Azole compounds, methods for their production, an antifungal composition, a method of obtaining a composition, the method of inhibiting the development and/or expansion of mushrooms in warm-blooded animals, the intermediate

 

(57) Abstract:

Describes the new azole compounds of General formula (I), its pharmaceutically acceptable salt or base, or a stereochemical isomeric form, where a and b together form a bivalent radical of the formula: - CH=, (), D is a radical (D1) or (D3), L is a radical (L1) or (L2), Alk is C1-4alcander, R1is a halogen; R2is hydrogen or halogen, R3is hydrogen or phenyl, R4is hydrogen or phenyl, R5is hydrogen or C1-6the alkyl, R6is hydrogen or C1-6the alkyl, or R5and R6together with the nitrogen atom to which they are attached, form a pyrolidine or substituted pieperazinove ring, and substituted pieperazinove ring substituted at the 4-position piperazinovogo rings1-6the alkyl, hydroxys1-6the alkyl. The compound of formula (I) is a new water-soluble azole fungicide broad-spectrum. Also describes the method of production thereof, an antifungal composition, a method of obtaining a composition, the method of inhibiting the development and/or expansion of mushrooms in warm-blooded animals, intermediate compounds. 7 C. and 4 h.p. f-crystals, 6 that the CLASS="ptx2">

The present invention relates to new water-soluble azole antifungal means a wide spectrum of action, and their predecessors, possessing antifungal activity.

Systemic mycoses (fungal infections) people in countries with a temperate climate are relatively rare, and many fungi, which can become pathogenic, normally coexist with the body or are common in the environment. However, over the past few decades, there is evidence of increasing frequency of a number of life-threatening fungal infections worldwide, and they currently represent the main danger for many sensitive to them patients, especially for those who are already hospitalized. A large part of the reason for this increase can be attributed to improved survival of patients with a weakened immune system and constant usage of antimicrobial agents. In addition, flora, typical of many conventional mycosis, also changes, and this circumstance is epidemiological sign of growing importance. Patients most at risk include patients with immune functions, weakened or as a direct result of immunosuppres the diseases, such as cancer, acute leukemia, invasive surgical technique or prolonged exposure to antimicrobial agents. The most common systemic mycosis in humans are candidiasis, aspergillosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, blastomycosis and cryptococcosis.

Increasingly for the treatment and prevention of systemic fungal infections in patients with weakened immune functions used antifungal agents such as ketoconazole, Itraconazole and fluconazole. However, as regards the resistance of fungi to some of these funds, particularly those with a more narrow spectrum of activity, such as fluconazole, it grows. Worse still, in the world of medicine recognize that about 40% of people suffering from severe systemic mycoses, can hardly or not be able to receive medication via oral administration. This failure is a consequence of the fact that such patients are in a coma or suffer from severe gastroparesis. Consequently, the use of insoluble or poorly soluble antifungal agents such as Itraconazole or saperconazole that hard to be administered intravenously, is very ZAT is antifungal means broad-spectrum, to which there is no resistance, and which can be administered intravenously. Antifungal agents, preferably, should also be available in pharmaceutical compositions suitable for oral administration. This allows your doctor to continue treatment with the same drug after the patient is removed from the state when he required intravenous mentioned drug.

U.S. patent 4267179 describes heterocyclic derivatives of (4-phenylpiperazin-1-yl-relaxometer-1,3-dioxolane-2-yl)-methyl imidazoles and 1,2,4-triazoles, suitable for use as an antifungal and antimicrobial agents. The above-mentioned patent includes Itraconazole, which is currently available as a fungicide broad-spectrum all over the world.

The U.S. patent describes new 4916134 4-[4-[4-[[2-(2,4-differenl)-2-( azolylmethyl)-1,3-dioxolane-4 - yl] methoxy] phenyl]-1-piperazinil]phenyl]triazolone with improved antimicrobial properties. The above-mentioned patent includes saperconazole.

U.S. patent 4791111 describes derivatives[[4-[[4-(4-phenyl-1-piperazinil)phenoxymethyl] -1,3-dioxolane-2-yl] methyl] - imidazoles which I as a connection with appropriate antimicrobial properties.

U.S. patent 5039676 describes asamati-substituted tetrahydrofuran related to the structure of some compounds of the present invention, referred to that they possess antifungal activity, and European patent EP 0539938 describes similar tizanidine tertrahydrofuran ring antifungal agents.

The present invention relates to new compounds of the formula (I)

(I)

their pharmaceutically acceptability salts accession acids or bases, and their stereochemical isomeric forms, wherein in the formula (I)

A and B together form a bivalent radical of the formula

-N=CH- (a)

-CH=N- (b),

-CH2-CH2- (c),

-CH=CH- (d),

-C(=O)-CH2(e) -

-CH2-C(=O)- (f),

when one hydrogen atom in the radicals (a) and (b) may be substituted C1-6is an alkyl radical, and up to two hydrogen atoms in the radicals (c), (d), (e) or (f) can be substituted C1-6-alkyl radicals;

D represents a radical of the formula

or

L represents a radical of the formula

or

where Alk represents a radical C1-4-alcander;

R1is a halogen;

Rl or haloethanol;

R4represents hydrogen, C1-6-alkyl, phenyl or haloethanol;

R5represents hydrogen or C1-6-alkyl;

R6represents hydrogen, C1-6-alkyl, C1-6-allyloxycarbonyl, or

R5and R6together with the nitrogen atom to which they are attached, form a pyrolidine, piperidine, morpholine, pieperazinove or substituted pieperazinove ring, and mentioned substituted pieperazinove ring is a pieperazinove ring, substituted in position 4 piperazinovogo ring C1-6-alkyl, hydroxy-C1-6-alkyl, amino-C1-6-alkyl, mono - or di-(C1-6-alkyl)amino-C1-6-alkyl.

In the above definitions and hereinafter, the term "halogen" defines fluorine, chlorine, bromine and iodine; "C1-6-alkyl" is a common name linear or branched hydrocarbon radicals containing from 1 to 6 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl, pentyl, or hexyl, and their possible branched isomers; the term "C1-6-alkyl" C1-6alkyloxy, amino-C1-6-alkyl, mono - or di-(C1-6-alkyl)amino-C1-6the alkyl has videostalone value.

Fannie non-toxic form of salts accession acids, which can form compounds of formula (I). They can conveniently be obtained by treating compound in free base form with such appropriate acids as inorganic acids, such as halogen acids, for example hydrochloric, Hydrobromic acid, etc. ; sulfuric acid; nitric acid; phosphoric acid, etc. or organic acids such as acetic, propanoic, oxiana, 2-oxopropanal, 2-oxopropanal, o, preventiva, Balandina, (Z)-2-Buendia, (E)-2-Buendia, 2-oxibutinina, 2,3-dissimulative, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, econsultancy, benzolsulfonat, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-oxybenzone, 4-amino-2-oxybenzone acid and similar acids. On the contrary, the salt form can be converted into the free base by treatment with alkali. The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic metal salts or accession amines by treatment with appropriate organic and inorganic bases. Suitable forms of salts of attaching the base include, for example, AMI such salts, salt accession of organic bases, e.g. the benzathine, methyl-D-glucamine, 2-amino-(hydroxymethyl)-1,3-propane diol, geranamine salts, and salts with amino acids such as, for example, arginine, lysine and the like acids. Conversely, by treating the acid salt form can be converted to the form of the free acid.

The term "salt accession acid" also includes hydrates and forms with the accession of the solvent, which is able to form compounds of formula (I). Examples of such forms are, for example, hydrates, alcoholate and the like solvate.

The term "stereochemical isomeric form, which is used here, refers to all possible isomeric forms, which can have compound of formula (I). If not specified or not specified otherwise, the chemical name of the compounds denotes the mixture of all possible stereochemical isomeric forms, with the mentioned mixtures containing all diastereomers and enantiomers of basic molecular structure. More precisely, stereogenic centers may have the R - or S-configuration; substituents of the divalent saturated cyclic hydrocarbon radicals, in particular the substituents in dioxolane or tertrahydrofuran ring the e form of the compounds of formula (I) are included in the scope of the present invention.

Accordingly, Alk represents methylene or ethandiyl;

a suitable value of R1is fluorine, chlorine or bromine, preferably fluorine;

a suitable value of R2is hydrogen, fluorine, chlorine or bromine, preferably fluorine;

a suitable value of R3is hydrogen or phenyl, preferably hydrogen;

a suitable value of R4is hydrogen or phenyl, preferably hydrogen;

a suitable value of R5is hydrogen, methyl or ethyl;

a suitable value of R6is hydrogen, methyl or ethyl; or

suitable is the case when R5and R6together with the nitrogen atom to which they are attached, form a pyrolidine ring or substituted pieperazinove ring.

Appropriate is when A and B together form a radical of formula (a), (b) or (c).

Compounds of interest are those compounds of formula I in which D represents the radical of formula (D1) or (D2).

Compounds that deserve particular attention are those compounds of formula (I) in which L represents a radical of the formula (L2), with R5and R6each and independence they are attached, form a pyrolidine ring or pieperazinove ring, substituted in its position 4 C1-6-alkyl or C1-6-alkyloxyaryl.

More interesting compounds are those of interest are compounds in which L represents a radical of the formula (L1).

Preferred compounds of formula (I) are those compounds of formula (I) in which D is a radical of formula (D1), with R1represents chlorine or fluorine, and R2represents a hydrogen, chlorine or fluorine; L represents a radical of the formula (L1), with R3and R4each and independently represents a phenyl or hydrogen.

The compounds of formula (I) in which the substituents in dioxolane or tertrahydrofuran ring ring have the CIS-configuration, i.e. thiazoleethanol Deputy and substituted phenylacetylenes Deputy located on one side of the plane dioxolane tertrahydrofuran ring or rings, are the preferred compounds.

More preferred compounds are selected from the group which includes

()-ammonium 1-[[4-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] - dryer�[4-[[2-(2,4-dichlorophenyl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl]-1 - piperazinil]phenyl] -4,5-dihydro-5-oxo - 1,2,4-triazole-1-yl] -methyl] - 2.2-dimethylpropionic;

monohydrate ()-ammonium 1-[[4-[4-[4-[4-[[2-(2-chlorophenyl)- 2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl]-1 - piperazinil] phenyl] -4,5-dihydro-5-oxo 1,2,4-triazole-1-yl]-methyl]- 2,2-dimethylpropanoate (of ester);

()-ammonium 1-[[4-[4-[4-[4-[[2-(4-forfinal)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl] -1 - piperazinil]phenyl]-4,5-dihydro-5-oxo 1,2,4-triazole-1-yl]methyl]- 2,2-dimethylpropanoate;

monohydrochloride() 1-[[4-[4-[4-[4-[[2-(2,4-differenl)- 2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl]-1 - piperazinil] phenyl] -4,5-dihydro-5-oxo 1,2,4-triazole-1-yl]methyl]- 2,2-dimethylpropyl-4-methyl-1-piperidineacetate; and

hemihydrate() 4-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy]phenyl]-1 - piperazinil]phenyl]-2-[3,3-dimethyl-2-(phosphonooxy)butyl]-2,4-dihydro - 3H-1,2,4-triazole-3-one.

Most preferred are

hemihydrate() 4-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy]phenyl]-1 - piperazinil]phenyl]-2-[3,3-dimethyl-2-(phosphonooxy)butyl] -2,4-dihydro - 3H-1,2,4-triazole-3-one, its isomeric forms and salts of attaching the base.

The compounds of formula (I) can be obtained mainly by acylation or fosforilirovanii predstavljaet a reactive useplease group, such as a hydroxyl group or a halogen. The above interaction can be performed using a known technique procedures alkylation or phosphorylation, for example, by stirring the reactants in an inert reaction solvent, optionally mixed with the base to capture the acid which is formed during the reaction.

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The compounds of formula (I) can also be obtained by the alkylation of a phenol of the formula (IV) alkylating reagent of formula (V), W2represents a reactive useplease group, such as halogen or sulfonyloxy. The above interaction is carried out by mixing the reagents in an inert solvent, optionally with addition of a suitable base to bind the acid which is formed during the reaction. In the compounds mentioned here and in the intermediate compounds, the substituents are the foregoing values, unless otherwise indicated.

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The intermediate compounds of formula (V) in which D is a radical of the formula D1described in U.S. patent N 4267179. The intermediate compounds of formula (V) in which D is a radical of the formula You L2moreover , the above-mentioned compounds are represented by formula (I-b), can also be obtained by acylation of the intermediate compounds of formula (II) with a reagent of formula (VI), and the subsequent interaction of the thus obtained intermediate of formula (VII) with an amine of formula (VIII), thus obtaining the compound of formula (I-b).

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The compounds of formula (I) can also be converted into each other such connection by means of transformations known in the art. For example, compounds in which L represents a radical of the formula L1moreover , the above-mentioned compounds are represented by formula (I-a) may participate in the following interconversion. The compounds of formula (I-a) in which R3and/or R4represents a C1-6-alkyl, phenyl or haloethanol can be converted to a compound of formula (I-a) in which R3and/or R4represent hydrogen, using known in the art methods of hydrolysis, for example, by reaction with sodium hydroxide in a suitable solvent, for example in water or 1,4-dioxane.

The compounds of formula (I-b) can be converted into other compounds of this formula in the following way. The compounds of formula (I-b), in the which R5and/or R6represents a C1-6-alkyl, known in the art alkylation reactions. The compounds of formula (I-b) in which R6represents hydrogen, can be converted into compounds of formula (I-b) in which R6represents a C1-6-allyloxycarbonyl, by means known in the art acylation reactions. On the contrary, the compounds of formula (I-b) in which R6represents a C1-6-allyloxycarbonyl, can be converted into compounds of formula (I-b) in which R6represents hydrogen, known in the art hydrolysis reactions.

Intermediate compounds of formula (II) can be obtained by alkylation reagent of formula (IX) alkylating reagent of formula (V) in accordance with the methods of alkylation described above to obtain compounds of formula (I).

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Intermediate compounds of formula (II) can also be obtained by alkylation reagent of formula (X) alkylating reagent of formula (V) in accordance with the alkylation procedures described above to obtain compounds of formula (I), and subsequent restoration educated thus the intermediate compounds of formula (XI). Mentioned recovery can the example, sodium borohydride, in an inert solvent, such as, for example, halogenated hydrocarbons such as dichloromethane, an alcohol, for example methanol, and mixtures thereof.

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The intermediate compounds of formula (X) described in U.S. patent 4931444.

Intermediate compounds of formula (XI) can also be obtained by alkylation of intermediates of formula (XII), in accordance with known in the art methods of alkylation, alkylating reagent of formula (XIII), with W3constitutes a suitable useplease group, for example halogen.

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Pure stereochemical isomeric forms of the compounds and intermediates of the present invention can be obtained by applying methods known in the art. Diastereoisomer can be separated by physical separation methods such as selective crystallization and techniques of chromatography such as liquid chromatography. Enantiomers can be separated from each other by the selective crystallization of their diastereomeric salts with active acids. On the other hand, the enantiomers can be divided chromatographic methods using chiral stationary is ohimicheskie isomeric forms of the appropriate starting compounds, provided that the reaction is stereospecific. If you need a specific stereoisomer of the compound is preferably synthesized by stereospecific methods of getting. In these methods are mainly used enantiomerically pure source materials. It is assumed, it is evident that the stereochemical isomeric forms of the compounds of formula (I) are included in the scope of the present invention.

The compounds of formula (I), their pharmaceutically acceptable salts accession acids or bases and their stereochemical isomeric forms are appropriate means to combat fungi and bacteria in vivo. In addition, the compounds of formula (I) are dissolved in aqueous solutions, making them suitable for intravenous administration. Discovered that these compounds are active against wide range of fungi, such as Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitidis, Sporothrix schenkii, Fonsecaea species, Microsporum canis, Paracoccidioldes immitis, Trichophyton species, Cladosporium carrionii, and against bacteria, such as, for example, Erysipelotrix insidiosa, Staphylococcus, such as Staphylococcus haemolyticus, Streptococcus, such as Streptococcus pyogenes.

Intermediate compounds of formula (II), pharmaceuticle disease prevention, associated with mycoses, and, thus, constitute another aspect of the present invention. Interest group of the compounds of the formula (II) are 4-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl] -1 - piperazinil]phenyl]-2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl) 1,2,4-triazole-3-one, its pharmaceutically acceptable salt accession acids and stereochemical isomeric form.

The present invention also relates to compositions for the treatment or prevention of fungal infections containing protivogribkova effective amount of the compounds of formula (I) or the intermediate compounds of formula (II) and a pharmaceutically acceptable carrier or diluent.

Taking into account their useful pharmacological properties, the compounds that are the subject of the present invention can be formulated into various pharmaceutical forms for entry. To obtain the pharmaceutical composition of the present invention, an effective amount of a compound, salt form of the attaching base or acid, as the active ingredient, combined with careful mixing with a pharmaceutically acceptable carrier, and this carrier can iicii are suitable as a standard dosage forms, suitable, preferably, for oral administration, rectal or subcutaneous administration, or for administration by parenteral injection. For example, upon receipt of a composition for oral dosage forms you can use any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols and the like in the case of liquid preparations for oral administration such as suspensions, syrups, elixirs and solutions; or to apply solid carriers such as starches, sugars, kaolin, lubricants, binders, dezintegriruetsja funds and similar substances - in the case of powders, pills, capsules and tablets. Due to the simplicity of introduction of greatest interest of the unit dosage forms for oral administration are tablets and capsules, in which, obviously, are solid pharmaceutical carriers. A carrier for parenteral compositions is generally sterile water, at least in most cases, although there may be other ingredients that enhance solubility, such as cyclodextrins. For example, can be prepared solutions for injection, in which the carrier comprises saline solution, glucose solution or a mixture of the x can be used suitable liquid carriers, suspendresume agents and similar substances. In the compositions suitable for subcutaneous administration, the carrier optionally includes a means of enhancing the penetration, and/or a suitable wetting agent, optionally combined with suitable additives of any nature, which is taken in small quantities, and which does not have a significant harmful effect on the skin. The aforementioned additives may facilitate the introduction into the skin and/or can provide the desired compositions. Such compositions can be administered in various ways, for example, in the form of a transdermal patch, is applied in the form of a spot on the affected area, be applied in the form of ointment. Especially advantageous to make the above pharmaceutical composition in the form of a standard dosage form for ease of administration and uniformity of dosage. Standard dosage form, referred to in the description and claims to refer to a physically separate unit, suitable for single doses, each unit contains a predetermined quantity of active ingredient calculated so as to obtain the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples capsules, pills, sachets of powder, pills, solutions or suspensions for injection, teaspoon, tablespoon and such, and lots of them separated in their own way.

Suitable derivatives of cyclodextrin (CD) are -, -, - cyclodextrins or ethers and mixed ethers in which one or more hydroxyl groups anhydrous glucose units of the cyclodextrin substituted C1-6-alkyl, in particular ethyl, stands or isopropyl; hydroxy-C1-6-alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxy-C1-6-alkyl, in particular carboxymethyl or carboxyethyl; C1-6-alkylcarboxylic, particularly acetyl; C1-6-allyloxycarbonyl-C1-6-alkyl or carboxy-C1-6-alkyloxy-C1-6-alkyl, in particular carboxyphenoxypropane or carboxitherapy; C1-6-alkylcarboxylic-C1-6-alkyl, in particular 2-acetylaminophenol. As complexants and/or solubilization deserve special attention-CD, 2,6-dimethyl--CD, 2-hydroxyethyl--CD, 2-hydroxyethyl--CD, 2-hydroxypropyl--CD and (2-carboxymethoxy)-propyl--CD, in particular 2-hydroxypropyl--CD.

The term "simple mixed ether" means production is slishnimi groups, such as, for example, hydroxiproline and hydroxyethylene.

Specialists in the treatment of warm-blooded animals suffering from diseases caused by fungi and/or bacteria can easily determine the effective amount according to the results of these experiments. In General, it is expected that the effective number should be from 0.01 mg/kg to 50 mg/kg body weight, preferably from 0.05 mg/kg to 20 mg/kg of body weight.

Experimental part

The stereochemical configuration of some compounds of formula (I) is experimentally determined. In such cases, a stereochemical isomeric form, which highlights the first, denoted "A" and the second, which allocate, designate "B".

A. the production of intermediate compounds

Example 1

To a mixture of 2-(2,4-differenl)-3-( 1,2,4-triazole-1-yl)-1,2-propane diol (30 g), methanesulfonic acid (50 ml) and dichloromethane (500 ml) under stirring and cooling (ice bath) is added dropwise 1-bromo-2,2-diethoxyethane (17 ml). After stirring for 3 hours at 0oC, the reaction mixture was poured into sodium bicarbonate (aqueous solution). The reaction product is extracted with dichloromethane, and the extract is dried, filtered and evaporated. Balance d>COOC2H549:1:20:30). The desired fraction of eluate evaporated, and receive 8 g(19,0) 1-[[2-(methyl bromide)-4-(2,4-differenl)-1,3-dioxolane-4-yl] methyl] 1,2,4-triazole; so pl. 76,3oC (intermediate compound 1).

Example 2

A mixture of 2-(3,3-dimethyl-2-oxobutyl)-2,4-dihydro-4-[4-[4-(4- hydroxyphenyl)-1-piperazinil]phenyl] 1,2,4-triazole-3-one (0.01 mol) and sodium hydride (0.012 mol) in dimethylformamide (100 ml) is stirred under nitrogen atmosphere at 70oC. Add the intermediate compound (1) (0.012 mol), and the mixture is stirred for another night. Again add the intermediate compound (1) (2 g) and the mixture stirred at 70oC for 6 hours and then overnight at room temperature. The mixture is evaporated, the residue is dissolved in dichloromethane and washed. The organic layer is dried, filtered and evaporated. The residue is purified column chromatography on silica gel (eluent CH2Cl2/hexane/ethyl acetate, 50/20/30). Purified fractions are collected and evaporated. The residue is optionally purified on a glass filter on silica gel/NH2(eluent CH2Cl2). Pure fractions are collected and evaporated. The residue is crystallized from ethyl acetate and obtain 2.2 g(31%) () 4-[4-[4-[4-[[4-(2,4-differenl)-4-( 1,2,4-triazole-1-ylmethyl)- 1,3-dioxolane-2-yl]-methoxy]venetiana 2).

Example 3

a) a Mixture of 2-(2,4-differenl)-2-( 1,2,4-triazole-1 - ylmethyl)-1,3-dioxolane-4-methanol (0.2 mol) pyridine (400 ml) and dichloromethane (250 ml) was stirred at room temperature. Add dropwise a solution of 4-cyanobenzaldehyde (0.22 mol) in dichloromethane (150 ml). The reaction mixture is stirred for 24 hours at room temperature. Dilute the reaction mixture with water. Separate the organic layer, dry it (MgSO4), filtered and evaporated the solvent. The residue is crystallized from methylbenzene. The crystals are filtered and dried. This fraction is purified column chromatography on a column of Chiracell OD (eluent C2H5OH). Fractions of the first peak are combined and evaporated the solvent. The residue is crystallized from 4-methyl-2-pentanone. The crystals are filtered and dried, gain of 21.2 g(24,9%) (+) [2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl]methyl-4-cyanobenzoate; so pl. 146,3oC; []2D0= +22,71o(c = 0.5% in methanol) (intermediate compound 3).

Combine the fractions of the second peak and the solvent is evaporated. The residue is crystallized from 4-methyl-2-pentanone. The crystals are filtered and dried, get 21,4 g(25,1%) (-) [2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methyl-4-CIE 4).

b) a Mixture of intermediate compound (3) (0,049 mol) and 50% sodium hydroxide solution (0,059 mol) in water (300 ml) and 1,4-dioxane (300 ml) is stirred for 24 hours at room temperature. The solvent is evaporated. The residue is treated with water and dichloromethane. The organic layer is separated, dried (MgSO4), filtered, and evaporated the solvent. The residue is crystallized from 4-methyl-2-pentanone. The crystals are filtered and dried, get a 10.1 g(70%) (+) 2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-methanol; so pl. 123,0oC; []2D0= +16,58o(c = 0.5% in methanol) (intermediate compound 5).

Such a method are also

(-) 2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3 - dioxolane-4-methanol; so pl. of 123.2oC; []2D0= -15,97o(c = 0.5% in methanol) (intermediate compound 6).

c) a Mixture of intermediate compound (5) (0.02 mol) and diethylethanamine (0.03 mol) in dichloromethane (50 ml) was stirred at room temperature. Add dropwise methanesulfonanilide (0.03 mol) and the reaction mixture stirred at room temperature overnight. The solvent is evaporated. The residue is treated with methylbenzol and water. A precipitate, which is filtered off, with revival and dried (vacuum; 40oC) obtain two fractions. These fractions are combined and recrystallized from 2,2'-oxybisethane and 4-methyl-2-pentanone. The precipitate is filtered off and dried (vacuum; 40oC) receive 5,88 g (78,3%) methansulfonate (+) 2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-methanol (ester); []2D0= +15,50o(c = 0.2% in methanol) (intermediate compound 7).

Such a method are also

methanesulfonate (-) 2-(2,4-differenl)-2-( 1,2,4-triazole-1 - ylmethyl)-1,3-dioxolane-4-methanol (ester); []2D0= -14,50o(c = 0.2% in methanol) (intermediate compound 8).

Example 4

a) a Mixture of 2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl)-4-[4-[4-(4- hydroxyphenyl)-1-piperazinil] phenyl] 1,2,4-triazole-3-one (0.046 mol), 2-(chlorodimethylsilyl)-2-methylpropane (0,063 mol) and imidazole (0,19 mol) in dimethylformamide (300 ml) is stirred for 4 hours at 50oC. the Reaction mixture was poured into water. The resulting precipitate is filtered off and dried, to obtain 21 g (83%) of the reaction product. Sample (1 g) is treated with 2,2'-oxybisethanol, filtered and dried, to obtain 0.7 g()-4-[4-[4-[4-[[(1,1-dimethylethyl)dimethylsilane] oxy]phenyl]-1 - piperazinil]phenyl]-2-(2-hydroxy-3,3-dimethylbutyl)-2,4-dihydro ol, the mixture of enantiomers) are divided into their component enantiomers column chromatography on a column of ChiracellROD (eluent n-hexane/2-propanol, 65/35). The fraction corresponding to the first chromatographic peak is collected, and the solvent is evaporated. The residue is crystallized from acetonitrile. The precipitate is filtered off and dried (vacuum; 50oC); get 1.56 g(7,8%) (-)-4-[4-[4-[4-[[(1,1-dimethylethyl)dimethylsilane] oxy] phenyl]-1 - piperazinil]phenyl]-2-(2-hydroxy-3,3-dimethylbutyl)-2,4-dihydro 1,2,4-triazole-3-one (intermediate compound 10). Collect the fraction corresponding to the second chromatographic peak, and the solvent is evaporated. The residue is crystallized from acetonitrile. The precipitate is filtered off and dried (vacuum; 50oC); receive 2.28 g(11,4%) (+)-4-[4-[4-[4-[[(1,1-dimethylethyl)dimethylsilane] oxy] phenyl] -1 - piperazinil]phenyl]-2-(2-hydroxy-3,3-dimethyl-butyl)-2,4-dihydro 1,2,4-triazole-3-one (intermediate compound 11).

c) a Mixture of intermediate (10) (0,0135 mol) with dichloromethane (150 ml) is stirred until complete dissolution. Add in one solution tetrabutylammonium in tetrahydrofuran (0.015 mol) and the reaction mixture is stirred for 1 hour at room temperature. The mixture was diluted with water (150 ml) and stirred during the course the t (vacuum; 60oC) obtain 4.7 g(79,6%) (-)-2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl)- 4-[4-[4-(4-hydroxyphenyl)-1-piperazinil] phenyl] 1,2,4-triazole-3-one; []2D0= -3,14o(c = 0.1% in dimethylformamide) (intermediate compound 12).

In a similar way we obtain (+)-2,4-dihydro-2-(2-hydroxy - 3,3-dimethylbutyl)-4-[4-[4-(4-hydroxyphenyl)-1-piperazinil] phenyl] 1,2,4-triazole-3-one; []2D0= +6,22o(c = 0.1% in dimethylformamide) (intermediate compound 13).

Example 5

The mixture-4-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl]methoxy]phenyl]-1 - piperazinil]phenyl]-2,4-dihydro 1,2,4-triazole-3-one (9.3 g), 1-bromo-3,3-dimethyl-2-butanone (2.8 g), sodium carbonate (6.4 g) and 1,3-dimethyl-2-imidazolidinone (52,2 g) is stirred for 5 hours at 100oC. After cooling, the reaction mixture was poured into water. The formed precipitate is filtered and dissolved in dichloromethane. The solution is dried, filtered and evaporated. The residue is purified column chromatography (silica gel; CH2Cl2/CH3OH, 98:2). Evaporated eluent of the desired fraction, and the residue is crystallized from 4-methyl-2-pentanone. The product is filtered and dried, to obtain 5.5 g(51,3%) 4-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl]Molochnoe connection 14).

Example 6

To a mixture of intermediate (14) (4.5 g), 1,4-dioxane (40 ml) and methanol (3 ml) is added dropwise a solution of tetrahydroborate sodium (0.3 g) in a little water. After stirring over night the reaction mixture was poured into water and acidified with acetic acid to approximately pH 5. The precipitate is filtered off, washed with water, dried and purified column chromatography (silica gel; CH2Cl2/CH3OH, 98:2). Evaporated eluent of the desired fraction, and the residue is crystallized from 2-propanol, to obtain 2.2 g(48,7%) 4-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)- 1,3-dioxolane-4-yl] methoxy] phenyl] -1-piperazinil] phenyl] -2,4-dihydro - 2-(2-hydroxy-3,3-dimethylbutyl) 1,2,4-triazole-3-one; so pl. 196,4oC (intermediate compound 15).

Example 7

To a mixture of intermediate (12) (0,00595 mol) C-dimethylformamide (50 ml) under stirring at room temperature add parts sodium hydride (0,00675 mol). The mixture is stirred for 90 minutes at room temperature. Add intermediate compound (7) (0,0054 mol) and the reaction mixture is stirred for 4 hours at 60oC. the Mixture is cooled, and the solvent is evaporated. The residue is treated with dichloromethane and water. Separate the organic layer, the bitch (eluent CH2Cl2/CH3OH, 96/4). Collect the pure fractions and evaporate the solvent. The residue is crystallized from 4-methyl-2-pentanone. The precipitate is filtered off and dried (vacuum; 50oC) receive 1,67 g(43,1%) (+)-[ (+)(B)]-4-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl] -1 - piperazinil]phenyl]-2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl) 1,2,4-triazole-3-one; so pl. 191,9oC; []2D0= +a 12.03o(c = 0.5% in dichloromethane) (intermediate compound 20).

Example 8

A mixture of intermediate compound (2) (0,0025 mol) with dichloromethane (100 ml) and methanol (100 ml) was stirred at room temperature. Add sodium borohydride (0,005 mol) and the mixture is stirred for 4 hours. Add water (100 ml), the mixture is stirred over night and share. The organic layer is washed, dried, filtered and evaporated. The residue is crystallized from ethyl acetate, and obtain 1.6 g(89,3%) () 4-[4-[4-[4-[[4-(2,4-differenl)- 4-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-2-yl]methoxy] phenyl] -1 - piperazinil] phenyl] -2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl) 1,2,4-triazole-3-one; so pl. 184,1oC (intermediate compound 24).

Example 9

A mixture of 2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl)-4-[4-[4-(4- hydroxyphenyl)-1-piperazinil] phenyl] 1,2,4-triol (the receipt of which is described in the application for the European patent N 0539938) (0,0033 mol) and sodium hydroxide (0.01 mol) in dimethylformamide (50 ml) is stirred under nitrogen atmosphere at 50oC for 4 hours, and then the mixture is stirred under nitrogen atmosphere at 60oC for 2 hours. The mixture is cooled and water is added. Product vykristallizovyvalas, filtered and dried. The residue is purified on a glass filter on silica gel (eluent CH2Cl2/CH3OH, 99/1). Pure fractions are collected and evaporated. The residue is recrystallized from dioxane/2,2'-oxybisethane and obtain 1.7 g(72%) () 4-[4-[4-[4-[[5-(2,4-differenl)tetrahydro-5-( 1,2,4-triazole-1-ylmethyl)-3-furanyl] methoxy] phenyl] -1 - piperazinil]phenyl]-2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl) 1,2,4-triazole-3-one; so pl. 210,8oC (intermediate compound 25).

Example 10

To a mixture of intermediate (15) (0,0082 mol) with dichloromethane (100 ml) with stirring, add chlorocatechol (0.02 mol). Added dropwise pyridine (0,037 mol) and the mixture stirred for 2 hours. Add 1N hydrochloric acid (50 ml), the mixture is stirred for 2 hours and share. The organic layer is washed with sodium hydrogen carbonate solution, dried, filtered and evaporated. The residue crystallized and treated with 4-methyl-2-pentanone/2,2'-oxybisethanol, obtain 6.3 g (96.8 per cent) of the product. Sample (1 g) is recrystallized from 4-methyl-2-pentanone, and obtain 0.6 g() 1-[[4-[4-[4-[4-[[2-(2,4-di is eazol-1-yl] methyl] - 2,2-dimethylpropanoate (intermediate compound 26).

Example 11

A mixture of ()-2,4-dihydro-4-(2-hydroxy-3,3-dimethylbutyl)- 2-[4-[4-(4-hydroxyphenyl)-1-piperazinil] phenyl] --1,2,4-triazole-3-one (0,0068 mol), methansulfonate () (2-(2,4-differenl)-2-(-1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-methanol (ester) (0,0082 mol) and sodium hydroxide (0,025 mol) in dimethylformamide (100 ml) is stirred under nitrogen atmosphere at 60oC for 4 hours. The mixture is cooled, water is added, and the mixture is stirred. The precipitate is filtered off and dried. The residue is purified on a glass filter on silica gel (eluent CH2Cl2/CH3OH/ethyl acetate/n-hexane, 48/2/30/20). Pure fractions are collected and evaporated. The residue is recrystallized from 4-methyl-2-pentanone, obtain 1.1 g(22%) () 2-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl] -1 - piperazinil] phenyl]-2,4-dihydro-4-(2-hydroxy-3,3-dimethylbutyl) 1,2,4-triazole-3-one; so pl. 201,2oC (intermediate compound 27).

Example 12

The mixture is stirred() 1-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl]-1 - piperazinil] phenyl] -3-(3,3-dimethyl-2-oxobutyl)-1,3-dihydro imidazol-2-it (0,0036 mol) with methanol (50 ml) and dichloromethane (50 ml). Add BL), and the mixture is stirred for 1 hour. The mixture is separated, and the aqueous layer was extracted with dichloromethane. The organic layer is dried, filtered and evaporated. The residue is purified on a glass filter with silica gel (eluent CH2Cl2/CH3OH, 99/1). Pure fractions are collected and evaporated. The residue is recrystallized from 4-methyl-2-pentanone get 1.9 grams(73%) () 1-[4-[4-[4-[[2-(2,4-differenl)- 2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl] -1 - piperazinil]phenyl]-3-(2-hydroxy-3,3-dimethylbutyl)-2-imidazolidinone; so pl. 196,8oC (intermediate compound 29).

B. obtain the final compounds

Example 13

A mixture of intermediate (15) (0,0014 mol), diphenylchlorophosphine (of 0.003 mol) and dimethyl-4-pyridylamine (1 g) in dichloromethane (30 ml) was stirred at room temperature for 2 hours. The mixture is purified on a glass filter with silica gel (eluent CH2Cl2/CH3OH, 98/2). Pure fractions are collected and evaporated.

The residue is recrystallized from 4-methyl-2-pentanone/2,2'-oxybisethane and obtain 1.1 g(83%) () 1-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl]-1 - piperazinil] phenyl] -4,5-dihydro-5-oxo 1,2,4-triazole-1-yl]methyl]- 2,2-dimethylpropanoate; so pl. 17 is xida sodium (5 g) in 1,4-dioxane (50 ml) was stirred at room temperature for 6 hours. Add water (200 ml), the mixture is filtered through dicalite and the filtrate acidified with hydrochloric acid to pH 2-3. The mixture is extracted three times with dichloromethane. The combined organic layers dried, filtered and evaporated. The residue is dissolved in a saturated solution of sodium bicarbonate (100 ml), the solution washed with 2,2'-oxybisethanol and extracted twice with dichloromethane (500 ml) and methanol (100 ml). The combined organic layers dried, filtered and evaporated. The residue is crystallized from 2-propanol and a small amount of water, get 1.2 g(46%) () 1-[[4-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl]methoxy]phenyl]-1 - piperazinil] phenyl] -4,5-dihydro-5-oxo 1,2,4-triazole-1-yl]methyl]-2,2-dimethylpropanoate sodium; so pl. 167,0oC (compound 2).

Example 15

A mixture of compound (1) (0,0038 mol) and 50% sodium hydroxide solution (5 g) in 1,4-dioxane (100 ml) was stirred at room temperature overnight. Add water (600 ml), the mixture is filtered through dicalite and the filtrate acidified with hydrochloric acid. The precipitate is filtered off (*) and the filtrate is extracted with dichloromethane. The mixture is evaporated. The residue, the precipitate (*) and 50% sodium hydroxide (5 g) was stirred at 60oC for 24 hours. Again add 50% sodium hydroxide (3 extracted with dichloromethane. The combined organic layers dried, filtered and evaporated. The residue is brought to a boil in methanol (70 ml), filtered and to the filtrate add methanol with ammonia (20 ml). The mixture is brought to a boil in 2-propanol (20 ml) and cooled. The mixture is filtered, the precipitate is dissolved in water (200 ml) and the solution washed twice with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid and extracted with dichloromethane three times. The combined organic layers dried, filtered and evaporated. The residue is dissolved in methanol (70 ml) and add methanol with ammonia (10 ml). The precipitate is filtered off and dried, to obtain 1.6 g(51%) () 1-[[4-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl]-1 - piperazinil]phenyl] -4,5-dihydro-5-oxo 1,2,4-triazole-1-yl]methyl]-2,2 - dimethylpropanoate ammonium; so pl. 189,6oC (compound 3).

Example 16

To the suspension() 1-[[4-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl]-1 - piperazinil] phenyl] -4,5-dihydro-5-oxo 1,2,4-triazole-1-yl]methyl]-2,2 - dimethylpropanoate (0.07 mol) in 1,4-dioxane (1400 ml) in the flow of N2add 50% sodium hydroxide (1.4 mol). The resulting suspension is heated to 60oC. the Reaction solution was stirred at 60oC mechanismes vigorously stirred for 1 hour. The mixture is filtered. The filtrate is acidified (pH 2,7) hydrochloric acid, and the resulting sediment is deposited. The aqueous layer was extracted with CH2Cl2(1x2 l; 1x1,5 l). The combined extracts are dried (Na2SO4), filtered, and evaporated the solvent. The residue (71,02 g; output of 124.7%) mixed with 2-propanol (1050 ml), heated to boiling, stirred and refluxed for 5 minutes, cooled in an ice bath with vigorous stirring, cooled to 20oC, and stirring is continued over night. The precipitate is filtered off, washed with 2-propanol (g ml), diisopropyl ether (CH ml) and dried (vacuum; 50oC) receive 48.10 per g hemihydrate() 4-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3 - dioxolane-4-yl]methoxy] phenyl] -1-piperazinil] phenyl]-2-[3,3-dimethyl - 2-(phosphonooxy)butyl]-2,4-dihydro-3H-1,2,4-triazole-3-one; so pl. 156,2oC (compound 17).

Example 17

To a mixture of compound (17) (0,005 mol) in water (70 ml) was added 1-deoxy-1-(methylamino)-D-glucit (0.02 mol), and the mixture is stirred until complete dissolution (30 minutes). Evaporate the solvent. Add toluene, and the mixture azeotropic on a rotary evaporator. Add ethanol (250 ml) and the mixture vigorously stirred. Cool the mixture in an ice bath and perimetry (20oC). The mixture is stirred for 18 hours at room temperature, and the resulting precipitate filtered off, washed with ethanol, diisopropyl ether (2x10 ml) and dried (vacuum; 50oC). Get 6,14 g (1). The filtrate is evaporated. The residue is dried (vacuum; 50oC) obtain 1.98 g (2). Fraction (1) crushed, vigorously stirred for 5 hours in ethanol (200 ml) and the resulting precipitate filtered off, washed with ethanol (4x5 ml) and dried (vacuum; 45-50oC; 64 hours). Get to 4.98 g of monohydrate() 4-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3 - dioxolane-4-yl]methoxy]phenyl]-1-piperazinil] phenyl]-2-[3,3-dimethyl - 2-(phosphonooxy)butyl]-2,4-dihydro-3H-1,2,4-triazole-3-one-1-deoxy - 1-(methylamine)-D-glucit (1:2) (compound 18).

Example 18

A mixture of intermediate (26) (0,0025 mol) and pyrrolidine (0.014 mol) in dimethylformamide (50 ml) was stirred at room temperature for 4 hours. Water is added, and the mixture is stirred. The precipitate is filtered off, washed with water and purified on a glass filter with silica gel (eluent 1 - CH2Cl2/CH3OH, 98/2, and eluent 2 - CH2Cl2/CH3OH, 95/5). Collecting appropriate fractions and evaporated. The residue is dissolved in dichloromethane (100 ml), and parmitano. The combined organic layers dried, filtered and evaporated. The oily residue is dissolved in dichloromethane, washed with sodium hydrogen carbonate solution, dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone, and obtain 1.1 g(53%) () 1-[[4-[4-[4-[4-[[2-(2,4- differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4 - yl] methoxy] phenyl] -1-piperazinil]phenyl]-4,5-dihydro-5-oxo 1,2,4-triazole-1-yl]methyl]-2.2-dimethylpropyl-1-pyrrolidineethanol; so pl. 156,7oC (compound 28).

Example 19

A mixture of intermediate (16) (0,0066 mol), dihydrochloride 4-methyl-1-piperazineethanol acid (0,013 mol), 1,3-dicyclohexylcarbodiimide (0,026 mol) and dimethyl-4-pyridylamine (0,026 mol) in dichloromethane (100 ml) was stirred at room temperature for 4 hours. Add 1N hydrochloric acid (200 ml), and the mixture is stirred for 1 hour. The precipitate is filtered off, add water (600 ml) and the mixture is separated (*). The aqueous layer was washed with dichloromethane (100 ml) and separated. The aqueous layer was neutralized with pyridine and extracted five times with dichloromethane. The combined organic layers dried, filtered and evaporated, to obtain 4.5 g of fraction 1. The organic layer (*) is washed with 1N hydrochloric acid (100 ml) and separated. The water layer is neutralized pyridine is t 2 g of fraction 2. Fractions 1 and 2 are combined and recrystallized from a mixture of 2% acetonitrile, water/2,2'-oxybisethane, and obtain 3.8 g (61%) of the hemihydrate of monohydrochloride() 1-[[4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-( 1,2,4-triazole-1-ylmethyl)- 1,3-dioxolane-4-yl] methoxy] phenyl]-1-piperazinil]phenyl]-4,5-dihydro-5-oxo 1,2,4-triazole-1-yl]methyl]-2,2-dimethylpropyl-4-methyl-1-piperidineacetate; so pl. 156,0oC (compound 32).

Example 20

A mixture of compound (17) (0,0034 mol) with hydrochloric acid in 2-propanol (10 ml) and dichloromethane (60 ml) is stirred and refluxed for 30 minutes. The mixture is evaporated. The residue is dissolved in water and filtered. The filtrate is neutralized with sodium hydrogen carbonate solution and extracted with dichloromethane. The organic layer is dried, filtered and evaporated. The residue is dissolved in 0.5 N hydrochloric acid (50 ml) and the solution washed three times with ethyl acetate (100 ml). The aqueous layer was neutralized with pyridine and extracted three times with dichloromethane. The combined organic layers dried, filtered and evaporated. The residue is crystallized from acetonitrile and a small amount of dimethylformamide, and obtain 1.3 g (46%) of monohydrochloride() 1-[[4-[4-[4-[4-[[2-(2,4-differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl] -1 - piperaz CLASS="ptx2">

Example 21

A mixture of the monohydrate () N-[1-[3-[[4-[4-[4-[4-[[2-(2,4- differenl)-2-( 1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4 - yl]methoxy]phenyl]-1-piperazinil] phenyl] -4,5-dihydro-5-oxo 1,2,4-triazole-1-yl]methyl]-2,2-DIMETHYLPROPANE]-3-oxopropyl]-1,4 - dihydro-4-pyridinoline] methylmethanamine (0,0024 mol) and pyrrolidine (0.01 mol) in dimethylformamide (50 ml) was stirred at room temperature for 1 hour. The mixture was poured into water and extracted three times with dichloromethane. The combined organic layers washed with water, dried, filtered and evaporated. The residue is dissolved in 0.5 N hydrochloric acid (500 ml) and the solution washed three times with ethyl acetate (100 ml). The aqueous layer was neutralized with pyridine and extracted three times with dichloromethane. The combined organic layers dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone and water (0.5 ml). The residue is purified on a glass filter with silica gel (eluent CH2Cl2/CH3OH, 96/4). The appropriate fractions are collected and evaporated. The residue is dissolved in 1N hydrochloric acid (50 ml), neutralized with pyridine and extracted five times with dichloromethane. The combined organic layers dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone and water (5 drops), obtain 1.1 g (51%) monohierarchical] phenyl]-4,5-dihydro-5-oxo 1,2,4-triazole-1-yl]methyl]- 2,2-dimethylpropyl-1 pyrrolidinedione; so pl. 154,4oC (compound 37).

C. Example of determination of physico-chemical properties

Example 22

Solubility

An excessive amount of compound added to 5 ml of solvent type solvent indicated in the table). The mixture is shaken for 1 hour at room temperature. The precipitate is filtered off. Measure the pH of the remaining solvent and indicate in table 5. The concentration was measured by UV-spectroscopy and indicate in the column "solubility".

D. Pharmacological examples

Example 23

Murine model of triple mycosis

Compound appreciate on their activity in a murine model of fungal growth, which simultaneously satisfy three avium - vaginal candidiasis, cutaneous Trichophyton and disseminated aspergillosis. Mice in groups of 10 individuals who previously given subcutaneous injections of estradiolvalerate (500 g), then inoculant, 0 day, as follows: 100000 colony forming units (CFU)/g of Aspergillus fumigatus B19119, intravenous; suspension containing 108cells of Candida albicans, intrawaginalno; and water suspension Trichophyton quinckeanum, slightly nagsasanay the skin of the back. Processing of test compounds (oral or intravenous) begin in Hamersley 6 day, selected samples by the number of CFU/g of Aspergillus fumigatus in the kidney and spleen, for the evaluation of skin lesions (0 = no visible lesions; 1 = multiple punctate lesions; 2 = moderate lesions; 3 = severe lesion) and to assess CFU of Candida albicans from vaginal smear.

Murine model of disseminated Candida

Mice in groups of 10 individuals, infect intravenous 8105SOME Candida albicans. Treatment starts on the day of infection, and repeat for 9 hours a day. CFU/g of Candida albicans in the kidneys determine for all mice who killed themselves or were killed on the 10th day.

Table 6 provides the lowest concentrations of these compounds, which give a reduction in the average number of Candida in 1 log (i.e., a 10-fold reduction) or greater, either on the triple helix model of mycosis, or on the model of disseminated infection Candida; and the lowest concentrations, which reduce the average skin lesions from skin dermatomycoses component below 1.0 on this model (NT = not tested, IV = intravenous).

Example 24

Determination of the sensitivity of fungi

To evaluate the activity of tested compounds in vitro using a set of cultures of Candida and the Department of culture of dermatophytes Microsporum canis, Trichophyton of gspence fungal substances, prepared from cultures slanted agar (mold). Check the connection will pipeinput from the main DMSO solution in water to obtain a series of 10-fold dilutions. Fungal inoculum suspended in a nutrient medium CYG (F. C. Odds, Journal of Clinical Microbiology, 29, (2735-S740, 1991) at approximately 50000 colony forming units (CFU) per 1 ml and added to aqueous scanned medicines.

Cultures were seeded in 96-well plates, and incubated them for 2 days at 37oC (Candida species) or for 5 days at 30oC (other mushrooms). The development of microculture measured by their optical density (OD) measured at a wavelength of 405 nm. OD for crops with target compounds calculated as a percentage of the OD of the control cultures without drugs. Inhibition of growth of 35% or less from the control samples are classified as significant inhibition.

Minimum inhibitory concentration (MIC) of intermediate compounds 15, 16, 17,18,24 is in the range from 0.01 to 10 μm for Candida glabrata, Candida krusei, Candida parapsilosis, atlantiscasino Candida albicans, Candida kefyr, Microsporum canis, Trichophton rubrum, Trichophton mentagrophytes, Cryptococcus neoformans, Aspergillus fumigatus.

E. Examples of songs

Used in these examples is in acid or its stereochemical isomeric form.

Example 25. Drops for oral administration

Dissolve 500 g of A. I. in 0.5 l of sodium hydroxide solution and 1.5 l of the polyethylene glycol at 60-80oC. After cooling to 30-40oC added 35 l of polyethylene glycol, and the mixture was thoroughly stirred. Then add a solution of 1750 Matricaria 2.5 l of purified water, and with stirring, add 2.5 l of cocoa of odesky and q glycol.s. up to a volume of 50 l, and get the solution drops for oral administration containing 10 mg/ml A. I. the Resulting solution is poured into suitable containers.

Example 26. Capsules

With vigorous stirring, mix 20 g A. I., 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of magnesium stearate. The resulting mixture then fill 1000 suitable hard gelatin capsules, each capsule contains 20 mg of the active ingredient.

Example 27. Tablets, film-coated

The receiving core component

A mixture of 100 g A. I., 570 g lactose and 200 g starch are thoroughly mixed, and then moisturize with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in 200 ml of water. The mixture in the form of a moist powder sieved, dried and again procee thoroughly mixed and pressed into tablets, getting 10,000 tablets each containing 10 mg of active ingredient.

Floor

To a solution of 10 g of methyl cellulose in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol (glycerin). Melt 10 g of polyethylene glycol and dissolved in 75 ml of dichloromethane. The last solution is added to the first solution, and then add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated ink suspension, and all homogenized. The core tablets are coated with the thus obtained mixture in an apparatus for coating.

Example 28. Injection

Dissolve 1.8 g of methyl-4-hydroxybenzoate and 0.2 g of sodium hydroxide in 0.5 l of boiling water for injection. After cooling to 50oC add with stirring, 0.05 grams propylene glycol and 4 g of A. I. the Solution is cooled to room temperature and add water for injection q.s. up to 1 l, obtaining a solution containing 4 mg/ml A. I. the Solution is sterilized by filtration and dispensed into a sterile container.

Example 29. Suppositories

Dissolve 3 g of A. I. solution of 3 g of 2,3-dioxymethylene acid in 25 ml polya the 55) q.s. to 300 G. of the Latter mixture is mixed with the first solution. Thus obtained mixture was poured into moulds at a temperature of 37-38oC, and form 100 suppositories each containing 30 mg/ml A. I.

1. Azole compounds of General formula I

< / BR>
their pharmaceutically acceptable salts accession acid or base, or a stereochemical isomeric form,

where a and b together form a bivalent radical of formula-CH=N-;

D is a radical of the formula

< / BR>
< / BR>
L is a radical of the formula

< / BR>
< / BR>
Alk is a radical C1-4alcander;

R1- halogen;

R2is hydrogen or halogen;

R3is hydrogen or phenyl;

R4is hydrogen or phenyl;

R5is hydrogen or C1-6alkyl;

R6is hydrogen or C1-6alkyl, or

R5and R6together with the nitrogen atom to which they are attached, form a pyrolidine or substituted pieperazinove ring, and the Deputy is in position 4 piperazinovogo ring and represents a C1-6alkyl or hydraxis1-6alkyl.

2. Connection on p. 1, where D represents the radical of formula (D1).

3. Connection on p. 2, where D represents the radical of formula (D11), in which R3and R4each and independently represents a phenyl or hydrogen.

4. Connection on p. 3, where the said compound is a() 4-[4-[4-[4-[[2-(2,4-differenl)-2-(1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl]methoxy]phenyl]-1-piperazinil]phenyl]-2-[3,3-dimethyl-2-(phosphonooxy)-butyl] -2,4-dihydro-3H-1,2,4-triazole-3-one, its stereochemical isomeric form or its salt attaching the base.

5. Antifungal composition comprising an active ingredient and a pharmaceutically acceptable carrier, characterized in that as the active ingredient it contains a compound according to any one of paragraphs.1 - 4 in protivogribkova effective amount.

6. The method of obtaining the composition of p. 5, characterized in that the compound according to any one of paragraphs.1 - 4 thoroughly mixed with a pharmaceutically acceptable carrier.

7. Method of inhibiting the development and/or expansion of mushrooms in warm-blooded animals, characterized in that it includes the introduction of the aforementioned warm-blooded animals protivogribkova effective amount of a compound according to any one of paragraphs. 1 to 4.

8. The compound of formula II

< / BR>
its pharmaceutically acceptable salt accession acid or stereochemical from the its a() 4-[4-[4-[4-[[2-(2,4-differenl)-2-(1,2,4-triazole-1-ylmethyl)-1,3-dioxolane-4-yl] methoxy] phenyl] -1-piperazinil] phenyl] -2,4-dihydro-2-(2-hydroxy-3,3-dimethylbutyl] 1,2,4-triazole-3-one, its pharmaceutically acceptable salt accession acid or its stereochemical isomeric form.

10. The method of obtaining the azole compounds of the formula I on p. 1, a-b, D and L are specified in paragraph 1 values, characterized in that the compound of formula II under item 8-a-b - and-D are specified in paragraph 1 values, acelerou or On-phosphorylate allermuir or fosforiliruyusciye reagent of formula III

W1-L

where W1- reactive tsepliaeva group, such as hydroxyl or halogen, and L have the values listed in paragraph 1, followed, if necessary, the transformation of the target product in the form of a salt by processing pharmaceutically acceptable acid or base and/or get their stereochemical isomeric form.

11. The method of obtaining the azole compounds of the formula I on p. 1-a-b - and-D are specified in paragraph 1 values, and L represents a radical of L2, characterized in that the compound of formula II under item 8-a-b and D are specified in paragraph 1 values, acelerou reagent of formula VI

< / BR>
where W1represents a reactive tsepliaeva group such as hydroxyl group or halogen, and W2- reactive tsepliaeva Gruaud interaction with the amine of formula VIII

< / BR>
where R5and R6are specified in paragraph (1 value, followed, if necessary, the transformation of the target product in the form of a salt by processing pharmaceutically acceptable acid or base and/or get their stereochemical isomeric form.

 

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