Method for producing triazole derivatives

专利摘要:
Compounds of the formula <IMAGE> (I) or a pharmaceutically or agriculturally acceptable acid addition salt thereof, wherein R is 5-chloro-2-pyridyl, or phenyl optionally substituted by one to three substituents, each independently selected from F, Cl, Br, I, CF3, C1-C4alkyl and C1-C4alkoxy; R1 is CN, CSNH2 or CONR2R3 where either (a) R2 is H or certain alkyl groups and R3 is H or certain alkyl, substituted alkyl, aralkyl, phenyl or cycloalkyl groups, or (b) R2 and R3 taken together with the nitrogen atom to which they are attached form a nitrogen heterocyclic group, optionally containing an oxygen atom or NR4 group, as a ring member and R4 is H, C1-C4alkyl; C2-C4alkanoyl or (C1-C4alkoxy)carbonyl; R5 and R6 are each H or CH3; methods for their use in combatting fungal infections in plants, seeds and animals, including humans, pharmaceutical and agricultural compositions containing them and intermediates therefor.
公开号:SU1313347A3
申请号:SU833646752
申请日:1983-09-28
公开日:1987-05-23
发明作者:Эдвард Джимер Джеффри；Ричардсон Кеннет
申请人:Пфайзер Корпорейшн (Фирма)；
IPC主号:

专利说明:

113
The invention relates to methods for producing triazole derivatives of the general formula
OH X
: Nt; -CH2-c-c-co-NH (i)
TSi
R
H
where R is 2,4-dichlorophenyl, 2,4-difluorophenyl, 4-chlorophenyl; X is hydrogen or methyl.
The purpose of the invention is to develop a method for producing new compounds with increased activity compared with the known antifungal activity.
Example 1. A) Preparation of 3-cyano-2- (2,4-dichlorophenyl) -1- (IH-1,2,4-triazol-1-yl) butan-2-ol.
Propionitrile (1.21 g) in anhydrous tetrahydrofuran (50 ml) is cooled to -72 ° C. A solution of n-butylity in normal hexane (14.2 ml, 1.55 mol ry) is slowly added, while the reaction temperature the mixture is maintained at -45 ° C. After stirring for about 30 minutes, 2- (1H-1,2,4-triazol-1-yl) -2, 4-dichloroacetophenone (2.56 g) is added in anhydrous tetrahydrofuran (50 ml) with stirring for 20 minutes, while the temperature of the mixture is maintained at -70 ° C. Stirring is continued at this temperature for one hour then at -10 ° C for 30 minutes and then glacial acetic acid (10 ml) is added in anhydrous tetrahydrofuran (15 ml). The reaction mixture thus obtained is heated to room temperature (20 ° C) until a pH of 8 units is reached. pH, by addition of sodium bicarbonate and ex-tragtion with ethyl acetate (three times 75 ml). The combined organic jKHe extracts are washed three times with water, dried with magnesium sulfate, evaporated and 20 ml of ether are added to the residue, which leads to obtain a white crystalline solid and a yellow solution. The solid is filtered off, dissolved in a small amount of methylene chloride, and the solution is introduced onto a fast chromatograph.
Which column is 11x2 cm in size, filled with 18 g of silica, the particle size of which corresponds to sieve No. 230-400. The elution process is carried out using a 5% (volume) solution of acetone in ether at a pressure of 1 psig. inch (0.07 kg / cm). The diastereoisomer 1 of compound (I) was eluted first in an amount of 0.79 g. M.p. equal to 178-180 ° C.
Calculated,%: C 50.2; H 3.9; N 18.0.
C ,, H ,, 0
Found,%: C 50.0; H 3.8; N 17.9.
The diastereoisomer 2 of compound (I) was eluted as follows in an amount of 0.244 g. So pl. equal to 202-205 ° C.
Calculated,%: C 50.2; H 3.9; N18, O.
C ,, H, iCl2N O
Found,%: C 50.4; H 3.9; N 17.6.
B) Preparation of 3-carbamoyl-2- (2,4-dichlorophenyl) -1 - (W-I, 2,4-triazol-1-yl) butan-2-ol hemihydrate.
Z-Cyano-2- (2,4-dichlorophenyl) -1- (1H-I, 2,4-triazol-1-yl) butan-2-ol (700 ml of diastereoisomer 1) is heated for 5 h 30 min at 90-95 ° C in 40% (volume) aqueous solution of sulfuric acid. The resulting solution was stirred at room temperature (20 ° C) for 19 hours, after which a saturated aqueous solution of sodium bicarbonate was added. At the same time, the value of hydrogen index rises to 8 units. pH This solution is extracted with ethyl acetate three times in 50 ml each. The combined organic extracts are washed with water, dried with magnesium sulfate and evaporated to give compound (I) in an amount of 105 mg after trituration with ether. M.p. equal to 215-217 ° C. Calculated,%: C 46.2; H 4.5; N 15.6.
C ,, .O, 5H20,
Found: C 46.8; H 4.5; N 15.5.
Example 2, 3-Carbamoyl-2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2-ol 1/4 hydrate with mp equal to 170-172 With get in example 1 by hydrolysis of the corresponding nitrile, but using 80% - WATER sulfuric acid.
Calculated,%: C, 51.9; H, 4.8; N 18.6.
C, H ,, 05, l / 4HjO
Found,%: C -52.0; H 4.8; N 18,5.
313
Example 3, Preparation of 2- (2,4-difluorophenyl) -3- (N-methylcarbamoyl) -1 - (1H-1,2,4-triazol-1-yl) butan-2-ol .
A mixture of diastereomeric nitriles obtained in example 1 (A), (3.9 g) is subjected to heating in sulfuric acid (80%, 100 ml) for 4 hours at 60 ° C. This reaction mixture is cooled, diluted with water (200 ml) and calcium carbonate in an amount of 50 g is added in small portions under external cooling conditions (ice on a bath). The mixture thus obtained is filtered and the filtered material is subjected to thorough washing with water (200 ml) and methanol (200 ml). The material obtained after washing is added to the filtrate, evaporated to dryness and the residue is extracted with ethyl acetate three times 100 ml. These extracts were combined, dried with magnesium sulfate, and evaporated to a white solid in an amount of 2.73 g. This material was absorbed on silica in an amount of 7 g by dissolving the mixture consisting of chloroform and methanol in a minimum amount at a volume ratio of 5 : 1, silicon dioxide is added and the solvent is evaporated. Silica is added as a suspension in ether to the silica in an amount of 25 g, and elution is carried out with ether containing increasing amounts of ethanol (2-10%). A portion of the least polar amide diastereoisomer is eluted first in the pure state and recrystallized from ethyl acetate to give. 105 mg of one isomer of colorless crystals of the compound (I). M.p. 223-225 ° C.
Calculated,%: C 53.0; H 5.1; N 19.0.
C ,, H, 5SSH40gFound,%: C 52.8; H 5.3; N 18.7.
The remaining product is eluted as a mixture containing the diastereomer described above and its more polar diastereoisomer at. ratio of 1: 4, which is determined using the method of nuclear magnetic resonance. As a result of the recrystallization from ethyl acetate, 404 mg of colorless crystals are obtained, having a mp of 186-189 C.
74
Calculated,%: C 53,, 0; H 5.1; N19.0. C ,, H, C1N40
Found,%: C 53.0; H 5.1; N 19.4. Example4. A) Preparation of 1-cyano-2- (2,4-dichlorophenyl) -3- (1H-1,2,4-triazol-1-yl) -propan-2-ol.
Scheme 1. K 2- (2,4-dichlorophenyl) -2- (1H- 1, 2,4-triazol-1-ylmethyl) oxirane (6.7 g) in dimethylformamide
(198 ml) at 60 ° C, sodium cyanide (2.84 grams of water) is added dropwise over 25 minutes. The mixture is heated to 60 ° C for 5 hours. The reaction mixture thus obtained is cooled,
poured into water (900 ml) and extracted with ethyl acetate (three times 150 ml). The combined organic extracts are washed with appended aqueous brine, dried with sodium sulfate and evaporated to a dry product, which is a pale yellow solid in the amount of 6.1 g, which is then triturated with ether. Received
the solid is recrystallized from ether / methanol to obtain as a result of compound (I) in the amount of 4.13 g (56% of the theoretical yield). M.p. 2 7-219 ° C.
Found,%: C 48.3; H 3.4; N18.4. C ,, H, oCL, N, 0
Calculated,%: C 48.5; H 3.4; N 18.8. Scheme 2. Acetonitrile in the amount of 2.25 g is dissolved in 100 ml of distilled tetrahydrofuran and the resulting solution is cooled to -70 ° C with nitrogen in an acetone bath. A solution of n-butyl lithium in hexane (39 ml) is added dropwise over 5 minutes. After stirring for 45 minutes at -70.degree. C., 2,4-dichloro-2- (1H-1, 2, 4-triazol-1-yl) acetophenone (12.8 g) is added dropwise over 15 minutes. in anhydrous tetrahydrofuran.
Stirring is continued for 1 h, while the temperature of the reaction mixture is -70 ° C. Glacial acetic acid (20 ml) in tetrahydrofuran (20 ml) is added dropwise.
The cooling bath is removed and the sms reaction is heated to 0 ° C. The reaction is terminated by injection into water (500 ml). Solid sodium carbonate is added to increase the value of
hydrogen index up to 8 units. pH After extraction with ethyl acetate (three times in 75 ml), the combined organic extracts are saturated.
51
brine (three times 50 ml each time), dried with sodium sulfate and evaporated to obtain a pale-yellow solid, which is thoroughly washed with ether, to give compound (I) in an amount of 6.61 g, which is 44.5% from theoretical output. This product is identical to the product obtained according to Scheme 1, which is confirmed by nuclear magnetic resonance and IR spectroscopy.
B) Preparation of 1-carbamo-1--2 (2,4-dichlorophenyl) -3- (1H-I, 2,4-triazol-1-yl) propan-2-ol,
. -Cyano-2- (2,4-dichlorophenyl) -3- (W-1, 2,4-triazol-1-yl) propan-2-ol (1.0 g) is heated to 60 ° C and maintained at this temperature for 2.5 h in sulfuric acid (10 ml, 80% -a). The reaction mixture is cooled to room temperature, carefully treated with water (100 ml) and the mixture is adjusted to pH 9 with solid sodium hydroxide. The resulting solution is extracted with methylene chloride (3 times 50 ml) and the combined extracts are evaporated to a resin, which is chromatographed on silica eluted with methyl enchloride containing 3% (volume) methanol, with an increase in methanol content of up to 6%. The fractions containing the product are collected and evaporated to give 0.91 g of a white solid. It is dissolved in a mixture of acetone and methylene chloride at the temperature of refluxing, and the product is precipitated by the addition of hexane, as a result of which small crystals (0.61 g) are obtained. M.p. 144-145,5 ° C.
Elemental analysis was carried out (after drying at 80 ° C).
Calculated,%: With 45.7; H 3.8; N17.8.
C, jHiiCl N40i
Found,%: C 45.5; H 3.8; N 17.5.
A compound containing R-4-chlorophenyl, X methyl, is prepared analogously.
And pime. 5. Pharmaceutical compositions for the treatment of fungal infections are prepared as follows.
(a) Capsule: 7 mac. The compounds of Example 1 (B) or 4 (B) are granulated with 3 parts of maize starch and 22 parts of lactose, and then 3 parts of maize starch and 1 hour of magnesium stearate are added, after which the mixture is again granulated
476
Hard gelatin capsules are filled and filled.
(b) Cream: 2 ma.ch. The compounds of Example 3 are dissolved in 10 parts of propylene glycol and mixed with 88 parts of the vanishing cream base.
(c) Cessary: 2 ma.h., the compounds of example 2 are suspended in 98 parts of the warm, liquefied base of suppositories, the mixture is poured into forms and cured.
Test antifungal activity.
The compounds of formula (I) can be used to treat topical fungal diseases caused by Candida species, Trichophyton, Microsporum, Epidermofiton, or fungal diseases of the mucous tissue caused by Candida albicans, as well as systematic fungal infections.
The antifungal activity of compounds (I) in vivo is evaluated using a series of doses with different levels of concentration, administered by intravenous or intraperitoneal injection, or by oral administration to mice inoculated with Candida albicans. The activity of the group after death, compared with the group of untreated after 48 hours. The dosage level at which 50% protection () from the flying effect against infection is provided is determined in this way.
For the treatment of humans, the antifungal compounds (I) can be injected -. in a pure form, but in general they are administered in a mixture with a pharmaceutical carrier selected depending on the intended route of administration in the body and standard pharmaceutical practice. Antifungal compounds may be administered orally in the form of tablets containing such excipients as starch or lactose, in capsules or granules, in pure form or mixed with excipients, in the form of elixirs or suspensions containing flavoring or coloring agents. They can be administered parenterally, for example, intravenously, intramuscularly or subcutaneously. With parenteral administration, the best way is to inject sterile aqueous solutions that may contain other substances, for example
713
measures salt or glucose to make these solutions isotonic with blood.
For oral and parenteral use for treating humans, the daily dosage of antifungal compounds (I) is, respectively, from 0.1 to 5 mg per 1 kg of body weight (in divided doses). These tablets or capsules of the compounds contain from about 5 mg to 0.5 g of the active compound for administration at one time, twice or several times. The physician in each case can determine the actual dosage that is most suitable for the patient, and depends on the age, weight, and response of the patient to the drug. The above dosages are given as examples for the average case and in individual cases be increased or decreased.
Antifungal compounds (I) can be introduced into the body in the form of suppositories (suppositories) or pessaries, or they can be applied topically in the form of lotions, creams, procedures, or powders. For example, they can be administered to the body in the form of creams in which antifungal compounds are introduced, consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin. They can also be administered in a concentration of from 1 to 10% in an ointment containing bleached wax (linen wax) or a softer paraffin base along with the necessary stabilizers and preservatives.
Compounds (I) and their salts are characterized by activity against a large number of plant pathogenic fungi (mold), including, for example, various types of rye, mildew and mold fungi. The compounds are suitable for treating plants and seeds in order to exclude or prevent the occurrence of these diseases.
For the purposes of gardening and agriculture, the compounds (I) and suitable for use in agriculture and horticulture salts are preferred to be used in the form of a composition prepared in such a way that it is suitable for this special application.
Neither did it satisfy the necessary requirements. Thus, compounds (I) can be used in the form of powders - dusts or granules, fertilizers for seed, aqueous solutions, dispersions or emulsions, using immersion, spraying methods, as well as aerosols and smokes. The compositions can also be applied in the form of dispersible powders, granules or concentrates which must be diluted before use. Such compositions may contain such conventional carriers, solvents or additives that are well known and suitable for use in agriculture and horticulture and are manufactured by conventional methods.
The table shows the dose values.
Rduo (mg / kg) obtained by oral administration to male infested with Candida albicans. For comparison, the data for the most effective used in the present
drug time - ketoconazole and
the closest analogue in structure. ,: g
Compounds of general formula (I) are less toxic than ketoconazole. Thus, the value of DC to the lie of compound 4 exceeds 750 mg / kg (with
orally administered to mice), for ketoconazole, LD 51-1 is 620 mg / kg.
Thus, the compounds of general formula (I) are 10 to 20 times greater than
well-known drug for antifungal activity and thus less toxic.
40

权利要求:
Claims (1)
[1]
Invention Formula
The method of producing triazole derivatives of the general formula
onkh
N N-CH2-t; -C-CO-CNT, R H
where R is 2,4-dichlrrphenyl, 2,4-difluorophene, 4-chlorofensh1; X is hydrogen or methyl, characterized in that the compound of the general formula
OH X
KSC2-C-C-W,
 k
where R and X have the indicated meanings, undergo controlled hydrolysis.
na aa m:
Editor P.Geershi
Compiled by S. Paul Kova
Tehred I.Popovich Proofreader A.Obruchar
Order 1983/58 Circulation 372Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., d.A / 5
Production and printing company, Uzhgorod, Projecto st., 4
02.02.83 with X - СНд.

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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GB8227978|1982-09-30|

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GB838302888A|GB8302888D0|1983-02-02|1983-02-02|Antifungal agents|

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