Derivatives of 1,2,4-triazole or their pharmaceutically acceptable salts, pharmaceutical composition and the intermediate

 

(57) Abstract:

Usage: as antifungicide drugs for the treatment of fungal diseases in animals, including humans. The essence of the invention: derivatives of 1,2,4-triazole of the formula

< / BR>
where R is phenyl, substituted by 1-2 halogen; R1- C1-4alkyl; R2is hydrogen or C1-4alkyl; Het is pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, unsubstituted or substituted C1-4the alkyl, C1-4alkoxy, halogen, cyanide, amine, or-NHCO2(C1-4) alkyl; or their pharmaceutically acceptable salts, pharmaceutical composition and intermediate compounds for obtaining derivatives of 1,2,4-triazole of the General formula

< / BR>
where R1, R2and R have the above values; Het1- pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, possibly substituted C1-4the alkyl, C1-4alkoxy, halogen, cyano or nitro-group, Y is the group to delete. 6 C. and 13 C.p. f-crystals, 3 tables.

The invention relates to new derivatives of triazole, which have antifungicide action and can be used to treat fungal infections in animals, including humans.

The invention relates to compounds fo what estately, each of which is independently from each other selected from halogen;

R1represents C1-4alkyl;

R2denotes H or C1-4alkyl; and

"Het", which are attached to adjacent carbon atom by a ring carbon atom, chosen from pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, "Het" optionally substituted C1-4the alkyl, C1-4alkoxy, halogen, CN, NH2or-NHCO2(C1-C4) alkyl.

In one aspect, the invention provides for obtaining compounds of formula (l) and their pharmaceutically acceptable salts, where "Het" is chosen from among such radicals as 2 - and 4-pyridinyl, pyridazinyl, 2 - and 4-pyrimidinyl and pyrazinyl, "Het" optionally substituted C1-C4the alkyl, C1-C4alkoxy, halogen, CN, NH2or-NHCO2(C1-C4by alkyl); and the radicals R, R1and R2have the values indicated above for compounds of formula (l).

In another aspect of "Het" represents pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl "Het", not necessarily contain as substituents C1-C4alkyl, C1-C4alkoxy, halo, or NH2.

When radical "Het" includes substituents, predmosti and C4alkyl and CNS group can be straight or branched.

When the radical is a substituted phenyl group, it includes for example 2-forfinal, 2-chlorophenyl, 2-bromophenyl, 2-itfeel, 2-triptoreline, 2,4-dichlorophenyl, 2,4-differenl, 2-chloro-4-forfinal, 2-fluoro-4-chlorophenyl and 2.5-differenl.

Preferably, the radical R represents a phenyl group substituted by 1-2 halogen (preferably F or Cl).

Also more preferably, the radical R represents a 2,4-differenl, 2,4-dichlorophenyl, 2-forfinal or 2-chlorophenyl.

Most preferably, R represents a 2,4-differenl.

Preferably the radical R1means methyl and the radical R2H or methyl.

Most preferably the radical R1means methyl and the radical R2H.

Preferably the radical "Het" to choose from groups such as pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, optionally substituted by 1 or 2 substituents, each of which is independently selected from C1-C4of alkyl, C1-C4alkoxy, halo, CN, NH2and-NHCO2(C1-C4the alkyl).

Also more predpochtitelney one of the Vice-CN, NH2or-NHCO2(C1-C4alkyl).

Preferred pyridinoline and pyrimidinylidene groups are 2 - and 4-pyridinyl and 2 - and 4-pyrimidinyl, all optionally substituted as indicated above.

Yet more preferably, "Het" is chosen from among groups such as pyridinyl (preferably 2 - and 4-pyridinyl), pyridazinyl, 2 - and 4-pyrimidinyl and pyrazinyl, all optionally substituted by one of the Vice CN, NH2or-NHCO2(C1-C4alkyl).

Most preferably, "Het" represents 2-pyridinyl, 4-pyridinyl or 4-pyrimidinyl.

Pharmaceutically acceptable salts of compounds of formula (l) include salts obtained by adding acids, which provide non-toxic salts, such as hydrochloride, hydrobromide, hydroiodide, sulfates or bisulfate, phosphate or acid phosphate, acetate, maleate, fumarate, lactates, tartratami, Paraty, gluconate, benzoate, methanesulfonate, benzosulfimide and para-toluenesulfonate.

Particularly preferred individual compounds are:

2-/2,4-differenl/-3-/pyridine-2-yl/-1-/1H-1,2,4-triazole-1-yl/butane-2-ol,

2-/2,4-differenl/-3-/pyridine-4-yl/-1-/1H-1,2,4-Tria is acceptable salt.

The compounds of formula (l) of the invention receive the following ways:

1. The compounds of formula

< / BR>
where the radicals R, R1and R2have the same meaning specified for formula (l), and "Het" represents a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, and "Het" optionally substituted C1-C4the alkyl, C1-C4alkoxy, halo; or CN can be obtained in the following way:

< / BR>
where the radicals R, R1, R2and "Het" have the same meaning specified for formula (La).

According to a typical method, the compounds of formula (II) are subjected to deprotonation by adding about one equivalent of the appropriate strong base, for example, diisopropylamide lithium, interact obtained salt (preferably lithium, sodium or potassium salt). in situ with a ketone of formula (III). The reaction is usually carried out from -80oto -50oC, preferably at -70oC, in an environment appropriate organic solvent, such as tetrahydrofuran or diethyl ether, in an inert atmosphere, e.g. nitrogen or argon.

The initial compounds of the formula (II) are known or can be obtained from a conventional method is 69442 or the United Kingdom patent 1 464 224) or can be obtained in a similar way; or

< / BR>
where the radicals R, R1, R2and "Het" are the same values that are specified for (La), and Y represents useplease group, for example, chlorine, bromine or C1-C4alkanesulfonyl group (such as methanesulfonate). Examples of acceptable salts of 1H-1,2,4-triazole salts are alkali metal (preferably sodium) and tetraalkylammonium (preferably Tetra-n-butylamine (see U.S. patent 4 259505).

The reaction is preferably carried out using as starting material epoxide (lY). If this process is used as a compound of the formula (Yl), the mechanism of the reaction dictates that at least partially epoxide of the formula (lY) was formed in situ under the reaction conditions. Therefore, such a process in this respect is similar to the one that involves the use of epoxy resin (lY) as the starting material.

When using salt 1H-1,2,4-triazole, the reaction is usually carried out at a temperature from room temperature to 100oC, preferably at about 60oC if you use a sodium salt of 1H-1,2,4-triazole, and preferably at room temperature when using the corresponding Tetra-n-butylammonium salt, in an environment appropriate organic restorelite, using 1H-1,2,4-triazole in the presence of a base, for example, Na2CO3or K2CO3preferably from 50oC to 100oC in an environment appropriate organic solvent, for example N, N-dimethylformamide or methanol.

Intermediate compounds of formula (lY) and (Yl) can be obtained by conventional methods, for example, as described in the "Examples" section, and as shown in schemes A and B:

< / BR>
where the radicals R, R1, R2and "Het" have the meanings specified for formula (La), and Y represents useplease group, preferably C1or Br.

In the usual procedure the compounds of formula (II) deprotonated by adding about one equivalent of the appropriate strong base, for example, diisopropylamide lithium, and the resulting ORGANOMETALLIC intermediate compound interacts in situ with the compound of the formula (Y). The reaction is usually carried out at a temperature from -80oto -50oC, preferably at about -70oC, in an environment appropriate organic solvent, such as tetrahydrofuran or diethyl ether, in an inert atmosphere, e.g. nitrogen or argon. The intermediate compound (Yl) it is not necessary to allocate, and Oatney temperature), and forms oxiran formula (lY).

The compounds of formula (Yl), when Y represents chlorine or bromine, can also be obtained by reacting epoxy resin (lY) with the corresponding halogenation in anhydrous conditions; or

Scheme B is provided at the end of the description,

where the radicals R, R1, R2and "Het" have the meanings specified for formula (La), and X the corresponding tsepliaeva group, for example, Cl, Br, l or methansulfonate.

According to the standard method, the compounds of formula (YIII), (l) and (X) is obtained directly from a complex ester of the formula (VII) by reaction with ORGANOMETALLIC intermediate compound, obtained as a rule by deprotonation of compounds of formula Het1-CH3or Het1-CHR1R2(compound II), where Het1, R1and R2have the same meaning specified for formula (lA), with approximately one equivalent of the appropriate strong base, for example, diisopropylamide lithium. The reaction is usually carried out at a temperature from -80oto -50oC, preferably at about -70oC, in an environment appropriate organic solvent, such as tetrahydrofuran or diethyl ether, in an inert atmosphere, for example, inpredictable a 3-pyridinyl or 5-pyrimidinyl and the radicals R and R1have the same meaning specified for formula (1A) can be easily obtained from a complex ester of the formula (VII) by reaction with ORGANOMETALLIC intermediate compound obtained by deprotonation of compounds of formula

< / BR>
where the radicals R1represents hydrogen or C1-C4alkyl, in situ, by the same method described in the previous paragraph. Intermediate-ketoester obtained after processing, are then hydrolysis/decarboxylation by processing the corresponding strong mineral acid, for example concentrated hydrochloric acid, preferably boiling, with the aim of obtaining the compounds of formula (VIII) or (IX).

In another embodiment, the compounds of formula (IX) and (X) can be obtained by the reaction of, respectively, the compounds of formula (VIII) or (IX), with approximately one equivalent of the appropriate base, e.g. sodium hydride, followed by alkylation of the formed carbanion in situ using appropriate agent alcyonaria. The reaction is usually carried out at a temperature of from 0oC to room temperature in an environment appropriate organic solvent, for example N,N-dimethylformamide.

Preferably alkali the OH[CH3(CH2)3]4NHSO4/H2O/CHCl3//C1-C4alkyl/X

X is preferably iodine, at a temperature of from 0oC to room temperature, typically at room temperature.

Epoxidation of ketones of formula (IX) or (X) is carried out using conventional methods, for example, using matilida dimethyloxazolidine (see for example, j A. C. S. (1965), 87, 13 53) or hermeticity (see, for example, Tel. Lett. (1986), 795).

(2) the Compound of formula (l) in which "Het" is monosubstituted by cyano to carbon atom nucleus, which is located next to the nitrogen atom of the nucleus, where "Het" represents a pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, and the radicals R, R1and R2and have the same meaning specified for formula (l), it is most convenient to get from unsubstituted predecessors "Het" method, shown in scheme C, is presented in the end of the description.

The method is illustrated for compounds of formula (l); where "Het" represents a pyridinyl, although a similar methodology applicable in all cases where "Het" has the values listed above in the description of this method, provided that "Het" must have at N-oxidized.

"Het" preferably represents pyridinyl or pyrimidinyl in this method.

Depending on the specific group "Het" and/or the provisions of its accession, there is a possibility of formation of two regioisomers in this process. These regioisomers, if they were formed, can be separated using conventional methods, for example, by the method of columnar chromatography.

Typically, the compound of formula (lB) are oxidized order to obtain the N-oxide of the formula lC. The preferred reaction carried out using 3-chloroperoxybenzoic acid, in an environment suitable solvent, for example dichloromethane, at a temperature of from 0oC to the temperature of its boiling point, preferably at room temperature. In another embodiment, the oxidation can be carried out using hydrogen peroxide in the corresponding C1-C4alanovoy acid, for example acetic acid.

As a result of processing N-oxide (lC), N,N-dimethylcarbamodithioato, with subsequent processing or trimethylsilylcyanation or potassium cyanide according to the method of W. K. Fife (j.Org. Chem. 48 1375 (1983) and others Hiterocycles 22, 1121 (1984) cyano-substituted compound (lE). The reaction is preferably carried out using N, N-dimethylcarbamoyl chloride and trimethylsilyl qi is dimethylcarbamoyl chloride to N-oxide and stirring the mixture for some time before adding trimethylsilyl cyanide.

(3) Some of the compounds of formula (l) can be obtained from other compounds of formula (l) by "interconversion functional groups carried out as follows.

(a) Cyano in "Het" can be turned into a-NHCO2(C1-C4alkyl) in the implementation of the next step of the procedure.

(1) Cenocoeliinae initially treated with C1-C4alkanol, for example, methanol, acidic conditions and is usually boiling to turn ceanography in-CO2(C1-C4alkyl) group.

In another embodiment, the hydrolysis of cyanocobalamine usually in alkaline or acidic conditions produces the corresponding carboxylic acid, which can then be atrificial with C1-C4alkanol in acidic conditions.

(2) Selenoamino group in turn-CONHNH2group by treatment of ester with hydrazine (preferably with hydrazine hydrate) in the appropriate organic solvent, for example, C1-C4alkanol, such as isopropanol, at a temperature from room temperature up to, and preferably, the temperature of its boiling point.

(3) And finally,- CONHNH2group privatem treatment with hydrazine carboxylic acid with nitrous acid, preferably at a temperature of about 0oC, with subsequent processing of the resulting gap azide and his handling of C1-C4alkanols, preferably by boiling;

(in) -NHCO2(C1-C4's Deputy in the radical "Het" can be converted into amine Deputy by hydrolysis under alkaline conditions, for example, using an aqueous solution of a hydroxide of sodium or potassium in C1C4alkanol (for example, ethanol or isopropanol) boiling;

(c) Aminosalicyclic in the radical "Het" can be turned into a Deputy of the formula-NH(C2-C4alkanoyl) by acylation or C2-C4alkanoyl a halide or anhydride of the acid of formula (C1-C4alkanoyl)2O. When using alkanoyl halide, the reaction is usually carried out at a temperature of from 0oC to room temperature in an environment appropriate organic solvent, e.g. methylene chloride, in the presence of an appropriate acid acceptor, e.g. triethylamine or pyridine. The reaction can also be carried out using pyridine and as a solvent, and as the acid acceptor. When using the anhydride, the reaction is usually carried out at temperatures up to the temperature of the UB>4alanovoy acid;

(d) Aminosalicylic on the radical "Het" can be turned into a Deputy formula NHCHO using conventional methods, for example, formirovanie in the presence of acetic-formic anhydride; or

(e) Aminosalicylic on the radical "Het" can be turned into halosubstituted first by reaction with sodium nitrite in an acceptable aqueous mineral acid, for example, an aqueous solution of hydrochloric acid or sulfuric acid, preferably at a temperature of about 0oC, with the aim of obtaining an intermediate diazonium salt. In the subsequent processing:

(I) chloride or copper bromide (l) in the radical "Het" is entered as Vice-atoms of chlorine or bromine;

(II) potassium iodide is an introduction to "Het" as Deputy iodine atom; or

(III) forborne acid causes precipitation of perborate the page, which can be filtered, dried and subjected to thermal decomposition with the purpose of introducing in "Het" fluorine as a substituent.

All of the above reactions are conventional and appropriate reagents and reaction conditions for their transformations and methods of selection of target products is well known to specialists in literature and presents neither is it at least one chiral center and therefore exist as pairs of enantiomers or diastereoisomeric pairs of enantiomers. When the radicals R1and R2have different meanings, compounds of formula (l) contain at least two chiral center (*), and so there are at least two diastereoisomeric pair of enantiomers, for example

.

The invention encompasses both individual stereoisomer of the compounds of formula (l), and mixtures thereof. The separation can be accomplished using conventional methods, for example by means of fractional crystallization, chromatography or GPIH stereoisomeric mixture of the primary connection, or a corresponding salt or its derivative. Most preferably diastereoisomer or separated diastereoisomer pair of enantiomers of compounds of formula (l), containing two chiral center, get separated from the intermediate, as illustrated below in the "Examples"section.

Preferred compounds of formula (l), where R2represents H, we have (2R, 3S) configuration, i.e.

.

Particularly preferred individual diastereoisomers are the following:

/2R, 3S/-2-/2,4-differenl/-3-/pyridine-2-yl/-1-/1H - 1,2,4-triazole-1-yl/butane-2-ol,

/2R, 3S/-2-/2,4-differenl/-3-/pyridine-4-yl/-1-/1H - 1,2,4-triazole-1-yl/butane-2-ol and

/2R, 3S/-2-/2,4-differenl/-3/pyrimidine salt can easily be obtained by displacement solutions, containing equimolar amounts of the free base and the acid. Salt usually falls out of the solution precipitates and can be filtered, or it can be removed by evaporation of the solvent.

The compounds of formula (l) and their salts are antifungicide agents suitable for the treatment or prevention of fungal diseases in animals and humans. For example, they can be used to treat topical fungal infections in humans caused by, among other organisms such classes as Candida, Trichophyton, Microsporcem or Epidermophyton or mycotic infections caused by Candida albicans (e.g.,). They can also be used for the treatment of chronic fungal infections caused by, for example, Candida albicans, Criptococcus neoformans, Aspergillus flavus, Aspergillus furmigatus, Coocidioides, Paracoccidioides, Histoplasma or Blastomyces.

Compounds of the invention was found to have unexpectedly high efficacy against clinically important fungi Aspergillus sp.

Evaluation of antifungal activity in vitro of the compounds of the invention can be a method to determine the minimum inhibitory concentration (M. I. K.), which represents the concentration of the tested compounds in an appropriate environment in which pregraduate compound at a certain concentration was inoculable standard culture of, for example, Candida albicans and then each plate was kept for 48 h at 37oC. Then the plates were examined for the presence or absence of fungus growth and recorded a corresponding value M. I. K. Other microorganisms used in these experiments may include Aspergillus fumigatus, Trichophyton spp, Microsporum spp, Epidermophuton flaccosum, Coccidioides immitis and Torulopsis glabrata.

Evaluation of the compounds of this invention in vivo can be accomplished by introducing intragastric or intravenous or oral consistent dosage of the substance to mice inoculated with, for example, stamp Candida albicans or Aspergillus fumigatus. The activity is based on survival of the reverse group mice after the death of the untreated group of mice. The level of dose at which the compound provides 50% protection against the lethal effect of the infection (RD50), is fixed.

Antifungicide activity of compounds against Aspergillus fumigatus was measured in vitro according to the method described above. The results are presented in table. 1.

To treat people antifungicide the compounds of formula (l) and their salts can be entered independently, but generally they should be entered in a mixture with a pharmaceutical carrier selected depending on the selected method V ingredients such as starch or lactose, or in capsules either alone or in mixture with the media, or in the form of Alexiou or suspensions containing flavouring agents or coloring agents. They can be administered parenteral, for example, intravenously, intramuscularly or subcutaneously. For parenteral introduction of their best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or glucose to make the solution isotopic blood.

For oral parenting introducing into the human body a daily dose level antifungicide compounds of formula (l) and their salts will be from 0.01 to 20 kg/mg (one-time or fractional doses) with the introduction of either oral or parenteral. Thus tablets or capsules of the compounds of formula (l) will contain from 5 mg to 0.5 g activitiesthese connection for the introduction of one or two or more times a day. In any case, the doctor will determine the appropriate dosage which will be most appropriate for the individual patient and which will depend on the age, weight and sensitivity of the individual patient. The above doses are given as an average; of course, there may be individual cases the inventions.

In another embodiment, antifungicide the compounds of formula (l) can be entered in the form of suppositories, or candles, or can be applied topically in the form of Asenov, solutions, creams, ointments or powders. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or you can enter them in a concentration from 1 to 10% in the composition of ointments containing white wax or white soft paraffin as the base together with such stabilizers which may be necessary.

In addition, it was found that the compound of formula (l), where R1and R2represent H, and the radicals R or "Het" have the same meaning indicated above for formula (l), have antifungicide action in animals, and that they are particularly effective against the fungus Aspergillus sp.

Thus, this invention relates also to pharmaceutical compositions containing a compound of formula (l) or its pharmaceutically acceptable salt together with a pharmaceutically acceptable diluent or carrier.

Further, the invention relates to compounds of formula (l) or their pharmaceutically acceptable salts for use as medicaments, in particular as antiphonitis acceptable salts or compositions for obtaining antifungicide agents.

In addition, the invention includes a method of treating animals (including humans) to cure or prevent a fungal infection, which comprises processing the specified living organism an effective amount of the compounds of formula (l) or a pharmaceutically acceptable salt or composition based on it.

The invention also includes any new intermediate compounds disclosed therein, such as the compounds of formula (IV), (VI), (IX) and (X).

The invention is illustrated by the following examples in which all temperatures are given inoC.

< / BR>
(l) 2-/2,4-Differenl/-2-/1-pyridin-2-yl/ethyl/oxiran.

To a solution of Diisopropylamine (3,18 g) in dry tetrahydrofuran (50 ml) under stirring was added H-utility (19.7 ml of 1.6 M solution in hexane) at 70oC under an atmosphere of dry nitrogen. The solution was stirred at -70oC for 0.17 hours, then 0,17 h at 0oC, and then re-cooled to -70oC. 2-Ethylpyridine (3,37 g) was added in the course of 0.08 h and the resulting red solution was stirred at -70oC for 0,33 h, and then with a syringe was added with stirring to a solution of 2-chloro-2',4' defloration (5,00 g) in dry is the temperature for 18 hours Added water (4 ml) and the solution evaporated. The remaining oil was treated with water (80 ml) and dichloromethane (100 ml). The organic layer was separated, washed with water (80 ml), and then Proektirovanie 2H hydrochloric acid (2 x 80 ml). The combined acid extracts were parselocale to pH 12 with 2H of sodium hydroxide solution and was Proektirovanie dichloromethane (3 x 75 ml). The combined organic fractions were dried (Na2SO4), evaporated and the residue was subjected to chromatography on silica gel. After elution with ethyl acetate, connections, and evaporation of the corresponding fractions obtained the specified compound (2.25 g) as a yellow oil which was used directly in the next stage.

(II) 2-/2,4-Differenl/-3-/pyridine-2-yl/-1-/1H-1,2,4-triazole - 1-yl/butane-2-ol.

A mixture of the product obtained in paragraph (1), (2.20 g) and sodium salt of 1H-1,2,4-triazole (1,53 g) in N,N-dimethylformamide (15 ml) was heated at 60ounder stirring for 18 h, and then evaporated. Was added water (50 ml) and the mixture was Proektirovanie with ethyl acetate (3 x 50 ml). The combined extracts were dried (Na2SO4), evaporated and the residue was subjected to chromatographic purification on silica gel. After elution with ethyl acetate, connections, and evaporated according to ostogo ether).

The results of the analysis,

Found:

C 61,69

H 4,73

N 16.88 IN

The calculation for C17H16F2N4O:

C 61,81

H 4,88

N 16,96

After elution, connections, and evaporation of the corresponding fractions obtained the specified connection, diastereoisomeric pair B, (0,63 g), TPL151-152o(simple ether).

The result of the analysis,

Found:

C 61,68

H 4,79

N 17,01

The calculation for C17H16F2N4O:

C 61,81

H 4,88

N 16,96

< / BR>
(l) 2-/2,4-Differenl/-2-/1 - pyridin-4-yl-ethyl/oxiran.

Diisopropylamide lithium obtained by adding n-butyl lithium (19.7 ml, 1.6 M solution in hexane) to a solution of Diisopropylamine (3,18 g) in dry tetrahydrofuran (50 ml) and the resulting solution was successively treated with 4-ethylpyridine (3,37 g) and a solution of 2-chloro-2',4'-defloration (5,00 g) in dry tetrahydrofuran (50 ml) according to the procedure described in example 1 (l). Processing of the reaction mixture as described above was allowed to obtain the specified connection (of 1.05 g) as a yellow oil, which was directly used in the next stage.

(II) 2-/2,4-Differenl/3--/pyridine-4-yl/-1-/1H-1,2,4-triazole-1-yl/ butane-2-ol.

the formamide (10 ml) by the method of example 1 (II), followed by chromatographic purification of the crude product on silica gel using dichloromethane/methanol (93:3) as eluent after connecting and evaporation of the corresponding fractions obtained the specified connection, diastereoisomer pair And (0,22 g), Tpl.161-163o(from a simple broadcast)

The results of the analysis,

Found:

C 61,87

H 4,89

N 16,96

The calculation for C17H16F2N4O:

C 61,81

H 4,88

N 16,96

After further elution with a mixture of dichloromethane/ methanol (97:3), compounds and evaporation of the corresponding fractions obtained the specified connection, diastereoisomeric pair B, (0.35 g), Tpl.156-158o(simple ether).

The results of the analysis,

Found:

C 61,79

H 4,86

N 17,32

The calculation for C17H16F2N4O:

C 61,81

H 4,88

N 16,96

< / BR>
2-/2,4-Differenl/-3-/pyridine/4/Il/-1-/1H-1,2,4-triazole-1 - yl/butane-2-ol.

The solution diisopropylamide lithium was prepared as described in example 1(l) EPA-0357241 from Diisopropylamine (40,4 g) and n-utility (160 ml of 2.5 M solution in hexane) in dry tetrahydrofuran (800 ml) under an atmosphere of dry nitrogen. To this solution at -70oadded 4-ethylpyridine (42.8 g), dropwise, with stirring, in the course of 0.17 hours the Solution was stirred at -70oduring 0,33 h, and then added in the course of 0.33 h a solution of 1-/2,4-differenl/2-/1H-1,2,4-triazole-1-yl/ethanol (89.2 g) in dry tetrahydrofuran (350 ml). the thief is allowed to warm to room temperature and diluted with water. The mixture was Proektirovanie three simple ether and the combined extracts washed with water. Water fraction was Proektirovanie once with ethyl acetate, the organic extracts combined, dried (Na2SO4and boiled away. The residue was dissolved in boiling dichloromethane, was added an equal volume of simple ether, and then the solution allowed to cool. The precipitation was filtered and received the original ketone (17.5 g). The filtrate is boiled away and the residue was subjected to chromatographic purification on silica gel. After the initial elution with a mixture of ethyl acetate/hexane (1: 1) received an additional amount of the original ketone. Further elution with ethyl acetate received the fractions containing the specified connection, diastereoisomers couple (without further processing). Then the solvent was replaced by ethyl acetate/methanol (19:1) and elution was continued to obtain pure fractions containing the specified connection, diastereoisomers couple B. These fractions were combined, boiled away and the residue was recrystallize from a mixture of dichloromethane, simple ester, resulting received the specified connection, diastereoisomeric pair B, (20,5 g), Tpl.155-157o(Yarm/300 MHz) spectrum identical NMR spectrum obtained for the sample deila received polymorph, Tpl.165-166,5oC.

The results of the analysis,

Found:

C 61,69

H 4,85

N 16,85

The calculation for C17H16F2N4O:

C 61,81

H 4,88

N 16,96

X-ray crystallography confirmed the stereochemistry diastereoisomeric pair B, as a racemic mixture of 2R, 3S) and (2S, 3R) diastereoisomers.

< / BR>
To a solution of Diisopropylamine (1.01 g) in dry tetrahydrofuran (30 ml) at -70oSince, under the atmosphere of dry nitrogen, with stirring was added n-utility (4,0 ml of 2.5 M solution in hexane). The solution was stirred at -70oFor 0.17 hours, then 0,17 h at 0oWith, then re-cooled to -70oC. was Added 4-ethylpyrimidine (1.08 g), the solution was stirred at -70oWith over 0,75 hours for 0.17 hours added a solution of 1-/2,4-differenl/-2-/1H-1,2,4-triazole-1-yl/athinon (2.23 g) in dry tetrahydrofuran (30 ml). The solution was stirred at -70oC for 1 h and then added acetic acid (1 ml). The solution is allowed to warm to room temperature and then diluted with water. A mixture of three Proektirovanie with ethyl acetate, and the combined extracts washed with water and abusively (Na2SO4). The solvent is boiled away and the residue was subjected to chromatographic Okhotny ketone. After further elution with ethyl acetate, connections, and evaporation of the corresponding fractions obtained the specified connection, diastereoisomers couple And, (0,305 g), Tpl.114-115,5oWith (simple ether/hexane).

The results of the analysis,

Found:

C 57,76

H 4,45

N 21,26

The calculation for C16H15F2N5O:

C 58,00

H 4,56

N 21,14

Further elution with ethyl acetate/methanol (19:1) connection and evaporation sootvetstvujushij factions have received the specified connection, diastereoisomeric pair B, (0,215), Tpl.104-105oWith (simple ether/hexane).

The results of the analysis,

Found:

C 57,63

H OF 4.44

N 21,36

The calculation for C16H15F2N5O:

C 58,00

H 4,56

N 21,14

Examples 4-7. See the table below for examples of the compounds of General formula

< / BR>
were obtained by methods similar to those used in example 2, by treating the corresponding emilyerotica diisopropylamide lithium, followed by reaction of the resulting carbanion in situ with the corresponding derivatives of 1-aryl-2-/1H - 1,2,4-triazole-1-yl/ethanone (PL. 2).

< / BR>
(l) 4-/1-Methylethyl/pyrimidine.

< is) and n-utility (27,0 ml of 2.5 M solution in hexane) in dry tetrahydrofuran (180 ml) under an atmosphere of dry nitrogen. To this solution was added dropwise, at -70oC for 0.17 hours a solution of 4-ethylpyrimidine (7,35 g) in dry tetrahydrofuran (20 ml). The solution was stirred at -70oC for 0.75 h and then added iodomethane (11,60 g). The mixture was stirred for another 3 h, and then warmed to room temperature. Added water and the solution boiled away to a small volume, then treated with ethyl acetate and water. The organic layer was separated, the aqueous layer was three times Proektirovanie with ethyl acetate, and the organic fraction objectively and dried (Na2SO4). After evaporation of the solvent was obtained an oil which was subjected to purification on a chromatographic column with silica gel, using as eluent dichloromethane/simple ether (9:1). The fractions containing the product were combined and boiled away, the remaining oil was overtaken and received the specified connection, (3,14 g), Tpl.52-56oC at 15 mm

(II) 2-/2,4-Differenl/-3-methyl-3-/pyrimidine-4-yl/-1- /1H-1,2,4-triazole-1-yl/butane-2-ol.

As a result of processing of the product obtained in paragraph (1) (2,46 g) diisopropylamide lithium (0,02 mol) in dry tetrahydrofuran, followed by treatment 1-/2,4-differenl/-2-/1H-1,2,4-triazole-1-yl/ethanol (4,49 g) by the method of Example 3 has received the specified sedins 59,15

H 4,87

N 20,41

The calculation for C17H17F2N5O:

C 59,12

H 4,96

N TO 20.28

Example 9. 2-/2,4-Differenl/-3-/pyridazin - 4-yl/-1-/1H-1,2,4 - triazole-1-yl/butane - 2-ol.

< / BR>
(l) 4-Ethylpyridine.

The solution diisopropylamide lithium was prepared as described in example 1 (1) EPA-057241 from Diisopropylamine (17.9 g) and n-utility (70,4 ml of 2.5 M solution in hexane) in dry tetrahydrofuran (300 ml) under an atmosphere of dry nitrogen. To this solution was added at -70o4-methylpyridazin, dropwise, with stirring, providing a temperature not higher than -60oC. Slowly, with stirring, was added iodomethyl (27,25 g), the solution was stirred at 70oC for 1 h, and then gave it to warm to room temperature. Added water and the solution evaporated to a small volume. Solution three Proektirovanie dichloromethane and the combined extracts dried (Na2SO4) and evaporated. The residue was subjected to chromatographic purification on silica gel, using as eluent ethyl acetate. The fractions containing the product were combined and boiled away, and the remaining oil surpassed, resulting in a specified compound (10.4 g) TKip.65-66oWith 0,1 mm

NMR (300 Mω) 8.97 (m, 2H, Harene) million shares.

(ll) 2-/2,4-Differenl/-3-/pyridazin-4-yl/-1-/1H-1,2,4 - triazole-1-yl/butane-2-ol.

The solution diisopropylamide lithium was prepared as described in example 1(l) EPA-0357241 from Diisopropylamine (2,02 g) and n-utility (8,0 ml of 2.5 M solution in hexane) in dry tetrahydrofuran (60 ml).

To this solution was added dropwise, under stirring at -70o4-ethylpyridine (2.16 g). The yellow solution was stirred for 0.4 h at -70oWith; and then added a solution of 1-/2,4-differenl/-2-/1H-1,2,4-triazole-1-yl/ethanone (4,46 g) in dry tetrahydrofuran (20 ml), keeping the temperature below -65oC. the Solution was stirred for 1 h at this temperature, and then added acetic acid (1 ml). The solution is allowed to warm to room temperature and diluted with water. A mixture of three Proektirovanie with ethyl acetate and the combined organic extracti washed with water and dried (Na2SO4). After evaporation of the solvent was obtained as crude product. Next, the crude product obtained after extraction combined aqueous fractions of dichloromethane obtained in this way both parts of crude product were combined and subjected hromatograficheskaja purification on silica gel. After elution with is allowed to get after connecting and evaporation of appropriate fractions of the specified connection, diastereoisomers couple And, (0,98 g), Tpl.172-174oC (from dichloromethane/simple ether).

The results of the analysis:

Found:

C 57,80

H 4,57

N 21,08

The calculation for C16H15F2N5O:

C 58,00

H 4,56

N 21,14

After further elution with a mixture of dichloromethane/methanol (50:1), compounds and evaporation of the corresponding fractions obtained the specified connection, diastereoisomeric pair B, (1.58 g/ Tpl.187-188o(From acetonitrile).

The results of the analysis,

Found,

WITH 58,00

N 4,54

N 21,14

The calculation for C16H15F2N5O:

C 58,00

N 4,56

N 21,14

Example 10. 2-/2,4 - Dichlorophenyl/-3-/pyridazin-4-yl/-1-/1H-1,2,4 - triazole-1-yl/butane-2-ol.

< / BR>
As a result of processing 4-ethylpyridine (2.16 g) diisopropylamide lithium (0,02 mol) in dry tetrahydrofuran, and then 1-/2,4 - dichlorophenyl/-2-/1H-1,2,4-triazole-1-yl/atenonol (5,12 g) by the method described in example 9(ll), received the specified connection, diastereoisomers couple And, (1.24 g), TPL174-177oC.

The results of the analysis,

Found:

C 52,22

H 4,12

N 19,05

The calculation for C16H15CL2N5O

C 52,75

H 4,15

N 19,23

Found:

C 52,41

H 4,08

N 18,85

The calculation for C16H15Cl2N5O

C 52,75

H 4,15

N 19,23

Example 11. 2-/2,4-Differenl/- 3-/pyrazin-2-yl/-1-/1H-1,2,4 - triazole-1-yl/butane-2-ol.

< / BR>
(l)1-/2,4-Differenl/-2-/pyrazin-2 - yl/alanon.

The solution diisopropylamide lithium was prepared using n-utility (20 ml, 2.5 M solution in hexane) and Diisopropylamine (of 5.06 g) in dry tetrahydrofuran (100 ml) under an atmosphere of dry nitrogen, as described in example 1(l). To this solution at -70oWith added 2-methylpyrazine (4,70 g) and the resulting purple solution was stirred at -70oC for 0.5 hours a Solution of methyl 2,4-differentiate (at 8.60 g) in dry tetrahydrofuran (75 ml) was added over 0.5 h and stirring was continued at -70oEven for 0.5 h was Added acetic acid (10 ml) and the temperature given the opportunity to rise to room temperature. The solution was diluted with water and the pH brought to 7 with sodium bicarbonate. A mixture of three Proektirovanie with ethyl acetate and the combined organic extracts were washed with water and dried (Na2SO4). The solvent is boiled away and the residue was subjected to chromatographic purification on silica gel. In the elution mixture was ethylacetoacetate of hexane and received the specified target connection, (5,90 g), Tpl.107-108oC.

The results of the analysis,

Found:

C 61,50

H 3,32

N 12,02

The calculation for C12H8F2N2O:

C 61,54

H 3,44

N 11,96

(ll) 1-(2,4-Differenl/-2-/pyrazin-2-yl/propanol-1-it.

A solution of sodium hydroxide (1.98 g) in water (40 ml) was dropwise added to a stirred, cooled on ice to a solution of the product obtained in paragraph (1) (5,80 g), iodomethane (8,79 g) and acid sulfate Tetra-n-butylamine (of 8.40 g) in chloroform (40 ml). The mixture was intensively stirred at room temperature for 3 h, and then diluted with water and dichloromethane. Added acetic acid (3 ml) and the pH of the aqueous layer was brought to 7 with sodium bicarbonate. The organic layer was separated, washed twice with water and dried (Na2SO4). After evaporation of the solvent obtained crude product in the form of oil (to 5.57 g) was used without further purification (10% of the source material (the product of part (1) identified by NMR spectroscopy).

(lll) 2-/2,4-Differenl/-2-/1-/pyrazin-2-yl/ethyl-oxiran.

n-Utility (9.3 ml of 2.5 M solution in hexane) (under stirring was added to a solution of the product obtained in paragraph (ll) (5.50 g), and bremgarten (U g) of the temperature of the mixture did not rise above -65oC. the Solution was stirred at -70ofor 6 h and then at room temperature for 18 hours the Solution was diluted with water and three times was Proektirovanie with ethyl acetate. The combined organic extracts were washed with water and dried (Na2SO4). After evaporation of solvent received oil that pass through the chromatographic column with silica gel. After elution with a mixture of ethyl acetate/hexane (1:5) received oil (4,80 g), which according to NMR spectroscopy contained CA. 70% of the specified connection together with impurities. This product was used directly without further purification.

(IV) 2/2,4-Differenl/-3-/pyrazin-2-yl/-1-/1H-1,2,4-triazole-1-yl/butane--2-ol.

Tetra-n-butylammonium salt of 1H-1,2,4-triazole (see U.S. patent 4 259 505) (of 5.45 g) under stirring was added to a solution of the product obtained in part (III) (2.30 g) in dry tetrahydrofuran (25 ml) at room temperature, and stirring was continued for 4 days. The solvent is then evaporated and the residue was treated with water and ethyl acetate. Added acetic acid (1 ml) and the mixture was filtered through Avicel (trade mark for a filter based on the cellulose). The organic layer was separated, washed three times with water and dried (Na2SOPL. 107-109oC (from dichloromethane/hexane).

The results of the analysis,

Found:

C 57,76

H OF 4.44

N 21,31

The calculation for C16H15F2N5O

C 58,00

H 4,56

N 21,14

After further elution with a mixture of ethyl acetate/methanol (19:1), compounds and evaporation of appropriate fractions were received by the specified connection, diastereoisomeric pair B, (0.29 g), TPL133-135o(From a mixture of dichloromethane/hexane).

The results of the analysis,

Found:

C 57,82

H 4,53

N 21,00

The calculation for C16H15F2N5O

C 58,00

H 4,56

N 21,14

< / BR>
(l) 1-/2,4-Differenl/-2-/pyridazin-3-yl/alanon.

As a result of processing 3-methylpyridazin (4,70 d) diisopropylamide lithium (0.05 m) in dry tetrahydrofuran, and then methyl 2,4-differenziata (8,80 d) according to the method described in example 11(l), received the specified connection, (3,40 g), TPL115,5-117,5oWith (simple ether).

The results of the analysis,

Found:

C 61,69

Methylation of the product obtained in paragraph (1) (3,30 g), iodomethane (5.0 g) by the method described in example 11 (II) has received the connection specified in the form of resin (2.25 g), which was used directly in the next stage.

(III) 2-/2,4-Differenl/-2-/1-/pyridazin-3-yl/ethyl/oxiran.

As a result of processing of the product obtained in part (II), (2.0 g) bromchlormethane (1,15 g) and n-butyllithium (5,28 ml of 1.6 M solution in hexane) according to the method described in example 11(III) has received the connection specified in the form of brave (1.20 g), which was used directly in the next stage.

(IV) 2-/2,4-Differenl/-3-/pyridazin-3-/-1-/1H-1,2,4-triazole-1-yl/butane-2-ol.

As a result of processing of the product obtained in part (III), (1.15 g) sodium salt of 1H-1,2,4-triazole (0.80 g) in N,N-dimethylformamide (15 ml) according to the method described in example 1(ll), followed by chromatography of the crude product on silica gel using as eluent a mixture of dichloromethane/methanol (50: 1), after connection and evaporation of appropriate fractions were initially given the specified connection, diastereoisomers couple And, (0.35 g), Tpl.134-135o(TK simple ether).

The results of the analysis,

Found:

C 58,04

H 4,57

N 20,87

NMR (300 MHz).

(CDCl3) of 1.20 (d, 2H, j 7.2 Hz, CH3), of 3.95 (q, 1H, j 7.2 Hz, CHCH3), Android 4.04 and 4,91 (g, 1H, j of 14.2 Hz, CH2); 6,18 (c, 1H, OH), PC 6.82 (m, 2H, Harene), to 7.67 (m, 1H, Harene), 7,56 (m, 2H, Harene), to 7.64 (s, 1H, Harene), 7,94 (s, 1H, Harene), 9,18 (m, 1H, Harene) million shares.

Example 13. 2-/2,4 - Differenl/-3- /pyridazin-2-yl/-1-/1H-1,2,4-triazole-1-yl/butane-2-ol.

< / BR>
(l) 1-/2,4-Differenl/-2-/pyridazin-2-yl/ethanol

As a result of processing 2-methylpyrimidine (8.50 g) diisopropylamide lithium (0.09 mole) in dry tetrahydrofuran, and then methyl 2,4-differenziata (15.5 g) by the method described in example 11/l, received the specified connection (3,65 g), Tpl.86-88oC (from hexane).

The results of the analysis,

Found:

C 61,67

H 3,41

N 12,01

The calculation for C12H8F2N2O

C 61,54

H 3,44

N 11,96

(II) 1-/2,4-Differenl/-2-/pyridazin-2-yl/propane-1-on.

By methylation of the product obtained in paragraph (1), (3.50 g) iodomethane (5.32 g) by the method described in example 11(II) have received the specified connection (3,30 g), T is the calculation for C13H10F2N2O

C 62,9

H 4,06

N 11,29

(III) 2-/2,4-Differenl/-2-/1-/pyrimidine-2-yl/ethyl oxirane.

As a result of processing of the product obtained in part (II), (3,10 g) chloromethylation (obtained from bremgarten (1.78 g) and 1.6 M solution of n-utility in hexane (8,20 ml) by the method described in example 11 (III) has received the connection specified in the form of resin (2.25 g), which was used directly in the next stage.

(IV) 2-/2,4-Differenl/-3-/pyrimidine-2-yl/-1-/1H-1,2,4-triazole-1-yl/butane-2-ol.

The result of the product obtained in part (III), (0,80 g) sodium salt of 1H-1,2,4-triazole (0,82 g) in N,N-dimethylformamide by the method described in example 12 (IV), followed by chromatography of the crude product on silica gel using as eluent ethyl acetate, after connecting and evaporation of appropriate fractions first got the specified connection, diastereoisomers couple And, (0.26 g), Tpl.193-195oC (from dichloromethane simple ether).

The results of the analysis,

Found:

C 57,50

H 4,57

N 21,03

The calculation for C16H15F2N5O

C 58,00

H 4,56

N 21,14

After further elution with a mixture of ethyl acetate/methanol (20:1),, to 0.055 g), Tpl.104-106oWith (simple ether).

The results of the analysis,

Found:

C 57,27

H 4,37

N 20,55

The calculation for C16H15F2N5O

C 58,00

H 4,56

N 21,14

Example 14. 2-/2,4-Differenl/-3-/pyridine-3-yl/-1-/1H-1,2,4-triazole-1-yl/butane-2-ol.

< / BR>
(I) 1-/2,4-Differenl/- 2-/pyridine-3-yl/ethanol.

The solution diisopropylamide lithium was prepared using n-utility (66 ml, 1.6 M solution in hexane) and Diisopropylamine (10.8 g) in dry tetrahydrofuran (200 ml), in dry nitrogen atmosphere as described in example 1 (I). To this solution at -79oWith dropwise added ethyl 3-pyridylacetate. The thick mixture was stirred at -70oC for 0.25 h and then added in the course of 0.05 h a solution of methyl 2,4-differentiate (18,36 g) in dry tetrahydrofuran (100 ml). The cooling bath was removed and the mixture was stirred at room temperature for 5 hours was Added acetic acid (12 ml) and the mixture was diluted with water and ethyl acetate. The organic layer was separated, dried (Na2SO4) and evaporated, resulting in an oil which was boiled with concentrated hydrochloric acid (40 ml) for 5 h, the Solution was boiled away, the residue was dissolved in water and added concentrically brine and dried (Na2SO4). After evaporation of solvent received oil that pass through the chromatographic column with silica gel. After elution with a mixture of dichloromethane/ethyl acetate (70:30) received the connection specified in the form of oil (6,98 g) which was used directly in the next stage.

(II) 1-/2,4-Differenl/-2-/pyridine--3-yl/propane-1-on.

By melirovanie of the product obtained at stage (I), (5.0 g) iodomethane (7.60 g) by the method described in example 11 (II) have received the specified connection in the form of oil (3,90 g) which was used directly in the next stage.

(III) 2-/2,4-Differenl/-2-1-/pyridine-3-yl/ethyl oxirane.

The solution matilida dimethylsulfoxide (to 36.5 ml of a 0.6 M solution in tetrahydrofuran) dropwise, with stirring, was added to a solution of the product obtained in part (II), (4,36 g) in tetrahydrofuran (35 ml) at -29oC. the Solution is allowed to warm to room temperature and stirring continued for 18 h and then diluted with water. The mixture was Proektirovanie with ethyl acetate, and the combined extracts dried (Na2SO4).After evaporation of the solvent has received the connection specified in the form of oil (4,50 g) which was used directly in the hiring of processing of the product, obtained in part (III), (4,30 g) sodium salt of 1H-1,2,4-triazole (3.0 g) in N,N-dimethylformamide (50 ml) according to the method described in example 1(II), followed by chromatography of the crude product on silica gel using ethyl acetate as eluent, compound and evaporation of appropriate fractions of the first mentioned connection, diastereoisomers couple And, (1.13 g), Tpl.113-114oWith (simple ether).

The results of the analysis,

Found:

C 62,10

H 4,90

N 16,96

The calculation for C17H16F2N4O:

C 61,81

H 4,88

N 16,96

Further elution with a mixture of ethyl acetate/methanol W (20:1), after connection and evaporation of the corresponding fractions obtained the specified connection, diastereoisomers couple, (1,25 d), Tpl.115-116oWith (simple ether).

The results of the analysis,

Found:

C 61,92

H 4,95

N 16,87

The calculation for C17H16F2N4O:

C 61,81

H 4,88

N 16,96

Example 15. 2/2,4-Differenl/-3- /2-cyano-4-yl)-1-/1H-1,2,4-triazole - 1-yl/butane-2-ol.

< / BR>
(I) 2/2,4-Differenl/-3-/1-oxidability-4-yl/-1-/1H-1,2,4-triazole - 1-yl/butane-2-ol.

The solution 2/2,4-differenl/-3- /pyridine-4-yl/-1-/1H-1,2,4-triommune (250 ml) was stirred at room temperature for 18 hours Then added another 3-chlormadinone acid (2.50 g) and stirring was carried out for 24 hours the Solution is boiled away and the residue was dissolved in a simple ether. The precipitate formed upon standing, was filtered, and skipped through the chromatographic column filled with silica gel. After elution with a mixture of dichloromethane/methanol/ 0.88 / l ammonia solution (100: 4: 0.5) received the connection specified in the form of solids, (20,00 g), Tpl.195-198oC.

(II) 2/2,4 - Differenl/-3-/2-cyano - 4-yl/-1-/1H-1,2,4-triazole - 1-yl/butane-2-ol.

A mixture of the product obtained in part (I), (20,0 g) and N,N-dimethylcarbamoyl chloride (6,80 g) in dichloromethane (250 ml) was stirred at room temperature for 2.5 days, resulting in a clear solution. Added trimethylsilyl cyanide (6,35 g) and stirring continued for 48 hours and Then added an additional amount of N,N-dimethylcarbamoyl chloride (1,30 g) and trimethylsilyl cyanide (1.30 grams) and the solution was stirred for 36 h then the reaction mixture is successively washed 10% potassium carbonate solution, brine and dried (MgSO4). Field evaporation of the solvent obtained solid substance was mixed with simple sulphuric ether, filtered, and the floor of the BR> C 60,89

H 4.24

N 19,44

The calculation for C18H15F2N5O:

C 60,84

H 4,25

N 19,71

< / BR>
(I) 2-/2,4-Differenl/-3-/1-oxidability-2-yl/-1- -/1H-1,2,4-triazole-1-yl/butane-2-ol.

A solution of 2-/2,4-differenl/-3-/1-pyridin-2-yl/-1- -/1H-1,2,4-triazole-1-yl/butane - 2-ol (diastereoisomeric pair B from example 1) (1.60 g) and 85% m/m 3-chlormadinone acid (1.60 g) in dichloromethane (10 ml) was stirred at room temperature for 36 h, and then processed as described in example 15(l), in the result, received the specified compound (0.92 g), Tpl.159-160oC.

The results of the analysis,

Found:

C 59,27

H 4,96

N 16,58

The calculation for C17H16F2N4O2:

C 58,96

H 4,45

N 15,47

(II) 2-/2,4-Differenl/-3-/6-cyanopyridine-2-yl/-1- -/1H-1,2,4-triazole-1-yl/butane-2-ol.

A mixture of the product obtained in paragraph (1), (0,90 g), N,N-dimethylcarbamoyl chloride (0,80 g) and trimethylsilyl cyanide (0,80 g) in dichloromethane (10 ml) was stirred at room temperature for 7 days and the resulting solution is boiled away. The residue was treated 5H hydrochloric acid (10 ml) and the mixture was stirred in an ultrasonic bath for 0,05 h, resulting in a clear solution. Wasp the ATA has received the connection specified in the form of a hydrochloric salt, (0.28 g), Tpl.219oC (with decomposition).

The results of the analysis,

Found:

C 55,19

H 4,10

N 18,00

The calculation for C18H15F2N5OHCl:

C 55,18

H 4,12

N 17,87

Acid filter parselocale (ca. pH 8) with 0.88 ammonia solution and the solution was Proektirovanie dichloromethane. The organic extract was dried (MgSO4and boiled away. The residue is rubbed with simple ether and was filtered, resulting received the connection specified in the form of a free base, (0,13 g), Tpl.144-146oC.

The results of the analysis,

Found:

C 60,85

H 4,25

N 19,71

The calculation for C18H15F2N5O:

C 60,48

H 4,17

N 19,90

< / BR>
(I) 2-/2,4-Differenl/-3-/1-oxidability-3-yl/-1- -/1H-1,2,4-triazole-1-yl/butane-2-ol.

A solution of 2-/2,4-differenl/-3-/pyridine-3-yl/-1- -/1H-1,2,4-triazole-1-yl/butane-2-ol (diastereoisomeric pair B from example 14) (1,00 g) and 85% m/m 3-chlormadinone acid (1,30 g) in dichloromethane (20 ml) was stirred at room temperature for 18 h and then boiled away. The residue was mixed with simple sulphuric ether, the solid was filtered and dried in getting the specified connection (0793 g) Tp is forfinal/-3-/2-cyano-5-yl/-1- -/1H-1,2,4-triazole-1-yl/butane-2-ol.

A mixture of the product obtained in paragraph (l) (0,93 g), N,N-dimethylcarbamoyl chloride (0.40 g) in dichloromethane (10 ml) was stirred at room temperature overnight. Added trimethylsilylacetamide (0.40 g) and stirring continued for 60 hours the Solution was washed in 10% sodium carbonate solution, the aqueous layer was separated and washed with dichloromethane. The organic layers were combined, dried (MgSO4and boiled away. The remainder pass through the chromatographic column with silica gel using a mixture of hexane/isopropanol (4:1) as eluent, resulting in a received 2-/2,4-differenl/-3-/2 - cyano-5-yl/-1- -/1H-1,2,4-triazole-1-yl/butane-2-ol, (0.18 g), Sopl.136-141oC.

The results of the analysis,

Found:

C 60,89

H 4,59

N 19,47

The calculation for C18H15F2N5O:

C 60,84

H 4,25

N 19,71

NMR (300 MHz).

(CDCl3)= 1,17 (d, 3H, j=7,1 Hz, CH3), 3,47 (q, 1H, j=7,1 Hz, CHCH3), 3,81, and is 4.85 (d, 1H, j=a 13.8 Hz, CH2), 5,19 (S,1H, OH), for 6.81 (m, 2H, Harene), 7,47 (m, 1H, Harene), of 7.75 (d,1H, j=8 Hz, pyridine H-3), 7,76 and 7,79 (S, 1H, triazole H), 8,10 (m, 1H, pyridine H-4), 8,80 (d, 1H, j=1.8 Hz, pyridine H-6) million shares.

After further elution with the same mixture of solvents, compounds and evaporation of appropriate oC.

The results of the analysis,

Found:

C 60,85

H 4,33

N 19,51

The calculation for C18H15F2N5O:

C 60,84

H 4,25

N 19,71

NMR (300 MHz).

d (CDCl3)= 1,17 (g, 3H, j=7,0 Hz, CH), 3.82 and 5.17 (g, 1H, j=a 13.8 Hz, CH2), 4.05 (square 1H, j=7,0 Hz, CHCH3), to 5.21 (c. 1H, OH), PC 6.82 (m, 2H, Harene), 7,46 (m, 1H, Harene), 7,60 (m, 1H, pyridine H-5), 7,76 and 7,83 (c. 1H, triazole H), 8,32 (m, 1H, pyridine H-4), 8,68 (m, 1H, pyridine H-6) million shares.

Example 18. 2-/2,4-Differenl/-3-/2-cyano-4-yl/-1- -/1H-1,2,4-triazole-1-yl/butane-2-ol and 2-/2,4-Differenl/-3-/6-cyano-4-yl/-1- -/1H-1,2,4-triazole-1-yl/butane-2-ol.

< / BR>
(I) 2-/2,4-Differenl/-3-/1-oxidability-2-yl/-1- -/1H-1,2,4-triazole-1-yl/butane-2-ol.

A solution of 2-/2,4-differenl/-3-/1-pyrimidine-4-yl/-1- -/1H-1,2,4-triazole-1-yl/butane-2-ol (diastereoisomeric pair B from example 3) (3,31 g) and 85% m/m 3-chlormadinone acid (2,03 g) in dichloromethane (20 ml) was stirred at room temperature for 48 hours Added additional 2,03 g 85%-Noah m/m 3-chlormadinone acid and stirring continued for 18 hours After implementation of all the activities described in example 15(l), received the specified connection (0,80 g), Tpl.157-160oC.

(II) 2-/2,4-Differenl/-3-/2 - tx2">

A mixture of the product obtained in paragraph (l), (0,80 g), N,N-dimethylcarbamoyl - chloride (0.50 g) in dichloromethane (10 ml) was stirred at room temperature for 2 hours was Added trimethylsilyl cyanide (0.50 g) and stirring continued for another 6 days. The solution has boiled away and the remainder pass through the chromatographic column with silica gel. After elution with a mixture of dichloromethane/methanol (100: 1) received the product, which again missed through a chromatographic column filled with silica gel. Elution was started with a simple ether, and the polarity of the eluent was gradually increased by adding up to 6% (by volume) of methanol. After combining and evaporating the source of the fractions containing the product obtained 2-/2,4-differenl/-3-/6-cyanopyrimidine-4-yl/-1- -/1H-1,2,4-triazole-1-yl/butane-2-ol, (30 mg), Tpl.148-149oC.

NMR (300 MHz).

(CDCl3)=of 1.16 (d, 3H, j=7,17 Hz, CH3), of 3.77 (square 1H, j=7,17 Hz, CHCH3), and 4.09 to 4,88 (g, 1H, j=14,15 Hz, CH2), 5,74 (C. 1H, OH), 6,85 (m, 2H, Harene), at 7.55 (m, 1H, Harene), 7,69 and 7.87 (c, 1H, triazole H), 7,89 (g, 1H, j=1 Hz, pyrimidine H-5), 9.24 (g, 1H, j=1 Hz, pyrimidine H-2) million shares.

After further elution, connections, and evaporation of the corresponding fractions obtained 2-/2,4-differenl/-3-/2-cyanopyrimidine-4-yl/-1- -/1H-1,2,4-Tr is R>
H 3,96

N 23,69

The calculation for C17H14F2N6O:

C 57,36

H 3.97

N AT 23.36

NMR (300 MHz).

d (CDCl3)=1,17 (g, 3H, j=7,16 Hz, CH3), to 3.73 (q, 1H, j=7,16 Hz, CHCH3), 3.99 and 4.99 (g, 1H, j=14,2 Hz, CH2), 5.39 (c, 1H, OH), PC 6.82 (m, 2H, Harene), 7,51 (m, 1H, Harene), 7,71 and 7,88 (c, 1H, triazole H), to 7.77 (g, 1H, j=5.3 Hz, pyrimidine H-5), 8,84 (g, 1H, j=5.3 Hz, pyrimidine H-6) million shares.

< / BR>
(I) 2-/2,4-Differenl/-3-/2-methoxycarbonylmethyl-4-yl/ -1-/1H-1,2,4-triazole-1-yl/butane-2-ol.

Suspension 2-/2,4-differenl/-3-/2-cyano-4-yl/1-1H - 1,2,4,-triazole-1-yl/butane-2-ol (see example 15) (5.0 g) in methanol (50 ml) was saturated with gaseous hydrogen chloride, boiled for 2 h and then left to stand at room temperature for 18 hours the Solution was boiled away and the residue was parselocale with dilute sodium bicarbonate solution. The mixture was Proektirovanie several times with dichloromethane and the combined extracts dried (MgSO4and boiled away. After recrystallization of the residues from methylacetate received the specified connection (4,90 g), Tpl.182-183oC.

(II) 4-3-/2,4-Differenl/-3-hydroxy-4-/1H-1,2,4-triazole-1-yl/buta-2 - yl Pirin-2-carboxylic acid hydrazide.

A solution of the product obtained in part (I), (3.80 g) and Ki mixture was Proektirovanie several times with dichloromethane. The combined extracts were washed with brine and dried (MgSO4). After evaporation of solvent received the specified connection (3,30 g) as an amorphous foam, which was used directly in the next stage.

(III) 2/2,4-differenl/-3-/2-ethoxycarbonylpyrimidine-4-yl)-1- /1H-1,2,4-triazole-1-yl/butane-2-ol.

The product obtained in part (II), (1.40 g) was dissolved in 6N hydrochloric acid and the solution was cooled to 0oC. dropwise, with stirring, was added a solution of sodium nitrite (0,276 g) in water (2 ml) and stirring was continued for 1 h Then the solution was parselocale solution of sodium bicarbonate and the resulting mixture a couple of times Proektirovanie dichloromethane. The combined organic extracts were dried (MgSO4and boiled away. The residue was dissolved in ethanol (50 ml) and the solution was heated for 2.5 h and then boiled away. The residue was recrystallize from simple broadcast and received the specified compound (1.12 g), Tpl.177-So.

The results of the analysis,

Found:

C 57,90

H A 5.25

N THE VALUE OF 16,81

The calculation for C20H21F2N5O3:

C 57,55

H 5,07

N 16.78 IN

< / BR>
A solution of the product obtained in example 19, (0,80 g), in ethanol (30 ml) containing 40% Kolko times Proektirovanie with ethyl acetate. The combined organic extracts were dried (MgSO4and boiled away, resulting in a resin. The resin was dissolved in a simple ether and after crystallization when standing this solution has received the specified compound (0.45 g), Tpl.182-185oC.

The results of the analysis,

Found:

C 59,34

H 5,03

N 19,92

The calculation for C17H17F2N5O:

C $ 59.13 USD

H 4,96

N TO 20.28

Example 21. 2/2,4-Differenl/-3-/2-ethoxycarbonylpyrimidine-5-yl)-1- /1H-1,2,4-triazole-1-yl/butane-2-ol.

< / BR>
(l) 2/2,4-Differenl/-3-/2-methoxycarbonylmethyl-5-yl)-1- /1H-1,2,4-triazole-1-yl/butane-2-ol.

As a result of processing 2-/2,4-differenl/-3-/2-cyano-5 - yl/-1-/1H-1,2,4-triazole-1-yl/butane-2-ol (see example 17) (1.0 g) in methanol (20 ml) in the presence of hydrogen chloride according to the method described in example 19 (I) has received the connection specified in the form of resin (0.75 g) which was used directly in the next stage.

(II) 5-[/3-/2,4-Differenl/-3-hydroxy-4-/1H-1,2,4-Tria - Zol-1-yl/]buta-2-Il/pyridine-2-carboxylic acid hydrazide.

As a result of processing of the product obtained in paragraph (1), (0.75 g), hydrazine hydrate (2.0 ml) in isopropanol (10 ml) according to the method described in example 19 (II) have received CLASS="ptx2">

(III) 2-/2,4-Differenl/-3-/2-ethoxycarbonylpyrimidine-5 - yl/-1-/1H-1,2,4-triazole-1-yl/butane-2-ol.

As a result of processing of the product obtained in part (II), (0.36 g) nitrous acid followed by heating the resulting azide intermediate compounds in ethanol according to the method described in example 19(III) has obtained the crude product, which pass through the chromatographic column with silica gel. In the elution by ethyl acetate, connections, and evaporation of the corresponding fractions obtained solid substance, which was led from a mixture of ethyl acetate/simple broadcast and received the specified compound (0.12 g), Tpl.167-168oC

The results of the analysis,

Found:

C 57,81

H 5,00

N 16,46

The calculation for C20H21F2N5O3:

C 57,55

H 5,07

N 16.78 IN

< / BR>
A solution of the product obtained in example 21, (70 ml) in isopropanol (4 ml) containing 50% aqueous hydroxyl potassium (4-drop), boiled for 4 h and then boiled away. To the residue was added water and the mixture was Proektirovanie several times with ethyl acetate. The combined organic extracts were washed with water and dried (MgSO4). After evaporation of solvent received the specified connection SNSN3), 3,93 and 4,77 (g, 1H, j=14,2 Hz, CH2), 4,63 (extended with. 2H, N H2), 6,54 (g, 1H, j= 8,5 Hz, pyridine H-3), of 6.75 (m, 2H, Harene), was 7.45 (m, 1H, Harene), CA. of 7.70 (m, 1H, pyridine H-4), 7,71 and 7,76 (S, triazole H) Of 8.04 (S, 1H, pyridine H-6) million shares.

Example 23. /-/-/2R, 3S/-2-/2,4-Differenl/-3-/pyridine-4-yl/-1- /1H-1,2,4-triazole-1-yl/butane-2-ol.

(l) 2-Acetoxy-2,,4,defloration.

A solution of 2-chloro-2', 4'- defloration (19,0 g) and anhydrous sodium acetate (16.4 g) in acetic acid (50 ml) was boiled for 4 h and then boiled away. The residue was treated with ethyl acetate and water. The organic layer was separated, washed with sodium bicarbonate solution and dried (Na2SO4). After evaporation of the solvent was obtained an oil which was washed with hexane. The resulting substance was filtered, washed with hexane and dried, resulting in a specified compound (16.2 g), Tpl.54-56o(See end of description).

(II) //-/2R, 3S/ 2S, 3R/ -1-Acetoxy-2-/2,4-differenl -/3-pyrimidine-4-yl/butane-2-ol.

The solution Diisopropylamine (30,3 g) in dry tetrahydrofuran (400 ml) was successively treated with n-butyllithium (188 ml of 1.6 M solution in hexane) and 4-ethylpyrimidine (32,4 g) by the method described in example 3. A solution of the product, parature -40 to -50oC. Then added acetic acid (30 ml) and the solution allowed to warm to room temperature. Added a simple ether (1000 ml) and water (1000 ml) and the mixture was shaken. The organic layer was separated, washed with brine and dried (MgSO4). The solvent was boiled away and the remainder pass through the chromatographic column silicagel. In the elution with a mixture of simple ether/hexane (1:4) received the first of the original ketone. After further elution with a mixture of simple ether/hexane (1:1), with a gradual decrease in the share of hexane until clean and simple ether, received semi-crystalline substance consisting of //-enantiomerically mixture of these compounds together with/2R,3R/ - /2S, 3S/- diastereoisomeric pair of enantiomers. A simple ether was added to obtain a clear solution, and then added hexane (20% by volume). The mixture was cooled and the resulting precipitate was filtered, washed with hexane and dried, resulting in received //- enantiomeric mixture of these compounds, (23.3 g), Tpl.102-103,5oC.

The results of the analysis,

Found:

C 59,68

H 5,09

N 8,55

The calculation for C16H16F2N2O3:

C 59,62

H 5,00

N 8,69

(III) //-/2R, 3S/ 2S, 3R/-2-/2,4-Deltorphin the wheelie to a solution of the product obtained in part (ll), (23.3 g) in methanol (80 ml) and stirring was carried out for 0,25 including Added water (150 ml) and the mixture cooled. The precipitate was filtered, washed with water and dried, resulting in a received these compounds, a (17.4 g), TPL148-150,5oC.

The results of the analysis,

Found:

C 59,80

H 5,09

N 10,12

The calculation for C14H14F2N2O2:

C 60,00

H 5,04

N 10,00

(IV) /-/-/2R, 3S/-2-/2,4-Differenl/-3-/pyrimidine-4-yl/ butane-1,2-diol.

/S/ -N-/TRIFLUOROACETYL/propyl chloride (72 ml of 1.0 M solution in dichloromethane) dropwise over 0.5 h was added to the chilled ice to a solution of the product obtained in part (lll) (16.7 g), and pyridine (8.7 ml) in dry dichloromethane (50 ml). The solution was stirred for 0.5 h, and then evaporated dichloromethane. Added ethyl acetate and water and the mixture was acidified to pH 3 using 2H hydrochloric acid. The organic layer was separated, sequentially washed with 0.1 H hydrochloric acid and water, and then dried (Na2SO4). The solvent is evaporated and the residue was passed through a chromatographic column filled with silica gel. The column was suirable a mixture of hexane (simple ether) diethylamine (65:30:5), and the fractions containing the original product were combined and you can ether specified (2R, 3S/-enantiomer, /4,78 g/ Tpl.91-92,5oC.

The subsequent elution of the column received a fraction containing a mixture of both (2R, 3S)-enantiomers in the form of their (S) -N-/TRIFLUOROACETYL/propyl esters. The appropriate fractions were combined and boiled away, and the residue was combined with the residue obtained after evaporation of the uterine fluid during crystallization. The mixture was dissolved in a small amount of diisopropyl simple ether, the solution was placed nucleating crystals of pure (2R, 3S)-product and cooled within 4 hours After filtering received another 1.9 g of pure (2R, 3S)-enantiomer in the form of (S)-N-/TRIFLUOROACETYL/propyl ether complex.

The absolute stereochemistry of the product was proved by x-ray crystallography.

The above-mentioned ester of the specified compound (6.0 g) was dissolved in methanol (28 ml) and added 2H sodium hydroxide solution (14 ml). After 0.25 h was added water (100 ml) and the mixture cooled on ice for 1 h the Precipitate was filtered, washed with water and dried, resulting in a specified compound (2.50 g), TPL147-148,5oC.

The results of the analysis,

Found:

C 59,94

H 5,16

N BECOMES 9.97

Methanesulfonanilide (1,15 g) was added with stirring to a solution of the product obtained in part (l), (2.35 g) and diisopropylethylamine (2.38 g) in dry tetrahydrofuran (30 ml) at a temperature of from -10 to -20oFrom under the atmosphere of dry nitrogen. The solution was stirred at the same temperature for 1 h and then added anhydrous potassium carbonate (7.0 g) and dry N,N-dimethylformamide (25 ml). The mixture was stirred at room temperature for 1.5 h, and then treated with water and simple ether. The organic layer was separated, washed with water and dried (Na2SO4). After evaporation of the solvent was obtained an oil which was immediately dissolved in methanol (50 ml). Added 1H-1,2,4-triazole (6.0 g) and anhydrous potassium carbonate (6.0 g) and the mixture was heated at 60oC and was stirred for 40 h, and then evaporated. The residue was treated with a mixture of ethyl acetate (simple ether 1:1 and water, the organic layer was separated and washed with water, then dried (Na2SO4). The solvent is boiled away and missed the remainder through a chromatographic column filled with silica gel. After the initial elution with ethyl acetate obtained fraction containing impurities, followed by elution with a mixture of ethyl acetate/methanol (20:1), connection and evaporation of the appropriate fra the tx2">

NMR (300 MHz).

d (SDS3) 1,13 (g, 3H, j 7,12 Hz, CH3), 3.68 (square 1H, j 7,12 Hz, CHCH3), 4,16 and 4,78 (g, 1H, j 14.1 Hz, CH2), 6.60 (c, 1H, OH), PC 6.82 (m, 2H, Harene), 7,44 (g, 1H, j 5.0 Hz, pyrimidine H-5), EUR 7.57 (m, 1H, Harene), to 7.61 and of 7.96 (c, 1H, triazole H), 8,77 (g, 1H, j 5.0 Hz, pyrimidine H-6), 9,17 (c, 1H, pyrimidine H-2) million shares.

It is believed that if in the above examples highlight diastereoisomers couple, it is a mixture of (2R, 3S) (2S, 3R) diastereoisomers.

< / BR>
N-utility (16.0 ml of 2.5 M solution in hexane) was added to stir the solution Diisopropylamine (the ceiling of 5.60 g) in dry toluene (80 ml) at -20oC in dry nitrogen atmosphere. The solution was stirred at -20oC for 0.5 h, then stirred at 0oC for another 0.5 h and then cooled before -70oC. during 0,08 h was added a solution of 4-chloro-6 ethylpyrimidine (5.70 g) in toluene (20 ml), the resulting yellow solution was stirred at -70oC for 1 h, and then added a solution of 1-/2,4-differenl/-2-/1H-1,2,4-triazole-1-yl/ethanol (8.92 g) in dry tetrahydrofuran (40 ml) in a period of 0.25 h, the Solution was stirred at -70oC another 0.7 h, and then dropwise added 5 ml of acetic acid. The solution was left to cool to room temperature and diluted with water. The mixture Ave the O4and after evaporation of the solvent obtained solid residue brown. Rubbed the solid residue with ether and received the titled compound as a pale yellow solid residue (6,45 g), Tpl.164-165oC.

Analysis

Found:

C 52,89

H 4,01

N 19,06

According to the calculation formula C16H14ClF2N5O:

C 52,23

H 3,83

N 19,15

Example 25. /2R, 3R/-2-/2,4-differenl/-3-/pyrimidine-4-yl/-1-/1H-1,2,4- -triazole-1-yl/butane-2-ol-dimesylate.

To a stirred solution of 2-/2,4-differenl/-3-/pyrimidine-4-ml/-1-/1H1,2,4-triazole-1-yl/butane-2-ol (0.70 g) in acetone (7 ml) was added dropwise methansulfonate (0.40 g). The mixture was cooled in ice for 1 h, was added 7 ml of acetone, precipitated yellow precipitate was filtered. The residue was mixed with acetone (prepared suspension (5 ml) and the mixture was heated under reflux with the addition of water (0.5 ml) to obtain a clear solution. The solution was filtered through a folded paper filter, the filtrate is cooled in ice and added three aliquot 5 ml of acetone through a ten-minute interval. After that, the mixture was stirred for 1.5 h after filtration obtained crystalline residue pale yellow (0.51 g), T:

C 41,30

H 4,33

N 13,38

S 12,25

F 7,26

Found:

C 41,12

H TO 4.41

N 13,14

S 12,35

F 7,06

Examples 26 and 27. The examples listed in the following table were obtained compounds of General formula:-

< / BR>
according to the method similar to the method used in example 3, the processing corresponding emilyerotica diisopropylamide lithium followed by reaction of the resulting carbanion in situ with the corresponding derivatives of 1-aryl-2-(1H-1,2,4-triazole-1-yl)-ethanone (PL.3).

Obtaining pharmaceutical compositions for internal injection containing the compound of example 23.

Received four compositions ((I) (IV)). Compositions (I) and (III) the methods and compositions (IV) method Century.

Composition (1): 20,64 mg/ml solution of compound of Example 23 in a mixture of 30: 25:5:40, volume, glycerol:propylene glycol:ethanol:water.

Composition (II): 23,31 mg/ml solution of compound of Example 23 in a mixture of 30: 10:60, volume, propylene glycol:ethanol:water.

Composition (III): 22,07 mg/ml solution of compound of example 23 in a mixture of 40: 30:30, three-dimensional, glycerol:propylene glycol:water.

Composition (IV): 20.7 mg/ml solution of compound of example 23 in 0.9 wt. salt solution containing 100 mg/ml hydroxypropyl - mechaniem together all components are in the ratio above.

2. In a suitable vessel placed above the solution in volume equal to 80% of the required amount of the final product.

3. To the solution was added the required amount of the compound of example 23 and stirred until dissolution.

4. The solution is brought to volume (100%) adding prior basis of paragraph 1. The resulting solution is stirred until a homogeneous state.

5. The solution is filtered through a sterile 0.2 of a micron sterile filter and aseptically filled suitable sterile containers.

Methods Century.

1. For the water component by volume of 80% of final volume was added at a temperature of 40oC the required amount of hydroxypropyl - b-cyclodextrin and sodium chloride.

2. The solution is stirred until dissolution.

3. After dissolving hydroxypropyl - b-cyclodextrin and sodium chloride solution is allowed to cool to room temperature.

4. To the solution was added the required amount of the compound of example 23 and stirred until dissolution.

5. After dissolution of all connections of the solution is brought to volume (100%) adding water and mix to ensure tatlises fill suitable sterile containers.

1. Derivatives of 1,2,4-triazole of the General formula I

< / BR>
or their pharmaceutically acceptable salt,

where R is phenyl, substituted by 1 to 2 substituents, each independently from each other selected from halogen;

R1WITH1C4alkyl;

R2N or1C4alkyl,

Het, which are attached to adjacent carbon atom by a ring carbon atom, chosen from pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, while Het optionally substituted C1C4the alkyl, C1- C4alkoxy, halogen, CYANOGEN, amino group, or-NHCO2(C1- C4the alkyl.

2. The compound of formula I under item 1, in which Het is chosen from pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, with possible Het substituted WITH1C4the alkyl, C1C4alkoxy, halogen or amino group.

3. The compound of formula I under item 1, in which Het is chosen from pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, possibly substituted by one or two substituents, each independently from each other selected from C1C4of alkyl, C1C4alkoxy, halogen, cyano-, amino -, or-NHCO2(C1C4the alkyl.

4. Connection formani cyano-, amino -, or-NHCO2(C1C4alkyl Deputy.

5. The compound of formula I according to any one of paragraphs.1 to 4, in which Het denotes 2-pyridinyl, 4-pyridinyl or 4-pyrimidinyl.

6. The compound of formula I on PP.1 5, in which R denotes a phenyl group substituted by one or two identical halosubstituted.

7. The compound of formula I on p. 6, in which R denotes 2,4-differenl, 2,4-dichlorophenyl, 2-forfinal or 2-chlorophenyl.

8. The compound of formula I according to p. 7, in which R denotes 2,4-differenl.

9. The compound of formula I according to any one of paragraphs.1 8, in which R1denotes methyl and R2denotes H or methyl.

10. The compound of formula I under item 9, in which R1denotes methyl and R2denotes H.

11. Connection on p. 1 representing 2-(2,4-differenl)-3-(pyridin-2-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol, 2-(2,4-differenl)-3-(pyridin-4-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol or 2-(2,4-differenl)-3-(pyrimidine-4-yl)- 1(1H-1,2,4-triazole-1-yl)butane-2-ol,

or their pharmaceutically acceptable salt.

12. The compound of formula I according to any one of paragraphs.1 11 in which R2denotes H and which has a configuration of (2R, 3S)

< / BR>
13. Pharmaceutical momposinatitle or diluent, characterized in that as the active ingredient it contains an effective amount of the compounds of formula I on p. 1 or its pharmaceutically acceptable salt.

14. The compound of formula I or its pharmaceutically acceptable salt according to any one of paragraphs.1 13 exhibiting antifungal activity.

15. Heterocyclic compound of General formula IV

< / BR>
where R, R1, R2have the values listed in paragraph 1, Het1represents pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, optionally substituted C1C4the alkyl, C1-4alkoxy, halogen, cyano - or nitro-group.

16. The compound of General formula VI

< / BR>
where R, R1, R2and Het have the meanings indicated above, means a group to delete.

17. The compound of General formula VI under item 16, where chlorine, bromine or1C4alkanesulfonyl.

18. The compound of General formula IX

< / BR>
where R, R1and Het1have the values specified above.

19. The connection formulas

< / BR>
where R, R1and Het1have the values specified above.

 

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BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

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R2=H-C3H7or n-C4H9;

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The invention relates to a neuroprotective (anti-ischemic and excited by blocking amino acid receptor) analogues 5-(1-hydroxy-2-piperidinophenyl)-2-(1H, 3H)-indole-defined formula (I), (II) and (III) below; their pharmaceutically acceptable salts; method of using these compounds in the treatment of stroke, traumatic brain injury or degenerative diseases of the CNS (Central nervous system), such as disease Alzheimer, senile dementia Alzheimers.com type, Huntington's disease and Parkinson's disease; and some of their intermediates

The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

The invention relates to a derivative of propionic acid, useful as fungicides, to fungicidal compositions containing them and to methods used to combat fungi, especially fungal infections of plants

The invention relates to an improved method of producing chlorinol containing o-hydroxyphenyl group, of General formula I-III I

< / BR>
where Ia 4-CL; 2-o-HOC6H6; R = 6-CH3< / BR>
IB 4-CL; 2-o-HOC6H4; R = 6-CF3< / BR>
IB 4-Cl; 2-o-HOC6H4; R = 6-C6H5< / BR>
Iك 4-Cl; 2-o-HOC6H4; R = 5-CN

Ia 4-Cl; 2-o-HOC6H4; R = 5-COOC2H5< / BR>
Ie 4-Cl; 2-o-HOC6H4; R = 5-C6H5< / BR>
If 4-Cl; 2-o-HOC6H4; R = H

Z 4-Cl; 6-o-HOC6H4; R = H

AI 2-Cl; 4-o-HOC6H4; R = H

IC 2-Cl; 4-o-HOC6H4; R = 6-C6H5< / BR>
IIa R = H

IIb R = 4' -OC3H7< / BR>
IIb R = 5' -Br

G R = 5' -NO2< / BR>
D R = 3' , 5' -Cl2< / BR>
IIIa R = H is used as intermediate products in the synthesis of universal stabilizers for polyethylene, i.e

The invention relates to a process for the preparation of new heterocyclic derivatives of acrylic acid, possess valuable fungicidal properties and which can find application in agriculture

The invention relates to a method for obtaining new pyrimidine derivatives possessing valuable fungicidal properties, which can find application in agriculture

The invention relates to new biologically active compounds derived amide alanovoy acid, three different methods for their preparation, herbicide composition and method for killing weeds that may find application in agriculture

The invention relates to a method for producing derivatives of General formula (I), which allows to improve the yield of these products
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