Triazole derivatives, pharmaceutical composition and intermediate products

 

(57) Abstract:

The invention relates to the derivatives of triazole, exhibiting antifungal activity. The essence of the invention: fungicidal compounds of the formula given in the description, and their pharmaceutically acceptable salts, where R is phenyl, substituted with 1-3 halozatkezelesi, R1- C1-C4-alkyl, X is CH or N, Y Is F or Cl, pharmaceutical composition and intermediate products. 5 C. and 15 C.p. f-crystals, 5 PL.

The invention relates to the derivatives of triazole, exhibiting antifungal activity.

More specifically, the present invention relates to 2-aryl-3-(3 - haloperidol-4-yl or 5-galerimizin-4-yl)-1-(1H-1,2,4-triazole-1-yl)alkane-2-Aulnay derived, applicable for controlling fungal infections in animals, including man.

Individual compounds of the present invention in a General sense described in our application for the European patent N 89307920.2 (EP-A-0357241), but none of them was especially revealed or confirmed by the example in the specified application.

Found that the compounds of the present invention have unexpectedly high level of antifungal activity, particularly against fungi of the species Aspergillus spp. the over long periods of half-life values (t1/2).

The invention offers triazole derivatives of General formula

,

and their pharmaceutically acceptable salts,

where R is phenyl, substituted with 1-3 halozatkezelesi;

R1- C1-C4-alkyl;

X is CH or N;

Y is F or Cl.

In the above definition of the compounds of formula (I) C3and C4- alkali can have a normal or ISO-structure.

Featured alkyl groups include methyl and ethyl.

Examples of R include 2-forfinal, 4-forfinal, 2-chlorophenyl, 4 - chlorophenyl, 2-bromophenyl, 2-iopener, 2,4-dichlorophenyl, 2,4-differenl, 2-chloro-4-forfinal, 2-fluoro-4-chlorophenyl, 2,5-differenl, 2,4,6 - tryptophanyl, 4-bromo-2,5-differenl.

Preferably, R is represented phenyl, substituted by 1 or 2 substituents, each independently selected from fluorine and chlorine.

Featured individual embodiments of R include 2-forfinal, 4-forfinal, 2,4-differenl, 2-chlorophenyl and 2,4-dichlorophenyl.

More preferably, when R represents 2-forfinal, 2,4 - differenl, 2-chlorophenyl or 2,4-dichlorophenyl. Preferably R1is methyl. Preferably X is N. Preferably, Y - F.

Pharmaceutically acceptable salts of compounds of formula (I), romkert, loggedout, sulfate or bisulfate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulfonate, bansilalpet and p-toluensulfonate. As an overview at an acceptable pharmaceutical salts see Berge and others, J. Pharm. Sci., 66, 1 - 19 (1977).

The compounds of formula (I) contain at least two chiral center (*) and thus exist in the form of at least two diastereoisomeric pairs of enantiomers, for example

.

The invention includes the individual stereoisomers of compounds of formula (I), and mixtures thereof. Separation of diastereoisomers may be achieved by conventional methods, for example by fractional crystallization, chromatography or HPLC diastereomeric mixture of compounds of formula (I) or an acceptable salt or its derivative. An individual enantiomer of the compounds of formula (I) can also be obtained from a corresponding optically pure intermediate or by resolution of the racemate using either HPLC application acceptable chiral media, or by fractional crystallization of the diastereoisomeric salts formed by reaction of the racemate with an acceptable optically active acid, for example 1R-(-)- or 1S-(+)-10-Campora the amount

.

Especially recommended individual embodiments of the compounds of the present invention include:

2R, 3S-2-(2,4-differenl)-3-(3-herperidin-4-yl)-1-(1H-1,2,4 - triazole-1-yl)butane-2-ol,

2R, 3S-2-(2-chlorophenyl)-3-(3-herperidin-4-yl)-1-(1H-1,2,4-trial-1 - yl)butane-2-ol,

2R, 3S-2-(2-forfinal)-3-(3-herperidin-4-yl)-1-(1H-1,2,4-triazole - 1-yl)butane-2-ol,

2R, 3S-2-(2,4-differenl)-3-(5-ftorpirimidinu-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol,

2R, 3S-2-(2,4-dichlorophenyl)-3-(5-ftorpirimidinu-4-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol and its pharmaceutically acceptable salts.

The compounds of formula (I), provided by the invention, can be obtained in the following ways:

1). All the compounds of formula (I) can be synthesized according to scheme 1,

where R1X and Y take the values specified for the compounds of formula (I).

In a typical method, the compound of formula (II) deprotonation the addition of approximately one equivalent of an acceptable reason, such as diisopropylamide lithium or bis(trimethylsilyl)amide, sodium or potassium, and the resulting salt (preferably a salt of lithium, sodium or potassium) is injected in situ in the reaction with the ketone of formula (III). The reaction is usually conducted at temperatures from -80 to -50oC, preferably at a diethyl ether, and in an inert atmosphere, for example nitrogen or argon.

The initial products of the formula (II) are either known compounds (see , for example, D. J. Comins, etc., Heterocycles 22, 339 (1984)), or can be obtained by conventional methods according to literature methods. The initial products of the formula (III) are either known (see, for example, EP-A-44605, EP-A-69442 or GB-A-1464224), or can be synthesized by methods similar to that shown in the aforementioned patents.

2). All the compounds of formula (I) can be obtained according to scheme 2,

where R, R1X and Y take the values specified for the compounds of formula (I), and Z is acceptable to the group that you want, for example, chlorine, bromine or C1-C4-alkanesulfonyl (such as methanesulfonamido). Examples of acceptable salts of the bases 1H-1,2,4-triazole include melodramatycheskye, preferably sodium and potassium, as well as tetraalkylammonium, preferably tetrabutylammonium (see U.S. patent 4259505) of salt.

The reaction recommend using as starting product of the epoxide of formula (IV). When used in the process of compounds of formula (VI) it is likely that the mechanism of the reaction is dictated at least partly educated in Uchen processes, using as starting product epoxide of formula (IV).

When using a basic salt, 1H-1,2,4-triazole reaction is usually carried out at a temperature from room temperature to 100oC, preferably at 60oC, when using the sodium salt of 1H-1,2,4-triazole and preferably at room temperature using the corresponding Tetra-n-butyl-ammonium salt in an acceptable organic solvent, for example N,N-dimethylformamide or tetrahydrofuran.

Or the reaction may be carried out using 1H-1,2,4-triazole in the presence of additional acceptable reason, such as Na2CO3or K2CO3preferably at 50 - 100oC in an acceptable solution, for example N,N-dimethylformamide, methanol or aqueous acetone.

Intermediate compounds of formulas (IV) and (VI) can be obtained by conventional methods, in General, the presented schemes 3 and 4

where

R, R1X and Y take the values specified for the compounds of formula (I), and Z represents the group that you want, preferably Cl or Br.

In a typical method, the compound of formula (II) deprotonation the addition of approximately one equivalent of an acceptable reason, such as organicheskoi compound is injected in situ in the reaction with the compound of the formula (V). Usually the reaction is carried out at a temperature of from -80 to -50oC, preferably at -70oC, in an acceptable organic solvent, for example tetrahydrofuran, toluene or diethyl ether, in an inert atmosphere, for example nitrogen or argon. The resulting compound of formula (VI) does not require the allocation and usually it cyclist in situ by mixing some time at a higher temperature, for example at room temperature, obtaining oxirane formula (IV).

The compound of formula (VI), where Z is chlorine or bromine, can be obtained by reaction of an epoxide of the formula (IV) with the appropriate kaleidotrope in anhydrous conditions.

Scheme 4 R, R', X And Y take the values specified for the compounds of formula (I), and Z1is acceptable to the group, for example, Cl, Br, I or methansulfonate.

In the conventional method, the compound of formula (VIII), (IX) or (X) is obtained directly from a complex ester of the formula (VII) by reaction with an ORGANOMETALLIC compound, an educated deprotonization compounds of formulas

,

in appropriate circumstances, where R1X and Y take the values specified for the compounds of formula (I) with about one equivalent acceptable base,and a temperature of from -80 to -50oC, preferably about -70oC,in an acceptable organic solvent, for example tetrahydrofuran or diethyl ether, in an inert atmosphere, for example nitrogen or argon.

Or the compound of formula (IX) or (X) can be respectively obtained by the reaction of compounds of formula (VIII) or (IX) with about one equivalent acceptable base such as sodium hydride, followed by alkylation in situ formed carbanion acceptable alkylating agent. The reaction is usually carried out at a temperature of from 0oC to room temperature in an acceptable organic solvent, for example N,N-dimethylformamide.

Alkylation of compounds of formula (VIII) or (IX) are recommended to carry out the terms of the transfer phase, for example, using the system NaOH/[CH3(CH2)]4NHSO4/ /H2O/CHCl3/ (C1-C4-alkyl)Z1(where Z1preferably represents iodine) at a temperature of from 0oC to room temperature, typically at room temperature.

Epoxidation of the ketone of formula (IX) or (X) is carried out by conventional methods, for example by use under the conditions dimethyloxazolidine (see, for example, J. A. C. S. (1965), 87, 1353) or hormati the tion, specified for the compounds of formula (I), and X = N can be synthesized according to scheme 5,

where R, R1and Y take the values specified for the compounds of formula (I), a Z2and Z3each independently selected from hydrogen and groups which can be selectively deleted recovery, provided that Z2and Z3can not both represent hydrogen. It is recommended that Z2represented a group that can be selectively removed by recovery, a Z3= N. It is recommended to remove selective recovery group was represented by a halogen (i.e. F, Cl, Br or I), and most preferably chlorine.

If the specified group is represented by a halide, preferably chlorine, then as a way to restore it is recommended that the hydrogenolysis. According to the conventional method, the compound of formula (XI) is subjected to hydrogenolysis using appropriate catalyst, for example palladium on charcoal, and acceptable solvent, for example ethanol, possibly in the presence of additional acceptable base, such as sodium acetate. The reaction can be carried out at a temperature from room temperature up to the boiling point of the solvent and a pressure of 1 to 5 atmospheres (100 to 500 kPa), but obychnomu (XI), where one of the Z2and Z3represents hydrogen and the other is the group which can be selectively removed by the reconstruction can be obtained in the usual way according to the scheme 6,

where R, R1and Y take the values specified for the compounds of formula (I), and one of the Z2and Z3represents hydrogen and the other is the group which can be selectively removed by recovery. The reaction can be carried out by a method similar to method (1).

Intermediate compounds of formula (XI), where one of the Z2and Z3represents hydrogen and the other is the group which can be selectively removed by the reconstruction can be also obtained by a method similar to the method (2).

The initial products of the formula (XII) can be synthesized by conventional methods, such as described in preparative section.

Intermediate compounds of formula (XI), where Z2and Z3each is represented by a group which can be selectively removed by the reconstruction can be obtained by a method similar to the method (2), using as starting product of the corresponding epoxide, which can be synthesized by a conventional method according to the scheme 7,

where R, Rthe u, which can be selectively removed by the restoration, and Z4represents chlorine or C1-C4-alkoxygroup.

All the above reactions are normal, the selection of appropriate reagents and conditions for these reactions, as well as methods for the isolation of target products shall be made in accordance with the literary sources and with reference to the examples given here.

Pharmaceutically acceptable salts formed by addition of acids, can be easily obtained joint by mixing solutions containing free base and acid target. Salt normally precipitates out of solution and is separated by filtration or produce evaporation of the solvent.

The compounds of formula (I) and their salts are to antifungal remedies applicable for the treatment or prevention of fungal infections in animals, including humans. For example, the compounds applicable to the treatment of local fungal infections of man, caused among other microorganisms fungi species of Candida, Trichophyton, Microsporum or Epidermophyton, or fungal infections caused by Candida albicans (e.g. oral thrush or candidiasis of the vagina). Connections can also be s, Aspergillus flavus, Aspergillus fumigatus, Coccidioides, Paracoccidiodes, Histoplasma or Blastomyces.

Compounds of the present invention was found to have unexpectedly high activity against clinically important species of fungi Aspirgillus, which is primarily attributed to unexpectedly good pharmokinetics properties of the compounds, with the result that they are characterized by a longer half-life (values t1/2).

Detection of antifungal activity in vitro of compounds can be performed by determining the minimum inhibitory concentration (MIC), i.e. the concentration of test compound in an acceptable environment in which a growth of a particular microorganism. In practice, the number of plates with agar, which caused the test compound at a certain concentration, infected with a standard culture of, for example Candida albicans, and each plate is then incubated for 48 h at 37oC. After that mark the presence or absence of the record growth of fungus, on what basis and determine the MIC. Other microorganisms, used in such tests may include: Aspergillus fumigatus species of Trichophyton, Microsporum species, Epidermophyton floccosum, Coccidioides immitis and Torulopsis glabrata.

Test compounds in vivo maim introduction to mice infected with a strain of Candida albicans or Aspergillus fumigatus. The activity in this case is based on survival of the group treated with compound mice after the death of the group of untreated mice the dose level at which the compound provides 50% protection against the lethal action of infection (ED50), notice. In the model, infection with Aspergillus species the number of mice cured from the infection after the sequence of doses, allows further definition of the activity.

For the treatment of human antifungal compounds of formula (I) can be used in pure form, but as a rule, they are administered in a mixture with a pharmaceutical carrier selected with regard to the intended route of administration and conventional pharmaceutical practices. For example, the compounds can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules, or bubbles in pure form or in a mixture with excipients, or in the form of elixirs, solutions or suspensions containing flavoring and coloring additives. Connections can be injectioni parenterally, for example intravenously, intramuscularly or subcutaneously. For parenteral administration the compounds are best used in the form of steeldogs, to make the solution isotonicity with blood.

The solubility of the compounds of formula (I) in the aquatic environment can be improved by forming a complex with a hydroxyalkyl derivative of cyclodextrin in obtaining appropriate pharmaceutical composition. It is recommended to apply a cyclodextrin was alpha-, beta - or gamma-cyclodextrin, most preferably beta - cyclodextrin. Featured hydroxyalkyl derivative is hydroxyproline derived.

Oral and parenteral patient a daily dosage level of the antifungal compounds of the formula (I) and their salts is 0.01 - 20 mg/kg (in single or divided dosage). Thus tablets or capsules of the compounds contain from 5 mg to 0.5 g of active compound for administration of a single dosage form or in two or more forms at a time depending on destination. In any case, the attending physician determines the actual dosage that is most appropriate for the individual patient and which will vary depending on age, weight and response of the particular patient. The above dosages are examples of averaged quantities and, of course, in some cases protivogribkovye the compounds of formula (I) can be used in the form of suppositories or vaginal suppository, or can be applied topically in the form of a lotion, solution, cream, ointment or powder - dust. For example, the compounds can be introduced into the cream, which is an aqueous emulsion of polyethylene glycols or liquid paraffin, or they may be introduced in a concentration of 1 - 10% ointment on the basis of white wax or white soft paraffin mixed with stabilizers or preservatives, if necessary.

Thus, the invention also provides a pharmaceutical composition comprising a compound of formula (I) or its pharmaceutically acceptable salt in a mixture with a pharmaceutically acceptable diluent or carrier.

The invention also provides a compound of formula (I) or its pharmaceutically acceptable salt, or a composition intended for use as a medicine, in particular as antifungal agents.

The invention further provides the use of compounds of formula (I) or its pharmaceutically acceptable salt or composition thereof to create antifungal agents.

The invention also proposes a method of processing animal (including humans) to cure or prevent a fungal infection, zakluchalsya acceptable salt or composition.

The invention also provides new intermediate compounds of formula (IV), (VI) and (XI), 4-ethyl-5-ftorpirimidinu and 4-chloro-6-ethyl-5 - ftorpirimidinu.

The following examples illustrate the synthesis of compounds of formula (I). I believe that the enantiomeric pair B, when it is mentioned in any of the following preparative examples or examples, and in the products of examples 1, 3, 4 and 5 (each of which received only one enantiomeric pair of two possible), is a racemic mixture of 2R,3S and 2S,3R-enantiomer.

Example 1. 3-(3-Chloropyridin-4-yl)-2-(2,4-differenl)-1-(1H-1,2,4 - triazole-1-yl)butane-2-ol (see diagram 8).

To a solution of Diisopropylamine (1.01 g, 10 mmol in dry THF (60 ml) at -60oC and in an atmosphere of nitrogen was added dropwise a 1.6 M solution of n-utility in hexane (6.25 ml, 10 mmol). The mixture is left to warm to -20oC, then cooled to -70oC and to the resulting solution diisopropylamide lithium (DAL) (10 mmol) at -70oC added dropwise to 1.41 g (10 mmol) 3-chloro-4-ethylpyridine (see D. L. Comins and other Heterocycles, 22, 339 (1984)). The resulting mixture was stirred at the same temperature for 15 minutes, then add a solution of 1-(2,4-differenl)-2-(1H-1,2,4 - triazole-1-yl) ethanol (2,23 g, 10 mmol) in THF (15 ml). The mixture is left NAGUSI by extraction with ethyl acetate (360 ml). The combined organic extracts are dried over magnesium sulfate, filtered, concentrated under reduced pressure and the title compound allocate "pulse" by chromatography on silica with elution by ethyl acetate. The product is recrystallized from ethyl acetate (yield 0,46 g), so pl. 182 - 184oC. Found, %: C 55,76; H 4,15; N 15,23 calculated for C17H15ClF2N4O, %: C 55,98, H 4,14, N 15,36.

Example 2. 2-(2,4-Differenl)-3-(3-herperidin-4-yl)-1- (1H-1,2,4-triazole-1-yl)butane-2-ol (see diagram 9).

The reaction is carried out according to methods analogous to the methods of example 1 but using 4-ethyl-3-herperidin (see preparative example 1) instead of 3-chloro-4-ethylpyridine as the original product. Column chromatography of the crude reaction product on silica by elution with ethyl acetate in the beginning after the merger and evaporation of appropriate fractions obtain the title compound (enantiomeric pair A) so pl. 178 -181oC, characterized by using1H-ANR spectroscopy.

1H-NMR (CDCl3) : 1,6 (d, 3H), of 3.95 (q, 1H), 4.7 and 5,15 (AB kV, 2H), 5,1. (c, 1H(OH)), and 6.5 (m, 1H), 6,7 (m, 1H), 6,95 (m, 1H), 7,45 (t, 1H), 7,8 (c, 1H), 7,95 (c, 1H), 8,15 (c, 1H), of 8.25 (d, 1H) h/million

Further elution with a mixture of ethyl acetate: methanol (95:5) after the B). The resulting product is subjected to further purification column chromatography on silica using as eluent a mixture of dichloromethane-methanol - to 0.88 aqueous ammonia (93:7:1). The target fractions are combined and their evaporation receive after washing with diethyl ether the title compound (enantiomeric pair B), so pl. 188 - 189oC. Found, %: C 57,63; H 4,32; N 15,71 calculated for C17H15F3N4O0,25H2O, %: C 57,87; H 4,43; N 15,88.

The enantiomeric pair B separated by HPLC using a chiral media (b(R)OG) and elution with a mixture of isopropanol-hexane (1:1). The appropriate fractions are combined and, after evaporation receive the separated individual enantiomers, each of which is contaminated chiral media.

Each contaminated enantiomer is subjected to further purification column chromatography on silica with elution with a mixture of dichloromethane-methanol (95: 5). The appropriate fractions are combined and evaporated to obtain after washing with a mixture of hexane-diethyl ether purified individual enantiomer.

One of the enantiomers: so pl. 57 - 59oC and []2D5- 59o(1 mg/ml in methanol), the other enantiomer: so pl. 56 - 57

.

Notes to the table.1.

(1) Column chromatography carried out on silica with gradient elution using first as eluent a mixture of ethyl acetate-dichloromethane (2:1) and then ethyl acetate. The obtained solid is washed with diethyl ether and obtain the target product.

(2) Information about the original product, see example 1.

(3) Information about the original product, see preparative example 1.

(4) Column chromatography carried out on silica with gradient elution using it as a first eluent mixture of ethyl acetate-dichloromethane (2: 1) and then ethyl acetate. The appropriate fractions are combined evaporated and the resulting product is subjected to further purification column chromatography on silica using as eluent a mixture of dichloromethane-methanol - to 0.88 aqueous ammonia (93:7:1). The appropriate fractions are combined to evaporate and washing of the residue with diethyl ether to obtain the target product.

(5) Poluchennuyu individual enantiomers, one of which has so pl. 83 - 84oC and []2D5-80o(C = 1 mg/ml in methanol) and the second is so pl. 78 - 79oC and []2D5+82o(C = 1 mg/ml in methanol).

(6) Column chromatography is performed on silica using as eluent a mixture of hexane-isopropanol-0.88 aqueous ammonia (80:20:1,5). The appropriate fractions are combined evaporated and the resulting product is subjected to further purification column chromatography on silica using as eluent a mixture of ethyl acetate-ethanol (97:3). The appropriate fractions are combined and, after evaporation receive separated pairs of enantiomers. Washing each pair of enantiomers diethyl ether to obtain the target product.

(7) Received a pair of enantiomers separated by HPLC by the method similar to that shown in example 2.

Example 7. 2-(2,4-Differenl)-3-(5-ftorpirimidinu-4-yl)-1- (1H-1,2,4-triazole-1-yl)butane-2-ol (see diagram 10).

A solution of 3-(4-chloro-5-herperidin-6-yl)-2-(2,4 - differenl)-1-(1H-1,2,4-triazole)-1-yl)butane-2-ol in the form of an enantiomeric pair B (see preparative example 2 (III)) (0,307 g, 0.8 mmol) in ethanol (20 ml) hydronaut at atmospheric pressure and room temperature in the presence of 10% palladation continue for another 1 h The catalyst was removed by filtration, the filtrate was concentrated in vacuo. "Pulse" chromatography of the residue on silica with elution with a mixture of ethyl acetate: methanol (97:3) receive after the merger and evaporation of appropriate fractions and washing with diethyl ether the title compound in the form of an enantiomeric pair B (0,249 g, 89%), so pl. 127oC. Found, %: C 55,08, H 4,00, N 19,96; calculated for C16H14F3N5O, %: C 55,01; H 4,01; N 20,05.

In 4 ml of methanol is dissolved sample of the title compound in the form of an enantiomeric pair B (0,105 g, 0.3 mmol) and 1R-(-)-10-camphorsulfonic acid (0.07 g, 0.3 mmol) and the mixture was incubated 2 h at 0oC. Filtering the formed crystalline substances receive 1R-(-)-10-camphorsulfonate 2R, 3S-2-(2,4-differenl)-3-(5-ftorpirimidinu - 4-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol,5 methanol (0.06 g), so pl. 176oC []2D5- 49,5o(C = 2 mg/ml in methanol). Found, %: C 53,09, H are 5.36, N 11,43 calculated for C26H30F3N5O5S0,5 methanol (0,052 g), so pl. 176oC []2D5+ 54,5o(C = 2 mg/ml in methanol).

Found, %: C 53,27; H 5,31, N 11,64; calculated for C26H30F3H5O5S]2D5- 62oC (C = 1 mg/ml in methanol is srabatyvayut as described above and receive 2S, 3R-2-(2,4-differenl)-3-(5 - ftorpirimidinu-4-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol (0,63 g), so pl., 127oC []2D5+ 59,9o(C = 2 mg/ml in methanol).

Example 8. 2-(2,4-Differenl)-3-(5-ftorpirimidinu-4-yl)-1- (1H-1,2,4-triazole-1-yl)butane-2-ol, enantiomeric pair B (see scheme 11).

B THF (200 ml) is added bis(trimethylsilyl)amide, sodium (79 ml of 1.0 M solution in THF) and the solution is cooled in nitrogen to -65oC. and Then for 30 min was added a solution of 4-ethyl-5-ftorpirimidinu (10 g) (see preparative example 8) in THF (100 ml). After stirring 3 h at -65oC fine sediment is treated with a solution of 1-(2,4-differenl)-2-(1H-1,2,4 - triazole-1-yl)ethanone (17,7 g) in THF (100 ml) was added 30 min dropwise. The solution is stirred for further 1 h at -65oC and then treated with acetic acid (20 ml). After heating to -20oC the solution washed with water (200 ml), the organic layer is separated and combined with the ethyl acetate (200 ml) back extract the aqueous phase. The combined organic layers are concentrated under reduced pressure and get solid, which was washed with diethyl ether (230 ml) and filtered. The filtrate is concentrated under reduced pressure and chromatographic on silica with elution with a mixture of diethyl ether is matographic oxide of silicon with a mixture of ethyl acetate/hexane (1:1) as eluent. The appropriate fractions are combined and evaporation under reduced pressure to obtain the purified title compound (0,82 g), so pl. 125 - 127oC. Found, %: C 54,89; H 4,06; N 19,66 calculated for C16H14F3N5O, %: C 55,01; H 4,01; N 20,05.

Example 9. 2-(2,4-Differenl)-3-(5-ftorpirimidinu-4-yl)-1-(1H-1,2,4 - triazole-1-yl)butane-2-ol, enantiomeric pair A.

The title compound was synthesized in a manner analogous to the method of example 7, using as starting product enantiomeric pair A 3-(4-chloro-5-ftorpirimidinu-6-yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)- butane-2-ol (see preparative example 2 (III)). The obtained product with so pl. 137oC. Found;% C 54,89; H 4,06; received 19.82 N calculated for C16H14F3N5O, %: C 55,01; H 4,01; N 20,05.

Example 10. 3-(5-Chloropyrimidine-4-yl)-2- (2,4-differenl)-1-(1H-1,2,4 - triazole-1-yl)butane-2-ol, enantiomeric pair B (see scheme 12).

The solution enantiomeric pair B of 3-(4,5-dichloropyrimidine-6-yl)-2-(2,4 - differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol (see preparative example 6 (III)) (0,58 g,1,46 mmol) in ethanol (20 ml) hydronaut at atmospheric pressure and room temperature in the presence of 10% palladium on coal (45 mg) and sodium acetate (122 mg, 1.5 mmol) within 7 hours and Then the catalyst tfiltervalidator receive after the merger and evaporation of appropriate fractions, the title compound (0.35 g, 72%), so pl. 128oC. Found;% C 51,68; H to 3.89; N 18,58 calculated for C16H14ClF2N5O : 1,5 (d, 3H), 4,4 (kV, 1H), 4,67 and 4,82 (AB kV, 2H), 6.35mm (c, 1H, HE), of 6.45 (m, 1H), 6,62 (m, 1H), 7,07 (m, 1H), 7,6 (c, 1H), 8,05 (c, 1H), 8,8 (c, 1H) h-million

Examples 12 to 16. Compounds of General formula

,

obtained in a manner analogous to the method of example 10, using as starting product of the corresponding 2-aryl - 3-(4-chloro-5-ftorpirimidinu-6-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2 - ol. (see tab. 2).

Notes to table 2.

(1) Column chromatography is performed on silica using as eluent a mixture of ethyl acetate-methanol (96:4)

(2) Column chromatography is performed on silica using as eluent isobutylmethylxanthine.

(3) Data source connection, see preparative example 3.

(4) Data source connection, see preparative example 4.

(5) Data source connection, see preparative example 5.

(6) Obtained enantiomeric pair separated by HPLC by the method similar to the method of example 2.

Example 17.

Aqueous salt solution of 2R,3S-2-(2,4-differenl)-3-(5 - ftorpirimidinu-4-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol and hydroxypropyl - - is = 0,41, 1 g) and dissolved in distilled water (about 7 ml). Add sodium chloride (90 mg) and dissolved, after which distilled water to bring the volume to 10 ml To the resulting solution add 2R, 3S-2-(2,4-differenl)-3-(5-ftorpirimidinu-4-yl)- 1-(1H-1,2,4-triazole-1-yl)butane-2-ol (100 mg) (see example 7) in a vessel, the mixture is treated with ultrasound for 15 min and then stirred for 2 days of mechanical rotation. Add a further quantity of hydroxypropyl- -cyclodextrin (200 mg) and the mixture is stirred by mechanical rotation of the vessel 1 h to obtain the desired solution.

Example 18. 2R,3S/2S,3R)-2-(2,4-differenl)-3- (5-ftorpirimidinu-4-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol (see diagram 13).

I. 2-(1-[4-Chloro-5-ftorpirimidinu-6-yl]ethyl)-2-(2,4-differenl) oxiran.

To a solution of Diisopropylamine (12,89 g) in THF (80 ml) at -10oC add p-utility (72,6 ml of 1.6 M solution in hexane). After stirring for 30 min at this temperature, the solution is cooled to -67oC and add a solution of 4-chloro-6-ethyl-5-ftorpirimidinu (18,64 g) in THF (80 ml) for 30 min at temperatures from -65 to -50oC. the Reaction mass was stirred at -65oC 1 h Then add a solution of 2-chloro-1,2,4 - differenl)ethanone (22.1 g) in THF (80 ml) at a temperature of from -65 to -40

1H-NMR (CDCl3) (as a mixture of two diastereoisomeric pairs of enantiomers): = 8,7 (s, 1H), and 7.3 - 7.5 (m, 1H), 6,7 - 6,9 (m, 2H), 3,9 (kV, 2H), 3.0 a (square, 2H), 1,4 (d, 3H) ppm, in respect of one enantiomeric pair; = 8,7 (s, 1H), 7,1 - 7,3 (m, 1H), 6,7 - 6,9 (m, 2H), 3,85 (kV, 1H), 2,95 (kV, 2H), 1,45 (d, 3H) ppm with respect to the other enantiomeric pair.

II. 2-(2,4-Differenl)-2-(1-[5-ftorpirimidinu-4-yl]ethyl) oxirane.

To a solution of the product of section I (6,37 g) in industrial methylated ethanol (63 ml) is added sodium acetate (1.66 g) and 5% palladium (coal) 50% humidity (0.64 g). The mixture hydronaut at a pressure of 40 psi at 40oC for 4 h, the cooled reaction mixture is filtered to remove catalyst and the filtrate phase is separated, evaporated under reduced pressure and the residue chromatographic on silica gel, elwira with methylene chloride. The desired fractions are combined and evaporated at reduced pressure and get named in the title compound (2.15 g) m/e 280.

1H-NMR (CDCl3) as a mixture of two diastereomeric pairs of enantiomers): = 9,0 (s, 1H), 8,45 (s, 1H), and 7.3 - 7.5 (m, 1H), 6,7 - 6,9 (m, 2H), 3,9 (kV, 2H), 3.0 a (kV, 2H), 1,4 (d, 3H) ppm with respect to one enantiomeric pair;

= 9,0 (s, 1H), 8,45 (s, 1H), 7,1 - 7,3 (m, 1H), 6,7 - 6,9 (m, 2H), 3,85 (kV, 1H), 2.95 and (q, 2H), 1,45 (d, 3H) ppm with respect to the other enantiomeric pair.

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

To a solution of sodium hydroxide (0.14 g) in methanol (7 ml) was added 1H-1,2,4-triazole (5 g) followed by the addition product section II (1 g). Stir the reaction mixture is heated at boiling for 6 hours, then evaporated in vacuum. The residue is distributed between methylene chloride (10 ml) and water (10 ml). Methylenchloride layer was separated, washed with water (410 ml), dried (magnesium sulfate) and the solvent is removed in vacuum. The remainder chromatographic on silica gel, elwira a mixture of 1:1 ethyl acetate-n-hexane to separate the two diastereoisomeric pairs of enantiomers. The desired fractions, the content is and melting 124 - 127oC. TCS (silica gel, ethyl acetate): Identical enantiomeric pair B obtained in example 7.

1H-NMR (CDCl3): = of 8.95 (s,1H), 8,65 (s, 1H), of 7.97 (s, 1H), 7,7 - of 7.55 (m, 1H). 7,55 (c, 1H), 6,9 - of 6.75 (m, 2H), 6,5 (c, 1H), 4.75 V - of 4.25 (q, 2H), from 4.2 to 4.1 (q, 1H) and 1.15 (d, 3H) ppm.

Example 19.

2R, 3S-2-(2,4-differenl)-3-(5-ftorpirimidinu-4-yl)-1-(1H-1,2,4 - triazole-1-yl)butane-2-ol bansilalpet.

To a solution of 2R,3S-2-(2,4-differenl)-3-(5-ftorpirimidinu-4-yl)- 1-(1H-1,2,4-triazole-1-yl)butane-2-ol from example 7 (8.0 mg) in ethyl acetate (120 ml) add benzosulfimide acid (3,62 g) and the resulting suspension is stirred at room temperature for 3 hours After cooling for 30 min, the mixture is filtered, washed with cold ethyl acetate and dried overnight under reduced pressure. Get the connection specified in the title of example, in the form of a white solid (9.7 g), so pl. 147 - 149oC.

Example 20. The tablets. 2R,3S-2-(2,4-differenl)-3-(5 - ftorpirimidinu-4-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol (the compound of example 7) (50 mg/dose), lactose (62 mg/dose), pre-gelatinising starch (21 ml/dose) and croscarmellose sodium (7.5 mg/dose) mixed together for 20 min, sift and further stirred for 20 minutes

Polyvinylpyrrolidon is to the mixture obtained above. The resulting mixture granularit and, if necessary, add more purified water (22,5 mg/dose).

Wet weight deagglomerated using the crusher Fitz (trade mark). The obtained granules are dried in an oven at 50oC as long as the moisture content in the granules will not be the same as the original in the original mixture (1%). Dry granules are sieved and mixed for 20 minutes Granules are then smeared stearate (1.5 mg/dose) and molded into tablets on special equipment for tableting.

If necessary, the tablets covered with a special coating.

The following preparative examples illustrate the synthesis of some new source of compounds used in the working examples.

Preparative example 1. 4-3-Ethyl-3-herperidin (see diagram 14).

To mix the solution GAVE (200 mmol) in dry THF (400 ml) (obtained by the method similar to the method of example 1) at -70oC and in an atmosphere of nitrogen was added dropwise 3-herperidin (20 g, 200 mmol). After 30 min at the same temperature to the reaction mixture dropwise add ethyliodide (60 g, 370 mmol) and the mixture is left to rise slowly to temperature -10 to -5oC, at which the allocation of education water (50 ml) and the organic phase is separated. The aqueous phase is extracted with ether (350 ml), the combined organic layers are dried over magnesium sulfate and concentrate under reduced pressure. Distillation of the resulting liquid at atmospheric pressure to obtain the title compound (13 g), so Kip. 154 - 158oC, characterized by using1H-NMR spectroscopy.1H-NMR (CDCl3) : a 1.25 (t, 3H, J = 10 Hz), 2,65 (q, 2H, J = 10 Hz), and 7.1 (t, 1H, J = 8 Hz), and 8.3 (d, 1H, J = 8 Hz), 8,33 (c, 1H) h/million

Preparative example 2. 3-(4-Chloro-5-ftorpirimidinu-6 - yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol (see diagram 15).

I. 6-Ethyl-5 - ftorpirimidinu-4(3H)-he.

To a solution of sodium methoxide (8,64 g, 160 mmol) in methanol (50 ml) at 0oC was added a solution of ethyl ester-corprationeducation acid (see E. D. Bergrmann etc., J. Chem. Soc., 1959, 3278, and D. J. Burton and others, Tet. Lett 30, 6113 (1989:)) (12,96 g, 80 mmol) and acetate of formamidine (8,32 g, 80 mmol) in methanol (50 ml) and the resulting mixture is stirred 1 h at 0oC, about a day at room temperature and finally for 30 minutes at boiling. The mixture is cooled and the excess of sodium methoxide is neutralized by adding glacial acetic acid (10 g). The reaction mixture was concentrated under reduced pressure, the residue is dissolved in hot ethyl acetate, insoluble acetate intothree what Yerevanian the ethyl acetate is obtained after combining the appropriate fractions and evaporation, and washing with diethyl ether the title compound (5.5 g, 48%), so pl. 105 - 106oC. Found;% C 50,38; H is 4.85; N quintiles these figures were 19.63 calculated for C6H7FN2O; %: C 50,70; H IS 4.93; N OF 19.72.

The title compound is also obtained by the method described in preparative example 7.

II. 4-Chloro-6-ethyl-5-ftorpirimidinu.

A mixture of the product of stage I (6.4 g, 45 mmol) and phosphorylchloride (30 ml) is boiled for 3 hours the Excess phosphorylchloride distilled off under reduced pressure, and the residue is transferred into ice-cold water. The resulting mixture is extracted with methylene chloride (350 ml), the combined organic extracts washed with water and dried over magnesium sulfate. The solvent is removed under reduced pressure and distillation of the resulting oil under reduced pressure to obtain the title compound (4,81 g, 66%), so Kip. 74oC at 22 mm Hg, characterized by using 1H-NMR spectroscopy.

1H-NMR (CDCl3: 1,3 (t, 3H, J = 10 Hz), 2,9 (q, 2H, J = 10 Hz), 8,68 (c, 1H) h/million

III 3-(4-Chloro-5-ftorpirimidinu-6-yl)-2-(2,4-differenl)- 1-(1H-1,2,4-triazole-1-yl)butane-2-ol.

To the solution GAVE (20 mmol) in THF1(50 ml) (obtained according to the method of example 1) in nitrogen atmosphere at -70oC dropwise within 15 min was added a solution of the product stabilat a solution of 1-(2,4 - differenl)-2-(1H-1,2,4-triazole-1-yl)ethanone (4,46 g, 20 mmol) in THF (50 ml) and the mixture was incubated 1 h at -70oC and then 1 h at -50oC. the Reaction mixture is neutralized by adding a solution of glacial acetic acid (1.2 g) in the form (10 ml) and the mixture is left to warm to room temperature. The organic phase is separated, the aqueous phase is extracted with ethyl acetate (20 ml), the combined organic layers are dried over magnesium sulfate and concentrate under reduced pressure. Column chromatography of the residue on silica with elution with a mixture of ethyl acetate-diethyl ether (3:2) initially receive after the merger and evaporation of appropriate fractions, and washing with diethyl ether enantiomeric pair In the title compounds (0,94 g, 12%), so pl. , 92oC. Found, %: C 49,93; H 3,57; N 18,17 calculated for C16H13,ClF3N5O, %: C 50,06; H 3,39; N 18,25.

Further elution after pooling and evaporation of appropriate fractions get enantiomeric pair A, the title compound contaminated with the starting ketone. Repeated recrystallization of the product from diethyl ether to obtain the product with so pl. 132oC. Found, %: C 49,93; H to 3.58; N 18,23 calculated for C16H13ClF3N5O, %: C 50,06; H 3,39, N 18,25.

I. THF can be replaced by t the ranks preparative method of example 2 (III), using as initial products 4-chloro-6-ethyl-5-ftorpirimidinu and the corresponding 1-aryl-2-(1H-1,2,4-triazole-1-yl)ethanone (see tab. 3).

Preparative example 6. 3-(4,5-Dichloropyrimidine-6 - yl)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol (see diagram 16).

I. 6-Ethylpyrimidine-4(3H)-he.

To a solution of sodium methoxide (4,19 kg, and 77.6 mol) and acetate of formamidine (3 kg, 28.8 mol) in methanol (45 l) at 5 - 10oC slowly add a solution of methyl ester propionyloxy acid (2.5 kg, 19.2 mol) in methanol (10 l), maintaining the temperature during addition below the 20oC. the resulting mixture was stirred for about a day at room temperature, and then adding concentrated hydrochloric acid to establish a pH of 7. The reaction mixture was concentrated under reduced pressure to a volume of about 10 l, diluted with water (10 l) and extracted with 2-butanone (230 l). The combined organic extracts are concentrated under reduced pressure to a volume of about 2 l and diluted with ethyl acetate (4 l). The desired product crystallizes from the solution (2.4 kg, 70%) after recrystallization from isopropanol receive a product with so pl. 132 - 134oC. Found, %: C 58,45; H 6,37; N 22,41. Calculated for C6H8N2O, %: C is Tadei I (18.6 g, 150 mmol) in concentrated hydrochloric acid (120 ml) at 30 - 40oC is added within 30 min of 30% aqueous hydrogen peroxide solution (18 ml) (slight increase in temperature) and the resulting mixture is stirred for about a day when the 40oC. the Mixture is concentrated under reduced pressure, the residue is suspended/dissolved in toluene and the toluene removed under reduced pressure. The residue is dissolved in phosphorus oxychloride (150 ml), boiled for 3 h, after which the excess phosphorus oxychloride is removed under reduced pressure. The residue is transferred into ice water, extracted with methylene chloride (350 ml), the combined organic extracts washed with water (30 ml) and dried over magnesium sulfate. The solvent is removed under reduced pressure and distillation of the resulting oil under reduced pressure to obtain the title compound (5.4 g, 20%), so Kip. 104oC at 22 mm Hg, characterized by using1H-NMR spectroscopy.

1H-NMR (CDCl3) : 1,3 (t, 3H, J = 10 Hz), 3.04 from (q, 2H, J = 10 Hz), 8,75 (c, 1H) h/million

III. 3-(4,5-Dichloropyrimidine-6-yl)-2-(2,4-differenl)-1-(1H - 1,2,4-triazole-1-yl)butane-2-ol.

K solution GAVE (to 13.6 mmol) in THF (50 ml) (obtained according to the method of example 1) at -70oC added dropwise 4,5-dichloro-6-ethylpyrimidine (the product of a hundred who make a solution of 1-(2,4-differenl)-2- (1H-1,2,4-triazole-1-yl)ethanone (2,97 g, 13.3 mmol) in THF (50 ml) at such a rate that the temperature of the reaction mixture does not exceed -50oC. After stirring 1 h at -70oC and 1 h at -50oC, the reaction mixture is neutralized by adding 10% aqueous acetic acid (11 ml). The organic phase is separated, the aqueous phase is extracted with ethyl acetate (220 ml) and the combined organic layers are dried over magnesium sulfate. After removal of the solvent under reduced pressure the residue was washed with diethyl ether (25 ml) and unreacted source ketone (1.7 g) is removed by filtration. The filtrate is concentrated under reduced pressure and the pulse" by chromatography of the residue on silica with elution with a mixture of ethyl acetate-diethyl ether (65:35) initially receive (after consolidation and evaporation of appropriate fractions and washing diethyl ether) enantiomeric pair In the title compound (670 mg, 13%, so pl. 124oC). Found, %: C 47,78; H 3,33: N 17,13 calculated for C16H13Cl2F2N5O, %: 48,0; H 3,25; N 17,50.

Further elution after pooling and evaporation of appropriate fractions and washing with diethyl ether to obtain the enantiomeric pair A title compound (527 mg, 10%), so pl. 137oC. Found, %: C 48,02, H 3,30; N 17,39, calc is mu 17).

I. 2,4-Dichloro-5-ftorpirimidinu.

K of phosphorus oxychloride (141,4 g) at 25oC add 5-fluorouracil (20 g) in powder form, obtained suspension is heated to 90oC and then for 1 h was added N,N-dimethylaniline (37,3 g). After that the reaction mixture boiled for 5 h and distillation remove 70 g of phosphorus oxychloride. The mixture is then cooled to 25oC and portions over 1 h to carry cooled to 0oC 3h. HCl. The title compound is extracted from the mixture with dichloromethane (270 ml). The combined dichloromethane layers washed with water (50 ml) and concentration in vacuo receive oil (24 g), characterized by using1H-NMR spectroscopy.

1H-NMR (CDCl3) : 8,5 (s, 1H) h/million MS: m/e = 166

II. 2,4-Dichloro-1,6-dihydro-6-ethyl-5-ftorpirimidinu.

The magnesium shavings (4,27 g) in tetrahydrofuran (56 ml) for 5 h was added a solution of brometane (19 g) in THF (10 ml). To the resulting suspension at 0oC for 1 h was added a solution of the product of stage I (24 g) in 1,2-dimethoxyethane (70 ml). The reaction mixture is neutralized with 10oC by adding glacial acetic acid (10 g) and obtain a solution of the title compound which was directly used in the next stage.

III. 2,4-Dichloro-6-Aut solution of potassium permanganate (23 g) in the form (260 ml), maintaining the temperature of the reaction mixture below 20oC. Then add 5 N. hydrochloric acid, followed by addition of a solution of metabisulfite sodium (14 g) in water (42 ml). After bleaching mixture the product is extracted with ethyl acetate (250 ml). Subsequent concentration of the organic layer receive oil. The oil is partitioned between dichloromethane (50 ml) and 2 N. a sodium hydroxide solution (105 ml), the organic layer washed with 5% brine (100 ml) and after concentrating obtain a solution of the title compound which was directly used in the next stage.

IV. 2-Chloro-6-ethyl-5-ftorpirimidinu-4(3H)-he.

It is obtained as a product in phase III solution was added water (6 ml), the mixture was stirred at 80oC with slow addition over 2 h 4 n sodium hydroxide solution. After that the reaction mixture is cooled and washed with dichloromethane (15 ml). The aqueous layer was added to dichloromethane (60 ml) and addition of concentrated hydrochloric acid to establish a pH of 1. The organic layer is separated and the addition of concentrated aqueous ammonia solution set pH 3. The precipitated ammonium chloride is filtered off, the filtrate is concentrated to a volume of 15 ml and diluted with utilizuyut and after drying (8 g) describe using 1H-NMR and mass spectrometry.

1H-NMR (DMCO-d6) : 7,3 (exchanged), and 2.4 (m, 2H), 1,1 (t, 3H) h/million MS: m/e = 176.

V. 6-Ethyl-5-ftorpirimidinu-4(3H)-he.

To the product stage IV (6 g) in ethanol (60 ml) is added sodium acetate (5.5 g) and 5% palladium on coal (0.6 g). The mixture hydronaut 3 h under a pressure of 3 atmospheres. The catalyst is filtered off, the filtrate is concentrated to a volume of 10 ml and then mixed with water (2 ml) and dichloromethane (80 ml). Add toluene (32 ml), the solution is concentrated to a volume of 5 to 6 ml and then mixed with an additional amount of toluene (8 ml). The isolated crystals of the title compound is filtered off and characterize using 1H-NMR and mass spectrometry (output of 3.9 g).

1H-NMR (DMCO-d6) : 8,0 (s, 1H), 2,5 (m, 2H) and 1.15 (t, 3H) h/million MS: m/e = 142.

Preparative example 8. 4-Ethyl-5-ftorpirimidinu (see diagram 18).

A mixture of 2,4-dichloro-6-ethyl-5-ftorpirimidinu (10 g) (see preparative example 7 (III)), sodium acetate (8,83 g), 5% palladium on coal ("humidity" 50%, 2 g) and methanol (30 ml) hydronaut 5 h at 50oC and a pressure of 3 atmospheres. The obtained suspension is carefully filtered through filtering means on the basis of cellulose filter pirok washed with additional met the spas of distillate. The distillate is partitioned between water (300 ml) and ether (400 ml) and the two phases are separated, the organic phase is washed with water (450 ml), dried over MgSO4and removal of solvent at room temperature and reduced pressure to obtain the title compound as a pale yellow liquid (2.2 g).

Preparative example 9. 2-Chloro-4-ethyl-5-ftorpirimidinu (see diagram 19).

I. Diethyl ether 2-methyl-2-(2-chloro-5-ftorpirimidinu-4-yl) propandiol acid.

Conduct the reaction at -10oC in THF (200 ml) between sodium hydride (60% dispersion in oil, 2.8 g) and diethyl ether methylmalonic acid (6 g). After 30 min at -10oC for 30 min was added a solution of 2,4-dichloro-5-ftorpirimidinu (5 g) (see preparative example 7) in THF (200 ml). The reaction mixture was partitioned between dichloromethane (200 ml) and water (200 ml), acidified with acetic acid and the layers separated. The organic layer is concentrated under reduced pressure and the resulting oil chromatographic on silica with elution with dichloromethane. As a result, after pooling and evaporation of appropriate fractions obtain the title compound (9 g), characterized by using 1H-NMR and mass spectrometry.

1H-NMR (CDCl3) : 8,5 the Hai I (3.2 g) was dissolved in acetic acid (25 ml) and diluted with 5 N. hydrochloric acid (10 ml). The mixture is heated at 100oC 16 h, cooled and partitioned between water (30 ml) and dichloromethane (45 ml). The dichloromethane layer is separated, dried and concentrated under reduced pressure to obtain oil. The title compound selected by chromatography on silica by elution with dichloromethane. The product is characterized using1H-NMR and mass spectrometry (exit 350 mg).

1H-NMR (CDCl3) : 8,4 (s, 1H), 2,9 (m, 2H), 1.5 a (t, 3H) h/million MS: m/e = 160.

Identifying activity in vivo in mice against Aspergillus fumigatus.

According to the General method of testing a group of mice infected by a strain of Aspergillus fumigatus. Then each mouse receives the test compound in standard dose 20 mg/kg twice daily for 5 days. On the tenth day of the define the state of the mice.

The activity is determined by the survival of the treated mice, after the death of mice in the group not receiving treatment, and the number of cured mice.

The results obtained in a comparative study using two compounds, as described in the working examples, and the two compounds are given in the application for the European patent N 89307920.2 (EP-A-0357241 table.4.

1. Triazole UB>-alkyl;

X is CH or N;

Y is F or Cl,

or their pharmaceutically acceptable salt.

2. Connection on p. 1, wherein R is phenyl, substituted by 1 or 2 halogen substituents.

3. Connection on p. 1, wherein R is phenyl, substituted by 1 or 2 substituents, each independently selected from fluorine and chlorine.

4. Connection on p. 3, wherein R is 2-forfinal, 4-forfinal, 2,4-differenl, 2-chlorophenyl or 2,4-dichlorophenyl.

5. Connection on p. 4, wherein R is 2-forfinal, 2,4-differenl, 2-chlorophenyl or 2,4-dichlorophenyl.

6. Connection PP.1 - 5, where R1is methyl.

7. The compound according to any one of paragraphs.1 - 6, where X - n

8. The compound according to any one of paragraphs.1 to 7, where Y - F.

9. The compound according to any one of paragraphs.1 to 8, characterized in that it has the 2R, 3S-configuration

< / BR>
10. Connection on p. 1, representing 2R,3S-2-(2,4-differenl)-3-(5-ftorpirimidinu-4-yl)-1-(1H-1,2,4-triazole-1-yl)butane-2-ol or its pharmaceutically acceptable salt.

11. The pharmaceutical composition exhibiting antifungal activity, including an active ingredient and a pharmaceutical acceptable carrier, distinguish the pharmaceutically acceptable salt according to any one of paragraphs.1 - 10.

12. The composition according to p. 11, characterized in that it contains a compound of the formula I in the form of a complex with a hydroxyalkyl derivative of cyclodextrin.

13. The composition according to p. 12, wherein the hydroxyalkyl derivative represented hydroxypropyl derivatives, and cyclodextrin represented by alpha - or beta-cyclodextrin.

14. The compound of formula I or its pharmaceutically acceptable salt according to any one of paragraphs.1 - 10 with antifungal activity.

15. The connection formulas

< / BR>
where Q represents a group of the formula

< / BR>
where R, R1X and Y have the meanings given in paragraph 1;

Z - tsepliaeva group.

16. The compound of formula VI under item 15, where Z is chlorine, bromine or1-4-alkanesulphonic.

17. The connection formulas

< / BR>
where R, R1and Y have the values listed in paragraph 1;

Z2and Z3each independently selected from hydrogen and groups which can be selectively deleted recovery, provided that Z2and Z3can't both be hydrogen.

18. Connection on p. 17, where the group is selectively removed by the restore is halogen.

19. Connection on p. 17, where Z2- chlorine and Z3-

 

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< / BR>
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(I)

where R and R1such that:

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or R and R1together with the nitrogen atom to which they are bound, form a piperazinil, substituted lower alkyl,

A -:

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or circuit< / BR>
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or one hydrogen atom and the other is a hydroxy radical or1-C4-alkyl,

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moreover, these compounds of formula (I) can nachtergaele or organic acids

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< / BR>
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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 the derivatives of triazolopyrimidine General formula (I), method of production thereof and to pharmaceutical compositions based on

The invention relates to new compounds for phytosanitary use with groups benzylidenemalononitrile or cycloalken

The invention relates to the field of pest control, in particular microbicide tool, a method for microbicide drug and the way to fight germs
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