1,4-dioxane and added dropwise to 0.08 ml (0.97 mmol) of pyridine. The reaction mixture was stirred at room temperature for 10 minutes and added dropwise 212 mg (0.97 mmol) of 4-bromobenzonitrile. The reaction mixture is heated to boiling point under reflux for 24 hours. When the reaction completed, the reaction mixture is cooled to room temperature and there is added water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer once washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and altroot under reduced pressure. The resulting crude product was then purified using flash chromatography on a column (or a mixture of ethyl acetate/n-hexane = 1/1), giving 208 mg (yield 53%) of the titled compound as oil.

1H-NMR (400 MHz, CDCl3): δ 4,95 (broadened s, 2H), 7,39 (d, 2H, J=8.7 Hz), 7,58 to 7.62 (m, 4H), with 8.05 (d, 2H, J=8.7 Hz).

Example 45

2-[5-(4-Bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide

Formula 52

130 mg (0.46 mmol) of N-(5-methanesulfonamido-2-yl)triftoratsetata dissolved in 5 ml of 1,4-dioxane and added dropwise to 0.04 ml (0.51 mmol) of pyridine. The reaction mixture was stirred at room temperature for 10 minutes and added dropwise 115 mg (0.51 mmol) of 4-bromobenzonitrile. The reaction mixture is stirred at a temperature of 110°With under reflux for 24 hours. When the reaction completed, the reaction mixture is cooled to room temperature and there is added water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer once washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered under reduced pressure. The resulting crude product was then purified using flash chromatography on a column (or a mixture of ethyl acetate/n-hexane = 3:7)that give 107 mg (yield 52%) of the named compound as a solid substance.

1 H-NMR (400 MHz, CDCl3): δ of 3.42 (s, 3H), at 7.55 (d, 2H, J=6,7 Hz), of 7.70 (d, 2H, J=6,7 Hz), 8,15 (d, 1H, J=8.5 Hz), 8,65 (DD, 1H, J1=8,5 Hz, J2=2.1 Hz), of 8.95 (d, 1H, J=2.1 Hz).

Melting point: 143-145°C.

Example 46

2-[5-(4-Methoxyphenyl)-3-trifluoromethyl-[1.2.4]triazole-1-yl]-5-methanesulfonamide

Formula 53

108 mg (yield 59%) of the named compound in the form of a solid gain in accordance with a technique similar to the method of obtaining the compound in example 45, except that they use 87 mg (0.51 mmol) of p-Antillid, instead of 4-bromobenzonitrile.

1H-NMR (400 MHz, CDCl3): δ of 3.25 (s, 3H), 3,85 (s, 3H), 6.90 to (d, 2H, J=6.8 Hz), 7,50 (d, 2H, J=6,7 Hz), 7,95 (d, 1H, J=8.5 Hz), to 8.45 (DD, 1H, J1=8,5 Hz, J2=2.1 Hz), of 8.95 (d, 1H, J=2.1 Hz).

Melting point: 138-139°C.

Example 47

2-Methanesulfonyl-5-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl] pyridine

Formula 54

130 mg (0.46 mmol) of N-(2-methanesulfonamido-5-yl)triftoratsetata dissolved in 5 ml of 1,4-dioxane and added dropwise to 0.04 ml (0.51 mmol) of pyridine, the Reaction mixture was stirred at room temperature for 10 minutes and added dropwise 115 mg (0.51 mmol) of 4-bromobenzonitrile. The reaction mixture is stirred at a temperature of 110°With under reflux for 24 hours. When the reaction floor is awn completed, the reaction mixture is cooled to room temperature and there is added water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer once washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered under reduced pressure. The resulting crude product was then purified using flash chromatography on a column (or a mixture of ethyl acetate/n-hexane = 3:7)that give 107 mg (yield 52%) of the named compound as a solid substance.

1H-NMR (400 MHz, CDCl3): δ of 3.42 (s, 3H), at 7.55 (d, 2H, J=6,7 Hz), of 7.70 (d, 2H, J=6,7 Hz), by 8.22 (d, 1H, J=8.5 Hz), 8,55 (DD, 1H, J1=8,5 Hz, J2=2.1 Hz), of 8.95 (d, 1H, J=2.1 Hz).

Melting point: 141-143°C.

Example 48

2-Methanesulfonyl-5-[5-(4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine of Formula 55

108 mg (yield 59%) of the named compound in the form of a solid gain in accordance with a technique similar to the method for obtaining compounds in example 47, except that they use 87 mg (0.51 mmol) of p-Antillid, instead of 4-bromobenzonitrile.

1H-NMR (400 MHz, CDCl3): δ of 3.25 (s, 3H), 3,85 (s, 3H), 6.90 to (d, 2H, J=6.8 Hz), 7,50 (d, 2H, J=6,7 Hz), the 7.85 (d, 1H, J=8.5 Hz), 8,35 (DD, 1H, J1=8,5 Hz, J2=2.1 Hz), of 8.90 (d, 1H, J=2.1 Hz).

Melting point: 136-137°C.

Example 49

3-[5-(4-Bromophenyl)-3-trifluoromethyl-[1,2,4]three the evils-1-yl]-6-methanesulfonamido

Formula 56

310 mg (1,09 mmol) of N-(6-methanesulfonamido-3-yl)triftoratsetata dissolved in 10 ml of 1,4-dioxane and added dropwise to 0.10 ml (1.20 mmol) of pyridine. The reaction mixture was stirred at room temperature for 10 minutes and added dropwise 264 mg (1.20 mmol) of 4-bromobenzonitrile. The reaction mixture is stirred at a temperature of 110°With under reflux for 24 hours. When the reaction completed, the reaction mixture is cooled to room temperature and there is added water and ethyl acetate. The aqueous layer was extracted twice with ethyl acetate. The combined organic layer once washed with a saturated solution of sodium chloride, dried over anhydrous magnesium sulfate and filtered under reduced pressure. The resulting crude product was then purified using flash chromatography on a column (or a mixture of ethyl acetate/n-hexane = 3:7), giving 220 mg (yield 45%) of the named compound as a solid substance.

1H-NMR (400 MHz, CDCl3): δ of 3.42 (s, 3H), at 7.55 (d, 2H, J=8.5 Hz), a 7.62 (d, 2H, J=8.5 Hz), scored 8.38 (d, 1H, J=9.0 Hz), to 8.45 (d, 1H, J=9.0 Hz).

Melting point: 174-181°C.

Example 50

3-[5-(4-Methoxyphenyl)-3-trifluoromethyl-[1.2.4]triazole-1-yl]-6-methanesulfonamido

Formula 57

183 mg (yield 42%) of the named compound in the form of a solid floor is given in accordance with the methodology analogous to the methods for obtaining compounds in example 49, except that the use of 205 mg (0.51 mmol) of p-Antillid, instead of 4-bromobenzonitrile.

1H-NMR (400 MHz, CDCl3): δ of 3.42 (s, 3H), 3,85 (s, 3H), 6,85 (d, 2H, J=6.8 Hz), 7,55 (d, 2H, J=6.8 Hz), to 8.20 (d, 1H, J=9.1 Hz), 8,35 (d, 1H, J=9.1 Hz).

Melting point: 185-186°C.

Experiments

1. Evaluation of selective MOR-2 inhibitory activity

1) Method

To pharmacologically to determine the selective MOR-2 inhibitory activity, measure the percentage of inhibition of MOR-1 and MOR-2 compounds of the present invention, shown in the examples, using the following methods.

A. The study of MOR-1 inhibitory activity, using U-937

Lymph cells are human U-937 (Korean Cell Line Bank, Seoul, Korea, Accession Number: 21593) cultivate and centrifuged. The collected cells were diluted with HBSS (x1, balanced salt Hanks solution) to a concentration of 1×106cells/ml 1 ml of the diluted cell solution was placed in each well of a 12-cell tablets, 5 μl of 1 μm solution of test compound in DMSO, and 5 μl of DMSO as a control added to the wells. The wells incubated in CO2the incubator at a temperature of 37°C for 15 minutes. Separately, 10 mm storable solution of arachidonic acid in ethanol, diluted ten times in ethanol to obtain 1 mm is actor arachidonic acid. Arachidonic acid acts as a substrate. Add 10 μl of 1 mm solution of arachidonic acid to each well and incubated in CO2the incubator at a temperature of 37°C for 30 minutes. The cell solution in each well is placed in a centrifuge test tube and centrifuged with a speed of 10,000 rpm at a temperature of 4°C for 5 minutes. The concentration of PGE2 in the collected cells and supernate determine quantitatively using monoclonal kit (Cayman Chemicals). Calculate the percent inhibition of PGE2 in the test group treated with the compound of the cells, with respect to the group of cells treated with DMSO. Based on calculated values oceanaut MOR-1 inhibitory activity.

b. The study of MOR-2 inhibitory activity using cell line RAW 264.7

2×106cells cell line RAW 264.7 (Korean Cell Line Bank, Seoul, Korea, Accession Number. 40071) are placed in each of the holes 12-cell plates. Each plate treated with 250 μm of aspirin and incubated at 37 ° °C for 2 hours. After replacement of the culture medium to a new cultural environment, a new culture medium treated with the test compound (10 nm) and incubated for 30 minutes. Then each well is treated with interferon ((100 units/ml) and lipolysaccharide (LPS, 100 ng/ml) and incubated for 18 hours. Cultural cf who do move into other test tubes. The concentration of PGE2 determine quantitatively using EIA kit (Cayman Chemicals).

2) test Results

The results of the tests are presented in Table 1 below. The percentage inhibition of MOR was calculated according to the following equation:

The percentage of inhibition = (PGE2 concentration in the tested raw sample connection) - the concentration of PGE2 in the tested processed sample of the compound)/(concentration of PGE2 in the tested raw sample connection)×100

Table 1

The percentage inhibition of cyclooxygenase (SOH)
SamplesCOX-1 (1 μm)MOR-2 (10 nm)
Link (Valdecoxib)28.85.47
Example 2529.27.62
Example 2638.810.53
Example 2713.816.04
Example 2810.128.62
Example 2916.76.23
Example 3018.67.32
Example 3116.55.66
Example 3219.912.6
Example 3319.219.23
Example 3423.526.82
Example 3511.838.65
Example 3621.66.23
Example 3723.78.92
Example 3819.55.95
Example 3912.532.62
Example 4018.7At 33.73
Example 4116.78.88
Example 4238.012.08
Example 4334.632.32
Example 4423.129.86
Example 4514.633.63
Example 4612.642.32
Example 4721.94.26
Example 4828.85.63
Example 4914.63.21
Example 5010.64.32

3) Evaluation

The test results obtained in vitro relative percent inhibition of MOR-1 and MOR-2, listed in Table 1.

As shown in Table 1, the ratio of inhibition (%) MOR-1 MOR-2 in examples 24 and 50 were equal to or higher than the reference Valdecoxib. This indicates n is then, that selective inhibition of MOR-1 to YEAR-2 this connection is the same or exceeds the connections on the link. In particular, in the case

1-(4-methanesulfonyl)-5-(4-methoxyphenyl)-3-Cryptor-1H-[1,2,4]triazole from example 28,

1-(4-methanesulfonyl)-5-(4-ethoxyphenyl)-3-Cryptor-1H-[1,2,4]triazole from example 35,

5-(3-chloro-4-methoxyphenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole from example 39,

5-benzo[1,3]dioxol-5-yl-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole from example 40,

4-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide from example 44,

2-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methysulfonylmethane of example 45, and

2-[5-(4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide from example 46, SOH-2 inhibiting activity was significantly higher compared with the data links. At the same time, MOR-1 inhibiting activity was similar or lower than in the reference. Thus, it should be noted that these compounds have excellent selectivity.

All connections from the examples, in addition to the compounds of examples 47, 49, and 50 showed MOR-2 inhibitory activity was higher than in the reference. Based on this result, it should also be noted that this compound reduces side effects by increasing the selectivity and improves effective is the terrain in the treatment of fever, pain and inflammation compared with the connection of the links.

2. Test for swelling of the paws of rats caused by carragenan

1) Method

For the day of testing, rats were selected in each group so that the average body weight was the same and rats were not fed until the day of testing. On the day of testing, rats were administered orally tested compounds and the reference product. After an hour volume (V0h) a predetermined portion of the left hind leg of the rat was measured using plethysmometer. In the left hind leg of rats subcutaneously injected with 100 μl of 1% solution of Cartagena, using a syringe with a volume of 1 ml. three hours after the injection of Cartagena, again measured volume (V3h) predetermined the left hind leg of the rat. Changes associated with tumor feet (T3h-T0hin the group of rats treated with the test compound, compared with the group of rats treated with the control product. Assuming that the percentage of inhibition of the group of rats treated with the control product, 0%, determine the percent inhibition of each test compound in swelling.

2) test Results

The results of the tests are presented in Table 2 below.

Table 2

Inhibitory effect (% inhibition) of cyclooxygenase (SOH)
Sample the Inhibitory effect (% inhibition)
Link 1 (Indomethacin)40.1
Link 2 (Celecoxib)23.9
Example 2721.7
Example 2823.3
Example 3419.3
Example 3532.3
Example 4339.1
Example 4428.8
Example 4521.6
Example 4633.4

3) Evaluation

The test results obtained in vitro relative percent inhibition of MOR listed in Table 2.

As shown in Table 2, the percentage of inhibition of the compounds in examples 27 to 46 against SOH was almost the same or higher than Celecoxib. This indicates that the compounds of the present invention have almost the same or higher MOR inhibitory efficiency compared with Celecoxib. In particular, in the case

1-(4-methanesulfonyl)-5-(4-ethoxyphenyl)-3-Cryptor-1H-[1,2,4]triazole from example 35,

4-[5-(4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide from example 43,

4-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide from example 44, and

2-[5-(4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methysulfonylmethane of PR is a measure 46, SOKH inhibiting efficiency was significantly higher compared with Celecoxib.

In addition, all the compounds of examples, in addition to the compounds of example 34, showed the same or higher inhibitory efficacy against MOR than Celecoxib. Therefore, it should be noted that the compounds of the present invention have better efficacy in the treatment of fever, pain and inflammation.

Industrial applicability

As follows from the above description, the present invention provides 1,2,4 triazole derivative or a nontoxic salt, method of its production and pharmaceutical composition containing the derivative or salt as an active ingredient. The pharmaceutical composition is effective in treating fever, pain and inflammation. In particular, by reducing the side effects of conventional non-steroidal anti-inflammatory agents, pharmaceutical composition useful for the treatment of patients with the disease peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulectomy, gastrorrhagia or gipoprotrombinemiey.

While the present invention particularly disclosed and described with reference to typical embodiments, the average person skilled in the art will be aware what can be made of various ISM is in the form and details of the invention, without deviation from the spirit and scope of the study the present invention, as defined in accordance with the following claims.

1. 1,2,4-Triazole derivative of the formula I

where R1represents a phenyl group, optionally substituted by one or two groups selected from C1-C6alkyl group, a C1-C6halogenoalkanes group, C1-C6alkoxygroup, halogen group, nitro group or cyanopropyl; storeyline group; C1-C6alkoxystyrene group; or pyridyloxy group;

R2represents a methyl or amino group;

A and b are carbon;

C and D independently represent carbon or nitrogen,

or its non-toxic salt.

2. 1,2,4-Triazole derivative according to claim 1, which is selected from the group consisting of:

1-(4-methanesulfonyl)-5-phenyl-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(4-chlorophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(4-bromophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

1-(4-methanesulfonyl)-5-(4-methoxyphenyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3-bromophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3-chlorophenyl)-1-(4-metasolv milfoil)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(3-triptoreline)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(2,4-acid)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(styryl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-[2-(4-methanesulfonyl)vinyl]-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(4-ethoxyphenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(4-tet.-butylphenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(4-cyanophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(4-nitro-2-chlorophenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

5-(4-chloro-4-methoxyphenyl)-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4] triazole;

5-benzo[1,3]dioxol-5-yl-1-(4-methanesulfonyl)-3-trifluoromethyl-1H-[1,2,4]triazole;

4-[2-(4-methanesulfonyl)-5-trifluoromethyl-2H-[1,2,4]triazole-3-yl]pyridine;

4-(5-p-tolyl-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzene-sulfanilamide;

4-[5-(4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide;

4-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]benzosulfimide;

2-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanesulfonamide;

2-[5-(4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-5-methanol is Anileridine;

2-methanesulfonyl-5-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]pyridine;

2-methanesulfonyl-5-[5-(4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-pyridine;

3-[5-(4-bromophenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methysulfonylmethane;

3-[5-(4-methoxyphenyl)-3-trifluoromethyl-[1,2,4]triazole-1-yl]-6-methysulfonylmethane,

or its non-toxic salt.

3. Amerasinghe derivative of formula 4

where R2, A, b, C, D have the meanings defined in claim 1;

n is an integer from 0 to 2.

4. A method of obtaining a 1,2,4-triazole derivative of formula 1

or its non-toxic salts, which consists in the fact that Amerasinghe derivative of formula 4A

interacts with acylchlorides formula 5

in the presence of a base,

where R1, R2, A, b, C, and D have the meanings given in claim 1.

5. A method of obtaining a 1,2,4-triazole derivative of formula 1

or its non-toxic salts, including interaction emersonvega derivative of formula 4b

with acylchlorides formula 5

in the presence of a base and oxidation of the compounds obtained by oxidizing agent, such as uranyl monoperoxyphthalate magnesium (MMR),

where R1, R2, A, b, C, and D have the meanings defined in claim 1, and m has a value of 0.

6. The method of obtaining the compounds of formula 1b

including the interaction of the compounds of formula 1A

with hydroxylamine or its salt in the presence of a strong base and a Lewis acid

where R1, A, b, C, and D have the meanings given in claim 1.

7. A method of obtaining a 1,2,4-triazole derivative of formula 1b

or its non-toxic salts, including interaction of the compounds of formula 6A

with hydroxylamine or its salt in the presence of a strong base and the Lewis acid and the oxidation of the compounds obtained by oxidizing agent, such as MRR,

where, R1, A, b, C, and D have the meanings defined in claim 1, and k is set to 0.

8. The method of obtaining the compounds of formula 4

including interaction hydrazine derivative of formula 2

with cryptorchidism formula 3

in the presence of a base,

where R2, A, b, C, and D have the meanings defined in claim 1, and n is an integer from 0 to 2.

9. Pharmaceutical composition having anti-inflammatory activity, containing as active ingredient a therapeutically effective amount of 1,2,4-triazole derivative or a nontoxic salt according to claim 1 and a pharmaceutically acceptable carrier.



 

Same patents:

FIELD: organic chemistry of heterocyclic compounds, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of pyrimidine of the general formula (I) and their pharmaceutically acceptable acid-additive salts possessing properties of neurokinin-1 (NK) receptors antagonists. In the general formula (I): R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)n-N(R)2, -N(R)2 or cyclic tertiary amine as a group of the formula: R1 means lower alkyl, lower alkoxyl, pyridinyl, pyrimidinyl, phenyl, -S-lower alkyl, -S(O2)-lower alkyl, -N(R)-(CH2)n-N(R)2, -O-(CH)-N(R)2, -N(R)2 or cyclic tertiary amine of the formula: that can comprise additional heteroatom chosen from atoms N, O or S, and wherein this group can be bound with pyrimidine ring by bridge -O-(CH2)n-; R2 means hydrogen atom, lower alkyl, lower alkoxyl, halogen atom or trifluoromethyl group; R3/R3' mean independently of one another hydrogen atom or lower alkyl; R4 means independently of one another halogen atom, trifluoromethyl group or lower alkoxyl; R means hydrogen atom or lower alkyl; R means independently of one another hydrogen atom or lower alkyl; X means -C(OH)N(R)- or -N(R)C(O)-; Y means -O-; n = 1, 2, 3 or 4; m means 0, 1 or 2. Also, invention relates to a pharmaceutical composition comprising one or some compounds by any claim among claims 1-19 and pharmaceutically acceptable excipients. Proposed compounds can be used in treatment, for example, inflammatory diseases, rheumatic arthritis, asthma, benign prostate hyperplasia, Alzheimer's diseases and others.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

21 cl, 1 tbl, 76 ex

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

SUBSTANCE: invention relates to compounds of the formula (I)

or their pharmaceutically acceptable salts or esters hydrolyzing in vivo and possessing activity inhibiting the cellular cycle and selective with respect to CDK-2, CDK-4 and CDK-6. Compounds can be used in cancer treatment. In the formula (I) R1 represents halogen atom, amino-group, (C1-C)-alkyl, (C1-C6)-alkoxy-group; p = 0-4 wherein values R1 can be similar or different; R2 represents sulfamoyl or group Ra-Rb-; q = 0-2 wherein values R2 can be similar or different and wherein p + q = 0-5; R3 represents halogen atom or cyano-group; n = 0-2 wherein values R3 can be similar or different; R4 represents hydrogen atom, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, phenyl or heterocyclic group bound with carbon atom wherein R4 can be optionally substituted at carbon atom with one or some groups Rd; R5 and R6 are chosen independently from hydrogen, halogen atom, (C1-C)-alkyl, (C2-C6)-alkenyl or (C3-C8)-cycloalkyl wherein R5 and R6 can be substituted at carbon atom independently of one another with one or some groups Re; Ra is chosen from (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C3-C8)-cycloalkyl, (C3-C8)-cycloalkyl-(C1-C6)-alkyl, phenyl, heterocyclic group, phenyl-(C1-C)-alkyl or (heterocyclic group)-(C1-C6)-alkyl wherein Ra can be substituted optionally at carbon atom with one or some groups Rg and wherein if indicated heterocyclic group comprises residue -NH- then its nitrogen atom can be optionally substituted with group chosen from the group Rh; Rb represents -N(Rm)C(O)-, -C(O)N(Rm)-, -S(O)r-, -OC(O)N(Rm)SO2-, -SO2N(Rm)- or -N(Rm)SO2- wherein Rm represents hydrogen atom or (C1-C6)-alkyl, and r = 1-2. Also, invention relates to methods for synthesis of these compounds, a pharmaceutical composition, method for inhibition and using these compounds.

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

24 cl, 3 sch, 166 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for synthesis of 1-91-methyl-2-(3,4-fullero[60]-pyrrolidinyl))-1H-1,2,4-triazole of the general formula (1): Method involves interaction of fullerene[60] with N-[(1,2,4-triazol-1-yl)methyl]-N,N-dimethylamine of the general formula: (R-CH2-N-(CH3)2 wherein R means taken in the mole ratio C60 : R-CH2-N-(CH3)2 = 0.01:(0.01-0.011) in the presence of Cp2TiCl2 as a catalyst taken in the amount 15-25 mole% relatively to fullerene[60], in argon atmosphere, in toluene medium as a solvent at temperature 140-160°C for 2-4 h. The end substance is prepared with the yield 78-86%. Compound of the formula (1) can be used as chelating agent, sorbent, biologically active compound and in the development of novel materials with required electronic, magnetic and optical properties.

EFFECT: improved method of synthesis.

1 tbl, 1 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: herbicides.

SUBSTANCE: invention relates to application of 2-diethylamino-6-methoxy-4-[(4'-ethoxycarnonyl-5'-methyl-1',2',3'-triazole)-1'yl]1,3,5,-triazine of formula as antidote against phytotoxic action of 2,4-dichlorophenoxyacetic acid herbicide onto germinated sunflower seeds.

EFFECT: more effective sunflower germ root length and hypocotyl elongation on background of phytotoxic 2,4-D herbicide action.

2 tbl, 3 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of N-heterocyclic compounds of the formula: , wherein n and m mean independently a whole number from 1 to 4; A means -C(O)OR1 or -C(O)N(R1)R2; W means -CH; R1 means hydrogen atom or (C1-C8)-alkyl; R means hydrogen atom, (C1-C8)-alkyl, heterocyclyl-(C1-C4)-alkyl chosen from the group comprising benzodioxolyl-, benzodioxanyl- or dihydrobenzofuranylalkyl or phenyl-(C1-C4)-alkyl substituted possibly with alkoxy-group; R4 means cyano-group or heterocyclyl chosen from the group comprising pyridinyl, morpholinyl, benzodioxolyl or benzodioxanyl-radical if m = 1; if m means from 2 to 4 then R4 can mean additionally hydroxy-group, -NR1R2 wherein R1 and R2 mean independently hydrogen atom, (C1-C8)-alkyl or benzyl-radical, -N(R1)-C(O)-R1, -N(R1)-C(O)-OR1, -N(R1)-S(O)t-R1 wherein R1 means hydrogen atom or (C1-C8)-alkyl, -N(R1)-C(O)-N(R1)2 wherein R1 means hydrogen atom; R5 means (C1-C8)-alkyl; t = 2, and their stereoisomers and pharmaceutically acceptable salts, pharmaceutical composition based on thereof and a method for treatment of diseases, in particular, rheumatic arthritis.

EFFECT: valuable medicinal properties of compounds and composition.

12 cl

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the general formula (I) in racemic form, enantiomer form or in any combinations of these forms possessing affinity to somatostatin receptors. In the general formula (I): R1 means phenyl; R2 means hydrogen atom (H) or -(CH2)p-Z3 or one of the following radicals: and Z3 means (C3-C8)-cycloalkyl, possibly substituted carbocyclic or heterocyclic aryl wherein carbocyclic aryl is chosen from phenyl, naphthyl and fluorenyl being it can be substituted, and heterocyclic aryl is chosen from indolyl, thienyl, thiazolyl, carbazolyl, or radicals of the formulae and and it can be substituted with one or some substitutes, or also radical of the formula: R4 means -(CH2)p-Z4 or wherein Z4 means amino-group, (C1-C12)-alkyl, (C3-C8)-cycloalkyl substituted with -CH2-NH-C(O)O-(C1-C6)-alkyl, radical (C1-C6)-alkylamino-, N,N-di-(C1-C12)-alkylamino-, amino-(C3-C6)-cycloalkyl, amino-(C1-C6)-alkyl-(C3-C6)-cycloalkyl-(C1-C6)-alkyl, (C1-C12)-alkoxy-, (C1-C12)-alkenyl, -NH-C(O)O-(C1-C6)-alkyl, possibly substituted carbocyclic or heterocyclic aryl; p = 0 or a whole number from 1 to 6 if it presents; q = a whole number from 1 to 5 if it presents; X means oxygen (O) or sulfur (S) atom n = 0 or 1. Also, invention relates to methods for preparing compounds of the general formula (I), intermediate compounds and a pharmaceutical composition. Proposed compounds can be used in treatment of pathological states or diseases, for example, acromegaly, hypophysis adenomas, Cushing's syndrome and others.

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

11 cl, 2 tbl

FIELD: organic chemistry, herbicides, agriculture.

SUBSTANCE: invention describes using 4,6-bis-(diethylamino)-2-[(2'-tetrazol-(2'H)-5'yl]-1,3,5-triazine of the formula: as an antidote against phytotoxic effect of herbicide 2,4-dichlorophenoxyacetic acid on sunflower germinated seeds. The proposed substance shows the enhanced effectiveness in increasing roots and hypocotyls length of seedlings and to expand assortment of the known antidotes.

EFFECT: valuable properties of antidote.

2 cl, 2 tbl, 3 ex

FIELD: medicine, pharmacy.

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

EFFECT: improved and valuable properties of compounds.

6 cl, 5 tbl, 19 ex

FIELD: organic chemistry, biochemistry, pharmacy.

SUBSTANCE: invention relates to new compounds of the formula (I):

eliciting inhibitory activity with respect to metalloproteinases and wherein R1 means phenoxy-group wherein phenyl residue can be substituted with one or some halogen atoms, hydroxy-, (C1-C6)-alkoxy-group, (C1-C6)-alkyl, cyano- or nitro-group; R2 means pyrimidine, pyrazine or its N-oxide or phenyl substituted with -SO2NR3R4 wherein R3 and R4 can be similar or different and mean hydrogen atom, direct-chain or branch-chain (C1-C6)-alkyl that can be substituted once or some times with the group OH, N(CH3)2, or it can be broken by oxygen atom, or it represents COR5 wherein R5 means (C1-C)-alkyl group that can be substituted with NH2. Also, invention relates to a pharmaceutical composition comprising above said compounds.

EFFECT: valuable biochemical properties of compounds and composition.

5 cl, 1 sch, 1 tbl, 10 ex

FIELD: medicine, pediatrics, pharmacy.

SUBSTANCE: invention relates to formulation of antibacterial preparation gatifloxacin prepared as a crystalline combined sediment of gatifloxacin and fatty acid. Method involves dissolving gatifloxacin and fatty acid in the weight ratio from 1:1.8 to 1:2.3 in solvent at heating up to boiling with reflux condenser, boiling this solution with reflux condenser for 2-3 h at stirring, cooling this solution at stirring to temperature about 18°C for 2.5-4 h to precipitate of crystalline combined sediment of gatifloxacin and fatty acid, keeping the prepared suspension of crystalline combined sediment at temperature 15-20°C for 2-4 h and isolating and drying the crystalline combined sediment. Also, invention describes a pharmaceutical composition used in treatment of infections and a method for treatment of infection by using the novel formulation of gatofloxacin. Crystalline combined sediment of gatifloxacin with stearic or palmitic acids taken in the narrow range of weight ratios masks bitter taste of gatifloxacin effectively.

EFFECT: improved preparing method, improved and valuable pharmaceutical properties of drug.

10 cl, 2 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of novel derivatives of 4,5-dihydro-1H-pyrazole that are strong antagonists of cannabinoid (CB1) receptor and useful in treatment of diseases associated with disorders of cannabinoid system. Compounds have the general formula (Ia) or (Ib) wherein symbols are given in the invention claim. Also, invention relates to method for synthesis of these compounds, their using, intermediate compounds for synthesis of proposed compounds and to a pharmaceutical composition comprising at least one of these compounds as an active component.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

15 cl, 1 tbl, 100 ex

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

SUBSTANCE: invention relates to novel derivatives of heteroaryl-substituted aminocyclohexane of the formula (I) and their pharmaceutically acceptable salts possessing the inhibitory effect on activity of 2,3-oxydosqualene-lanosterolcyclase (OSC). In the formula (I) V means a simple bond, oxygen atom (O), -CH=CH-CH2- or -C≡C-; m and n = 0-7 independently of one another and m+n = 0-7 under condition that m is not 0 if V means O; o = 0-2; A1 means hydrogen atom, lower alkyl, hydroxy-lower alkyl or lower alkenyl; A2 means lower alkyl, or A1 and A2 are bound and form 5-6-membered cycle, and -A1-A2- means (C4-C5)-alkylene; A3 and A4 mean hydrogen atom independently of one another; A5 means hydrogen atom, lower alkyl; A6 means pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl optionally substituted with one substitute chosen independently from the group including halogen atom, lower alkyl, lower alkoxy-group and 5-6-membered heteroaryl comprising nitrogen or sulfur atom as a heteroatom, Also, invention relates to a pharmaceutical composition and using proposed compound for preparing medicinal agents. Proposed compounds can be used in treatment of such diseases as hypercholesterolemia, hyperlipemia, arteriosclerosis, vascular diseases, mycosis, parasitic infections, cholelithiasis, tumors and/or hyperproliferative disorders, and/or in disordered tolerance to glucose and diabetes mellitus.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

24 cl, 7 sch, 28 ex

FIELD: organic chemistry.

SUBSTANCE: invention relates to method for production of tetrasubstituted imidazole derivatives of formula I , wherein R1 represents phenyl optionally substituted with halogen atom or trifluorimethyl; R2 represents heteroaryl, namely 5 or 6 membered monocyclic aromatic ring system containing one heteroatom, such as nitrogen; R3 represents hydrogen or aryl(C1-C5)-alkyl; R4 represents group of formula wherein p = 0-9, integer represents hydroxy; or pharmaceutically acceptable salts thereof. Claimed method includes reaction of compound of formula VIII , wherein L1 and L2 are independently C1-C4-alkyl and R1 and R2 are as mentioned above; with compound of formula X , wherein R3 has abovementioned meanings to produce respective compound of formula XI , wherein R1, R2, R3, R4, L1 and L2 have abovementioned meanings; cycling of XI in acidic conditions at pH approximately 7 to produce respective compound of formula XII , wherein R1, R2 and R3 have abovementioned meanings; reaction of XII with POBr3 PBr5 or mixture thereof to produce respective compound of formula XIII , wherein R1, R2 and R3 have abovementioned meanings; bromine substitution in XIII by reaction thereof with compound of formula XIV: H-R4 to produce respective compound of formula I. Method for production of intermediated and crystal form of compound of formula II also are disclosed.

EFFECT: new compound with p38 kinase inhibiting activity.

20 ck, 2 tbl, 12 ex

FIELD: organic chemistry, pharmacy.

SUBSTANCE: invention describes a novel salt of desloratadine, namely, desloratadine semisulfate of the formula: and a method for synthesis of the parent compound, namely, desloratadine disulfate used in preparing semisulfate and a pharmaceutical composition containing a novel salt. Desloratadine semisulfate possesses improved solubility that provides advantage in preparing the pharmaceutical composition.

EFFECT: improved properties of compound.

5 cl, 6 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to anthranylamide derivative selected from compound of formula I or N-oxides thereof, wherein R1 represents methyl, F, Cl, Br; R2 represents F, Cl, Br, I, CF3; R3 represents CF3, Cl, Br, OCH2CF3; R4a represents C1-C4-alkyl; R4b represents H, CH3; and R5 represents Cl, Br, and agriculturally acceptable salt thereof. Also disclosed are composition for pest controlling containing biologically effective amount of formula I and at least one additional component selected from group comprising surfactants, solid and liquid diluents; composition for invertebrate insect controlling containing biologically effective amount of formula I and at least one additional biologically active compound or agent. Also disclosed are method for insect controlling as well as intermediates such as benzoxazinone and parasolocarboxylic acid derivatives.

EFFECT: compounds with insecticide activity, useful in insect controlling.

20 cl, 16 tbl, 33 ex

FIELD: organic chemistry, agriculture.

SUBSTANCE: invention relates to ortho-substituted arylamides of formula I , wherein J represents phenyl ring or pyrazole ring each substituted with one or two substitutes independently selected from R5; K represents -NR1C(=A)- or -NR1SO2-; L represents -C(=B)NR2-, -SO2NR2- or -C(=B)-; A and B represent O; R1 and R2 represent H; R3 represents C1-C6-alkyl optionally substituted with one or more substitutes, independently selected from group containing CN, NO2, C1-C4-alkylsulfonyl and C2-C6-alkoxycarbonyl; each R4 independently represents C1-C6-alkyl, halogen or CN; each R5 independently represents C1-C6-alkyl, halogen or C1-C4-haloalkoxy or pyridinyl optionally substituted with one substitute independently selected from R9; wherein R9 represents halogen; n = 1-2; with the proviso, that when K represents -NR1C(=A)- L is not -C(=B)NR2-, and salts thereof, method for insect controlling by using abovementioned compounds. Intermediate for synthesis of target compounds having formula 2 also is disclosed.

EFFECT: compounds with insecticide activity, useful in insect controlling.

15 cl, 21 tbl, 9 ex

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to heterocyclic compounds of general formula I with PGl2 receptor agonist activity. In formula R1 and R2 represent independently optionally substituted phenyl; Y represents N, N-O or CR5; Z represents N or CR6; A represents NR7; D represents alkylene or alkenylene; or A and D may together form divalent group; E represents phenylene or direct bond, or D and E may together form divalent group; G represents O, S, SO, SO2; R3 and R4 represent hydrogen atom or alkyl; Q represents carboxyl, alkoxycarboxyl, tetrazolyl, carbamoyl or -CONH-SO-R10 group. Prostaglandin I2(PGl2) is potent inhibitor of platelet aggregation and may be effectively used in treatment of vascular diseases, arteriosclerosis, hypertension, etc.

EFFECT: new compounds and drugs for platelet aggregation inhibition and treatment of vascular and other diseases.

15 cl, 3 tbl, 109 ex

FIELD: organic chemistry, medicine, neurology, pharmacy.

SUBSTANCE: invention relates to derivatives of pyridazinone or triazinone represented by the following formula, their salts or their hydrates: wherein each among A1, A2 and A3 represents independently of one another phenyl group that can be optionally substituted with one or some groups chosen from the group including (1) hydroxy-group, (2) halogen atom, (3) nitrile group, (4) nitro-group, (5) (C1-C6)-alkyl group that can be substituted with at least one hydroxy-group, (6) (C1-C6)-alkoxy-group that can be substituted with at least one group chosen from the group including di-(C1-C6-alkyl)-alkylamino-group, hydroxy-group and pyridyl group, (7) (C1-C6)-alkylthio-group, (8) amino-group, (9) (C1-C6)-alkylsulfonyl group, (10) formyl group, (11) phenyl group, (12) trifluoromethylsulfonyloxy-group; pyridyl group that can be substituted with nitrile group or halogen atom or it can be N-oxidized; pyrimidyl group; pyrazinyl group; thienyl group; thiazolyl group; naphthyl group; benzodioxolyl group; Q represents oxygen atom (O); Z represents carbon atom (C) or nitrogen atom (N); each among X1, X2 and X3 represents independently of one another a simple bond or (C1-C6)-alkylene group optionally substituted with hydroxyl group; R1 represents hydrogen atom or (C1-C6)-alkyl group; R2 represents hydrogen atom; or R1 and R2 can be bound so that the group CR2-ZR1 forms a double carbon-carbon bond represented as C=C (under condition that when Z represents nitrogen atom (N) then R1 represents the unshared electron pair); R3 represents hydrogen atom or can be bound with any atom in A1 or A3 to form 5-6-membered heterocyclic ring comprising oxygen atom that is optionally substituted with hydroxyl group (under condition that (1) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; and each among A1, A2 and A3 represents phenyl group, (2) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o,p-dimethylphenyl group; A2 represents o-methylphenyl group, and A3 represents phenyl group, or (3) when Z represents nitrogen atom (N) then each among X1, X2 and X3 represents a simple bond; A1 represents o-methylphenyl group; A2 represents p-methoxyphenyl group, and A3 represents phenyl group, and at least one among R2 and R means the group distinct from hydrogen atom) with exception of some compounds determined in definite cases (1), (3)-(8), (10)-(16) and (19) given in claim 1 of the invention. Compounds of the formula (I) elicit inhibitory activity with respect to AMPA receptors and/or kainate receptors. Also, invention relates to a pharmaceutical composition used in treatment or prophylaxis of disease, such as epilepsy or demyelinization disease, such as cerebrospinal sclerosis wherein AMPA receptors take part, a method for treatment or prophylaxis of abovementioned diseases and using compound of the formula (I) for preparing a medicinal agent used in treatment or prophylaxis of abovementioned diseases.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

32 cl, 10 tbl, 129 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes derivatives of 4-phenylpyridine of the following general formulae: (IA)

and (IB) wherein R1 means and , or -NH(CH2)2OH, -NR3C(O)CH3 or -NR3C(O)-cyclopropyl; R2 means methyl or chlorine atom; R3 means hydrogen atom or methyl; R means hydrogen atom or -(CH2)2OH; n = 1 or 2, and their pharmaceutically acceptable acid-additive salts. Also, invention describes a medicinal agent possessing effect of agonist of NK-1 receptors based on these compounds. Proposed compounds show good affinity degree to NK-1 receptors and can be used in treatment or prophylaxis of diseases associated with these receptors.

EFFECT: valuable medicinal properties of compounds and agent.

10 cl, 1 tbl, 14 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to derivatives of adamantine, in particular, to a new method for preparing adamant-1-yl-containing azoles of the general formula I-VIII: wherein R1 means ; R2 means ; R3 means ; R4 means ; R5 means ; R6 means ; R7 means , and R8 means . Indicated derivatives of adamantine are semifinished products used in synthesis of biologically active substances. Proposed method for preparing these compounds involves using a new method for synthesis of adamant-1-yl-containing azoles that includes the addition reaction of azoles: 2-methylimidazole, 3(5)-methylpyrazole and 4-methylpyrazole, 3,4-dinitropyrazole, 1,2,4-triazole, 3-methylpyrazole, 3-nitro-1,2,4-triazole and 5-methyltetrazole to 1,3-dehydroadamantane in the mole ratio of 1,3-dehydroadamantane to azole = 1:1 in diethyl ether medium at temperature 100°C for 4-5 h.

EFFECT: improved preparing method.

8 ex

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