Derivatives of 1,2,4-triazole or their pharmaceutically acceptable salts

 

(57) Abstract:

Usage: for the treatment and prevention of fungal infections. The inventive product - derivatives of 1, 2, 4 - triazole f-ly I, where Ar is phenyl substituted by at least 1 halogen. R1- C1- C4alkyl; R2- C1- C5alkyl, monosubstituted hydroxy, C1- C4alkoxy, carbarnoyl, C1- C4alkylthio, cyano or C1- C4alkoxycarbonyl, nitrogen-containing heterocyclic group containing 3 to 6 carbon atoms, and substituted oxopropoxy or unsubstituted heterocyclic group containing 1 to 2 atom On the number of heteroatoms and 3 to 6 carbon atoms; n is 0,1 or 2. The connection has fungicidal activity. Connection structure of f-crystals I:

4 C. p. F.-ly, 1 table.

The invention relates to a series of new derivatives of 1-(triazole-1-yl)-2-phenyl-3-(substituted thio-, sulfinil or sulfonyl)-2-alkanol with antifungal activity, which therefore can be used to treat and prevent fungal infections, especially internal infections in humans and animals.

A number of derivatives of 1-(triazole-1-yl)-2-phenyl-3-(substituted thio-, sulfinil or sulfonyl)-2-alkanolamine differ from the compounds according to the invention, the compounds according to the invention have some specific substituents on tio, sulfanilic or sulfonyloxy group. In the compounds according to the invention have considerably better fungicidal activity than the known compounds.

Compounds according to the invention is a compound of the formula I

where Ar represents an unsubstituted phenyl group substituted by at least one halogen atom;

R1an alkyl group having 1-4 carbon atoms;

R2an alkyl group having 1-5 carbon atoms, once substituted by hydroxy; C1-C4alkoxy, carbamoyl,1-C4alkylthio, cyano or1-C4alkoxycarbonyl, nitrogen-containing heterocyclic group having 3-6 carbon atoms, substituted oxopropoxy or unsubstituted heterocyclic group containing 1-2 oxygen atoms as heteroatoms and 3-6 carbon atoms.

n is zero, one, or two, and their pharmaceutically acceptable salts.

Compounds according to the invention can be obtained by different methods, which are known to produce compounds of this type. For example, a suitable method involves reacting a compound of the group and Z represents mercaptopropyl, or Z' and Z ' together represent apachegroup with the compound of the formula III

X R2(in which R2has early specific values, and if Z' is oxygraph, X represents a halogen atom, sulfonyloxy or carboxyl alloctype or, if Z' or Z ' together represent apachegroup, then X is mercaptopropyl); or with a compound of formula III, in which the active group, other than those referred to group X, is protected by obtaining the compounds of formula I in which n is zero; and optional oxidation of the compounds of formula I in which n is equal to zero, obtaining the compounds of formula I, in which n is one or two; and optionally removing any protective groups.

Compounds according to the invention show valuable fungicidal activity and can be used to treat and prevent fungal infections in humans and animals. They can be administered orally or locally and, if desirable, can be obtained in medicinal forms with conventional pharmaceutically acceptable excipients, such as carriers, fillers, dispersing means and diluents for preparation of suitable dosage f the e oral administration to an adult patient the daily dose is 50-2000 mg, more preferably 100 to 600 mg, which can be entered as a one-time, single dose or as fractional dose, for example, from one to three times a day.

The following examples show the receipt of some compounds according to the invention and experiment, showing the biological activity of compounds. These examples are given for information, formulas target compounds, but it should be noted that these formulas do not reflect any specific steric configuration.

P R I m e R 1. (2R, 3R)-2-(2,4-differenl)-3-/(2-oxyethyl)-thio/ -1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
70 mg (1,60 mmole) of sodium hydride (in the form of a 55% by weight dispersion in mineral oil) was washed with hexane and then suspended in 3 ml of dimethylformamide. To the resulting suspension in a nitrogen atmosphere under ice cooling was added 187 mg (2.4 mmole) of 2-mercaptoethanol and the mixture was stirred 10 minutes at the end of this time was added to a mixture of 200 mg (0,80 mmole) of (2R, 3R)-2-(2-4-differenl)-3-methyl-2-/(1H-1,2,4-triazole-1-yl)-methyl/ -oxirane (obtained as described in the publication EP 332387) and the resulting mixture was stirred at 50-60aboutC for 30 minutes the mixture is Then cooled, after which it was diluted with ethyl acetate. The mixture was washed with a saturated aqueous solution is which was purified by chromatography on a column of 10 g of silica gel, using as eluent a mixture of ethyl acetate and hexane in the ratio of 4:1 and received 195 mg of target compound indicated in the title of the example. Pure specimen, melting at 89-90aboutS, was obtained by recrystallization from a mixture of ethyl acetate and hexane.

Specific rotation ()25D-85,9about(0,58, chloroform).

Absorption spectrum in the infrared region (KBr).maxcm-1: 3447, 3234, 1615.

Spectrum of nuclear magnetic resonance (CDCl3million days of 1.14 (3H, doublet, J 7 Hz), 2,6-3,1 (3H, multiplet), of 3.45 (1H, Quartet, J 7 Hz), 3,83 (2H, triplet, J 6.5 Hz) of 4.83 (1H, doublet, J 14,5 Hz), is 4.85 (1H, broad), 5,14 (1H, doublet, J 14,5 Hz), the 5.51 (1H, singlet), 6,5-7,0 (2H, multiplet), 7,2-7,6 (1H, multiplet), 7,74 (1H, singlet), 8,03 (1H, singlet).

P R I m m e R 2. (2R, 3R)-2-(2,4-differenl)-3-/(2-oxyethyl)- sulfonyl/-1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
96 mg high (0.56 mmole) of 3-chloroperbenzoic acid was added to a solution of 84 mg (0,26 mmole) of (2R, 3R)-2-(2,4-differenl)-3-/ (2-oxyethyl)-thio/-1-(1H-1,2,4-triazole-1-yl)-2-butanol (obtained as described in example 1) in 1 ml of methylene chloride and the mixture was stirred at room temperature for 15 minutes To the end of this time the reaction mixture was diluted with ethyl acetate and washed successively with an aqueous solution of sulfinate. Then it was dried and the crude product after removal of the solvent was purified column chromatography, passing through a column of 5 g of silica gel, using as eluent a mixture of ethyl acetate, chloroform and ethanol in the ratio 10:10:1 by volume, and obtained 63 mg of target compound indicated in the title of example, in the form of solids. Clean the sample with a melting point of 122aboutWas obtained by recrystallization of this solid from a mixture of ethyl acetate-benzene.

Specific rotation ()D25-55,8about(C0,48, chloroform)

Absorption spectrum in the infrared region (HBr),maxcm-1: 3389, 1616.

Spectrum of nuclear magnetic resonance (CDCl3million days of 1.27 (3H, doublet, J 7 Hz), and 3.3 (1H, broad), 3,4-3,6 (2H, multiplet), 3,76 (1H, Quartet, J Hz), 4,22 (2H, triplet, J 6 Hz) 5,01 (1H, doublet, J 14 Hz), 5,43 (1H, doublet, J 14 Hz), 5,6 (1H, broad), 6,6-7,0 (2H, multiplet), a 7.1 to 7.6 (1H, multiplet), 7,79 (1H, singlet), of 7.90 (1H, singlet).

P R I m e R 3. (2Rx, 3Rx)-2-(2,4-differenl)-3/(3-oksipropil) -thio/-1-1,2,4-triazole-1-yl)-2-butanol.

< / BR>
Repeating the method similar to that described in example 1, but using 50 mg (2Rx, 3Rx)-2-(2,4-differenl)-3-methyl-2-/(1H-1, 2,4-triazole-1-yl)- methyl/-oxirane (polucen is confident the target compounds the melting point of 119-120aboutC (after recrystallization from a mixture of ethyl acetate and benzene).

Absorption spectrum in the infrared region (chloroform), maxcm-1: 3420, 1618, 1598, 1500.

Spectrum of nuclear magnetic resonance (CDCl3million days of 1.15 (3H, doublet, J 7 Hz), a 1.7-2.1 (2H, multiplet), 2,6-3,1 (3H, multiplet), to 3.34 (1H, Quartet, J 7 Hz), of 3.78 (2H, triplet, J 6 Hz), 4,82 (1H, doublet, J 14 Hz), 4,9 (1H, broad band), 5,10 (1H, doublet, J 14 Hz), 6,6-7,0 (2H, multiplet, a 7.1 to 7.6 (1H, multiplet), of 7.75 (1H, singlet), 7,89 (1H, singlet).

P R I m e R 4. (2R, 3R)-2-(2,4-differenl)-3-/(methoxycarbonylmethyl)-thio/-1- (1H-1,2,4-triazole-1-yl)-2-butanol.

< / BR>
64,2 mg (0,42 mmole) methyl ester bromoxynil acid and 48 mg (0.35 mmole) of potassium carbonate were added to a solution of 100 mg (0.35 mmole) of (2R,3R)-2-(2,4-differenl)-3-mercapto-1- (1H-1,2,4-triazole-1-yl)-2-butanol (obtained as described in the publication of the Japan patent N Hei 3-128338) in 3 ml of anhydrous dimethylformamide and the mixture was stirred at room temperature for 1 h after this time the reaction mixture was diluted with benzene and washed with a saturated aqueous solution of sodium chloride, and then the solvent was removed by distillation under reduced pressure. Thus obtained crude product was purified column was chromatically 120 mg of target compound, specified in the title of the example. Clean the sample with a melting point of 86-87aboutS, was obtained by recrystallization from a mixture of acetone-hexane.

Specific rotation ()D25-116,5about(C0,84, chloroform).

Absorption spectrum in the infrared region (KBr),maxcm-1: 3200 (broad band), 1742.

Spectrum of nuclear magnetic resonance (CDCl3million days of 1.17 (3H, doublet, J 7 Hz), of 3.46 (2H, singlet), 3,49 (1H, Quartet, J 7 Hz), of 3.80 (3H, singlet, 4,84 (1H, doublet,J 15 Hz), 5,15 (1H, singlet), is 5.18 (1H, doublet, J 15 Hz), 6,5-7,0 (2H, multiplet), a 7.1 to 7.6 (1H, multiplet), 7,73 (1H, singlet), 7,87 (1H, singlet).

P R I m e R 5. (2R, 3R)-3-(cyanomethylene)-2-(2,4-differenl)- 1-(1H, 1,2,4-triazole-1-yl)-2-butanol and its oxalate

< / BR>
90 mg (1.2 mmole) of anhydrous chloroacetonitrile and 112 mg (1,11 mmole) of triethylamine was added to a solution of 301 mg (1.05 mmole) of (2R, 3R)-2-(2,4-differenl)-3-mercapto-1-(1H-1,2,4-triazole-1-yl) -2-butanol in 12 ml of anhydrous methylene chloride and the mixture was stirred at room temperature for 5 hours after this time the reaction mixture was distributed between ethyl acetate and dilute aqueous sodium carbonate solution under ice cooling. The organic layer was washed twice, each time with a saturated aqueous solution of sodium chloride, paleoceanic product was purified chromatographia on a column of silica gel, using the method of gradient elution with a mixture of ethyl acetate, hexane, changing the ratio of 1:1 to 2:1 by volume) as eluent and received 280 mg of target compound indicated in the title of the example.

Specific rotation ()D25= -158,5about(C1,11, chloroform).

Absorption spectrum in the infrared region (chloroform),maxcm-1: 3410, 1620, 1600, 1500.

Spectrum of nuclear magnetic resonance (CDCl3million d.: of 1.23 (3H, doublet, J 7 Hz), 3,48 (1H, Quartet, J Hz), to 3.58 (2H, singlet), 5,02 (2H, broad singlet), are 5.36 (1H, broad singlet), about 6.5, and 7.1 (2H, multiplet), and 7.1 to 7.7 (1H, multiplet), and 7.8 (1H, singlet), 7,87 (1H, singlet).

35,9 mg (0,339 mmole) of oxalic acid was added to a solution of 110 mg (0,339 mmole) of the obtained compound in 5 ml of ethyl acetate. The residue obtained by distillation of the solvent was recrystallized from a mixture of diethyl ether and hexane, and received 133 mg of oxalate target compound, melting point 113-116aboutC.

Specific rotation ()D25-72,4about(from 0.55, methanol).

P R I m e R 6. (2R, 3R)/3-(cyanomethyl)-sulfonyl/-2-(2,4-differenl)-1-(1H - 1,2,4-triazole-1-yl)-2-butanol and its nitrate

< / BR>
117 mg (0,678 mmole) 3-chlormadinone acid under ice cooling was added to RA is example 5) in 2 ml of methylene chloride. The reaction mixture was heated to room temperature, after which it was stirred 2 h and then mixed with a water solution of sodium thiosulphate and dilute aqueous sodium bicarbonate solution, then the mixture was extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and then the solvent was removed under reduced pressure. The obtained oily residue was purified column chromatography on silica gel, using a gradient elution method with a mixture of ethyl acetate-hexane variable ratio from 1:1 to 2:1 by volume) as eluent and received 82 mg of target compound indicated in the title of example, in the form of butter.

Specific rotation ()D25-64,8about(of 0.52, chloroform).

Absorption spectrum in the infrared region (chloroform),max.cm-1: 3360, 1620, 1600, 1510.

Spectrum of nuclear magnetic resonance (CDCl3million d: to 1.37 (3H, doublet, J 7.5 Hz), 3,90 (1H, Quartet, J 7.5 Hz), of 4.44 (2H, singlet), equal to 4.97 (1H, doublet, J 15 Hz), 5,43 (1H, doublet, J 15 Hz), 6,09 (1H, singlet), about 6.5, and 7.1 (2H, multiplet), a 7.1 to 7.6 (1H, multiplet), 7,81 (1H, singlet), 7,83 (1H, singlet).

0.7 ml of 2% weight by volume solution of nitric acid in diethyl ether was added to a solution of 77 mg (0,22 stylizowane from a mixture of ethyl acetate-benzene and obtained 72 mg of nitrate target compound, the melting point 143-147about(With Razlog.).

Specific rotation ()D25-29,8about(of 0.52, methanol).

P R I m e R 7. (2R, 3R)-2-(4-chlorophenyl)-3-(cyanomethylene)-1 -(1H-1,2,4-triazole-1-yl)-2-butanol and its oxalate

< / BR>
Following the procedure similar to that described in example 5, but using 80 mg of (2R, 3R)-2-(4-chlorophenyl)-3-mercapto-1- (1H-1,2,4-triazole-1-yl)-2-butanol as a starting material, was obtained 77 mg of target compound indicated in the title of example, in the form of butter.

Specific rotation ()D25-141about(from 0.51, chloroform).

Absorption spectrum in the infrared region (chloroform),max.cm-1: 3430, 1610, 1508, 1498.

Spectrum of nuclear magnetic resonance (CDCl3million days of 1.24 (3H, doublet, J 7 Hz), 3,26 (1H, Quartet, J 7 Hz), 3,53 (2H, singlet), 4,58 (1H, doublet, J 14 Hz), 5,02 (1H, doublet, J 14 Hz), 5,13 (1H, broad singlet), 6,23 (4H, singlet) of 7.70 (1H, singlet), of 7.75 (1H, singlet).

A solution of 71 mg of target compound in a mixture of ethyl acetate and hexane was mixed with a molar equivalent of oxalic acid and was treated with the traditional method. Received 77 mg of oxalate target compound, melting point 76-80aboutC (decomp.).

Specific rotation ()D25-33,1 (C0,51, methanol).

P p Olya) 2-bromoacetamide and 48 mg (0.35 mmole) of potassium carbonate were added to a solution of 100 mg (0.35 mmole) of (2R, 3R)-2-(2,4-differenl)-3-mercapto-1-(1H-1,2,4-thiazol-1-yl)-2-butanol in 3 ml of anhydrous dimethylformamide and the mixture was stirred at room temperature for 1 h after this time the reaction mixture was diluted with benzene and washed with a saturated aqueous solution of sodium chloride, after which the solvent is kept at reduced pressure. Nominally pure product, thus obtained, recrystallized from a mixture of acetone-hexane and received 90 mg of target compound indicated in the title of the example, the melting point of 144-145aboutC.

Specific rotation ()D25-39,9about(C1,03, methanol).

Absorption spectrum in the infrared region (BKr),maxcm-1: 3366, 3219, 1658.

Spectrum of nuclear magnetic resonance (destinationy dimethyl sulfoxide DMCO-d6million d:

of 1.03 (3H, doublet, J 7 Hz), 3,21 (1H, doublet, J 14,5 Hz), 3,29 (1H, doublet, J 14,5 Hz), 3,60 (1H, Quartet, J 7 Hz), 4,74 (1H, doublet, J 14,5 Hz), to 4.98 (1H, doublet, J 14,5 Hz), 6,24 (1H, singlet), 6,6-7,0 (1H, multiplet), 7,0-7,5 (3H, multiplet), a 7.62 (2H, singlet), of 8.27 (1H, singlet).

P R I m e R 9. (2R,3R)-3/-(carboxylmethyl)-sulfonyl/- 2-(2,4-differenl-1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
149 mg (0,86 mmole) 3-chlormadinone acid was added to a solution of 140 mg (0,41 mmole) of (2R,0 ml of methylene chloride and the mixture was stirred at room temperature left for the night. At the end of this period the reaction mixture was washed successively with an aqueous solution of sodium thiosulfate, diluted aqueous sodium bicarbonate solution and saturated aqueous sodium chloride, after which the solvent was removed by distillation under reduced pressure. The solid residue was recrystallized from a mixture of methanol and hexane and received 120 mg of target compound indicated in the title of the example, the melting point of 184-185aboutC.

Specific rotation ()D25-35,4about(C1,00, dimethylformamide).

Absorption spectrum in the infrared region (KBr),maxcm-1: 3367, 3286, 1670.

Spectrum of nuclear magnetic resonance (hexadeuterated dimethyl sulfoxide + D2O), m D.

to 1.14 (3H, doublet, J 7 Hz), 3,39 (2H, singlet), 4,42 (1H, Quartet, J 7 Hz), to 4.81 (1H, doublet, J 14,5 Hz), 5,31 (1H, doublet, J 14,5), 6,4-7,0 (1H, multiplet), 7,0-7,5 (2H, multiplet), to 7.64 (1H, singlet), 8,31 (1H, singlet).

P R I m e R 10. (2R, 3R)-2-(2,4-differenl)-3-/(R and S)-2-oxazolidin-4-yl-)thio/-1-(1H-1,2,4-triazole-1-yl)-2-butanol and its paratoluenesulfonyl

< / BR>
Under ice cooling to 22.5 mg (0,52 mmole) of sodium hydride (in the form of a 55% by weight dispersion in mineral oil) was added to 5 ml of methanol with the following) 4-acetoxy-2-azetidinone to the resulting mixture. Then the mixture was stirred for 30 minutes under ice cooling. At the end of this time the reaction mixture was mixed with water and was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, after which the solvent was removed by distillation under reduced pressure. The resulting oil residue was then purified by chromatography on a column of silica gel using a mixture of ethyl acetate-hexane as eluent, and received 150 mg (yield 37%) of target compound indicated in the title of example, in the form of a foam containing a mixture of diastereoisomers in the ratio of 1:1.

Specific rotation ()D25-26,5about(C1,10, chloroform).

Absorption spectrum in the infrared region(chloroform)maxcm-1: 3400 (broad band), 1760.

Spectrum of nuclear magnetic resonance (hexadeuterated dimethyl sulfoxide + D2O) million D.

1,23 (1.5 N, doublet of doublet, J 7 and 1 Hz), 1,33 (1,5 H, doublet, J 7 Hz), 2,89 (0.5 N, double doublet, J 15 and 2.4 Hz), 2,94 (0.5 N, doublet of doublet, J 15 and 2.4 Hz), 3,37 (0.5 N, Quartet, J 7 Hz), 3.43 points (0.5 N, Quartet, J 7 Hz), 3.43 points (0.5 N, doublet of doublet, J 15 and 5 Hz), 3,49 (0.5 N, doublet of doublet, J 15 and 5 Hz), 4,85 (0.5 N, doublet of doublet, J 14 and 1 Hz), 4,87 (0.5 N, doublet, J 14 Hz), 4,96 (0.5 N, doublet of doublet, J 14 and 1 Hz), 5,07 (0.5 N, doublet, J14 Hz), 5,09 (0.5 N, double), 7,80 (0.5 N, singlet), 7,82 (0.5 N, singlet), 7,84 (0.5 N, singlet).

47 mg of p-toluenesulfonic acid (monohydrate) was added to a solution of 87 mg of the above compound in ethyl acetate and the mixture is then freed from solvent by distillation. The residue is triturated with diethyl ether and received 121 mg p-toluensulfonate mixture of the compound as amorphous powder.

P R I m e R 11. (2R, 3R)-2-(2,4-differenl)-3-/(1,3-dioxolane-2-yl)-methyl-thio/-1-(1H-1,2,4-triazole-1-yl)-2-butanol and its oxalate

< / BR>
Performing a process similar to that described in example 1, but using 193 mg (2R, 3R)-2-(2,4-differenl)-3-methyl-2-/ (1H-1,2,4-triazole-1-yl)-methyl/-oxirane and 160 mg (1,3 dioxolane-2-yl)-methyl, received 178 mg of target compound in the form of butter.

Specific rotation ()D25-56about(C0,53, methanol).

Spectrum of nuclear magnetic resonance (CDCl3million days of 1.16 (3H, doublet, J 7 Hz), 2.91 in (2N, Doubleday peak, J 5 Hz), 3,57 (1H, Quartet, J 7 Hz), 3,8-4,2 (4H, multiplet), to 4.87 (1H, doublet, J 14 Hz), of 4.95 (1H, singlet), of 5.15 (1H, triplet, J 5 Hz), 5,19 (1H, doublet, J 14 Hz), 6,6-7,0 (2H, multiplet), 7,2-7,6 (1H, multiplet), 7,78 (1H, singlet), 7,88 (1H, singlet).

A solution of this compound in a mixture of ethyl acetate and hexane was mixed with a molar equivalent of oxalic acid and theC.

P R I m e R 12. (2R, 3R)-3-/(1-cyanoethyl)-thio/-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
134 mg (1.00 mmol) 2-bromopropionitrile and 69 mg (0,50 mmole) of potassium carbonate were added to a solution of 143 mg (0,50 mmole) of (2R, 3R)-2-(2,4-differenl)-3-mercapto-1-(1H-1,2,4-triazole-1-yl) -2-butanol in 3 ml of dimethylformamide and the resulting mixture was stirred at room temperature for 1 h in nitrogen atmosphere. Then the reaction mixture was dissolved in benzene and the resulting solution was sequentially washed with water and saturated aqueous sodium chloride. Then the solvent was removed by distillation under reduced pressure, after which the obtained oily residue was purified preparative thin-layer chromatography on silica gel, using as developing solvent a mixture of ethyl acetate-hexane in the ratio of 3:2 by volume, and has obtained 57 mg of stereoisomer And the target compounds (having a lower polarity) in the form of oil and 72 mg of stereoisomer. The target compounds (having a higher polarity) in the form of a crystal: these crystals were recrystallized from a mixture of benzene and hexane and was given a clean sample with a melting point 66-68aboutC.

Stereoisomer A.

Specific rotation ()D25-192

Spectrum of nuclear magnetic resonance (DCl3) million days of 1.24 (3H, doublet, J 7 Hz), of 1.64 (3H, doublet, J 7 Hz), 3,54 (1H, broad Quartet, J 7 Hz), 3,90 (1H, Quartet, J 7 Hz), of 4.90 (1H, doublet, J 14 Hz), 5,10 (1H, doublet, J 14 Hz), 5,26 (1H, singlet), 6,5-7,0 (2H, multiplet), a 7.1 to 7.6 (1H, multiplet), 7,79 (1H, singlet), 7,80 (1H, singlet).

To a solution of 57 mg of this compound and 17 ml of oxalic acid, dissolved in 2 ml of ethyl acetate was added hexane and the crystals, which were isolated precipitate was collected by filtration, and received 60 mg of oxalate stereoisomer And a melting point of 137-138aboutC.

Stereoisomer Century

Specific rotation ()D25-46,0about(from 0.83, chloroform).

Absorption spectrum in the infrared region (chloroform)maxcm-1: 3400, 1615, 1498.

Spectrum of nuclear magnetic resonance (CDCl3million days of 1.24 (3H, doublet, J 7 Hz), of 1.64 (3H, doublet, J 7 Hz), 3,51 (1H, broad Quartet, J 7 Hz), is 4.93 (1H, Quartet, J 7 Hz), 4,99 (2H, singlet), 5,28 (1H, singlet), 6,5-7,0 (2H, multiplet), a 7.1 to 7.6 (1H, multiplet), 7,76 (1H, singlet), 7,83 (1H, singlet).

P R I m e p 13. (2R, 3R)-3-/(1-cyanoethyl)-sulfinil/-2-(2,4-differenl)-1-(1H - 1,2,4-triazole-1-yl)-2-butanol and its nitrate

< / BR>
(1). 205 mg (1,19 mmole) 3-chlormadinone acid under ice cooling and stirring to a solution of 402 mg (the scientists as described in example 12) in 15 ml of methylene chloride and the resulting mixture was stirred at the same temperature for 30 minutes After this time the reaction mixture is washed with 5% weight by volume aqueous solution of sodium thiosulfate and 3% aqueous sodium bicarbonate solution in this order and the solvent was removed by distillation under reduced pressure. The resulting oil residue was then purified column chromatography through silica gel (15 g), using as eluent a mixture of ethyl acetate and hexane in the ratio 4:1 by volume, and received 381 mg of the target compound in the form of oil. The product was a mixture of two diastereomers, which separation was performed, passing through a column of Lobar and using ethyl acetate as eluent, and was obtained 220 mg of pure isomer with higher polarity in the form of butter.

Absorption spectrum in the infrared region (chloroform),max.cm-1: 3390, 2550, 1615, 1500.

Spectrum of nuclear magnetic resonance (CDCl3million days of 1.13 (3H, doublet, J 7 Hz), 1,74 (3H, doublet, J 7 Hz), of 3.69 (1H, Quartet, J 7 Hz), 3,76 (1H, Quartet, J 7 Hz), 4,91 (2H, singlet), 5,78 (1H, singlet), about 6.5, and 7.1 (2H, multiplet), and 7.1 to 7.7 (1H, multiplet), 7,80 (1H, singlet), 7,92 (1H, singlet).

5% by weight by volume aqueous solution of nitric acid (one molar equivalent) in diethyl ether was added to a solution of the obtained compound, dissolved the CLASS="ptx2">

(2). Similarly, as described above, 570 mg of isomer (2R, 3R)-3-/(1-cyanoethyl)-thio/-2-(2,4-differenl)-1-(1H-1,2,4 - triazole-1-yl)-2-butanol (obtained as described in example 12) was oxidized with one molar equivalent of 3-chlormadinone acid and the crude product was purified column chromatography through silica gel. Received 521 mg of target compound in the form of an oil mixture of two diastereomers, which separation was carried out by chromatography on a column of Lobar, and received 228 mg of pure isomer with higher polarity in the form of butter.

Absorption spectrum in the infrared region (chloroform),maxcm-1: 3400, 2255, 1620, 1505.

Spectrum of nuclear magnetic resonance (CDCl3million days of 1.11 (3H, doublet, J 7 Hz), of 1.65 (3H, doublet, J 7 Hz), and 3.72 (1H, Quartet, J7 Hz), of 3.78 (1H, Quartet, J 7 Hz), 4,89 (2H, singlet), by 5.87 (1H, singlet), about 6.5, and 7.1 (2H, multiplet), and 7.1 to 7.7 (1H, multiplet), 7,80 (1H, singlet), of 7.97 (1H, singlet).

5% by weight by volume aqueous solution of nitric acid (one molar equivalent) in diethyl ether was added to the solution obtained above compound in diethyl ether, and received the nitrate target compound in the form of crystals, melting point 128-131aboutC.

P R I m e R 14. (2R, 3R)-2-(2,4-differenl)-3-(methoxymethyl-Isopropylamine was added to a solution of 400 mg (1,40 mmole) of (2R, 3R)-2-(2,4-dottorati)-3-mercapto-1-(1H-1,2,4 - triazole-1-yl)-2-butanol in 10 ml of methylene chloride at 0aboutWith stirring and the resulting mixture was stirred at the same temperature for 15 minutes, after which the mixture was stirred at room temperature for 30 minutes, after this time the reaction mixture was mixed with diluted aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The extract was dried and then concentrated by distillation of solvent under reduced pressure. The resulting crystalline residue is then recrystallized from a mixture of ethyl acetate and hexane and received 235 mg of target compound indicated in the title of the example, the melting point of 110-112aboutC.

Specific rotation ()D25-55about(C0,59, chloroform).

Absorption spectrum in the infrared region (KBr), maxcm-1: 3186 (wide band), 1615, 1499.

Spectrum of nuclear magnetic resonance (CDCl3million days of 1.18 (3H, doublet, J 7 Hz), 3,50 (3H, singlet) and 3.59 (1H, Quartet, J 7 Hz), 4,63 (1H, doublet, J 12 Hz), 4,88 (1H, doublet, J 14 Hz), 4,84 (1H, doublet, J 14 Hz), 4,88 (1H, singlet), 6,5-7,0 (2H, multiplet), 7,2-7,6 (1H, multiplet), of 7.75 (1H, singlet), 7,89 (1H, singlet).

P R I m e R 15. (2R, 3R)-2-(2,4-differenl)-3-/(methoxymethyl)- sulfonyl/-1-(1H-1,2,4-triaz alali to a solution of 190 mg (of 0.58 mmole) of (2R, 3R)-2-(2,4-differenl)-3-methoxymethyl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol (obtained as described in example 14) in 7 ml of methylene chloride and the resulting mixture was stirred at the same temperature for 5 minutes, after which the mixture was stirred at room temperature for 1 h, after this time the reaction mixture was mixed with an aqueous solution of sodium sulfite and then with a dilute aqueous solution of acid sodium carbonate and was extracted with ethyl acetate. Then the extract was dried and concentrated by distillation of solvent. The crude residue was purified column chromatography through silica gel, using a mixture of ethyl acetate-hexane in the ratio of 1:1 by volume as the eluent, and received 171 mg of target compound indicated in the title of example, in the form of solids. Clean the sample with a melting point of 102-103aboutWas obtained by recrystallization of this solid from a mixture of benzamycin.

Specific rotation ()D25-108about(from 0.51, chloroform)

Absorption spectrum in the infrared region (KBr),maxcm-1: 3439, 1617, 1505.

Spectrum of nuclear magnetic resonance (CDCl3million days of 1.26 (3H, doublet, J 7 Hz), of 3.77 (3H, singlet), 3,81 (1H, Quartet, J 7 Hz) 4,50 (1H, doublet, J 12 Hz), equal to 4.97 (1H(1H, singlet), 7,86 (1H, singlet).

P R I m e R 16. (2R, 3R)-2-(4-chlorophenyl)-3-(methoxymethyl)- 1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
Following the procedure described in example 14, but using 360 mg of (2R, 3R)-2-(4-chlorophenyl)-3-mercapto-(1H-1,2,4-triazole-1-yl)-2-butanol as a starting material, was obtained 220 mg of target compound indicated in the title of example, in the form of a solid after purification column chromatography on silica gel using a mixture of ethyl acetate-hexane 2:1 by volume) as eluent. Clean the sample with a melting point 122aboutWith was obtained by recrystallization from a mixture of ethyl acetate-hexane.

Specific rotation ()D25-12,0about(of 0.50, chloroform).

Spectrum of nuclear magnetic resonance (CDCl3million 120 days (3H, doublet, J 7 Hz) and 3.31 (1H, Quartet, J 7 Hz), 3,47 (3H, singlet), 4,55 (1H, doublet, J 12 Hz), 4,58 (1H, doublet, J 14 Hz), was 4.76 (1H, singlet), to 4.81 (1H, doublet, J 12 Hz), the 4.90 (1H, doublet, J 14 Hz), 7,25 (4H, singlet), 7,82 (2H, singlet).

P R I m e R 17. (2R, 3R)-2-(4-chlorophenyl)-3-/(1-methoxyethyl)- thio/-1-(1H-1,2,4-triazole-1-yl)-2-butanol and its oxalate

< / BR>
267 mg (2,82 mmole) chloride 1-ethoxyethylene, then 219 mg (1,69 mmole) of diisopropylethylamine was added at 0aboutWith and was stirring his to a solution of 401 mg (1,4 Japan N Hei 2-35928) in 8 ml of methylene chloride. Then the cooling bath was removed and the resulting mixture was stirred at room temperature for 1 h, after this time the reaction mixture was mixed with diluted aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The extract was dried and concentrated by distillation of solvent under reduced pressure. The obtained oily residue was purified column chromatography through silica gel, using a mixture of ethyl acetate-hexane 2:1 by volume as the eluent, and received 245 mg of target compound indicated in the title of example, in the form of oil. The product was a mixture of two diastereomers in a ratio of 1:1.

Absorption spectrum in the infrared region (chloroform),maxcm-1: 3350, 1515, 1495.

Spectrum of nuclear magnetic resonance (CDCl3million D. 1,20, of 1.26 (3H, doublet, J 7 Hz), 1,47, of 1.50 (3H, doublet, J 6 Hz), 3,30, to 3.38 (3H, singlet), 3,13, of 3.32 (1H, Quartet, J 7 Hz), 4,47, 4,5 (1H, doublet, J 14 Hz), 4,80 (1H, Quartet, J 6 Hz), 4,88, 5,02 (together 1H, each doublet, J 14 Hz), 5,00, of 5.05 (together 1H, each singlet), 7,00-of 7.55 (4H, multiplet), 7,75, 7,79 (together 1H, each singlet), 7,83, of 7.96 (together 1H, each signle).

One molar equivalent of oxalic acid was added to a solution of 155 mg of the obtained compound in ethyl acetate and Soedineniya, melting at is 147.5-149aboutC.

P R I m e R 18. (2R,3R)-2-(2,4-(differenl)-3- (methylthiomethyl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
31 mg (0,70 mmole) of sodium hydride (in the form of a 55% by weight dispersion in mineral oil) was washed with anhydrous hexane and then suspended in 2 ml of dimethylformamide. Then at 0aboutWith stirring was added 100 mg (0.35 mmole) of (2R, 3R)-2-(2,4-differenl)-3-mercapto-1-(1H-1,2,4-triazole-1-yl) -2-butanol are added to the resulting suspension. After the termination of allocation of gaseous hydrogen to the mixture was added 67 mg (0,70 mmole) chloride methylthiomethyl. Then the resulting mixture was stirred at room the same temperature for 1 h, after this time the reaction mixture was distributed between ethyl acetate and aqueous solution of sodium chloride. The organic layer was dried and concentrated by distillation of solvent. The crude product obtained was purified column chromatography through silica gel, using a mixture of ethyl acetate-hexane in the ratio of 3:1 by volume) as eluent and received 105 mg of target compound indicated in the title of example, in the form of solids. The net sample (78 mg) with a melting point of 108-109aboutWith was obtained by recrystallization of this solid"ptx2">

Spectrum of nuclear magnetic resonance (CDCl3million days of 1.17 (3H, doublet, J 7 Hz), of 2.25 (3H, singlet), 3,63 (1H, broad Quartet, J 7 Hz), of 3.77 (2H, singlet), is 4.85 (1H, doublet, J 14 Hz), to 5.08 (1H, doublet, J 14 Hz), 8.6 out of 7.0 (2H, multiplet), 7,2-7,6 (1H, multiplet), 7,76 (1H, singlet), 7,82 (1H, singlet).

P R I m e R 19. (2R, 3R)-2-(4-chlorophenyl)-3-(methylthiomethyl)- 1-(1H-1,2,4-triazole-1-yl)-2-butanol

< / BR>
Performing a procedure similar to that described in example 17, but using 150 mg of (2R, 3R)-2-(4-chlorophenyl))-3-mercapto-1-(1H - 1,2,4-triazole-1-yl)-2-butanol as a starting material, was obtained 138 mg of target compound indicated in the title of the example, the melting point 163-163,5aboutAfter recrystallization from a mixture of ethyl acetate-hexane.

Specific rotation ()D25-217about(1,05, chloroform).

Spectrum of nuclear magnetic resonance (CDCl3million days of 1.20 (3H, doublet, J 7 Hz), measuring 2.20 (3H, singlet), 3,32 (1H, Quartet, J 7 Hz), 3,71 (2H, singlet), 4,55 (1H, doublet, J 14 Hz), 4,56 (1H, singlet), of 5.05 (1H, doublet, J 14 Hz), 7,10 was 7.45 (4H, multiplet), 7,76 (1H, singlet), 7,83 (1H, singlet).

Absorption spectrum in the infrared region (KBr),maxcm-1: 3184, 1511, 1492.

P R I m e R 20. (2R, 3R)-3-(cyanomethylene)-2-(2,4 - differenl)-1-(1H-1,2,4-triazole-1)-2-butanol

< / BR>
205 mg (1,19 mmole) 3-PI is tilty)-2-(2,4-differenl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol (obtained as described in example 5) in 7 ml of methylene chloride and the resulting mixture was stirred at the same temperature for 20 minutes After this time the reaction mixture was distributed between ethyl acetate and aqueous solution of sodium sulfite. The organic layer was collected and washed with diluted aqueous sodium bicarbonate solution and then saturated aqueous sodium chloride, the solvent was removed by distillation under reduced pressure. The resulting residue was then purified column chromatography through silica gel (10 g). Elution with a mixture of ethyl acetate-benzene in the ratio 4:1 by volume) gave 113 mg of one isomer of the target compound indicated in the title of the example, with a lower polarity in the form of a crystalline mass, which was recrystallized from a mixture of ethyl acetate-hexane, and was given a clean sample with a melting point 138-140aboutC.

Specific rotation ()D25-155about(from 0.53, chloroform).

Absorption spectrum in the infrared region (KBr),maxcm-1: 3505, 2250, 1618, 1598, 1504.

Spectrum of nuclear magnetic resonance (CDCl3million days of 1.06 (3H, doublet, J 7 Hz), to 3.64 (1H, doublet, J 16.5 Hz), of 3.77 (1H, Quartet, J 7 Hz), 4,08 (1H, doublet, J 16.5 Hz), to 4.98 (1H, doublet, J 14 Hz), with 5.22 (1H, doublet, J 14 Hz), of 5.82 (1H, singlet), 6,7-6,9 (2H, multiplet), 7,2-7,4 (1H, multiplet), 7,76 (1H, singlet), 7,81 (1H, singlet).

Further eleirovania what pay attention in the form of a crystalline mass, which is recrystallized from a mixture of acetone, diisopropyl ether and was given a clean sample with a melting point 80-84aboutC.

Specific rotation ()D25-139about(C0,55, chloroform).

Absorption spectrum in the infrared region (KBr),maxcm-1: 3260, 2250, 1618, 1598, 1520.

Spectrum of nuclear magnetic resonance (CDCl3million days to 1.22 (3H, doublet, J 7 Hz), 3,74 (1H, Quartet, J 7 Hz), 3,90 (2H, singlet), a 4.83 (1H, doublet, J 14 Hz), is 5.06 (1H, doublet, J 14 Hz), USD 5.76 (1H, singlet), 6,6-6,9 (2H, multiplet), to 7.4 and 7.5 (1H, multiplet), 7,83 (1H, singlet), 7,92 (1H, singlet).

P R I m e R 21. (2R, 3R)-2-(2,4-differenl)-3-(tetrahydrofuran - 3-ylthio)-1-(1H-1,2,4-triazole-1-yl)-2-butanol and its oxalate

< / BR>
20 mg (0,46 mmole) of sodium hydride (as a 55% by weight dispersion in mineral oil) was washed with hexane and then suspended in 1.5 ml of dimethylformamide. 130 mg (0,46 mmole) of (2R, 3R)-2-(2,4-differenl)-3-mercapto-1-(1H-1,2,4-triazole - 1-yl)-2-butanol was added to the resulting suspension in a nitrogen atmosphere under ice cooling and the mixture was stirred 10 minutes after this time was added 92 mg (0.55 mmole) of ()-3-(methanesulfonate)-tetrahydrofuran to the mixture and the resulting mixture was stirred at 60-65aboutWith two hours. After this time the mixture was cooled, p is istorical was removed by distillation under reduced pressure. The crude product thus obtained was subjected to chromatography through 15 g of silica gel, using as eluent a mixture of ethyl acetate-hexane 2: 1 by volume) and received 139 mg of the mixture of target compound indicated in the title of the example, and unidentified side product in the form of oil, the separation of which is conducted by passing through a column of Lobar using ethyl acetate, and received 85 mg pure sample of the target compound in the form of butter.

Absorption spectrum in the infrared region (chloroform),max.cm-1: 3425, 1615, 1595.

Spectrum of nuclear magnetic resonance (CDCl3million days of 1.15 (3H, doublet, J 7 Hz), 1,57-to 2.65 (2H, multiplet), to 3.33 (1H, Quartet, J 7 Hz), 3,4-4,5 (5H, multiplet), 4,82 (1H, doublet, J 15 Hz), 4,94 (1H, singlet), 5,14 (1H, doublet, J 15 Hz), from 6.4 to 7.1 (2H, multiplet), and 7.1 to 7.7 (1H, multiplet), 7,76 (1H, singlet), 7,87 (1H, singlet).

One molar equivalent of oxalic acid was added to a solution of 73 mg of the above compound in ethyl acetate and precipitated from solution crystals adding hexane was collected by filtration and obtained 56 mg of oxalate target compound with a melting point of 162-164aboutC.

Experiment.

Antifungal activity.

Groups of mice (beep each time each mouse was administered 20 mg/kg of the test compounds orally. Fungicidal activity was evaluated by survival curve through 9 days after infection. Survival was estimated at percent in two days after infection in the control group not receiving medication (control group). The data given in the table.

As can be seen from the presented results, the compounds according to the invention show a much higher fungicidal activity than the known compound ketoconazole used for comparison.

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

< / BR>
where Ar is phenyl, substituted by at least one halogen atom;

R1WITH1WITH4-alkyl;

R2WITH1WITH5-alkyl, monosubstituted hydroxy, C1- C4-alkoxy, carbarnoyl,1WITH4-alkylthio, cyano - or1WITH4-alkoxycarbonyl, nitrogen-containing heterocyclic group containing 3 to 6 carbon atoms and substituted by oxopropoxy or unsubstituted heterocyclic group containing 1 to 2 oxygen atom as heteroatoms and 3 to 6 carbon atoms;

n is 0, 1 or 2,

or their pharmaceutically acceptable salts.

2. Connection on p. 1, representing 3-(cyanomethylene)-2- (2,4-differenl)-1-(1H-1,2,4-s a 2-[(4-chlorophenyl)-3-) (1-methoxymethyl)-thio)-1-] 1H-1,2,4-triazole-1-yl] -2-butanol, or its pharmaceutically acceptable salt.

4. Connection on p. 1, representing 3-[(cyanomethyl)-sulfinil)-2(2,4 - differenl)-1-)1H-1,2,4-triazole-1-yl] -2-butanol, or its pharmaceutically acceptable salt.

5. Connection on p. 1 representing 2-(2,4-differenl)-3-) (tetrahydrofuran-3-yl)-thio)-1-)1H-1,2,4 - triazole-1-yl)-2-butanol, or its pharmaceutically acceptable salt.

 

Same patents:

The invention relates to new 3[2H]-pyridazinone derived, as well as to receive them, containing their insecticidal acaricide, nematocide, fungicidal compositions for use in agriculture and horticulture; compositions for removing ticks from animals, where these compositions contain these derivatives as the active ingredient

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to new biologically active compounds, namely, the derivative of 4-aminophenol of the formula I

XNROR1where R1represents a group WITH/ABOUT/УZ;

Y represents a single bond, 0, NR7or; Z represents hydrogen, pyridyl; phenyl which may be substituted with halogen, nitro, lower alkoxy or carboxy; lower alkyl which may be substituted by hydroxy, lower acyloxy, carboxy, lower alkoxycarbonyl, CONR8R9, phenyl/lower/ alkoxy, phenyl, halogen, cyano or NR10R11;

R2, R3, R5and R6that may be the same or different, represent hydrogen, lower alkyl or alkenyl, lower alkoxy or halogen;

R4and R7that may be the same or different, represent hydrogen or lower alkyl;

X 4.5-dihydropyrazolo or pyrazolyl, which may be substituted WITH3-C6-cycloalkyl or phenyl which can be substituted by trihalomethyl;

R8, R9, R10, R11which may be the same or different, represent hydrogen, lower alkyl or benzyloxycarbonyl, or their N-alkyl

The invention relates to the production of new proizvodnyh of thiazolidine that are used in pharmaceutical compositions

The invention relates to a method for obtaining complex diesters of alkyl substituted 4-hydroxy-piperidino connection of some complex organic esters, in particular to a method for producing a complex of diesters of alkyl-substituted 4-hydroxy-piperidino compounds of esters of dicarboxylic acids using a catalyst system containing the basic inorganic compound and a polar aprotic organic compound

The invention relates to optical active derivative triazolinones alcohol having optical activity (+), General formula (I):

(I) where X means a hydrogen atom or a chlorine atom, and the asterisk shows the asymmetric carbon atom, which can be used as a herbicide active ingredient

The invention relates to optically active derivative triazolinones alcohol having optical activity (-) of General formula (1):

< / BR>
(I) where X means a hydrogen atom or a chlorine atom, and the asterisk shows the asymmetric carbon atom, which can be used as fungicidal active ingredient

The invention relates to a series of new oxetanone derivatives, the molecular structure of which is characterized by the presence of four-membered rings containing an oxygen atom (i.e

The invention relates to chemical compositions for protecting plants, particularly to fungicidal compositions based on the derived 1-phenyl-2-(1,2,4-triazole-1-yl)-propene

The invention relates to the chemistry of heterocyclic compounds, namely, to a method for producing 4-amino-1,2,4-triazole, which can be used as intermediate for the production of dyes, drugs, corrosion inhibitors, additives for plastics, etc

The invention relates to a method for producing derivatives of triazole, exhibiting antifungal activity, namely the method of production of 2-aryl-3-(3-haloperidol-4-yl or 5-galerimizin-4-yl)-1-(1H-1,2,4-triazole-1-yl)alkyl-2-Aulnay derivatives, applicable to combat fungal infections of animals and humans

The invention relates to the chemistry of heterocyclic compounds, and in particular to an improved method for producing a 1-vinyl-1,2,4-triazole, which is used as a monomer for the synthesis of water-soluble and swollen polymers having valuable technical and biological properties

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: 5-aryl-1H-1,2,4-triazole derivatives of general formula I

, pharmaceutically acceptable salts thereof or pharmaceutical composition containing the same are described. In formula R1 is C1-C6-alkyl, C1-C6-haloalkyl or phenyl; R2 is C3-C8-cycloalkyl; phenyl optionally substituted with one or more substituents selected from C1-C4-alkyl; halogen, hydroxyl, C1-C4-alkoxy, nitro, di-(C1-C4)-alkylamino, C1-C4-alkylsulphonyl, C1-C4- alkylsulphonylamino, and methylenedioxy; phenyl-(C1-C4)-alkyl, wherein phenyl is substituted with C1-C4-alkoxy; or pyridil. New compounds are effective and selective cyclooxygenase-2 (COX-2) inhibitors and useful in treatment of inflammations.

EFFECT: new compounds for inflammation treatment.

10 cl, 36 ex, 1 tbl

Up!