HU211595A9 - 1-[(2-fluorophenyl)(4-fluorophenyl)phenylmethyl]-1h-imidazole - Google Patents

Description

HU 211 595 A9

The present invention relates to 1 - [(2-fluorophenyl) - (4-fluorophenyl) phenylmethyl) -1H-imidazole and its pharmaceutically acceptable salts, as well as a process for its preparation and its use as an antifungal drug. and veterinary preparations.

It has been described more than 20 years ago and disclosed in ZA 68/5392 and ZA 69/0039 that certain ring-substituted N-tritylimidazoles of formula II are effective as plant pathogenic and animal pathogenic antifungal agents. Many such compounds have since been produced and tested for their antifungal activity. In 1972, K. H. Büchel, W. Draber, E. Regei and M. Plemple, Arzneim. Forsch. 22, 1260-1272 (1972) collected the physical and pharmacological data of 112 such compounds.

In addition, N-tritylimidazoles containing a halogen substituent in one of the above rings have been described as a fungicide in French patent application FR-A-1600990.

Despite the suitability of already known commercial fungicides, research in this field is still very intensive. New compounds (miconazole, econazole ...) and in particular bifonazole (1 - [(4-biphenyl) phenylmethyl] -1H-imidazole) have been introduced on the market to combat fungal infections, in particular species that are old. have already become resistant to compounds. These infections are a serious problem especially in large cities and hospitals.

However, the first formula of ZA 68/5392 and its equivalents includes all difluoro-substituted N-tritylimidazole (those that are substituted on one phenyl ring and those that are substituted on two different phenyl rings). however, none were actually produced. or investigated on this occasion. According to an article quoted by Arzneimittel in Forschung, none of the difluoro-substituted compounds was known as a fungicide in 1972.

To the best of our knowledge, 1- [bis (4-fluorophenyl) phenylmethyl] -1H-imidazole is the only N-tritylimidazole described which is difluoro substituted on various phenyl rings. This compound is mentioned in EP 165 777 but only for the prevention of estrogen dependent diseases, especially in breast cancer, and this therapeutic indication is unrelated to the indication of the present invention.

Some are dichloro- or chlorofluoro- N -tritylimidazole. which are disubstituted on different phenyl rings are known, but have been shown to have a very low fungal activity when tested in a few cases (see Arzneim. Forsch.). The quantitative structure effect relationship! attempts to investigate mono-, di-, and trisubstituted N-tritylimidazoles have failed to reveal structural factors that would have been responsible for the antifungal activity (see same article). Therefore, it cannot be predicted in advance how effective a particular disubstituted compound is unless it has been prepared and tested. Other unforeseen features.

such as the absorption property and / or the low toxicity may play an important role in the overall therapeutic effect. Finally, a novel compound may be surprisingly effective against certain species of fungi and therefore may have an advantage over known compounds in certain diseases.

In view of the state of the art, substituted N-trityl imidazoles, known as fungicides, are understood to have several selection inventions in the past. Patents have been granted for special compounds that are particularly useful even if a valid general claim to which these compounds belong has already existed. For example, 1 - [(2-chlorophenyl) - (2'-chlorophenyl) phenylmethyl] -1H-imidazole is patented alone in U.S. Patent 4,052,409, although the compound has been claimed, but is not described in South Africa Patent ZA 68/5392.

It is noted that the fungicidal activity of the difluoro-N-tritylimidazoles (III) substituted on the various phenyl rings has not been sufficiently investigated (neither known nor tested, only the trifluoro-substituted compound tested and found no effect). Therefore, the following new compounds were prepared and tested: 1 - [(2-fluorophenyl) - (3-fluorophenyl) phenylmethyl] -1H-imidazole (UR-4055), 1 - [(2-fluorophenyl) phenyl) - (4-fluorophenyl) phenylmethyl] -1H-imidazole (UR-4056), 1- [bis (3-fluorophenyl) phenylmethyl] -1H-imidazole (UR4057), 1- [(3-Fluoro-phenyl) - (4-fluoro-phenyl) -phenylmethyl] -1H-imidazole (UR-4058) and 1- [bis (4-fluorophenyl) -phenylmethyl] -1H- imidazole (UR-4059 referred to in EP 165 777 without providing identification data or manufacturing instructions). The examples of the invention detail the process for preparing the five compounds in good yield.

In preliminary tests, all five compounds showed fungicidal activity. Surprisingly, however, only one compound, 1 - [(2-fluorophenyl) - (4-fluorophenyl) phenylmethyl] -1H-imidazole (Formula I) or UR-4056, is the subject of the present invention. , exhibited very good activity against certain species, while exhibiting good tolerance (DL ₅₀ = 691 mg / kg in mouse), good lipolysis (hanging at P = 3.09 in a mixture of octanol and water) and good pharmacokinetics.

The surprisingly good fungicidal effect of UR 4056 can be better estimated by comparing it with bifonazole, a recently developed commercially available fungicide. 18-20. Examples show some comparative tests in which UR-4056 is somewhat more effective than bifonazole in many cases. Therefore, the invention also relates to pharmaceutical compositions for the treatment of fungal infections in humans and animals, characterized in that it contains an antifungal effective amount of 1 - [(2-fluorophenyl) - (4-fluorophenyl) phenylmethyl] -1 H-imidazole or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable inert excipient.

The pharmaceutically acceptable salt is 1- (2-fluoro-1)

A9 phenyl) - (4-fluorophenyl) phenylmethyl-1H-imidazole refers to those derived from physiologically acceptable inorganic and organic acids such as sulfuric acid, hydrogen halogen (hydrochloric acid). hydrobromic acid), sulfonic acid such as methanesulfonic acid, p-toluenesulfonic acid, phosphoric acid, mono-, di- and trihydroxycarboxylic acids such as acetic acid, maleic acid, fumaric acid, tartaric acid, lactic acid, citric acid, citric acid we get.

Pharmaceutically acceptable inert excipients include solid, semi-solid or liquid diluents, fillers and all types of formulation aids. Pharmaceutical compositions include tablets, pills, capsules, granules, solution, suspension, emulsion, suppository, paste, ointment, gel cream, lotion, powders and sprays, which are 1 - [(2-fluorophenyl) - (4-fluorine) -phenyl) -phenylmethyl] -1H-imidazole.

The invention further relates to the use of 1 - [(2-fluorophenyl) (4-fluorophenyl) phenylmethyl] -1H-imidazole or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of fungal infections in humans and animals.

The compound of the invention may be mixed with pharmaceutically acceptable carriers and administered orally to both humans and animals, tablets, capsules, coated tablets, syrups, solutions, powders, and the like. in the form of injection, rectal or vaginal intrauterine administration, in the form of ovules, vaginal tablets, ointments, creams, pessaries, lotions 8-500, preferably 30250 mg / kg body weight daily, and topically, creams, lotions. ointment, emulsion, solution, shampoo, powder, gel, etc. in the form of 0.1-5%. However, it may be necessary to deviate from these dosage ranges and, in particular, depending on the condition and weight of the patient to be treated and the nature and severity of the disease and the nature, route of administration, timing and interval of administration. it is sufficient, while in other cases the ceiling must be exceeded. The optimum dosage and route of administration will, of course, be determined by one of ordinary skill in the art. Example 21 illustrates the most preferred dosage forms.

According to the present invention, the compounds of formula (III), and in particular 1 - [(2-fluorophenyl) - (4-fluorophenyl) phenylmethyl] -1H-imidazole, can be prepared in three steps as described in Examples 1, 2 and Reaction Scheme 3.

J) Carbinol formation

Scheme 1

2) Chloride formation

Scheme 2

3) Production of the final product

Scheme 3

In Method A, Step 1, the difluorobenzophenone of formula (IV) is reacted with the phenylmagnesium bromide of formula (V). to give the carbinol of formula (VI).

This reaction may be carried out between 0 ° C and the reflux temperature of the mixture in an ethereal solvent such as diethyl ether or a mixture of an ethereal solvent and a hydrocarbon such as benzene or toluene. Unreacted starting materials can be separated by distillation of an aqueous suspension (100 ° C) and the resulting carbinol can be used in the next step without further purification.

Alternatively, the carbinol of formula (VI) may be prepared according to method B, i.e., monofluorobenzophenone of formula (VII) and fluorophenylmagnesium bromide of formula (VIII). Although the yield is slightly lower with this method, it is an advantage that the starting difluorobenzophenone is not commercially available or difficult to produce. The experimental conditions of this method are the same as those described in Method A.

In a second step, a carbinol of formula (VI) is heated with thionyl chloride in the presence or absence of a solvent to give the corresponding chloride of formula (IX). This compound can be isolated or identified or used in the next step as is.

In the final step, the intermediate of formula IX is reacted with the lithium salt of imidazole in a polar solvent such as acetonitrile at 0-40 ° C for 5 minutes to 3 hours to give the final product of formula III. The reaction starts immediately and does not require heating. According to the literature [Arzneim. Forsch., 1972, 22, 1260] imidazole alone reacts with structurally similar chlorides, but requires heating and longer periods. Thus, the process disclosed herein provides a clearer and faster route to the preparation of compounds of formula (III). Lithium imidazolate can be readily prepared. by reacting imidazole with a lithium base such as N-butyllithium or lithium hydroxide.

The following examples further illustrate the invention.

Example 1 [(2-Fluoro-phenyl) - (3-fluoro-phenyl) -phenyl] -carbinol

2.91 g (0.12 mol) of magnesium turnings are added to a 1 liter oven-dried flask together with 50 ml of anhydrous ether. A solution of 1-bromo-2-fluorobenzene (20.12 g, 0.115 mol) in anhydrous ether (50 ml) was added slowly with vigorous stirring at a rate that allowed gentle reflux. After the addition was complete, the reaction mixture was stirred at reflux for 1 hour and then cooled to 5-10 ° C. A solution of 2-fluorobenzophenone (20 g, 0.1 mol) in anhydrous benzene (50 ml) was added and the mixture heated to reflux for 6 hours. The mixture was cooled to room temperature and carefully added to a mixture of ice and 1N aqueous hydrochloric acid. After stirring for 30 minutes, the organic phase was separated, washed with 10% aqueous sodium bicarbonate and then with water. The solvents were removed by rotary evaporation. Water was added and the mixture was heated to 100 ° C to distill water containing unreacted starting materials (15 hours). The mixture was cooled to room temperature and the water was decanted. The resulting white solid, which is pure by thin layer analysis,

It is dried over phosphorus pentoxide A9 and used in the next step without further purification. For analysis, a sample was recrystallized from ether / petroleum ether to give a white crystalline solid.

Melting point: 108-110 ° C.

IR (KBr) y: 3584, 3470, 3059.1609, 1585.1481, 1445, 1434, 1348, 1270, 755, 699 ^cm-1 Analysis calculated for C ₁₉ H ₁₄ F ₂ O wherein:

Calculated: C, 77.01; H, 4.76; F, 12.82; Found: C, 77.00; H, 4.90; F, 12.40.

Example 2 [(2-Fluoro-phenyl) - (4-fluoro-phenyl) -phenyl] -carbinol The procedure described in Example 1 was followed but phenyl-magnesium bromide was reacted with 2,4'-difluorobenzophenone and the The title compound was obtained in 97% yield. Recrystallization gives an analytical sample.

Melting point: 86.4-86.8 'C.

IR (KBr) γ 3591, 3465, 3077, 1597, 1575, 1502, 1481, 1445, 1337, 1269, 1224, 835, 759 cm ^-1 Anal. ₉ H ₁₄ F ₂ O:

Calculated: C, 77.0 * 1; H, 4.76; F, 12.82; Found: C, 77.22; H, 4.28; F, 12.70.

Example 3 [Bis (3-fluorophenyl) phenyl] carbinol

Following the procedure of Example 1, 3-fluorophenylmagnesium bromide is reacted with 3-fluorobenzophenone to give the title compound in 97% yield. Recrystallization gives an analytical sample.

114-116 ° C.

IR (KBr) Y: 3572, 3459, 3061, 1585, 1481, 1435, 12332, 786, 755, 699 cm. Analysis for C ₁₉ H ₄ F ₂ O:

Calculated: C, 77.01; H, 4.76; F, 12.82; Found: C, 76.97; H, 5.25; F, 12.51.

Example 4 1- (3-Fluoro-phenyl) - (4-fluoro-phenyl) -phenyl] -carbinol The procedure of Example 1 was followed except that 4-fluoro-phenyl-magnesium bromide and 3-fluoro-benzophenone were used. The title compound was obtained in 90% yield. An analytical sample was prepared by recrystallization.

Melting point: 85-92 ° C.

IR (KBr) γ: 3580, 3445, 3057, 1607, 1597. 1585. 1500, 1479, 1435, 1230, 821.699 cm ^-1 Anal. ₉ H | _{By the} formula ₄ F ₂ O:

Calculated: C, 77.0 * 1; H, 4.76; F, 12.82; Found: C, 77.11; H, 5.01; F, 12.63.

Example 5 [Bis (4-fluorophenyl) phenyl] carbinol

Example 1, but using phenylmagnesium bromide and 4.4'-difluorobenzophenone. The title compound was obtained in 84% yield. An analytical sample is prepared by recrystallization.

Melting point: 90-93 ° C.

IR (KBr) γ: 3469.3058. 1599, 1503, 1234, 1158, 1010, 832, 699 cm ^-1

Analysis of C | According to the formula ₉ Hi ₄ F ₂ O:

Calculated: C, 77.01; H, 4.76; F, 12.82; Found: C, 77.11; H, 5.01; F, 12.63.

Example 6 [(2-Fluorophenyl) (3-fluorophenyl) phenyl] chloromethane 20 g. 12.82 g in 67.5 mmol of [(2-fluorophenyl) - (3-fluorophenyl) phenyl] carbinol (obtained in Example 1) cooled to 0 ° C with vigorous stirring 108 mmol of thionyl chloride was passed. After the reaction started (gas evolution), the remaining thionyl chloride was added all at once and the reaction mixture was heated under reflux for 4 hours. The volatiles were removed in vacuo and the remaining traces of thionyl chloride were removed twice by azeotropic evaporation with toluene. The resulting residue was dissolved in petroleum ether and precipitated by cooling to -20 ° C. The solid was filtered off and dried. The title compound was obtained as a slightly cream solid (18.1 g, 85%).

Melting point: 69.2-71.6 ° C.

IR (KBr) γ: 3110, 1638, 1618, 1512, 1475, 1300, 1258,

788, 770 cm ^-1

Analysis for C ₁₉ H | ₃ according to the formula C1F ₂ :

calculated:

C, 72.50. H, 4.16; Cl, 11.26; F, 12.07; Found:

C, 72.62; H, 4.04; Cl, 11.42; F, 11.90.

Example 7 [(2-Fluoro-phenyl) - (4-fluoro-phenyl) -phenyl] -chloromethane The procedure was the same as in the previous example, but the carbinol obtained in Example 2 was used and the title compound was 83%. production.

M.p. 65.2-65.7 C IR (KBr) δ: 3054, 1603, 1574, 1502, 1480, 1442, 1228,

1162, 838. 759 cm ¹

Analysis for C ₁₉ H ₁₃ ClF ₂ :

calculated:

C, 72.50; H, 4.16; Cl, 11.26; F, 12.07; Found:

C, 72.73; H, 4.36; Cl, 10.86; F, 11.98.

EXAMPLE 8 [Bis (3-f [(3'-phenyl) -phenyl] -chloromethane) The procedure of Example 6 was followed using the carbinol obtained in Example 3. The title compound was obtained in 93% yield.

Melting point: 70-73 ° C.

IR (KBr) γ 3080, 1621, 1598, 1495, 1450, 1250, 780, 750 cm ^-1

Analysis using the formula C ₉ H ₃ C ₃ F ₂ :

calculated:

C, 72.50; H, 4.16; Cl, 11.26; F, 12.07; Found:

C, 71.95. H, 4.26; Cl, 11.24; F, 11.83.

Example 9 [(3-Fluoro-phenyl) - (4-fluoro-phenyl) -phenyl] -chloromethane Example 6 but Example 4

A9 carbinol was used and the title compound was obtained in 80% yield.

Melting point: 59.8-61.8 ° C.

IR (KBr) γ: 3061, 1606, 1587, 1503, 1482, 1443, 1435,

1236, 1162, 780, 744, 697 ^cm-1

Analysis for C ₁₉ H ₁₃ ClF ₂ :

calculated:

C, 72.50; H, 4.16; Cl, 11.26; F, 12.07; Found:

C, 71.41; H, 3.96; Cl, 10.59; F, 11.96

Example 70 1Bis (4-Fluorophenyl) phenyl] -chloromethane

Example 6 was repeated using the carbinol of Example 5 to give the title compound in 71% yield.

Melting point: 45-47 ° C.

IR (KBr) γ 3080, 1660, 1610, 1515, 1235, 845, 570 ^cm-1

Analysis for C ₁₉ H ₁₃ ClF ₂ ;

calculated:

C, 72.50; H, 4.16; Cl, 11.26; F, 12.07; Found:

C, 72.52; H, 4.46; Cl, 10.76; F, 12.41.

Example 11

Lithium imidazolate

a) Imidazole and n-butyllithium

A solution of imidazole (1.56 g, 22.9 mmol) in cold tetrahydrofuran (100 mL) was cooled to -60 ° C with 14 mL,

A solution of 22.9 mmol of 1.6 M n-butyllithium in hexane was added. The mixture is slowly warmed to room temperature to give a white precipitate. The suspension was stirred for 1.5 hours, then cooled to 0 ° C and filtered. The resulting white solid was dried in vacuo over phosphorus pentoxide at 50 ° C for 18 hours to give 1.66 g (98%) of product. This material is hygroscopic and should therefore be stored in a desiccator for storage. production is apparently unaffected by the presence of moisture.

IR (KBr) γ: 3417, 3121, 3017, 2914, 2823, 2793, 2697,

2614, 2539, 1495, 1429, 1326, 1262, 1055, 936 ^cm-1

b) Imidazole and lithium hydroxide

A solution of 6.8 g (0.1 mole) of imidazole and 4.19 g (0.1 mole) of lithium hydroxide monohydrate in 50 ml of water was distilled on a rotary evaporator. Ethanol was added and the mixture was again concentrated twice to remove residual water. The residual white solid was dried in vacuo over 50 'Con of phosphorus pentoxide for 12 hours to give 7.83 g of product containing various amounts of water. As in the previous case, the presence of water in the compound does not affect the yield of the next step.

Example 72] -1 (2-Fluorophenyl) -3-fluorophenyl) phenylmethyl] -thiimidazole (UR-4055) g, 16.87 mmol [(2-Fluorophenyl) - ( To a solution of 3-fluorophenyl) phenyl] chloromethane (obtained in Example 6) in acetonitrile (15 mL) was added lithium imidazolate (1.37 g, 18.5 mmol) and the temperature rose slightly to 40 ° C. The mixture was stirred at room temperature for 2 hours and then added to cold water. The resulting solid was filtered, washed with water to neutral and dried. 5.61 g (96%) of a white solid are obtained. TLC analysis showed traces of carbinol, presumably already present in chloride. Recrystallization from acetonitrile gave an analytical sample.

Melting point: 145-148 ° C.

IR (KBr) γ. 3429, 3064, 1609, 1587, 1482, 1445, 1276, 1230, 1209, 1072.752 cm '

Analysis for C ₂₂ H ₁₆ F ₂ N ₂ ;

calculated:

C, 76.28; H, 4.66; N, 8.08; F, 10.97; Found:

C, 76.56; H, 4.69; N, 7.98; F, 10.35.

Example 13] - [(2-Fluoro-phenyl) - (4-fluoro-phenyl) -phenylmethyl] -1H-imidazole (UR-4056)

Example 12 was repeated using [(2-fluorophenyl) (4-fluorophenyl) phenyl] chloromethane, obtained according to Example 7, to give the title compound in 99% yield. Recrystallization from acetonitrile gave an analytical sample.

Melting point: 164-167 ° C.

IR (KBr) γ; 3118, 1601, 1574, 1504, 1481, 1443, 1225,

1165, 1075,831,819, 758 ^cm-1

Analysis using the formula C ₂₂ H _{1 6} F ₂ N ₂ :

calculated:

C, 76.28; H, 4.66; N, 8.06; F, 10.97; Found:

C, 76.06; H, 4.63; N, 8.02; F, 10.92.

Example 14

- [Bis-3-fluorophenyl) phenylmethyl] -1H-imidazole (UR-4057)

Example 12 was repeated using [bis (3-fluorophenyl) phenyl] chloromethane, obtained according to Example 8, to give the title product in 94% yield. Recrystallization from acetonitrile gave an analytical sample.

Melting point: 165-167 ° C.

IR (KBr) γ: 3067, 1607, 1586, 1480, 1431, 1273, 1229,

1209, 1073, 786, 750, 699 cm ^-1

Analysis using the formula C ₂₂ H ₁₆ F ₂ N ₂ :

calculated:

C, 76.28; H, 4.66; N, 8.08; F, 10.97; Found:

C, 76.84; H, 4.81; N, 8.09; F, 10.71.

Example 75 1- (3-Fluorophenyl) - (4-fluorophenyl) phenylmethyl] -1H-imidazole (UR-4058)

Example 12 is followed but Example 9

[(3-Fluoro-phenyl) - (4-fluoro-phenyl) -phenyl] -chloromethane was obtained in A9 to give the title compound in 100% yield. An analytical sample was prepared by recrystallization from acetonitrile.

138-141 ° C.

IR (KBr) γ 3063, 1610, 1600, 1586, 1500, 1480, 1441,

1233, 1207, 1161, 1070,900,815, 752, 697 cm ^-1 Analysis according to C ₂₂ H ₁₆ F ₂ N ₂ :

calculated:

C, 76.28; H, 4.66; N, 8.08; F, 10.97; 10 Results found:

C, 76.56; H, 4.92; N, 7.99; F, 10.81.

Example 16

-1Bis (4-fluorophenyl) phenylmethyl] -1H-imidalol (UR-4059)

Example 12 was repeated except that [bis (4-fluorophenyl) phenyl] chloromethane obtained in Example 10 was used. The title compound was obtained in 92% yield. Recrystallization from acetonitrile gave an analytical sample.

Melting point 135-138 ”C.

IR (KBr) γ: 3106. 3056. 3042. 1599, 1505, 1239, 1229,

1214. 1168, 1109, 1076. 824, 747.703 cm ^-1

Analysis for C

From the formula H _l6 F ₂ N ₂ :

calculated:

C, 76.28. H, 4.66; N, 8.08; F, 10.97; Found:

C, 76.28. H, 4.67. N% = 7.89, F% = 10.21.

Example 17

1 - [(2-Fluorophenyl) (4-fluorophenyl) phenylmethyl] -1H-imidazole (UR-4056)

Example 13 was repeated using lH-imidazole instead of lithium imidazolate to give the title compound in 71% yield after flash chromatography. The analytical data corresponds to Example 13.

Example 18

The fungicidal activity of 1 - [(2-fluorophenyl) - (4-fluorophenyl) phenylmethyl] -1-imidazole was demonstrated by its ability to inhibit the growth of various yeast and filamentous fungal species in vitro. The effect was recorded as the MIC value, which is the minimum amount of product required to completely inhibit the growth of the test organism in vitro. The test was carried out as follows: the ethanolic solution of the fungicide was diluted with DST agar (pH 6.5) or diluted with Emmon's Sabouraud dextrose agar and thus between 10 and 0.01 mcg / ml or 80 and 0.16 mcg / ml concentrations were obtained. The inoculum was standardized in the order of 1x10 cfu / ml and 10 ml of each organism was inoculated onto the agar surface. Incubation was then performed at 30 ° C for 3 days (DST). or 2 days (Emmon agar) for yeasts and 10 days for filamentous fungi. After incubation, zones of inhibition were measured and compared with the inoculated drug-free control to obtain an MIC.

The following table shows the MICs of UR-4056 and bifona30 zol for various organisms in DST and Emmon medium.

MIC (mc / ml) DST agar Emmon's Sabouraud dextrose agar UR-4056 bifonazole UR-4056 bifonazole C. albicans ATCC 10231 1 1 0.4 0.63 C. albicans ATCC 28516 0.5 2.5 0.04 0.63 C. guilliermon dii SQ 2210 1 > 10 0.16 5 C. tropicalis SQ 1647 1 > 10 0.63 10 C. guilliermon dii (clínica) 5 > 10 5 40 C. albicans serotype B 0.5 > 10 0.31 20 C. albicans serotype A 1 2.5 1.25 2.5 S. cerevisiae ATCC 9763 0.1 0.25 0.31 0.63 C. pseudotropicalis ATCC 28838 0,025 0.05 0.63 1.25 Rhodotorula rubra 0.1 0.05 0.08 0.04 C. parapsilosis (clínica) 0.5 > 10.00 0.08 20 T. glabrata (clínica) 0.05 0.05 0.31 0.16 T. mentagrophvtes ATCC 9972 0.25 1 1.25 5 T. meniagrophytes ATCC 9129 0.05 2.5 0.31 2.5 Aspergillus niger 0.25 0.1 2.50 2.5 Aspergillus flavus 1 > 10 2.5 80 Aspergillus fumigatus (1) 0.5 0.1 0.63 0.31 Aspergillus fumigatus (2) 0.5 1 1.25 1.25

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MIC (mc / ml) DST agar Emmon's Sabouraud dextrose agar UR-4056 bifonazole UR-4056 bifonazole Microsporum gypseum 0.5 0.1 1.25 0.63 Microsporum gypseum (-) 0.1 2.5 0.63 5 Microsporum audouini ATCC 9079 0.05 0.05 0.63 5 Microsporum canis (clínica) 0,025 0,025 0.63 2.5 T. mentagrophytes (clínica) (1) 0.1 0.5 1.25 5 T. mentagrophytes (clínica) (2) > 10,000 > 10,000 40 80 T. mentagrophytes (clínica) (3) 0.25 1 0.16 5 T. mentagrophytes (clínica) (4) 0.1 0.5 1.25 5 T. mentagrophytes (clínica) (5) 0.1 1 1.25 5

EXAMPLE 19 Concentrations of 7) and thus 8 to 0.062 mcg / ml

Five different isolates of shake cultures were obtained. The vaccine size was 10 cm ³ cfu / ml. The percentage inhibition of growth was determined by spectrophotometry at 24 hours and 48 hours after incubation at 28 ° C. The 20 was stored (450 nm). A solution of 1 - [(2-fluorophenyl) - (4-fluorine) was prepared as follows. .

C. parapsilosis

Fungicidal concentration in mcg / ml growth 24 hours 48 hours UR-4056 bifonazole UR-4056 bifonazole 0.062 0.4 99.85 2.42 100 0,125 0.6 80.14 0.72 100 0.25 . 0.2 61.05 0.68 93,82 0.5 0.2 39.85 0.5 78.23 1 0:33 25.59 0.28 68.09 2 0.06 16.01 0.24 37.14 4 0.27 9.02 0.24 19.94 ⁸ 0.6 9 0.2 19

C. guilliermondii

Fungicidal concentration in mcg / ml growth 24 hours 48 hours UR-4056 bifonazole UR-4056 bifonazole 0.062 21.73 100 76.55 100 0,125 15.95 92.18 49.38 100 0.25 7.96 62.32 23.05 96.67 0.5 2.82 39.79 15.46 88.59 1 1.03 29.89 6.66 85.9 2 0 12.82 1.84 40.32 4 0 7.57 0.08 20.03 8 0 7.4 0.06 18.48

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C. albicans ATCC 10231

Fungicidal concentration in mcg / ml growth 24 hours 48 hours UR-4056 bifonazole UR-4056 bifonazole 0.062 37.43 98.73 75.41 99.14 0,125 26.01 97.85 67.19 99.12 0.25 23,46 83.55 59.01 94.25 0.5 21.03 46.15 57 78.31 1 14.41 23.32 44.33 49.26 2 5.42 4.74 27.55 19.66 4 1.84 2.68 12.38 16.82 8 1.15 2.13 12.79 12.73

C. tropicalis

Fungicidal concentration in mcg / ml growth 24 hours 48 hours UR-4056 bifonazole UR-4056 bifonazole 0.062 10:29 96.28 17.91 100 0125 3.51 94.11 12:55 100 0:25 2.61 85.52 12.49 95.3 0.5 2.1 62.73 4:43 79.5 1 1.52 49.02 3.97 75 _ 2 0.43 10.85 0.77 69.02 4 0.45 3.07 0.09 17.33 8 0:38 1.82 0 6

T. glabrata

Fungicidal concentration in mcg / ml growth 24 hours 48 hours UR-4056 bifonazole UR-4056 bifonazole 0.062 69.09 5.69 99.39 92.36 0125 28.05 2.85 99.39 83.29 0.25 15.58 2.08 99 21,23 0.5 10.05 1.79 99 6.15 1 3.34 1.08 94.37 4.2 2 2.83 0.68 19.82 2.28 4 1.16 0:42 14.85 3.93 | - 8 0.32 0.6 4:12 3

HU 211 595 A9

Example 20

The fungicidal activity of 1 - [(2-fluorophenyl) (4-fluorophenyl) phenylmethyl] -1H-imidazole and bifonazole was determined by dilutions of a Sabouraud gentamicin fermentation broth series using microplates. The fungicide was diluted in 50% ethanol to give concentrations between 40 and 0.015 mcg / ml. The vaccine was 10 ⁶ cfu / ml for yeast and 10 ⁷ cfu / ml for dermatophytes. Incubation was performed at 37 ° C for 2 days in yeast and at 29 ° C for 7 days in dermatophytes. MIC values were determined as in Example 18. The MIC distributions for the 9 organisms are shown in the following tables.

Table 1

MIC distribution (number of C. albicans strains = 50)

Fungicide > 40 40 20 10 5 2.5 1.2 0.6 0.3 0.15 0.078 0,038 <0.038 UR-4056 - - - 5 31 11 2 - 1 - - - - bifonazole 4 - 1 11 28 6 - - - - - - -

Table 2

MIC distribution (number of C. tropicalis strains = 30)

Fungicide > 40 40 20 10 5 2.5 1.2 0.6 0.3 0.15 0.078 0,038 <0.038 UR-4056 - - - 8 13 4 3 1 - - 1 - - bifonazole 27 - - 1 2 - - - - - - - -

Table 3

MIC distribution (number of C. parapsilosis strains 10 = UR-4056/14 = Bifonazole)

i Fungicide > 40 40 20 10 5 2.5 1.2 0.6 0.3 0.15 0.078 0,038 <0.038 j UR-4056 - - - 2 - - 1 2 2 1 - - 2 ! bifonazole _1 10 - - 2 _ - - 1 - - - -

Table 4

MIC distribution (number of C. guilliermondii strains = 5)

- Fungicide > 40 40 20 10 5 2.5 1.2 0.6 0.3 0.15 0.078 0,038 <0.038 UR-4056 - - - - - - 2 2 1 - - - - bifonazole 5 - - - - - - - - - - - -

Table 5

MIC distribution (number of C. krusei strains = 5)

Fungicide > 40 40 20 10 5 2.5 1.2 0.6 0.3 0.15 0.078 0,038 <0.038 UR-4056 1 - - - - 2 1 - 1 - - - - bifonazole 3 - - 1 - 1 - - - - - - -

Table 6

MIC distribution (number of T. glabrata strains 10 = UR-4056/15 = Bifonazole)

Fungicide > 40 40 20 10 5 2.5 1.2 0.6 0.3 0.15 0.078 0,038 <0.038 UR-4056 1 - 1 4 2 1 - 1 - - - - - bifonazole 2 - - 3 5 3 - 1 - 1 - - -

Table 7

MIC distribution (number of T. mentagrohytes strains = 17)

Fungicide > 40 40 20 10 5 2.5 1.2 0.6 0.3 0.15 0.078 0,038 <0.038 UR-4056 - - - - - - 3 11 2 1 - - - bifonazole - - - - - 5 10 1 - - - 1

HU 211 595 A9

Table 8

MIC distribution (number of M. canis strains = 13)

Fungicide > 40 40 20 10 5 2.5 1.2 0.6 0.3 0.15 0.078 0,038 <0.038 UR-4056 - - - - - 4 5 - 4 - - - - bifonazole - - - - 5 4 2 - - - 1 - 1

Table 9

MIC distribution (number of T. rubrum strains = 6)

Fungicide > 40 40 20 10 5 2.5 1.2 0.6 0.3 0.15 0.078 0,038 <0.038 UR-4056 - - - - - 1 1 - - 4 - - - bifonazole - - - - 1 - 1 1 1 - - - 2

Example 21 4. Skin spray 1. Gynecological tablet UR-4056 1g UR-4056 500 mg Benzyl alcohol 5g Citric acid 140 mg 20 Hydroxypropyl cellulose 10g Sodium citrate 195 mg isopropanol 44g Lactose 314 mg Builder 12/114 (40:60) 40g Microcrystalline cellulose 240 mg Polyethylene glycol sorbitan oleate 4 mg Magnesium stearate 35 mg 25 PATENT CLAIMS Crosslinked polyvinylpyrrolidinone 85 mg

2. Gynecological cream

UR-4056 2g Sorbitan fatty acid ester ² g 30 Polyoxyethylene sorbitan fatty acid ester 1.5 g Artificial spermaceti 3g Cetyl stearyl alcohol 3.5 g Isopropyl myristate 13.5 g Benzyl alcohol ¹ g 35 Monosodium citrate 0.03 g Cleaned water 73.47 g 3. Skin cream UR-4056 1g 40 Dimethylacetamide 2g White petrolatum 25g Stearyl alcohol 22g Propylene glycol 12g Sodium laureth sulfate L5 g 45 methylparaben 0.3 g Cleaned water 32.6 g

Claims (4)

1. 1 - [(2-Fluoro-phenyl) - (4-fluoro-phenyl) -phenylmethyl] -1H-imidazole or a pharmaceutically acceptable salt thereof. 2. A process for the preparation of 1 - [(2-fluorophenyl) - (4-fluorophenyl) phenylmethyl] -1H-imidazole or a pharmaceutically acceptable salt thereof, characterized in that [(2-fluorophenyl) -4- fluorophenyl) phenyl] chloromethane is reacted with imidazole or lithium imidazolate in a polar inert solvent such as acetonitrile at a temperature between 0 ° C and the reflux temperature of the solvent for 5 minutes to 3 hours. A pharmaceutical composition for the treatment of fungal infections in humans and animals, characterized in that the fungicidal amount is 1 - [(2-fluorophenyl) - (4-fluorophenyl) phenylmethyl] -1H-imidazole or a pharmaceutically acceptable salt thereof. containing a pharmaceutically acceptable inert excipient. Use of 1 - [(2-fluorophenyl) (4-fluorophenyl) phenylmethyl] -1H-imidazole or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of fungal infections in humans or animals. HU 211 595 A9 lnt.Cl. ⁶ : C 07 D 233/62