FI74280B - FOERFARANDE FOER FRAMSTAELLNING AV TERAPEUTISKT ANVAENDBARA AZOLDERIVAT. - Google Patents

Description

1 74280

A process for the preparation of therapeutically useful azole derivatives

This invention relates to a process for the preparation of therapeutically useful triazole and imidazole compounds having fungicidal activity. The compounds according to the invention can be used in pharmaceutical and veterinary compositions, in particular in compositions which, when administered orally or topically, are active against fungal diseases of humans and other animals. These compositions are particularly useful in the treatment of candidiasis and human dermatophyte infections.

The compounds of the formula can be prepared by the process of the invention

OH

1 I 2

20 Y -N — CH »- C — CH„ N -Y I

K ^ {i

lv Ra ^ -N

wherein R * is a lower alkyl group, benzyl optionally substituted by one or two halogens, or phenyl optionally mono- or di-substituted by halogen, methyl, nitroxy, phenyl and / or 1 2 phenoxy, and Y and Y represents a group = CH- or = N-, and their salts, lower alkanoyl esters and 2,6-di-30-chlorobenzyl ethers.

Compounds of formula I may be prepared by reacting 1,3-dihalopropan-2-ol of formula II

OH

1 1 2

35 X - CH "-C - CH" - X II

2 j 2 R 1 _____ - r ~ 2 74280 1 2 wherein X and X, which may be the same or different, are halogen atoms (preferably chlorine or bromine) and R 1 is as defined above, to react with imidazole or 1,2,4-triazole or its with a salt (e.g. sodium salt). This reaction can be carried out in a suitable solvent such as methanol, ethanol, acetonitrile or dimethylformamide at a temperature between 20 and 100 ° C. Preferably, dihalopropan-2-ol is added to the excess sodium salt of the heterocyclic base in dimethylformamide at 100 ° C. The product can be isolated by adding the solution to water, followed by recrystallization.

1,3-Dihalopropan-2-ols of formula II can be prepared by reacting 1,3-dihaloacetone with a suitable Grignard reagent in a known manner (e.g. Johnson et al., J. Org. Chem. 27 (1962), p. 15). 2241 - 2243).

Compounds of formula I may also be prepared by subjecting CHO 1 1 of formula

20 R -C

i m CH '

I X

N-y

k J

25, wherein and Y 1 are as defined above, to react with imidazole or 1,2,4-triazole or a salt thereof (e.g., a sodium salt) in a suitable solvent by the method described above.

Epoxides of formula III can be prepared by reacting a ketone of formula IV 74280 3 0 1

R -C

1 iv CH0 I x

N-y

5 W J

wherein R * and Y 2 are as defined above, to react with dimethyl-10-oxosulfonium methylilide (Corey and Chaykovsky, JACS 87 (1965), pp. 1353-1364) or with dimethylsulfonium methylide (Corey and Chaykovsky, JACS, 84, p. 3782 ).

The compounds of formula IV can be prepared by the methods disclosed in the patent literature, in particular in GB Patents 1,533,705 and 1,533,706.

Alternatively, compounds of formula I may also be prepared by reacting a compound of formula V 20

O

1 II 2

Y -N - CH_-C —CH_-N -Y V

K ^ ^

^ N ^ ^ N

25 1 2 where Y and Y are as defined above, to react with a Grignard reagent of formula

R1-Mg-X VI

30 wherein R * and X are as defined above, by methods known from the literature (e.g. Johnson et al., J. Org. Chem. 27 (1962), pp. 2241-2243).

Compounds of formula V may be prepared by reacting 1,3-dihaloacetone with imidazole or 1,2,4-triazole or a salt thereof (e.g. the sodium salt) in a suitable solvent by the method described above.

4,74280

The salts of the compounds of formula I can be prepared in a conventional manner.

Ethers are prepared by treating the sodium salt of the alcohol with reactive halogenated compound 5 (2,6-dichlorobenzyl chloride). Esters are prepared in a similar manner by treating the sodium salt of an alcohol with an acid chloride (e.g., acetyl chloride).

The compounds of the invention may contain chiral centers. Such compounds are generally obtained in the form of racemic mixtures. However, these and other mixtures can be separated into the individual isomers by methods known in the art.

Lower alkyl groups may be straight-chain or branched groups containing 1 to 6, preferably 1 to 4 carbon atoms.

The salts of the compounds of formula I may be salts with inorganic or organic acids, for example hydrochloric, nitric, sulfuric, acetic, toluenesulphonic or oxalic acid. The salts may also be quaternary salts.

The compounds of the present invention may be used as an active ingredient in a pharmaceutical or veterinary fungicidal mixture. Such a mixture comprises a compound of formula I as defined above, or a salt, ether or ester thereof, in association with a pharmaceutically or veterinarily acceptable diluent or carrier.

Examples of compounds prepared according to the invention are shown in Table I.

74280

Table I

1 ^ I

Compound R1 y1 y2 Melting point (° C) 1 4-Cl-C, H = N- = N-153-155 ° 6 4 2 C, Hc- = N- = N-99-101 3 4-FC, H. - = N- = N-124-126 6 4 4 2,4-diCl-CcH_ = N- = N-183-186

v J

5 2,4-diCl-CgH3-CH2- = N- = N- 137-140 6 4-CH - C, H = N- = N- 179-180 ° 3 6 4 7 4-C, Hc-C , H.- = N- = N- 165-170 6 5 6 4 8 4-CHoO-C, H, - = N- = N- 141-143 3 6 4 9 '2-Cl-C, H - = N- = N- 145-148 64 o 10 4-C, HcO-C, H, - = N- = N- 163-165 6 5 6 4 11 2,4-diCl-C6H3- = CH- = CH- 160-175 12 2,4-diCl-C6H3- = N- -CH- 169-170 ° 13 nC .H_- = N- = N- 61-62 ° - 4 9 14 4-Cl-C, H.CH_ - = N- = N- 6 4 2 15 2-Cl-CgH4CH2- = N- = N- 16 2,6-diCl-CgH3CH2- = N- = N- 17 CgH5CH2- = N- = N- 101-102 ° 18 2,6-diCl-CgH3- = N- = N- 19 2- (CgH50) CgH4- = N- = N-20 tC.HQ- = N- = N- 85-87 ° - 4 9 21 i -C4Hg- = N- = N- 22 3,4-diCl-CgH3- = N- = N- 140-145 ° aqueous ethanol / water 1: 9 23 t_C4H9 = N- = CH- 129-130 ° t - = tertiary i- = isodiCl- = dichloro- 6 74280

The pharmaceutical and veterinary compositions containing the compounds of the invention may be in conventional pharmaceutical forms, for example tablets, capsules, emulsions or aqueous or oily solutions or suspensions, or suitably for topical use, for example as an ointment, salve or gel. The composition may contain conventional pharmaceutical excipients and may be prepared by conventional pharmaceutical methods.

Preferred pharmaceutical or veterinary compositions are those suitable for oral administration, and in particular tablets and capsules.

The fungicidal activity of the compounds according to the invention and their low teratological side effects are apparent from the experimental results set out below.

A. Antifungal activity Candidia albicans (fungus caused by cadidias) and Trichophyton menta-grohytes. var. against quinkeanum was shown as follows:

Female mice weighing approximately 30 g were injected subcutaneously with 0.5 mg of estradiol benzoate on Friday. The following Monday (day 0), their walls were shaved and orally dosed with test compounds.

25 They were then inoculated into the vagina of Candida albicans and Trichophyton mentagrophytes var. quinkeanum on the back, and were then given a second dose of the same compound. Dosing was repeated once daily on days 1-4. On day 7, skin lesions were assessed visually and vaginal samples 30 were taken for agar culture. Groups of five mice were used and the compounds were initially administered at 250 mg / kg. The dose was then gradually reduced until the lowest effective dose (MED) was found.

The results are shown in Table A below.

In these experiments, compounds of the formula prepared according to the invention were used

O

li

N N CH- C - CH N N

5 ^ I, ^ 12 1 (formula I, where Y and Y are each = N-, R is given in the table).

10

Table A

Lowest effective dose (mg / kg)

Candida Trichophyton 15 albicans mentagrophytes _R __ (var. Quinkeanum) 4-fluorophenyl 100 50 4-chlorophenyl 2,5 10 2-chlorophenyl 2,5 25 20 4-trifluoromethylphenyl 10 25 2,4-dichlorophenyl__2,5__2,5_

The same experiment was performed using the previously known compounds shown below. Type C compounds are described in GB Patent 1,529,818 and EP Patent 15,756; and type B compounds in EP 15,756. The MED values obtained are given in the table.

___ - 1 8 74280

CH2-C (OH) -AzCH2-C (OH) -CH

5 0 “- * 0— *

Type C Type B

In these formulas, Az represents a 1,2,4-triazole group.

Type C Type B

R_R ^ _Trichoph. Candida Trichoph. Candida H 2 -Cl 50 100 100 100 15 4-C1 50 50 250 100 4-C1 2-F 25 25 50 50 2,4-Cl2 5 1,0 50 50 4-F 2,5 2,5 100 100 _4HF_2_j_5_2j_5_25_25 20

The teratological (malformative effect) of the compounds was studied as follows:

The test compound was added to co-cultures prepared from differentiating rat fetal limb embryonic cells (LB cells) taken from 13.5-day-old fetuses and used at appropriate concentrations in dimethyl sulfoxide. Each co-culture comprised 35 nutrient culture dishes with at least 3 LB-30 cell colonies, each approximately 6 mm in diameter. The highest concentration of test compound used was the highest concentration soluble in the medium (Ham's F 12 supplemented with 10% fetal calf serum, antibiotics and L-glutamine). Control cultures were treated with dimethyl sulfoxide alone.

9 74280 After a growth period of 5 days, the number of colonies of differentiated cells (chondrocytes) was determined. An average was calculated for the control experiment and for each concentration of test compound, and based on these, the concentration that inhibited the formation of colonies of differentiated cells by 50% relative to the reference value was estimated; this concentration is IC ^ g. The following Table B shows the IC 50 values for azole derivatives prepared according to the invention as well as those already known (GB patent publication 10 1,529,818 and EP patent publication 15,756).

Table B

^ From GB 1529818 and

Type G Compounds known from EP 15756 (AzCH2) 2-c (oh) -r1 AzCH2-C r1 20 R Compounds prepared according to the invention (Az is (Az is a 1,2,4-triazole group) a 1,2,4-triazole group) R_IC50_R_R ^ _IC50_ 4-F 50 4-F 4-F 8 25 4-Cl 1.0 2,4-Cl2 0.5 2-Br 0.06 4-Cl 35 4-Cl 4-C1 5.0 4- Br 3.0 30 2,4-Cl2 7,5 2,4-Cl2 2,4-Cl2 0,5 4-CF3 150 4 ~ CF3 4-CF3 14 2-F 40 2,4-F2 2,4- F2 6.5 4-CF3 8.0 35 ___ - τ ~ 10 74280

As the above results show, the novel compounds according to the invention are unexpectedly advantageous compared to the previously known compounds of similar structure, given their good fungicidal activity and significantly lower teratological effect.

The following examples illustrate the invention. Temperatures are given in degrees Celsius (° C).

Example 1 This example illustrates the preparation of 1,3-bis- (1,2,4) -triazolyl-2-p-chlorophenyl-propan-2-ol (Compound No. 1 in Farm I).

Step 1 Grignard's reagent prepared from p-chloroiodobenzene (0.22 mol) in sodium-dried diethyl ether (65 ml) and magnesium turnings (0.24 g) .7 was added dropwise over one hour to the stirred 1,3-dichloro position. (0.2 mol) in a solution of sodium-dried diethyl ether (270 ml) keeping the temperature at -60 ° C. The mixture was further stirred for one hour at -60 ° C after the addition was complete. Glacial acetic acid (21 mL) in diethyl ether (320 mL) was added dropwise to the solution and the temperature was allowed to warm to 0 ° C. The solution was washed with water (2 x 150 mL) and dried over Na 2 SO 4. Removal of the solvent gave a pale yellow oil which was distilled under reduced pressure to give 1,3-dichloro-2-p-chlorophenylpropan-2-ol (85%) b.p. 100-2 ° / 26.6 Pa.

Step 2 1,2,4-Triazole (0.045 mol) was added portionwise to a stirred suspension of sodium hydride (0.045 mol - using a 50% oil suspension) in dimethylformamide 30 (15 ml) and stirring was continued until effervescence ceased. 1,3-Dichloro-2-p-chlorophenyl-propan-2-ol (0.015 mol) in dimethylformamide (5 ml) was added dropwise to the solution at 20 ° C and stirring was continued at 100 ° C for 6 hours. After cooling to room temperature, the mixture was poured into water and the solid formed was filtered off and washed with diethyl ether. Recrystallization from ethyl acetate afforded the title compound as a crystalline solid (50% yield), m.p. 153-155 ° C.

74280 11

Example 2 This example illustrates the preparation of 1,3-bis- (1,2,4) -triazolyl-2- (2,4-dichlorophenyl) propan-2-ol (Compound No. 4 in Table I). 5 Step 1 Grignard reagent prepared by adding 30 g of 2,4-dichloroiodobenzene (0.11 mol) to 3.0 g of magnesium turnings (0.125 g atoms) in refluxing ether (200 ml in total) over a period of three hours 12.7 g were added dropwise: 1,3-dichloroacetone (0.10 mol) - stirred in 100 ml of dry ether in a dry ice-acetone bath - for 45 minutes. The reaction mixture was further stirred for 4 hours, allowing the cooling bath to warm to about 0 ° C and adding 10 mL of acetic acid in 100 mL of ether over 5 minutes.

The mixture was diluted with 400 mL of water and the ether layer was separated and washed sequentially with potassium metabisulfite solution (ca. 10%), water and brine. Filtration through anhydrous sodium sulfate and evaporation in vacuo afforded 27.2 g of a pale brown oil. This crude mixture of 1,3-20 dichloro-2- (2,4-dichlorophenyl) propan-2-ol and 1,2-epoxy-3-chloro-2- (2,4-dichlorophenyl) propane was used directly in the following stage.

Step 2 Sodium hydride (50% Ö1dispersion) 14.4 g (0.3 mol) was washed twice in 60-80 petrol, suspended in 50 ml of dry DMF under argon and 1,2,4-triazole 21 g (0.30 mol) DMF in 60 ml was added over 30 minutes at 50 ° C. After the evolution had ceased (about 30 minutes after the addition), the crude dichloride / epoxide mixture prepared above, 27.2 g in total, was added in 25 ml of DMF containing washings for 10 minutes at 25-35 ° C: stirring. After the addition, the reaction mixture was heated with stirring for 6 hours at 100 ° C. It was then stirred at room temperature and most of the DMF was evaporated in vacuo at about 50-80 ° C.

_ - T ~ ____ 12 74280

The dark residue was partitioned between 200 ml of water and 200 ml of chloroform. The aqueous portion was re-extracted with chloroform (2 x 100 mL) and the combined extracts were washed with 100 mL of water and 100 mL of brine. Filtration through anhydrous sodium sulfate and evaporation in vacuo afforded 20.5 g of a moist brown solid. Trituration in 200 ml of boiling ether and filtration (cold) gave 10.2 g of 1,3-bis- (1,2,4) -triazolyl-2- (2,4-dichlorophenyl) propan-2-ol as a pale as an off-white solid m.p. 182-185 ° C, from pure chromatography (silica gel K60; ethyl acetate: methanol, 4: 1). Chromatography of the basic liquids from trituration on silica gel in CH 2 Cl 2 and development with ethyl acetate followed by methanol / ethyl acetate (1: 4) further afforded 0.90 g of one pure material. Total yield 33% (calculated from dichloroacetone).

Analysis for c 13 H 15 Cl 2 2N 6 ° (339):

Calculated: C 46.0 H 3.50 N 24.8

Found: C 45.9 H 3.6 N 24.7 PMR CDCl 3 (90 MH 3) & 4.83 (q, 4H, CH 2 N), 5.64 (s, 1H, OH), 7.31 £ m (ABX ), 3H, Ar 7, 7.83 (s, 2H, Tr), 8.07 (s, 2H, Tr) ppm.

The remaining compounds of Table I, i.e. Compounds Nos. 3-23, were prepared in the same manner as in Examples 1 and 2 using the appropriate starting materials. The details of the crystallization and other purification procedure are as follows: 25 Compound Recrystallization, details and remarks on Preparation 1 from ethyl acetate 2 ethyl acetate: ether after silica chromatography 30 3 ethyl acetate: 74280 13 3 Imidazole was used instead of triazole in step 2. Chromatographed using alumina.

9 The crude solid was triturated with ether. Recrystallization from ethyl acetate.

Example 3 This example illustrates the preparation of 1,3-bis- (1,2,4-triazolyl-2-n-butyl-propan-2-ol (Example No. 13 in Table I)).

Step 1 Grignard reagent / prepared from n-butyl-10 bromide (0.08 mol) in sodium-dried ether (50 ml) and magnesium turnings (0.08 g atoms) was added dropwise over one hour to a stirred 1,3-dichloroacetone ( 0.08 mol) in a solution of sodium-dried diethyl ether (100 ml) kept at -60 °. The mixture was further stirred for one hour at -60 ° after the addition was complete. Glacial acetic acid (10 ml) was added dropwise and the temperature was allowed to rise to 0 °. The solution was washed with water (2 x 150 mL) and dried over anhydrous sodium sulfate. Removal of the solvent gave a pale red liquid which was distilled under oil pump vacuum to give 1,3-dichloro-2-n-butylpropan-2-ol (30%) b.p. 44 ° / 5.3 Pa.

Step 2 1,2,4-Triazole (0.067 mol) was added portionwise to a stirred suspension of sodium hydride (0.067 mol - using a 50% oil suspension) in dimethylformamide (30 ml) and stirring was continued until effervescence ceased. 1,3-Dichloro-2-n-butyl-propan-2-ol (0.022 mol) in dimethylformamide (5 ml) was added dropwise to the solution at 20 ° C, and stirring was continued at room temperature for 24 hours. The mixture was poured into water and the solid formed was filtered off and dried. Recrystallization from ethyl acetate afforded the title compound (30%), m.p. 61-62 ° C.

74280 14

Example 4 This example illustrates the preparation of 2- (2,4-dichlorophenyl) -1- (imidazol-1-yl) -3- (1,2,4-triazol-1-yl) -2-propanol. (Compound No. 12 in Table I)

Sodium hydride (50% suspension in oil - 2.23 g) was suspended in dimethylformamide (30 ml) under argon and cooled in a water bath while imidazole (3.2 g) was added portionwise. A solution of 2- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-ylmethyl) oxirane (6.4 g) in dimethylformamide (30 ml) was added and the mixture was heated at 80 ° C. for two hours. The mixture was cooled, poured into water (200 ml) and extracted with methylene dichloride. The organic extract was washed twice with water and brine twice, dried over sodium sulfate and filtered. The solvent was evaporated under reduced pressure and the residue was chromatographed on a K60 silica column eluting with 0-7% methanol in methylene chloride to give 2- (2,4-dichlorophenyl) -1- (imidazol-1-yl) -2- (1,2,4-triazole). -1-yl) -2-propanol, m.p. 169-170 ° C.

2- (2,4-Dichlorophenyl) -2- (1,2,4-triazol-1-ylmethyl) oxirane, which was used as a starting material in the process described above, can be prepared as follows: OC-2,4-trichloroacetophenone (20 g) was dissolved in acetonitrile (25 ml) and added dropwise to a refluxing solution of 1,2,4-triazole (6.2 g) and potassium carbonate (13.4 g) in acetonitrile (25 ml). When the addition was complete, the solution was allowed to cool and stirred for two hours. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed twice with water and twice with brine, dried over sodium sulfate and filtered. The filtrate was evaporated to dryness under reduced pressure and the residue was chromatographed on a K60 silica column eluting with ethyl acetate to give 2,4-dichloro-OC- (1,2,4-triazol-35-yl) acetophenone which, crystallized from ethyl acetate / 60-80 petroleum ether, had a melting point. 116-117 ° C.

15 74280

Sodium hydride (50% dispersion in oil - 1.82 g) was washed three times with 40-60 petroleum ether and trimethylsulfoxonium iodide (8.03 g) was added under nitrogen followed by dry dimethyl sulfoxide (37 ml) dropwise.

After the addition was complete, the mixture was stirred for 30 minutes, then a solution of 2,4-dichloro-OC- (1,2,4-triazol-1-yl) acetophenone (8.5 g) in dimethyl sulfoxide (25 ml) was added dropwise and after the addition was complete, the reaction mixture was heated at 50 ° C for two hours. The resulting solution was poured into water (200 mL) and extracted with methylene dichloride. The organic layer was separated, washed twice with brine, dried over sodium sulfate and filtered and the filtrate was evaporated to dryness to give the desired starting material, 2- (2,4-dichlorophenyl) -2- (1,2,4-triazol-1-yl) oxirane as a red solid. as an oil used in the above method without further purification.

Reaction Scheme 20 25 CH 3 CN 1 J c / Cl 35 74280 16

Example 5 This example illustrates the preparation of 1,3-bis- (1,2,4-triazol-1-yl) -2-tert-butylpropan-2-ol (Compound No. 20 in Table I).

Step 1, A solution of dimethylsulfonium methylide in dry dimethyl sulfoxide (70 ml) was prepared from sodium hydride (0.066 mol) and triturated from trimethyloxosulfonium iodide (0.066 mol) under a nitrogen blanket. A solution of 1,2,4-triazol-1-ylpina-10 column (0.06 mol) in dry dimethyl sulfoxide (30 ml) was added dropwise at room temperature, and the mixture was stirred at room temperature for 5 hours. The solution was poured into water, extracted with diethyl ether (200 ml), the extract washed with water (3 x 150 ml) and dried over anhydrous sodium sulfate. Evaporation of the solvent gave an oil which was purified by column chromatography (silica gel K60, eluting with ethyl acetate / petroleum ether (60-80 °), 7: 3) to give 2-tert-butyl-3- (1.2) as a pale green oil. (4-triazol-1-yl) propylene oxide (50%).

Step 2. 2-tert-Butyl-3- (1,2,4-triazol-1-yl) -propylene oxide (0.011 mol) and sodium triazole £ 0.022 mol - prepared from 1,2,4-triazole (0.022 mol) and sodium hydride (0.022 mol) was boiled in dimethylformamide (20 ml) at 50 ° C for 6 hours. The dimethylformamide was removed in vacuo, the residual oil was dissolved in chloroform (100 mL), the solution was heated with water (3 x 70 mL), and the solution was dried over anhydrous magnesium sulfate. Removal of the solvent and purification by column chromatography (silica gel K60; ethyl acetate / methanol 4: 1) gave the title compound in 45% yield, m.p. 85-87 ° C (crystallization from diethyl ether).

Example 6 This example illustrates the preparation of 2-tert-butyl-1- (imidazol-1-yl) -3- (1,2,4-triazol-1-yl) propan-2-ol (Compound n: o 23 in Table I).

2-tert-butyl-3- (1,2,4-triazol-1-yl) propylene oxide (0.011 mol) and sodium imidazole £ 0.022 mol - prepared from 1,2,4-triazole (0.022 mol) and sodium hydride-17,74280 (0.022 mol) was heated in dry dimethylformamide (50 ml) at 60 ° C for 12 hours. The dimethylformamide was removed in vacuo, the residue was dissolved in chloroform (100 ml), the solution was washed with water (3 x 70 ml) and dried over anhydrous magnesium sulfate. Evaporation of the solvent gave a wet solid which was crystallized from diethyl ether to give the title compound as a light brown crystalline solid in 30% yield, m.p. 128-130 ° C.

Example 7 A mixture of 5, 10, 25, 50, 100 or 250 parts of Compound No. 4 of Table I and 70 parts of calcium carbonate and 200 parts of 10% corn starch paste was dried and then passed through a 16 mesh screen. 5 parts of magnesium stearate were added and the granules were compressed to give 15 sets of tablets suitable for oral administration for therapeutic purposes.

This active ingredient may be replaced with a therapeutically equivalent amount of any of the other triazole derivatives defined above.

20 Example 8

A mixture of 2, 5, 10, 25, 50 or 100 parts of Compound No. 4 of Table I, 500 parts of lactose and 100 parts of corn starch was treated with a sufficient amount of corn starch for 10 h to obtain a granular mass. Each mixture is passed through a 16 mesh screen, dried, mixed with 8 parts of magnesium stearate and compressed into tablets to give a series of tablets suitable for oral administration for therapeutic purposes.

The active ingredient may be replaced therapeutically with an equivalent amount of any of the other triazole derivatives defined above.

Example 9

A mixture of 10 parts of Compound No. 4 of Table I and 190 parts of wheat germ oil is filled into soft gelatin capsules to give capsules suitable for therapeutic use for oral administration.

18 74280

The active ingredient may be replaced with a therapeutically equivalent amount of any of the other triazole derivatives defined above.

Example 10 A solution containing 10 parts of Compound No. 4 of Table I in 83 parts of water, 250 parts of glycerol and 125 parts of ethyl alcohol is mixed with a solution containing 300 parts of sucrose in 150 parts of water. A suitable flavoring and coloring agent is then added orally for therapeutic purposes to produce a syrup suitable for administration.

The active ingredient may be replaced with a therapeutically equivalent amount of any of the triazole derivatives defined above.

15 Example 11

A mixture of three parts of acacia gum and 1.5 parts of trangant gum is added to a mixture of one part of compound No. 4 of Table I and 33.7 parts of liquid paraffin. A solution containing 0.1 part of cetyl alcohol polyoxyethylene condensate, 40 parts of sucrose, 0.03 parts of propyl p-hydroxybenzoate, 0.3 parts of methyl p-hydroxybenzoate, a suitable flavoring agent and 0.002 parts of foodstuff is slowly added to the thoroughly ground mixture 20 with stirring. in some water.

The mixture is then homogenized in a conventional manner known in the art to produce an emulsion suitable for oral administration for therapeutic purposes.

The active ingredient may be replaced with a therapeutically equivalent amount of any other triazole derivative as defined above.

Example 12

A mixture of 0.5 parts of the fine compound of Table I No. 4 in three parts of propylene glycol and two parts of ethylene glycol monoether was added to a stirred mixture of four parts of lanolin and 90.5 parts of molten soft white paraffin. The resulting mixture was allowed to cool to room temperature with rapid stirring to give a homogeneous ointment containing 0.5% by weight of the active ingredient suitable for topical administration for therapeutic purposes.

The active ingredient may be replaced by another triazole derivative as defined above to produce similar creams.

Example 13

A solution of one part of Compound No. 4 of Table I in 20 parts of ethanol and 27 parts of diethylene glycol monoethyl ester was prepared, then 50 parts of purified water was added, followed by two parts of carboxymolymethylene eluting agent (Carbapol 940 - trademark) to give a fine for topical administration for therapeutic purposes.

The active ingredient may be replaced by any other triazole or imidazole compound or derivative described above.

Example 14 This example illustrates the preparation of the acetyl ester (i.e. acetate) of the compound of Example 4 (Compound No. 4 in Table I).

The reaction was as follows: 25 N Λ - * r \ h \\

li \\ \ / N

Il N n \ n / 30 ™ I \ CH2 / OCOCHj C-CH „“ yS -> Yf n | Cl C1

Cl 20 74280

1.70 g (5 mmol) of the compound of Example 4 (Compound No. 4 in Table I) was heated on a steam bath for 7 hours in 40 ml of acetic anhydride containing 100 mg of 4-dimethylaminopyridine. The reaction mixture was evaporated in vacuo to give an orange gum. This was dried in vacuo overnight and dissolved in hot ethyl acetate / ether and cooled to give 840 mg of a pale off-white solid, m.p. 176-179 ° C. Purify by thin layer chromatography on silica (ethyl acetate / methanol 9: 1).

Analysis for C 47.24 / 3.70 / 22.0 C 15 H 14 Cl 2 N 6 O 2 (381) F 47.7 / 3.8 / 21.3 PRM-DMSO-d 6 90 MHz 62.04 (s, 3H, CH 3 CO), 5.17 (q, 4H, CH 2 N), 7.20 - 7.23 (q / d, 2H, Ar), 7.60 (d, 1H, Ar), 7.97 - 8.33 (s / s) , 2H each, Tr) ppm.

Example 15 This example illustrates the preparation of the compound of Example 1 2,6-dichlorobenzyl ether (Compound No. 1 in Table I).

The reaction was as follows:

m O

^ p c \ 25 I CH ^ CH2k Λ / γ) CH \ / / = »W / = 7

P f Ί H

ci N-1 / C1

The compound of Example 1 (Compound 1 in Table I) 3.04 g (10 mmol) was added portionwise to 0.5 g of a 50% NaH dispersion in oil (washed from oil 60-80 with petrol) at 20-35 ° C: in 15 ml of dimethylform-21,74280 amide. After the evolution of H 2 was complete, 2.0 g of 2,6-dichlorobenzyl chloride (10 mmol) in 20 ml of dimethylformamide was added and the reaction mixture was stirred at 90-100 ° C for 48 hours. It was then partitioned between ethyl acetate and water and the organic layer was separated and washed 3 times with water and once with brine. Drying over anhydrous sodium sulfate and evaporation in vacuo afforded 4.40 g of a pale yellow oil. Cooled in ether / ethyl acetate to give 1.2 g of a tarry solid and 1.35 g of a pale yellow solid (second crop). The first yield of m.p. recrystallization of the combined yields was 133-139 ° C to give 2.20 g of almost colorless solutions, m.p. 133-138 ° C. Purified by thin layer chromatography on silica gel (ethyl acetate / CH 3 OH, 9: 1).

Analysis: C 48.0 / 4.2 / 16.8 for C 20 H 17 Cl 3 N 6 O 2 H 2 O (463.5; 36) F 47.7 / 3.9 / 16.7 PMR CDCl 3 -DMSO-d 6 (90 MHz) £ 3.21 (s, H 2 O), 4.90 (s, 2H, CH 3 O), 4.97 (s, 4H, CH 2 N), 7.30 (m, 7H, Ar), 7.80-20 , 15 (s / s, 2H each, Tr) ppm.

Claims (4)

A process for the preparation of a therapeutically useful azole derivative of the formula 5 OH 1 1 2 Y-N - CH-- C-CHO- N - YI KJ · f * 3 wherein R 2 is a lower alkyl group, is substituted with one or two halogens, or a phenyl optionally mono- or disubstituted with halogen, methyl, methoxy, phenyl and / or phenoxy, and Y and Y denote a group = CH- or = N- ; and salts, lower alkanoyl esters and the 2,6-dichlorobenzyl ether thereof, characterized in that a) a 1,3-dihalogenpropan-2-ol of formula 20 f X II In R1 and X, X and X, which may be the same or different, are halogen atoms and are as defined above, with imidazole or 1,2,4-triazole or a site thereof, as, for example, the sodium salt, or b) reacting a compound of the formula 30 2-π R - C N - Y1 26 7 4 2 8 0 11 .. wherein R and Y are as defined above, with iraidazole or 1,2,4-triazole or a site thereof, or c) reacting a ketone of formula = 0 1 "R Is defined above, with dimethyloxosulfonium methylide or dimethylsulphonium methylide and then reacts the obtained epoxide of formula III with imidazole or 1,2,4-triazole or a or d) reacting a ketone of formula O 1 in '2 Y-N-CH-C-CH »-N- \ V K ^ ^ where Y and Y are as defined above, with a Grignard reagent of the formula R!-Mg-X VIri where R! is defined above and X is a halogen atom, or e) reacting a 1,3-dihaloacetone with imidazole or 1,2,4-triazole or a site thereof, and reacting the obtained ketone of formula V with a Grignard reagent of formula VI; if desired, the obtained compound of formula I converts to a site, a 2,6-dichlorobenzyl ether or a lower alkanoyl ester. 2. A process according to claim 1, characterized in that 1,3-bis- (1,2,4-triazolyl) -2- (2,4-dichlorophenyl) propan-2-ol is prepared.