DK158543B - ANALOGY PROCEDURE FOR THE PREPARATION OF BIS-AZOLYL COMPOUNDS - Google Patents

Description

in DK 1585438

The invention relates to an analogous process for the preparation of novel bis-azolyl compounds of the general formula I defined below, which compounds are useful as fungicides. The compounds of the invention can be included in pharmaceutical and veterinary products and especially such products which are orally or topically effective against fungal diseases in humans and other animals. These products are particularly useful for the treatment of candidiasis and human derma-topophytic infections.

10

Triazole derivatives with fungicidal action are known from British Patent No. 1,529,818, similar to Hungarian Patent No. 178,586. Further triazole derivatives are known from European Patent Specification No. 15,756. However, by the method of the invention, novel compounds are prepared which structurally clearly deviate from the above-mentioned known compounds.

The novel compounds prepared by the analogy process of the invention have the general formula I

OH

Y1 - N CHO - C CH9 - N - Yz III II ™ 25 in which γΐ and Y2, which are the same or different, are N or CH and R 1 is an alkyl group or a cycloalkyl group each optionally halogenated or (C C4) alkoxy-substituted and each containing up to 6 carbon atoms, or R 1 is phenyl or benzyl, both of which may be optionally substituted by one or more of the following substituents: halogen, alkyl or halo-alkyl, each containing from 1 to 5 carbon atoms, alkoxy or haloalkoxy, each containing from 1 to 4 carbon atoms, nitro, cyano, hydroxy, alkylthio of 1 to 4 carbon atoms, or phenyl, halogenophenyl, phenoxy or vinyl and wherein the benzyl's alkyl moiety is optionally substituted by alkyl containing from 1 to 4 carbon atoms, or with phenyl,

DK 158543 B

2 as well as salts, metal complexes, ethers which are alkyl, alkenyl, alkynyl, aryl or aralkyl ethers, and esters which are alkanoyl, benzoyl or sulfonoyl esters thereof.

The compounds of this 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.

10

In the present method, e.g. a compound of the above Formula I wherein R * is either an alkyl group containing from 1-6 carbon atoms, optionally halogenated or (C 1 -C 4 alkoxy substituted, or is cyclopentyl or cyclohexyl, each optionally halogenated or (C C4) alkoxy substituent.

A compound of formula I above may also be prepared wherein R 1 is phenyl or benzyl and both may optionally be substituted one or more times by halogen, methyl, methoxy, trifluoromethyl, trifluoromethoxy, phenyl, halogenophenyl, phenoxy or vinyl. wherein the alkyl portion of the benzyl is optionally substituted with methyl, ethyl or phenyl.

The salts may be the salts with inorganic or organic acids, e.g. hydrochloric acid, nitric acid and sulfuric acid; acetic acid, p-to-1uenesulfonic acid or oxalic acid. The salts can also be quaternary salts.

30 The metal complex is suitably a complex containing as metal, copper, zinc, manganese or iron.

A compound of the invention may be included as an active ingredient in a product which may contain a carrier for the active ingredient.

Examples of the compounds which can be prepared by the process of the invention are given in Table I.

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3

TABLE I

5 _______ ———— '!

Compound R * Y ^ Y Y Melting point? ° C) 10 1 4-C1-C6H4-. = N- = N- 153-155 2 C6H5 “= N- = N- 99-101 3 4-F-CgH4- = 11- = N- 124-126 4 2,4-diCl-C6H3 = N- = N - 183-186 15 5 2/4-diCl-C6H3-CH2- = N- = N- 137-140 6 4_cH - C, H, - = N- = N- 179-180 3 6 4 7 4-C6H5 -C6H4- = N- = N- 165-170 8 4-CH30-C6H4- = N- = N- 141-143 9 2-Cl-C6H4- = N- = N- 145-148 20 10 4-CgH50- C6H4- = N- = N- 163-165 11 2-CF3-C6H4- = N- = N- 12 2,4-diCl-C6H3- = CH- = CH-160-175 13 2/4-diCl-C6H3 - = N- -CH- 169-170 14 n-C4H9- = N- = N- 61-62 25 4-Cl-C6H4CH2- = N- = N— 16 2-Cl-C6H4CH2- = N- = N - 17 2,6-diCl-C6H3CH2- = N- = N- 18 4-CH30-C6H4CH2- = N- = N- 19 C6H5CH2- = N- = N- 101-102 qn OD & 2,4-diClC6H3CH - = N- = N- 21 4-Cl-C6H4CH- = N- = N- ^ 6H5 22 4-C1-CH-CH- = N- = N-

35 ° * I

'* - 1 _____!

4 DK 158543B

TABLE I continued · 5

Compound γΐ γ2 Melting point (° C) 10 23 2,6-diClC6H3- = N- = N- 24 4-CF30CgH4- = N- = N- 2,4,6-triClC6H2- = N- = N-26 4- (C1-C6H4) C6H4- = N- = N- 27 2- (C6H50) C6H4- = N- = N- 28 4-CH2 = CH-C6H4- = N- = N- 126_128 29 t-C4H9 - = N- = N- 85-87 30 i-C4Hg- = N- = N- 31 (\ - = N- = N- 20 '-' 32 t-C4HgCH2 = N- = N- 33 3.4- diClC6H3- = N- = N- 140-145 ag ethanol / water 1: 9 25 34 t_C4H9 = N- = CH- 129-130 35 4-CF3-C6H4- = N ~ = N-164-165 In the above The following abbreviations are used in the table: 30 t- = tertiary i- = iso () - = cyclohexyl 35 '-' did = dichloro-triCl = trichloro-

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5

The compounds of the general formula I set forth above can be prepared according to the invention by reacting a 1,3-dihalogenpropan-2-o1 of the general formula II: f χΐ -ch2-c-ch2-x2 (I1 *

Wherein X and X, which may be the same or different, are each halogen (chlorine or bromine) and have the meaning given above, with imidazole or 1,2,4-triazole or a salt thereof (e.g. the sodium salt). This reaction can be carried out in a suitable solvent, such as methanol, ethanol, acetonitrile or dimethylformamide, at a temperature of 20-100 ° C. The dihalogenpropan-2-ol is preferably added to an excess of the 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. The 1,3-dihalo-propan-2 oils can be prepared by reacting a 1,3-dihaloacetone with the appropriate Grignard reagent according to known methods (e.g., Johnson et al. , J. Org. Chem., 1962, 27, 2241-2243). '-.

The compounds I can also be prepared according to the invention by reacting a compound of the general formula IH: CH0 2 \ 0 R1 - c ^ (III) CH2 N-Y1

Si /

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6 wherein R 1 and Y 2 have the meanings defined above, with imidazole or 1,2,4-triazole or a salt thereof (e.g., the sodium salt) in a suitable solvent by the above procedure.

5

The compounds of the general formula I according to the invention can also be prepared by reacting a ketone of the general formula IV: 0 CH2 (IV) N-jY1

ISLAND

wherein R ^ and Y ^ have the meaning defined above, with dimethyloxosulfonium methylide (Corey and Chaykovsky, JACS, 1965, 87, 1353-1364) or dimethylsulfonium methylide (Corey and Chaykovsky, JACS., 84, 3782) using those in the literature and then reacting the resulting epoxide of the general formula III with imidazole or 1,2,4-triazole or a salt thereof.

25

Compounds (IV) can be prepared by methods set forth in the patent literature, cf. in particular British Patents Nos. 1533705 and 1533706 *

A compound of formula I prepared according to the invention

can, if desired, be converted into a salt, a metal complex, an ether or an ester thereof.

The salts and metal complexes of the compounds of general formula I can be prepared from the latter in known manner.

For example, the complexes may be prepared by reacting the non-complexed compound with a metal salt in a suitable solvent.

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7

The ethers are prepared by treating the sodium salt of the alcohol with a reactive halogenated compound (e.g., methyl = bromide or iodide, benzyl chloride or allyl bromide). The esters are prepared in a similar manner by treating the sodium = 5 salt of the alcohol with an acid chloride (e.g. -acetyl chloride, benzoyl chloride or methanesulfonyl chloride).

The pharmaceutical and veterinary products may be in a conventional pharmaceutical form suitable for oral administration, e.g. a tablet, a capsule, an emulsion or an aqueous or oily solution or suspension, or suitable for topical application, e.g. a cream, ointment or gel. The product may contain conventional pharmaceutical excipients and may be prepared by conventional pharmaceutical methods.

Preferred pharmaceutical or veterinary products are products suitable for oral administration and especially tablets and capsules.

20

The anti-fungal effect of the active ingredients of the Candica Albicans products on causative fungi of candidiasis and Trichophyton mentagrophytes was. quinkeanum was detected as follows; 2 5

Female mice of approx. 30 g was injected subcutaneously one Friday with 0.5 mg estradiol benzoate. The following Monday (day 0), they were cut on their backs and then dosed orally with the compounds to be examined. They are then seeded with Candida albicans 30 in the vagina and Trichophyton mentagrophytes were. quinkeanum on the back and then given another dose of the same compound. The dosage is repeated once daily on days 1-4.

On day 7, skin lesions are determined visually and vaginal specimens are taken for agar culture. A group of 5 mice is used and 35 compounds are initially dosed in an amount of 250 mg / kg.

The dose is then gradually reduced until one is determined.

minimal effective dose (MED). In this experiment, compound 4 of Table I was effective on Candida at a concentration of 1 mg / kg. |

8 in DK 158543 B

/

In order to demonstrate the pharmaceutical fungicidal effect of the compounds of the invention, the following experiments have been carried out.

5 The antifungal effect against Candida albicans, a candidiosis-inducing fungus, and Trichophyton mentagrophytes were. quin-keanum, a ringworm-inducing fungus, was detected as follows.

1q Female mice of approx. 30 g was injected subcutaneously one Friday with 0.5 mg estradiol benzoate. The following Monday (day 0), they are shaved on their backs and dosed orally with the test compounds. They are then seeded with Candida albicans in the vagina and Trichophyton menta-grohytes var. quinkeanum on the back and given another dose of the same compound. The dosage is repeated once daily on days 1-4. On the seventh day, the lesions are assessed visually and vaginal specimens are taken for agar culture. Groups of five mice are used and compounds are initially dosed in an amount of 250 mg / kg. The dose is then reduced stepwise until determination 20 of a Minimum Effective Dose (MED).

The results are given in the following table in which the listed compounds have the general formula: Γ

N-N-CHo-C-CHo-N-N

U i u 30 35

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9

Least effective dose (mg / kg) 5 Ri Candida Trichophyton albicans mentagrophytes (variegated quinkeanum) 4-fluorophenyl 100 50 1Q 4-chlorophenyl 2,5 10 2-chlorophenyl 2,5 25 4-trifluoromethylphenyl 2,4-dichlorophenyl 2, 2.5 2.5 _______; _:

To detect the lower teratological potential of the compounds (type 6) of the invention compared to the compounds (type C) of British Patent No. 1529818 and European Patent No. 15756, the following experiments have been conducted.

The test compound is added to replicate cultures of differentiating rat embryonic 1 (LB) cells (differentiating rat embryonic limb bud cells) taken from 13.5 days of embryo at a suitable concentrate in the onion region in dimethyl sulfoxide.

Each replicate is a 35 mm culture dish containing at least three islets of LB cells with a diameter of approx. 6 mm. The highest concentration of the compound under study was the maximum soluble in culture medium (Ham's F12, supplemented with 10% fetal calf serum, antibiotics and L-glutamine). Control cultures were treated exclusively with dimethyl sulfoxide.

The number of foci of differentiated cells (chondrocytes) formed during five days of culture was determined. The mean of control and each concentration of test compound was calculated and then the concentration determined at 35

DK 158543 B

which generated differential focus by inhibiting 50% of the control value, "IC50".

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DK 158543B

11

The following examples illustrate the invention.

Example 1 This example illustrates the preparation of the compound 1,3-bis- (1,2,4) -1riazolyl-2-p-chlorophenylpropan-2-o1 (Compound No. 1 in Table 1)

Preparation of Starting Material 10 IniQ-JL · Gr ignard reagent [prepared from p-chloroiodine benzene (0.22 mol) in sodium-dried diethyl ether (65 mils and magnesium chips (0.24 g atoms)] was run over Drop 1 hour to a stirred solution of 1,3-dichloroacetone (0.2 mole) in sodium-dried diethyl ether (270 ml) kept at -60 ° C. The mixture is stirred for an additional 1 hour at -60 ° C. After completion of the addition, glacial acetic acid (21 ml) in diethyl ether (320 ml) was added dropwise and the temperature was allowed to rise to 0 ° C. The solution was washed with water (2 x 150 ml) and dried (Na 2 SO 4). Removal of the solvent gave a pale-2q yellow oil which was distilled at the oil pump to give 1,3-dichloro-2-p-chlorophenylpropan-2-ol (85%), bp 100-102 ° C / 0.2 mmHg .

Process a) 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% suspension in oil) in dimethylformamide (15 ml) and the stirring was continued until the shower ceased. 1,3-Dichloro-2-p-chlorophenylpropan-2-ol (0.015 mol) in 1 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 resulting solid was filtered off and washed with ethyl ether. Recrystallization from ethyl acetate gave the title compound ice as a crystalline solid (yield 50%), m.p.

153-155 ° C.

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12

The remaining compounds in Table I, i.e., compounds Nos. 3-32 were prepared in a similar manner as described in Examples 1 and 2 using appropriate starting compounds. Details of crystallization and other 5 purification methods are as follows:

Compound No. Recrystallization Details and Preparations for Preparation 10 1 From ethyl acetate.

2 From ethyl acetate: Ether after chromatography on silica, 3 ~ From ethyl acetate: 60-80 gasoline after chromatography on silica.

4 From ethyl acetate after chromatography on 15 silica.

5 From chromatography on silica.

6 From ethyl acetate after chromatography on silica 7 From chromatography on silica.

20 8 Imidazole was used in place of triazole in step 2. Chromatographed on alumina. Recrystallized from methanol / ethyl acetate as oxalate salt.

9 Solid crude product decomposed with ether. On crystallization from ethyl acetate.

Example 2

This example illustrates the preparation of the compound 1,3-bis- (T, 2,4) -tri-zoly 1-2- (2,4-dichloropheny 1) -pr opano 1 - 2 - o 1 (Compound no. 4 from Table I) 30

Preparation of starting material

Step 1. A Grignard reagent (prepared by adding 30 g of 2,4-dichlorodiodo benzene (0.11 mol), to 3.0 g of magnesium = chips (0.125 g of atoms), in refluxing ether (200 ml total) over 3 hours) was dropped to 12.7 g of 1.3 dichloro = acetone (0.10 mol) - stirred in 100 ml of dry ether in a dry ice-acetone bath over 45 minutes. The reaction mixture was stirred for a further 4 hours, allowing the cooling bath to

DK 158543B

13 assume the temperature approx. 0 ° C / and 10 ml of acetic acid was added to 100 ml of ether over 5 min.

It was diluted with 400 ml of water and the ethereal layer 5 separated and washed successively with potassium metabisulphite solution (about 10%), water and saturated brine. Filtration through anhydrous anhydrous sodium sulfate and evaporation in vacuo gave 27.2 ml of a light brown oil. This crude mixture of 1,3-dichloro-. 2- (2,4-dichlorophenyl) propan-2-ol and 1,2-epoxy-3-chloro-2- (2,4-dichlorophenyl) propane were used directly in the next; step. - - i

Process b) Step 2, Sodium hydride (50% dispersion in oil) 14.4 g (0.3 mole) was washed with 60-80 gasoline twice, suspended in 50 ml of dry DMF under argon and 1.2 trizole 21 g (0.30 mol) in 60 ml of DMF was added over 30 min. at a temperature below or equal to 50 ° C. After the cessation of hydrogen evolution (ca.

20 30 min. after the addition), the crude dichloride / epoxide mixture, 27.2 g total, was salted to 25 ml DMF including washing. liquids over 10 min. at 25-35 ° C with stirring. After the addition, the reaction mixture was heated under stirring for 6 hours at 100 ° C. It was then stirred overnight at room temperature and the majority of DMF was evaporated in vacuo at ca. 50-80 ° C. The dark residue was partitioned with 200 ml of water and 200 ml of chloroform. The aqueous portion was extracted again with chloroform (2 x 100 ml) and the combined extracts washed with 100 ml of water and 100 ml of brine. Filtration through anhydrous sodium sulfate and evaporation in vacuo gave 20.5 g of moist brown solid. Decomposition with 200 ml of boiling ether and filtration (cold) gave 10.2 g of 1,3-bis (1,2,4) -triazolyl-2- (2,4-di = chlorophenyl) propan-2-ol as a light brown solid, m.p. 182-185 ° C, pure at H.c. (silica gel K60, ethyl acetate: methanol 4: 1). The mother liquor from the titrations on chromatography on silica gel in CH 2 Cl 2 and developing with ethyl acetate followed by methanol / ethyl acetate (1: 4) gave an additional 0.90 g of material | of the same purity. Total yield: 33% (calculated on DCA).

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14

Analysis: Calculated for C ^H ^Cl₂NgO

C, 46.0; H, 3.50; N, 24.8. Found: C, 45.9H, 3.6; N, 24.7.

5 p.m. CDCl3 (90 MH3) δ 4.83 (q, 4H, CH 2 N} 5.64 (s, 1H, OH), 7.31 '(m (ABX), 3H, Ar), 7.83 (s, 2H) , Tr), 8.07 (s, 2H, Tr) ppm, -

Example 3 10

This example illustrates the preparation of the compound 1,3-bis- (1,2,4) -triazolyl-2β-n-butylpropane-2-Q1 - (Example # 14 from Table I) Preparation of starting material

Step 1. The Grignard reagent [prepared from n-butyl bromide (0.08 mole) in sodium dried ether (50 ml) and magnesium shavings (0.08 g atoms)] was added dropwise to a stirred solution of 1,3-dichloroacetone (0.08 mole) in Na = 20 tri-dried diethyl ether (100 ml) kept at -60 ° C. The mixture was stirred for a further 1 hour at -60 ° C after completion of addition. Glacial acetic acid (10 ml) was added dropwise and the temperature allowed to rise to 0 ° C. The solution was washed with water (2 x 150 ml) and dried over anhydrous sodium sulfate. 25 Removal of the solvent gave a pink liquid which was distilled at the oil pump to give 1,3-dichloro-2-n-butylpropane-2 o 1 (30%), boiling point 44 ° C / 0.04 mm Hg.

Process a) Step 2. 1,2,4-TriazoT (0.067 mol) was added portionwise to a stirred suspension of sodium hydride (0.076 mol - using 50% suspension in oil) in dimethylformamide (30 ml) and stirring was continued. until the shower ceased.

1,3-Dichloro-2-n-butylpropan-2-ol (0.022 mol) in dimethyl = formamide (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 resulting solid was filtered off and dried. Recrystallization from ethyl acetate gave the title compound (30%), m.p. 61-62 ° C.

Example '4

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15

This example illustrates the preparation of the compound 2- (2,4-dichlorophenyl) -1- (imidazol-1-yl) -3- (1,2,4-triazol-5'-yl) -2-propanol (compound no. 13 from Table I)

Final step, process c)

Sodium hydride (50% suspension in oil - 2.23 g) was suspended in dimethylformamide (30 ml) under an argon atmosphere and cooled in a water bath, while imidazole (3.2 g) was added portionwise. A solution of 2- (2,4-dichlorophenyl) -2- (1,2,2,4-triazol-1-ylmethyl) oxirane (6.4g) in dimethylformamide (30ml) was added and the mixture heated to 80 ° C for 2 hours. The mixture was cooled, poured into water (200 ml) and extracted with methylene dichloride. The organic extract was washed with water twice and with brine twice, dried over sodium spiffate and filtered. The solvent was evaporated under reduced pressure and the residue was chromatographed on a K60 silical column eluting with 0-7% methanol in methylene dichloride to give 2- (2,4-dichloro-phenyl) -1- (imidazole-1 yl) -3- (1,2,4-triazol-1-yl) -2-propanol, m.p. 169-170 ° C.

Preparation of Starting Material 2- (2,4-Dichlorophenyl) -2- (1,2,4-triazol-1-ylmethyl) oxirane used as starting material in the above process can be prepared as follows:

Step 1 ! 30 α-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). After completion of the addition, the solution was allowed to cool and stirred for 2 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.

16 DK 158543B

and the residue was chromatographed on a K60 silica column eluting with ethyl acetate to give 2,4-dichloro-α- (1,2,4-triazol-1-yl) acetophenone, which after recrystallization from ethyl acetate / 60-80 petroleum ether, m.p. 116-117 ° C.

Step 2

Sodium hydride (50% dispersion in oil - 1.82 g) was washed three times with 4Ό-80 petroleum ether and trimethylsulfoxonium = 1 ° iodide (8.03g) was added under a nitrogen atmosphere followed by dry dimethylsulfoxide (37ml) dropwise . After the addition was complete, the mixture was stirred for 30 minutes, whereupon a solution of 2,4-dichloro-α- (1,2,4-triazol-1-yl) -acetophenone (8.5 g) in dimethylsulfoxide was added dropwise. (25 ml) and after completion of the addition, the reaction mixture was heated to 50 ° C for 2 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 required starting material 2- (2,4-dichloro = phenyl) -2- ( 1,2,4-triazol-1-yl) oxirane as a red oil used in the above process without further purification.

The reaction scheme is: 25 ry t /; triazole ^ CH-sCN ·. JO Jl * 30 Cl ^^^^ Cl J Cl ^^^^ Cl '35' \ f x 'V'jfi,

"Jot

Example 5

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17

This example illustrates the preparation of the compound 1,3-bis- (1,2,4-triazol-1-yl) -2-t-butylpropan-2-ol (Example 5 No. 29 from Table 1).

Step 1. A solution of dimethyloxosulphonium methylide was prepared under nitrogen from sodium hydride (0.066 mol) and powdered trimethyloxosulphonium iodide (0.066 mol) in 10 dry dimethylsulphoxide (70 ml). A solution of 1,2,4-triazol-1-yl pinacolone (0.06 mol) in dry dimethyl sulphoxide (30 ml) was added at room temperature and the solution stirred at room temperature for 5 hours. The solution was poured into water, extracted with diethyl ether (200 ml), washed with water (3 x 150 ml) and dried over anhydrous sodium sulfate. Removal of the solvent gave an oil which was purified by column chromatography (silica K60 eluted with ethyl acetate / petroleum ether (60-80) 7: 3 to give 2-t-butyl-3- (1,2,4-triazole) -1-yl) propylene oxide (50%) as a light green oil.

20

Step 2. 2-t-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)] were heated in dimethylformamide (20 ml) at 50 ° C for six hours. The dimethylformamide was removed in vacuo and the oil dissolved in chloro

mold (100 mo), heated with water (3 x 70 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent gave an oil which was purified by column chromatography (silica gel K60; ethyl acetate: methanol 4: 1) to give the title compound (45%) mp 85-87 ° C (recrystallized from diethyl ether). IN

Example 6 This example illustrates the preparation of the compound 2-t-butyl-1- (imidazol-1-yl) -3- (1,2,4-triazol-1-yl) -propan-2-ol (compound no. 34 from Table 1).

i 18

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2-t-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 (0.022 mol)) was heated in dry dimethylformamide (50 ml) for 12 hours at 60 ° C. The dimethyl formamide was removed in vacuo and the residue dissolved in chloro form (100 ml), washed with water (3 x 70 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent gave a moist brown solid, which upon recrystallization from diethyl ether gave the title compound (30%) as a light brown crystalline solid, mp 128-130 ° C.

Example 7

A mixture of 5, 10, 25, 50, 100 or 250 parts of Compound No. 4 of Table I with 70 parts of calcium carbonate and 200 parts of a 10% corn starch paste is dried and then passed through a 16 mesh screen. 5 parts of magnesium stearate are added and the grains are pressed into tablets suitable for oral administration for therapeutic purposes.

20

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

25

Example 8

A mixture of 2, 5, 10, 25, 50 or 100 parts of Compound No. 4 from Table I, 500 parts of lactose and 100 parts of corn starch is treated with a sufficient 10% corn starch paste 30 to obtain a granular mass. Each mixture is passed through a 16 mesh screen, dried, mixed with 8 parts of magnesium stearate and pressed into tablets to obtain tablets suitable for oral administration for therapeutic purposes.

The active ingredient may be replaced by a therapeutically equivalent amount of any other triazole derivative previously defined. 35

Example 9c!

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19

A mixture of 10 parts of compound # 4 from Tables I and 190 parts of wheat germ oil is filled into soft gelatin capsules to obtain capsules suitable for oral administration for therapeutic purposes.

The active ingredient may be replaced by a therapeutically equivalent amount of any other triazole derivative.

10 as previously defined.

Example 1 Qc

A solution of 10 parts of compound # 4 from Table I in 83 parts of water, 250 parts of glycerol and 125 parts of ethyl alcohol is mixed with a solution of 300 parts of sucrose in 150 parts of water. A suitable flavoring and coloring agent is then added to form a syrup suitable for oral administration for therapeutic purposes. . > 20 -

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

Example 11

A mixture of 3 parts of acacia rubber and 1.5 parts of tragacanth rubber is added to a mixture of 1 part of Compound No. 4 in Table I and 33.7 parts of liquid paraffin. To the carefully decomposed mixture is slowly added with stirring a solution of 0.1 part cetyl alcohol polyoxyethylene condensate, 40 parts sucrose, 0.03 parts propyl p-hydroxybenzoate, 0.3 parts methyl. p-hydroxybenzoate, a suitable flavoring agent and 0.005 parts of edible dye in 110 parts of water. The mixture is then homogenized in the usual manner to form an emulsion well suited for oral administration for therapeutic purposes.

20

DK 158543B

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

Example 12

A mixture of 0.5 parts of finely divided compound # 4 according to Table I propionamide in 3 parts of propylene glycol 03 2 parts of ethylene glycol = monoether was added to a stirred mixture of 4 parts of lanolin 10 and 90.5 parts of melted soft white paraffin. The resulting mixture was allowed to cool to room temperature with vigorous stirring to obtain a uniform ointment containing 0.5% by weight of active ingredient suitable for topical administration for therapeutic purposes.

15

The active ingredient may be replaced by another triazole = derivative as previously defined to obtain similar ointments.

Example 13

A solution of 1 part of compound # 4 from Table I was prepared in 20 parts of ethanol and 27 parts of diethylene = glycol monoethyl ester, to which 50 parts of purified water was added, followed by 2 parts of a carboxypolymethylene gelling agent ( "Carbapol 940" trademark) to obtain a fine-dispersed gel suitable for topical administration for therapeutic purposes. The active ingredient may be substituted with any other triazole or imidazole compound or derivative as previously described. .

Example 14

This example illustrates the preparation of acetyl esters (i.e., the acetal) of the compound of Example 4 (compound no.

4 of Table 1).

35

DK 158543B

21

The reaction was as follows: 5N-y * N -ry O O '

XN ^ XN

1/03 / = rN I

The compounds of Example 4 (Compound No. 4 of Table I) 1.70 g (5 mmol) were heated on a steam bath for 1 hour. - 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 which was dried under vacuum overnight 2® and dissolved in hot ethyl acetate / ether and cooled to give 840 mg of a light brown solid, mp 176-179 ° C. Pure by thin layer chromatography on silica gel (ethyl acetate / methanol 9: 1).

Analysis: C 47.24 / 3.70 / 22.0 C15H14C12N602 (381) F 47.7 / 3.8 / 21.3 PMR-DMSO - d, 90 ΜΗ δ 2.04 (s, 3H, CH CQ) 5.17 bz -j (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, Tf) -ppm.

Example 5

This example illustrates the preparation of the 2,6-dichlorobenzyl ether of the compound of Example 1 (Compound No. 1 in Table I). The reaction was as follows: | j! i i 22

DK 158543B

0. o. '1 0H I Y- \ r \ - »^ / \ / 0

5 ^ CH2— »I ^ / CH ^ C ^ 2 W

0 ύ V

Cl.

The compound of Example 1 (Compound No. 1 of Table I) was added 3.04 g (10 mmol) in portions to 0.50 g of 50% NaH dispersion in oil (washed oil-free with 60-80 gasoline) at 20-35 ° C in 15 ml of DMF. After the ^ evolution ceased, 2.0 g of 2,6-dichlorobenzyl chloride (10 mmol) was added.

Q

In DMF and the reaction mixture was stirred at 90-100 ° C

for 48 hours. It is partitioned between ethyl acetate and water and the organic layer separated and washed three times with water and once with brine. Drying with anhydrous Na 2 SO 4 and evaporation in vacuo gave 4.40 g of a pale yellow oil. After cooling 20 ·.

in ether / ethyl acetate 1.2 g · of a tar-like solid and 1.35 g of a light yellow solid (second yield) were obtained, and the first yield had a melting point of 133-139 ° C. Recrystallization of the combined yields yielded 2.20 g of the near-colorless plates, m.p. 133-138 ° C. Purely by thin layer chromatography on silica gel (ethyl acetate / CH 2 OH; 9: 1).

Analysis: C 48.0 / 4.2 / 16.8 for C 20 H 17 Cl 3 M 6 O 2 H 2 O (463.5; 36) F 47.7 / 3.9 / 16.7 Pm. CDCU-CMSO-d, - (90 MHJ δ 3.21 OO li (s ', H 2 O) 4.90 (s, 2H, CH 2 O), 4.97' (s, 4H, CH 2 N), 7.30 ( m, 7H, Ar), 7.80 / 8.15 (.s / s, 2H each, Tr. ppm.

35

Claims (1)

23 DK 158543B Patent claims. Analogous Process for Preparing a Bis-Azolyl Compound of General Formula I | OH y - N -CH2- C -CH2- N -y2! 10 1 ^ jJ I I (I) N r! N is in which Vi and Y 2, which are the same or different, are N or CH and R 1 is an alkyl group or a cycloalkyl group each optionally halogenated or (C 1 -C 4) alkoxy substituted and each; contains up to 6 carbon atoms or R 1 is phenyl or benzene; nzyl, both of which may be optionally substituted by one or more of the following substituents: halogen, alkyl or halo-alkyl each containing from 1 to 5 carbon atoms, alkoxy, or haloalkoxy each containing from 1 to 4 carbon atoms, nitro , cyano, hydroxy, alkylthio having 1 to 4 carbon atoms, or phenyl, halophenyl, phenoxy or vinyl, and wherein the alkyl portion of the benzyl is optionally substituted with alkyl containing from 1 to 4 carbon atoms, or with phenyl, and salts, metal complexes, ethers , which are alkyl, alkenyl, alkynyl, aryl or aral cool ethers, and esters which are alkanoyl, benzoyl or sulfonoyle esters, characterized in that either one or more of 30 Γ (a) 3-dihalo-propan-2-ol of the general formula: wherein χΐ and X2, which may be the same or different, are each halogen, and R 1 has the meaning previously defined, with imidazole or 1,2,4-triazole or a salt thereof, or 10 (b) translates a compound of general formula III *. CH0 I 2χ 0 R1 - C1 <1IX> 15 <fH2 N-Y1 wherein R 1 and Y 1 have the previously defined meanings, 20 with imidazole or 1,2,4-triazole or a salt thereof, or (c) reacting a ketone of the general formula IV: O 11 R 1 - (2 CH 2 N-Yl (IV) '' J where R 1 and yl have the previously defined meanings, with dimethyloxosulfonium methylide or dimethylsulfonium methylide, and then react the resulting epoxide with the general formula III with imidazole or 1,2,4-triazole or a salt thereof, and if desired then converts the compound of the general formula I into a salt, a metal complex, an ether or an ester thereof. 15 20 25 30 j 35