Derivatives of triazole amide type, a pharmaceutical composition and method for prevention or treatment of

 

(57) Abstract:

This invention relates to the derivatives of triazole amide type or their pharmacologically acceptable salts of formula (I)

where Ar1represents a phenyl group or similar group; Ar2represents fenelonov group or similar group; X represents a sulfur atom or methylene group; R1represents a hydrogen atom or a C1-3is an alkyl group; R2represents a hydrogen atom or a C1-3alkyl group, and R3is an optionally substituted group6-10-aryl group or similar group; and to pharmaceutical compositions based on them having antifungal activity, and the method of prevention or treatment of fungal infection. The technical result is to provide new compounds having valuable pharmacological properties. 3 N. and 19 C. p. F.-ly, 2 tab.

The technical field

The present invention relates to the derivatives of triazole amide type, which have high antifungal activity, or their pharmaceutically acceptable prodrugs or salts; to medicines (yo what whiteskin songs intended for the treatment of fungal infections, which contain these compounds; the use of these compounds in the production of pharmaceuticals (especially antifungal agents) and to a method for prevention or treatment of fungal infections, which includes the introduction of these compounds warm-blooded animal (particularly human) if necessary.

Prior art

There are many compounds, triazole type as a means for the treatment of fungal infections in human or animal. One of the most widely known compounds, triazole type is fluconazole. However, there are fungal infections that are impossible in a clinical setting to treat fluconazole, and therefore there is a need for other compounds with a higher antifungal activity.

Compounds similar to the compounds of the present invention, indicated in the description of the patent application of Japan No. Hei-8-333350, Hei-10-279567 and Hei-11-80135.

The applicant has done a lot of work to find compounds having very high antifungal activity, and found that the compounds of formula (I) (hereinafter in the description of soedinenie. As a result of this discovery was created by the present invention.

Description of the invention

The present invention relates to:

(1) a triazole derivative (I) of the amide type or its pharmacologically acceptable prodrug or salt.

where Ar1represents a phenyl group or a phenyl group substituted by 1-3 substituents (the substituents selected from a halogen atom and triptorelin group);

Ar2represents fenelonov group, fenelonov group, substituted by 1 or 2 substituents (the substituents selected from a fluorine atom and chlorine atom), Neftyanoy group or Neftyanoy group, substituted by 1 or 2 substituents (the substituents selected from a fluorine atom and chlorine atom).

X represents a sulfur atom or methylene group;

R1represents a hydrogen atom or a C1-3is an alkyl group;

R2represents a hydrogen atom or a C1-3is an alkyl group;

R3represents a C6-10-aryl group, a C6-10-aryl group, substituted by 1-5 substituents selected from foster group, heteroaryl group, heteroaryl group, for rancilio group, substituted by 1-5 substituents selected from foster group A;

replacement group a includes C1-6is an alkyl group, a C1-6is an alkyl group substituted by 1-5 substituents (the substituents selected from a halogen atom, a hydroxyl group, ceanography and C1-6-CNS group), C1-6-CNS group, C1-6-CNS group, substituted by 1-5 substituents (the substituents selected from a halogen atom, a hydroxyl group, ceanography and C1-6-CNS group), C1-6-alkanoyloxy group2-6-alkanoyloxy group substituted by 1-5 substituents (the substituents selected from a halogen atom, a hydroxyl group, ceanography and C1-6-CNS group), C1-6-alkanoyloxy,2-6-alkanoyloxy, substituted by 1-5 substituents (the substituents selected from a halogen atom, a hydroxyl group, ceanography and C1-6-CNS group), halogen atom, hydroxyl group, amino group, mercaptopropyl, karbamoilnuyu group, a nitrogroup, a cyano, a carboxyl group, a group of the formula - S(O)nR4(where R4represents a C1-6is an alkyl group or a C1-6is an alkyl group substituted by 1-5 substituents (the substituents selected group, WITH3-6-cycloalkyl group and (C3-6-cycloalkyl) C1-6is an alkyl group;

(2) a medicinal product containing a derivative of triazole amide type, or its pharmacologically acceptable prodrug or salt as an active ingredient described in (1).

In the above description:

“Halogen atom” in the definition of the Deputy AG1and substituting group And represents, for example, fluorine atom, chlorine, bromine and iodine; preferably fluorine atom or chlorine, and most preferably a fluorine atom.

“C1-3is an alkyl group” in the definitions of R1and R2represents an alkyl group with straight or branched chain, having from 1 to 3 carbon atoms, for example methyl, ethyl, sawn or ISO-propyl group; preferably a methyl or ethyl group, and most preferably a methyl group.

“C6-10-aryl group” in the definition of R3represents an aromatic hydrocarbon group having 6 to 10 carbon atoms, for example phenyl, indenolol or naftalina group, preferably phenyl group.

“Heteroaryl group” in the definition of R3such a heterocyclic group. “Monocyclic aromatic heterocyclyl group” represents a 5 - or 6-membered aromatic heterocyclyl group containing 1 to 4 nitrogen atoms, oxygen or sulfur, for example follow, thienyl, pyrrolidinyl, pyrazolidine, imidazolidine, oxazolidine, isoxazolidine, thiazolidine, triazolyl, tetrazolyl, pyridyloxy, pyramidalnou, pyridazinyl or perilou group; preferably pyridyloxy or thiazolidine. “Condensed aromatic heterocyclyl group” represents a 5 - or 6-membered aromatic heterocyclyl group which contains 1 to 4 nitrogen atoms, oxygen or sulphur and condensed with 1 or 2 benzene rings or 5 - or 6-membered aromatic heterocyclyl groups containing 1 to 4 nitrogen atoms, oxygen or sulfur. Examples of such condensed heterocyclyl group include isobenzofuranyl, bromanil, xantener, femoxetine, indolizinyl, isoindolyl, indolyl, indazoles, purinol, hemolysins, ethanolic, hinely, phthalazine, naphthyridine, honokalani, hintline, carbazolyl, carbolines, acridines, isoindolines and benzothiazolyl; preferably benzothiazolyl.

Predpochtitel 1 or 2 nitrogen atom, oxygen, or sulfur, or a bicyclic heterocyclyl group, which represents a 5 - or 6-membered aromatic heterocyclyl group which has 1 or 2 nitrogen atom, oxygen or sulphur and condensed with the benzene ring. More preferred heteroaryl group is follow, thienyl, pyridyloxy, isoxazolidine, thiazolidine or benzothiazolyl group; and most preferred group is pyridinol, thiazolidine or benzothiazolyl group.

“C7-14-kalkilya group” in the definition of R3represents a C1-4is an alkyl group, substituted C6-10-aryl group. “C6-10aryl group” has the same meaning as defined above. “C1-4is an alkyl group represents an alkyl group with straight or branched chain, having from 1 to 4 carbon atoms, for example methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene or tert-boutelou group; preferably a methyl or ethyl group, and most preferably a methyl group. “C7-14-kalkilya group” represents, for example, benzyl, fenetylline, phenylpropionyl, phenylbutyl group and more preferably a benzyl group.

In addition, in the definition of R3aryl ring “C6-10-aryl group” and “C7-14-aranceles group” optionally substituted by 1-5 substituents selected from foster group, and “heteroaryl group” in the definition of R3optionally substituted by 1 or 2 substituents selected from foster group A.

“C1-16is an alkyl group” in the definition of a replacement group (provided that C1-6is an alkyl group” in the definition of R4not included) represents an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, for example methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert-boutelou, pentelow or hexoloy group; preferably C1-3is an alkyl group and more preferably a methyl group.

“C1-6is an alkyl group substituted by 1-5 substituents (the substituents selected from a halogen atom, a hydroxyl group, ceanography and C1-6-CNS group)” in the determination of the replacement group is an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, substituted by 1-5 substituents selected from atom Gal is chlormethyl, chloroethyl, dichloroethyl, trichloroethyl, tetrachloroethyl, chloropropyl, chlorobutyl, chloropentyl, chlorhex, vermeil, deformity, trifluoromethyl, foradil, defloratin, triptorelin, tetraborates, pentafluoroethyl, forproper, direcror, cryptochromes, tetrafluoropropyl, pentafluoropropyl, pentafluoroethyl, pentafluorophenyl, Pentaflex, methyl bromide, bromacil, dibromoethyl, bromopropyl, hydroxymethyl, hydroxyethyl, dihydroxyethyl, hydroxypropyl, dihydroxypropyl, hydroxybutyl, hydroxyphenyl, hydroxyhexyl, hydroxydiphenyl, hydroxycitrate, hydroxytyrosol, hydroxyterminated, hydroxycitronellal, Hydrometerological, hydroxychloride, hydroxypropyl, cyanomethyl, cyanoethyl, cyanopropyl, cyanomethyl, cyanoethyl, cyanogenesis, cyanobiphenyl, cyanopiperidine, centerplace, cyanoacrilate, centeredcontent, centerparcs, langeronii, cyanohydrine, ciangherotti, ciangherotti, teenagerssex, methoxymethyl, methoxyethyl or similar group.

The preferred “C1-6is an alkyl group substituted by 1-5 substituents, the substituents selected from a halogen atom, a hydroxyl group, cyanogenesis 1-4 substituents (the substituents selected from a halogen atom, hydroxyl group and cyanopropyl). More preferred is an alkyl group having from 1 to 4 carbon atoms, substituted by 1-4 substituents (the substituents selected from a fluorine atom, chlorine atom, hydroxyl group and ceanography), for example permetrina, deformational, triptoreline, 2-florachilena, 2,2,2-triptoreline, 1,1,2,2-tetrafluoroethylene, panafcortelone, 3-forproperty, trichlorethylene, 2-chloraniline, 3-chloropropylene, 2-hydroxyethylene, 3-hydroxiproline, 2,3-dihydroxypropyl, 1-hydroxy-1-mtilatila, 1-methyl-3-hydroxiproline, 1-methyl-2-hydroxiproline, 1-methyl-1-hydroxiproline or cyanomethylene group. Most preferred is triptoreline or cyanomethylene group.

“C1-6-CNS group” in the definition of a replacement group and the replacement fragment replacement group And is a CNS group with a straight or branched chain, having from 1 to 6 carbon atoms, for example metaxylene, amoxilina, propoxyimino, isopropoxyphenol, betaxolol, isobutoxide, second-butoxyl, tert-butoxyl, pentyloxy or hexyloxy. The preferred “C1-6-CNS group, not only the traveler or ethoxyline group.

“C1-6-CNS group, substituted by 1-5 substituents (the substituents selected from a halogen atom, a hydroxyl group, ceanography and C1-6-CNS group) is a CNS group with a straight or branched chain, having from 1 to 6 carbon atoms, substituted by 1-5 substituents, and the substituents selected from a halogen atom, a hydroxyl group and ceanography, for example chlorotoxin, dichloroethylene, trichloroethylene, chlorethoxyfos, diplomatically, trichlorethylene, chloropentane, chlorhexidine, formicoxenini, diplomatically, trifloromethyl, foretokening, diplomatically, cryptgetuserkey, tetrafluorethylene, panafcortelone, forproposals, tetrafluoropropylene, perpetrate, perhexiline, cryptocraphically, tetrafluoropropylene, bromelicola, pomatoceros, bronirovochnoy, bromouracil, bromopentane, Bromhexine, hydroxyethyloxy, hydroxypropoxy, dihydroxypropane, hydroxybutyrate, hydroxyethyloxy, hydroxyhexyloxy, hydroxycarboxylic, hydroxycitronellal, hydroxycarboxylic, hydroxymetoprolol, hydroxythiofentanyl, cyanopiperidine, cyanocobalamine, cyanoacetylmorpholine, centerofrotation, centerinformation, (hydroxymethyl) hydroxyethoxyphenyl, methoxymethyl or tert-butoxymethyl group.

The preferred “C1-6-CNS group, substituted by 1-5 substituents (the substituents selected from a halogen atom, a hydroxyl group, ceanography and C1-6-CNS group) is a CNS group having from 1 to 4 carbon atoms, substituted by 1-5 substituents (the substituents selected from a halogen atom, a hydroxyl group and cyanopropyl). More preferred is a CNS group having from 1 to 4 carbon atoms, substituted by 1-5 substituents (the substituents selected from a fluorine atom, chlorine atom and a hydroxyl group), for example chlorotoxin, dichloroethylene, trichloroethylene, 2-chlorotoxin, 2,2-diplomatically, 2,2,2-trichlorethylene, 3-chlorpromazine, formicoxenini, diplomatically, triptoreline, 2-peritonsillar, 2,2-diplomatically, 2,2,2-triptoreline, 1,1,2,2-tetrafluoroethylene, pentafluorostyrene, 3,3-forproposals, 2,2,3,3-tetrafluoropropoxy, 2-hydroxyethyl the hydroxy-1,1-diplomatically, 4-hydroxy-2,2,3,3-tetracarboxylate or 1-(hydroxymethyl)-2-hydroxyethoxyphenyl group. Most preferred is triptoreline or tetrafluoropropoxy group.

“C1-6-alcoolica group” in the definition of a replacement group And represents alkanoyloxy group with a straight or branched chain, having from 1 to 6 carbon atoms, for example formyl, acetyl, propionyl, butyryloxy, isobutyryloxy, valerino, isovaleryl, pivaloyl or hexanoyl group. The preferred “C1-6-alcoolica group” represents alkanoyloxy group having from 1 to 3 carbon atoms, and more preferred is an acetyl group.

“C2-6-alcoolica group substituted by 1-5 substituents (the substituents selected from a halogen atom, a hydroxyl group, ceanography and C1-6-CNS group)” in the determination of the replacement group And represents alkanoyloxy group with a straight or branched chain, having from 2 to 6 carbon atoms, substituted by 1-5 substituents selected from a halogen atom, a hydroxyl group, ceanography and C1-6-CNS group, for example hydroxyazetidine, porazitelnuyu, deftroy, triphosphopyridine, chloropropionyl, bromopropionyl, chlorbutanol, terbutaline, differmaterially, triptorelin, ftordezoksiuridin, deferreddocumentimpl, cyanomethylene, (hydroxymethyl)methylpropionyl, hydroxyvalerate, cyanovinylene, Peralillo, hydroxyquinoline or methoxyacetyl group.

The preferred “C2-6-alcoolica group substituted by 1-5 substituents (the substituents selected from a halogen atom, a hydroxyl group, ceanography and C1-6-CNS group) is alkanoyloxy group having from 2 to 6 carbon atoms, substituted by 1-4 substituents, the substituents selected from a halogen atom, a hydroxyl group and cyanopropyl). More preferred is alcoolica group having from 2 to 4 carbon atoms substituted by 1 to 3 substituents (the substituents selected from a fluorine atom and a hydroxyl group), for example hydroxyazetidine, porcelina, deperately, trifluoracetyl, 2-hydroxypropylamino, 3-hydroxypropylamino, 2-hydroxybutyryl, 3-hydroxybutyryl, 4-hydroxybutyryl or 2-methyl-2-hydroxypropylamino group. Most preferred is trawley alkanoyloxy, having from 1 to 6 carbon atoms, for example, formyloxy, acetoxy, propionyloxy, butyryloxy, isobutyryloxy, valeriote, isovalerianic, pivaloyloxy or hexaniacinate. The preferred “C1-6-alkanoyloxy is alkanoyloxy having from 1 to 3 carbon atoms. A more preferred group is acetoxygroup.

“C2-6-alkanoyloxy, substituted by 1-5 substituents (the substituents selected from a halogen atom, a hydroxyl group, ceanography and C1-6-CNS group)” in the determination of the replacement group And is alkanoyloxy straight or branched chain, having from 2 to 6 carbon atoms, substituted by 1-5 substituents selected from a halogen atom, a hydroxyl group, ceanography and C1-6-CNS group, for example, hydroxyacetone, peracetate, deferasirox, triptoreline, cyanoacetate, hydroxypropionate, forproposals, deformationally, cryptosporidiosis, chloropropionate, bromopropionate, hydroxybutyrate, chlorobutyrate, terbutaline, deformations, cryptosporidiosis, targetranslations, deferribacteres, cyanovalerianic, (g is lexi or methoxyethoxy.

The preferred “C3-6-alkanoyloxy, substituted by 1-5 substituents (the substituents selected from a halogen atom, a hydroxyl group, ceanography and C1-6-CNS group), is alkanoyloxy having from 2 to 6 carbon atoms, substituted by 1-4 substituents (the substituents selected from a halogen atom, a hydroxyl group and cyanopropyl). More preferred is alkanoyloxy having from 2 to 6 carbon atoms, substituted by 1-4 substituents (the substituents are a hydroxyl group), such as hydroxyacetone, hydroxypropionate, hydroxybutyrate, hydroxyvalerate or hydroxyhexanoate. Most preferred is hydroxyacetone or hydroxypropionitrile.

“C1-6is an alkyl group” in the definition of R4represents an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, and “C1-6is an alkyl group substituted by 1-5 substituents” in the definition of R4represents an alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, substituted by 1-5 substituents, which are the same or different halogen atoms. until, hexyl, chloromethyl, dichloromethyl, trichloromethyl, chloroethyl, dichloroethyl, trichloroethyl, tetrachloroethyl, chloropropyl, chlorobutyl, chloropentyl, chlorhex, vermeil, deformity, trifluoromethyl, foradil, defloratin, triptorelin, tetraborates, pentafluoroethyl, forproper, direcror, cryptochromes, tetrafluoropropyl, methyl bromide, bromacil, dibromoethyl, bromopropyl or similar group. R4preferably represents will alcinous group having from 1 to 3 carbon atoms, or an alkyl group having from 1 to 3 carbon atoms, substituted by 1-5 substituents (the substituents are fluorine atoms, for example methyl, ethyl, propyl, isopropyl, vermeil, deformity, trifluoromethyl, 2-foretel, 2,2,2-triptorelin, pentafluoroethyl or similar group. More preferred is a methyl or triptorelin group.

“C2-6-Alchemilla group” in the definition of a replacement group And represents alkenylphenol group with a straight or branched chain, having from 2 to 6 carbon atoms and one double bond, for example atenolol, propanolol, methylpropenyl, ethylpropylamine, butenyloxy, methylbutadiene, ethylbutanol, pentanediol, methylpentanediol, hexanediol or similar group.

“C3-C6-cycloalkyl group” in the definition of a replacement group a represents a saturated aliphatic cyclic hydrocarbon group having 3 to 6 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo or similar group.

“(C3-6-cycloalkyl) C1-6is an alkyl group” in the definition of a replacement group And represents a C1-6is an alkyl group substituted WITH one3-6is an alkyl group, for example cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopentylamine, cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, cyclohexylpropionate, cyclohexylmethanol, cyclohexylamino group or similar.

Replacement group And preferably represents a substituting group A1, which includes1-6is an alkyl group, a C1-6is an alkyl group, substituted by 1-4 substituents (replaces maxillo group, substituted by 1-5 substituents (the substituents selected from a halogen atom, a hydroxyl group and ceanography), C1-6-alkanoyloxy group2-6-alkanoyloxy group, substituted by 1-4 substituents (the substituents selected from a halogen atom, a hydroxyl group and ceanography), C1-6-alkanoyloxy,2-6-alkanoyloxy, substituted by 1-4 substituents (the substituents selected from a halogen atom, a hydroxyl group and ceanography), halogen atom, hydroxyl group, karbamoilnuyu group, a nitrogroup, cyano, carboxyl group, and a group of the formula - S(O)nR4(where R4represents a C1-6is an alkyl group or a C1-6is an alkyl group substituted by 1-5 substituents (substituents selected from halogen atoms), and n represents 0, 1 or 2).

Replacement group And more preferably is a replacement group A2, which includes the C1-3is an alkyl group, a C1-4is an alkyl group, substituted by 1-4 substituents (the substituents selected from a fluorine atom, chlorine atom, hydroxyl group and ceanography), C1-3-CNS group, C1-4-CNS group, substituted by 1-5 substituents (the substituents selected from a fluorine atom, chlorine atom and the representatives (the substituents selected from a fluorine atom and a hydroxyl group), C1-3-alkanoyloxy,2-6-alkanoyloxy, substituted by 1-4 substituents (the substituents are a hydroxyl group), halogen atom, hydroxyl group, karbamoilnuyu group, a nitrogroup, cyano, carboxyl group, and a group of the formula - S(O)nR4(where R4represents a C1-3is an alkyl group or a C1-3is an alkyl group substituted by 1-5 substituents (the substituents are fluorine atoms); and n represents 0, 1 or 2).

Replacement group And most preferably is a replacement group A3, which includes methyl group, triptorelin group, cyanomethyl group, triptoreline group, tetrafluoropropoxy group, acetyl group, acetoxyl, fluorine atom, chlorine atom, bromine atom, iodine atom, hydroxyl group, karbamoilnuyu group, a nitrogroup, cyano, carboxyl group, triptoreline, methanesulfonyl group and trifloromethyl group.

When a fragment is selected from foster group a-A3 has substituents, the preferred number of substituents is 1 or 2.

AG1represents, for example, phenyl, florfenicol, periodending, fluorine(trifluoromethyl)phenyl, bronchosparing, chlorophenyl, chloro(trifluoromethyl)phenyl, bromophenyl, bromo(trifluoromethyl)phenyl, iodine(trifluoromethyl)phenyl, dichloraniline, differenly, dibromophenyl, triptorelin or trichlorophenyl group.

AG1preferably represents a phenyl group substituted by 1-3 substituents (Deputy represents a fluorine atom, a chlorine atom or triptorelin group), for example 2-florfenicol, 2-chloraniline, 3-florfenicol, 3-chloraniline, 4-florfenicol, 4-chloraniline, 4-(trifluoromethyl)phenyl, 2,3-differenly, 2-fluoro-3-chloraniline, 2,3-dichloraniline, 2,4-differenly, 2-fluoro-4-chloraniline, 2,4-dichloraniline, 2-fluoro-4-(trifluoromethyl)phenyl, 2,5-differenly, 2-fluoro-5-chloraniline, 2,5-dichloraniline, 2,6-differenly, 2,3,4-triptorelin or 2,3,5-triptorelin group.

AG1more preferably represents a phenyl group substituted by 1 or 2 substituents (Deputy represents a fluorine atom, a chlorine atom or triptorelin group), for example 2-florfenicol, 4-florfenicol, 2-chloraniline, 4-chloraniline, 4-(trifluoromethyl)phenyl who predpochtitelno AG1is a 2-florfenicol, 4-florfenicol, 4-chloraniline, 2,4-dichloraniline or 2,4-differenly group.

Most preferably AG1represents a 2,4-differenly group.

AG2represents, for example, 1,2-fenelonov, 1,3-fenelonov, 1,4-fenelonov, 1,2-Neftyanoy, 1,3-Neftyanoy, 1,4-Neftyanoy, 1,5-Neftyanoy, 1,6-Neftyanoy, 1,7-Neftyanoy, 1,8-Neftyanoy, 2,3-Neftyanoy, 2,4-Neftyanoy, 2,5-Neftyanoy, 2,6-Neftyanoy, 2-fluoro-1,4-fenelonov, 3-chloro-1,4-fenelonov, 2-chloro-1,4-fenelonov, 3-chloro-1,4-fenelonov, 2,6-debtor-1,4-fenelonov or 2,6-dichloro-1,4-fenelonov group.

AG2preferably represents 1,4-phenylene, 1,4-phenylene, substituted by 1 or 2 substituents, 2,6-naftilan or 2,6-naftilan, substituted by 1 or 2 substituents (Deputy represents a fluorine atom or a chlorine atom). More preferred is 1,4-fenelonov or 1,4-fenelonov group, substituted by 1 or 2 substituents (Deputy represents a fluorine atom or a chlorine atom), and most preferred is 1,4-fenelonov group.

X preferably represents a sulfur atom or methylene group, and more predpochtitel group or ethyl group, preferably C1-3is an alkyl group and most preferably a methyl group.

R2represents, for example, a hydrogen atom, methyl group or ethyl group, preferably a hydrogen atom or methyl group, and most preferably a hydrogen atom.

R3represents, for example, benzyl, chloraniline, tormentilla, cyanobenzyl, nitrobenzyloxy, (trifluoromethyl)benzyl, naphthylmethyl, bromonaphthalene, phenyl, taillow, (trifluoromethyl)phenyl, hydroxymethylamino, hydroxyethylamino, cyanomethylene, florfenicol, chloraniline, differenly, dichloraniline, pentafluorophenyl, bromperidol, itfinally, hydroxyproline, cyanovinylene, carboxyphenyl, dicyanovinyl, carcinogenisis, cyanophthalide, nitroaniline (triptoreline)phenyl, (tetrafluoropropoxy)phenyl, acetylphenyl, (TRIFLUOROACETYL)phenyl, carbamoylphenoxy, methylthiophenyl, methylsulfinylphenyl, methylsulfonylamino, (trifluoromethyl)tiffaniejoy, (triptorelin)phenyl, (trifloromethyl)phenyl, carboxyphenyl, naftalina, tomatillo, Garnavillo, pyridinol, methoxypyridine, oxazolidinyl, isoxazolyl or thiazolidine group.

R3preferably a represents a 6-10 membered aryl group, 6-10-membered aryl group, substituted by 1-5 substituents selected from foster group, 5 - or 6-membered heteroaryl group or a 5 - or 6-membered heteroaryl group, substituted by 1 or 2 substituents selected from foster group A. More preferably, R3represents a 6-10 membered aryl group, or 6-10-membered aryl group, substituted by 1-5 substituents selected from foster group A. Even more preferably R3represents a phenyl group substituted by 1-5 substituents selected from foster group, or unsubstituted phenyl group. More and particularly preferably R3represents a phenyl group substituted by 1-5 substituents selected from foster group A1 or unsubstituted phenyl group. Even more particularly preferably, R3represents a phenyl group substituted by 1-5 substituents selected from foster group A2 or unsubstituted phenyl group. Still more preferably3represents fenilrepresents (tetrafluoropropoxy)phenyl, cyanophenyl, cyanomethylene, florfenicol, chloraniline, bromperidol, itfinally, (trifluoromethyl)phenyl, (triptoreline)feelnow (triptoreline)phenyl, methylphenyl, carcinogenisis, nitroaniline, tetrafluoroaniline, dicyanovinyl, acetylphenyl, acetoxyphenyl, fortunately, carbamoylphenoxy, carboxyphenyl, hydroxyphenyl, (methanesulfonyl)phenyl or (trifloromethyl)phenyl group.

The term “pharmaceutically acceptable prodrug” of the compound (I) means derivative of compound (I) having a protected hydroxyl group or a similar group, which can be broken down by chemical or biological process (for example, due to hydrolysis) with the introduction of the derivative in the body of the living animal with obtaining the source of the generic compound (I) or its salt. Can be easily determined whether a derivative of the compound (I) in such a prodrug. A derivative of the compound (I) having a protected hydroxyl group or a similar group, administered during the study orally or intravenously to a subject animal such as a mouse or a rat, and is organisme of the test animal, found the original compound (I) or its salt, in the study it is believed that a derivative is a prodrug of compound (I). The compound (I) of the present invention has a hydroxyl group, and a triazole group and the NH group, when R2the compound (I) is a hydrogen atom. Using these functional groups can be obtained pharmaceutically acceptable prodrug. Examples of these prodrugs include, for example, prodrugs, hydroxyl group or NH group which is modified acyl group.

Used in this description, the term “acyl group” includes, for example, aliphatic acyl group, aromatic acyl group, alkoxycarbonyl group, aracelikarsaalyna group, aminoacyl group, fastonline group or similar.

“Aliphatic acyl group” includes alkanoyloxy group having from 1 to 20 carbon atoms, for example formyl, acetyl, propionyl, butyryloxy, isobutyryloxy, pentanoyl, pivaloyl, valerino, isovaleryl, octanoyl, nonanoyl, technology, 3-methylnonanoic, 8-methylnonanoic, 3-ethyloctanoic, 3,7-dimethylacetanilide, undecanoyl, dodecane, 4-methylpentanol, 13,13-dimethylacetanilide, heptadecanoyl, 15-methylhexadecanoic, octadecanoyl, 1-methylheptadecyl, nanotechnology and Ihsanoglu.

These aliphatic acyl group may optionally have from 1 to 3 multiple bonds and substituents, such as hydroxyl group, phosphate group or a carboxyl group.

“Aromatic acyl group” includes arylcarbamoyl group having from 7 to 11 carbon atoms, for example benzoyloxy, -naftolin or naftolin. Aryl ring of these aromatic acyl groups may optionally have one or more substituents such as an alkyl group having from 1 to 4 carbon atoms, halogen atom, CNS group, hydroxyl group, carboxyl group, alkoxycarbonyl group having from 1 to 4 carbon atoms, hydroxyalkyl group having from 1 to 4 carbon atoms, alkylphosphonyl group having from 1 to 4 carbon atoms, or carboxialkilnuyu group having from 2 to 5 carbon atoms.

“Alkoxycarbonyl group or aracelikarsaalyna group” includes alkoxycarbonyl group having from 2 to 20 carbon atoms, supremelearning group, having from 8 to 20 carbon atoms, for example benzyloxycarbonyloxy. These alkoxycarbonyl group or aryl ring these aracelikarsaalyna groups may optionally have one or more substituents such as an alkyl group having from 1 to 4 carbon atoms, halogen atom, CNS group having from 1 to 4 carbon atoms, a hydroxyl group, a phosphoric group, a carboxyl group, alkoxycarbonyl group having from 1 to 4 carbon atoms, hydroxyalkyl group having from 1 to 4 carbon atoms, alkylphosphonyl group having from 1 to 4 carbon atoms, or carboxialkilnuyu group having from 2 to 5 carbon atoms.

“Aminoaniline group” includes an amino acid group, for example pilliow, Alamillo, lazily, phenylalaninol, glutaminol and asparaginyl; aminoalcohols group having from 1 to 10 carbon atoms, for example-alaninol, aminobutyryl or aminoacetanilide.

“Fastonline group” includes fastonline, monoalkylphenols group, where the alkyl part has from 1 to 20 carbon atoms, for example methylphosphonyl, ethylestrenol, propylphosphine, butylphosphino, decylphosphonic or a, for example dimethylphosphino, diethylphosphino, dipropylamino, dibutylethanolamine, dodecylphosphocholine or dioctadecyl; or similar group.

The compound (I) or its pharmaceutically acceptable prodrug has the main triazole group and may form an additive salt of the base. When R3has a carboxyl group, the compound (I) or its pharmaceutically acceptable prodrug can form an additive salt of the base. The expression “pharmaceutically acceptable salt” means those salts which are farmacevtichesky acceptable.

Additive salt of the acid include inorganic acid salts, such as hydrochloride, hydrobromide, sulphates, nitrates and phosphates, salts of carboxylic acids, for example acetates, fumarate, maleate, oxalates, malonate, succinate, citrates and malty; sulphonate salts, such as methanesulfonate, econsultancy, benzosulfimide and toluensulfonate; salts of amino acids such as glutamate and aspartate; and similar salts. Preferred salts are salts of inorganic acids or salts of carboxylic acids. The preferred salts are hydrochloride, nitrates, fumarate, maleate or oxalates.

When the compound (I), its pharmaceutically acceptable prodrug or salt, allow to stand, and therefore it is exposed to the atmosphere, it can absorb water to form hydrate. The compound (I) or its pharmaceutically acceptable prodrug or salt can absorb the solvent with the formation of MES. The present invention includes a data hydrate and solvate.

The carbon atom attached to AG1the compound (I) is an asymmetric carbon, and therefore, there are optical isomers, having the specified asymmetric carbon is in the S - and R-configuration. When R1is an alkyl group, the carbon atom attached to R1is also asymmetric carbon. The compound (I) by the specified asymmetric carbon can exist in the form of diastereoisomers. In addition, due to the SS="ptx2">

Formula (I) includes one of the above isomers, and mixtures thereof.

The above optical isomer can be allocated to the traditional method of optical resolution or can be obtained by asymmetric synthesis. Diastereoisomer and CIS - or TRANS-isomer can be allocated to the traditional method of selection, such as fractional recrystallization or chromatography. Of the selected isomers preferred compounds (I) have the following formula (I’)

Preferred compounds of formula (I) of the present invention include:

(1) connection, where AG1represents a phenyl group substituted by 1 or 2 substituents (the substituents selected from a fluorine atom, chlorine atom and triptorelin group)

(2) connection, where AG1is a 2-florfenicol, 4-florfenicol, 4-chloraniline, 2,4-dichloraniline or 2,4-differenly group

(3) connection, where AG1represents a 2,4-differenly group

(4) connection, where AG2represents 1,4-fenelonov group or 1,4-fenelonov group, substituted by 1 or 2 substituents (the substituents selected from a fluorine atom and chlorine atom), 2,6-Neftyanoy the chlorine),

(5) connection, where AG2represents 1,4-fenelonov group or 1,4-fenelonov group, substituted by 1 or 2 substituents,

(6) connection, where AG2represents 1,4-fenelonov group

(7) the compound, where X is a sulfur atom,

(8) the compound, where X represents a methylene group,

(9) the compound, where R1represents a C1-3is an alkyl group,

(10) the compound, where R1represents a methyl group,

(11) the compound wherein R2is a hydrogen atom,

(12) the compound wherein R3represents a C6-10-aryl group, a C6-10-aryl group, substituted by 1-5 substituents selected from foster group, 5 - or 6-membered heteroaryl group or a 5 - or 6-membered heteroaryl group, substituted by 1 or 2 substituents selected from foster group a,

(13) the compound, where R3represents a C6-10-aryl group or6-10-aryl group, substituted by 1-5 substituents selected from foster group a,

(14) the compound, where R3represents a phenyl group substituted by 1-5 substituents selected from substituting the aryl group or heteroaryl group, substituted by 1-2 substituents selected from foster group a,

(16) the compound, where R3represents a benzyl group or a benzyl group substituted by 1 or 2 substituents selected from foster group a,

(17) the compound, where R3represents a 4-(2,2,3,3-tetrafluoropropoxy)phenyl, 4-cyanophenyl, 4-cyanomethylene, 4-florfenicol, 4-chloraniline, 4-bromperidol, 4-itfinally, 4-(trifluoromethyl)phenyl, 4-(triptoreline)phenyl, 4-(triptoreline)phenyl, 4-methylphenyl, 3-chloro-4-cyanoaniline, 4-nitroaniline, 2,3,5,6-titrator-4-cyanophenyl, 3,4-dicyanovinyl, 4-acetylphenyl, 4-acetoxyphenyl, 2-fluoro-4-cyanoaniline, 4-carbamoylphenoxy, 4-carboxyphenyl, 4-hydroxyphenyl, 4-(methanesulfonyl)phenyl or 4-(trifloromethyl)phenyl group.

(18) connection, where the substituting group And is a replacement group A1, which includes the C1-6is an alkyl group, a C1-6is an alkyl group, substituted by 1-4 substituents, the substituents selected from a halogen atom, a hydroxyl group and ceanography), C1-6-CNS group, C1-6-CNS group, substituted by 1-5 substituents (the substituents is nilou group, substituted by 1-4 substituents (the substituents selected from a halogen atom, a hydroxyl group and ceanography), C1-6-alkanoyloxy,2-6-alkanoyloxy, substituted by 1-4 substituents (the substituents selected from a halogen atom, a hydroxyl group and ceanography), halogen atom, hydroxyl group, karbamoilnuyu group, a nitrogroup, cyano, carboxyl group, and a group of the formula - S(O)nR4(where R4represents a C1-6is an alkyl group or a C1-6is an alkyl group substituted by 1-5 substituents (substituents selected from halogen atoms), and n represents 0, 1 or 2),

(19) connection, where the substituting group And is a replacement group A2, which includes the C1-3is an alkyl group, a C1-4-akilou group, substituted by 1-4 substituents (the substituents selected from a fluorine atom, chlorine atom, hydroxyl group and ceanography), C1-3-CNS group, C1-4-CNS group, substituted by 1-5 substituents (the substituents selected from a fluorine atom, chlorine atom and a hydroxyl group), C1-3-alkanoyloxy group, C2-4-alkanoyloxy group substituted by 1-3 substituents (the substituents selected from a fluorine atom and a hydroxyl group) which represent a hydroxyl group), halogen atom, hydroxyl group, karbamoilnuyu group, a nitrogroup, cyano, carboxyl group, and a group of the formula - S(O)nR4(where R4represents a C1-3is an alkyl group or a C1-3is an alkyl group substituted by 1-5 substituents (the substituents are fluorine atoms), and n represents 0, 1 or 2),

(20) connection, where the substituting group And is a replacement group A3, which includes methyl group, triptorelin group, cyanomethyl group, cryptometer, tetrafluoropropoxy, acetyl group, acetoxyl, fluorine atom, chlorine atom, bromine atom, iodine atom, hydroxyl group, karbamoilnuyu group, a nitrogroup, cyano, carboxyl group, triptoreline, methanesulfonyl group and trifloromethyl group.

Among the compounds listed in (1) to(20), also preferred is a compound, each Deputy of which is optionally selected from the groups listed in (1) to(20). Such preferred compounds are represented in the following recitals (21) and (22):

(21) connection, where AG1represents a 2,4-differenly group; AG2represents 1,4-fenil> represents a hydrogen atom; R3represents a phenyl group substituted by 1 or 2 substituents selected from foster group A3

(22) connection, where AG1represents a 2,4-differenly group; AG2represents 1,4-fenelonov group; X represents a sulfur atom; R1represents a methyl group; R2represents a hydrogen atom; R3represents a 4-(2,2,3,3-tetrafluoropropoxy)phenyl, 4-cyanophenyl, 4-cyanomethylene, 4-florfenicol, 4-chloraniline, 4-bromperidol, 4-itfinally, 4-(trifluoromethyl)phenyl, 4-(triptoreline)phenyl, 4-(triptoreline)phenyl, 4-methylphenyl, 3-chloro-4-cyanoaniline, 4-nitroaniline, 2,3,5,6-titrator-4-cyanophenyl, 3,4-dicyanovinyl, 4-acetylphenyl, 4-acetoxyphenyl, 2-fluoro-4-cyanoaniline, 4-carbamoylphenoxy, 4-carboxyphenyl, 4-hydroxyphenyl, 4-(methanesulfonyl)phenyl or 4-(trifloromethyl)phenyl group.

When the compound (I) has two or more substituents selected from foster groups And A3, such substituents may be the same or different.

Examples of compound (I) of the present invention LASS="ptx2">

In table 1 used the following abbreviations with the following values:

Me: methyl, CN: cyano (attached via a carbon atom), Et: ethyl, Ph: phenyl, 1,4-PH is 1,4-phenylene, Np: naphthyl, 2,6-Np: 2,6-naftilan, Rog: pyridyl, Thz: thiazolyl, Tet: Tetra.

As an example, the compound of example 1-1 has the following formula (Ia):

the compound of example 14-4 has the following formula (1b)

and the compound of example 1-21 has the following formula (1C)

From the presented examples of preferred compounds are compounds of examples with the following numbers:

1-1, 1-2, 1-3, 1-4, 1-9, 1-11, 1-21, 1-22, 2-1, 2-2, 2-3, 2-4, 2-9, 2-11, 2-21, 2-22, 2-25, 3-1, 3-2, 3-3, 3-4, 3-9, 3-11, 3-21, 3-22, 4-1, 4-2, 4-3, 4-4, 4-9, 4-11, 4-21, 4-22, 4-25, 5-1, 5-2, 5-3, 5-4, 5-9, 5-11, 5-21, 5-22, 6-1, 6-2, 6-3, 6-4, 6-9, 6-11, 6-21, 6-22, 7-1, 7-2, 7-3, 7-4, 7-9, 7-11, 7-21, 7-22, 8-1, 8-2, 8-3, 8-4, 8-9, 8-11, 8-21, 8-22, 9-1, 9-2, 9-3, 9-4, 9-9, 9-11, 9-21, 9-22, 10-1, 10-2, 10-3, 10-4, 10-9, 10-11, 10-21, 10-22, 11-1, 11-2, 11-3, 11-4, 11-9, 11-11, 11-21, 11-22, 13-1, 13-2, 13-3, 13-4, 13-9, 13-11, 13-21, 13-22, 14-1, 14-3, 15-1, 15-3, 16-1, 16-2, 16-3, 16-4, 16-9, 16-11, 16-21, 16-22, 17-1, 17-2, 17-3, 17-4, 17-9, 17-11, 17-21, 17-22, 18-1, 18-2, 18-3, 18-4,1, 29-21, 29-22, 40-1, 40-2, 41-1 and 41-2.

Of the above compounds (I), more preferred compounds include:

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(2,2,3,3-tetrafluoropropoxy)benzanilide (the compound of example 1-1),

6-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(2,2,3,3-tetrafluoropropoxy)-2-naphthanilide (the compound of example 1-2),

4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(2,2,3,3-tetrafluoropropoxy)benzanilide (the compound of example 1-3),

4’-cyano-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 2-1),

4’-cyano-6-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-2-naphthanilide (compound of example 2-2),

4’-cyano-4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]benzanilide (compound of example 2-3),

4’-cyano-6-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-2-naphthanilide (compound of example 2-4),

4’-cyano-4-[5-[[2-(2,4-differenl)

4’-cyano-3-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 2-25),

4’-(cyanomethyl)-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 3-1),

4’-chloro-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide(compound of example 4-1),

4’-chloro-6-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-2-naphthanilide (compound of example 4-2),

4’-chloro-4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]benzanilide (compound of example 4-3),

4’-chloro-6-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-2-naphthanilide (compound of example 4-4),

4’-chloro-3-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 4-25),

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-feranzano (compound of example 5-1),

6-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazo the Nile)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-feranzano (compound of example 5-3),

6-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl’]-4’-fluoro-2-naphthanilide (compound of example 5-4),

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(trifluoromethyl)benzanilide (compound of example 6-1),

6-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(trifluoromethyl)-2-naphthanilide (compound of example 6-2),

4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(trifluoromethyl)benzanilide (compound of example 6-3),

6-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(trifluoromethyl)-2-naphthanilide (compound of example 6-4),

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(triptoreline)benzanilide (the compound of example 7-1),

6-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(triptoreline)-2-naphthanilide (compound of example 7-2),

4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(triptoreline)benzanilide (compound of example 7-3),

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(triptoreline)benzanilide (compound of example 8-1),

6-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(triptoreline)-2-naphthanilide (compound of example 8-2),

4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(triptoreline)benzanilide (compound of example 8-3),

6-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(triptoreline)-2-naphthanilide (compound of example 8-4),

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-methylbenzamide (compound of example 9-1),

4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-methylbenzamide (compound of example 9-3),

4’-bromo-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 10-1),

4’-bromo-6-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-2-naphthanilide (compound of example 10-2),

4’-bromo-4 the Omer 10-3),

4’-bromo-6-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-2-naphthanilide (compound of example 10-4),

3’-chloro-4’-cyano-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 11-1),

3’-chloro-4’-cyano-6-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-2-naphthanilide (compound of example 11-2),

3’-chloro-4’-cyano-4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]benzanilide (compound of example 11-3),

3’-chloro-4’-cyano-6-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-2-naphthanilide (compound of example 11-4),

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-nitrobenzamide (compound of example 13-1),

4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-nitrobenzamide (compound of example 13-3),

4’-cyano-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl-2’,3’,5’,6’-titrator]benzanilide (compound of example 14-1),

4’-ceiled (compound of example 14-3),

3’,4’-dicyano-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 15-1),

3‘,4‘-dicyano-4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]benzanilide (compound of example 15-3),

4’-acetyl-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 16-1),

4’-acetyl-4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]benzanilide (compound of example 16-3),

4’-acetoxy-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 17-1),

4’-acetoxy-4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]benzanilide (compound of example 17-3),

4’-cyano-2-fluoro-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 18-1),

4’-cyano-2’-fluoro-6-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-2-naphthanilide (compound of example 18-2),

4’-cyano-2’-fluoro-4-[5-[3-(2,4-deer CLASS="ptx2">

4’-cyano-2’-fluoro-6-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-2-naphthanilide (compound of example 18-4),

4’-carbarnoyl-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 24-1),

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-identidied (compound of example 25-1),

4-[N-[4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzoyl]amino]benzoic acid (compound of example 26-1),

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-hydroxybenzamide (compound of example 27-1),

6-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-hydroxy-2-naphthanilide (compound of example 27-2),

4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-hydroxybenzamide (compound of example 27-3),

6-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-hydroxy-2-naphthanilide (compound of example 27-4),

4-[5-[[2-(2,4-Tirrenia of example 28-1),

6-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,C-dioxane-2-yl]-4’-(methanesulphonyl)-2-naphthanilide (compound of example 28-2),

4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(methanesulphonyl)benzanilide (compound of example 28-3),

6-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(methanesulphonyl)-2-naphthanilide (compound of example 28-4),

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(trifloromethyl)benzanilide (compound of example 29-1),

6-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(trifloromethyl)-2-naphthanilide (compound of example 29-2),

4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(trifloromethyl)benzanilide (compound of example 29-3),

6-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(trifloromethyl)-2-naphthanilide (compound of example 29-4),

2’,4’-dichloro-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-diox-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]benzanilide (compound of example 40-2),

2’-chloro-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(trifluoromethyl)benzanilide (compound of example 41-1) and

2’-chloro-4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(trifluoromethyl)benzanilide (compound of example 41-2).

Even more preferred compounds of the above compounds include:

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(2,2,3,3-tetrafluoropropoxy)benzanilide (the compound of example 1-1),

4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(2,2,3,3-tetrafluoropropoxy)benzanilide (the compound of example 1-3),

4’-cyano-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 2-1),

4’-cyano-4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]benzanilide (compound of example 2-3),

4’-chloro-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 4-1),

4’-chloro-4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-feranzano (compound of example 5-1),

4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-feranzano (compound of example 5-3),

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(trifluoromethyl)benzanilide (compound of example 6-1),

4-[5-[3-(2,4-differenl)-3-hydroxy-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(trifluoromethyl)benzanilide (compound of example 6-3),

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(triptoreline)benzanilide (the compound of example 7-1),

4-[5-[3-(2,4-differenl)-3-hydroxy-2~methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(triptoreline)benzanilide (compound of example 7-3),

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(triptoreline)benzanilide (compound of example 8-1),

4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4'-(triptoreline)benzanilide (compound of example 8-3),

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-methylbenzamide (compound of example 9-1),

4-[5-[3-(2,4-D. the number 9-3),

3’-chloro-4’-cyano-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 11-1),

3’-chloro-4’-cyano-4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]benzanilide (compound of example 11-3),

4’-cyano-2’-fluoro-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 18-1),

4’-cyano-2’-fluoro-4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]benzanilide (compound of example 18-3),

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-hydroxybenzamide (compound of example 27-1),

4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-hydroxybenzamide (compound of example 27-3),

4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(methanesulphonyl)benzanilide (compound of example 28-1),

4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(methanesulphonyl)benzanilide (compound of example 28-3),

4-[5-[[2-(2,�ylides (compound of example 29-1),

4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(trifloromethyl)benzanilide (compound of example 29-3),

2’,4’-dichloro-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 40-1),

2’,4’-dichloro-4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]benzanilide (compound of example 40-2),

2’-chloro-4-[5-[[2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(trifluoromethyl)benzanilide (compound of example 41-1) and

2’-chloro-4-[5-[3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]-4’-(trifluoromethyl)benzanilide (compound of example 41-2).

Particularly preferred compounds of the above compounds (I) include:

4’-cyano-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 2-1),

4’-cyano-4-[TRANS-5-[(2S,3R)-3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]benzanilide (compound of example 2-3),

4’-chloro-4-[TRANS-5-[[(1R,2R)-2-(2,4-deltorphin the ASS="ptx2">

4’-chloro-4-[TRANS-5-[(2S,3R)-3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]benzanilide (compound of example 4-3).

The compound (I) of the present invention can be easily obtained is illustrated below by way of a and B.

[Method A]

Method And represents the process of obtaining the compound (I) and is illustrated in the following reaction scheme.

In the above reaction scheme AG1, AG2, X, R1, R2and R3have the same meanings as above.

According to the method And by reacting carboxylic acid derivative of the formula (II) or its reactive derivative with the amine compound of the formula (III) to obtain the amide compounds of formula (IV) (stage-1) and the subsequent interaction of the compounds of formula (IV) with the compound of the formula (V) (stage-2) get the connection formula (I). Each stage of the method (A) described below.

Stage A-1 is the method of obtaining the amide compounds of formula (IV) and includes the interaction of the carboxylic acid derivative of the formula (II) or its reactive derivative with the amine compound of the formula (III) in an inert solvent.

Proraso known to specialists in this field. Carboxylic acid derivative of the formula (II) can be obtained, for example, by metaliterature derived dicarboxylic acid (Ar2(CO2H)2), the restoration of one of the ester groups esterified compounds (AG2(CO2CH3)2) using Red-Al or similar reducing agent, the oxidation product of activated manganese dioxide and the subsequent hydrolysis permissionaires connection (AG2CO2CH3) (SNO)).

The amine compound of the formula (III) is commercially available or can be obtained by methods well known to specialists in this field.

Used on stage A-1 solvent is not specifically limited, but it should not have an adverse influence on the reaction, and it should dissolve the starting compound to some extent. Such solvents include aprotic solvents, for example halogenated hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene or xylene; ethers, such as diethyl ether or tetrahydrofuran; NITRILES, such as acetonitrile; heteroaryl base, containing Writely include halogenated hydrocarbons, ethers, and heteroaryl base containing one or more nitrogen atoms. Particularly preferred solvents are dichloromethane, tetrahydrofuran or pyridine.

When on stage A-1 uses the carboxylic acid derivative of the formula (II), then can be used binder. This binder is not specifically limited provided that it can be usually used in organic synthesis as a binder. Examples of such reagents include carbodiimides, such as dicyclohexylcarbodiimide.

When on stage A-1 uses a reactive carboxylic acid derivative, such carboxylic acid derivative of the formula (II) is converted into active chemical compound of the formula OHC-Ar2-COZ (where Z represents a removable group, for example halogen atom, asiagraph, cyano, C1-6-alkylsulfonates, such as methanesulfonamido, halogen-C1-6-alkylsulfonates, such as triftormetilfullerenov, C1-6-alkanoyloxy, such as pivaloyloxy, or heteroaryl group, such as imidazolidine group or thiazolidine group, or connected to asanoha reactive carboxylic acid derivative of the formula (II) with the compound of the formula (III) in the presence of a base, such as triethylamine, diisopropylethylamine, pyridine or 4-(N,N-dimethylamino)pyridine.

Reagents, leading to the reactive carboxylic acid derivative of the formula (II) include, for example, thionylchloride, such as thionyl chloride; reactive derivatives of phosphoric acid, such as phosphorus oxychloride or diphenylphosphoryl; acid anhydrides, such as pivaloyloxy, oxalicacid and the like; reactive derivatives of sulfonic acid, such as methanesulfonate or anhydride triftormetilfullerenov acid; reactive derivatives of carbonates, such as phosgene, trichloromethylcarbonate, triphosgene or 1,1’-carbonyldiimidazole; reactive derivatives of oxalic acid, such as oxacillin; preferably thionyl chloride or oxalicacid. The quantity of the reagent is in the range from 1 to 10 equivalents relative to the amount of carboxylic acid derivative of the formula (II) is preferably in the range from 1 to 2 equivalents.

The amount of coupling an amine of formula (III) is in the range from 0.5 to 2 molar equivalents relative to the amount of carboxylic acid derivative of the formula (II) or its KhIMIChESKIE reaction at the stage-1 depends on various factors, such as the original connection, the reagent and the solvent, and usually it is between-20 ° C and the boiling point of the reaction solvent, preferably between 0 ° C and room temperature.

The reaction time on the stage-1 depends on various factors, such as the original compound, reagent, solvent and reaction temperature. It usually takes from 10 minutes to 24 hours, preferably from 1 to 2 hours.

After performing the reaction in stage a-1 the desired compound (IV) is recovered from the reaction mixture by conventional methods. For example, the reaction mixture or the residue obtained by concentrating the reaction mixture is distributed between water and is not miscible with water with an organic solvent, and then the organic layer is washed with water and concentrated to obtain the desired connection.

Stage a-2 can be performed by reacting the aldehyde compound of the formula (IV) with an alcohol compound of the formula (V) in the presence of acatalasemia reagent in an inert solvent, and water generated during the reaction in stage a-2, removed from the reaction mixture during the reaction.

On stage a-2 as a starting compound instead of the alcohol compound of the formula shall have the meanings above; and R7represents a C1-6is an alkyl group or a C6-14-aryl group).

“C1-6is an alkyl group” in the definition of R7includes alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, for example methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, second-boutelou, tert-boutelou, pentelow, isopentanol, 2-methylbutanol, neopentyl, 1-ethylpropyl, hexeline, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group, preferably alkyl group with straight or branched chain, having from 1 to 4 carbon atoms.

“C6-14-aryl group” include an aromatic hydrocarbon group having 6 to 14 carbon atoms, such as phenyl group, indenolol group, naftalina group or antarctilyne group, preferably phenyl group. Mentioned “aryl group” may be optionally condensed with cycloalkyl group having from 3 to 10 atoms uglerodnoi.

Alcohol compound of the formula (V) can be obtained by the same method, which is disclosed in the descriptions of published patent applications in Japan No. Hei-8-333350 and Hei-11-80135, or similar methods.

The compound of formula (VI) can be obtained as intermediate compounds in a method of producing an alcohol compound of the formula (V) presented in the above descriptions. Sol in alcohol compounds of formula (V) can be obtained by removing the protective group of the compounds of formula (VI).

Two primary hydroxyl group of an alcohol compound of the formula (V) can be optionally protected by three (1-6-alkyl)silyl group, which consists of a silicon atom substituted with three C1-6-alkyl groups, for example trimethylsilyloxy, triethylsilyl, triisopropylsilyl, dimethylethoxysilane, diethylethanolamine or tert-butyldimethylsilyloxy, and it is preferable trimethylsilyl group.

The amount of alcohol compounds of the formula (V) is in the range from 0.5 to 2 molar equivalents relative to the amount of aldehyde compounds of formula (IV), preferably from 0.9 to 1.2 molar equivalents.

Used on stage a-2 dissolve it dissolves the starting compound to some extent. Such solvents include aprotic solvents, for example halogenated hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene or xylene; ethers, such as diethyl ether or tetrahydrofuran; and the like solvents. Preferred solvents include halogenated hydrocarbons or ethers, and particularly preferred is dichloromethane or tetrahydrofuran.

Examples acatalasemia reagent used in stage a-2, include inorganic acids such as hydrochloric acid, sulfuric acid or nitric acid; a Lewis acid such as boron TRIFLUORIDE, zinc chloride, magnesium bromide, titanium tetrachloride or aluminum chloride; sulfonic acids such as methanesulfonate acid, benzolsulfonat acid, p-toluensulfonate acid, camphorsulfonic acid or triftormetilfullerenov acid; carboxylic acids such as formic acid, acetic acid, triperoxonane acid, oxalic acid or citric acid; and similitude agents, such as chlorotrimethylsilane or trimethylsilyltrifluoromethane; preferably sulfonic CI is the future of the reagent is in the range from 1 to 3 molar equivalents relative to the amount of the alcohol compound of the formula (V). When the aldehyde compound has a basic group, it is necessary to use the acid number of which is equivalent to the number of the main group.

Formed during the interaction of water are removed by azeotropic distillation of the reaction solvent by evaporation under reduced pressure or by using dehydrating, such as molecular sieves.

The reaction temperature in stage-2 depends on various factors, such as acatalasemia reagent, the original compound and the solvent. Usually it is between 0C and the boiling point of the reaction solvent, preferably between 5C and 40C.

The reaction time on the stage-2 depends on various factors, such as acatalasemia reagent, the original compound, the solvent and the reaction temperature. It usually takes from 0.5 to 24 hours, preferably from 1 to 5 hours.

After performing the reaction in stage a-2, the reaction mixture was neutralized with an aqueous solution of sodium bicarbonate or similar solution, and then the desired compound of formula (I) is recovered from the reaction mixture by conventional means. For example, the reaction mixture or the residue obtained by concentrating reactionally washed with water and concentrated to obtain the desired product.

Thus obtained the desired product (I), if necessary, can then be purified by conventional means, such as recrystallization, pereosazhdeniya or chromatography.

In addition, when the product from step a-2 has a protective group, the resulting product can be converted to the desired compound (I) removing the protective group.

Reaction conditions for the removal of the protective group depend on the type of the protective group. The reaction removal can be accomplished by conventional means, well known to the experts in this field (see “Protective Groups in Organic Synthesis”, 2ndEdition, Ed. By T. W. Greene & P. G. M. Wuts, 1991, John Wiley & Sons, Inc. or similar document).

[Method]

Method is another method of obtaining the compound (I) and is illustrated in the following reaction scheme.

In the above reaction scheme AG1, AG2, X, R1, R2and R3have the same meanings as above; and R8represents a C1-6is an alkyl group or a C6-14-aryl group.

“C1-6is an alkyl group” in the definition of R8includes alkyl group with straight or branched chain, having from 1 to 6 carbon atoms, for example untilnow, isopentanol, 2-methylbutanol, neopentyl, 1-ethylpropyl, hexeline, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2, 2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl or 2-ethylbutyl group, preferably alkyl group with straight or branched chain, having from 1 to 4 carbon atoms.

“C6-14-aryl group” include an aromatic hydrocarbon group having 6 to 14 carbon atoms, such as phenyl group, indenolol group, naftalina group or antarctilyne group, preferably phenyl group.

R8in these groups preferably represents a methyl group.

According to the method In the interaction alcohol compounds of formula (V) with the compound of the formula (VII) in the presence of acatalasemia reagent in an inert solvent, carried out by the method similar to that described for stage-2, where the formed water is removed during the reaction from the reaction mixture to obtain the compounds of formula (VIII) (stage-1), and the subsequent interaction of the compounds of formula (VIII) are connected (I) (stage-2).

Stage-1 is a way of obtaining dioxane compounds of the formula (VIII), and it is carried out by reacting an alcohol compound of the formula (V) with an aldehyde compound of the formula (VII) in the presence of acatalasemia reagent in an inert solvent, and formed in the reaction water is removed from the reaction mixture during the reaction.

Aldehyde compound of the formula (VII) is commercially available or can be obtained by methods well known to specialists in this field. Aldehyde compound of the formula (VII) can be obtained, for example, derived by the esterification of dicarboxylic acids (AG2(CO2N)2), the restoration of one of the ester groups esterified compounds (AG2(CO2CH3)2) using Red-Al or similar reducing agent and subsequent oxidation product of activated manganese dioxide.

The specified stage can be performed according to the method similar to that described for stage-2.

Stage-2 can be performed by reacting the compounds of formula (VIII) with an amine compound of the formula (III) in the presence of an activating agent in an inert solvent.

Use the e effect on the reaction and that it dissolves the starting compound to some extent. Such solvents include aprotic solvents, for example halogenated hydrocarbons such as dichloromethane, chloroform or 1,2-dichloroethane; aromatic hydrocarbons such as benzene, toluene or xylene; ethers, such as diethyl ether or tetrahydrofuran; or mixtures thereof. Of these solvents, preferred solvents include aromatic hydrocarbons or halogenated hydrocarbons, and particularly preferred solvent is toluene.

Used in stage-2, the activating agent is not specifically limited provided that it can be used in organic synthesis as a reagent for the conversion of ester to amide. Examples of such activating agents include (lower alkyl) aluminum, such as trimethylaluminum or triethylaluminum; alkali metal cyanide such as sodium cyanide; hydroxycobalamin aromatic heterocyclic compounds containing one or more nitrogen atoms, such as 2-hydroxypyridine; bases such as sodium methoxide or utility; or halogenated boron compounds, such as tribromide boron. From these activating agents are preferred compounds (lower alisporites at stage-2, is in the range from 1 to 5 molar equivalents relative to the amount of the ester compounds of formula (VIII) and is preferably from 1.5 to 3.0 molar equivalents.

The amount of coupling an amine of formula (III) is in the range from 0.5 to 5 molar equivalents relative to the amount of the ester compounds of formula (VIII) is preferably in the range from 0.9 to 2.5 molar equivalents.

The reaction temperature in stage-2 depends on various factors, such as activating agent, the original compound and the solvent. Usually it is between room temperature and the boiling point of the reaction solvent, preferably between 50 and 90.

Reaction time on stage-2 depends on various factors, such as activating agent, the original compound, the solvent and the reaction temperature. It usually takes from 0.5 to 24 hours, preferably from 1 to 5 hours.

After performing the reaction in stage-2 to the reaction mixture an aqueous solution of sodium bicarbonate or similar compound for decomposition of the activating agent and then from the reaction mixture highlight the desired compound (I) in accordance with conventional methods. Thus, the water and water-immiscible organic solvent, and the organic layer washed with water and then concentrated to obtain the desired product.

Thus obtained the desired product of formula (I), if necessary, can then be purified by conventional means, such as recrystallization, pereosazhdeniya or chromatography.

In addition, when the product stage-2 has a protective group, such product may be converted to the desired compound (I) removing the protective group using methods such as those disclosed in method A.

Pharmaceutically acceptable prodrugs of compound (I) can be obtained by conventional methods known to experts in this field. Such pharmaceutically acceptable prodrugs using conventional methods can be obtained by different acyl derivatives by acylation of the hydroxyl group of compound (I).

The compound (I) or obtained in this way its pharmaceutically acceptable prodrug can be converted into a pharmaceutically acceptable salt by treatment with an acid or base in a solvent.

Used solvents are not specifically limited and include, for example, aromatic hydrocarbons as diethyl ether, tetrahydrofuran or dioxane; esters, such as ethyl acetate; alcohols, such as methanol or ethanol; ketones, such as acetone; NITRILES such as acetonitrile; hydrocarbons, such as hexane or cyclohexane; or mixtures thereof.

Used acid is not specifically limited provided that they are pharmaceutically acceptable acid. Examples of such acids include inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid or nitric acid; carboxylic acids such as acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid or malic acid; sulfonic acids such as methanesulfonate acid, econsultancy acid, benzolsulfonat acid or toluensulfonate acid; or amino acids, such as glutamina acid or aspartic acid.

Used the base is not specifically limited provided that they are pharmaceutically acceptable base. Examples of such bases include the hydroxides or carbonates of alkali metal such as lithium, sodium or potassium); the hydroxides or carbonates of alkaline earth and cyclohexylamine.

The desired salt may be typically selected from a solution of the compound (I) and acid or base in the form of crystals or powder by adding a solvent which does not dissolve the desired salt in the solution containing the specified salt or by evaporating the solvent from a solution containing the desired salt.

The compound (I) and their pharmaceutically acceptable salts show good antifungal activity against many eumycetes. Examples of eumycetes include Candida species, Aspergillus species, Cryptococcus species, Mucor species, Histoplasma species, Blastomyces species, species Coccidioides, Paracoccidioides species, Trichophyton species, Epidermophyton species, Microsporum species, Malassezia species, type Psuedallescheria, Sporothrix species, type Rhinosporidium, Fonsecaea species, type Wangiella, Phialophora species, Exophiala species, Cladosporium species, Alternaria species, species Aureobasidium, Chaetomium species, Curvularia species, type Cereals, type Mycocentrospora, Phoma species, type Hendersonula, Scytalidium species, type Corynespora, type Leptospheria, type Madurella, view Neotestudina, Scedosporium species, type Pyrenochaeta, Geotrichum species, Trichosporon species, species Chrysosporium, Coprinus species, species Schizophyllum, type Pneumocystis, type Conidiobolus, Basidiobolus species, Paecilomyces species, Penicillium species, Acremonium species, species of Fusarium, Scopulariopsis species, Saccharomyces species, type of Cephalosporium, type Loboa, type Rhizopus, Rhizomucor species or species Absidia.

Pharmaceutically acceptable prodrug of compound (I) producing the compound (I) or its salt with chemical or biological reoccu antifungal activity. The compound (I), their pharmaceutically acceptable prodrugs and their pharmaceutically acceptable salts can be used as a drug, preferably as antifungal agents. The compound (I), its pharmaceutically acceptable prodrug or salt can be entered by themselves or in a mixture with pharmaceutically acceptable(and) excipients(s), diluent(s) and similar compounds in the form of standard dosage forms, such as tablets, capsules, granules, powders, syrups or similar forms intended for oral administration, or in the form of standard dosage forms, such as injections or similar forms, intended for parenteral administration.

The pharmaceutical compositions can be obtained by known methods using additives such as excipient, disintegrating agents, lubricants, stabilizers, corrigentov, suspendresume agents, diluents and solvents for the composition.

Examples of excipients include derivatives of sugars, such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, a-starch, dextrin or karboksimetilcelljuloza, the hypromellose, carboxymethylcellulose, intramolecular stitched sodium carboxymethyl cellulose; gum Arabic, dextran; pullulan; derived silicates such as silicic acid anhydride, synthetic aluminum silicate or aluminate-metasilicate sodium; derivatives of phosphates such as calcium phosphate; derived carbonates such as calcium carbonate; and sulfates such as calcium sulfate, and the like.

Examples of the binder include excipient, such as those referred to above, gelatin, polyvinylpyrrolidone, macrogol, and the like.

Examples of disintegrating agents include excipient, such as those mentioned above, derivatives chemically modified starch or cellulose, such as nitrocresols, nitrocarburization starch, crosslinked polyvinylpyrrolidone and similar tools.

Examples of lubricants include talc; stearic acid; derivatives of metaliteracy, such as calcium stearate or magnesium stearate; colloidal silica; waxes such as beeswax or spermaceti; boric acid; glycol; carboxylic acids such as fumaric acid or adipic acid; natrocarbonatite, such as benzoylacrylate; derivatives of silicic acids such as silicic acid anhydride or silicic acid hydrate; derivatives of starches, such as those referred to above in respect of excipients, and similar substances.

Examples of stabilizers include derivatives of ester of para-hydroxybenzoic acid, such as methylparaben or propylparaben; derivatives of alcohols, such as chlorobutanol, benzyl alcohol or finitely alcohol; benzylaniline; derivatives of phenol such as phenol or cresol; thimerosal; acetic anhydride; and sorbic acid and similar compounds.

Examples corrigentov include sweeteners, podnikatel, improves the taste of substances, and the like additives commonly used for such purposes.

Examples suspendida agents include Polysorbate 80, sodium carboxymethyl cellulose and similar substances.

Examples of the solvent composition include water, ethanol, glycerin and the like solvents.

The dose of compound (I), its pharmaceutically acceptable prodrugs or pharmaceutically acceptable salts will vary depending on many factors, such as patient's age, symptoms, and similar factor the mg) per day for once as the lower limit to 2000 mg (preferably 1000 mg) per day for once as the upper limit. Suitable level of dose intravenous adult human ranges from 0.1 mg (preferably 0.5 mg) per day for once as the lower limit of 600 mg (preferably 500 mg) per day for once as the upper limit. The compound (I), its pharmaceutically acceptable prodrug or pharmaceutically acceptable salt can be entered either as a single dose, or, if necessary, the dose may be divided into appropriate padosi entered depending on the symptoms of the patient, from one to six times a day.

[The best option for carrying out the invention]

The following examples, examples, test examples and compositions are intended to further illustrate the present invention and are not intended to limit the scope of the invention in any way.

Example 1

4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]4’-(2,2,3,3-tetrafluoropropoxy)benzanilide and its CIS-isomer (compound of example 1-1)

(1) Commercially available 4-formylbenzoate acid (5.0 g, 33.3 mmol) was dissolved in a mixture of anhydrous tetrahydrofuran (100 ml) and anhydrous N,N-dimethylformamide (1 mll). The mixture was stirred at room temperature for 30 minutes and then at 40 ° C for 20 minutes. The reaction mixture was concentrated under reduced pressure and then under vacuum to obtain 4-formylbenzoate. 4-(2,2,3,3-tetrafluoropropoxy)aniline (646 mg, 2.9 mmol), described in Chem. Pharm. Bull., 44 (2), 314 (1996) and N,N-diisopropylethylamine (1,21 ml, 7.0 mmol) was dissolved in anhydrous tetrahydrofuran (8 ml) and the mixture was cooled with stirring to 0. To the mixture was added dropwise the above solution of 4-formylbenzoate (561 mg, of 3.33 mmol) in anhydrous tetrahydrofuran (2 ml). The resulting mixture was stirred at room temperature for 17 hours and then at 40 ° C for 20 minutes. At the end of mixing to the reaction mixture in a bath with ice was added saturated aqueous sodium bicarbonate solution and the mixture was distributed between ethyl acetate and water. The organic layer is successively washed with 0.5 n hydrochloric acid, saturated aqueous sodium bicarbonate, water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline residue was recrystallized from a mixture of ethyl acetate and hexane to obtain 4-formyl-4’-(2,2,3,3-titrator the

An NMR spectrum (400 MHz, CDCl3) memorial plaques: 4,37 (2H, t, J=12 Hz), 6,07 (1H, TT, J=53, 5 Hz), 6,97 (2H, d, J=9 Hz), to 7.61 (2H, d, J=9 Hz), to 7.77 (1H, s), 8,03 (4H, s), 10,12 (1H, s).

The IR spectrum v max (KBR)cm-1: 3329, 1699, 1649, 1256, 1108;

Mass spectrum m/z (EI): 355 (M+), 133 (100%), 105.

(2) To a mixture of 4-formyl-4’-(2,2,3,3-tetrafluoropropoxy)benzanilide (300 mg, 0.84 mmol) obtained in example 1(1), (2R,3R)-2-(2,4-differenl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol (disclosed in the description of the patent application of Japan No. Hei-8-333350; 253 mg, 0.70 mmol), monohydrate p-toluensulfonate acid (160 mg, 0.84 mmol) in anhydrous tetrahydrofuran (10 ml) and anhydrous dichloromethane (5 ml) was added molecular sieve 4A (3 g). The resulting mixture was stirred at room temperature for 2 days. To the reaction mixture at 0C was added an aqueous solution of sodium bicarbonate and the mixture was filtered to remove the molecular sieves. The filtrate was distributed between ethyl acetate and water. The organic layer was washed with saturated wodnym solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained oily residue was subjected to chromatography on a column of silica gel using as eluent a mixture of a solids and then using as eluent a mixture of ethyl acetate-hexane (4:1) was obtained CIS-isomer (55 mg, yield 11%) as a colourless oil. The TRANS-isomer was recrystallized from a mixture of ethyl acetate-simple isopropyl ether to obtain white loose crystals.

TRANS-isomer:

Melting point: S.

An NMR spectrum (400 MHz, CDCl3) memorial plaques: to 1.21 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), 3,76 (1H, t, J=11 Hz), of 3.78 (1H, t, J=11 Hz), 4,36 (2H, t, J=12 Hz), 4,42 (1H, DDD, J=11, 5, 2 Hz), 4,55 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, d, J=1 Hz), is 5.06 (1H, d, J=14 Hz), 5,54 (1H, s), 6,07 (1H, TT, J=53, 5 Hz), 6,7-6,8 (2H, m), to 6.95 (2H, d, J=9 Hz), 7.3 to 7.4 (1H, m), to 7.59 (2H, d, J=9 Hz), a 7.62 (2H, d, J=9 Hz), 7,74 (1H, s), 7,80 (2H, s), 7,88 (2H, d, J=9 Hz).

The IR spectrum max (KBR)cm-1: 3322, 1656, 1512, 1251, 1139.

Mass spectrum m/z (FAB): 697 (M++1).

Specific rotation: []25D-59 (C=0,57, l3).

CIS-isomer:

An NMR spectrum (400 MHz, CDCl3) memorial plaques: to 1.23 (3H, d, J=7 Hz), up 3.22(1H, t, J=2 Hz), 3,44 (1H, square, J=7 Hz), 4,2-4,5 (4H, m), 4,35 (2H, t, J=12 Hz), to 4.87 (1H, d, J=14 Hz), equal to 4.97 (1H, s), of 5.15 (1H, d, J=14 Hz), to 5.66 (1H, s), 6,07 (1H, TT, J=53, 5 Hz), 6,7-6,8 (2H, m), to 6.95 (2H, d, J=8 Hz), 7,3-7,5 (1H, m), to 7.59 (2H, d, J=8 Hz), to 7.64 (2H, d, J=8 Hz), to 7.77 (1H, s), 7,78 (1H, s), 7,79 (1H, s), 7,88 (2H, d, J=8 Hz).

Mass spectrum m/z (FAB): 697 (M++1).

Example 2

4’-cyano-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]Manzanillo reaction using commercially available 4-aminobenzonitrile (343 mg, 2.9 mmol), N,N-diisopropylethylamine (1,21 ml, 7.0 mmol), 4-formylbenzoate (561 mg, of 3.33 mmol) and 4-(dimethylamino)pyridine (catalytic amount) and the reaction mixture was treated in a manner similar to the method of example 1(1), obtaining an oily residue. The residue was subjected to chromatography on a column of silica gel using as eluent a mixture of ethyl acetate-hexane (2:1) to obtain 4’-cyano-4-formylbenzoate (81 mg, yield 11%) as a pale yellow solid, which was recrystallized from ethyl acetate to obtain pale yellow friable crystals.

Melting point: S.

Range of NMR 270 MHz, (DMSO-d6) memorial plaques: a 7.85 (2H, d, J=8 Hz), 8,00 (2H, d, J=8 Hz), 8,08 (2H, d, J=8 Hz), 8,15 (2H, d, J=8 Hz), 10,13 (1H, s), 10,85 (1H, s).

The IR spectrum max (KBR)cm-1: 3368, 2223, 1685, 1518.

Mass spectrum m/z (EI): 250 (M+), 133 (100%), 105.

(2) Following a method similar to the method of example 1(2), reaction was carried out using 4’-cyano-4-formylbenzoate (75 mg, 0.30 mmol) obtained in example 2 (1), (2R,3R)-2-(2,4-differenl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazole-1-yl)butanol (98 mg, 0.27 mmol) and monohydrate p-toluensulfonate acid (62 mg, 0.32 mmol) and the reaction mixture was treated by the way, the white solid and the CIS isomer (20 mg, yield 12%) as a white solid. The TRANS-isomer was recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

TRANS-isomer:

Melting point: S.

An NMR spectrum (270 MHz, CDCl3) memorial plaques: 1,22 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), 3,76 (1H, t, J=11 Hz), with 3.79 (1H, t, J=11 Hz), 4,42 (1H, DDD, J=11, 5, 2 Hz), 4,55 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, d, J=1 Hz), of 5.05 (1H, d, J=14 Hz), of 5.55 (1H, s), 6,7-6,8 (2H, m), 7.3 to 7.4 (1H, m), the 7.65 (2H, d, J=8 Hz), to 7.68 (2H, d, J=8 Hz), 7,80 (2H, s), 7,80 (2H, d, J=8 Hz), 7,89 (2H, d, J=8 Hz), to 7.93 (1H, s).

The IR spectrum max (KBR)cm-1: 3371, 2225, 1679, 1512, 1319, 1139.

Mass spectrum m/z (FAB): 592 (M++1)

Specific rotation: []25D-52 (C=0,60, AcOEt).

CIS-isomer:

An NMR spectrum (270 MHz, Dl3) memorial plaques: to 1.23 (3H, d, J=7 Hz), up 3.22 (1H, t, J 2 Hz), 3,44 (1H, square, J=7 Hz), 4,2-4,5 (4H, m), a 4.86 (1H, d, J=14 Hz), equal to 4.97 (1H, s), of 5.15 (1H, d, J=14 Hz), 5,67 (1H, s), 6,6-6,8 (2H, m), 7,3-7,5 (1H, m), to 7.67 (2H, d, J=8 Hz), to 7.67 (2H, d, J=8 Hz), 7,78 (1H, s), 7,79 (1H, s), 7,80 (2H, d, J=8 Hz), 7,88 (2H, d, J=8 Hz), 8,02 (1H, ush.C).

Mass spectrum m/z (FAB): 592 (M++1)

Example 3

4’-Cyano-6-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-2-naphthanilide (compound of example 2-2)

(1) To a solution of komadina to-50C, was added dropwise Red-Al (and 0.61 ml of a 65% solution in toluene, product of Aldrich, 2.1 mmol). The resulting mixture was stirred at 50C for 1 hour and then at room temperature for 1.5 hours. To the reaction mixture was sequentially added ethyl acetate, water, 0.5 n aqueous solution of (+)-tartrate of potassium and the mixture was distributed between ethyl acetate and water. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The obtained residue was subjected to chromatography on a column of silica gel using as eluent a mixture of ethyl acetate-hexane (2:1) with the obtained methyl 6-hydroxymethyl-2-naphthalenesulfonate (288 mg, yield 65%) as a white solid, which was recrystallized from a mixture of ethyl acetate-hexane to obtain loose crystals.

Melting point: S.

An NMR spectrum (400 MHz, Dl3) memorial plaques: 1,80 (1H, t, J=6 Hz), 3,99 (3H, s), the 4.90 (2H, d, J=6 Hz), 7,55 (1H, d, J=9 Hz), 7,8-7,9 (2H, m), of 7.96 (1H, d, J=9 Hz), 8,07 (1H, d, J=9 Hz), 8,61 (1H, s).

The IR spectrum max (KBR)cm-1: 3252, 1716.

Mass spectrum m/z (EI): 216 (M+, 100%).

Elemental analysis:

Calculated for C13H12ABOUT3From: 72,21 N: 5,59 N: 0,00

An NMR spectrum (400 MHz, CDCl3) memorial plaques: of 3.97 (3H, s), 7,98 (1H, DD, J=8, 1 Hz), with 8.0 and 8.1 (2H, m), 8,13 (1H, DD, J=8, 1 Hz), a 8.34 (1H, s), to 8.62 (1H, s), 10,16 (1H, s).

The IR spectrum max (KBR)cm-1: 1718, 1696, 1682

Mass spectrum m/z (EI): 214 (M+, 183 (100%)

Elemental analysis:

Calculated for C13H10ABOUT3From: 72,89 N: 4,71 N: 0,00

Found: 72,60 N: 4,53 N: 0,00

(3) Solution of methyl 6-formyl-2-naphthalenesulfonate (227 mg, 1.06 mmol) obtained in example 3(2), (2R,3R)-2-(2,4-differenl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol (381 mg, 1.06 mmol) and monohydrate p-toluensulfonate acid (363 mg, at 1.91 mmol) in anhydrous tetrahydrofuran (50 ml) is then the vacuum pump. A solution of the residue in anhydrous tetrahydrofuran (40 ml) was concentrated in accordance with the above methodology. This procedure was repeated twice. A solution of the obtained residue in tetrahydrofuran (50 ml) was poured into saturated aqueous sodium bicarbonate solution, cooled under stirring to 0C. The mixture was extracted with ethyl acetate and the organic layer was washed with an aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The oily residue was subjected to chromatography on a column of silica gel using as eluent a mixture of ethyl acetate-hexane (1:2) to give methyl 6-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-2-naphthalenesulfonate (TRANS-isomer, 331 mg, yield 56%) in the form of a white solid substance and then using as eluent a mixture of ethyl acetate-hexane (3:1) to obtain methyl 6-[CIS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-2-naphthalenesulfonate (CIS-isomer, 77 mg, yield 14%) in the form of a colorless oil. The TRANS-isomer was recrystallized from a mixture of ethyl acetate-hexane to obtain white fluffy crystals.

TRANS-Is=7 Hz), the 3.5 to 3.6 (1H, m), 3,81 (1H, t, J=11 Hz), 3,83 (1H, t, J=11 Hz) to 3.99 (3H, s), 4,46 (1H, DDD, J=11, 5, 2 Hz), 4,58 (1H, DDD, J=11, 5, 2 Hz), a 4.86 (1H, d, J=14 Hz), of 5.05 (1H, s), is 5.06 (1H, d, J=14 Hz), to 5.66 (1H, s), 6,7-6,8 (2H, m), 7.3 to 7.4 (1H, m), 7,66 (1H, d, J=9 Hz), 7,80 (2H, s), to $ 7.91 (1H, d, J=9 Hz), 7,98 (1H, d, J=9 Hz), 8,01 (1H, s), 8,07 (1H, DD, J=9, 1 Hz), 8,61 (1H, C).

The IR spectrum max (KBR)cm-1: 3445, 1718, 1708, 1139.

Mass spectrum m/z (FAB): 556 (M++1).

Elemental analysis:

Calculated for C28H27F2N3O5S: 60,53 N: 4,90 N: 7,56 F: 6,84

Found: 60,52 N: 4,86 N: 7,56 F: 6,87

CIS-isomer:

An NMR spectrum (400 MHz, Dl3) memorial plaques: 1,24 (3H, d, J=7 Hz), 3,23 (1H, t, J=2 Hz), 3,4-3,6 (1H, m) to 3.99 (3H, s), 4,2-4,5 (4H, m), 4,88 (1H, d, J=14 Hz), equal to 4.97 (1H, d, J=1 Hz) to 5.17 (1H, d, J=14 Hz), 5,78 (1H, s), 6,6-6,8 (2H, m), 7,3-7,5 (1H, m), 7,71 (1H, DD, J=9, 1 Hz), to 7.77 (1H, s), 7,79 (1H, s), to $ 7.91 (1H, d, J=8 Hz), 7,98 (1H, d, J=8 Hz), 8,03 (1H, s), 8,07 (1H, DD, J=9, 1 Hz), 8,61 (1H, s).

Mass spectrum m/z (FAB): 556 (M++1).

(4) To a solution of commercially available 4-aminobenzonitrile (85 mg, to 0.72 mmol) in anhydrous toluene (4 ml) at room temperature in a nitrogen atmosphere under stirring was added dropwise trimethylaluminum (of 0.67 ml, 1.07 M solution of n-hexane, to 0.72 mmol). After stirring the mixture at room temperature for 10 minutes, to the mixture was added dropwise a solution of methyl 6-[Tr the ATA (100 mg, 0.18 mmol) in anhydrous toluene (3 ml). Formed mixture was stirred at 80 ° C for 2.5 hours. At the end of mixing to the reaction mixture at room temperature was sequentially added water and 0.5 n aqueous solution of (+)-tartrate of potassium. The mixture was distributed between ethyl acetate and water. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to chromatography on a column of silica gel using as eluent a mixture of ethyl acetate-hexane (3:1) to obtain the specified title compound (99 mg, yield 85%) as a colourless oil, which was recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

Melting point: S.

An NMR spectrum (400 MHz, CDCl3) memorial plaques: to 1.23 (3H, d, J=7 Hz), to 3.38 (1H, square, J=7 Hz), 3,5-3,6 (1H, m), 3,82 (1H, t, J=11 Hz), a-3.84 (1H, t, J=11 Hz), 4,46 (1H, DDD, J=11, 5, 2 Hz), 4,59 (1H, DDD, J=11, 5, 2 Hz), a 4.86 (1H, d, J=14 Hz), is 5.06 (1H, d, J=1 Hz), is 5.06 (1H, d, J=14 Hz), of 5.68 (1H, s), 6,7-6,8 (2H, m), 7,3-7,5 (1H, m), of 7.69 (2H, d, J=9 Hz), of 7.70 (1H, d, J=9 Hz), 7,80 (2H, s), a 7.85 (2H, d, J=9 Hz), a 7.92 (1H, DD, J=9, 1 Hz), 8,00 (2H, d, J=9 Hz), of 8.06 (1H, s) to 8.12 (1H, s), 8,39 (1H, s).

The IR spectrum max (KBR)cm-1: 3395, 2225, 1681, 1513, 1138.

Mass spectrum CLASS="ptx2">

4’-cyano-4-[TRANS-5-[(2S,3R)-3-(2,4-differenl)-3-hydroxy-2-methyl-4-(1H-1,2,4-triazole-1-yl)butyl]-1,3-dioxane-2-yl]benzanilide and its CIS-isomer (compound of example 2-3)

Following the procedure of example 1(2), reaction was carried out using 4’-cyano-4-formylbenzoate (78 mg, 0.31 mmol) obtained in example 2(1), (4S,5R)-5-(2,4-differenl)-2-(hydroxymethyl)-4-methyl-6-(1H-1,2,4-triazole-1-yl)-1,5-hexandiol (disclosed in the description of the patent application of Japan No. Hei-11-80135: 100 mg, 0.29 mmol) and monohydrate p-toluensulfonate acid (99 mg, 0.52 in ml) and the reaction mixture was treated in a manner similar to the method of example 1(2), with the TRANS-isomer is specified in the header of the compound (100 mg, yield 59%) as a white solid and the CIS isomer (23 mg, yield 14%) as a colourless oil. The TRANS-isomer was recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

TRANS-isomer:

Melting point: S.

An NMR spectrum (500 MHz, CDCl3) memorial plaques: 0,86 (3H, d, J=7 Hz) and 1.15 (1H, DDD, J=14, 10, 2 Hz), 1,49 (1H, DDD, J=14, 10, 2 Hz), 2,0-2,1 (1H, m), 2,2-2,3 (1H, m), 3,60 (1H, t, J=11 Hz), 3,62 (1H, t, J=11 Hz), 4,23 (1H, DDD, J=11, 5, 2 Hz), 4,35 (1H, DDD, J=11, 5, 2 Hz), 4,50 (1H, d, J=14 Hz), the 4.90 (1H, s), 4,96 (1H, d, J=14 Hz), the 5.51 (1H, s), 6,6-6,8 (2H, m), 7,3-7,5 (1H, m), of 7.64 (2H, d, J=8 Hz), to 7.67 (2H, d, J=8 Hz), 7,79 (1.

Mass spectrum m/z (FAB): 574 (M++1).

Specific rotation: []25D-60 (C=0,56, l3).

CIS-isomer:

An NMR spectrum (400 MHz, CDCl3) memorial plaques: to 0.78 (3H, d, J=7 Hz), 1,5-1,8 (2H, m), 2,1-2,3 (1H, m), 2,5-2,6 (1H, m), 4,0-4,3 (4H, m) and 4.65 (1H, d, J=14 Hz), was 4.76 (1H, s), 4,91 (1H, d, J=14 Hz), the ceiling of 5.60 (1H, s), 6,6-6,8 (2H, m), 7,3-7,5 (1H, m), to 7.61 (2H, d, J=8 Hz), to 7.64 (2H, d, J=8 Hz), 7,76 (1H, s), 7,78 (1H, s), 7,81 (2H, d, J=8 Hz), 7,88 (2H, d, J=8 Hz), 8,18 (1H, ush.C).

Mass spectrum m/z (FAB): 574 (M++1).

Example 5

4’-Cyano-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-3-feranzano (compound of example 2-21)

(1) Methyl 3-fluoro-4-bromoethylene (80 mg, 0.32 mmol), described in J. Med. Chem., 35 (5) 877 (1992), was dissolved in a mixture of anhydrous DMSO (4.5 ml) and anhydrous dichloromethane (3 ml). To the solution was cooled to 0C, was added dropwise with stirring dehydrate the triethylamine-N-oxide (180 mg, of 1.62 mmol) and the mixture was stirred at room temperature for 2 hours. To the reaction mixture were added water and the formed mixture was distributed between a mixture of ethyl acetate and hexane (1:1) and water. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and using as eluent a mixture of ethyl acetate-hexane (1:10) to give methyl 3-fluoro-4-formylbenzoate (29 mg, yield 48%) as white solids

An NMR spectrum (400 MHz, CDCl3) memorial plaques: of 3.97 (3H, s), a 7.85 (1H, d, J=11 Hz), of 7.9 to 8.0 (2H, m), 10,43 (1H, s).

Mass spectrum, m/z (EI): 182 (M+, 100%).

(2) Following the method of example 3(3), reaction was carried out using methyl 3-fluoro-4-formylbenzoate (105 mg, of 0.58 mmol) obtained in example 5(1), (2R,3R)-2-(2,4-differenl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol (207 mg, of 0.58 mmol) and monohydrate p-toluensulfonate acid (199 mg, 1.04 million ml) and the reaction mixture was treated in a manner similar to the method of example 3(3), to obtain methyl 4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-doksan-2-yl]-3-perbenzoate (TRANS-isomer, 106 mg, yield 35%) and methyl 4-[CIS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl) propyl]thio]-1,3-dioxane-2-yl]-3-perbenzoate (CIS-isomer, 29 mg, yield 10%) as a colourless oil.

TRANS-isomer:

An NMR spectrum (400 MHz, Dl3) memorial plaques: to 1.21 (3H, d, J=7 Hz), 3,35 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), of 3.77 (1H, t, J=11 Hz), with 3.79 (1H, t, J=11 Hz), 3,93 (3H, s), 4,39 (1H, DDD, J=11, 5, 2 Hz) to 4.52 (1H, DDD, J=11, 5, 2 Hz), 4,84 (1H, d, J=14 Hz), is 5.06 (1H, d, J=1 Hz), of 5.05 (1H, d, J=14 Hz), 5,79 (1H, s), 6,7-6,8 (2H, m), 7.3 to 7.4 (1H, m), 7,6-7,8 (2H, m), 7,80 (2H, s), 7,86 (1H, DD, J=8, 1 Hz).

Mass spectrum m/zUB>5N3F3m/z 524,1467

Found 524,1457

CIS-isomer:

An NMR spectrum (400 MHz, Dl3) memorial plaques: of 1.18 (3H, d, J=7 Hz), 3,1-3,2 (1H, m), 3,40 (1H, square, J=7 Hz), a 3.87 (3H, s), 4,2-4,5 (4H, m), a 4.83 (1H, d, J=14 Hz), of 4.95 (1H, d, J=1 Hz), 5,12 (1H, d, J=14 Hz), of 5.84 (1H, s), 6,6-6,8 (2H, m), 7,2-7,4 (1H, m), 7,66 (1H, DD, J=11, 1 Hz), 7,7-7,8 (1H, m), 7,73 (1H, s), 7,76 (1H, s), 7,81 (1H, DD, J=8, 1 Hz).

Mass spectrum m/z (FAB): 524 (M++1).

(3) Following the method of example 3(4), reaction was carried out using commercially available 4-aminobenzonitrile (98 mg, 0.83 mmol), trimethylaluminum (0,78 ml, 1.07 M solution of n-hexane, 0.83 mmol) and methyl 4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-3-perbenzoate (109 mg, 0.21 mmol) obtained in example 5(2), and the reaction mixture was treated in a manner similar to the method of example 3(4), obtaining specified in the title compound (95 mg, yield 75%) as a colourless oil, which was recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

Melting point: 110S.

An NMR spectrum (400 MHz, Dl3) memorial plaques: 1,22 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,5-3,6 (1H, m), of 3.78 (1H, t, J=11 Hz), 3,80 (1H, t, J=11 Hz), to 4.41 (1H, DDD, J=11, 5, 2 Hz), of 4.54 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, d, J=14 Hz), 5,07 (1H, s) 5,80 (1H, Jerusalem. -1: 3343, 2226, 1685, 1512, 1141.

Mass spectrum m/z (FAB): 610 (M++1).

The mass spectrum of high resolution (FAB):

Calculated for C30H27O4N5F3S m/z 610,1736

Found 610,1750.

Specific rotation: []25D-65(C=0,53, l3).

Example 6

4’-Cyano-3-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 2-25).

(1) Following the method of example 3(3), reaction was carried out using methyl 3-formylbenzoate described in Chem. Weg., 45, 1585(1912), (188 mg, 1.2 mmol), (2R,3R)-2-(2,4-differenl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol (412 mg, 1.2 mmol) and monohydrate p-toluensulfonate acid (394 mg, 2.1 mmol) and the reaction mixture was treated in a manner similar to the method of example 3(3) to obtain methyl 3-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-3-benzoate (228 mg, yield 39%) as a colourless oil.

An NMR spectrum (400 MHz, Dl3) memorial plaques: to 1.21 (3H, d, J=7 Hz), 3,34 (1H, square, J=7 Hz), 3,4-3,6 (1H, m in), 3.75 (1H, t, J=11 Hz), of 3.78 (1H, t, J=11 Hz), 3,93 (3H, s) to 4.41 (1H, DDD, J=11, 4, 2 Hz), a 4.53 (1H, DDD, J=11, 4, 2 Hz), is 4.85 (1H, d, J=14 Hz), is 5.06 (1H,ptx2">

Mass spectrum m/z (FAB): 506 (M++1)

(2) Following the method of example 3(4), reaction was carried out using commercially available 4-aminobenzonitrile (138 mg, 1.2 mmol), trimethylaluminum (1.08 ml, 1.07 M solution of n-hexane, 1.2 mmol) and methyl 3-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzoate (147 mg, 0.29 mmol) obtained in example 6(1), and the reaction mixture was treated in a manner similar to the method of example 3(4), obtaining specified in the title compound (162 mg, yield 94%) as a pale yellow oil, which was recrystallized from a mixture of ethyl acetate-hexane to obtain pale yellow friable crystals.

Melting point: 105C.

An NMR spectrum (400 MHz, Dl3) memorial plaques: 1,22 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), of 3.77 (1H, t, J=11 Hz), 3,80 (1H, t, J=11 Hz), 4,42 (1H, DDD, J=11, 4, 2 Hz), 4,56 (1H, DDD, J=11, 4, 2 Hz), is 4.85 (1H, d, J=14 Hz), is 5.06 (1H, d, J=14 Hz), to 5.08 (1H, s) to 5.56 (1H, s), 6,7-6,8 (2H, m), 7.3 to 7.4 (1H, m), 7,56 (1H, t, J=8 Hz), to 7.68 (2H, d, J=8 Hz), 7,71 (1H, d, J=8 Hz), 7,80 (2H, s), 7,81 (2H, d, J=8 Hz), 7,92 (1H, d, J=8 Hz), 7,98 (1H, s), 8,00 (1H, ush.C).

The IR spectrum max (KBR) cm-1: 3331, 2225, 1681, 1514, 1139.

Mass spectrum m/z (FAB): 592 (M++1).

Specific rotation: []25D-64 (C=0,56, l3).

Example 7

the l]benzanilide and its CIS-isomer (compound of example 3-1)

(1) Following the method of example 2(1), reaction was carried out using commercially available 4-aminobenzamide (329 mg, 2.5 mmol), N,N-diisopropylethylamine (of 0.91 ml, 5.2 mmol), 4-formylbenzoate (350 mg, 2.1 mmol) and 4-(dimethylamino)pyridine (catalytic amount) and the reaction mixture was treated in a manner similar to the method of example 2(1), to obtain 4’-(cyanomethyl)-4-formylbenzoate (370 mg, yield 67%) in the form of a pale yellow solid, which was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to obtain a pale yellow friable crystals.

Melting point: S.

An NMR spectrum (270 MHz, Dl3) memorial plaques: of 3.77 (2H, s), 7,37 (2H, d, J=8 Hz), 7,69 (2H, d, J=8 Hz), to 7.84 (1H, ush.C) 8,02 (2H, d, J=8 Hz), of 8.04 (2H, d, J=8 Hz), 10,13 (1H, s).

The IR spectrum max (KBR)cm-1: 3343, 2253, 1699, 1666, 1597, 1526.

Mass spectrum m/z (FAB): 265 (M++1).

(2) Following the method of example 1(2), reaction was carried out using 4’-(cyanomethyl)-4-formylbenzoate (160 mg, 0.61 mmol) obtained in example 7(1), (2R,3R)-2-(2,4-differenl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol (189 mg, of 0.53 mmol) and monohydrate p-toluensulfonate acid (181 mg, 0.96 mmol) and the reaction mixture was treated with SPO is de pale yellow solid and the CIS isomer (35 mg, yield 11%) as a white solid. The TRANS-isomer was recrystallized from a mixture of ethyl acetate-tetrahydrofuran with getting loose white crystals, and a CIS-isomer was recrystallized from a mixture of ethyl acetate-hexane to obtain pale yellow friable crystals.

TRANS-isomer:

Melting point: S.

An NMR spectrum (400 MHz, Dl3) memorial plaques: 1,22 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), of 3.7-3.9 (2H, m), 3,76 (2H, s), 4,42 (1H, DDD, J=11, 5, 2 Hz), 4,55 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, s), of 5.05 (1H, d, J=14 Hz), 5,54 (1H, s), 6,7-6,8 (2H, m), 7.3 to 7.4 (1H, m), 7,35 (2H, d, J=8 Hz), 7,63 (2H, d, J=8 Hz), 7,80 (3H, ush.C) to 7.68 (2H, d, J=8 Hz), 7,89 (2H, d, J=8 Hz).

The IR spectrum max (KBR)cm-1: 3372, 2250, 1663, 1517, 1139.

Mass spectrum m/z (FAB): 606 (M++1).

Specific rotation: []25D-68 (or=0.51, l3).

CIS-isomer:

Melting point: S.

An NMR spectrum (270 MHz, Dl3) memorial plaques: to 1.23 (3H, d, J=7 Hz), up 3.22 (1H, t, J=2 Hz), 3,44 (1H, square, J=7 Hz), of 3.75 (2H, s), 4,2-4,5 (4H, m), to 4.87 (1H, d, J=14 Hz), 4,96 (1H, s), of 5.15 (1H, d, J=14 Hz), 5,67 (1H, s), 6,6-6,8 (2H, m), 7.3 to 7.4 (1H, m), 7,34 (2H, d, J=8 Hz), the 7.65 (2H, d, J=8 Hz), to 7.68 (2H, d, J=8 Hz), 7,78 (1H, s), 7,79 (1H, s), 7,82 (1H, ush.C) 7,88 (2H, d, J=8 Hz).

The IR spectrum max (KBR)cm-1: 3408, 2250, 1669, 1516, 1135.

Mass spectrum m/z (EI): 605 (M+, 133 (100%).

3-dioxane-2-yl]benzanilide and its CIS-isomer (compound of example 4-1)

(1) Following the method of example 2(1), reaction was carried out using commercially available 4-Chloroaniline (354 mg, 2.8 mmol), triethylamine (0.7 ml, 5.0 mmol), 4-formylbenzoate (700 mg, 4.2 mmol) and 4-(dimethylamino)pyridine (catalytic amount) and the reaction mixture was treated by following the procedure of example 2(1), to obtain 4’-chloro-4-formylbenzoate (489 mg, yield 68%) as a white solid, which is recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

Melting point: S.

An NMR spectrum (270 MHz, Dl3) memorial plaques: 7,37 (2H, d, J=9 Hz), to 7.61 (2H, d, J=9 Hz), 7,82 (1H, ush.C) 8,02 (4H, s), 10,12 (1H, s).

The IR spectrum max (KBR) cm-1: 3294, 1703, 1645, 1531, 1091.

Mass spectrum m/z (EI): 259 (M+), 133 (100%).

Elemental analysis:

Calculated for C14H10ClNO2From: 64,75 N: 3,88 N: 5,39

Found: 64,48 N: A 3.87 N: ARE 5.36

(2) Following the method of example 3(3), reaction was carried out using 4’-chloro-4-formylbenzoate (300 mg, 1.2 mmol), (2R, 3R)-2-(2,4-differenl)-3-[[1-hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol (359 mg, 1.0 mmol) and monohydrate p-toluensulfonate acid (342 mg, 1.8 mmol) and the reaction mixture was treated with Ihad 48%) as a colourless solid substance and the CIS isomer (82 mg, yield 14%) as a colourless oil. The TRANS-isomer was recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

TRANS-isomer:

Melting point: S.

An NMR spectrum (270 MHz, Dl3) memorial plaques: 1,22 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), 3,76 (1H, t, J=11 Hz), of 3.78 (1H, t, J=11 Hz), 4,42 (1H, DDD, J=11, 5, 2 Hz), 4,55 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), 5,04 (1H, d, J=1 Hz), of 5.05 (1H, d, J=14 Hz), 5,54 (1H, s), 6,7-6,8 (2H, m), 7,2-7,5 (1H, m), 7,35 (2H, d, J=8 Hz), to 7.61 (2H, d, J=8 Hz), a 7.62 (2H, d, J=8 Hz), 7,76 (1H, ush.C), 7,80 (2H, s), 7,88 (2H, d, J=8 Hz).

The IR spectrum max (KBR)cm-1: 3396, 1659, 1531, 1140, 1080.

Mass spectrum m/z (FAB): 601 (M++1).

Elemental analysis:

Calculated for C29H27ClF2N4O4S: 57,95 N: 4,53 N: TO 9.32 F: 6,32

Found: 58,02 N: 4,74 N: 9,20 F: 6,20

Specific rotation: []25D-63 (C=0,63, l3).

CIS-isomer:

An NMR spectrum (270 MHz, Dl3) memorial plaques: to 1.23 (3H, d, J=7 Hz), 3,21 (1H, t, J=2 Hz), 3,44 (1H, square, J=7 Hz), 4,2-4,5 (4H, m), a 4.86 (1H, d, J=14 Hz), 4,96 (1H, s), of 5.15 (1H, d, J=14 Hz), to 5.66 (1H, s), 6,6-6,8 (2H, m), 7,2-7,5 (1H, m), 7,34 (2H, d, J=8 Hz), to 7.61 (2H, d, J=8 Hz), the 7.65 (2H, d, J=8 Hz), 7,78 (1H, s), 7,79 (1H, s), 7,82 (1H, ush.C), 7,87 (2H, d, J=8 Hz).

Mass spectrum m/z (FAB): 601 (M++1).

Example 9

4’-Chloro-3-[TRANS-5-[[(1R,2R)-2-(2,4-dipt is 5)

Following the procedure of example 3(4), reaction was carried out using commercially available 4-Chloroaniline (81 mg, 0,63 mmol), trimethylaluminum (0,59 ml, 1.07 M solution in n-hexane, to 0.63 mmol) and methyl 3-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-[1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzoate (80 mg, 0.16 mmol) obtained in example 6(1), and the reaction mixture was treated in a manner similar to the method of example 3(4), obtaining specified in the title compound (80 mg, yield 84%) as a pale yellow oil, which was recrystallized from a mixture of ethyl acetate-hexane to obtain pale yellow friable crystals.

Melting point: 90 ° C.

An NMR spectrum (400 MHz, Dl3) memorial plaques: 1,22 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,7 (1H, m), of 3.77 (1H, t, J=11 Hz), 3,80 (1H, t, J=11 Hz), 4,42 (1H, DDD, J=11, 5, 2 Hz), 4,5-4,6 (1H, m), is 4.85 (1H, d, J=14 Hz), of 5.06 (1H, d, J=14 Hz), 5,07 (1H, s) to 5.56 (1H, s), 6,7-6,9 (2H, m), 7,3-7,5 (1H, m), 7,35 (2H, d, J=8 Hz), 7,53 (1H, t, J=8 Hz), to 7.61 (2H, d, J=8 Hz), to 7.68 (1H, d, J=8 Hz), 7,80 (2H, s), of 7.82 (1H, s), to $ 7.91 (1H, d, J=8 Hz), of 7.97 (1H, s).

The IR spectrum max (KBR) cm-1: 3307, 1659, 1528, 1139.

Mass spectrum m/z (FAB): 601 (M++1).

Specific rotation: []D25-65 (C=0,49, l3).

Example 10

4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-Tria

(1) Following the method of example 1(1), reaction was carried out using commercially available 4-foronline (308 mg, 2.8 mmol), triethylamine (0.7 ml, 5.0 mmol), 4-formylbenzoate (700 mg, 4.2 mmol) and 4-(dimethylamino)pyridine (catalytic amount) and the reaction mixture was treated in a manner similar to the method of example 1(1), to obtain 4’-chloro-4-formylbenzoate (527 mg, yield 78%) as a white solid, which is recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

Melting point: S.

An NMR spectrum (270 MHz, Dl3) memorial plaques: 7,10 (2H, t, J=9 Hz), to 7.61 (2H, DD, J=9, 5 Hz), 7,80 (1H, ush.C) 8,02 (4H, s), 10,12 (1H, s).

The IR spectrum max (KBR) cm-1: 3321, 1704, 1650, 1515, 1219.

Mass spectrum m/z (EI): 243 (M+, 133 (100%).

Elemental analysis:

Calculated for C14H10FN2From: 69,13 N: 4,14 N: 5,76

Found: 69,00 N: A 3.87 N: OF 5.82

(2) Following the method of example 3(3), reaction was carried out using 4’-fluoro-4-formylbenzoate (300 mg, 1.2 mmol), (2R, 3R)-2-(2,4-differenl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol (385 mg, 1.1 mmol) and monohydrate p-toluensulfonate acid (366 mg, 1.9 mmol) and the reaction mixture was obrabecim is, Ihad 48%) as a colourless oil and the CIS isomer (78 mg, yield 12%) as a colourless oil. The TRANS-isomer was recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

TRANS-isomer:

Melting point: S.

An NMR spectrum (270 MHz, Dl3) memorial plaques: 1,22 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), 3,76 (1H, t, J=11 Hz), of 3.78 (1H, t, J=11 Hz), 4,42 (1H, DDD, J=11, 5, 2 Hz), 4,55 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, s), is 5.06 (1H, d, J=14 Hz), 5,54 (1H, s), 6,7-6,8 (2H, m), was 7.08 (2H, t, J=8 Hz), 7,3-7,5 (1H, m), of 7.5 to 7.7 (2H, m), 7,63 (2H, d, J=8 Hz), of 7.75 (1H, ush.C), 7,80 (2H, s), 7,88 (2H, d, J=8 Hz).

The IR spectrum max (KBR) cm-1: 3330, 1654, 1510, 1212, 1139.

Mass spectrum m/z (FAB): 585 (M++1).

Specific rotation: []25D-68 (C=0.64 in l3).

CIS-isomer:

An NMR spectrum (270 MHz, CDCl3) memorial plaques: to 1.23 (3H, d, J=7 Hz), 3,21 (1H, t, J=2 Hz), 3,44 (1H, square, J=7 Hz), 4,2-4,5 (4H, m), a 4.86 (1H, d, J=14 Hz), 4,96 (1H, s), of 5.15 (1H, d, J=14 Hz), to 5.66 (1H, s), 6,6-6,8 (2H, m), 7,07 (2H, t, J=8 Hz), 7,2-7,5 (1H, m), of 7.5 to 7.7 (2H, m), the 7.65 (2H, d, J=8 Hz), 7,78 (2H, ush.C) 7,79 (1H, s), 7,88 (2H, d, J=8 Hz).

Mass spectrum m/z (FAB): 585 (M+).

Example 11

4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(trifluoromethyl)benzanilide and its CIS-isomer (compound of example ski available 4-(trifluoromethyl)aniline (446 mg, 2.8 mmol), triethylamine (0.6 ml, 4.4 mmol), 4-formylbenzoate (700 mg, 4.2 mmol) and 4-(dimethylamino)pyridine (catalytic amount) and the reaction mixture was treated in a manner similar to the method of example 2(1), with 4-formyl-4’-(trifluoromethyl)benzanilide (577 mg, 71% yield) as a white solid, which was recrystallized from a mixture of ethyl acetate-hexane to obtain white fluffy crystals.

Melting point: S.

An NMR spectrum (270 MHz, CDCl3) memorial plaques: to 7.67 (2H, d, J=9 Hz), 7,80 (2H, d, J=9 Hz), to 7.93 (1H, ush.C), with 8.05 (4H, s), 10,13 (1H, s).

The IR spectrum max (KBR)cm-1: 3312, 1702, 1650, 1533, 1322.

Mass spectrum m/z (EI): 293 (M+, 133 (100%).

(2) Following the method of example 3(3), carried out the reaction using 4-formyl-4’-(trifluoromethyl)benzanilide (300 mg, 1.0 mmol), (2R,3R)-2-(2,4-differenl)-3-[[1-hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol (334 mg, of 0.93 mmol) and monohydrate p-toluensulfonate acid (318 mg, 1.7 mmol) and the reaction mixture was treated in a manner similar to the method of example 3(3), with the TRANS-isomer is specified in the title compound (275 mg, yield 47%) as a white solid and the CIS isomer (58 mg, yield 10%) as a colourless oil. The TRANS-isomer paracrystal the P>Melting point: S.

An NMR spectrum (270 MHz, CDCl3) memorial plaques: 1,22 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), of 3.77 (1H, t, J=11 Hz), with 3.79 (1H, t, J=11 Hz), to 4.41 (1H, DDD, J=11, 5, 2 Hz), 4,55 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, d, J=1 Hz), of 5.05 (1H, d, J=14 Hz), of 5.55 (1H, s), 6,7-6,8 (2H, m), 7,3-7,5 (1H, m), of 7.64 (4H, d, J=8 Hz), 7,78 (2H, d, J=8 Hz), 7,80 (2H, s), of 7.90 (2H, d, J=8 Hz), to $ 7.91 (1H, ush.C).

The IR spectrum max (KBR)cm-1: 3399, 1665, 1531, 1325, 1139.

Mass spectrum m/z (FAB): 635 (M++1).

Elemental analysis:

Calculated for C30H27F5N4O4S: 56.78 HAS N: 4,29 N: 8,83 F: 14,97

Found: 56,70 N: 4,46 N: 8,90 F: 14,67

Specific rotation: []25D-64 (C=0,54, l3).

CIS-isomer:

An NMR spectrum (270 MHz, Dl3) memorial plaques: to 1.23 (3H, d, J=7 Hz), up 3.22 (1H, t, J=2 Hz), 3,44 (1H, square, J=7 Hz), 4,2-4,5 (4H, m), a 4.86 (1H, d, J=14 Hz), 4,96 (1H, s), of 5.15 (1H, d, J=14 Hz), 5,67 (1H, s), 6,6-6,8 (2H, m), 7,2-7,5 (1H, m), of 7.64 (2H, d, J=8 Hz), to 7.67 (2H, d, J=8 Hz), 7,78 (1H, s), 7,79 (1H, s), 7,79 (2H, d, J=8 Hz), 7,89 (2H, d, J=8 Hz), to 7.93 (1H, ush.C).

Mass spectrum m/z (FAB): 635 (M++1).

Example 12

4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(triptoreline)benzanilide (the compound of example 7-1)

(1) Following the method of example 3(3), Khujand is arvanil)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol (1.0 g, 2.8 mmol) and monohydrate p-toluensulfonate acid (952 mg, 5.0 mmol) and the reaction mixture was treated in a manner similar to the method of example 3(3), to obtain methyl 4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-3-benzoate (936 mg, yield 67%) as a white solid, which was recrystallized from a mixture of ethyl acetate-hexane to obtain white prismatic crystals.

Melting point: S.

An NMR spectrum (270 MHz, Dl3) memorial plaques: to 1.21 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m in), 3.75 (1H, t, J=11 Hz), of 3.77 (1H, t, J=11 Hz), to 3.92 (3H, s) to 4.41 (1H, DDD, J=11, 5, 2 Hz), a 4.53 (1H, DDD, J=11, 5, 2 Hz), 4,84 (1H, d, J=14 Hz), to 5.03 (1H, s), is 5.06 (1H, d, J=14 Hz), 5,52 (1H, s), 6,7-6,8 (2H, m), 7,3-7,5 (1H, m), EUR 7.57 (2H, d, J=8 Hz), 7,79 (2H, s), of 8.06 (2H, d, J=8 Hz).

The IR spectrum max (KBR)cm-1: 3421, 1722, 1279, 1139.

Mass spectrum m/z (FAB): 506 (M++1).

Elemental analysis:

Calculated for C24H25F2N3O5S: 57,02 N: 4,99 N: 8,31 F: 7,52

Found: 57,03 N: 5,10 N: 8,32 F: 7,62

Specific rotation: []25D-81 (C=0,56, l3).

(2) Following the method of example 3(4), reaction was carried out using commercially available 4-(triptoreline)aniline (123 mg, 0.69 mmol), trimethylaluminum the azole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzoate (100 mg, 0.20 mmol) obtained in example 12(1), and the reaction mixture was treated in a manner similar to the method of example 3(4), obtaining specified in the title compound (122 mg, yield 95%) as a white solid, which was recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

Melting point: 180C.

An NMR spectrum (270 MHz, Dl3) memorial plaques: 1,22 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), 3,76 (1H, t, J=11 Hz), of 3.78 (1H, t, J=11 Hz), 4,42 (1H, DDD, J=11, 5, 2 Hz), of 4.54 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), 5,04 (1H, s), is 5.06 (1H, d, J=14 Hz), of 5.53 (1H, s), 6,7-6,8 (2H, m), 7,22 (2H, d, J=8 Hz), 7,3-7,5 (1H, m), to 7.61 (2H, d, J=8 Hz), to 7.67 (2H, d, J=8 Hz), 7,79 (2H, s), 7,87 (2H, d, J=8 Hz), of 7.97 (1H, ush.C).

The IR spectrum max (KBR) cm-1: 3390, 1656, 1511, 1265, 1140.

Mass spectrum m/z (FAB): 651 (M++1).

Elemental analysis:

Calculated for C30H27F5N4O5S: 55,38 N: 4,18 N: 8,61 F: 14,60

Found: 55,35 N: 4,13 N: CHARGED 8.52 F: 14,32

Specific rotation: []25D-60 (C=0,55, l3).

Example 13

4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-(triptoreline)benzanilide (compound of example 8-1)

Following the procedure of example 3(4), ethylaluminum (1.1 ml, 1.07 M solution of n-hexane, 1.2 mmol) and methyl 4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzoate (150 mg, 0.30 mmol) obtained in example 12(1), and the reaction mixture was treated by following the method similar to the method of example 3(4), obtaining specified in the title compound (184 mg, yield 93%) as a colourless oil, which was recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

Melting point: S.

An NMR spectrum (400 MHz, CDCl3) memorial plaques: 1,22 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), 3,76 (1H, t, J=11 Hz), with 3.79 (1H, t, J=11 Hz), 4,42 (1H, DDD, J=11, 5, 2 Hz), 4,55 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, d, J=1 Hz), is 5.06 (1H, d, J=14 Hz), of 5.55 (1H, s), 6,7-6,8 (2H, m), 7,3-7,5 (1H, m), of 7.64 (2H, d, J=8 Hz), to 7.67 (2H, d, J=8 Hz), 7,74 (2H, d, J=8 Hz), 7,80 (2H, s), 7,87 (1H, ush.C), 7,89 (2H, d, J=8 Hz).

The IR spectrum max (KBR) cm-1: 3320, 1667, 1527, 1139, 1122.

Mass spectrum m/z (FAB): 667 (M++1).

Specific rotation: []25D-64 (C=0,54, l3).

Example 14

4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-methylbenzamide (compound of example 9-1)

Following the procedure of example 3(4), carried out the reaction of hexane, 1.2 mmol) and methyl 4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzoate (150 mg, 0.30 mmol) obtained in example 12(1), and the reaction mixture was treated in a manner similar to the method of example 3(4), obtaining specified in the title compound (166 mg, yield 96%) as a pale yellow oil, which was recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

Melting point: S.

An NMR spectrum (400 MHz, CDCl3) 5 M. D.: to 1.21 (3H, d, J=7 Hz), to 2.35 (3H, s) to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), 3,76 (1H, t, J=11 Hz), of 3.78 (1H, t, J=11 Hz), 4,42 (1H, DDD, J=11, 5, 2 Hz), of 4.54 (1H, DDD, J=11, 5, 2 Hz)that is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, s), is 5.06 (1H, d, J=14 Hz), 5,54 (1H, s), 6,7-6,8 (2H, m), 7,18 (2H, d, J=8 Hz), 7.3 to 7.4 (1H, m), 7,52 (2H, d, J=8 Hz), to 7.61 (2H, d, J=8 Hz), 7,73 (1H, ush.C), 7,80 (2H, s), 7,88 (2H, d, J=8 Hz).

The IR spectrum max (KBR) cm-1: 3322, 1666, 1515, 1139.

Mass spectrum m/z (FAB): 581 (M++1).

Specific rotation: []25D-70 (C=0,50, l3).

Example 15

4’-Bromo-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 10-1)

Following the procedure of example 3(4), carried out the reaction using commercentre-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzoate (150 mg, 0.30 mmol) obtained in example 12(1), and the reaction mixture was treated in a manner similar to the method of example 3(4), obtaining specified in the title compound (182 mg, yield 95%) as a white solid, which was recrystallized from ethyl acetate to obtain white loose crystals.

Melting point: S.

An NMR spectrum (400 MHz, CDCl3) memorial plaques: to 1.21 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), 3,76 (1H, t, J=11 Hz), of 3.78 (1H, t, J=11 Hz), to 4.41 (1H, DDD, J=11, 5, 2 Hz), 4,55 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, d, J=1 Hz), is 5.06 (1H, d, J=14 Hz), 5,54 (1H, s), 6,7-6,8 (2H, m), 7.3 to 7.4 (1H, m), 7,49 (2H, d, J=9 Hz), 7,56 (2H, d, J=9 Hz), a 7.62 (2H, d, J=9 Hz), 7,76 (1H, ush.C), 7,80 (2H, s), 7,88 (2H, d, J=9 Hz).

The IR spectrum max (KBR) cm-1: 3399, 1660, 1529, 1139.

Mass spectrum m/z (FAB): 645 (M++1).

Elemental analysis:

Calculated for C29H27BrF2N4O4S: 53,96 N: 4,22 N: 8,68 F: OF 5.89

Found: 53,86 N: 4,32 N: 8,55 F: 5,98

Specific rotation: []25D-66 (C=0,64, l3).

Example 16

3’-chloro-4’-cyano-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 11-1)

Following the procedure of example 3(4), carried out reacts 1.07 M solution in n-hexane, 1.2 mmol) and methyl 4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(IH-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzoate (150 mg, 0.30 mmol) obtained in example 12(1), and the reaction mixture was treated in a manner similar to the method of example 3(4), obtaining specified in the title compound (167 mg, yield 90%) as a colourless oil, which was recrystallized from a mixture of ethyl acetate-simple isopropyl ether to obtain white loose crystals.

Melting point: 115S.

An NMR spectrum (400 MHz, CDCl3) memorial plaques: to 1.21 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), 3,76 (1H, t, J=11 Hz), of 3.78 (1H, t, J=11 Hz), 4,42 (1H, DDD, J=11, 5, 2 Hz), 4,55 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, d, J=1 Hz), of 5.05 (1H, d, J=14 Hz), 5,54 (1H, s), 6,7-6,8 (2H, m), 7,2-7,4 (1H, m), and 7.6 to 7.7 (4H, m), 7,80 (2H, s), 7,88 (2H, d, J=8 Hz), 7,98 (1H, ush.C) 8,02 (1H, d, J=2 Hz).

The IR spectrum max (KBR) cm-1: 3426, 2229, 1685, 1503, 1139, 1077.

Mass spectrum m/z (FAB): 626 (M++1).

Specific rotation: []25D-59 (C=0,55, l3).

Example 17

4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl] N-(4-pyridyl)benzamide and its CIS-isomer (compound of example 12-1)

(1) Following the method of example 1(1), was carried out by reaction with opticard (400 mg, 2.4 mmol) and the reaction mixture was treated in a manner similar to the method of example 1(1), to obtain a crystalline residue, which was recrystallized from a mixture of tetrahydrofuran and hexane to obtain 4-formyl-N-(4-pyridyl)benzamide (214 mg, yield 56%) as white loose crystals.

Melting point: S.

An NMR spectrum (400 MHz, CDCl3) memorial plaques: 7,79 (2H, d, J=6 Hz), 8,08 (2H, d, J=8 Hz), 8,15 (2H, d, J=8 Hz), 8,51 (2H, d, J=6 Hz), 10,13 (1H, s), 10,81 (1H, s).

The IR spectrum max (KBR) cm-1: ‘3234, 1700, 1596, 1512, 1330.

Mass spectrum m/z (EI): 226 (M+), 133 (100%).

(2) Following the method of example 3(3), carried out the reaction using 4-formyl-N-(4-pyridyl) benzamide (200 mg, 0.88 mmol), (2R,3R)-2-(2,4-differenl)-3-[[(1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol (318 mg, 0.88 mmol) and monohydrate p-toluensulfonate acid (469 mg, 2.5 mmol) and the reaction mixture was treated in a manner similar to the method of example 3(3), with the TRANS-isomer is specified in the title compound (187 mg, yield 37%) as a white solid and the CIS isomer (86 mg, yield 17%) as a colourless oil. The TRANS-isomer was recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

TRANS-isomer:

The IR spectrum max (KBR) cm-1: 3414, 1684, 1593, 1139.

Mass spectrum m/z (FAB): 568 (M++1).

Specific rotation: []25D-42 (C=0.45, and CH3IT).

CIS-isomer:

An NMR spectrum (400 MHz, CDCl3) memorial plaques: of 1.20 (3H, d, J=7 Hz), 3,12 (1H, s), the 3.65 (1H, square, J=7 Hz), 4,3-4,6 (4H, m), is 4.93 (1H, d, J=14 Hz), to 5.17 (1H, d, J=14 Hz), 5,72 (1H, s), 6,7-7,0 (2H, m), 7.3 to 7.4 (1H, m), to 7.67 (2H, d, J=8 Hz), 7,68 (1H, s), to 7.84 (2H, d, J=7 Hz), of 7.96 (2H, d, J=8 Hz), of 8.25 (1H, s), 8,44 (2H, d, J=7 Hz).

Mass spectrum m/z (FAB): 568 (M++1).

Example 18

4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4-nitrobenzamide (compound of example 13-1)

Following the procedure of example 3(4), reaction was carried out using commercially available 4-nitroaniline (165 mg, 1.2 mmol), trimethylaluminum (1.1 ml, 1.07 M solution in n-hexane, 1.2 mmol) and methyl 4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzoate (150 mg, 0.30 mmol) obtained in example 12(1), and the reaction mixture was treated with way, model solids, which is recrystallized from a mixture of ethyl acetate-hexane to obtain pale yellow fluffy crystals.

Melting point: S.

An NMR spectrum (400 MHz, CDCl3) memorial plaques: 1,22 (3H, d, J=7 Hz), 3,37 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), 3,76 (1H, t, J=11 Hz), with 3.79 (1H, t, J=11 Hz), 4,42 (1H, DDD, J=11, 5, 2 Hz), 4,55 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, d, J=1 Hz), of 5.05 (1H, d, J=14 Hz), of 5.55 (1H, s), 6,7-6,8 (2H, m), 7.3 to 7.4 (1H, m), the 7.65 (2H, d, J=9 Hz), 7,80 (2H, s), 7,86 (2H, d, J=9 Hz), of 7.90 (2H, d, J=9 Hz), of 8.09 (1H, ush.C) of 8.27 (2H, d, J=9 Hz).

The IR spectrum max (KBR) cm-1: 3397, 1681, 1501, 1140.

Mass spectrum m/z (FAB): 612 (M++1).

Elemental analysis:

Calculated for C29H27F2N5O6S: 56,95 N: 4,45 N: OF 11.45 F: 6,21

Found: 57,24 N: 4,25 N: 11,32 F: 6,13

Specific rotation: []25D-62 (or=0.51, l3).

Example 19

N-(4-cyano-1-naphthyl)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzamide (compound of example 38-1)

Following the procedure of example 3(4), reaction was carried out using commercially available 4-amino-1-naphthalenethiol (200 mg, 1.2 mmol), trimethylaluminum (1.1 ml, 1.07 M solution in n-hexane, 1.2 mmol) and methyl 4-[TRANS-5-[[(1R,2R)-2-(2,4-differenece 12(1), and the reaction mixture was treated in a manner similar to the method of example 3(4), obtaining specified in the title compound (73 mg, yield 38%) as a pale yellow oil, which was recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

Melting point: S.

An NMR spectrum (400 MHz, CDCl3) memorial plaques: 1,22 (3H, d, J=7 Hz), 3,37 (1H, square, J=7 Hz), 3,5-3,6 (1H, m), of 3.78 (1H, t, J=11 Hz), 3,81 (1H, t, J=11 Hz), of 4.44 (1H, DDD, J=11, 5, 2 Hz), of 4.57 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), is 5.06 (1H, s), is 5.06 (1H, d, J=14 Hz), to 5.58 (1H, s), 6,7-6,8 (2H, m), 7,2-7,5 (1H, m), of 7.70 (2H, d, J=8 Hz), 7,80 (2H, s), 7,6-7,8 (2H, m), of 7.9 to 8.1 (2H, m), of 8.00 (2H, d, J=8 Hz), with 8.33 (1H, d, J=8 Hz), 8,43 (1H, d, J=8 Hz), 8,46 (1H, ush.C).

The IR spectrum max (KBR) cm-1: 3409, 2221, 1662, 1528, 1139.

Mass spectrum m/z (FAB): 642 (M++1).

Specific rotation: []25D-62 (C=0,58, l3).

Example 20

4’-Cyano-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-2’,3’,5’,6’-tetrafluorobenzene (compound of example 14-1)

Following the procedure of example 3(4), reaction was carried out using commercially available 4-amino-2,3,5,6-tetrafluorobenzoate (227 mg, 1.2 mmol), trimethylaluminum (1.1 ml, 1.07 M solution in n-hexane, 1.2 mmol) and(150 mg, 0.30 mmol) obtained in example 12(1), and the reaction mixture was treated in a manner similar to the method of example 3(4), obtaining specified in the title compound (84 mg, yield 42%) as a colourless oil, which was recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

Melting point: S.

An NMR spectrum (400 MHz, CDCl3) memorial plaques; to 1.22 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,5-3,6 (1H, m), 3,76 (1H, t, J=11 Hz), with 3.79 (1H, t, J=11 Hz), 4,43 (1H, DDD, J=11, 5, 2 Hz), 4,56 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, d, J=14 Hz), is 5.06 (1H, s), of 5.55 (1H, s), 6,7-6,8 (2H, m), 7.3 to 7.4 (1H, m), 7,66 (1H, s), to 7.67 (2H, d, J=8 Hz), 7,80 (2H,s), 7,94 (2H, d, J=8 Hz).

The IR spectrum max (KBR) cm-1: 3290, 2245, 1684, 1505, 1140.

Mass spectrum m/z (FAB): 664 (M++1).

Specific rotation: []25D-61 (C=0,49, l3).

Example 21

3’,4’-Dicyano-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 15-1)

Following the procedure of example 3(4), reaction was carried out using commercially available 4-aminophthalonitrile (170 mg, 1.2 mmol), trimethylaluminum (1.1 ml, 1.07 M solution in n-hexane, 1.2 mmol) and methyl 4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-a noticeable mixture was treated in a way similar to the method of example 3(4), obtaining specified in the title compound (129 mg, 71% yield) as a yellow oil, which was recrystallized from a mixture of ethyl acetate-hexane to obtain pale yellow friable crystals.

Melting point: S.

An NMR spectrum (400 MHz, CDCl3) memorial plaques: 1,24 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), 3,76 (1H, t, J=11 Hz), with 3.79 (1H, t, J=11 Hz), 4,42 (1H, DDD, J=11, 5, 2 Hz), 4,56 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, d, J=14 Hz), of 5.05 (1H, d, J=1 Hz), of 5.55 (1H, s), 6,7-6,8 (2H, m), 7,3-7,5 (1H, m), to 7.67 (2H, d, J=8 Hz), 7,80 (2H, s), 7,80 (1H, d, J=8 Hz), 7,89 (2H, d, J=8 Hz), of 8.00 (1H, DD, J=8, 2 Hz), 8,14 (1H, s), of 8.27 (1H, d, J=2 Hz).

The IR spectrum max (KBR) cm-1: 3341, 2232, 1688, 1139.

Mass spectrum m/z (FAB): 617 (M++1).

Specific rotation: []25D-63 (C=0,60, l3).

Example 22

4’-Acetyl-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl] benzanilide (compound of example 16-1)

(1) Following the method of example 1(1), reaction was carried out using commercially available p-aminoacetophenone (309 mg, 2.3 mmol), triethylamine (of 0.48 ml, 3.4 mmol) and 4-formylbenzoate (500 mg, 3.0 mmol) and the reaction mixture was treated in a manner similar to the method of example 1(1), the receipt of 4’-acetyl-4-formylbenzoate (552 mg, yield 90%) as a pale yellow friable crystals.

Melting point: S.

An NMR spectrum (400 MHz, DMSO-d6) memorial plaques: 2,56 (3H, s), 7,95 (2H, d, J=8 Hz), 8,00 (2H, d, J=8 Hz), 8,07 (2H, d, J=8 Hz), 8,16 (2H, d, J=8 Hz), 10,13 (1H, s), 10,77 (1H, ush.C).

The IR spectrum max (KBR) cm-1: 3348, 1703, 1679, 1659, 1529.

Mass spectrum m/z (EI): 267 (M+), 133 (100%).

(2) Following the method of example 3(3), reaction was carried out using 4’-acetyl-4-formylanahalamine (200 mg, 0.75 mmol), (2R,3R)-2-(2,4-differenl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol (256 mg, 0.71 mmol) and monohydrate p-toluensulfonate acid (243 mg, 1.3 mmol) and the reaction mixture was treated in a manner similar to the method of example 3(3), with the TRANS-isomer is specified in the title compound (280 mg, yield 65%) as a white solid, which was recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

TRANS-isomer:

Melting point: S.

An NMR spectrum (400 MHz, CDCl3) memorial plaques: 1,22 (3H, d, J=7 Hz), 2,61 (3H, s), 3,3-3,4 (1H, m), 3,4-3,6 (1H, m), of 3.77 (1H, t, J=11 Hz), with 3.79 (1H, t, J=11 Hz), 4,42 (1H, m), 4,55 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, s), is 5.06 (1H, d, J=14 Hz), of 5.55 (1H, s), 6,7-6,8 (2H, m), 7,3-7,5 (1H, m), of 7.64 (2H, d, J=8 Hz), to 7.77 (2H, d, J=8 Hz), 7,80 (2H, s), of 7.90 (2H, m/z (FAB): 609 (M++1).

Elemental analysis:

Calculated for C31H30F2N4O5S: 61,17 N: equal to 4.97 N: OF 9.21 F: 6,24

Found: 61,24 N: 4,93 N: 9,00 F: 6,20

Specific rotation: []25D-59 (C=0,54, l3).

Example 23

4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-hydroxybenzamide (compound of example 27-1)

Following the procedure of example 3(4), carried out the reaction using 4-(tert-butyldimethylsilyloxy)aniline (266 mg, 1.2 mmol), described in J. Org. Chem., 54(1), 51 (1998), of trimethylaluminum (1.1 ml, 1.07 M solution in n-hexane, 1.2 mmol) and methyl 4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(IH-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzoate (150 mg, 0.30 mmol), obtained in example 12(1), and the reaction mixture was treated in a manner similar to the method of example 3(4), to obtain 4’-(tert-butyldimethylsilyloxy]-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (182 mg, yield 88%) in the form of a colorless oil.

An NMR spectrum (400 MHz, CDCl3) memorial plaques: 0,20 (6N, C) 0,99 (N, C) to 1.21 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), 3,76 (1H, t, J=11 Hz), of 3.78 (1H, t, J=11 Hz), 4,42 (1H, DDD, J=, is), of 7.48 (2H, d, J=8 Hz), 7,60 (2H, d, J=8 HZ), 7,69 (1H, s), 7,80 (2H, s), 7,87 (2H, d, J=8 Hz).

Mass spectrum m/z (FAB): 697 (M++1).

(2) Tetra-n-butylammonium (and 0.40 ml, 1 mol/l tertrahydrofuran ring solution, the product Tokyokasei Kougyo Kabushiki Kaisha, 0.40 mmol) was added dropwise to a solution of 4’-(tert-butyldimethylsilyloxy)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (186 mg, 0.27 mmol) obtained in example 23(1), in tetrahydrofuran (6 ml), cooled to 0C with stirring. The resulting mixture was stirred at 0C for 20 minutes. At the end of mixing to the reaction mixture at 0C was added a saturated aqueous solution of sodium bicarbonate. The resulting mixture was distributed between ethyl acetate and water. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crystalline residue was recrystallized from a mixture of tetrahydrofuran and ethyl acetate to obtain specified in the title compound (136 mg, yield 87%) as white loose crystals.

Melting point: S.

An NMR spectrum (400 MHz, CDCl3) memorial plaques: 1,10 (3H, d, J=7 Hz), 3,3-3,5 (1H, m), 3,57 (1H, square, J=7 Hz), 3,76 (1H, t, J=11 Hz), 3,76 (1H, t, 7,52 (2H, d, J=9 Hz), 7,54 (2H, d, J=9 Hz), to 7.67 (1H, s), 7,94 (2H, d, J=9 Hz), of 8.27 (1H, s), 9,26 (1H, ush.C) of 10.05 (1H, ush.C).

The IR spectrum max (KBR) cm-1: 3286, 1652, 1513, 1139.

Mass spectrum m/z (FAB): 583 (M++1).

Specific rotation: []25D-50 (C=0,20, THF).

Example 24

4’-Acetoxy-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 17-1)

Acetic anhydride (1.5 ml) was added dropwise to a solution of 4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-4’-hydroxybenzamide (40 mg, 0.07 mmol) obtained in example 23(2), in anhydrous pyridine (3 ml), cooled to C, under stirring. Formed mixture stirred at room temperature overnight. At the end of stirring, the reaction mixture was poured at 0C in a saturated aqueous solution of sodium bicarbonate. The resulting mixture was distributed between ethyl acetate and water. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain specified in the title compound (43 mg, yield 100%) as a colourless oil. the ka melting point: 127S.

An NMR spectrum (400 MHz, CDCl3) memorial plaques: 1,22 (3H, d, J=7 Hz), 2,31 (3H, s) to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), 3,76 (1H, t, J=11 Hz), of 3.78 (1H, t, J=11 Hz), 4,42 (1H, DDD, J=11, 5, 2 Hz), 4,55 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, s), is 5.06 (1H, d, J=14 Hz), 5,54 (1H, s), 6,7-6,8 (2H, m), 7,11 (2H, d, J=8 Hz), 7.3 to 7.4 (1H, m), a 7.62 (2H, d, J=8 Hz), 7,66 (2H, d, J=8 Hz), 7,80 (3H, s), 7,88 (2H, d, J=8 Hz).

The IR spectrum max (KBR) cm-1: 3372, 1670, 1509, 1139.

Mass spectrum m/z (FAB): 625 (M++1).

Specific rotation: []25D-63 (C=0,55, l3).

Example 25

4’-Cyano-2’-fluoro-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 18-1)

(1) To a solution of commercially available 3,4-difterential (2.0 g, 14.4 mmol) in anhydrous di(ethylene glycol)dimethyl ether (10 ml), cooled to C, with stirring, was added dropwise 4-methoxybenzylamine (5.6 ml, to 43.1 mmol). The resulting mixture was stirred at 120C for 1 hour. At the end of stirring, the reaction mixture was poured at room temperature in a saturated aqueous solution of sodium bicarbonate. Formed and the mixture was distributed between ethyl acetate and water. The organic layer was washed saturated aqueous sodium chloride, dried the Yali hexane to obtain 3-fluoro-4-[(4-methoxybenzyl)amino]benzonitrile (of 2.26 g, yield 61%) as white fluffy crystals.

Melting point: S.

An NMR spectrum (400 MHz, CDCl3) memorial plaques: 3,81 (3H, s), 4,34 (2H, d, J=6 Hz), of 4.77 (1H, ush.C) of 6.65 (1H, t, J=9 Hz), make 6.90 (2H, d, J=9 Hz), 7,2-7,3 (4H, m).

The IR spectrum max (KBR) cm-1: 3376, 2211, 1356, 1248.

Mass spectrum m/z (EI): 256 (M+), 121 (100%).

(2) To a solution of 3-fluoro-4-[(4-methoxybenzyl)amino]benzonitrile (1.0 g, 3.9 mmol) obtained in example 25(1), in anhydrous dichloromethane (20 ml), cooled with stirring to 0 C, was added dropwise triperoxonane acid (1 ml). The resulting mixture was stirred at room temperature overnight. At the end of stirring, the reaction mixture was poured at 0C in a saturated aqueous solution of sodium bicarbonate. Formed and the mixture was distributed between ethyl acetate and water. The organic layer was washed saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The remaining oil was subjected to chromatography on a column of silica gel using as eluent a mixture of ethyl acetate-hexane (1:6) to give 4-amino-3-perbenzoate (252 mg, yield 47%) as a pale orange solid, which was recrystallized from a mixture of etelaat the l2) memorial plaques: to 4.23 (2H, ush.C) 6,76 (1H, t, J=9 Hz), 7,2-7,3 (2H, m).

The IR spectrum max (KBR) cm-1: 3449, 3353, 2224, 1641.

Mass spectrum m/z (EI): 136 (M+, 100%).

(3) Following the method of example 3(4), carried out the reaction using 4-amino-3-perbenzoate (129 mg, 0.95 mmol) obtained in example 25(2), trimethylaluminum (0,89 ml, 1.07 M solution in n-hexane, 0.95 mmol) and methyl 4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzoate (120 mg, 0.24 mmol) obtained in example 12(1), and the reaction mixture was treated in a manner similar to the method of example 3(4), obtaining specified in the title compound (134 mg, yield 92%) as a white solid, which was recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

Melting point: S.

An NMR spectrum (500 MHz, CDCl3) memorial plaques: 1,22 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), 3,76 (1H, t, J=11 Hz), with 3.79 (1H, t, J=11 Hz), 4,42 (1H, DDD, J=11, 5, 2 Hz), 4,55 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, d, J=14 Hz), of 5.05 (1H, s), of 5.55 (1H, s), 6,7-6,8 (2H, m), 7.3 to 7.4 (1H, m), 7,45 (1H, d, J=12 Hz), 7,53 (1H, d, J=8 Hz), 7,66 (2H, d, J=8 Hz), 7,79 (2H, s), to $ 7.91 (2H, d, J=8 Hz), by 8.22 (1H, ush.d, J=4 Hz), 8,73 (1H, t, J=8 Hz).

The IR spectrum max (KBR) cm-1: 3435, 2232, 1686, 1520, 1139.

Mass spectrum m/z (="ptx2">

N-(4-Cyanobenzyl)-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzamide and its CIS-isomer (compound of example 19-1)

(1) Following the method of example 2(1), carried out the reaction using 4-cyanobenzylidene (329 mg, 2.5 mmol), disclosed in J. Am. Chem. Soc., 81, 4328 (1959), N,N-diisopropylethylamine (0,91 ml 5/2 mmol), 4-formylbenzoate (350 mg, 2.1 mmol) and 4-(dimethylamino)pyridine (catalytic amount) and the reaction mixture was treated in a manner similar to the method of example 2(1), to obtain N-(4-cyanobenzyl)-4-formylbenzoate (308 mg, yield 56%) as a white solid, which was recrystallized from ethyl acetate to obtain white fluffy crystals.

Melting point: S.

An NMR spectrum (270 MHz, CDCl3) memorial plaques: 4,74 (2H, d, J=6 Hz), 6,59 (1H, ush.C) of 7.48 (2H, d, J=8 Hz), the 7.65 (2H, d, J=8 Hz), 7,95 (2H, d, J=8 Hz), to 7.99 (2H, d, J=8 Hz), 10,10 (1H, s).

The IR spectrum max (KBR) cm-1: 3319, 2223, 1706, 1642, 1542.

Mass spectrum m/z (El): 264 (M+, 133 (100%).

Elemental analysis:

Calculated for C16H12N2O2From: 72,72 N: 4,58 N: OR 10.60

Found: 72,89 N: A 4.83 N: 10,51

(2) Following the method of example 1(2), was carried out by reaction with BL(1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazole-1-yl]-2-butanol (237 mg, 0.66 mmol) and monohydrate p-toluensulfonate acid (151 mg, 0.79, which mmol) and the reaction mixture was treated using a method similar to the method of example 1(2), with the TRANS-isomer is specified in the title compound (137 mg, yield 34%) as a white solid and the CIS isomer (82 mg, yield 21%) as a white solid. The TRANS-isomer was recrystallized from a mixture of tetrahydrofuran-hexane to obtain white loose crystals.

TRANS-isomer:

Melting point: S.

An NMR spectrum (270 MHz, CDCl3) memorial plaques: to 1.21 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m in), 3.75 (1H, t, J=11 Hz), of 3.77 (1H, t, J=11 Hz), and 4.40 (1H, DDD, J=11, 5, 2 Hz), a 4.53 (1H, DDD, J=11, 5, 2 Hz), 4.72 in (2H, d, J=6 Hz), 4,84 (1H, d, J=14 Hz), 5,04 (1H, s), of 5.05 (1H, d, J=14 Hz), 5,52 (1H, s), 6,51 (1H, ush.t), 6,7-6,8 (2H, m), 7,3-7,5 (1H, m), 7,46 (2H, d, J=8 Hz), to 7.59 (2H, d, J=8 Hz), the 7.65 (2H, d, J=8 Hz), 7,79 (2H, s), of 7.82 (2H, d, J=8 Hz).

The IR spectrum max (KBR) cm-1: 3302, 2229, 1636, 1541, 1139.

Mass spectrum m/z (FAB): 606 (M++1).

Specific rotation: []25D-64 (C=0,50, l3).

CIS-isomer:

Melting point: S.

An NMR spectrum (270 MHz, CDCl3) memorial plaques: 1,22 (3H, d, J=7 Hz), 3,20 (1H, t, J=2 Hz), 3,43 (1H, square, J=7 Hz), 4,2-4,5 (4H, m), 4,71 (2H, d, J=6 Hz), a 4.86 (1H, d, J=14 Hz), of 4.95 (1H, s), of 5.15 (1H, d, J=14 Hz), 5,64 (1H, s), of 6.52 (1H, ush.t, J=6 Hz range max (KBR) cm-1: 3283, 2229, 1634, 1543, 1135.

Mass spectrum m/z (FAB): 606 (M++1).

Specific rotation: []25D-75 (C=0,53, l3).

Example 27

4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-N-(2-thiazolyl)benzamide and its CIS-isomer (compound of example 20-1)

(1) Following the method of example 2(1), reaction was carried out using commercially available 2-aminothiazole (333 mg, 3.3 mmol), N,N-diisopropylethylamine (1,21 ml, 7.0 mmol), 4-formylbenzoate (468 mg, 2.8 mmol) and 4-(dimethylamino)pyridine (catalytic amount) and the reaction mixture was treated in a manner similar to the method of example 2(1), with 4-formyl-N-(2-thiazolyl)benzamide (355 mg, yield 55%) in the form of a pale yellow solid, which was recrystallized from a mixture of ethyl acetate-hexane to obtain pale yellow friable crystals.

Melting point: S.

An NMR spectrum (270 MHz, CDCl3) memorial plaques: 7,02 (1H, d, J=4 Hz), 7,14 (1H, d, J=4 Hz), with 8.05 (2H, d, J=8 Hz), 8,17 (2H, d, J=8 Hz), 10,15 (1H, s), 11,92 (1H, ush.C).

The IR spectrum max (KBR) cm-1: 3149, 1691, 1671, 1549.

Mass spectrum m/z (EI); 232 (M+, 133 (100%).

(2) Following the method of example 1(2), was carried out by the reaction is phenyl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazole-1-yl]-2-butanol (270 mg, 0.75 mmol) and monohydrate p-toluensulfonate acid (357 mg, 1.88 mmol) and the reaction mixture was processed using a method similar to the method of example 1(2), with the TRANS-isomer is specified in the title compound (64 mg, yield 15%) as a white oil and the CIS isomer (29 mg, yield 7%) as a colourless oil. The TRANS-isomer was recrystallized from a mixture of tetrahydrofuran-hexane to obtain white loose crystals.

TRANS-isomer:

Melting point: S.

An NMR spectrum (270 MHz, CDCl3) memorial plaques: 1,22 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), of 3.77 (1H, t, J=11 Hz), with 3.79 (1H, t, J=11 Hz), 4,43 (1H, DDD, J=11, 5, 2 Hz), 4,56 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, s), of 5.05 (1H, d, J=14 Hz), to 5.56 (1H, s), 6,7-6,8 (3H, m), 7,01 (1H, d, J=4 Hz), 7,2-7,4 (1H, m), 7,31 (1H, d, J=4 Hz), 7,66 (2H, d, J=8 Hz), 7,80 (2H, s), of 8.00 (2H, d, J=8 Hz).

The IR spectrum max (KBR) cm-1: 3409, 1672, 1543, 1139.

Mass spectrum m/z (FAB): 574 (M++1).

Specific rotation: []25D-30 (C=0,09, Meon).

CIS-isomer:

Melting point: S.

An NMR spectrum (270 MHz, Dl3) memorial plaques: to 1.23 (3H, d, J=7 Hz), up 3.22 (1H, t, J=2 Hz), 3,47 (1H, square, J=7 Hz), 4,2-4,5 (4H, m), to 4.87 (1H, d, J=14 Hz), 4,99 (1H, s), 5,16 (1H, d, J=14 Hz), of 5.68 (1H, s), 6,6-6,8 (3H, m), 7,00 (1H, d, J=4 Hz), 7,30 (1H, d, J=4 Hz), 7,3-7,5 (1H, m), of 7.69 (2H, d, J=8 Hz), 7,78 (1H, s), 7,80 (1H, s), 8,01 (2H, d[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzamide and its CIS-isomer (compound of example 39-1)

Following the procedure of example 1(1), a solution of 4-formylbenzoate (561 mg, of 3.33 mmol) in anhydrous tetrahydrofuran (6 ml) was added dropwise to a solution of commercially available 2-aminobenzothiazole (416 mg, 2.8 mmol) and triethylamine (of 0.62 ml, 4.4 mmol) in tetrahydrofuran was cooled under stirring to 0C. Formed mixture was stirred at 0C for two hours. At the end of mixing to the reaction mixture in a bath with ice was added saturated aqueous sodium bicarbonate solution. The resulting mixture was distributed between ethyl acetate and water. The organic layer was sequentially washed with saturated aqueous sodium bicarbonate solution, water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The crystalline residue was recrystallized from ethyl acetate to obtain pale yellow friable crystals (346 mg). Following the procedure of example 3(3), carried out the reaction using yellow friable crystals (300 mg), (2R,3R)-2-(2, 4-differenl)-3-[[1-(hydroxymethyl)-2-hydroxyethyl]thio]-1-(1H-1,2,4-triazole-1-yl]-2-butanol (258 mg, to 0.72 mmol) and monohydrate p-toluensulfonate acid (685 mg, 3.6 mmol) and the reaction mixture was treated with use of the (141 mg, yield 31%) as a colourless oil and the CIS isomer (63 mg, yield 14%) as a colourless oil. The TRANS-isomer was recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

TRANS-isomer:

Melting point: S.

An NMR spectrum (270 MHz, CDCl3) memorial plaques: 1,22 (3H, d, J=7 Hz), to 3.36 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), 3,76 (1H, t, J=11 Hz), with 3.79 (1H, t, J=11 Hz), 4,42 (1H, DDD, J=11, 5, 2 Hz), 4,55 (1H, DDD, J=11, 5, 2 Hz), is 4.85 (1H, d, J=14 Hz), of 5.05 (1H, d, J=14 Hz), is 5.06 (1H, s), of 5.55 (1H, s), 6,7-6,8 (2H, m), 7,2-7,5 (3H, m), to 7.67 (2H, d, J=8 Hz), 7,73 (1H, d, J=8 Hz), 7,80 (2H, s), 7,86 (1H, d, J=8 Hz), 8,01 (2H, d, J=8 Hz), 9,98 (1H, ush.C).

The IR spectrum max (KBR) cm-1: 3409, 1678, 1539, 1139.

Mass spectrum m/z (FAB): 624 (M++1).

Specific rotation: []25D-64 (C=0,59, l3).

CIS-isomer:

An NMR spectrum (270 MHz, CDCl3) memorial plaques: to 1.23 (3H, d, J=7 Hz), 3,23 (1H, t, J=2 Hz), 3,44 (1H, square, J=7 Hz), 4,2-4,5 (4H, m), to 4.87 (1H, d, J=14 Hz), to 4.98 (1H, s), of 5.15 (1H, d, J=14 Hz), 5,67 (1H, s), 6,6-6,8 (2H, m), a 7.2 to 7.5 (3H, m), of 7.70 (2H, d, J=8 Hz), of 7.75 (1H, d, J=8 Hz), 7,78 (1H, s), 7,80 (1H, s), 7,86 (1H, d, J=8 Hz), 8,01 (2H, d, J=8 Hz), becomes 9.97 (1H, ush.C).

Mass spectrum m/z (FAB): 624 (M++1).

Example 29

4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]-N-[(1-naphthyl)methyl]benzamide (compound of example, the number of the available 1-naphthylethylene (187 mg, 1.2 mmol), trimethylaluminum (1.1 ml, 1.07 M solution in n-hexane, 1.2 mmol) and methyl 4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzoate (150 mg, 0.30 mmol) obtained in example 12(1), and the reaction mixture was treated in a manner similar to the method of example 3(4), obtaining specified in the title compound (170 mg, yield 91%) as a white solid, which was recrystallized from a mixture of ethyl acetate-hexane to obtain white loose crystals.

Melting point: S.

An NMR spectrum (270 MHz, CDCl3) memorial plaques: 1,19 (3H, d, J=7 Hz), 3,34 (1H, square, J=7 Hz), 3,4-3,6 (1H, m), of 3.73 (1H, t, J=11 Hz in), 3.75 (1H, t, J=11 Hz), to 4.38 (1H, DDD, J=11, 5, 2 Hz), 4,51 (1H, DDD, J=11, 5, 2 Hz), a 4.83 (1H, d, J=14 Hz), 5,02 (1H, s) of 5.03 (1H, d, J=14 Hz), 5,10 (2H, d, J=5 Hz), of 5.48 (1H, s), 6,32 (1H, ush.t, J=5 Hz), 6,7-6,8 (2H, m), 7,2-7,4 (1H, m), 7,4-7,6 (6N, m), 7,7-7,8 (4H, m), 7,8-8,0 (2H, m), 8,0-8,2 (1H, m).

The IR spectrum max (KBR) cm-1: 3328, 1646, 1539, 1139.

Mass spectrum m/z (FAB); 631 (M++1).

Specific rotation: []25D-61 (C=0,59, l3).

Example 30

4’-Carbarnoyl-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide (compound of example 24-1)

Following the procedure of example 3 is uminia (2.2 ml, 1.07 M solution in n-hexane, 2.4 mmol) and methyl 4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzoate (150 mg, 0.30 mmol) obtained in example 12 (1), and the reaction mixture was treated in a manner similar to the method of example 3(4)with obtaining specified in the title compound (66 mg, yield 37%) as a white solid, which was recrystallized from a mixture of ethyl acetate-hexane to obtain a pale orange loose crystals.

Melting point: 230S.

An NMR spectrum (400 MHz, CDCl3) memorial plaques: a 1.11 (3H, d, J=7 Hz), 3,3-3,5 (1H, m) to 3.58 (1H, square, J=7 Hz), of 3.77 (2H, t, J=11 Hz), a 4.3 to 4.5 (2H, m), to 4.81 (1H, d, J=14 Hz), 4,91 (1H, d, J=14 Hz), 5,67 (1H, s), of 6.02 (1H, s), the 6.9 to 7.0 (1H, m), 7,1-7,3 (3H, m), 7,58 (2H, d, J=8 Hz), 7,68 (1H, s), 7,8-7,9 (5H, m), of 8.00 (2H, d, J=2 Hz), of 8.27 (1H, s), 10,48 (1H, s).

The IR spectrum max (KBR) cm-1: 3386, 1659, 1526, 1139.

Mass spectrum m/z (FAB): 610 (M++1).

Specific rotation: []25D-40 (C=0,18, Meon).

Example 1 test

Antifungal activity in vitro

Antifungal activity of the tested compounds was evaluated in accordance with their minimum any abscopal concentrations (MIC), which was determined by the following methods.

For Candida albicans and Aspergillus fumigatus IP is but)propanesulfonic acid. For Cryptococcus neoformans used yeast nitrogen-containing basic environment, pH of which was brought to 7.0 using 0,165 M 3-(morpholino)propanesulfonic acid.

Preparation of fungal solution for inoculation: every subject fungal solution Candida albicans and Cryptococcus neoformans were incubated on agar Sabouraud's medium at 35C for 48 hours. About five colonies of the tested fungi having a diameter of 1 mm, suspended in physiological solution and the transparency of the suspension was brought to 0.5 degrees Macfarland. The suspension is diluted a thousand times, were obtained by dilution of the formed suspension of the above liquid medium and used for Candida albicans. The suspension is diluted a hundred times, were obtained by dilution of the formed suspension of the above liquid medium and used for Cryptococcus neoformans. Aspergillus fumigatus were incubated at 35C on potato agar with dextrose for five days. Spores on the agar medium were collected using saline containing 0.05% Tween 80, and using the counter blood cells, the number of spores was brought to 2.5 x 107/ml. Diluted a thousand times, the suspension is prepared by dilution of the formed suspension of spores of the above liquid medium and used which was dissolved in 100% dimethyl sulfoxide and 100% dimethyl sulfoxide was carried out by serial twofold dilutions of each compound. The final concentration of dimethyl sulfoxide was brought to a value not more than 1% dilution above each liquid medium, respectively.

Assessment method: each diluted test compound (100 μl), fungal solution for inoculation (80 μl) and Alamar blue color solution (20 ml), was added to each of the wells of microtiter tablet having 96 wells. Formed mixture incubated at 35C (30C for Aspergillus fumigatus). When svetopolskaya the ability of the control sample microorganism cultures at 570 nm was higher than the value of 0.6, determine the values of the MIC. MIC was defined as the lowest concentration of compound that causes at least 80% inhibition of microorganism cultures (IC80compared with the control sample, to which was added the test compound.

The smaller the value of the MIC of the tested compounds, the greater its potential antifungal activity.

The results of the comparison compounds of formula (I) of this invention with the compound obtained in example 40 (Comparative compound a) description of the patent application of Japan No. Hei-8-333350, shown below in table 2.

The example 1 composition

Solid is th capsule, then the capsule was washed and dried to obtain the desired solid capsules.

Example 2 composition

Soft capsule

The mixture of compounds obtained in example 1 in a digestible oil such as soybean oil, cottonseed oil or olive oil, received and entered in gelatin using a pump to obtain soft capsules containing 100 mg of active ingredient, which is then washed and dried to obtain the desired soft capsules.

Example 3 composition

Pill

The following components were mixed and using a paste of corn starch was carried out by wet granulation of the mixture. Formed granules were dried and extruded teletrauma machine to obtain the required tablets (each weighing 490 mg).

If necessary, the tablet may be coated with a suitable intersolubility the floor.

Industrial applicability

The compound (I) and their pharmaceutically acceptable prodrugs, and pharmaceutically acceptable salts show in the present invention is very high antifungal activity. These compounds are suitable for treatment and prevention of fungus is Oli:

where AG1represents a phenyl group or a phenyl group substituted by 1-3 substituents (the substituents selected from a halogen atom and triptorelin group);

AG2represents fenelonov group, fenelonov group, substituted by 1 or 2 substituents (the substituents selected from a fluorine atom and chlorine atom), Neftyanoy group or Neftyanoy group, substituted by 1 or 2 substituents (the substituents selected from a fluorine atom and chlorine atom);

X represents a sulfur atom or methylene group;

R1represents a hydrogen atom or a C1-3is an alkyl group;

R2represents a hydrogen atom or a C1-3is an alkyl group;

R3represents a C6-10-aryl group, a C6-10-aryl group, substituted by 1-5 substituents selected from the group of substituents, pyridyl, thiazolyl, benzothiazolyl, oxazolyl or isoxazolyl,7-14-aracelio group or7-14-aracelio group substituted by 1-5 substituents selected from the group of substituents AS;

a group of deputies And includes C1-6is an alkyl group, a C1-6-alkyl groupcontrol group, WITH1-6-CNS group, substituted by 1-5 substituents (the substituents selected from a halogen atom, a hydroxyl group, ceanography and C1-6-CNS group)1-6-alkanoyloxy group1-6-alkanoyloxy, halogen atom, hydroxyl group, amino group, mercaptopropyl, karbamoilnuyu group, a nitrogroup, a cyano, a group of the formula-S(O)nR4(where R4represents a C1-6is an alkyl group or a C1-6is an alkyl group substituted by 1-5 substituents (the substituents selected from halogen atoms), and n represents 0, 1 or 2).

2. The compound or its pharmacologically acceptable salt p. 1, where AG1represents a phenyl group substituted by 1 or 2 substituents (the substituents selected from a fluorine atom, chlorine atom and triptorelin group).

3. The compound or its pharmacologically acceptable salt p. 1, where AG1represents a 2,4-differenly group.

4. The compound or its pharmacologically acceptable salt according to any one of paragraphs.1-3, where AG2represents 1,4-fenelonov group.

5. The compound or its pharmacologically acceptable salt according to any one of paragraphs.1-4, where X PP.1-4, where X represents a methylene group.

7. The compound or its pharmacologically acceptable salt according to any one of paragraphs.1-6, where R1represents a C1-3is an alkyl group.

8. The compound or its pharmacologically acceptable salt according to any one of paragraphs.1-6, where R1represents a methyl group.

9. The compound or its pharmacologically acceptable salt according to any one of paragraphs.1-8, where R2represents a hydrogen atom.

10. The compound or its pharmacologically acceptable salt according to any one of paragraphs.1-9, where R3represents a C6-10-aryl group or6-10-aryl group, substituted by 1-5 substituents selected from the group of substituents A.

11. The compound or its pharmacologically acceptable salt according to any one of paragraphs.1-9, where R3represents a phenyl group or a phenyl group substituted by 1-5 substituents selected from the group of substituents A.

12. The compound or its pharmacologically acceptable salt according to any one of paragraphs.1-9, where R3represents pyridyl, thiazolyl, benzothiazolyl, oxazolyl or isoxazolyl.

13. The compound or its pharmacologically acceptable salt according to any one of paragraphs.1-9, where R3pray Deputy A.

14. The compound or its pharmacologically acceptable salt according to any one of paragraphs.1-13, where the group of substituents And represents a group of the substituents A1, which includes1-6is an alkyl group, a C1-6is an alkyl group, substituted by 1-4 substituents (the substituents selected from a halogen atom and cyanopropyl)1-6-CNS group1-6-CNS group, substituted by 1-5 substituents (the substituents selected from a halogen atom, a hydroxyl group and cyanopropyl)1-6-alkanoyloxy group1-6-alkanoyloxy, halogen atom, hydroxyl group, karbamoilnuyu group, a nitrogroup, a cyano and a group of the formula-S(O)nR4(where R4represents a C1-6is an alkyl group or a C1-6is an alkyl group substituted by 1-5 substituents (the substituents selected from halogen atoms); and n represents 0, 1 or 2).

15. The compound or its pharmacologically acceptable salt according to any one of paragraphs.1-13, where the group of substituents And represents a group of deputies A2, which includes1-3is an alkyl group, a C1-4is an alkyl group, substituted by 1-4 substituents (the substituents selected from a fluorine atom, atom hli (these substituents selected from a fluorine atom, chlorine atom and a hydroxyl group), WITH1-3-alkanoyloxy group1-3-alkanoyloxy, halogen atom, hydroxyl group, karbamoilnuyu group, a nitrogroup, a cyano and a group of the formula-S(O)nR4(where R4represents a C1-3is an alkyl group or a C1-3is an alkyl group substituted by 1-5 substituents (the substituents selected from fluorine atoms); and n represents 0, 1 or 2).

16. The compound or its pharmacologically acceptable salt according to any one of paragraphs.1-13, where the group of substituents And represents a group of deputies A3, which includes a methyl group, triptorelin group, cyanomethyl group, cryptometer, tetrafluoropropoxy, acetyl group, an acetoxy group, a fluorine atom, chlorine atom, iodine atom, hydroxyl group, karbamoilnuyu group, a nitrogroup, cyano, triptoreline, methanesulfonyl group and trifloromethyl group.

17. The compound or its pharmacologically acceptable to any one of paragraphs.1-16 selected from the group comprising

4’-cyano-4-[TRANS-5-[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide,

4’-ptx2">

4’-chloro-4-[TRANS-5[[(1R,2R)-2-(2,4-differenl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazole-1-yl)propyl]thio]-1,3-dioxane-2-yl]benzanilide.

18. Pharmaceutical composition having antifungal activity, containing the compound or its pharmacologically acceptable salt according to any one of paragraphs.1-17 and a pharmacologically acceptable carrier or diluent.

19. The compound or its pharmacologically acceptable salt according to any one of paragraphs.1-17, possessing antifungal activity.

20. The compound or its pharmacologically acceptable salt according to any one of paragraphs.1-17 as an active ingredient of a medicinal product for the prevention or treatment of fungal infections.

21. A method of preventing or treating a fungal infection involving the introduction of a warm-blooded animal, if necessary, an effective amount of the compound or its pharmacologically acceptable salt according to any one of paragraphs.1-17.

22. The method according to p. 21, where warm-blooded animal is a human.

 

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