Triazolone compounds or their pharmacologically acceptable salts and antifungal composition

 

(57) Abstract:

Describes the new triazolone compounds of General formula I, where the values of AG1, AG2, R0, R1-R5, p, q, s, r, A indicated in paragraph 1 of the formula expressing the antifungal activity. Also described antifungal composition based on them. 2 S. and 11 C.p. f-crystals, 2 PL.

The present invention relates to 1,2,4-triazolone to the compound of formula (I), which is especially effective for the treatment of fungal diseases of humans and animals.

Background of the invention

In the publication of unexamined Japanese patent application (KOKAI) N Sho 61-85369 indicates that the connection similar to the connection of the present invention, in which part of the molecule, the corresponding part of the molecule formula

-A-(CO)p-(R2C=CR3)q-(C=C)r-(R4C=CR5)s-Ar2< / BR>
in the formula (I) represents an alkyl, cycloalkylcarbonyl or cycloalkyl group, has antifungal activity.

However, for the development of more effective antifungal agents by the authors of the present invention have conducted intensive studies, the result of which was

The present invention relates to the compound of formula (I)

< / BR>
where Ar1represents a phenyl group or a phenyl group having 1-3 substituent (where these substituents are a halogen atom or triptorelin group);

Ar2represents a phenyl group, a 5 - or 6-membered aromatic heterocyclic group (where the aromatic heterocyclic group has at least one nitrogen atom, oxygen or sulphur, or phenyl group, or a 5 - or 6-membered aromatic heterocyclic group having 1-3 substituent [where these substituents are lower alkyl group; a lower alkoxy group; a halogen atom; a lower alkyl group substituted by an atom or atoms of halogen; lower alkoxy group substituted by an atom or atoms of halogen; nitro group; cyano group; the group-S(O)mR6(R6represents a lower alkyl group which may be substituted by an atom or atoms of halogen and m is 0, 1 or 2) or a group-NHCOR7(where R7represents a lower alkyl group, and which aromatic heterocyclic group has at least one nitrogen atom, oxygen or sulfur];

R0represents a hydrogen atom or a lower al is SUP> may be the same or different and represent a hydrogen atom, a lower alkyl group or a lower alkyl group substituted by an atom or atoms of halogen, where q and/or s is 2, and each of R2, R3, R4and R5independently represents a group, which may be the same or different groups R2, R3, R4and R5respectively;

n is 0, 1 or 2;

p is 0 or 1;

q, r and s is 0, 1 or 2;

A represents A 4-7-membered aliphatic carbocyclic group containing 4-7 carbon atoms, or 4-7-membered aliphatic heterocyclic group having at least one nitrogen atom, oxygen or sulfur;

or its pharmacologically acceptable salt.

The above-mentioned halogen atom is, for example, fluorine atom, chlorine or bromine, preferably fluorine atom or chlorine.

The lower alkyl group is, for example, methyl, ethyl, sawn, ISO-propyl, bucilina, isobutylene, second-bucilina or tert-bucilina group, and preferably methyl, ethyl, sawn or ISO-propyl group.

The lower alkoxy group is, for example, methoxy, ethoxy-, propoxy-, isopropoxy, butoxy-, ISI group.

5 - or 6-membered aromatic heterocyclic group, Ar2is, for example, furilla, thienyl, pyrrolidine, pyrazolidine, imidazolidine, oxazolidine, thiazolidine, perederina, piramidalnaya or perazella group, and preferably furilla, thienyl, pyrrolidine or Peregrina group.

4-7-membered aliphatic carbocyclic group containing 4-7 carbon atoms and represented by A is, for example, CYCLOBUTANE, cyclopentane, cyclohexane or cyclobutanone ring, and preferably CYCLOBUTANE, cyclopentane or cyclohexane ring.

4-7-membered aliphatic heterocyclic group having at least one nitrogen atom, oxygen or sulfur and represented by A is, for example, azetidinone, pyrolidine, piperidine, homopiperazine, oxetanone, tertrahydrofuran ring, tetrahydropyrrole, titanoboa, tetrahydrothiophene, pentamethylbenzophenone, 1,4,5,6-tetrahydropyrimidine, 1,3-dioxane, 1,3-diciannove, dihydrokainate, tetrahydroquinoline, dihydrothiazine or tetrahydrothiophene ring, and preferably azetidinone, piperidine, 1,3-dioxane, 1,4,5,6-tetrahydropyrimidines connection, where:

Ar1is dichloraniline, differenly, chloraniline, florfenicol, (trifluoromethyl)phenyl or fluoro(trifluoromethyl)phenyl group; preferably 2,4-dichloraniline, 2,4-differenly, 4-chloraniline, 4-florfenicol, 4-(trifluoromethyl)phenyl or 2-fluoro-4-(trifluoromethyl)phenyl group; and particularly preferably 2.4 to dichloraniline, 2,4-differenly or 4-(trifluoromethyl)phenyl group;

Ar2is florfenicol, chloraniline, differenly, dichloraniline, (trifluoromethyl)phenyl, (trichloromethyl)phenyl, fluoro-(trifluoromethyl)phenyl, (deformedarse)phenyl, (triptoreline)phenyl, (2,2,2-triptoreline)phenyl, (1,1,2,2-tetrafluoroethoxy)phenyl, (2,2,3,3-tetrafluoropropoxy)phenyl, fluoro-(2,2,3,3-tetrafluoropropoxy) phenyl, nitrophenyl, fluorine-nitroaniline, cyanovinylene, chlorine-cyanoaniline, (methylthio)phenyl, (methylsulfinyl)phenyl, (methylsulphonyl)phenyl, (triptoreline)phenyl, (trifloromethyl)phenyl, (trifloromethyl)phenyl, chloropyridine, (trifluoromethyl)pyridyloxy, (2,2,3,3-tetrafluoropropoxy)pyridyloxy, (trifluoromethyl)follow, chlorine-thienyl, or (trifluoromethyl)thienyl g)phenyl, 4-(trichloromethyl)phenyl, 2-fluoro-4-(trifluoromethyl) phenyl, 4-(deformedarse)phenyl, 3-(triptoreline)phenyl, 4-(triptoreline)phenyl, 4-(2,2,2-triptoreline)phenyl, 4-(1,1,2,2-tetrafluoroethoxy)phenyl, 4-(2,2,3,3-tetrafluoropropoxy)phenyl, 2-fluoro-4-(2,2,3,3-tetrafluoropropoxy) phenyl, 4-nitroaniline, 2-fluoro-4-nitroaniline, 4-cyanoaniline, 2-chloro-4-cyanoaniline, 4-(methylthio)phenyl, 4-(methylsulfinyl)phenyl, 4-(methylsulphonyl)phenyl, 4-(triptoreline)phenyl, 4-(trifloromethyl)phenyl, 4-(trifloromethyl)phenyl, 6-chloro-3-pyridinol, 6-(trifluoromethyl)-3-pyridinol, 5-chloro-2-pyridinol, 6-(2,2,3,3-tetrafluoropropoxy)-3-pyridinol, 5-(trifluoromethyl)-2-follow, 5-chloro-2-thienyl or 5-(trifluoromethyl)-2-thienyl group; and particularly preferably 4-chloraniline, 4-(triptoreline)phenyl, 4-(trifloromethyl)phenyl, 4-(trifluoromethyl)phenyl, 4-(triptoreline)phenyl or 4-(2,2,3,3-tetrafluoropropoxy)phenyl group;

R0represents a hydrogen atom, a methyl, ethyl or sawn group; preferably a hydrogen atom, a methyl or ethyl group; and especially preferably a hydrogen atom or methyl group;

R1is mate the flax methyl group;

R2, R3, R4and R5may be the same or different and represent a hydrogen atom, methyl, ethyl, sawn or triptorelin group; preferably a hydrogen atom, methyl or triptorelin group; and especially preferably a hydrogen atom or triptorelin group;

n is 0, 1 or 2, particularly preferably 0;

p is 0 or 1, and particularly preferably 0;

q is 0, 1 or 2 and particularly preferably 1;

r is 0, 1 or 2, particularly preferably 0 or 1;

s is 0, 1 or 2 and particularly preferably 1;

A represents CYCLOBUTANE, cyclopentane, cyclohexane, azetidinone, pyrolidine, piperidine, tertrahydrofuran ring, tetrahydropyrrole, tetrahydrothiophene, 1,3-dioxane, 1,3-diciannove, tetrahydrooxazolo or tetrahydrothiophene ring; preferably CYCLOBUTANE, cyclohexane, azetidinone, piperidine, 1,3-dioxane, 1,3-diciannove, tetrahydroquinoline or tetrahydrothiophene ring; and especially preferably cyclohexane, piperidine, 1,3-dioxane or 1,3-diciannove ring.

The preferred compound (I) may be, for example, a compound in which Arthe; R0represents a hydrogen atom or methyl group; R1represents a methyl group; and the portion of the molecule represented by the formula

-S(O)n-A-(CO)p-(R2C=CR3)q-(C=C)r-(R4C=CR5)s-Ar

is a group, Oksanas in table 1.

Preferred compounds in table 1 are compounds having substituents 4, 6, 7, 13, 16, 18, 22, 25, 32, 36, 40, 43, 44, 47, 52, 53, 61, 63, 71, 76, 96, 107, 123, 127, 142, 174, 176, 177, 178, 181, 182, 183 and 186, and particularly preferred compounds are:

2-(2,4-differenl)-3-[[2-[2-[4-(trifluoromethyl)phenyl] vinyl]- 1,3-dioxane-5-yl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol (compound corresponding to example 2);

2-(2,4-differenl)-1- (1H-1,2,4-triazole-1-yl)-3- [[2-[2-[4- (triptoreline)phenyl] vinyl]-1,3-dioxane-5-yl] thio]-2-butanol (compound corresponding to example 11);

2-(2,4-differenl)-1- (1H-1,2,4-triazole-1-yl)- 3-[[2-[4-[4- (trifluoromethyl)phenyl] - 1,3-butadiene-1-yl]- 1,3-dioxane-5-yl] thio]-2-butanol (compound corresponding to example 15);

2-(2,4-differenl)-3- [[2-[4-[4-(2,2,3,3-tetrafluoropropoxy) phenyl] -1,3-butadiene-1-yl] - 1,3-dioxane-5-yl] thio] - 1-(1H-1,2,4-triazole-1-yl)-2 - butanol (compound corresponding to example 16);

2-(2,4-differenl)-3- [[2-[4-[4-(chlorophenyl)-5,5,5-Cryptor - 1,3 - pentadiene-1,3-pins(2,4-differenl)-3- [[1-[4-(triptoreline) cynnamoyl] piperidine-4-yl] thio] -1- (1H-1,2,4-triazole-1-yl)-2 - butanol (compound corresponding to example 21);

2-(2,4-differenl)-3- [[1-[4-nitrocinnamyl] piperidine-4-yl] thio] -1- (1H-1,2,4-triazole-1-yl)-2 - butanol (compound corresponding to example 23);

2-(2,4-differenl)-1- (1H-1,2,4-triazole-1-yl)-3- [[1-[5-[4- (triptoreline) phenyl] - 2,4-pentadienyl] piperidine-4-yl]thio]-2 - butanol (compound corresponding to example 24);

3-methyl-1- (1H-1,2,4-triazole-1-yl)-2- [4-(trifluoromethyl)phenyl]-3- [[2-[4-trifluoromethyl)phenyl]- 1,3-butadiene-1-yl]-1,3 - dioxane-5-yl]thio]-2 - butanol (compound corresponding to example 31);

2-(2,4-differenl)-1- (1H-1,2,4-triazole-1-yl)-3- [[2-[4- (triptoreline) phenyl]-1,3-butadiene-1-yl]- 1,3-dioxane-5-yl]thio]-2 - butanol (compound corresponding to example 32);

3-[[2-[4-[4-(2,2,3,3-tetrafluoropropoxy) phenyl] -1,3-butadiene-1-yl] - 1,3-dioxane-5-yl]thio]- 1-(1H-1,2,4-triazole-1-yl)-2- [4-(trifluoromethyl) phenyl] -2-butanol (compound corresponding to example 33);

1-(1H-1,2,4-triazole-1-yl)-2- [4-(trifluoromethyl)phenyl] -3- [[2-[4-[4- (trifluoromethyl) phenyl] -1,3-butadiene-1-yl]- 1,3-dioxane-5-yl]thio]-2 - butanol (compound corresponding to example 34);

2-(2,4-differenl)-1- (1H-1,2,4-triazole-1-yl)-3- [[2-[4-[4- (trifloromethyl) phenyl]-1,3-butadiene-1-yl]- 1,3-dioxane-5-yl]thio]-2 - butanol (compound corresponding to example 35);

2-(2,4-differenl)- 1-(1H-1,2,4-triazole-1-yl)-3- [[4-[4
2-(2,4-differenl)-1- (1H-1,2,4-triazole-1-yl)-3- [[2-[6- [4-(trifluoromethyl) phenyl] -1,3,5-hexatriene-1-yl]- 1,3-dioxane-5-yl]thio]-2 - butanol (compound corresponding to example 37);

2-(2,4-differenl)- 3-methyl-1-(1H-1,2,4-triazole-Il)-3- [[2-[4-[4-(trifluoromethyl) phenyl]-1,3-butadiene-1-yl]- 1,3-dioxane-5-yl] thio]-2 - butanol (compound corresponding to example 38);

2-(2,4-differenl)-1- (1H-1,2,4-triazole-1-yl)-3- [[2-[4-[4- (trifluoromethyl) phenyl] -1-butene-3-in-1-yl]- 1,3-dioxane-5-yl]thio]-2 - butanol (compound corresponding to example 39).

Triazolone compound (I) of the present invention has at least two asymmetric carbon atoms and therefore it can exist as optical isomers and diastereomers. In the case of optical isomers both antipode can be obtained by means of optical resolution or asymmetric synthesis. In addition, the diastereomers can be separated by standard methods of separation, such as fractional recrystallization and chromatography. The compound (I) of the present invention includes one of these isomers or a mixture thereof.

Triazolone compound (I) of the present invention can be used as antifungal agent directly or in the form of a pharmacologist is such acids, such as hydrochloric acid, Hydrobromic acid, sulfuric acid and nitric acid; salt of carboxylic acids, such as acetic acid, fumaric acid, maleic acid, oxalic acid, malonic acid, succinic acid, citric acid and malic acid; salt of sulfonic acids, such as methanesulfonate acid, econsultancy acid, benzolsulfonat acid and toluensulfonate acid, and the salts of amino acids such as glutamic acid and aspartic acid; however, preferred is a salt of carboxylic acids.

In addition, the compounds of the present invention also includes a hydrate of compound (I) and a salt hydrate of compound (I).

The compound (I) and its pharmacologically acceptable salt, obtained in accordance with the present invention, have excellent antifungal activity, and if the compound (I) and its pharmacologically acceptable salt is used as an antifungal agent, they can be entered either in the form in which they were received, or in the form of a mixture, for example, with a suitable pharmacologically acceptable excipients or diluent as orally, for example in the form of tablets, capsules, granules, parathas can be obtained by known methods using additives, such as fillers (for example, derivatives of sugars, such as lactose, sucrose, glucose, mannitol and sorbitol; starch derivatives such as corn starch, brewed with boiling water, potato starch, a-starch, dextrin and karboksimetilirovaniya starch; cellulose derivatives such as crystalline cellulose, low hydroxypropyl-substituted cellulose, calcium-containing carboxymethylcellulose and sodium carboxymethylcellulose with bridge connection; Arabian gum; dextrin; Pullulan; and derivatives, salts of silicic acid, such as volatile silicic acid anhydride, synthetic aluminum silicate and marialuisa meta-silicic acid; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; and sulfate derivatives such as calcium sulfate; binders (for example, the above-mentioned fillers, gelatin; polyvinylpyrrolidone and Macrogol); dezintegriruetsja agents (for example, the above-mentioned fillers, chemically modified derivatives of starch-cellulose, such as nitrocresols, sodium-containing karboksimetilirovaniya starch and polyvinylpyrrolidone with a bridge connection); oil (e.g., land; waxes, such as beeswax and spermaceti; boric acid; glycol; carboxylic acid such as fumaric acid and adipic acid; carboxylate sodium, such as sodium benzoate; sulfates such as sodium sulfate; leucine; laurilsulfate, such as sodium lauryl sulfate and lauryl sulfate, magnesium; silicic acid, such as silicic acid anhydride and silicic acid hydrate and derivatives of starch above when determining fillers); stabilizers (for example, p-hydroxybenzoate, such as methyl and propyl para-aminobenzoic acid); alcohols, such as chlorobutanol, benzyl alcohol and phenethyl alcohol; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; acetic anhydride and sorbic acid); corrigentov (for example, sweeteners; Takashimaya substance and commonly used odorants); suspendresume agents (e.g., Polysorbate 80 and sodium-containing carboxymethylate cellulose); thinners and solvents for drugs (e.g., water, ethanol and glycerol). Although the exact dose may vary depending on the condition and age of the patient, however, preferably, if this dose is given 1 to 6 times a day depending on the condition of the patient is Ino 5 mg), and the upper limit is 2000 mg (preferably 1000 mg) for adults; and in the case of intravenous administration of the lower dose limit is 0.1 mg at each administration (preferably 0.5 mg), and the upper limit is 600 mg (preferably 500 mg) for adults.

Of the compounds of formula (I) of the present invention, the compound (Ia) in which R0represents a hydrogen atom, and n = 0, can be obtained in accordance with the following reaction scheme:

< / BR>
(where Ar1and R1are the same and are defined above, and R8has the formula

-A-(CO)p-(R2C=CR3)q-(C=C)r-(R4C=CR5)s-Ar,

defined above). More specifically, the desired compound (Ia) are obtained by reaction of epoxy compound (2) described in the publication of unexamined Japanese patent application (KOKA1) N Hei 2-191262 (June 27, 1990), mercaptan (3) or acetic acid ether derivative in the basic environment. The solvent used in this reaction is preferably an alcohol, such as methanol, ethanol and propanol; aprotic solvent, such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile and tetrahydrofuran. However, if the reaction provodyaschemu solvents are alcohols or water. As the base in this reaction can be used sodium hydride, sodium methoxide, ethoxide sodium, lithium methoxide, tert-piperonyl potassium, lithium hydroxide, sodium hydroxide and potassium hydroxide. The amount used is 0.1-2 molar equivalent of the compound (2). Mercaptan (3) or explicitate derivative (4) is used in 1-3 molar equivalents. The reaction is carried out at a temperature from room temperature to 100oC for 2-10 hours. The compound (Ia) can be obtained by treating the reaction mixture by standard methods (oily product obtained by extraction with an organic solvent followed by evaporation of the solvent, and then purified using column chromatography or recrystallization).

In particular, R8SH (3) or R8SAc (4) used in the above reaction, can be obtained by the method described below. More specifically, the compound (3) or (4) in which A, R8represents a 1,3-dioxane ring, and p = 0, can be obtained using known compounds (5) [see: O. E. Van Lohuizen, P. E. Verkade, Rec. trav. chim., 78, 460 (1959)] as a starting compound according to the following reaction scheme (reaction srvc Prov./BR>< / BR>
< / BR>
< / BR>
< / BR>
(where R2, R3, R4, R5, Ar2, q, r and s are defined above). Of the unsaturated aldehydes (6) used in the above reaction, the compound (6a) in which r = 0, can be obtained through the unsaturated complex ester (7a) in accordance with the following scheme (with regard to the reaction conditions and method of selection at every stage, their descriptions, see the comparative examples 8, 9, 10, 20, 21, 22, 23, 33 and 49):

< / BR>
< / BR>
< / BR>
< / BR>
(where R2, R3, R4, R5, Ar2, q and s are defined above, and DIBAL-H denotes the hydride diisobutylaluminum).

Of the above aldehyde (6) the compound (6b) where r = 1 or 2, can be mainly obtained through the unsaturated complex ester (7b) in accordance with the following reaction scheme (with regard to the reaction conditions and isolation technique, described in comparative examples 44, 45, 46, 47 and 48):

< / BR>
< / BR>
< / BR>
< / BR>
(where R2, R3, R4, R5, q, r and s are defined above, and DIBAL-H denotes the hydride diisobutylaluminum).

In addition, compound (3b) or (4b) in which A, R8group R8SH (3) or R8SAc (4) represents a 4-7-membered nitrogen-containing g is the accordance with the following scheme (with regard to the reaction conditions and the method of allocation in each stage, their description is given in comparative examples 16 and 17):

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
(where R2, R3, R4, R5, q, r and s are defined above, t = 3, 4, 5 or 6, and Boc represents tert-butoxycarbonyl).

The acid chloride (10) used in the above reaction, can be obtained by treating the carboxylic acid obtained by alkaline decomposition of unsaturated complex ester (7a) or (7b), described above, with thionyl chloride.

Of the compounds of the present invention having the formula (I), compound (Ia) in which R0represents a hydrogen atom, and n = 0 can also be obtained in accordance with the following scheme:

< / BR>
(where Ar1, R1and R8defined above, and X represents a chlorine atom, bromine or iodine, methanesulfonate, benzosulfimide or toluensulfonate). More specifically, the desired compound (Ia) are obtained by reaction of a derivative triethylphosphite (11) described in the publication of unexamined Japanese patent application (KOKAI) N Hei 3-240778 (October 28, 1991), with an alkylating agent (12) in the presence of a base. Solvents suitable for this reaction is methanol, ethanol, propanol, butanol, dimethylformamide, dimethylacetamide is etc. Base, which can be used in this reaction is triethylamine, diisopropylethylamine, sodium hydride, sodium methoxide, ethoxide sodium, lithium methoxide, tert-piperonyl potassium, sodium hydroxide, potassium hydroxide, etc., while the amount used of the base is 1-3 molar equivalents, based on the number of connections (11). Alkylating agent (12) is used in the amount of 1-3 molar equivalents. The reaction temperature is from -50oC to 100oC, and the time of reaction is from 2 to 10 hours. The compound (Ia) can be obtained by treating the reaction mixture by standard methods (oily product obtained by extraction with an organic solvent followed by evaporation of the solvent, purified by column chromatography or recrystallization).

Alkylating agent R8-X (12) used in the above reaction, can be obtained in accordance with the following reaction scheme. The compound (12a), in which A in R8represents a 1,3-dioxane ring, and p = 0, can be obtained, for example, by reaction delovogo compound (13) obtained by processing the above-mentioned compound (5) acid is R>< / BR>
< / BR>
< / BR>
(where R2, R3, R4, R5, Ar2, q, r and s are defined above). In addition, compound (12b) in which A, R8represents a 4-7-membered nitrogen-containing heterocyclic group (azetidin, pyrrolidin, piperidin, homopiperazin), and p = 1 can be obtained, for example, by reaction of the compound (14) obtained by processing the above-mentioned cyclic amine derivative (8) hydrochloric acid, with the above acid chloride (10) in the presence of a base such as triethylamine

< / BR>
< / BR>
< / BR>
(where R2, R3, R4, R5, Ar2, q, r, s and t are the same as defined above).

Of the compounds of the present invention having the formula (I), compound (Ib) in which R0represents a hydrogen atom, n = 0, p = 0, and A represents A 1,3-dioxane ring, can also be obtained in accordance with the following reaction scheme:

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
(where Ar1, Ar2, R1, R2, R3, R4, R5, p, q and r are the same as defined above). More specifically, the desired compound (Ib) obtained by performing the reaction of the above-mentioned epoxy compound (2) with deoxynucleotidyl same conditions, in which carry out the reaction of the compounds (2) and (4), resulting in a receive connection (16), which is subjected to reactions release a standard method, such as treatment with an acid, and then the obtained compound (17) is subjected to reaction with the above-mentioned aldehyde compound (6). The reaction of the compound (17) with compound (6) is usually carried out in acidic conditions. Acid, which can be used in this reaction is, for example, hydrogen chloride, sulfuric acid, nitric acid, boron TRIFLUORIDE, methansulfonate acid, benzolsulfonat acid and p-toluensulfonate acid, the amount used of the acid is 1-2 molar equivalents per compound (17). The aldehyde (6) use 1-2 molar equivalent. As the solvent used aprotic solvent, such as methylene chloride, chloroform, 1,2-dichloroethane, benzene, toluene, xylene, diethyl ether and tetrahydrofuran. The reaction is carried out at a temperature from 0oC to the boiling point of the solvent for a period of from 2 to 10 hours. Although the water produced in the reaction may be removed by azeotropic distillation, however, as the dehydrating agent can be isolation sodium bicarbonate, and then processed in accordance with standard techniques (oily product obtained by extraction with an organic solvent followed by evaporation of the solvent, purified by column chromatography or recrystallization).

Of the compounds of the present invention, compound (Ic) in which R0represents a hydrogen atom, n = 0, p = 1, and A represents A 4-7-membered nitrogen-containing heterocyclic group (azetidin, pyrrolidine, piperidine, homopiperazine), can be obtained in accordance with the following reaction scheme:

< / BR>
< / BR>
< / BR>
(where Ar1, Ar2, R1, R2, R3, R4, R5, q, r, s and t are the same as defined above, and Boc represents tert-butoxycarbonyl). More specifically, the desired compound (Ic) obtained by the reaction of the above-mentioned epoxy compound (2) with a mercaptan (18), obtained by processing the above deoxynucleotide derivative (9) the alkali in the same conditions in which he conducted the reaction of the compound (2) with compound (3), resulting in a receive connection (19), which is subjected to reaction released by treatment with acid in accordance with technical standard is (20) and (10) is carried out in an inert solvent, such as benzene, toluene, methylene chloride, chloroform or tetrahydrofuran, in the presence of an appropriate base standard methods (see comparative examples NN 13, 14, 18 and 19).

Of the compounds of the present invention of formula (I) compound in which n = 1 or n = 2, can be obtained by a method described below. More specifically, the compound (I) in which n = 1 can be obtained by oxidation of compound (I) in which n = 0, obtained by the above method, in a solvent by using 1 equivalent of oxidizing agent, and the compound (I) in which n = 2, can be obtained by oxidation of this compound with 2 or more equivalents of oxidizing agent. The choice is specifically used in the reaction solvent is not critical provided that it does not inhibit the reaction and can dissolve the starting compound to some extent; however, the preferred solvent is a halogenated hydrocarbon, such as methylene chloride and chloroform. As the oxidizing agent can be used, for example, peracetic acid and 3-chloroperbenzoic acid. This reaction is carried out at a temperature of 0-50oC, and preferably at room temtem processing of the reaction mixture by standard methods (after washing the reaction mixture with an aqueous solution of sodium bicarbonate, the crude product obtained by evaporation of the solvent, purified by means of chromatography or recrystallization).

Of the compounds of the present invention having the formula (I), compound (Id) in which R0is lower alkyl and n = 0, can be obtained in accordance with the following reaction scheme:

< / BR>
(where Ar1, R0, R1and R8are the same as defined above). More specifically, the desired compound (Id) are obtained by reaction of brometea (21) received in accordance with the methodology described in the publication of unexamined Japanese patent applications (KOKAI), NO. Hei 7-2802 (6 Jan. 1995), with the above mercaptan (3) or explicilty derivative (4) in alkaline conditions, and as a result of this reaction is a thioester derivative of (22), which is then subjected to reaction with iodide trimethylsulfoxonium and 1,2,4-triazole in the presence of a base. The solvent used in the reaction of compound (21) with compound (3) or (4) are preferably alcohols such as methanol, ethanol and propanol, as well as the base can be used sodium hydroxide, potassium hydroxide, sodium methoxide and ethoxide sodium. The solvent used in the reaction turned anal and tert-butanol, and aprotic solvents such as dimethylformamide, dimethylacetamide, dimethylsulfoxide, acetonitrile and tetrahydrofuran. As the base in this reaction can be used sodium hydride, sodium methoxide, ethoxide sodium, lithium methoxide, tert-piperonyl potassium, lithium hydroxide, sodium hydroxide and potassium hydroxide in a quantity amounting to 2 to 5 equivalents based on the amount of compound (22). Iodide trimethylsulfoxonium and 1,2,4-triazole are used in 1-2 molar equivalents based on the amount of compound (22), respectively. The reaction is carried out at a temperature of from room temperature to 100oC for 2-10 hours. Compound (Id) (n = 0) can be obtained by treating the reaction mixture by standard methods (crude product obtained by extraction with an organic solvent followed by evaporation of the solvent, purified by column chromatography or recrystallization). Of the compounds (I), the compound (Ie) in which n = 0, p = 0, and A represents A 1,3-dioxane ring, can be obtained from compound (23) (in which R8refers to a group represented by the formula:

< / BR>
and which is a compound (Id) obtained in the above way) through the receipt of Tirol (24) is UP>1
, Ar2, R1, R2, R3, R4, R5, q, r and s are defined above). The reaction conditions in the respective stages of the reaction similar to the reaction conditions in the reaction (16) ---> (17) ---> (I b).

In more detail, the present invention is described below in the respective examples, comparative examples and experimental examples, in the examples of the preparation of drugs, which, however, should not be construed as limiting the invention.

In particular, aldehyde compounds used in the examples were synthesized by the methods described in the literature and/or quotations taken from the literature (where the literature is indicated in brackets). Aldehyde compounds, for which the literature is not specified, are commercially available or they can be obtained by the known methods described in the literature given in the examples in brackets or quotes taken from this literature, or methods described in the comparative examples of the present description.

The best option of carrying out the invention

Example 1

(2R,3R)-2-(2,4-Differenl)-3-[[TRANS-2-[(E)-1-methyl-2-[4- (trifluoromethyl)phenyl]vinyl]-1,3-dioxane-5-yl]thio]-2-butanol

< / BR>
In 2 ml of dimethylformamide was dissolved 166 mg (0,48 the example 7, and then added 110 mg (0.44 mmol) of (2R, 3S)-2-(2,4-differenl)-3-methyl-2-[(1H-1,2,4-triazole-1-yl)methyl] oxirane and 0.15 ml (0.24 mmol) of a 1.6 M solution of sodium methylate in methanol under nitrogen atmosphere and the resulting mixture was stirred for six hours at a temperature of 55oC. After cooling, the reaction mixture was diluted with ethyl acetate and the resulting mixture was washed with a saturated aqueous solution of sodium chloride. An oily substance obtained by distillation of the solvent was subjected to column chromatography on 15 g of silica gel, and then suirable hexane/ethyl acetate (2:1), resulting in a received 180 mg (yield = 74%) of target compound in the form of an oily substance.

NMR spectrum (60 MHz, CDCl3) million D.: 1,19 (3H, d, J = 7 Hz), 1,90 (3H, d, J = 1.5 Hz), to 3.34 (1H, q, J = 7 Hz), 3,0 - 3,9 (3H, m), 4,1 - 4,6 (2H, m), 4,80 (1H, d, J = 14 Hz), 4,94 (1H, s), 5,02 (1H, d, J = 1 Hz), of 5.05 (1H, d, J = 14 Hz), 6,4 - 7,0 (3H, m) and 7.1 and 7.6 (1H, m), 7,40 (2H, d, J = 9 Hz), a 7.62 (2H, d, J = 9 Hz), 7,80 (2H, s).

Example 2

(2R,3R)-2-(2,4-Differenl)-3- [[TRANS-2-[(E)-2-[4-(trifluoromethyl) phenyl] vinyl]-1,3-dioxane-5-yl]thio]- 1-(1H-1,2,4-triazole-1-yl)-2 - butanol

< / BR>
Reaction and treatment were carried out by the method described in example 1 using (2R,3S)-2-(2,4-differenl)-3-methyl-2-[(1H-1,2,4-triazole-1-yl)methyl] oxirane and TRANS-5-(acetylthio)-2-[(E)-2-[4-melting = 73 - 75oC).

Specific rotation []2D5= -73,8o(=to 1.00, CHCl3).

NMR spectrum (270 MHz, CDCl3) million D.: 1,19 (3H, d, J = 7,3 Hz) to 3.34 (1H, q, J = 7,3 Hz), 3.43 points (H, TT, J = and 11.2, 4.6 Hz), the 3.65 (1H, t, J = 11.2 Hz), to 3.67 (1H, t, J = 11.2 Hz), 4,33 (1H, DDD, J = 11,2, 4,6, 2.0 Hz), 4,46 (1H, DDD, J = 11,2, 4,6, 2.0 Hz), 4,82 (1H, d, J = 13,8 Hz), to 5.03 (1H, d, J = 13,8 Hz), 5,04 (1H, Shir.C.), 5,14 (1H, d, J = 4.6 Hz), and 6.25 (1H, DD, J = 15,8, 4.6 Hz), 6,7 - 7,8 (2H, m), 6,83 (1H, d, J = 15,8 Hz), 7,3 was 7.45 (1H, m), 7,49 (2H, d, J = 6.8 Hz), 7,58 (2H, d, J = 6.8 Hz), 7,79 (2H, s).

Example 3

(2R, 3R)-3-[[TRANS-4- [(E)-2-(4-chlorophenyl)vinyl] cyclohexyl]thio]- 2-(2,4-differenl)-1- (1H-1,2,4-triazole-1-yl)-2 - butanol

< / BR>
Reaction and treatment were carried out using the method described in example 1 using (2R, 3S)-2-(2,4-differenl)-3-methyl-2-[(1H-1,2,4 - triazole-1-yl)methyl] oxirane and TRANS-1-(acetylthio)-4-[(E)-2-(4-chlorophenyl)vinyl]cyclohexane, resulting in the obtained target compound with a melting point of 64 - 66oC and output, constituting 31%.

Specific rotation []2D5= -84,1o(c = 2,69, CHCl3).

NMR spectrum (270 MHz, CDCl3) million D.: of 1.16 (3H, d, J = 7,3 Hz), 1,2 - 1,6 (4H, m), 1,9 - 2,0 (2H, m), from 2.1 to 2.25 (3H, m), 2,70 (1H, TT, J = and 11.2, 4.0 Hz), to 3.36 (1H, square, J = 7,3 Hz), 4,60 (1H, s), a 4.83 (1H, d, J = a 13.9 Hz), 5,10 (1H, d, J = a 13.9 Hz), 6,11 (1H, DD, J = 15,8, 7,3 Hz), 6,32 (1H, d, J = 15,8 Hz), 6,74 (2H, t-like,inyl]-1,3 - dioxane-5-yl] thio] -2-(2,4-differenl)- 1-(1H-1,2,4-triazole-1-yl)-2 - butanol

< / BR>
In 14 ml of methylene chloride was dissolved 294 mg (0.82 mmol) of (2R,3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio] -1- (1H-1,2,4-triazole-1-yl)-2-butanol as described in comparative example 2, and then added 191 mg (1.15 mmol) of TRANS-4-chlorocinnamamide [Bull. Chem. Soc. Japan 52, 555 (1979)] and 233 mg (1,23 mmol) monohydrate para-toluensulfonate acid and 1.5 g of molecular sieves 4, after which the reaction mixture was stirred for 1 hour and 15 minutes. To the reaction mixture was added aqueous sodium bicarbonate solution, and then the mixture was stirred for ten minutes, followed by removal of the molecular sieves by filtration. The organic layers were collected and dried, and the solvent is kept at reduced pressure. Thus obtained oily substance was subjected to column chromatography on 15 g of silica gel, was suirable hexane/ethyl acetate (3:2) as solvent and received 280 mg (yield 67%) of target compound (TRANS isomer (A)) as an oily product. After that, the obtained oily substance was suirable a mixture of hexane/ethyl acetate (1:1), resulting in a received 35 mg (yield 8%) of the CIS isomer (B) in the form of an oily substance.

Specific rotation [A][]2D5= -68(c = 1,22, CHCl33) million D.: (A) to 1.19 (3H, d, J = 7,3 Hz) to 3.34 (1H, q, J = 7,3 Hz) to 3.41 (1H, TT, J = and 11.2, 4.6 Hz), to 3.64 (1H, t, J = 11.2 Hz), 3,66 (1H, t, J = 11.2 Hz), 4,32 (1H, DDD, J = 11,2, 4,6, and 2.6 Hz), of 4.44 (1H, DDD, J = 11.2 Hz, 4.6 Hz, the 2.6 Hz), 4,82 (1H, d, J = a 13.9 Hz), free 5.01 (1H, s), 5,04 (1H, d, J = a 13.9 Hz), 5,11 (1H, d, J = 4.6 Hz), x 6.15 (1H, DD, J = 15,8, 4.6 Hz), 6,7 - 6,8 (2H, m), 6,76 (1H, d, J = 15,8 Hz), 7,25 was 7.45 (5H, m), 7,78 (2H, s); (B) to 1.21 (3H, d, J = 7,3 Hz), 3,11 (1H, s-like), a 3.50 (1H, q, J = 7,3 Hz), from 4.2 to 4.4 (4H, m), 4,88 (1H, J = 14,5 Hz), is 4.93 (1H, s), 5,16 (1H, d, J = 14,5 Hz), 5,23 (1H, d, J = 4.6 Hz), 6,21 (1H, DD, J = 16,5 - 4,6 Hz), 6,65 is 6.8 (2H, m), 6,76 (1H, d, J = 16.5 Hz), 7,25 was 7.45 (5H, m), to 7.77 (1H, s), 7,80 (1H, s).

The ethyl acetate was dissolved 54 mg of the compound (A) and to the resulting solution was added 19 mg of oxalic acid, after which the reaction mixture was added hexane. Precipitated crystals were collected by filtration, resulting in a received 65 mg salt of oxalic acid with a melting point 89 - 92oC. in a Similar way was obtained oxalate (B) cm so pl. 94 - 98oC.

Example 5

(2R, 3R)-2-(2,4-Differenl)-3-([TRANS-2-[(E)-2-pyridyl) vinyl]-1,3-dioxane-5-yl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
In 5 ml of methylene chloride was dissolved 120 mg (0.33 mmol) (2R,3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio] -1-(1H-1,2,4-triazole-1-yl)-2-butanol and the resulting solution was added 60 mg (0.45 mmol) of TRANS--(3-pyridyl)acrolein (J. Med. Chem. 18, nemesvari for 1 hour and 15 minutes. To the reaction mixture were added an aqueous solution of sodium bicarbonate, the mixture was stirred for 10 minutes, and then the molecular sieves were removed by filtration and the mixture was extracted with chloroform. An oily substance obtained by evaporation of the solvent, were first dried, and then subjected to column chromatography on 15 g of silica gel, was suirable a mixture of hexane/ethyl acetate (1:4 to 1:5) and received 82 mg (yield = 52%) of target compound (TRANS-isomer A) as an oily product. Then the obtained oily product was suirable with ethyl acetate - 5% methanol - ethyl acetate, which was obtained 28 mg (yield 15%) of the CIS isomer B in the form of a solid substance with so pl. 118 - 125oC.

NMR spectrum (270 MHz, CDCl3) million D.: (A) a 1.20 (3H, d, J = 7,3 Hz) to 3.34 (1H, q, J = 7,3 Hz), 3,43 (1H, TT, J = and 11.2, 4.6 Hz), the 3.65 (1H, t, J = 11.2 Hz), 3,68 (1H, t, J = 11.2 Hz), 4,33 (1H, m), 4,46 (1H, m), a 4.83 (1H, d, J = a 13.9 Hz), 5,04 (1H, C) 5,04 (1H, d, J = 13,9), 5,14 (1H, d, J = 4.0 Hz), and 6.25 (1H, DD, J = 16.5, and 4.0 Hz), 6,7 - 6,8 (2H, m), for 6.81 (1H, d, J = 16.5 Hz), 7,29 (1H, DD, J = 7,9, and 4.6 Hz), 7,3 was 7.45 (1H, m), 7,73 (1H, dt, J = 7,9, 1 Hz), 8,51 (1H, DD, J = 4,6, 1 Hz), to 8.62 (1H, d, J = 1 Hz); (B) to 1.22 (3H, d, J = 7,3 Hz), 3,13 (1H, Shir.C) a 3.50 (1H, q, J = 7,3 Hz), from 4.2 to 4.4 (4H, m), 4,88 (1H, d, J = a 13.9 Hz), 4,94 (1H, s) to 5.17 (1H, d, J = a 13.9 Hz), of 5.26 (1H, d, J = 4.6 Hz), of 6.31 (1H, DD, J = 16.5, and 4.6 Hz), 6,65 is 6.8 (2H, m), for 6.81 (1H, d, J = 16.5 Hz), 7,26 (1H, DD, J = 7,9, and 4.6 Hz), 7,74 (1H, TD, J arvanil)-3- [[TRANS-2-[(E)-2-[4-(trifluoromethyl) phenyl] vinyl]-1,3-dioxane-5-yl] thio]-1-(1H-1,2,4-triazole-1-yl)-2 - butanol

< / BR>
Reaction and treatment were carried out using the method described in example 4 using (2R,3R)-2-(2,4-differenl)-3- [(1,3 - dihydroxy-2-propyl)thio]- 1-(1H-1,2,4-triazole-1-yl)-2 - butanol and TRANS-4-(trifluoromethyl)cinnamaldehyde as described in comparative example 22, resulting in a received target compound as the main product (yield 62%). Physical and spectral data were consistent with the data of the compounds described in example 2.

Example 7

(2R, 3R)-2-(2,4-Differenl)-3-[[TRANS-2-[(E)-2-(4-forfinal) vinyl] -1,3-dioxane-5-yl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
Reaction and treatment were carried out by the method described in example 4 using (2R,3R)-2-(2,4-differenl)-3- [(1,3-dihydroxy-3-propyl)thio] - 1-(1H-1,2,4 - triazole-1-yl)-2 - butanol and TRANS-4-portenabled [Arch. Pharm. 316, 574 (1983), which received the target connection, namely the main product, in the form of an oily substance with a yield of 66%.

NMR spectrum (60 MHz, CDCl3) million D.: of 1.20 (3H, d, J = 7 Hz), 3,1 - 3,9 (4H, m), 4,1 - 4,6 (2H, m), 4,78 (1H, d, J = 14 Hz), 4,99 (1H, d, J = 1.5 Hz), is 5.06 (1H, d, J = 14 Hz), 5,09 (1H, d, J = 4 Hz), 6,07 (1H, DD, J = 16.4 Hz), 6,79 (1H, d, J = 16 Hz), 6.5 to about 7.6 (7H, m), 7,78 (2H, s).

The compound obtained was mixed with 1 equivalent of oxalic acid in ethyl acetate/hexane, financial p is R, 3R)-2-(2,4-Differenl)-3-[[(TRANS-2-[(E)-2-[2-fluoro-(4 - trifluoromethyl)phenyl]vinyl]-1,3-dioxane-5-yl]thio]-1-(1H-1,2,4 - triazole-1-yl)-2-butanol

< / BR>
Reaction and treatment were carried out by the method described in example 4 using (2R,3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio] -1- (1H-1,2,4-triazole-5-yl)-2-butanol and TRANS-2-fluoro-4-(trifluoromethyl) cinnamaldehyde, resulting in a received target connection, namely the main product, in the form of an oily substance with a yield of 66%.

Specific rotation []2D5= -72(c = 0,63, CHCl3).

NMR spectrum (270 MHz, CDCl3) million D.: of 1.20 (3H, d, J = 7,0 Hz) to 3.34 (1H, q, J = 7.0 Hz), 3,43 (1H, TT, J = 11,3, 4.6 Hz), the 3.65 (1H, t, J = 11.3 Hz), 3,68 (1H, t, J = 11.3 Hz), 4,34 (1H, m), 4,46 (1H, m), a 4.83 (1H, d, J = 14,0 Hz), 5,04 (d, J = 14,0 Hz), 5,04 (1H, d, J = 1.1 Hz), further 5.15 (1H, d, J = 4, 2 Hz), 6,36 (1H, DD, J = 16,3, 4,2 Hz), 6,7 - 6,8 (2H, m), 6,97 (1H, d, J = 16.0 Hz), 7,3 was 7.45 (3H, m), 7,58 (1H, t, J = 7,6 Hz), 7,79 (2H, s).

Example 9

(2R, 3R)-2-(2,4-differenl)-3-[[TRANS-2-[(E)-2-[4-(methylsulphonyl) phenyl]vinyl]-1,3-dioxane-5-yl]thio]-1-(1H-1,2,4-triazole-1-yl)- 2-butanol

< / BR>
Reaction and treatment were carried out using the method described in example 4 using (2R, 3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2 - propyl)thio] -1-(1H-1,2,4-triazole-1-yl)-2-butanol and TRANS-4-(methylsulphonyl)cinnamaldehyde, financial p

NMR spectrum (60 MHz, CDCl3+ D2O) million D.: of 1.20 (3H, d, J = 7 Hz), of 3.00 (3H, s) to 3.33 (1H, q, J = 7 Hz), 3.5 to 4.0 (3H, m), 4,2 - 4,8 (2H, m), 4,80 (1H, d, J = 14 Hz), to 5.08 (1H, d, J = 14 Hz), further 5.15 (1H, d, J = 4 Hz), 6,30 (1H, DD, J = is 17.4 Hz), make 6.90 (1H, d, J = 17 Hz), 6,55 - 7,0 (2H, m), 7,2 - 7,6 (1H, m), 7,58 (2H, d, J = 8 Hz), 7,80 (2H, s), 7,94 (2H, d, J = 8 Hz).

Example 10

(2R, 3R)-2-(2,4-Differenl)-3-[[TRANS-2-[(E)-2-(4-nitrophenyl) vinyl]-1,3-dioxane-5-yl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
Reaction and treatment were carried out by the method described in example 4 using (2R,3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio] -1- (1H-1,2,4-triazole-5-yl)-2-butanol and TRANS-4-nitrocinnamyl, resulting in a received target connection (the main product) in the form of an oily substance with a yield of 40%.

Specific rotation []2D5= -64,1(c = 2,43, CHCl3).

NMR spectrum (270 MHz, CDCl3) million D.: 1,19 (3H, d, J = 7,3 Hz), the 3.35 (1H, q, J = 7,3 Hz), 3,44 (1H, TT, J = 11.2 Hz, 4.6 Hz), 3,66 (1H, t, J = 11.2 Hz), 3,68 (1H, t, J = 11.2 Hz), 4,34 (1H, m), 4,46 (1H, m), a 4.83 (1H, d, J = a 13.9 Hz), 5,04 (1H, d, J = a 13.9 Hz), 5,04 (1H, s), 5,16 (1H, d, J = 4.0 Hz), 6,32 (1H, DD, J = 16.5 Hz, 4.0 Hz), 6,7 - 6,8 (2H, m), 6.87 in (1H, d, J = 16.5 Hz), was 7.36 (1H, m), 7,53 (2H, d, J = 8.6 Hz), 7,79 (1H, s), 7,80 (1H, s), 8,19 (2H, d, J = 8.6 Hz).

This compound was mixed with one equivalent of oxalic acid in a mixture of ethyl acetate/hexa 11

(2R, 3R)-2-(2,4-Differenl)-1- (1H-1,2,4-triazole-1-yl)-3- [[TRANS-2-[(E)-2-[4-(triptoreline) phenyl]vinyl]-1,3-dioxane-5-yl] thio]-2 - butanol

< / BR>
Reaction and treatment were carried out using the method described in example 4 using (2R,3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio]-1- (1H-1,2,4-triazole-5-yl)-2-butanol and TRANS-4-(triptoreline) cinnamaldehyde as described in comparative example 33, resulting in a received target connection, namely the main product, in the form of an oily substance with a yield of 43%.

Specific rotation []2D5= -77(c = 0,52, CHCl3).

NMR spectrum (270 MHz, CDCl3) million D.: of 1.20 (3H, d, J = 7,3 Hz) to 3.34 (1H, q, J = 2.3 Hz), 3,42 (1H, TT, J = 11.2 Hz, 4.6 Hz), the 3.65 (1H, t, J = 11.2 Hz), to 3.67 (1H, t, J = 11.2 Hz), 4,32 (1H, DDD, J = 11,2, 4,6, 2.0 Hz), of 4.45 (1H, DDD, J = 11,2, 4,6, 2.0 Hz), a 4.83 (1H, d, J = 14,5 Hz), free 5.01 (1H, s) of 5.03 (1H, d, J = 14,5 Hz), 5,12 (1H, d, J = 4.0 Hz), x 6.15 (1H, DD, J = 16.5 Hz, 4.0 Hz), 6,7 - 6,8 (2H, m), 6,79 (1H, d, J = 16.5 Hz), 7,17 (2H, d, J = 8.6 Hz), 7,3 was 7.45 (1H, m), 7,42 (2H, d, J = 8.6 Hz), 7,79 (2H, s).

Example 12

(2R, 3R)-3-[[TRANS-2-[(E)-2-[4-cyanophenyl)vinyl] -1,3 - dioxane-5-yl]thio] -2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)- 2-butanol

< / BR>
Reaction and treatment were carried out using the method described in example 4 using (2R,3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio]-1- (1H-1,2,4-the first connection (the main product) in the form of an oily substance with a yield of 66%.

Specific rotation []2D5= -78(c = 0,52, CHCl3).

NMR spectrum (270 MHz, CDCl3) million D.: of 1.20 (3H, d, J = 7,0 Hz) to 3.34 (1H, Shir.kV, J = 7,0 Hz), 3,43 (1H, TT, J = 11.3 Hz, 4.8 Hz), the 3.65 (1H, t, J = 11.3 Hz), to 3.67 (1H, t, J = 11.3 Hz), 4,33 (1H, m), 4,46 (1H, m), a 4.83 (1H, d, J = 14,2 Hz), to 5.03 (1H, d, J = 1.2 Hz), 5,04 (1H, d, J = 14,2 Hz), 5,14 (1H, d, J = 4,1 Hz), 6,28 (1H, DD, J = 16.1 Hz, 4,1 Hz), 6,7 - 6,8 (2H, m), PC 6.82 (1H, d, J = 16.1 Hz), was 7.36 (1H, m), 7,49 (2H, d, J = 8,3 Hz), a 7.62 (2H, d, J = 8,3 Hz), 7,79 (2H, s).

This compound was mixed with one equivalent of oxalic acid in ethyl acetate/hexane, resulting in getting salt of oxalic acid in the form of crystals, so pl. 164 - 165oC.

Example 13

(2R,3R)-2-(2,4-Differenl)-3-[[TRANS-2-[(E)-2-methyl-2- [4-(trifluoromethyl)phenyl] vinyl] -1,3-dioxane-5-yl] thio]-1-(1H-1,2,4 - triazole-1-yl)-2-butanol

< / BR>
Reaction and treatment were carried out by the method described in example 4 using (2R,3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio] -1- (1H-1,2,4-triazole-1-yl)-2-butanol and TRANS--methyl-4-(trifluoromethyl) cinnamaldehyde, resulting in a received target connection (the main product) in the form of an oily substance with a yield of 73%.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.20 (3H, d, J = 7,1 Hz) of 2.16 (3H, s) to 3.36 (1H, square, J = 7,1 Hz) to 3.41 (1H, TT, J = 11.3 Hz, 4.6 Hz), 3,66 (1H, t, J = 11.3 Hz), 3,68 (1H, tn, m), 7,3 was 7.45 (1H, m), 7,51 (2H, d, J = 8,3 Hz), to 7.59 (2H, d, J = 8,3 Hz), 7,79 (2H, s).

Example 14

(2R, 3R)-3-[[TRANS-2-[(E)-2-(5-chloro-2-thienyl)vinyl] - 1,3-dioxane-5-yl] thio]-2-(2,4-differenl)-1-(1H-1,2,4 - triazole-1-yl)-2-butanol

< / BR>
Reaction and treatment were carried out by the method described in example 4 using (2R,3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio] -1- (1H-1,2,4-triazole-5-yl)-2-butanol and TRANS--(5-chloro-2-thienyl) acrolein [Chem. Abst. 51 1284h (1941)], resulting in the obtained target compound in the form of an oily substance with a yield of 50%.

Specific rotation []2D5= -75,7(c = 0,56, CHCl3).

NMR spectrum (270 MHz, CDCl3) million D.: 1,19 (3H, d, J = 7,3 Hz) to 3.33 (1H, square , J = 7,3 Hz), 3,40 (1H, TT, J = and 11.2, 4.6 Hz), 3,62 (1H, t, J = 11.2 Hz), to 3.64 (1H, t, J = 11.2 Hz), 4,36 (1H, m), 4,42 (1H, m), 4,82 (1H, d, J = 13,8 Hz), 5,02 (1H, Shir.C.), to 5.03 (1H, d, J = 13,8 Hz), is 5.06 (1H, d, J = 4.6 Hz), 5,88 (1H, DD, J = 15,8, 4.6 Hz), 6,7 - 6,85 (3H, m), 6,78 (2H, s), of 7.36 (1H, m), 7,87 (2H, s).

This compound was mixed with 1 equivalent of oxalic acid in ethyl acetate/hexane, resulting in getting salt of oxalic acid in the form of crystals with so pl. 53 - 57oC.

Example 15

(2R, 3R)-2-(2,4-Differenl)- 1-(1H-1,2,4-triazole-1-yl)-3- [[TRANS-2-[(1E, 3E)-4- [4-(trifluoromethyl)phenyl]- 1,3-butadiene-1 - yl]- 1,3-dioxane-5-yl] thio]-2 - butanol

Specific rotation []2D5= -69,8(c = 1.00, it CHCl3).

NMR spectrum (270 MHz, CDCl3) million D.: 1,19 (3H, d, J = 7,3 Hz) to 3.33 (1H, square, J = 7,3 Hz), 3,40 (1H, TT, J = 11.2 Hz, 4.6 Hz), 3,62 (1H, t, J = 11.2 Hz), to 3.64 (1H, t, J = 11.2 Hz), 4,30 (1H, m), 4,42 (1H, m), 4,82 (1H, d, J = a 13.9 Hz), free 5.01 (1H, s), to 5.03 (1H, d, J = a 13.9 Hz), is 5.06 (1H, d, J = 4.6 Hz), of 5.84 (1H, DD, J = 15,2, 4.6 Hz), 6,60 (1H, d, J = 15,2, a 10.6 Hz), was 6.73 (1H, d, J = 15,8 Hz), 6,7 - 6,8 (2H, m), 6,85 (1H, DD, J = 15,8, a 10.6 Hz), 7,3 was 7.45 (1H, m), 7,49 (2H, d, J = 8.6 Hz), 7,56 (2H, d, J = 8.6 Hz), 7,78 (2H, s).

Example 16

(2R, 3R)-2-(2,4-Differenl)-3-[[TRANS-2-[(1E, 3E)-4-[4- (2,2,3,3-tetrafluoropropoxy)phenyl] -1,3-butadiene-1-yl] - 1,3-dioxane-5-yl] thio] -1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
Reaction and treatment were carried out using the method described in example 4 using (2R,3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio]-1- (1H-1,2,4-triazole-5-yl)-2-butanol and (2E, 4E)-5-[4-(2,2,3,3-tetrafluoropropoxy)phenyl] -2,4-pentadienyl described in comparative example 32, resulting in a received target connection, with so pl. 75 - 85oC (crystallization from a mixture of hexane/ether), and represents the city of Jerusalem. (c = 0,56, CHCl3).

NMR spectrum (270 MHz, CDCl3) million D.: of 1.18 (3H, d, J = 7,0 Hz) to 3.33 (1H, q, J = 7.0 Hz), 3,39 (1H, TT, J = 11,3, 4,8 Hz), 3,62 (1H, t, J = 11.3 Hz), to 3.64 (1H, t, J = 11.3 Hz), 4,30 (1H, m), 4,35 (2H, Shir.T., J = 11.8 Hz), to 4.41 (1H, m), 4,82 (1H, d, J = 14.1 Hz), 4,99 (1H, d, J = 1.6 Hz), to 5.03 (1H, d, J = 14.1 Hz), 5,04 (1H, d, J = 4.6 Hz), of 5.75 (1H, DD, J = 15,7, 4.6 Hz), the 6.06 (1H, TT, J = 53,0, 5,1 Hz), 6,56 (1H, DD, J = 15,7, 10,2 Hz), to 6.57 (1H, d, J = 15,0 Hz), of 6.68 (1H, DD, J = 15,0, 10,2 Hz), 6,7 - 6,8 (2H, m), to 6.88 (2H, d, J = 8.7 Hz), 7.3 to 7.4 (1H, m), 7,37 (2H, d, J = 7.8 Hz), 7,79 (2H, s).

Example 17

(2R, 3R)-3-[[TRANS-2- [(1E,3E)-4-(6-chloro-3-pyridyl)- 1,3-butadiene-1-yl]- 1,3-dioxane-5-yl] thio] - 2-(2,4-differenl)-1- (1H-1,2,4-triazole-1-yl)-2 - butanol

< / BR>
Reaction and treatment were carried out using the method described in example 4 using (2R,3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio]-1- (1H-1,2,4-triazole-5-yl)-2-butanol and (2E,4E)-5-(6-chloro-3-pyridyl)-2,4-pentadienyl described in comparative example 38, the result has been the target compound (melting point = 88 - 90oC), namely the main product, in the form of a crystalline solid with the yield amounting to 69%.

Specific rotation []2D5= -74(c = 0,59, CHCl3).

NMR spectrum (270 MHz, CDCl3) million D.: 1,19 (3H, d, J = 7,1 Hz) to 3.33 (1H, q, J = 7,1 Hz), 3,40 (1H, TT, J = 11,3, a 4.7 Hz), 3,62 (1H, t, J = 11.3 Hz), to 3.64 (1H, d, J = 15,5 Hz), to 6.58 (1H, DD, J = 15,1, 10.5 Hz), 6,7 - 6,8 (2H, m), to 6.80 (1H, DD, J = 15,5, 10.5 Hz), 7,28 (1H, d, J = 8,3 Hz), 7.3 to 7.4 (1H, m), of 7.70 (1H, DD, J = 8,3, 2,5 Hz), 7,79 (2H, s) of 8.37 (1H, d, J = 2.5 Hz).

Example 18

(2R, 3R)-2-(2,4-Differenl)- 3-[[TRANS-2-[(1E, 3Z)-4-(4-chlorophenyl)-5,5,5-Cryptor-1,3-pentadien - 1-yl] -1,3-dioxane-5-yl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
Reaction and treatment were carried out using the method described in example 4 using (2R,3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio]-1- (1H-1,2,4-triazole-5-yl)-2-butanol and (2E, 4Z)-5-(4-chlorophenyl)-6,6,6-Cryptor-2,4-hexadienal described in comparative example 52, resulting in a received target connection (main product) in the form of oily substance with a yield = 31%.

Specific rotation []2D5= -59,4(c = 0,90, CHCl3).

NMR spectrum (270 MHz, CDCl3) million D.: 1,19 (3H, d, J = 7,3 Hz) to 3.33 (1H, Shir.kV., J = 7,3 Hz), 3,40 (1H, TT, J = and 11.2, 4.6 Hz), 3,61 (1H, t, J = 11.2 Hz), to 3.64 (1H, t, J = 11.2 Hz), or 4.31 (1H, m), 4,43 (1H, m), 4,82 (1H, d, J = a 13.9 Hz), 5,02 (1H, s) of 5.03 (1H, d, J = a 13.9 Hz), 5,09 (1H, d, J = 4,6 Hz), 5,96 (1H, DD, J = 15,2, 4.6 Hz), 6,50 (1H, d, J = 11,9 Hz), 6,7 - 6,8 (2H, m), 6,9 - 7,1 (1H, m), 7,25 to 7.4 (5H, m), 7,79 (2H, s).

Example 19

(2R, 3R)-2-(2,4-Differenl)-3-[[TRANS-2-[(1E, 3E)- 2-methyl-4-[4-(trifluoromethyl)phenyl] -1,3-butadiene-1-yl] -1,3 - dioxane-5-yl] thio] -1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>

Specific rotation []2D5= -68(c = 0,50, CHCl3).

NMR spectrum (270 MHz, CDCl3) million D.: of 1.27 (3H, d, J = 7,1 Hz) to 1.99 (3H, s) to 3.34 (1H, q, J = 7,1 Hz), 3,39 (1H, TT, J = 11,3, 4,8 Hz) to 3.64 (1H, t, J = 11.3 Hz), 3,66 (1H, t, J = 11.3 Hz), 4,30 (1H, m) to 4.41 (1H, m), a 4.83 (1H, d, J = 14.1 Hz), free 5.01 (1H, s), 5,04 (1H, d, J = 14.1 Hz), 5,32 (1H, d, J = 6.2 Hz), to 5.66 (1H, d, J = 6.2 Hz), of 6.66 (1H, d, J = 16.1 Hz), 6,7 - 6,8 (2H, m) 6,86 (1H, d, J = 16.1 Hz), 7.3 to 7.4 (1H, m), 7,51 (2H, d, J = 8,4 Hz), EUR 7.57 (2H, d, J = 8,4 Hz), 7,78 (2H, s).

Example 20

(2R, 3R)-2-(2,4-Differenl)-3-[[TRANS-2-[(1E, 3E)- 3-methyl-4-[4-(trifluoromethyl)phenyl] -1,3-butadiene-1-yl] -1,3 - dioxane-5-yl] thio] -1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
Reaction and treatment were carried out using the method described in example 4 using (2R,3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio]-1- (1H-1,2,4-triazole-5-yl)-2-butanol and (2E,4E)-4-methyl-5-[4-(trifluoromethyl)phenyl] -2,4-pentadienyl, resulting in a received target connection (main product) in the form of an oily substance with a yield of 69%.

Specific rotation []2D5= -63,4(c = 1.07, and CHCl3).

NMR spectrum (270 MHz, CDCl3) million days: 1, ,83 (1H, d, J = 14,2 Hz), free 5.01 (1H, s), 5,04 (1H, d, J = 14,2 Hz), 5,09 (1H, d, J = 4.6 Hz), of 5.81 (1H, DD, J = 16,0, 4.6 Hz), 6,60 (1H, s), 6,63 (1H, d, J = 16.0 Hz), 6,7 - 6,8 (2H, m), 7.3 to 7.4 (1H, m), 7,38 (2H, d, J = 8,2 Hz), to 7.59 (2H, d, J = 8,2 Hz), 7,79 (2H, s).

Example 21

(2R, 3R)-2-(2,4-Differenl)-3-[[1-[((E)-4-(triptoreline) cynnamoyl] piperidine-4-yl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
Method A:

To a mixture containing 150 mg (0,340 mmol) dihydrochloride (2R,3R)-2-(2,4-differenl)-3-(1H-1,2,4-triazole-1-yl)-3- [(piperidine-4-yl)thio] -2-butanol as described in comparative example 14, and 3 ml of dichloromethane, was added 142 μl (1,02 mmol) of triethylamine at a temperature of 0oC in nitrogen atmosphere and after 5 minutes was added 128 mg (0,510 mmol) of (E)-4-(triptoreline)cinnamonitrile. The resulting mixture was stirred at the same temperature for 30 minutes and after removal of the solvent to the thus obtained residue was added ethyl acetate, and the mixture is then washed with an aqueous solution of sodium chloride. After removal of the solvent the residue was subjected to column chromatography on silica gel, was suirable with ethyl acetate and received 160 mg (yield 81%) of target compound as a colourless foam.

NMR spectrum (270 MHz, CDCl3) million D.: 1,19 (3H, d, J = 7,0 Hz), 1,6 - 1,8 (2H, m), 2,0 - 2,1 (2H, m), to 3.0 - 3.2 (2H, m) to 3.35 (1H, square, J = 7,0 Hz), the 3.2 and 3.4 (1H, m), 4,0 - 4,1 (1H, m), 4,, Is, J = 8.5 Hz), the 7.65 (1H, d, J = 15,5 Hz), 7,78 (2H, s), 7,82 (1H, s).

The IR spectrummax(KBr), cm-1: 3421, 1695, 1686, 1617, 1591.

Mass spectrum m/e: 582, 563, 522, 500, 427, 359, 299, 258, 215, 187, 144, 101, 82.

Method B:

In 4 ml of dimethylformamide was dissolved 327 mg (0,875 mmol) 4-(acetylthio)-1-[(E)-4-(triptoreline)cynnamoyl] piperidine described in comparative example 16, and 200 ml (coefficient was 0.796 mmol) of (2R,3S)-2-(2,4-differenl)-3-methyl-2-[(1H-1,2,4-triazole-1-yl) methyl] oxirane, and then to the mixture was added 129 μl (0,613 mmol) of 28% solution of sodium methylate in methanol under nitrogen atmosphere and the resulting mixture was stirred for 3 hours at a temperature of 50oC. After cooling, the reaction mixture was diluted with ethyl acetate, and then washed with water and saturated aqueous sodium chloride.

After evaporation of the solvent the oily substance was subjected to column chromatography on silica gel and was suirable with ethyl acetate, resulting in a received 275 mg (yield 59%) of compound as a colourless foam. The compound obtained is identical with the connection method A, as evidenced by NMR, IR and MS spectra.

Example 22

(2R,3R)-2-(2,4-Differenl)-3-[[1-[((E)-4-methylcinnamic) piperidine-4-yl] thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
Connected the s 21 (method A).

NMR spectrum (270 MHz, CDCl3) million D.: 1,19 (3H, d, J = 7,0 Hz), 1,6 - 1,8 (2H, m), of 2.0 - 2.2 (2H, m), is 2.37 (3H, s), to 3.0 - 3.2 (2H, m), the 3.2 and 3.4 (1H, m) to 3.35 (1H, square, J = 7,0 Hz), 4,0 - 4,2 (1H, m), 4,4 - 4,6 (1H, m), a 4.83 (1H, d, J = a 13.9 Hz), 4,84 (1H, s), 5,09 (1H, d, J = a 13.9 Hz), 6,7 - 6,8 (2H, m), 6,85 (1H, d, J = 15,5 Hz), 7,18 (2H, d, J = 8,3 Hz), 7.3 to 7.4 (1H, m), the 7.43 (2H, d, J = 8,3 Hz), the 7.65 (1H, d, J = 15,5 Hz), to 7.77 (1H, s), 7,82 (1H, s).

The IR spectrummax(KBr) cm-1: 3333, 1645, 1599.

Mass spectrum m/e: 512, 510, 452, 430, 425, 367, 357, 289, 229, 224, 188, 145, 117, 82.

Example 23

(2R,3R)-2-(2,4-Differenl)-3-[[1-[((E)-4-nitrocinnamyl) piperidine-4-yl] thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
The connection in the form of a slightly yellowish foam was obtained from (E)-4-nitrocinnamyl method (method A) described in example 21.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.26 (3H, d, J = 6.6 Hz), 1,6 - 1,9 (2H, m), to 2.1 - 2.3 (2H, m), 3,1 - 3,3 (2H, m), 3,3 - 3,5 (1H, m), 3,42 (1H, square, J = 6.6 Hz), 4,0 - 4,2 (1H, m), 4,4 - 4,6 (1H, m), 4,89 (1H, d, J = a 13.9 Hz), to 4.92 (1H, s), further 5.15 (1H, d, J = a 13.9 Hz), 6,7 - 6,9 (2H, m), 7,10 (1H, d, J = 15,5 Hz), between 7.4 to 7.5 (1H, m), 7,73 (2H, d, J = 8,9 Hz), of 7.75 (1H, d, J = 15,5 Hz), 7,86 (2H, d, J = 8,9 Hz), 8,29 (1H, s), 8,32 (1H, s).

The IR spectrum max(KBr) cm-1: 3361, 1649, 1612, 1518, 1345.

Mass spectrum m/e: 544, 525, 513, 483, 461, 388, 365, 284, 260, 224, 219, 176, 144, 130, 82.

Example 24

(2R, 3R)-2-(2,4-Differenl)-1- (1H-1,2,4-triazole-1-yl)-3- [[1-(2E,4E)-5-[4-(triptoreline)phenyl]-2,4-Penta is reformatory)phenyl] -2,4-pentadienoic method (method A), described in example 21.

NMR spectrum (270 MHz, CDCl3) million D.: 1,19 (3H, d, J = 6.6 Hz), 1,5 - 1,8 (2H, m), of 2.0 - 2.2 (2H, m), of 3.0 to 3.3 (3H, m) to 3.34 (1H, square, J = 6.6 Hz), 3,9 - 4,1 (1H, m), 4,3 - 4,5 (1H, m), a 4.83 (1H, d, J = a 13.9 Hz), 4,82 (1H, s) 5,08 (1H, d, J = a 13.9 Hz), 6,50 (1H, d, J = 14,5 Hz), 6,7 - 6,8 (2H, m), 6.8 or 6.9 (2H, m), 7,20 (2H, d, J = 8,9 Hz), 7,3 - 7,5 (2H, m), 7,47 (2H, d, J = 8,9 Hz), 7,78 (1H, s), 7,82 (1H, s).

The IR spectrummax(KBr) cm-1: 3395, 1639, 1616, 1596.

Mass spectrum m/e: 608, 589, 548, 526, 453, 433, 385, 325, 241, 224, 213, 144, 127, 82.

Example 25

(2R, 3R)-2-(2,4-Differenl)-1- (1H-1,2,4-triazole-1-yl)-3- [[1-[((E)-3-(pyridin-4-yl)-acryloyl]piperidine-4-yl]thio]-2-butanol

< / BR>
Compound as a colorless foam was obtained from 4-acetylthio-1-[(E)-3-(pyridin-4-yl)-acryloyl] piperidine (method B) described in example 21.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.20 (3H, d, J = 6.6 Hz), 1,6 - 1,8 (2H, m), of 2.0 - 2.2 (2H, m), to 3.0 - 3.2 (2H, m) to 3.35 (1H, square, J = 6.6 Hz), the 3.2 and 3.4 (1H, m), 3,9 - 4,1 (1H, m), 4,3 - 4,5 (1H, m), a 4.83 (1H, d, J = 14,5 Hz), a 4.86 (1H, s), 5,09 (1H, d, J = 14,5 Hz), 6,7 - 7,8 (2H, m), 7,06 (1H, d, J = 15.2 Hz), 7.3 to 7.4 (1H, m), 7,37 (2H, d, J = 5,9 Hz), EUR 7.57 (1H, d, J = 15.2 Hz), 7,78 (1H, s), 7,81 (1H, s) 8,64 (2H, d, J = 5,9 Hz).

The IR spectrum max(KBr) cm-1: 3420, 1651, 1615, 1598.

Mass spectrum m/e: 499, 439, 417, 410, 365, 344, 307, 275, 247, 216, 144, 132, 104, 82.

Example 26

(2R,3R)-2-(2,4-Differenl)-3-[[1-[((E)-4-(triptoreline) cynnamoyl]AZE is R,3R)-2-(2,4-differenl)-1- (1H-1,2,4-triazole-1-yl)-3- [(azetidin-3-yl)thio] -2 - butanedisulfonate method (method A), described in example 21.

NMR spectrum (270 MHz, CDCl3) million D.: 1,17 (3H, d, J = 7,1 Hz), 3,32 (1H, square, J = 7,1 Hz), 4,0 - 4,3 (3H, m), 4,5 - 4,6 (1H, m), 4,6 - 4,7 (1H, m), a 4.86 (1H, d, J = 14,2 Hz), of 5.05 (1H, d, J = 14,2 Hz), 5,09 (1H, s), to 6.43 (1H, d, J = 15.7 Hz), 6,7 - 6,8 (2H, m), 7,22 (2H, d, J = 8,2 Hz), 7.3 to 7.4 (1H, m), 7,56 (2H, d, J = 8,2 Hz), the 7.65 (1H, d, J = 15.7 Hz), 7,79 (1H, s), 7,81 (1H, s).

The IR spectrum max(KBr) cm-1: 3376, 1656.

Mass spectrum m/e: 554, 535, 472, 384, 331, 271, 224, 215, 187, 127, 87.

Example 27

(2R, 3R)-2-(2,4-Differenl)-3-[[TRANS-2-[(1E,3E)-4- (2,4-differenl)-1,3-butadiene-1-yl] -1,3-dioxane-5-yl] thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
The reaction was carried out as described in example 4 using (2R, 3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2 - propyl)thio] -1-(1H-1,2,4-triazole-5-yl)-2-butanol and (2E, 4E)-5-(2,4-differenl)-2,4-pentadienyl, resulting in a received target connection, namely the main product, in the form of oily substance with a yield = 61%.

Specific rotation []2D5= -79,1(c = 1.04 million, CHCl3).

NMR spectrum (270 MHz, CDCl3) million D.: of 1.18 (3H, d, J = 7,0 Hz) to 3.33 (1H, q, J = 7.0 Hz), 3,39 (1H, TT, J = 11.3 Hz, 4.6 Hz), 3,62 (1H, t, J = 11.3 Hz), to 3.64 (1H, t, J = 11.3 Hz), 4,30 (1H, m) to 4.41 (1H, m), 4,82 (1H, d, J = 14,0 Hz), 5,00 (1H, s), to 5.03 (1H, d, J = 14,0 Hz), of 5.05 (1H, d, J= 4.6 Hz), 5,79 (1H, DD, J = 15,2, 4.6 Hz), to 6.58 (1H, DD, J = 15,2, 9.5 Hz), 6,65 - 6,9 (6) - Rev. XI)-3-pyridyl] -1,3-butadiene-1-yl] 1,3-dioxane-5-yl] thio]-1-(1H-1,2,4-triazole-5-yl)-2-butanol

< / BR>
In 11 ml of methylene chloride was dissolved 404 mg (1.12 mmol) of (2R,3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio] - 1-(1H-1,2,4-triazole-1-yl)-2-butanol and 501 mg (1,73 mmol) (2E,4E)-5-[6-(2,2,3,3-tetrafluoropropoxy)-3-pyridyl] -2,4-pentadienyl described in comparative example 37, and to the resulting solution was added 320 mg (1,68 mmol) paratoluenesulfonyl acid monohydrate and 4 g of molecular sieves 4, after which the mixture was stirred for one hour at room temperature. The reaction mixture was poured into 20 ml of 3% aqueous solution of sodium bicarbonate under ice cooling and the mixture was stirred for five minutes. After that, the molecular sieves were removed by filtration and the organic layer was collected into fractions were dried and the solvent evaporated under reduced pressure. 908 mg of the thus obtained oily substance was subjected to column chromatography on 19 g of silica gel and was suirable hexane/ethyl acetate (1:1), resulting in a received 448 mg (yield 63%) of target compound in the form of an oily product.

Specific rotation []2D5= -58,6(c = 0,52, CHCl3).

NMR spectrum (270 MHz, CDCl3) million D.: 1,19 (3H, d, J = 7,0 Hz) to 3.33 (1H, q, J = 7.0 Hz), 3,39 (1H, TT, J = 11.2 Hz, 4.8 Hz), 3,62 (1H, t, J = 11.2 Hz), to 3.64 (1H, d, J = a 13.9 Hz), of 5.05 (1H, d, J = 4.5 Hz), 5,78 (1H, d, J = 15,5, and 4.5 Hz), 6,01 (1H, TT, J = 53,1, 4.6 Hz), 6,51 - 6,62 (2H, m), 6,65 - of 6.78 (3H, m), for 6.81 (1H, d, J = 8.6 Hz), 7,35 (1H, m), 7,74 (1H, DD, J = 8.6 Hz, 2.3 Hz), 7,79 (2H, s), 8,11 (1H, d, J = 2.3 Hz).

Example 29

(2R, 3R)-2-(2,4-Differenl)-3- [(TRANS-2-[(1E, 3E)-1-methyl - 4-[4-(trifluoromethyl)phenyl] - 1,3-butadiene-1-yl] - 1,3-dioxane-5-yl]thio]- 1-(1H-1,2,4-triazole-1-yl)- 2-butanol

< / BR>
The reaction was carried out as described in example 4 using (2R, 3R)-2-(2,4-diphenyl)-3-[(1,3-dihydroxy-2-propyl) thio]-1-(1H-1,2,4-triazole-5-yl)-2-butanol and (2E,4E)-2-methyl-5-[4-(trifluoromethyl) phenyl]-2,4-pentadienyl, resulting in a received target connection (main product) in the form of oily substance with a yield = 31%.

NMR spectrum (270 MHz, CDCl3) million D.: 1,19 (3H, d, J = 7,3 Hz), was 1.94 (3H, c) to 3.34 (1H, q, J = 7,3 Hz), 3,39 (1H, TT, J = and 11.2, 4.6 Hz), to 3.36 (1H, t, J = 11.2 Hz), the 3.65 (1H, t, J = 11.2 Hz), 4,33 (1H, m), of 4.44 (1H, m), a 4.83 (1H, d, J = a 13.9 Hz), 4,89 (1H, s), 5,02 (1H, s), 5,04 (1H, d, J = a 13.9 Hz), 6,41 (1H, d, J = 11.2 Hz), 6,62 (1H, d, J = 15,8 Hz), 6,7 - 6,8 (2H, m), to 7.09 (1H, DD, J = 15,8, 11.2 Hz), was 7.36 (1H, m) to 7.50 (2H, d, J = 8.6 Hz), 7,56 (2H, d, J = 8.6 Hz), 7,79 (1H, s), 7,80 (1H, s).

Example 30

(RS)-3-Methyl-1-(1H - 1,2,4-triazole-1-yl)-2-[(4-(trifluoromethyl)phenyl] -3-[[TRANS-2-[(E)-2- [4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxane-5-yl]thio]-2-butanol

< / BR>
The reaction was carried out as described in example 4, using (RS)sustained fashion example 55, and TRANS-4-(trifluoromethyl)cinnamaldehyde described in comparative example 22, resulting in a received target compound as a colourless foam.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.36 (3H, s) to 1.37 (3H, s), of 3.5 - 3.7 (3H, m), 4,2 - 4,3 (1H, m), 4,4 - 4,5 (1H, m), 5,02 (2H, s), 5,11 (1H, d, J = 4,1 Hz), 5,44 (1H, s), and 6.25 (1H, DD, J = 16,2, 4,1 Hz), at 6.84 (1H, d, J = 16.2 Hz), between 7.4 to 7.6 (8H, m), of 7.70 (1H, s), to 7.93 (1H, s).

The IR spectrummax(KBr) cm-1: 3404, 1618, 1508, 1328.

Mass spectrum m/e: 587, 568, 331, 298, 256, 201, 159, 131.

Example 31

(RS)-3-Methyl-1-(1H-1,2,4-triazole-1-yl)-2-[4-(trifluoromethyl) phenyl] -3-[[TRANS-2-[(1E, 3E)-4-[(trifluoromethyl)phenyl] -1,3-butadiene-1-yl] - 1,3-dioxane-5-yl]thio]-2-butanol

< / BR>
The reaction was carried out as described in example 4, using (RS)-3-[(1,3-dihydroxy-2-propyl)thio] -3-methyl-2-[4-trifluoromethyl) phenyl]-1-(1H-1,2,4-triazole-1-yl)-2-butanol as described in comparative example 55, and (2E, 4E)-5-[4-(trifluoromethyl)phenyl] -2,4 - pentadienyl described in comparative example 25, the result has been the target connection, namely the main product in the form of a colorless foam.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.36 (3H, s) to 1.37 (3H, s), 3,4 - 3,7 (3H, m), 4,2 - 4,3 (1H, m), 4,4 - 4,5 (1H, m), free 5.01 (2H, s), 5,02 (1H, d, J = 4.3 Hz), of 5.39 (1H, s), of 5.83 (1H, DD, J = 15,2, a 4.3 Hz), 6,59 (1H, DD, J = 15,2, to 10.7 Hz), 6,63 (1H, d, J = 15,8 Hz), 6,85 (1H, DD,ptx2">

Mass spectrum m/e: 614, 541, 494, 478, 406, 348, 256, 211.

Example 32

(2R, 3R)-2-(2,4-Differenl)-1- (1H-1,2,4-triazole-1-yl)-3- [[TRANS-2-[(1E, 3E)-4-[4- (triptoreline)phenyl]- 1,3-butadiene-1-yl]- 1,3-dioxane-5-yl]thio]-2-butanol

< / BR>
The reaction was carried out by a method similar to that described in example 4 using (2R,3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio] -1- (1H-1,2,4-triazole-5-yl)-2-butanol and (2E,4E)-5-[4-(triptoreline)phenyl]-2,4-pentadienyl, resulting in a received target connection (the main product) in the form of a colorless foam.

NMR spectrum (270 MHz, CDCl3) million D.: 1,19 (3H, d, J = 7,1 Hz), 3,3 - 3,5 (2H, m), 3,62 (1H, t, J = 11,4 Hz) to 3.64 (1H, t, J = 11,4 Hz), or 4.31 (1H, DDD, J = 11,4, 4,7, 2,1 Hz), 4,42 (1H, DDD, J = 11,4, 4,7, 2,1 Hz), a 4.83 (1H, d, J = 14.1 Hz), free 5.01 (1H, s), to 5.03 (1H, d, J = 14.1 Hz), is 5.06 (1H, d, J = 4.5 Hz), of 5.83 (1H, DD, J = 15,7, and 4.5 Hz), 6,60 (1H, DD, J = 15,7, 10,3 Hz), 6,62 (1H, d, J = 15.7 Hz), 6,7 - 7,8 (2H, m), at 6.84 (1H, DD, J = 15,7, 10,3 Hz), 7.3 to 7.4 (1H, m), 7,44 (2H, d, J = 8,3 Hz), 7,60 (2H, d, J = 8,3 Hz), 7,79 (2H, s).

The IR spectrummax(KBr) cm-1: 3389, 1621, 1680, 1621, 1501, 1117.

Mass spectrum m/e: 599, 580, 557, 530, 500, 438, 338, 376, 346, 284, 258, 224, 183.

Example 33

(2R*, 3R*)-3-[[TRANS-2-([1E, 3E)-4-[4-(2,2,3,3- tetrafluoropropoxy)phenyl] -1,3-butadiene-1-yl] -1,3-dioxane-5-yl]thio]-1- (1H-1,2,4-triazole-1-yl)-2-[4-(trifluoromethyl)phenyl]-2-butanol

< / BR>
The reaction Provo is-triazole-5-yl)-2-[4-(trifluoromethyl)phenyl] -2-butanol and (2E,4E)-5-[4-(2,2,3,3-cryptocracy)phenyl] -2,4-pentadienyl, described in comparative example 32, resulting in the obtained target compound (the main product) in the form of an oily substance.

NMR spectrum (270 MHz, CDCl3) million D.: 1,22 (3H, d, J = 6.6 Hz), and 3.16 (3H, q, J = 6.6 Hz), 3,34 (1H, TT, J = and 11.2, 4.6 Hz), to 3.58 (1H, t, J = 11.2 Hz), 3,61 (1H, t, J = 11.2 Hz), 4,27 (1H, m), 4,35 (2H, Shir.T., J = 11,9 Hz), 4,39 (1H, m), of 4.57 (2H, d, J = a 13.9 Hz), of 4.77 (1H, s), 5,02 (1H, d, J = 4.6 Hz), to 5.03 (1H, d, J = a 13.9 Hz), 5,72 (1H, DD, J = 15,8, 4.6 Hz), equal to 6.05 (1H, TT, J = 52,8 that 5.3 Hz), 6.5 to 6.75 (3H, m), to 6.88 (2H, d, J = 8.6 Hz), was 7.36 (2H, d, J = 8.6 Hz), 7,39 (2H, d, J = 8.6 Hz), 7,54 (2H, d, J = 8.6 Hz), 7,71 (1H, s), 7,83 (1H, s).

Example 34

(2R*, 3R*)-1-(1H-1,2,4-Triazole-1-yl)-2-[4- (trifluoromethyl)phenyl] -3-[[TRANS-2-([1E, 3E)-4-[4-(trifluoromethyl)phenyl] - 1,3-butadiene-1-yl]-1,3-dioxane-5-yl]thio]-2-butanol

< / BR>
The reaction was carried out in the manner described in example 1 using (2R*, 3R*)-3-methyl-2- [(1H-1,2,4-triazole-1-yl)methyl] oxirane and TRANS-5-(acetylthio)-2- [(1E, 3E)-4-[4-(trifluoromethyl)phenyl]-1,3-butadiene-1-yl]-1,3-dioxane, resulting in the obtained target compound in the form of an oily substance with 71% yield.

NMR spectrum (270 MHz, CDCl3) million D.: 1,22 (3H, d, J = 7,0 Hz), 3,17 (1H, q, J = 7.0 Hz), to 3.36 (1H, TT, J = 11,3, 4,7 Hz) and 3.59 (1H, t, J = 11.3 Hz), 3,62 (1H, t, J = 11.3 Hz), 4,27 (1H, DDD, J = 11,3, 4,7, 2.2 Hz), 4,39 (2H, DDD, J = 11,3, 4,7, 2.2 Hz), of 4.57 (1H, d, J = 14,0 Hz), 4,80 (1H, s) of 5.03 (1H, d, J = 14,0 Hz), 57,49 (2H, d, J = 8,3 Hz), 7,54 (2H, d, J = 8,3 Hz), EUR 7.57 (2H, d, J = 8,4 Hz), 7,71 (1H, s), 7,83 (1H, s).

Example 35

(2R,3R)-2-(2,4-Differenl)-1- (1H-1,2,4-triazole-1-yl)-3-[[TRANS-2-([1E, 3E)-4-[4- (trifloromethyl)phenyl]-1,3-butadiene-1-yl]-1,3-dioxane-5-yl] thio]- 2-butanol

< / BR>
The reaction was carried out as described in example 4 using (2R, 3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio] -1- (1H-1,2,4-triazole-5-yl)-2-butanol and (2E, 4E)-5-[4-(trifloromethyl)phenyl] -2,4-pentadienyl, resulting in the target connection, namely the main product, in the form of a colorless foam.

NMR spectrum (270 MHz, CDCl3) million D.: 1,19 (3H, d, J = 7,0 Hz), 3,3 - 3,5 (2H, m), 3,62 (1H, t, J = 11.3 Hz), to 3.64 (1H, t, J = 11.3 Hz), 4,30 (1H, DDD, J = 11,3, 4,8, and 2.3 Hz), 4,42 (1H, DDD, J = 11,3, 4,8, and 2.3 Hz), a 4.83 (1H, d, J = 14.1 Hz), free 5.01 (1H, s), to 5.03 (1H, d, J = 14.1 Hz), is 5.06 (1H, d, J = 4.5 Hz), of 5.83 (1H, DD, J = 15,9, and 4.5 Hz), 6,60 (1H, DD, J = 15,9, a 10.6 Hz), 6,62 (1H, d, J = 15,9 Hz), 6,7 - 6,8 (2H, m), at 6.84 (1H, DD, J = 15,9, a 10.6 Hz), 7.3 to 7.4 (1H, m), 7,44 (2H, d, J = 8,3 Hz), 7,60 (2H, d, J = 8,3 Hz), 7,79 (2H, s).

Mass spectrum m/e: 616, 600, 547, 400, 370, 342, 284, 252, 224, 183.

Example 36

(2R,3R)-2-(2,4-Differenl)-1- (1H-1,2,4-triazole-1-yl)-3-[[TRANS-4-([1E, 3E)-4-[4- (trifluoromethyl)phenyl]- 1,3-butadiene-1-yl] cyclohexyl]thio]- 2-butanol

< / BR>
The reaction was carried out by a method similar to that described in example 1 using (2R, 3S)-2-(2,4-giften-1-yl] cyclohexane, described in comparative example 43, resulting in the obtained target compound with a yield 59%, and so pl. 74 - 76oC.

Specific rotation []2D5= -83(c = 0,90, CHCl3).

NMR spectrum (270 MHz, CDCl3) million D.: 1,1 - 1,6 (4H, m) of 1.17 (3H, d, J = 7 Hz), of 1.8 - 2.0 (2H, m), of 2.0 - 2.2 (2H, m), 2,69 (1H, TT, J = 12.3 Hz), the 3.35 (1H, q, J = 7 Hz), with 4.64 (1H, s, OH), a 4.83 (1H, d, J = 15 Hz), 5,10 (1H, d, J = 15 Hz), of 5.83 (1H, DD, J = 15.7 Hz), to 6.22 (1H, DD, J = 15,7, 10 Hz), 6.48 in (1H, d, J = 15 Hz), 6,74 (1H, t, J = 8 Hz), for 6.81 (1H, DD, J = 15, 10 Hz), 7,1 - 7,5 (2H, m), 7,45 (2H, d, J = 8 Hz), 7,54 (2H, d, J = 8 Hz), 7,76 (1H, s), to 7.84 (1H, s).

The IR spectrummax(CHCl3) cm-1: 1615, 1500, 1325, 1125, 1068.

Mass spectrum m/e: 563, 544, 340, 310, 277, 224, 159, 127.

Example 37

(2R,3R)-2-(2,4-Differenl)-1- (1H-1,2,4-triazole-1-yl)-3-[[TRANS-2-([1E, 3E,5E)-6-[4- (trifluoromethyl)phenyl]- 1,3,5-hexatriene-1-yl] -1,3-dioxane-5-yl] thio]- 2-butanol

< / BR>
The reaction was carried out as described in example 4 using (2R, 3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio] -1- (1H-1,2,4-triazole-1-yl)-2-butanol and (2E,4E,6E)-7-[4-(trifluoromethyl)phenyl]-2,4,6-heptatriene described in comparative example 28, the result has been the target compound as the main product in the form of oily substance with a yield amounting to 65%.

NMR-spectrum ( 4,29 (1H, m), and 4.40 (1H, m), a 4.83 (1H, d, J = 14,5 Hz), 5,00 (1H, s), 5,02 (1H, d, J = 14,5 Hz), to 5.03 (1H, d, J = 4.6 Hz), 5,74 (1H, DD, J = 15,2, 4.6 Hz), 6,35 - 6,55 (3H, m), 6,59 (1H, d, J = 15.2 Hz), 6,7 - 6,8 (2H, m), 6,89 (1H, DD, J = 15,2, 9.9 Hz), 7,35 (1H, m), of 7.48 (2H, d, J = 8.6 Hz), 7,56 (2H, d, J = 8.6 Hz), 7,78 (1H, s), 7,79 (1H, s).

Example 38

(RS)-2-(2,4-Differenl)-3-methyl-1- (1H-1,2,4-triazole-1-yl)-3-[[TRANS-2-([1E, 3E)-4-[4- (trifluoromethyl)phenyl]-1,3-butadiene-1-yl]-1,3-dioxane-5-yl] thio]- 2-butanol

< / BR>
The reaction was carried out as described in example 4, using (RS)-2-(2,4-differenl)-3- [[(1,3-dihydroxy-2-propyl) thio] -3-methyl-1- (1H-1,2,4-triazole-1-yl) -2-butanol and (2E,4E)-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienyl described in comparative example 25, the result has been the target compound as the main product in the form of a colorless foam.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.36 (6H, s), 3,5 - 3,6 (2H, m), 3,6 - 3,8 (2H, m), 4,2 - 4,4 (1H, m), 4,4 - 4,6 (1H, m), is 4.93 (1H, d, J = 14.1 Hz), to 5.03 (1H, d, J = 4.3 Hz), 5,23 (1H, d, J = 14.1 Hz), to 5.56 (1H, s), of 5.84 (1H, DD, J = 15,4, the 4.3 Hz), 6,5 - 6,7 (3H, m), 6,7 - 6,9 (2H, m) to 7.50 (2H, d, J = 8,4 Hz), EUR 7.57 (2H, d, J = 8,4 Hz), and 7.6 to 7.7 (1H, m), 7,74 (1H, s), with 8.05 (1H, s).

Example 39

(2R, 3R)-2-(2,4-Differenl)-1- (1H-1,2,4-triazole-1-yl)-3-[[TRANS-2-([(E)-4-[4- (trifluoromethyl)phenyl] -1-butene-3-in-1-yl] -1,3-dioxane-5-yl]thio]- 2-butanol

< / BR>
The reaction was carried out as described in example 4 using (2R, 3R) the EN-4-Inal, described in comparative example 48, resulting in a received target connection, namely the main product, in the form of an oily substance with a yield of 70%.

Specific rotation []2D5= -65,1(c = 0,97, CHCl3).

NMR spectrum (270 MHz, CDCl3) million D.: 1,19 (3H, d, J = 7,0 Hz) to 3.33 (1H, q, J = 7.0 Hz), 3,39 (1H, TT, J = 11,4, a 4.9 Hz), 3,60 (1H, t, J = 11,4 Hz), 3,62 (1H, t, J = 11,4 Hz), 4,30 (1H, m), 4,42 (1H, m), a 5.0 to 5.1 (2H, m), 5,04 (1H, d, J = 3.2 Hz), 6,12 (1H, d, J = 16.0 Hz), 6,18 (1H, DD, J = 16,0, and 3.2 Hz), 6,7 - 6,8 (2H, m), of 7.36 (1H, m), 7,54 (2H, d, J = 8.5 Hz), 7,58 (2H, d, J = 8.5 Hz), 7,79 (2H, s).

Example 40

(2R, 3R)-2-(2,4-Differenl)-3- [[TRANS-2-phenyl-1,3 - dioxane-5 - yl]thio]- 1-(1H-1,2,4-triazole-1-yl) -2-butanol

< / BR>
In 20 ml of dimethylformamide was dissolved 1,65 g (to 6.57 mmol) of (2R,3S)-2-(2,4-differenl)-3-methyl-2-(1H-1,2,4-triazole-1-yl)methyl] oxirane and 2.00 g (8,40 mmol) of TRANS-4-(acetylthio)-2-phenyl-1,3-dioxane as described in comparative example 1, and the resulting solution was added 2.5 ml (4.00 mmol) of 1.6 M solution of sodium methylate in methanol under nitrogen atmosphere, then the mixture was heated with stirring at a temperature of 65oC for 2 hours. After cooling, to the reaction mixture were added ethyl acetate and the resulting mixture was washed with a saturated aqueous solution of sodium chloride and dried off, and rastvoriteli chromatography on 60 g of silica gel and was suirable benzene/ethyl acetate (5: 1), resulting received 2,53 g (yield 91%) of target compound in the form of solids. This solid is recrystallized from ethyl acetate/hexane, resulting in a net product so pl. 58 - 60oC.

Specific rotation []2D5= -88(c = 1.07, and CHCl3).

The IR spectrummax(CHCl3) cm-1: 3400, 1615, 1500, 1139.

NMR spectrum (270 MHz, CDCl3) million D.: to 1.21 (3H, d, J = 7,3 Hz) to 3.36 (1H, q, J = 7,3 Hz), 3,48 (1H, TT, J = 11,2, 4,6 Hz in), 3.75 (1H, t, J = 11.2 Hz), of 3.77 (1H, t, J = 11.2 Hz), and 4.40 (1H, DDD, J = 11,2, 4,6, and 2.6 Hz), 4,51 (1H, DDD, J = 11,2, 4,6, and 2.6 Hz), 4,84 (1H, d, J = a 13.9 Hz), 5,02 (1H, s), of 5.05 (1H, d, J = a 13.9 Hz), 5,49 (1H, s), 7,7 - 7,8 (2H, m), 7,3 was 7.45 (4H, m), 7,45 - 7,53 (2H, m), 7,79 (2H, s).

Example 41

(2R, 3R)-2-(2,4-differenl)-1- (1H-1,2,4-triazole-1-yl)-3- [(TRANS-2-[(1E, 3E)-4-(2,3,5-tryptophanyl)- 1,3-butadiene-1-yl]- 1,3-dioxane-5-yl]thio] -2-butanol

< / BR>
In 10 ml of tetrahydrofuran was dissolved 568 mg (2R,3R)-2-(2,4-differenl)-3-[(1,3-dihydroxy-2-propyl)thio]-1- (1H-1,2,4-triazole-1-yl)-2-butanol as described in comparative example 2, 412 mg of (2E,4E)-5-(2,3,5-trichlorophenyl)-2,4-pentadienyl as described in comparative example 60, and 440 mg (1.89 mmole) (+)-camphorsulfonate. The resulting solution was concentrated and dried under reduced pressure. The residue was dissolved in 10 Mildura evaporation was repeated five times. The residue then was dissolved in 10 ml of tetrahydrofuran and the resulting solution was left for 2 hours in 5oC. then the solution was slowly poured into ice saturated aqueous solution of Na2CO3and the product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous NaCl solution, followed by distillation of the solvent. The resulting residue was subjected to chromatography using 20 g of silica gel and was suirable using a mixed solvent of ethyl acetate-hexane (1:1) to obtain 582 mg (yield 61%) of target compound as amorphous solid.

Specific rotation []2D5= -42,5(c = 1,14, CHCl3)

The IR spectrummax(KBr) cm-1: 3419, 1617, 1500, 1388, 1275, 1140, 1049, 967.

NMR spectrum (270 MHz, CDCl3) million D.: 1,19 (3H, d, J = 7 Hz), to 3.33 (1H, q, J = 7 Hz), 3,40 (1H, TT, J = 11, 5 Hz), 3,62 (1H, t, J = 11 Hz), to 3.64 (1H, t, J = 11 Hz), 4,30 (1H, DDD, J = 11, 5, 2 Hz), 4,43 (1H, DDD, J = 11, 5, 2 Hz), a 4.83 (1H, d, J = 14 Hz), free 5.01 (1H, s) of 5.03 (1H, d, J = 14 Hz), 5,07 (1H, d, J = 4 Hz), by 5.87 (1H, DD, J = 15, 4 Hz), 6,4 - 6,8 (4H, m), 6,97 (1H, d, J = 15 Hz), 7,2 - 7,4 (1H, m), of 7.36 (1H, d, J = 2 Hz), 7,44 (1H, d, J = 2 Hz), 7,79 (2H, s).

Mass spectrum (FAB) m/e 602 (M+H)+).

Comparative example 1

TRANS-4-(acetylthio)-2-phenyl-1,3-dioxane

oC in nitrogen atmosphere for one hour. After cooling, to the reaction mixture was added benzene, and the mixture is then washed with water and the solvent evaporated. Thus obtained brown residue was subjected to column chromatography on silica gel and the fractions polyuretane mixed solvent of benzene and hexane (2:1), was collected and then recrystallized from a mixed solvent of benzene - hexane, resulting in received 8,99 g (43% yield) of the target compound with a melting point of 95 - 96oC.

NMR spectrum (270 MHz, CDCl3) million D.: is 2.37 (3H, s), with 3.79 (2H, t, J = 11.2 Hz), a 4.03 (1H, TT, J = and 11.2, 4.6 Hz), or 4.31 (2H, DD, J = and 11.2, 4.6 Hz), vs. 5.47 (1H, s), 7,35 is 7.5 (5H, m).

The IR spectrummax(CHCl3) cm-1: 1690, 1383, 1146, 1084.

Mass spectrum m/e: 238 (M+), 237, 195, 162 (100%), 149, 116, 107, 73.

Comparative example 2

(2R, 3R)-2-(2,4-Differenl)-3-[(1,3-dihydroxy-2-propyl] thio] -1- (1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
In 3.5 ml of methanol was dissolved 253 mg (2R,3R)-2-(2,4-differenl) -3-[[TRANS-2-phenyl - 1,3-dioxane-5-yl] thio] -1- (1H - 1,2,4-triazole-1-yl) -2-butanol obtained in example 40, and to the resulting solution was added 0.35 ml 4 N. hydrochloric acid in dioxane, and then the mixture was stirred at room temperature for over 10 minutes, was filtered and the filtrate was concentrated under reduced pressure. Thus obtained oily substance was subjected to column chromatography on 5 g of silica gel, and then suirable 10% methanol/ethyl acetate and received 179 mg (yield 88%) of target compound in the form of a viscous oily product.

Specific rotation []2D5= -61(c = 1,05, CHCl3).

The IR spectrummax(CHCl3) cm-1: 3400, 1618, 1500.

NMR spectrum (60 MHz, CDCl3+ D2O) million D.: of 1.20 (3H, d, J = 6.5 Hz), 3,0 - 4,0 (6H, m), 4,80 (1H, d, J = 14 Hz), 5,16 (1H, d, J = 14 Hz), 6,6 - 7,0 (2H, m), the 7.43 (1H, TD, J = 9.8 Hz), 7,74 (1H, s), 7,86 (1H, s).

Comparative example 3

TRANS-5-[(4-Chlorobenzyl)thio]- 2-phenyl-1,3-dioxane

< / BR>
240 mg (5,50 mmol) of 55% sodium hydride were washed with hexane, and then suspended in 15 ml of dimethylformamide, was added 903 mg (5,70 mmol) of 4-chlorobenzylidene and the resulting suspension was stirred in nitrogen atmosphere. After 15 minutes, to the mixture was added 1.66 g (4,96 mmol) of CIS-5-(para-toluensulfonate)-2-phenyl-1,3-dioxane and the resulting mixture was stirred for one hour at a temperature of 75oC. After cooling, to the reaction mixture was added benzene, and the mixture was washed with water and then aqueous solution of chlorine is Wali of the mixed solvent of benzene - hexane, resulting in received 670 mg (yield 42%) of target compound in the form of chapeaurouge crystalline solid, so pl. 95 - 99oC.

NMR spectrum (60 MHz, CDCl3) million D.: to 3.02 (1H, TT, J = 11,2, 5 Hz), 3 (2H, t, J = 11 Hz), and 3.72 (2H, s), is 4.21 (2H, DD, J = 11.5 Hz), of 5.39 (1H), 7,30 (5H, s), 7,38 (4H, s).

Comparative example 4

2-[(4-Chlorobenzyl)thio]-1,3-propandiol

< / BR>
In 10 ml of methanol was dissolved 750 mg of TRANS-5-(Chlorobenzyl)thio]-2-phenyl-1,3-dioxane and the resulting solution was added a 4 n solution of hydrogen chloride in dioxane (1 ml), and then the resulting mixture was stirred for one hour at room temperature. After adding to the reaction mixture of 750 mg of sodium bicarbonate (powder) obtained mixture was stirred for 15 minutes and then the solids were removed by filtration and the solvent drove away. To the resulting residue were added ethyl acetate and any insoluble matter was removed by filtration. The crystals formed by evaporation of the solvent was recrystallized from a mixed solvent of benzene - hexane, resulting in received 468 mg (yield 86%) of target compound with so pl. 70 - 75oC.

Comparative example 5

TRANS-5-[(4-Chlorobenzyl)thio] -2-is benzyl)thio]-1,3-propane diol and 375 mg (1,75 mmol) of (E)-4-(trifluoromethyl) - methylcinnamaldehyde and to the resulting solution was added 3 mg of para-toluensulfonate acid, and then the mixture was heated under reflux in nitrogen atmosphere for two hours. After cooling, the reaction mixture was washed with an aqueous solution of sodium bicarbonate. The residue obtained by evaporation of the solvent was subjected to column chromatography on 15 g of silica gel. Faction, polyinosine mixed solvent of hexane - ethyl acetate (9:1), was collected and the thus obtained solid substance was washed with hexane, resulting in received 370 mg (yield 59%) of target compound with so pl. 93 - 95oC.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.87 (3H, s), 2,99 (1H, TT, J = and 11.2, 4.6 Hz), to 3.58 (2H, DD, J = 11,9, 11.2 Hz), to 3.73 (2H, s), is 4.15 (2H, DD, J = 11,9, and 4.6 Hz), to 4.87 (1H, s), of 6.68 (1H, Shir.C), 7,25 of 7.3 (4H, m), of 7.36 (2H, d, J = 7.9 Hz), EUR 7.57 (2H, d, J = 7.9 Hz).

Comparative example 6

TRANS-5-[(4-chlorbenzyl)sulfinil]-2-[(E)-1-methyl-2-[4- (trifluoromethyl)phenyl]vinyl]-1,3-dioxane

< / BR>
In 10 ml of methylene chloride was dissolved 382 mg (0.89 mmol) of TRANS-5-[(4-Chlorobenzyl)thio]-2-[(E)-1-methyl-2-[4- (trifluoromethyl)phenyl]vinyl]-1,3-dioxane and the resulting solution was added 188 mg (0,92 mmol) m-chloroperoxybenzoic acid (purity 85%), and then the mixture was stirred for 15 minutes. The reaction mixture was washed with an aqueous solution of sodium bicarbonate and a solid receiving what about the received 328 mg (yield 83%) of target compound, so pl. 192 - 194oC.

NMR spectrum (60 MHz, CDCl3) million D.: a 1.88 (3H, d, J = 1.5 Hz), 2,8 - 3,3 (1H, m), 3.8 to 4.5 (4H, m) to 4.01 (2H, s), of 4.95 (1H, s), of 6.73 (1H, Shir.C.), 7,15 to 7.75 (8H, m).

Comparative example 7

TRANS-4-(acetylthio)-2- [(E)-1-methyl-2-[4-(tryptomer) phenyl] vinyl]-1,3-dioxane

< / BR>
In 8 ml of a mixed solvent of tetrahydrofuran and acetonitrile (1:1) was dissolved 309 mg (0,696 mmol) of TRANS-5-[(4-chlorbenzyl)sulfinil-2-[(E)-1-methyl-2-[4-(tryptomer) phenyl]vinyl]-1,3-dioxane and the resulting solution was added 500 mg (of 4.67 mmol) of 2,6-lutidine. To the obtained mixture under stirring for about 5 minutes at a temperature of 0oC one drop was added 500 mg (2.4 mmol) triperoxonane anhydride. After 10 minutes, to the reaction mixture was added about 5 ml of an aqueous solution of sodium bicarbonate and the mixture was stirred for 5 minutes, and then was extracted with ethyl acetate. After evaporation of the solvent formed an oily residue (350 mg) which was dissolved in 5 ml of methylene chloride and to the solution was added 210 mg of triethylamine at 0oC C and then adding to the reaction mixture 109 mg acetylchloride. After keeping for 5 minutes, the reaction mixture was washed with water and the solvent drove away. The remainder podvergaetsia which received 186 mg (yield 77%) of target compound in the form of a crystalline solid. The crystalline solid was recrystallized from a mixed solvent of benzene - hexane, resulting in lamellar crystalline solid, so pl. 128 - 129oC.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.92 (3H, s), a 2.36 (3H, s), 3,70 (2H, t, J = 11.2 Hz), of 3.96 (1H, TT, J = and 11.2, 4.6 Hz), 4,25 (2H, DD, J = and 11.2, 4.6 Hz), 4,94 (1H, s) 6,70 (1H, Shir.C), 7,39 (2H, d, J = 8,2 Hz), to 7.59 (2H, d, J = 8,2 Hz).

Comparative example 8

Ethyl (2E,4E)-3-methyl-5-[4-(trifluoromethyl)phenyl]-2,4-pentadienoic

< / BR>
45 mg (1,03 mmol) of 55% sodium hydride were washed with hexane, and then superdurable in 3 ml of 1,2-dimethoxyethane and to the obtained mixture under stirring in nitrogen atmosphere at a temperature of 0oC was added 273 mg (1,03 mmol) of triethyl 3-methyl-4-phosphonocrotonate. After 15 minutes, to the mixture was added 100 mg (or 0.57 mmol) of 4-(trifluoromethyl)benzaldehyde and the mixture was stirred for ten minutes. After adding to the reaction mixture with ice water, the mixture was extracted with ethyl acetate. After evaporation of the solvent the crude product was subjected to column chromatography on 5 g of silica gel and was suirable mixed solution of ethyl acetate - hexane (4: 96), resulting in a received 159 mg (yield 97%) of target compound in the form of a mixture (5:1) (2E,4E)-isomer and (2Z, 4E)-is of 6.6 Hz), to 2.41 (3H, s), 4,20 (2H, q, J = 6.6 Hz), 5,95 (1H, s) 6,86 (1H, d, J = 16.5 Hz), to 6.95 (1H, d, J = 16.5 Hz), 7.5 to the 7.65 (4H, m); (2Z,4E)-isomer (main signal): 2,14 (3H, s), of 5.82 (1H, s), 6,92 (1H, d, J = 16.5 Hz), 8,49 (1H, d, J = 16.5 Hz).

Comparative example 9

(2E,4E)-3-Methyl-5-[4-(trifluoromethyl) phenyl]-2,4-pentadien-1-ol

< / BR>
A solution of 150 mg (of 0.53 mmol) of ethyl (4E)-3-methyl-5-[4-(trifluoromethyl)phenyl]- 2,4-pentadienoic ((2E)/(2Z) = 5/1) (described in comparative example 8) in 2 ml of toluene was stirred at 0oC and the resulting solution was added 0.7 ml (1.06 mmol) of a 1.5 M solution of hydride diisobutylaluminum in toluene. After 20 minutes, to the reaction mixture were added ice water and the mixture was stirred for ten minutes. Any insoluble matter was removed by filtration through Celite and then the filtrate was extracted with ethyl acetate and dried, then the solvent is evaporated and obtained oily substance. This oily substance was chromatographically on columns with 5 g of silica gel and was suirable mixed solvent 30-40% ethyl acetate - hexane, resulting in received 90 mg of target compound in the form of an oily substance.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.34 (1H, Shir.C.), of 1.93 (3H, s), 4,37 (2H, d, J = 6.5 Hz), by 5.87 (1H, t, J = 6.5 Hz), to 6.58 (1H, d, J = 16.1 Hz), to 6.88 (1H, d, J = 16.1 Hz), to 7.50 (2H, d, J = 8.5 Hz), EUR 7.57 (2H, d, J = 8.5 G is 10 ml of methylene chloride was dissolved 460 mg (1,90 mmol) (2E,4E)-3-methyl-5-[4-(trifluoromethyl)phenyl] -2,4-pentadien-1-ol and to the mixture was added 5 g of active manganese dioxide, and then the resulting mixture was stirred at room temperature for 30 minutes. Solids were removed by filtration and the filtrate was concentrated, and then purified using chromatography on silica gel (eluting solvent: 4% ethyl acetate/hexane), resulting in a received 460 mg of the desired product as an oily substance.

NMR spectrum (270 MHz, CDCl3) million D.: is 2.41 (3H, s), 6,13 (1H, d, J = 8.0 Hz), of 6.96 (1H, d, J = 16.1 Hz), to 7.09 (1H, d, J = 16.1 Hz), 7,55 to 7.7 (4H, m), 10,19 (1H, d, J = 8.0 Hz).

Comparative example 11

4-(Acetylthio)-1-(tert-butoxycarbonyl)piperidine

< / BR>
In 40 ml of dimethylformamide was dissolved 4.12 g (14.7 mmol) of 1-(tert-butoxycarbonyl)-4-(methanesulfonate)of piperidine and the obtained solution was added 2,53 g (2,12 mmol) thioacetate potassium, and then the mixture was stirred for 4 hours at a temperature of 105oC in nitrogen atmosphere. After cooling, the reaction mixture was diluted with ethyl acetate and washed with water, and then saturated aqueous sodium chloride, after which the solvent evaporated. Thus obtained residue was subjected to column chromatography on silica gel, and then faction, polyinosine mixed solvent of hexane - ethyl acetate (5: 1), were collected, resulting in UB>3) million D.: a 1.46 (9H, s), 1,5 - 1,6 (2H, m), 1,9 - 2,0 (2H, m), of 2.33 (3H, s), 3,0 - 3,1 (2H, m), of 3.5 - 3.7 (1H, m), 3,8 - 3,9 (2H, m).

Mass spectrum m/e: 259, 244, 216, 202, 186, 183, 160, 144, 127, 116, 97, 84, 57.

Comparative example 12

1-(Tert-butoxycarbonyl)-4-mercaptopyridine

< / BR>
In dry methanol was dissolved 520 mg (2 mmol) 4-(acetylthio)-1-(tert-butoxycarbonyl)of piperidine and to the mixture was added 420 μl (2 mmol) of a 28% solution of sodium methylate in methanol under ice cooling in a nitrogen atmosphere, and then the mixture was stirred for 40 minutes. Then to the mixture was added 173 μl of acetic acid, the solvent is kept at room temperature and the residue was diluted with ethyl acetate. The resulting mixture was sequentially washed with an aqueous solution of sodium bicarbonate and aqueous sodium chloride solution and after removal of the solvent was obtained 430 mg reddish-orange oily substance. This substance was used in subsequent reactions without purification.

NMR spectrum (270 MHz, CDCl3) million D.: a 1.46 (9H, s), 1,5 - 1,6 (2H, m), 1,9 - 2,0 (2H, m), 2.8 to 3.0 (3H, m), 3,9 - 4,1 (2H, m).

Mass spectrum m/e: 217, 202, 184, 161, 144, 127, 117, 84, 82.

Comparative example 13

(2R, 3R)-2-(2,4-Differenl)-3- (1H-1,2,4-triazole-1-yl)-3- [[1-(tert-butoxycarbonyl) piperidine-4-yl]thio] -2-butanol

oC in an atmosphere of nitrogen was added 86 mg (1.97 mmol) of 55% sodium hydride, and then the mixture was stirred at the same temperature for 20 minutes. To the reaction mixture were added 503 mg (2.0 mmol) of (2R, 3R)-2-(2,4-differenl)-3-methyl-2-[(1H - 1,2,4-triazole-1-yl)methyl]oxirane and the mixture was stirred for 3 hours at a temperature of 60oC. After cooling, the reaction mixture was diluted with ethyl acetate and then washed with water and saturated aqueous sodium chloride. An oily substance obtained by evaporation of the solvent was subjected to column chromatography on silica gel and was suirable with ethyl acetate, resulting in a received 557 mg (yield 53%) of target compound in the form of an oily substance.

NMR spectrum (270 MHz, CDCl3) million D.: 1,17 (3H, d, J = 6.6 Hz), of 1.47 (9H, s), 1,4 - 1,6 (2H, m), 1,9 - 2,1 (2H, m), 2,9 - 3,1 (3H, m) to 3.34 (1H, q, J = 6.6 Hz), 3,9 - 4,1 (2H, m), of 4.77 (1H, s), 4,82 (1H, d, J = 14,2 Hz), 5,09 (1H, d, J = 14,2 Hz), 6,7 - 6,8 (2H, m), 7.3 to 7.4 (1H, m), to 7.77 (1H, s), 7,82 (1H, s).

The IR spectrummax(KBr) cm-1: 3401, 1691.

Mass spectrum m/e: 468, 408, 395, 365, 321, 284, 253, 224, 188, 166, 144, 127.

Comparative example 14

(2R, 3R)-2-(2,4-Differenl)-3- (1H-1,2,4-triazole-1-yl)-3- [(piperidine-4-yl)thio]- 2-butanol digid-(tert-butoxycarbonyl)piperidine-4-yl] thio] -2-butanol and the solution was added 2,63 ml (10.5 mmol) solution of 4 N. hydrogen chloride in ethyl acetate, and then the mixture was stirred for 8 hours at a temperature of 40oC. After cooling, the precipitated substance was collected by filtration and washed with hexane, resulting in received 460 mg (yield 100%) of the desired compound as a colorless powder.

NMR spectrum (270 MHz, DMSO-d6+ CDCl3) million D.: of 1.23 (3H, d, J = 6.6 Hz), of 1.8 - 2.0 (2H, m), of 2.3 - 2.5 (2H, m), 3.1 to 3.4 (3H, m), 3,74 (1H, q, J = 6.6 Hz), 4,79 (1H, d, J = 14,2 Hz), of 5.05 (1H, d, J = 14,2 Hz), 5,3 - 5,6 (1H, Shir.C.), 6.8 or 6.9 (1H, m), of 7.0, and 7.1 (1H, m), 7,2 - 7,3 (1H, m), 7,79 (1H, s), of 8.28 (1H, s).

The IR spectrummax(KBr) cm-1: 3366, 3094, 2725, 2483.

Mass spectrum m/e: 368, 308, 286, 284, 253, 224, 213, 183, 165, 144, 116, 113, 84.

Comparative example 15

Hydrochloride 4-(acetylthio)piperidine

< / BR>
In 45 ml of ethyl acetate was dissolved 1.25 g (4,82 mmol) 4-(acetylthio)-1-(tert-butoxycarbonyl)piperidine as described in comparative example 11, and to the solution was added 12.0 ml (48.2 mmol) of 4 n solution of hydrogen chloride in ethyl acetate, and then the mixture was stirred at a temperature of 50oC for 4 hours. After cooling, the precipitated solid was collected by filtration and washed with hexane, resulting in received 885 mg (yield 94%) of target compound in the form of a slightly yellowish powder.

Comparative example 16

4-(Acetylthio)-1-[(E)-4-(triptoreline) cynnamoyl]-piperidine

< / BR>
In 17 ml of dichloromethane added 1.28 g (6,53 mmol) of the hydrochloride of 4-(acetylthio)of piperidine and the resulting suspension under stirring and under cooling with ice for one drop was added, and 2.27 ml (16.3 mmol) of triethylamine. To the reaction mixture drop by drop) was added 1.80 g (7,18 mmol) of (E)-4-(triptoreline)cinnamonitrile dissolved in 6 ml of dichloromethane, and the resulting mixture was stirred under ice cooling for one hour. Then the reaction mixture was subjected to column chromatography on silica gel and was suirable mixed solvent of hexane - ethyl acetate(2:1 - 1:1), resulting received 2,32 g (95% yield) of target compound in the form of a slightly yellowish solid.

NMR spectrum (270 MHz, CDCl3) million D.: 1,5 - 1,7 (2H, m), 1,9 - 2,1 (2H, m), of 2.34 (3H, s), 3,1 - 3,3 (1H, m), 3,3 - 3,5 (1H, m), of 3.7 - 3.8 (1H, m), 3,9 - 4,0 (1H, m), 4,2 - 4,4 (1H, m), 6,85 (1H, d, J = 15,5 Hz), 7,21 (2H, d, J = 8.6 Hz), rate of 7.54 (2H, d, J = 8.6 Hz), 7,63 (1H, d, J = 15,5 Hz).

Mass spectrum m/e: 373, 330, 298, 256, 228, 215, 187, 158, 136, 116, 101.

Comparative example 17

3-(Acetylthio)-1-(tert-butoxycarbonyl)azetidin

< / BR>
Compound as an orange oily substance was obtained from 1-(tert-butoxycarbonyl)-3-(IU is>) million D.: the 1.44 (9H, s), of 2.33 (3H, s), 3,81 (2H, DD, J = 9,0, 5,5 Hz), 4,1 - 4,2 (1H, m), 4,37 (2H, t, J = 9,0 Hz).

Comparative example 18

(2R, 3R)-2-(2,4-Differenl)-1- (1H-1,2,4-triazole-1-yl)-3- [[1-(tert-butoxycarbonyl) azetidin-3-yl]thio] -2-butanol

< / BR>
Compound as a pale yellow foam was obtained from 3-(acetylthio)- 1-(tert-butoxycarbonyl)azetidine the method described in comparative examples 12 and 13.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.13 (3H, d, J = 7,1 Hz) of 1.45 (9H, s), with 3.27 (1H, q, J = 7,1 Hz), of 3.7 - 3.9 (2H, m), 3,9 - 4,0 (1H, m), 4,2 - 4,4 (2H, m), 4,84 (1H, d, J = 14.1 Hz), to 4.98 (1H, s), 5,04 (1H, d, J = 14.1 Hz), 6,7 - 6,9 (2H, m), 7.3 to 7.4 (1H, m), 7,78 (1H, s), 7,80 (1H, s).

The IR spectrummax(KBr) cm-1: 3405, 1701.

Mass spectrum m/e: 441, 425, 385, 367, 341, 311, 284, 252, 224, 119, 183, 165, 141, 127, 88.

Comparative example 19

The dihydrochloride (2R,3R)-2-(2,4-differenl)-1- (1H-1,2,4-triazole-1-yl)-3- [(azetidin-3-yl)thio]-2-butanol

< / BR>
The connection in the form of a slightly yellowish powder was obtained from (2R,3R)-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-3- [[tert-butoxycarbonyl)azetidin-3-yl]thio]-2-butanol as described in comparative example 14.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.16 (3H, d, J = 6.6 Hz), 3,52 (1H, q, J = 6.6 Hz), 3,9 - up was 4.3 (3H, m), 4,3 - 4,6 (2H, m), to 4.98 (1H, d, J = 14,2 Hz), 5,43 (1H, d, J = 14,2 Hz), 6,6 - 6,9 (2H, m), 7,2 - 7,4 (1H, m), 8,40 (1H, s), of 8.95 (1H, with(20,7 mmol) of 55% sodium hydride were washed with hexane, and then suspended in 60 ml of 1,2-dimethoxyethane and to the resulting suspension while stirring at 0oC in nitrogen atmosphere for one drop was added 4,63 g (20,7 mmol) triethylphosphate. After 15 minutes, to the mixture was added to 2.00 g (11.5 mmol) of 4-(trifluoromethyl)benzaldehyde at 0oC and the mixture was stirred for 15 minutes. After addition of ethyl acetate the mixture was washed with water. After drying the oily residue, obtained after evaporation of the solvent was subjected to chromatography on a column of silica gel and was suirable 4% ethyl acetate/hexane, resulting in a received target compound with a melting point of 31 32,5oC, and yield = 98%.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.35 (3H, t, J = 7,3 Hz), 4,48 (2H, q, J = 7,3 Hz), 6,51 (1H, d, J = 16.2 Hz), 7,66 (4H, s), of 7.69 (1H, d, J = 16.2 Hz).

Comparative example 21

TRANS-4-(trifluoromethyl)cinnamony alcohol

< / BR>
In 15 ml of toluene was dissolved 3.00 g (12.3 mmol) of ethyl TRANS-4-(trifluoromethyl)cinnamate and to the solution with stirring and at a temperature of 0oC was added 16.4 ml (24.6 mmol) of a 1.5 M solution of hydride diisobutylaluminum in toluene. After 20 minutes, to the reaction mixture were added ice water and the mixture was stirred for 10 minutes and then nerastvorim the solvent drove and received a crystalline residue. This residue was recrystallized from a mixed solvent of benzene - hexane, resulting in received of 2.36 g (yield 96%) of target compound with so pl. 53 - 55oC.

NMR spectrum (270 MHz, CDCl3) million D.: 1.55V (1H, t, J = 5,9 Hz), 4,37 (2H, Shir. so ), 6,46 (1H, dt, J = 16,2, a 5.3 Hz), to 6.67 (1H, d, J = 16.2 Hz), 7,46 (2H, d, J = 8,3 Hz), EUR 7.57 (2H, d, J = 8,3 Hz).

Comparative example 22

TRANS-4-(trifluoromethyl)cinnamaldehyde

< / BR>
In 30 ml of methylene chloride was dissolved 2.15 g of TRANS-4-(trifluoromethyl)tsinnamonovogo alcohol and to the solution at a temperature of 0oC was added 14 g of active manganese dioxide, and then the resulting mixture was stirred for 15 minutes, after which the mixture was stirred another 2 hours at room temperature. The formed solid substance was removed by filtration and the filtrate was concentrated to obtain a crystalline residue. This residue was recrystallized from a mixed solvent of benzene - hexane, resulting in a received target connection with the release of 90%, and so pl. 60 - 61oC.

NMR spectrum (270 MHz, CDCl3) million D.: is 6.78 (1H, DD, J = 16,2, 7,3 Hz), 7,53 (1H, d, J = 16.2 Hz), 7,69 (4H, s), 9,76 (1H, d, J = 7,3 Hz).

The IR spectrummax(KBr) cm-1: 1680, 1630, 1321, 1173, 1123, 1066.

Mass spectrum m/e 200 (M+), 199, 171, 151, 145, 131, (100%)4,51 g (103 mmol) of 55% sodium hydride were washed with hexane, and then suspended in 70 ml of 1,2-dimethoxyethane and to the resulting suspension at 0oC in nitrogen atmosphere with stirring drop by drop) was added 25,9 (103 mmol) triethylphosphate. After 15 minutes, to the resulting mixture at the same temperature was added 10.0 g (57,4 mmol) of 4-(trifluoromethyl)Basalyga and the mixture was stirred for 10 minutes. The reaction mixture was poured into ice water, and then extracted with ethyl acetate. The oily residue obtained by evaporation of the solvent was subjected to column chromatography on silica gel and was suirable 6% ethyl acetate/hexane to obtain 11.2 g (yield 72%) of target compound in the form of an oily substance.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.32 (3H, t, J = 7,3 Hz), 4,24 (2H, q, J = 7,3 Hz), equal to 6.05 (1H, d, J = 15.2 Hz), 6,85 - 7,0 (2H, m), 7,44 (1H, DDD, J = 15,2, 7,9, and 2.6 Hz), 7,55 (2H, d, J = 8.6 Hz), to 7.61 (2H, d, J = 8.6 Hz).

Comparative example 24

(2E,4E)-5-[4-(Trifluoromethyl)phenyl]-2,4-pentadien-1-ol

< / BR>
Ethyl (2E, 4E)-5-[4-(trifluoromethyl)phenyl] -2,4-pentadienoic was treated with a hydride diisobutylaluminum manner similar to that described in comparative example 21, the resulting target compound with a quantitative yield.

NMR spectrum (270 MHz, CDCl3) million D.: 1,47 (1H, t, J = 8.6 Hz), 7,56 (2H, d, J = 8.6 Hz).

Comparative example 25

(2E,4E)-5-[4-(Trifluoromethyl)phenyl]-2,4-pentadienyl

< / BR>
(2E, 4E)-5-[4-(Trifluoromethyl)phenyl] -2,4-pentadien-1-ol was treated with active manganese dioxide by the method described in comparative example 22, resulting in a received target connection with the release of 92%.

NMR spectrum (270 MHz, CDCl3) million D.: 6,33 (1H, DD, J = 15,2, 7,3 Hz), 7,0 - to 7.35 (3H, m), 7,60 (2H, d, J = 8.6 Hz), to 7.64 (2H, d, J = 8.6 Hz), 9,65 (1H, d, J = 7,3 Hz).

Comparative example 26

Ethyl (2E,4E,6E)-7-[4-(trifluoromethyl)phenyl]-2,4,6-heptatriene

< / BR>
(2E, 4E)-5-[4-(Trifluoromethyl)phenyl]-2,4-pentadienyl was subjected to reaction with triethylphosphite the method described in comparative example 20, the received target connection with the release of 95%.

NMR spectrum (270 MHz, CDCl3) million D.: is 1.31 (3H, t, J = 7,3 Hz) to 4.23 (2H, q, J = 7,3 Hz), 5,96 (1H, d, J = 15.2 Hz), of 6.49 (1H, DD, J = 15,2, 11.2 Hz), 6,72 (1H, DD, J = 15,2, a 10.6 Hz), was 6.73 (1H, d, J = 15,8 Hz) 6,94 (1H, DD, J = 15,8, a 10.6 Hz), 7,37 (1H, DD, J = 15,2, 11.2 Hz), 7,51 (2H, d, J = 8.6 Hz), 7,58 (2H, d, J = 8.6 Hz).

Comparative example 27

(2E,4E,6E)-7-[4-(Trifluoromethyl)phenyl]- 2,4,6-heptadien-1-ol

< / BR>
Ethyl (2E, 4E, 6E)-7-[4-(trifluoromethyl)phenyl]-2,4,6-heptatriene was treated with a hydride diisobutylaluminum the method described in comparative primer.: of 1.41 (1H, t, J = 5.3 Hz), 4,25 (2H, t, J = 5.3 Hz), 5,95 (1H, dt, J = 15,0, a 5.3 Hz), 6,3 - 6,5 (3H, m), to 6.57 (1H, d, J = 15.2 Hz), 6,90 (1H, m), 7,47 (2H, d, J = 8.6 Hz), 7,55 (2H, d, J = 8.6 Hz).

Comparative example 28

(2E,4E,6E)-7-[4-(Trifluoromethyl)phenyl] -2,4,6-heptadienal

< / BR>
(2E, 4E,6E)-7-[4-(Trifluoromethyl)phenyl]-2,4,6-heptadien-1-ol was treated with active manganese dioxide by the method described in comparative example 22, resulting in a received target connection with the release of 88%.

NMR spectrum (270 MHz, CDCl3) million D.: 6,23 (1H, DD, J = 15,2, 7.9 Hz), 6,62 (1H, DD, J = 14,5, 11.2 Hz), PC 6.82 (1H, d, J = 15,8 Hz), at 6.84 (1H, DD, J = 14,5, 9.9 Hz), 6,98 (1H, DD, J = 15,8, 9.9 Hz), 7,19 (1H, DD, J = 15,2, 11.2 Hz), 7,54 (2H, d, J = 8.6 Hz), to 7.61 (2H, d, J = 8.6 Hz), 9,62 (1H, d, J = 7.9 Hz).

Comparative example 29

4-(2,2,3,3-Tetrafluoropropoxy)benzaldehyde

< / BR>
1,90 g (of 43.5 mmol) of 55% sodium hydride were washed with hexane, and then suspended in 25 ml of N,N-dimethylacetamide and the resulting suspension at a temperature of 0oC in nitrogen atmosphere was slowly added to 5.3 g (43 mmol) of 4-hydroxybenzaldehyde. After the termination of allocation of gaseous hydrogen to the reaction mixture were added 11,14 g (39 mmol) of 2,2,3,3-tetrafluoropropyl para-toluensulfonate and the resulting mixture was heated at a temperature of 120oC under stirring for 2 hours and 15 minutes. After ohla the Ali water. After drying the solvent drove and got a cent to 8.85 g (yield 96%) of target compound in the form of an oily substance.

NMR spectrum (270 MHz, CDCl3) million D.: of 4.45 (2H, Shir.triplet, J = 11,9 Hz), the 6.06 (1H, TT, J = 53,3, 4.6 Hz), 7,06 (2H, d, J = 8.7 Hz), 7,88 (2H, d, J = 8.7 Hz), to 9.93 (1H, s).

Comparative example 30

Ethyl (2E,4E)-5-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4 - pentadienoic

< / BR>
4-(2,2,3,3-Tetrafluoropropoxy)benzaldehyde was subjected to reaction with triethylphosphate the method described in comparative example 23, resulting in a received target connection so pl. 65 - 66oC and the yield 74%.

NMR spectrum (270 MHz, CDCl3) million D.: is 1.31 (3H, t, J = 7,3 Hz) to 4.23 (2H, q, J = 7,3 Hz), 4,37 (2H, Shir.T., J = 11,9 Hz), 5,95 (1H, d, J = 15.2 Hz), the 6.06 (1H, TT, J = 53,5, 4.6 Hz), 6,77 (1H, DD, J = 15,2, 9.9 Hz), 6,86 (1H, d, J = 15.2 Hz), 6,91 (2H, d, J = 8.6 Hz), 7,42 (1H, DD, J = 15,2, 9.9 Hz), 7,44 (2H, d, J = 8.6 Hz).

Comparative example 31

(2E,4E)-5-[4-(2,2,3,3-Tetrafluoropropoxy) phenyl]-2,4 - pentadien-1-ol

< / BR>
Ethyl (2E, 4E)-5- [4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-pentadienoic was treated with a hydride diisobutylaluminum the method described in comparative example 21, resulting in a received target connection so pl. 95 - 97oC and yield = 95%.

NMR spectrum (270 MHz, CDCl3) million D.: 1,39 (1H, t, J = 5 Hz), 4,2 is C), 6,69 (1H, DD, J = 15,5, 10,3 Hz), to 6.88 (2H, d, J = 8.7 Hz), was 7.36 (2H, d, J = 8.7 Hz).

Comparative example 32

(2E,4E)-5-[4-(2,2,3,3-Tetrafluoropropoxy) phenyl]-2,4 - pentadienyl

< / BR>
Ethyl (2E,4E)-5- [4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2,4-pentadien-1-ol was treated with active manganese dioxide by the method described in comparative example 22, resulting in a received target connection so pl. 53 - 55oC and yield of 96%.

NMR spectrum (270 MHz, CDCl3) million D.: of 4.38 (2H, Shir.triplet, J = 11,9 Hz), the 6.06 (1H, TT, J = 52,8, 4.6 Hz), and 6.25 (1H, DD, J = 15,2, 7.9 Hz), make 6.90 (1H, DD, J = 15,8, 9,2 Hz), 6,94 (2H, d, J = 8.6 Hz), 6,97 (1H, d, J = 15,8 Hz), 7,25 (1H, DD, J = 15,2, 9,2 Hz), of 7.48 (2H, d, J = 8.6 Hz), being 9.61 (1H, d, J = 7.9 Hz).

Comparative example 33

TRANS-4-(triptoreline)cinnamaldehyde

< / BR>
570 mg (3.0 mmol) 4-(triptoreline)benzaldehyde and 913 mg (3.0 mmol) (triphenylphosphorane)of acetaldehyde was heated under reflux in 7.5 ml of toluene in a nitrogen atmosphere for 1 hour and 45 minutes. After distillation of the toluene under reduced pressure, the thus obtained residue was purified by column chromatography on 20 g of silica gel. Faction, polyinosine mixed solvent of acetic acid - hexane (1:10), were collected, resulting in a received 387 mg (yield 60%) of target compound in the form of mass is H, d, J = 15,8 Hz), to 7.61 (2H, d, J = 8.6 Hz), 9,72 (1H, d, J = 7,3 Hz).

The IR spectrummax(CHCl3) cm-1: 1680, 1508, 1259.

Mass spectrum m/e: 216 (M+), 215, 187, 175, 162, 131 (100%), 119, 101.

Comparative example 34

Ethyl 6-(2,2,3,3-tetrafluoropropoxy)nicotinate

< / BR>
840 mg (or 19.3 mmol) of 55% sodium hydride were washed with hexane and suspended in 40 ml of dimethylformamide, and then to the suspension at 0oC in nitrogen atmosphere was slowly added 3.00 g (22.7 mmol) of 2,2,3,3-tetrafluoropropanol. After cessation of gas (hydrogen) to the resulting mixture at the same temperature for approximately 30 minutes, one drop was added 3,40 g (to 18.3 mmol) of ethyl 6-chloro-nicotinate, dissolved in 15 ml of dimethylformamide. After complete addition, the mixture was stirred for 30 minutes and then the reaction mixture was poured into ice water and was extracted with benzene. After drying the extract, the solvent is kept off and the thus obtained oily substance was purified by column chromatography on silica gel (eluent: mixed solvent of benzene - hexane, 1:1), resulting in a received 4.42 g (yield 86%) of target compound in the form of an oily substance.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.40 (3H, t, J = 7.2 Hz), 4,39 (S="ptx2">

The IR spectrum max(CHCl3) cm-1: 1717, 1604, 1119.

Mass spectrum m/e 281 (M+), 236 (100%), 180, 152, 151, 123, 122, 98.

Comparative example 35

2-(2,2,3,3-Tetrafluoropropoxy)-5-(hydroxymethyl)pyridine

< / BR>
Ethyl 6-(2,2,3,3-tetrafluoropropoxy)nicotinate was subjected to reaction recovery hydride diisobutylaluminum the method described in comparative example 21, resulting in a received target compound in the form of an oily substance with a yield of 100%.

NMR spectrum (270 MHz, CDCl3) million D.: 1,69 (1H, t, J = 5.8 Hz), of 4.66 (2H, d, J = 5.8 Hz), 4,74 (2H, Shir.T., J = 12,8 Hz), 6,01 (1H, TT, J = 53,1, 4.6 Hz), at 6.84 (1H, d, J = 8.5 Hz), 7,69 (1H, DD, J = 8,5, 2,5 Hz) to 8.12 (1H, d, J = 2.5 Hz).

Mass spectrum m/e 239 (M+), 210, 188, 169, 138 (100%), 109, 108, 78.

Comparative example 36

6-(2,2,3,3-Tetrafluoropropoxy)nicotinamidase

< / BR>
2-(2,2,3,3-Tetrafluoropropoxy)-5-(hydroxymethyl)pyridine was treated with active manganese dioxide by the method described in comparative example 22, resulting in a received target compound in the form of an oily substance with a yield of 96%.

NMR spectrum (270 MHz, CDCl3) million D.: a 4.86 (2H, Shir.T., J = 12,8 Hz), 6,01 (1H, TT, J = 53,3, 4,4 Hz), 6,97 (1H, d, J = 8.6 Hz), 8,15 (1H, DD, J = 8,6, and 2.3 Hz), 8,65 (1H, d, J = 2.3 Hz).

Mass spectrum m/e 237 (M
< / BR>
The target compound with a melting point of 88 - 89oC was obtained from 6-(2,2,3,3-tetrafluoropropoxy)nicotinanilide in stage 3 by the method described in comparative examples 23, 24 and 25.

NMR spectrum (270 MHz, CDCl3) million D.: 4,78 (2H, Shir.T., J = 12,6 Hz), 6,01 (1H, TT, J = 53,3, and 4.5 Hz), 6,28 (1H, DD, J = 15,2, 7.9 Hz), 6.87 in (1H, d, J = 8.7 Hz), 6,85 - 7,0 (2H, m), 7,25 (1H, DDD, J = 15,2, 7,8, 2,5 Hz), the 7.85 (1H, DD, J = 8,7, 2,5 Hz), 8,23 (1H, d, J = 2.5 Hz), 9,63 (1H, d, J = 7.9 Hz).

The IR spectrummax(CHCl3) cm-1: 1677, 1626, 1591, 1488, 1290, 1120.

Mass spectrum m/e 287 (M+), 260, 188, 178, 160, 145, 128, 117, 81, 69 (100%).

Comparative example 38

(2E,4E)-5-(6-Chloro-3-pyridyl)-2,4-pentadienyl

< / BR>
The target compound in the form of an oily substance was obtained in the stage from 6-chloronicotinamide the method described in comparative examples 23, 24 and 25.

NMR spectrum (270 MHz, CDCl3) million D.: 6,32 (1H, DD, J = 15,2, and 7.8 Hz), of 6.96 (1H, d, J = 15,4 Hz), 7,05 (1H, DD, J = 15,4, 9.8 Hz), 7,26 (1H, DD, J = 15,2, 9.8 Hz), was 7.36 (1H, d, J = 8,3 Hz), 7,80 (1H, DD, J = 8,3, 2,5 Hz), 8,48 (1H, d, J = 2.5 Hz), to 9.66 (1H, d, J = 7,8 Hz).

Comparative example 39

4-[(4-Chlorobenzyl)thio]cyclohexylidene]methylotrophy ether

< / BR>
146 mg (3,34 mmol) of 55% sodium hydride were washed with hexane and suspended in 18 ml of dimethyl sulfoxide, and then the WM is alali 1.26 g (3,34 mmol) chloride methoxybutyrophenone. Then to the reaction mixture was added 426 mg (1,67 mmol) 4-[(4-Chlorobenzyl)thio] cyclohexanone dissolved in 5 ml of dimethylsulfoxide. To the mixture was added water and the mixture was extracted with toluene. After drying the extract, the crude product obtained by evaporation of the solvent, was chromatographically on columns with 20 g of silica gel and was suirable mixed solvent methylene chloride - hexane (1:4), resulting in a received 370 mg (yield 78%) of target compound in the form of an oily substance.

NMR spectrum (270 MHz, CDCl3) million D.: 1,2 - 1,5 (2H, m), 1,7 - 2,0 (3H, m), of 2.0 - 2.2 (1H, m), 2,5 - 2,8 (2H, m), 3,53 (3H, s), 3,71 (2H, s), 5,77 (1H, s), 7,27 (4H, s).

The IR spectrummax(CHCl3) cm-1: 2935, 1689, 1491, 1443, 1123.

Mass spectrum m/e: 282, 157, 124, 109.

Comparative example 40

TRANS-4-[(4-Chlorobenzyl)thio]cyclohexanecarboxaldehyde

< / BR>
In 20 ml of acetone was dissolved 955 mg (3.4 mmol) of 4-[(4-Chlorobenzyl)thio] cyclohexylidene] methylotroph ether and to the solution was added 5 ml of water, and then 1 ml of 5 N. hydrochloric acid. The resulting mixture was stirred for 20 minutes at 55oC. the mixture is Then concentrated under reduced pressure and the residue was extracted with ethyl acetate. After drying of the extract raw prospect who has yirawala mixed solvent of methylene chloride - hexane (1:3), resulting in a received 865 mg (yield 95%) of target compound in the form of a mixture (1:1) TRANS-isomer and CIS-isomer, which represents an oily product.

The obtained product was stirred in 15 ml of 0.07 n solution of sodium methylate in methanol at room temperature for 2-3 hours. To the mixture was added 0.2 ml of acetic acid and the resulting mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium chloride. After drying of the mixture solvent drove away, resulting in a received 865 mg of a mixture (4:1) target of CIS - and TRANS-compounds in the form of solids. This solid was recrystallized from a mixed solvent of ether - hexane to obtain 220 mg of the target compound in the TRANS-form, so pl. 44 - 46oC.

NMR spectrum (270 MHz, CDCl3) million D.: 1.2 to 1.5 (4H, m), 1,9 - of 2.15 (2H, m), of 2.15 to 2.35 (1H, m), 2,35 is 2.55 (1H, m), of 3.73 (2H, s), 7,27 (5H, s), being 9.61 (1H, s).

The signal of the CIS isomer occurs when to 3.67 (2H, s) and for 9.64 (1H, s).

The IR spectrummax(CHCl3) cm-1: 2927, 1732, 1493, 1448, 1092.

Mass spectrum m/e: 268, 240, 127, 125, 110.

Comparative example 41

4-Chlorbenzyl-TRANS-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]- 1,3-butadienyl] cyclohexylsulfamic

< / BR>
50 mg (1,14 mmol) of 55% sodium hydride washed 2.5 hours at 55oC. the resulting mixture was cooled to room temperature and added 607 mg (1,26 mmol) chloride (E)-4-(trifluoromethyl)cinnamyl] triphenylphosphine. Then to the mixture was added 170 mg (0,63 mmol) of TRANS-4-[(4-Chlorobenzyl)thio] cyclohexanecarboxaldehyde, after which the mixture is stirred for 15 minutes at room temperature. The resulting mixture was diluted with toluene and washed with water and aqueous NaCl solution. Then the mixture was dried and the crude product obtained by evaporation of the solvent was subjected to column chromatography using 5 g of silica gel and was suirable mixed solvent methylene chloride - hexane (1:2). Elyuirovaniya fraction recrystallized from hexane and received 86 mg (yield 31%) of target compound having a melting point of 142 - 144oC.

NMR spectrum (270 MHz, CDCl3) million D.: 1,1 - 1,3 (2H, m), 1,3 - 1,5 (2H, m), 1,7 - 2,0 (2H, m), of 2.0 - 2.2 (2H, m) of 2.64 (1H, TT, J = 12,4 Hz), 3,74 (2H, s), of 5.81 (1H, DD, J = 15.7 Hz), of 6.20 (1H, DD, J = 15, 10 Hz), 6,47 (1H, d, J = 16 Hz), for 6.81 (1H, DD, J = 16, 10 Hz), 7,29 (4H, s), 7,46 (2H, d, J = 8 Hz), 7,55 (2H, d, J = 8 Hz).

The IR spectrummax(KBr) cm-1: 1641, 1612, 1490, 1326, 1167, 1127, 1069.

Mass spectrum m/e: 436, 417, 403, 311, 277, 235, 159, 125.

Comparative example 42

4-Chlorbenzyl TRANS-4-[(1E,3E)-4-[4-(trifluoromethyl)phenyl]- 1,3-buns-4-[(1E, 3E)-4-[4-(trifluoromethyl)phenyl] - 1,3-butadienyl] cyclohexylsulfamate and to the resulting solution at 0oC was added 104 mg (0.48 mmol) of m-chloroperbenzoic acid (purity 80%), after which the mixture is stirred for 5 minutes. To the reaction mixture were added an aqueous solution of sodium sulfite and ethyl acetate, then the organic layer was washed with an aqueous solution of sodium bicarbonate and an aqueous solution of NaCl. Then the mixture was dried and the crude product obtained by evaporation of the solvent was recrystallized from a mixture of ethyl acetate - hexane, resulting in received 168 mg (yield 77%) of target compound having a melting point of 212 - 214oC.

NMR spectrum (270 MHz, CDCl3) million D.: 1,1 - 1,3 (2H, m), 1,5 - 1,8 (2H, m), of 1.9 - 2.3 (5H, m), 2,42 (1H, TT, J = 12,4 Hz), a 3.87 (1H, d, J = 13 Hz), of 3.97 (1H, d, J = 13 Hz), 5,80 (1H, DD, J = 15, 7 Hz), to 6.22 (1H, DD, J = 15, 10 Hz), 6.48 in (1H, d, J = 16 Hz), to 6.80 (1H, DD, J = 16, 10 Hz), 7,25 (2H, d, J = 8 Hz), was 7.36 (2H, d, J = 8 Hz), was 7.45 (2H, d, J = 8 Hz), 7,55 (2H, d, J = 8 Hz).

The IR spectrummax(KBr) cm-1: 1612, 1492, 1325, 1168, 1128, 1069.

Mass spectrum m/e: 452, 436, 327, 278, 277, 159, 125.

Comparative example 43

TRANS-1-(acetylthio)-4-[(1E, 3E)-4-[4-(trifluoromethyl)phenyl] - 1,3-butadiene-1-yl]cyclohexane

< / BR>
In 11 ml of a mixed solvent of tetrahydrofuran - acetonitrile (8:3) XID and to the resulting solution was added 168 mg (1.57 mmol) of 2,6-lutidine. Then, stirring at 0oC, to the mixture was added 165 mg (0,79 mmol) of anhydride triperoxonane acid. After 3 minutes, to the mixture was added aqueous sodium bicarbonate solution, after which the resulting mixture was extracted with ethyl acetate. The oily residue obtained by evaporation of the solvent, was dissolved in 10 ml of methylene chloride and to the mixture at 0oC was added 119 mg (1,17 mmol) of triethylamine, and then was added 62 mg (0,79 mmol) acetylchloride. After 1 hour the reaction mixture was diluted with ethyl acetate and washed with an aqueous solution of sodium bicarbonate and an aqueous solution of NaCl. After drying the mixture, the crude product obtained by evaporation of the solvent was subjected to column chromatography using 5 g of silica gel and was suirable a mixture of methylene chloride - hexane (1: 1) and then purified on a column of Rover [GrosseB, a mixed solvent of ethyl acetate - hexane (1:19)] and received 98 mg (yield 70%) of target compound having a melting point of 113 - 115oC.

NMR spectrum (270 MHz, CDCl3) million D.: 1.2 to 1.5 (4H, m), 1.7 to 1.9 (2H, m), of 2.0 - 2.2 (3H, m), 2,31 (3H, s), 3,37 (1H, TT, J = 12,4 Hz), of 5.82 (1H, DD, J = 15.7 Hz), of 6.20 (1H, DD, J = 15, 10 Hz), 6,47 (1H, d, J = 16 Hz), for 6.81 (1H, DD, J = 16, 10 Hz) was 7.45 (2H, d, J = 8 Hz), 7,54 (2H, d, J = 8 Hz).

The IR spectrummax(KBr) cm-1: 1688, 1613, 1326,Il)phenyl]-2-propyl-1-ol

< / BR>
In 50 ml of diethylamine was dissolved 5.0 g (22 mmol) of 4-bromo,- triptoreline and 1.25 g (22 mmol) propargilovyh alcohol and to the solution was added 80 mg (0.11 mmol) chloride bis(triphenylphosphine)palladium (II) and 40 mg (0.22 mmol) of copper iodide (I), after which the mixture is stirred for 35 minutes at 50oC. Then, to this mixture was added 40 mg (0.06 mmol) chloride bis(triphenylphosphine)palladium (II) and the resulting mixture was stirred for another 35 minutes. Then the mixture was cooled to room temperature, diluted with benzene and filtered, and the filtrate washed with water. After drying the mixture, the crude product obtained by evaporation of the solvent was subjected to column chromatography using 50 g of silica gel and was suirable a mixture of ethyl acetate - hexane (3:17), resulting in received of 2.21 g (yield 50%) of target compound in the form of an oily product.

NMR spectrum (270 MHz, CDCl3) million D.: 1,8 (1H, Shir., OH), to 4.52 (2H, s), 7,54 (2H, d, J = 9 Hz), EUR 7.57 (2H, d, J = 9 Hz).

The IR spectrummax(CHCl3) cm-1: 3610, 1618, 1324, 1172, 1133, 1069, 1019, 844.

Mass spectrum m/e: 200, 183, 171, 151, 131.

Comparative example 45

3-[4-(Trifluoromethyl)phenyl]-2-propenal

< / BR>
In 20 ml of methylene chloride was dissolved of 2.21 g (11.0 mmol) of 3-[4-(trifluoromethyl)reagent dess-Martin. To the mixture was added benzene, and any insoluble matter was removed by filtration, then the filtrate was concentrated and got to 1.83 g (yield 84% of target compound in the form of an oily product).

NMR spectrum (270 MHz, CDCl3) million D.: to 7.68 (2H, d, J = 9 Hz), 7,71 (2H, d, J = 9 Hz), to 9.45 (1H, s).

The IR spectrummax(CHCl3) cm-1: 2197, 1664, 1324, 1175, 1138.

Mass spectrum m/e: 198, 197, 170, 151, 120.

Comparative example 46

Ethyl (E)-5-[(4-trifluoromethyl)phenyl]-2-penten-4-INOUT

< / BR>
181 mg (of 4.54 mmol) of 55% sodium hydride were washed with hexane, and then suspended in 10 ml of 1,2-dimethoxyethane and to the resulting suspension, stirring at 0oC in nitrogen atmosphere, was added 1,02 g (of 4.54 mmol) of triethyl 4-phosphonoacetate. After 20 minutes, to the mixture was added 500 mg (2,52 mmol) 3-[4-(trifluoromethyl)phenyl] -2-propenal and the resulting mixture stirred for 20 minutes. The reaction mixture was diluted with ethyl acetate and then added ice, after which the organic layer is washed with water. The crude product obtained by removal of the solvent was subjected to column chromatography using 15 g of silica gel and was suirable benzene, resulting in received 488 mg (yield 72%) of target compound in the form of an oily product 16 Hz), of 7.5 to 7.7 (4H, m).

The IR spectrummax(CHCl3) cm-1: 1712, 1622, 1316, 1174, 1134.

Mass spectrum m/e: 268, 240, 223, 195, 183, 175.

Comparative example 47

(E)-5-[4-(Trifluoromethyl)phenyl]-2-penten-4-in-1-ol

< / BR>
In 4 ml of toluene was dissolved 480 mg (1,79 mmol) of ethyl (E)-5-[4-(trifluoromethyl)phenyl] -2-penten-4-enoate and to the resulting solution, stirring at 0oC, was added 2.38 ml (3.58 mmol) of a 1.5 M solution of hydride diisobutylaluminum-toluene. After 10 minutes, to the mixture was added ice, and any insoluble matter was removed by filtration through celite. Then the organic layer was dried and the crude product obtained by evaporation of the solvent was subjected to column chromatography using 15 g of silica gel and was suirable a mixture of ethyl acetate - hexane (3:17), resulting in a received 353 mg (yield 87%) of target compound in the form of an oily product.

NMR spectrum (270 MHz, CDCl3) million D.: 1,60 (1H, Shir., OH), or 4.31 (2H, W), of 5.99 (1H, d, J = 16 Hz), 6,40 (1H, dt, J = 16.5 Hz), 7,54 (2H, d, J = 9 Hz), EUR 7.57 (2H, d, J = 9 Hz).

Comparative example 48

(E)-5-[(4-Trifluoromethyl)phenyl]-2-penten-4-Inal

< / BR>
In 4 ml of methylene chloride was dissolved 350 mg (1.56 mmol) of (E)-5-[4-(trifluoromethyl)phenyl] -2-penten-4-in-1-ol and to the resulting solution was added to the CTV was removed by filtration, and the filtrate was concentrated. Then the filtrate was subjected to column chromatography using 10 g of silica gel and was suirable a mixture of ethyl acetate-hexane (1:24), resulting in a received 245 mg (yield 70%) of the desired product as an oily substance.

NMR spectrum (270 MHz, CDCl3) million D.: to 6.58 (1H, DD, J = 16, 8 Hz), PC 6.82 (1H, d, J = 16 Hz), 7,63 (4H, s), 9,65 (1H, d, J = 8 Hz).

The IR spectrum max(CHCl3) cm-1: 1670, 1325, 1132, 1119, 1107, 1072, 845.

Mass spectrum m/e: 224, 196, 195, 175, 170, 146.

Comparative example 49

Methyl (Z)-4-chloro -- (trifluoromethyl)cinnamic

< / BR>
In 10 ml of tetrahydrofuran was dissolved 150 mg (0.47 mmol) of bis(2,2,2-triptorelin)(methoxycarbonylmethyl)phosphonate and to the resulting mixture, stirring at -78oC in nitrogen atmosphere, was added drop of 0.94 ml (0.47 mmol) of 0.5 M solution hexamethyldisilazide potassium toluene. Then to the mixture was added 622 mg (2,66 mmol) of 18-crown-6, the resulting mixture was stirred 20 minutes and was added to the solution obtained by dissolving 98 mg (0.47 mmol) of 4'-chloro-2,2,2-trifurcation in 1 ml of tetrahydrofuran. The temperature of the reaction mixture was slowly brought to room temperature, after which was added a saturated aqueous solution of ammonium chloride and the mixture was extracted with ethylacetate (elwira 4% ethyl acetate-hexane) using silica gel, as a result, we received 89 mg (yield 70%, with a content of about 1/10 (E)-isomer of the target compound in the form of an oily product).

NMR spectrum (270 MHz, CDCl3) million D.: of 3.85 (3H, s), 6,34 (1H, s), 7,34 (2H, d, J = 8.6 Hz), 7,39 (2H, d, J = 8.6 Hz).

Comparative example 50

(Z)-4-Chloro--(trifluoromethyl)cinnamaldehyde

< / BR>
The target compound was obtained in stage 2 of methyl (Z)-4-chloro--(trifluoromethyl)cinnamate in relation to the description given in comparative examples 21 and 22, in the form of an oily product (yield 81%).

NMR spectrum (270 MHz, CDCl3) million D.: 6,36 (1H, d, J = 7,3 Hz), 7,38 (2H, d, J = 8.6 Hz), 7,44 (2H, d, J = 8.6 Hz), of 10.21 (1H, square, J = 7,3, 2.0 Hz).

Comparative example 51

Methyl (2E,4Z)-5-(4-chlorophenyl)-6,6,6-Cryptor-2,4-hexadienoic

< / BR>
(Z)-4-Chloro--(trifluoromethyl)cinnamaldehyde and trimethylphosphate was subjected to reaction by the method described in comparative example 23, the result of which has been the target compound in the form of an oily product from the market, comprising about 90% (separation and purification was performed by column chromatography).

NMR spectrum (270 MHz, CDCl3) million D.: 3,81 (3H, s), x 6.15 (1H, d, J = 15.2 Hz), 6,59 (1H, d, J = 11,9 Hz), 7,31 (2H, d, J = 8.6 Hz), 7,38 (1H, d, J = 8.6 Hz), 7,78 (1H, ddcv., J = 15,2, 11,9, 2.0 Hz).

Cf is eat, shown in comparative examples 21 and 22 were obtained in stage 2 of the target compound from methyl (2E,4Z)-5-(4-chlorophenyl)-6,6,6-Cryptor-2,4-hexadienoic (71% yield).

NMR spectrum (270 MHz, CDCl3) million D.: 6,37 (1H, DD, J = 15,2, 7,3 Hz), 6,72 (1H, d, J = 11,9 Hz), 7,33 (2H, d, J = 8.6 Hz), 7,40 (2H, d, J = 8.6 Hz), to 7.64 (1H, DKW, J = 15,2, 11,9, 2 Hz), 9,74 (1H, d, J = 7,3 Hz).

Comparative example 53

2-Methyl-2-[(TRANS-2-phenyl - 1,3-dioxane-5-yl)thio] -4'- (trifluoromethyl) propiophenone

< / BR>
3.8 ml of dimethylformamide was dissolved 619 mg (2.10 mmol) of 2-bromo-2-methyl-4'-(trifluoromethyl)propiophenone and 500 mg (2.10 mmol) of TRANS-4-acetylthio-2-phenyl-1,3-dioxane and to the resulting solution, stirring at room temperature in a nitrogen atmosphere, was added to 0.44 ml (2.10 mmol) of a 28% solution of sodium methoxide - methanol. After 30 minutes the reaction mixture was added water, then the mixture was extracted with ethyl acetate. After evaporation of solvent received 860 mg (yield 100%) of target compound in the form of a solid substance.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.61 (6H, s), 4,42 (1H, TT, J = 11,6, 5.0 Hz), to 3.64 (2H, t, J = 11,6 Hz), of 4.12 (2H, DD, J = 11,6, 5.0 Hz), 5,38 (1H, s), 7,3 - 7,5 (5H, m), to 7.68 (2H, d, J = 8,2 Hz), 8,19 (2H, d, J = 8,2 Hz).

Comparative example 54

(RS)-3-Methyl-3- [(TRANS-2-phenyl-1,3-dioxane-5-yl)thio] -1- (1H-1,2,4-triazole-1-yl) -2-butanol
<) iodide trimethylsulfoxonium, 381 mg (6,79 mmol) of potassium hydroxide and 264 mg (3,82 mmol) of 1,2,4-triazole was heated, stirring 5.7 ml of t-butanol at 80oC for 6 hours. After cooling, the reaction mixture was distributed between chloroform and water and CHLOROFORMATES layer was separated and was dried, followed by evaporation of the solvent. Thus obtained oily product was subjected to column chromatography on silica gel and was suirable a mixture of ethyl acetate - hexane (1: 1), resulting in a received 605 mg (yield 74%) of target compound in the form of a foamy substance.

NMR spectrum (270 MHz, CDCl3) million D.: to 1.38 (3H, s) of 1.39 (3H, c), 3,55 to 3.8 (3H, m) to 4.33 (1H, m), of 4.54 (1H, m), 5,02 (2H, s), lower than the 5.37 (1H, s), 5,44 (1H, s), and 7.3 and 7.6 (5H, m), 7,73 (1H, s), 7,94 (1H, s).

Comparative example 55

(RS)-3-[(1,3-Dihydroxy-2-propyl)thio] -3-methyl-2-[4-(trifluoromethyl) phenyl]-1-(1H-1,2,4-triazole-1-yl)- 2-butanol

< / BR>
(RS)-3-Methyl-3-[(TRANS-2-phenyl-1,3-dioxane-5-yl)thio] -1-(1H - 1,2,4-triazole-1-yl)-2-butanol was treated with HCl in methanol as described in comparative example 2, resulting in the obtained target compound in the form of a foamy substance.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.30 (3H, s) of 1.42 (3H, s) to 3.35 (1H, m), 3,55 to 3.8 (3H, m), of 3.96 (1H, DD, J = 10,9, a 5.4 Hz), a 4.83 (3H, s), of 5.26 (1H, d, J = 14.6 Hz), of 5.34 (1H, d, J = 14.6 Hz), 7,53 (2H, d, J = 8,3 Hz), of 7.70 (1H, s), < / BR>
In 50 ml of methanol was dissolved 5.00 g of CIS-2-phenyl-4- (p-toluensulfonyl)-1,3-dioxane and the resulting solution was added 5 ml of 4 n HCl-dioxane, after which the mixture is stirred 2 hours at room temperature. To the reaction mixture was added 3.5 g of powder NaHCO3and the mixture is stirred for 10 minutes. Then the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. Thus obtained oily product was subjected to column chromatography on silica gel and was suirable with ethyl acetate, resulting in a received 3,70 g (yield 100%) of target compound in the form of an oily product.

NMR spectrum (60 MHz, CDCl3) million D.: is 2.40 (3H, s), 3,30 (2H, s), of 3.73 (4H, d, J = 4.5 Hz), 4,55 (1H, quintet, J = 4.5 Hz), 7,33 (2H, d, J = 8 Hz), to 7.84 (2H, d, J = 8 Hz).

Comparative example 57

CIS-4-(p-toluensulfonyl)-2-[(1E, 3E)-4-[4-(trifluoromethyl)phenyl] -1,3-butadiene-1-yl]-1,3-dioxane

< / BR>
4.5 ml of methylene chloride was dissolved 200 mg (0.81 mmol) of 2-(p-toluensulfonyl)-1,3-propane diol and 206 mg (of 0.91 mmol) (2E, 4E)-5-[4-(trifluoromethyl)phenyl] -2,4-pentadienyl and to the resulting solution was added 15 mg of p-toluensulfonate acid and 0.8 g of molecular sieve 4, after which the mixture is stirred for 1 hour at 0oC. Then to the reactions the e sieve was removed by filtration and the filtrate was extracted with methylene chloride. The oily product obtained by evaporation of the solvent was separated using preparative thin layer chromatography on silica gel (manifesting solvent: 20% ethyl acetate-hexane), resulting in a received 107 mg (yield 29%) of TRANS-isomer with lower polarity, and 153 mg (yield 42%) of the CIS isomer with higher polarity, in the form of an oily product, respectively.

NMR spectrum (270 MHz, CDCl3the CIS isomer, million D.: of 2.45 (3H, s) to 3.99 (2H, Shir.D., J = 13,2 Hz), 4,19 (2H, Shir.D., J = 13,2 Hz), of 4.45 (1H, Shir.C) 5,09 (1H, d, J = 4.6 Hz), of 5.82 (1H, DD, J = 15,2, 4.6 Hz), to 6.57 (1H, DD, J = 15,2, 10.5 Hz), 6,63 (1H, d, J = 15.2 Hz), PC 6.82 (1H, DD, J = 15,2, 10.5 Hz), was 7.36 (2H, d, J = 8.6 Hz), of 7.48 (2H, d, J = 8.6 Hz), 7,56 (2H, d, J = 8.6 Hz), the 7.85 (2H, d, J = 8.6 Hz).

Comparative example 58

Ethyl (2E,4E)-5-(2,3,5-trichlorophenyl)-2,4-pentadienoic

< / BR>
3,00 (12,0 mmol) triethylphosphate was dissolved in 15 ml of tetrahydrofuran, to the resulting solution at -78oC in an atmosphere of nitrogen was added to 1.41 g (12.6 mmole) of tert-butoxide potassium, followed by stirring the resulting mixture at -78oC for 30 minutes to obtain a brown solution. Then to the reaction mixture was added a solution of commercially available 2,3,5-trichlorobenzaldehyde (2.10 g, 10.0 mmol) in 5 ml of tetrahydrofuran, after which whether saturated aqueous solution of NH4Cl and the product was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated NaCl solution. The residue obtained by distillation of the solvent was recrystallized from hexane to obtain 310 mg (yield 11%) of target compound in the form of a crystalline mass of yellow color, having a melting point of 82 83oC. the mother liquor was subjected to column chromatography using 20 g of silica gel and was suirable mixed solvent of ethyl acetate-hexane (1:1) to obtain the additional 1.63 g (yield 53%) of target compound in the form of a crystalline mass of yellow.

The IR spectrum max(KBr) cm-1: 1711, 1295, 1282, 994.

NMR spectrum (270 MHz, CDCl3) million D.: of 1.33 (3H, t, J = 7 Hz), 4,25 (2H, sq J = 7 Hz), between 6.08 (1H, d, J = 15 Hz), 6,83 (1H, DD, J = 15, 11 Hz), 7,25 (1H, d, J = 15 Hz), 7,42 (1H, d, J = 2 Hz), 7,46 (1H, DD, J = 15, 11 Hz), to 7.50 (1H, d, J = 2 Hz).

Mass spectrum m/e: 304, 259, 231, 196.

Comparative example 59

(2E,4E)-5-(2,3,5-trichlorophenyl)-2,4-pentadien-1-ol

< / BR>
1.63 g (5,34 mmole) of ethyl (2E,4E)-5-(2,3,5-trichlorophenyl)-2,4 - pentadienoic was dissolved in 10 ml of toluene and at -78oC in an atmosphere of nitrogen was added 11.7 ml (about 11.7 mmole) of 1.0 M solution of diisobutylaluminium in toluene, followed by stirring the resulting CME and and gave it to warm to room temperature for 2 hours. The resulting suspension was filtered through Celite and the precipitate washed with ethyl acetate. The filtrate and wash solution were combined and after removal of the solvent was obtained crystalline residue. By trituration of the residue from a mixed solvent of diisopropyl ether-hexane received 1.39 g (yield 99%) of target compound in the form of needle crystals of pale yellow color with a melting point of 116 - 118oC.

The IR spectrummax(KBr) cm-1: 3302, 1091, 987.

NMR spectrum (270 MHz, CDCl3) million D.: 1,41 (1H, t, J = 5 Hz), 4,30 (2H, Shir.t, J = 5 Hz), between 6.08 (1H, dt, J = 15, 5 Hz), of 6.49 (1H, Shir.DD, J = 10 Hz), 6,76 (1H, DD, J = 15, 10 Hz), make 6.90 (1H, d, J = 15 Hz), 7,35 (1H, d, J = 2 Hz), was 7.45 (1H, d, J = 2 Hz).

Mass spectrum m/e: 262, 244, 199.

Comparative example 60

(2E,4E)-5-(2,3,5-trichlorophenyl)-2,4-pentadienyl

< / BR>
to 1.00 g (of 3.80 mmol) (2E,4E)-5-(2,3,5-trichlorophenyl)-2,4-pentadien-1-ol was dissolved in 15 ml of methylene chloride, was added 10 g of active manganese dioxide, followed by stirring the resulting mixture for 2 hours at room temperature. The reaction mixture was filtered, then the solvent evaporated. The resulting crystalline residue was recrystallized from diisopropyl ether to obtain 862 mg (yield 87%) of zelenog is 56, 1120.

NMR spectrum (270 MHz, CDCl3) million D.: 6,34 (1H, DD, J = 15, 8 Hz), 6,97 (1H, DD, J = 15, 11 Hz), 7,31 (1H, DD, J = 15, 11 Hz), 7,38 (1H, d, J = 15 Hz), 7,46 (1H, d, J = 2 Hz), 7,54 (1H, d, J = 2 Hz), 9,67 (1H, d, J = 8 Hz).

Mass spectrum m/e: 260, 255, 197, 162.

Experimental example 1

Mice (one group consisted of 10 mice), which were inoculated 4 - 9106Candida albicans, is administered orally 20 mg/kg of drugs after 1, 4 and 24 hours, and then within 21 days after infection was assessed by the degree of survival of mice. Table 2 presents the results of the comparison compounds (I) of the present invention with commercially available compound Fluconasol. This comparison showed that the compound (I) detects a wonderful antifungal activity.

Example obtain 1 drug

Capsule

Connection examples 1 to 39 and 40 to 50 mg

Lactose - 128 mg

Corn starch - 70 mg

Magnesium stearate 2 mg- ---------- - 250 mg

The resulting powder was stirred and passed through a sieve of 60 mesh, after which the powder was encapsulated in a gelatin capsule No. 3, containing 250 mg of the drug.

Example of getting a drug 2

Tablet

Connection examples 1 to 39 and 40 to 50 mg

Lactose - 126 mg

Corn starch - 23 mg

and using corn starch as a finishing agent and drained, then using teletrauma machine produced 200 mg tablets. If necessary, the tablets may be coated in a sugar coating.

The compound having General formula (I) or its pharmacologically acceptable salt of the present invention have excellent antifungal activity and can be used as antifungal agents.

1. Triazolone compounds of General formula

< / BR>
where Ar1represents a phenyl group or phenyl group having 1 to 2 substituent, where these substituents are a halogen atom or triptorelin group;

Ar2represents a phenyl group, a 5 - or 6-membered aromatic heterocyclic group, where the specified heterocyclic group having one nitrogen atom or sulfur, specified phenyl group or 5 - to 6-membered aromatic heterocyclic group optionally has 1, 2 or 3 substituent, where these substituents are lower alkyl group, lower alkoxygroup, halogen atom, lower alkyl group substituted by an atom or atoms of halogen, lower alkoxygroup, substituted atom or halogen atoms, the nitro-group, a cyano or a group S(O)mR6, gleave 0, 1 or 2;

R0represents a hydrogen atom or a lower alkyl group;

R1represents a lower alkyl group;

R2, R3, R4and R5may be the same or different and represent a hydrogen atom, a lower alkyl group or a lower alkyl group substituted by an atom or atoms of halogen;

p is 0 or 1;

q and s is 0, 1 or 2;

r is 0 or 1;

A represents A 4 - to 7-membered aliphatic carbocyclic group containing 4 to 7 carbon atoms, or 4 to 7-membered aliphatic heterocyclic group having at least one nitrogen atom or oxygen;

or their pharmacologically acceptable salts.

2. Triazolone compound or its pharmacologically acceptable salt p. 1, where Ar1represents a phenyl group having 1 or 2 substituent, where specified, the Deputy represents a fluorine atom, a chlorine atom or triptorelin group.

3. Triazolone compound or its pharmacologically acceptable salt under item 1 or 2, where Ar2represents a phenyl group, a 5 - or 6-membered aromatic heterocyclic group, where the specified aromatic heterocyclic group having one nitrogen atom or sulfur, and decree of the body, where these substituents are lower alkyl group, halogen atom, lower alkyl group substituted by an atom or atoms of halogen, lower alkoxygroup, substituted atom or halogen atoms, the nitro-group, a cyano or a group S(O)mR6where R6represents a lower alkyl group which may be substituted by an atom or atoms of halogen and m is 0, 1 or 2.

4. Triazolone compound or its pharmacologically acceptable salt PP.1 to 3, where Ar2represents a phenyl group or pyridyloxy group, or phenyl group, pyridyloxy group or thienyl group having 1 or 2 substituent, where these substituents are lower alkyl group; a halogen atom; a lower alkyl group substituted by an atom or atoms of halogen; lower alkoxygroup, substituted atom or halogen atoms; a nitro-group; a cyano or the group-S(O)mR6where R6represents a lower alkyl group which may be substituted by an atom or atoms of halogen and m is 0, 1 or 2.

5. Triazolone compound or its pharmacologically acceptable salt PP.1 to 4, where R0represents a hydrogen atom or methyl group.

7. Triazolone compound or its pharmacologically acceptable salt PP. 1 - 6, where R2, R3, R4and R5may be the same or different and represent a hydrogen atom, a lower alkyl group or a lower alkyl group substituted by fluorine atoms.

8. Triazolone compound or its pharmacologically acceptable salt PP. 1 to 7, where R2, R3, R4and R5may be the same or different and represent a hydrogen atom or a methyl group, or a methyl group substituted by fluorine atoms.

9. Triazolone compound or its pharmacologically acceptable salt PP.1 - 8, where A represents A 5 - or 6-membered aliphatic carbocyclic group containing 5 or 6 carbon atoms, or 4 to 6-membered aliphatic heterocyclic group having at least one nitrogen atom or oxygen.

10. Triazolone compound or its pharmacologically acceptable salt PP.1 - 8, where A represents A 5 - or 6-membered aliphatic carbocyclic group containing 5 or 6 carbon atoms, or 4 to 6-membered aliphatic heterocyclic group having 1 or 2 nitrogen atom or oxygen.

11. Triazolone connection or parmacotto.

12. Triazolone connection on p. 1, selected from the group including

2-(2,4-Differenl)-3-[[2-[2-[4-(trifluoromethyl)phenyl] vinyl] -1,3-dioxane-5-yl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol;

2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-3-[[2-[2-[4-(triptoreline)phenyl]vinyl]-1,3-dioxane-5-yl]thio]-2-butanol;

2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-3-[[2-[4-[4-(trifluoromethyl)phenyl]-1,3-butadiene-1-yl]-1,3-dioxane-5-yl]thio]-2-butanol;

2-(2,4-differenl)-3-[[2-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl] -1,3-butadiene-1-yl]-1,3-dioxane-5-yl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol;

2-(2,4-differenl)-3-[[2-[4-[4-(chlorophenyl)-5,5,5-Cryptor-1,3-pentadien-1-yl]-1,3-dioxane-1-yl]thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol;

2-(2,4-differenl)-3-[[1-[4-(triptoreline)cynnamoyl] piperidine-4-yl] thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol;

2-(2,4-differenl)-3-[[1-(4-nitrocinnamyl)piperidine-4-yl] thio]-1-(1H-1,2,4-triazole-1-yl)-2-butanol;

2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-3-[[1-[5-[4-(triptoreline)phenyl]-2,4-pentadienyl]piperidine-4-yl]thio]-2-butanol;

3-methyl-1-(1H-1,2,4-triazole-1-yl)-2-[4-(trifluoromethyl)phenyl] -3-[[2-[4-(trifluoromethyl]phenyl]-1,3-dioxane-5-yl]thio]-2-butanol;

2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-3-[[2-[4-(triptoreline)phenyl]-1,3-butadiene-1-yl]-1,3-dioxane-5-yl]thio]-2-butanol;

3-[[2-[4-[4-(2,2,3,3-ritratto the 1-(1H-1,2,4-triazole-1-yl)-2-[4-(trifluoromethyl)phenyl] -3-[[2-[4-[4-(trifluoromethyl]phenyl]-1,3-butadiene-1-yl]-1,3-dioxane-5-yl]thio]-2-butanol;

2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-3-[[2-[4-[4-(trifloromethyl)phenyl] -1,3-butadiene-1-yl] -1,3-dioxane-5-yl]thio)-2-butanol;

2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-3-[[2-[4-[4-(trifluoromethyl)phenyl]-1,3-butadiene-1-yl]cyclohexyl]thio)-2-butanol;

2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-3-[[2-[6-[4-(trifluoromethyl)phenyl]-1,3,5-hexatriene-1-yl]-1,3-dioxane-5-yl]thio]-2-butanol;

2-(2,4-differenl)-3-methyl-1-(1H-1,2,4-triazole-1-yl)-3-[[2-[4-[4-(trifluoromethyl)phenyl]-1,3-butadiene-1-yl]-1,3-dioxane-5-yl]thio]-2-butanol or

2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-3-[[2-[4-[4-(trifluoromethyl)phenyl]-1,3-butene-3-in-1-yl]-1,3-dioxane-5-yl]thio]-2-butanol,

or their pharmacologically acceptable salts.

13. Antifungal composition comprising an active ingredient and a pharmacologically acceptable excipient or diluent, characterized in that it contains as active ingredient an effective amount of the compounds of the triazole or its pharmacologically acceptable salt according to PP.1 - 12.

 

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