Triazole derivatives useful in therapy

The present invention relates to new triazole compounds, a pharmaceutical agent, the use of triazole compounds, a process for their preparation and new intermediates. Triazole compounds are useful in therapy, especially in the treatment of fungal infections in humans and other mammals.

A large number of antifungal triazole compounds are known. For example, European Patent Application No. 0440372, Example 7, discloses (2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoro-4-pyrimidinyl) -1 - (1H-1,2 , 4-triazol-1-yl) butan-2-ol (also known as voriconazole), showing particularly good activity against the clinically important Aspergillus spp. Fungi. However, this compound has poor solubility in aqueous environments, making it necessary to use complexing agents to obtain satisfactory aqueous preparations such as intravenous injections. European Patent Application No. 0440372 suggests co-formulation with cyclodextrin derivatives to improve solubility, however it is always advantageous to use as few ingredients as possible in the formulation to minimize the possibility of side effects in patients.

187 237

British Patent Application No. 2128193 discloses the use of phosphoric acid esters for use on plants as fungicides and insecticides.

In an article by Maurin et al., Int. J. Pharm, 1993, 94 (1-3), 11-14, α- (2,4-difluorophenyl) -a - [(1- (2- (3-pyridyl) bismesylate is disclosed ) phenylethenyl)] -1H-1,2,4-tri <o: olo-1-ethanol and is reported to be an antifungal agent with good solubility.

Other triazole antifungal agents are known from European Patent Application No. 0576201 and International Patent Application Publication No. WO 97/01552.

European Patent Application No. 0413674 discloses the production of prodrugs of therapeutically acting glycosidase inhibitors by phosphorylation of a free hydroxyl group in a molecule. However, phosphorylation of a tertiary hydroxyl group has not been described.

It has now been found that triazole antifungal compounds of the tertiary hydroxyl group type, including (2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoro-4-pyrimidinyl) -1- (1H- 1,2,4-triazol-1-yl) butan-2-ol, can be converted into prodrugs with significantly increased solubility, readily convertible in vivo to release the moiety having the desired activity.

The invention therefore relates to new triazole compounds of general formula I

R'-OP (O) (OH) 2

In which R¹ means a group of formula Ia

<img file="PL187237B1_D0001.tif" />

Ia wherein R2 is phenyl substituted by one or more halogen; R³is hydrogen or CH3; R³a is hydrogen and R is⁴ is a 5- or 6-membered nitrogen-containing heterocyclic ring optionally substituted by one or more substituents selected from halogen, -CH = CH- (C6H4) -OCH2CF2CHF2 and cyanophenyl; and their pharmaceutically acceptable salts.

Preferred triazole compounds are compounds of general formula I in which R2 is 2,4-difluorophenyl and R³ is hydrogen or methyl.

Preferred triazole compounds are compounds of the general formula I in which R4 is triazolyl, pyrimidinyl or thiazolyl.

Particularly preferred triazole compounds of the invention include 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) -2-propyl dihydrogen phosphate or (2R, 3S) dihydrogen phosphate -2- (2,4-difluorophenyl) -3- (5-fluoro-4-pyrimidinyl) -1- (1H-1,2,4-triazol-1-yl) -2-butyl; and their pharmaceutically acceptable salts.

Preferred specific R1 groups may be:

(and-

<img file="PL187237B1_D0002.tif" />

187 237 (b)

<img file="PL187237B1_D0003.tif" />

(C)

<img file="PL187237B1_D0004.tif" />

(D)

<img file="PL187237B1_D0005.tif" />

(E)

<img file="PL187237B1_D0006.tif" />

Triazole antifungal compounds corresponding to the above groups (a) - (e) are:

(a) D-0870 (developed by Zeneca, see also example 19 in European Patent Application 0472392);

(b) fluconazole (sold by Pfizer, see also British Patent Application 2099818);

(c) the compound of Example 7 of European Patent Application 0440372, also known as voriconazole;

(d) the compound of Example 8 of this patent application; and (e) ER-30346 (see Drugs of the Future, 1996, 21 (1): 20-24, Tetrahedron Letters, vol. 37, 45, pp. 8117-8120, 1996 and European Patent Application No. 0667346, example 88) .

The compounds of the invention differ from the known compounds because a tertiary hydroxyl group in a triazole antifungal compound has never before been used to form a functional group.

187 237

Mention may be made of such pharmaceutically acceptable salts as alkali metal salts and phosphate moieties, e.g. disodium or dipotassium salts, as well as salts with an amino counterion, e.g. salts of ethylenediamine, glycine or choline.

The invention also relates to a pharmaceutical composition comprising the active substance and a pharmaceutically acceptable excipient, diluent or carrier, the feature of which as active substance comprises the above defined compound of general formula I or a pharmaceutically acceptable salt thereof.

In addition, the invention relates to the use of the above-defined new triazole compounds of general formula I, and pharmaceutically acceptable salts thereof, as a pharmaceutical.

The invention also relates to the use of the above-defined triazole compounds of the general formula I and their pharmaceutically acceptable salts, for the manufacture of a medicament intended for use in the treatment or prevention of fungal infections.

The invention further relates to a process for the preparation of the above-defined compound of general formula I, or a pharmaceutically acceptable salt thereof, which consists in that ia) a compound of formula II

Roh II in which R¹ has the meaning given above, it is reacted with a phosphorylating agent of formula III

RaRbN-P (ORc) (OR^d) III in which R^and and R^d they are irreversible to you₆aahill, phenyl or substituted phenyl, albb&gt; together with the nitrogen to which they are attached may be a ring such as ρΐεη morpholine ring; and Rc and R^d are hydroxyl protecting groups, preferably benzyl optionally substituted with one or more halogen atoms to form a phosphite of formula IV

R1-OP (ORc) (ORd) IV in which R¹, Rc and Rd are as defined above; or ib) a compound of formula II r'oh II in which R1 is as defined above, is reacted with PCh to give a compound of formula VI

R 1 -O-PCl₂ VI in which R1 is as defined above, which is then reacted with a compound of formula

R1OP (O) (ORc) (ORd)

ROH and / or RdOH in which Rc and R^d have the meanings given above to give the phosphite of formula IV;

and then ii) the obtained compound of formula IV is reacted with an oxidizing agent to form a compound of formula V

187 237 in which R¹ has the above meaning, and R^c and R^d are hydroxyl protecting groups, preferably benzyl optionally substituted with one or more halogen atoms;

iii) removing the hydroxyl protecting groups from the compound of formula V to give a compound of general formula I; and iv) if necessary or necessary, the resulting compound is converted into a pharmaceutically acceptable salt or vice versa.

The invention also relates to new intermediates of the general formula V R'-OP (O) (ORc) (OR^d) V wherein R1 is a group of formula Ia

<img file="PL187237B1_D0007.tif" />

in which R² is phenyl substituted with one or more halogen; R³ is hydrogen or CH3; R^3a is hydrogen, R⁴ is a 5- or 6-membered nitrogen-containing heterocyclic ring optionally substituted with one or more substituents selected from halogen, CH = CH- (C6H4) -OCH2CF2CHF2 and cyanophenyl; and Rc and Rd, hydroxyl protecting groups, are independently benzyl optionally substituted by one or more halogen.

According to variant ia), the phosphorylation reaction can be carried out using a solvent which does not adversely affect the reaction, e.g. methylene chloride, in the presence of a mild acid, e.g. tetrazole, 5-methyltetrazole or pyridinium hydrobromide, and optionally 4-dimethylaminopyridine, at room temperature or higher.

The obtained phosphite compound of formula IV is then reacted with an oxidizing agent, e.g., an peracid, such as 3-chloroperbenzoic acid or H2O2, to give a compound of formula V. This reaction can be carried out using a solvent that does not adversely affect the reaction, e.g. methylene chloride or ethyl acetate below room temperature, e.g. from 0 ° C to -20 ° C.

By cleaving the hydroxyl protecting groups on the compound of formula V, the above compound of formula I is prepared.

Alternatively, the phosphites of formula IV can be prepared according to the method defined in ib).

Reaction of the compound of formula II with PCl₃ in the presence of a base, it may be carried out using a solvent which does not adversely affect the reaction, e.g. methylene chloride or ethyl acetate, at a temperature from -20 ° C to 20 ° C, e.g. at 0 ° C. Suitable bases are pyridine and N-methylimidazole.

The resulting compound of formula VI is then reacted with a compound of formula RcOH and / or R^dOH, to give the above compound of formula IV. This reaction is carried out without isolating the compound of formula VI at about room temperature.

The hydroxyl protecting group Rc and R^d they can be 2,6-dichlorobenzyl or 2-chloro-6-fluorobenzyl. Benzyl groups can be removed by catalytic hydrogenation, e.g. over Pearlman's catalyst or using palladium on carbon, or using bromotrimethylsilane.

In the case of step iii) in the presence of sodium acetate or sodium hydroxide, the disodium salt can be prepared directly.

Compounds of formulas II and III are either known or can be prepared by known methods.

187 237

It will be apparent to those skilled in the art that sensitive groups may require protection and deprotection during the synthesis of compounds of the invention. This can be accomplished using known methods, e.g. those described in the "Protective Groups in Organic Synthesis" by TW Greene and P. G M. Wuts, John Wiley and Sons Inc, 1991.

The compounds of the invention are useful because they exhibit pharmacological activity in living organisms, including humans. In particular, these compounds are useful in the treatment or prevention of fungal infections. For example, they find use in the topical treatment of fungal infections in humans caused, among others, by Candida, Trichophyton, Microsporum or Epidermophyton species, or mucosal infections caused by Candida albicans (e.g. thrush and vaginal candidiasis). They may also be useful in the treatment of systemic fungal infections caused e.g. by Candida (e.g. Candida albicans), Cryptococcus neoformans, Aspergillus flavus, Aspergillis fumigatus, Coccidioides, Paracoccidiodes, Histoplasma or Blastomyces.

In vitro evaluation of the antifungal activity of the compounds of the invention can be carried out by determining the minimum inhibitory concentration (mic), i.e. the concentration of the test compound in the appropriate medium at which no growth of the given microorganism occurs. In practice, a series of agar plates, each containing the test compound at a given concentration, are inoculated with a standard culture, e.g. Candida albicans, after which each plate is incubated for 48 hours at 37 ° C. The plates are then examined for the presence or absence of fungal growth and the appropriate mic values ​​determined. Other microorganisms that can be tested in these tests are Aspergillus fumigatus, Trichophyton spp., Microsporum spp., Epidermophyton floccosum, Coccidioides immitis and Torulopsis glabrata.

Some compounds of the invention, although active in vivo, may not show activity in these in vitro tests.

In vivo evaluation of compounds of the invention can be carried out using a series of doses administered intraperitoneally or intravenously to mice infected with e.g. Candida albicans or Aspergillus fumigatus. Activity is assessed by survival in a given group of mice after death of the untreated group. The dose level at which the compound provides 50% protection against the lethal effect of the infection is determined (PD_Sabout). In the case of the Aspergillus spp. Infection model, the number of mice cured of infection after a given dose allows further evaluation of activity.

When used in humans, the compounds of the invention may be administered alone, but are generally administered in a mixture with pharmaceutically acceptable carriers selected according to the intended route of administration and in accordance with standard pharmaceutical practice. For example, they can be administered orally in the form of tablets containing excipients such as starch or lactose, or in capsules or knobs, alone or in a mixture with excipients, or in the form of elixirs; solutions or suspensions containing flavoring or coloring matter. They can also be injected parenterally, e.g. intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used as an aqueous solution that may contain other substances, e.g. enough salt or glucose to make the solution isotonic with blood.

For oral or parenteral administration to human patients, the daily dose level of the compounds of the invention will be 0.01-20 mg / kg (in single or divided dose) when administered orally or parenterally. Thus, tablets or capsules with these compounds will contain from 5 mg to 0.5 g of active substance and will be administered one, two or more at a time, as needed. In any case, your doctor will determine the specific dose that is most appropriate for you and will vary depending on your age, weight and response. The above dosages are exemplary of the average case, however, there may of course be individual cases in which smaller or larger doses will be needed, which are within the scope of the invention.

Alternatively, the compounds of the invention may be administered in the form of a suppository or pessary, or may be applied topically in the form of a lotion, solution, cream (e.g. containing an aqueous emulsion of polyethylene glycols or liquid paraffin), or they may be

187 237 apply, at a concentration of 1 - 10%, to the ointment containing white wax or soft white paraffin and, if necessary, stabilizers and preservatives.

Aqueous formulations for intravenous administration are particularly preferred.

Example 1

2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) -2-propyl dihydrogen phosphate 2- (2,4-difluo.phenyl) -1, 3-bis (1H-1,2,4-triazol-1-yl) -2-propyl

Method A.

<img file="PL187237B1_D0008.tif" />

<img file="PL187237B1_D0009.tif" />

Nitrogen in the atmosphere , a solution of 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol (also known as fluconazole, 10.0 g , 32.6 mmol), 1H-tetrazole (6.85 g, 97.8 mmol) and dibenzyloxy (diisopropylamido) phosphorus (22.55 g, 65.2 mmol) in methylene chloride (10θ mL) was stirred at room temperature for 2 hours. The mixture was then cooled to 0 ° C and a solution of 3-chloroperbenzoic acid (13.5 g, 50-55% w / w, 39.1 mmol) in methylene chloride (50 mL) was added while maintaining the temperature at 0 ° C. The resulting mixture was allowed to warm to room temperature for 1 hour and then washed with aqueous sodium metabisulfite and sodium bicarbonate solutions. After drying over magnesium sulfate, the solvent was removed and replaced with methyl isobutyl ketone (37 mL) and methyl t-butyl ether (74 mL). After granulation at -10 ° C for 1 hour, the product was filtered off and washed with ice-cooled methyl isobutyl ketone and methyl t-butyl ether (1: 3, 15 ml), and then dried under vacuum at 50 ° C for 18 hours, in to give the title compound (16.05 g, 87%). Mp = 93 ° C.

Found: C, 57.12; H, 4.46; N, 14.85. Calcd for C27H25F2N-O4P: C, 57.24; E, 4.46; N, 14.84%. m / z 567 (MH +).

'H NMR (300 MHz, CDCla) δ = 4.90 (d, 2H), 4.95 (d, 2H), 5.05 (d, 2H), 5.19 (d, 2H), 6.58 -6.73 (m, 2H), 6.88-6.95 (m, 1H), 7.20-7.30 (m, 4H), 7.32-7.38 (m, 6H), 7 , 80 (s, 2H), 8.36 (s, 2H).

Method B

<img file="PL187237B1_D0010.tif" />

While stirring, 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-triazol-1-yl) propan-2-ol (also known as ethyl acetate) was added to ethyl acetate (1530 mL). fluconazole, 306 g, 1.00 mole) and pyridine (237.3 g, 3.00 mole), and then it was cooled to 0 ° C. Phosphorus trichloride (137.4 g, 1.00 mol) was added dropwise to the reaction mixture kept at 0-5 ° C,

187 237 and then the reaction mixture was allowed to warm to 15 ° C over 30 minutes. Then, benzyl alcohol (216 g, 2.00 mol) was added over 30 minutes at 15-20 ° C. After a further 30 minutes, hydrogen peroxide (27.5% w / w in water, 373 g) was added to this mixture, maintained at 15-20 ° C. After 30 minutes, the aqueous phase was removed and the organic phase was washed with aqueous sodium metabisulphite solution and then diluted with hydrochloric acid and water. The solvent was removed under reduced pressure and replaced with mesyl isobutyl ketone (850 ml) and t-butyl methyl ether (1132 ml). After granulation at 20 ° C for 1 hour and at 0 ° C for 1 hour, the product is filtered off and washed with ice-cooled t-butyl methyl ether (2 x 220 ml), then dried under vacuum at 50 ° C for 18 hours and the title compound was obtained (358 g, 63%). The melting point and spectroscopic data were identical to the product from method A.

(b) 2- (2,4-difluorophenyl) -1,3-bis (1H-1,2,4-tnazol-1-yl) -2-propyl dihydrogen phosphate

<img file="PL187237B1_D0011.tif" />

<img file="PL187237B1_D0012.tif" />

A suspension of the compound of step (a) (9.80 g, 17.3 mmol) and sodium hydroxide (1.38 g, 34.6 mmol) in water (26 ml) was hydrogenated using 5% palladium on carbon as a catalyst ( 50% dispersion, 1.0 g), at room temperature and 414 kPa (60 lb / caP), for 20 hours. The solution was filtered through a bed of ceUtu (trade mark) and washed with water (5 ml). Toluene was separated and the aqueous phase was cooled to 0 ° C, followed by the addition of sulfuric acid (1.70 g, 17.3 mmol). The resulting suspension was granulated at 0 ° C for 1 hour, then filtered, washed with water (2x5 mL) and dried under vacuum at 50 ° C to give the title compound (5.80 g, 87%). Mp = 223-224 ° C.

Found: C, 40.28; H, 3.39; N, 21.63. Calcd for C13H13F2N6O4P: C, 40.43; H, 3.39; N, 21.76%.

'H NMR (300 MHz, DMSO) δ = 5.07 (d, 2H) 5.24 (d, 2H), 6.77-6.83 (m, 1H), 7.00-7.18 (m , 2H), 7.75 (s, 2H), 8.53 (s, 2H).

Example 2

2- (2,4-difluorophenyl) -1,3-bis- (1H-1,2,4-triazol-1-yl) -2-propyl disodium salt

<img file="PL187237B1_D0013.tif" />

F

F

187 237

A solution of the compound of Example 1 (a) (10.0 g, 17.7 mmol) and sodium acetate (2.90 g, 35.3 mmol) in ethanol (160 mL) and water (20 mL) was hydrogenated over Pearlman's catalyst (1.00 g) at room temperature at 345 kPa (50 lb / caP) for 16 hours. The solution was filtered through a Celite® bed, and the solvents removed under reduced pressure to give a thick syrup. This syrup was dissolved in ethanol (100 mL) by sonication and heated to reflux. The resulting solution was allowed to cool slowly and then granulated at room temperature for 1 hour. The product was filtered off, washed with ethanol (10 ml) and dried under vacuum at 50 ° C to give the title compound (4.48 g, 59%). Mp - 160-162 ° C.

'H NMR (300 MHz, D20) δ = 5.01 (d, 2H), 5.40 (d, 2H), 6.60 (m, 1H), 6.79 (m, 1H), 7.11 (m, 1H), 7.63 (s, 2H), 8.68 (s, 2H).

Example 3

(2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoro-4-pyrimidinyl) -1- (1H-1,2,4-triazol-1-yl) -2-butyl dihydrogen phosphate (a) Dibenzyl- (2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoro-4-pyrimidinyl) -1- (1H-1,2,4-triazol-1-yl) phosphate ) -2-butyl

<img file="PL187237B1_D0014.tif" />

<img file="PL187237B1_D0015.tif" />

Under nitrogen (2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoro-4-pyrimidinyl) -1- (1H-1,2,4-triazol-1-yl) - butan-2-ol (compound of example 7, EP 0440372, also known as voriconazole, 17.0 g, 48.7 mmol), 4-dimethylaminopyridine (10.2 g, 83.5 mmol), 1H-tetrazole (10.2 g, 146.5 mmol) and dibenzyloxy (diisopropylamido) phosphorus (33.6 g, 97.4 mmol) in methylene chloride (100 mL) was stirred at reflux for 2 hours, and then at room temperature for 16 hours. The reaction mixture was washed with hydrochloric acid followed by sodium bicarbonate, dried over magnesium sulfate and concentrated. The crude phosphite was purified by column chromatography (silica gel, 300 g, gradient elution from 3: 1 to 1: 1 hexane / ethyl acetate) to give a pale yellow oil. This oil was dissolved in methylene chloride (100 mL) and cooled to -10 ° C, followed by the addition of a solution of 3-chloroperbenzoic acid (14.8 g, 57% w / w, 48.9 mmol) in methylene chloride (100 ml), maintaining the temperature

187 237 below 0 ° C. The resulting mixture was allowed to warm to room temperature over 10 minutes and then washed with aqueous sodium metabisulfite solution and sodium bicarbonate. After drying over magnesium sulfate and concentration, the crude product was purified by column chromatography (silica gel, 300 g, eluted with ethyl acetate) to give the title compound as a thick syrup (17.86 g, 60%).

m / z 610 (MH +).

NMR (300 MHz, CDC () δ = 1.39 (d, 3H), 4.41 (q, 1H), 4.79 (d, 2H), 4.96 (d 2H), 5.34 (d , 1H), 5.40 (d, 1H), 6.59-6.66 (m, 1H), 6.72-6.82 (m, 1H), 7.02-7.18 (m, 3H ), 7.273, 37 (m, 8H), 7.79 (s, 1H), 8.46 (d, 1H), 8.52 (s, 1H), 8.90 (d, 1H).

(b) (2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoro-4-pyrimidinyl) -1- (1H-1,2,4-triazol-1-yl) - dihydrogen phosphate 2-butylmercaptan

<img file="PL187237B1_D0016.tif" />

A solution of the compound of step (a) (5.0 g, 8.83 mmol) in methanol (100 mL) was hydrogenated over Pearlman's catalyst (1.0 g) at room temperature at 60 psi (60 lb / in)²) for 16 hours. The solution was filtered through a bed of celite (trade mark) and concentrated. The crude product was redissolved in hot methanol (20 mL) and granulated at 0 ° C for 1 hour. After filtration and washing with methanol (5 ml), the product was dried under vacuum at 50 ° C to give the title compound (1.72 g, 49%). Mp = 145-146 ° C.

Ή NMR (300 MHz, DMSO) δ = 1.31 (d, 3H), 4.01 (q, 1H), 5.31 (d, 1H), 5.42 (d, 1H), 6.90- 6.97 (m, 1H), 7.04-7.14 (m, 1H), 7.20-7.30 (m, 1H), 7.95 (s, 1H), 8.70 (d, 1H), 8.73 (s, 1H), 8.89 (d, 1H).

Example 4

(2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoro-4-pyrimidinyl) -1- (1H-1,2,4-triazol-1-yl) -2-butyl dihydrogen phosphate (alternative recipe) (a) Bis (2-chloro-6-fluorobenzyl) phosphate - (2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoro-4-pyrimidinyl) -1 - ( 1H-1,2,4-triazol-1-yl) -2-butyl

<img file="PL187237B1_D0017.tif" />

F

(2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoiO-4-pyrimidinyl) -1- (1H-1,2,4-triazol-1-yl) butan-2- solution olu (the compound of Example 7, EP 0440372, also known as voriconazole,

10.0 g, 28.6 mmol) and 1-methylimidazole (9.40 g, 114 mmol) in methylene chloride (30 mL) was cooled to 0 ° C, and then, while maintaining the temperature below 10 ° C, a trichloride solution was added

187 237 phosphorus (4.73 g, 34.4 mmol) in methylene chloride (20 mL). After 15 minutes at 0-10 ° C, a solution of 2-chloro-6-fluorobfzyzyl alcohol (12.0 g, 74.4 mmol) in methylene chloride (40 ml) was added. After 30 minutes while cooling to a temperature below 20 ° C, hydrogen peroxide (25 ml, 30% solution in water) was added dropwise to this mixture. Then after 1 hour, the reaction mixture was separated and the organic phase was washed with water (2 x 100 mL), dried over magnesium sulfate and concentrated. The resulting viscous oil was granulated with t-butyl methyl ether (60 ml) at 0 ° C for 2 hours. The product was filtered off, washed with t-butyl methyl ether (20 ml), dried under vacuum at 50 ° C for 18 hours to give the title compound as a white crystalline solid (18.1 g, 88% yield). Mp = 140-M1 ° C.

Ή NMR (300 MHz, CDCl₃) δ = 1.39 (d, 3H), 4.33 (q, 1H), 5.08 (d, 1H), 5.13 (d, 1H), 5.27 (d, 1H), 5, 31 (d, 1H), 5.32 (d, 1H), 5.42 (d, 1H), 6.60-6.75 (m, 2H), 6.92-7.07 (m, 2H) , 7.11-7.37 (m, 5H), 7.81 (s, 1H), 8.44 (d, 1H), 8.61 (s, 1H), 8, 91 (s, 1H) ( b) (2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoiO-4-pyrimidinyl) -1- (1H-1,2,4-triazol-1-yl) -2 dihydrogen phosphate butyl

<img file="PL187237B1_D0018.tif" />

F

Mixture of compound from step (a) (50 g, 70 mmol), sodium hydroxide (8.40 g, 210 mmol), 5% palladium on carbon as catalyst (10 g) in toluene (450 ml) and water (150 ml) subjected to hydrogenation at room temperature at 414 kPa (60 lb / caa)²) for 24 hours. The reaction mixture was filtered through celite (trade mark) and then the toluene layer was separated and discarded. The aqueous layer was washed with methylene chloride (2 x 75 mL) and toluene (2 x 75 mL), then cooled to 0 ° C, and then sulfuric acid (10.3 g, 105 mmol) was added. After granulation at 0 ° C for 1 hour, the product was filtered off, washed with water (60 ml) and dried under vacuum at 50 ° C for 16 hours to give the title compound (20.5 g, 68%). The results of 1 H NMR were identical to those obtained in Example 3 (b).

Found: C, 44.48; H, 3.45; N, 16.19. Calculated for CHH11F3N5O4P: C, 44.77; H, 3.52; N, 16.31%.

Example 5

(2R, 3S) -2- (2,4-difluorophenyl) -3- (5-fluoro-4-pyrimidinyl) -1- (1H-1,2,4-triazol-1-yl) -2- butyl (2-hydroksyftylo) trimftyloamoniowfgo

<img file="PL187237B1_D0019.tif" />

HO

187 237

While stirring, a solution of choline bicarbonate (75% w / w in water, 110 g, 500) was added over 10 minutes to a suspension of the compound of Example 3 (b) (214.7 g, 500 mmol) in acetone (2070 mL) mmol). The slurry was heated to reflux for 20 minutes, filtered through a bed of celite (trade mark) to remove insoluble material, then cooled to 20 ° C and granulated for 1 hour. The resulting product was filtered off, washed with acetone (2 x 250 ml) and dried under vacuum at 20 ° C for 18 hours to give the title compound (233.3 g, 74%). Mp = 114-115 ° C.

Ή NMR (300 MHz, DMSO) δ = 1.23 (d, 3H), 3.07 (s, 9H), 3.38 (t, 2H), 3.60 (q, 1H), 3.78 ( q, 2H), 5.50 (s, 2H), 6.72-6.80 (m, 1H), 6.94-7.02 (m, 1H), 7.36-7.42 (m, 1H), 7.82 (s, 1H), 8.59 (d, 1H), 8.78 (d, 1H), 9.35 (s, 1H).

Example 6

2- (2,4-difluorophenyl) -1- {3 - [(E) -4- (2,2,3,3-tetrefluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl dihydrogen phosphate } -3- (1H- 1,2,4-triazol-1-yl) -2-propyl (a) Dibenzyl-2- (2,4-difluorophenyl) -1- {3 - [(E) -4 - (2,2,3,3-tetrefluoropropoxy) styryl] -1H-1,2,4-triazol-1-yl} -3- (1H-1,2,4-triazol-1-yl) -2 -propyl

<img file="PL187237B1_D0020.tif" />

Under nitrogen (2- (2,4-difluorophenyl) -1- {3 - [(E) -4- (2,2,3,3-tetrafluoropropoxy) styryl) -1H-1,2,4-triazol-1 -yl} -3- (1H-1,2,4-triazol-1-yl) propan-2-ol (racemic compound of example 19, EP 0472392, 475 mg, 0.88 mmol), 1H-tetrazole (185 mg, 2.64 mmol) and dibenzyloxy (diisopropylamido) phosphorus (607 mg, 1.76 mmol) in methylene chloride (5 mL) was stirred at room temperature for 20 hours. The mixture was cooled to 0 ° C. and then, while maintaining the temperature below 20 ° C, hydrogen peroxide (1.0 mL, 30% solution in water) was added dropwise. The resulting mixture was stirred at 20 ° C for 30 minutes, and then the organic layer was separated, which was washed with water. dried over magnesium sulfate and the solvent evaporated. The resulting pale yellow oil was purified by column chromatography (silica gel, eluting with ethyl acetate / hexane) to give the title compound as a thick syrup (595 mg, 84%).

'' H NMR (300 MHz, CDCl3) δ = 4.37 (t, 2H), 4.91 (d, 2H), 4.97 (d, 2H), 5.02 (d, 1H), 5, 07 (d, 1H), 5.16 (d, 1H), 5.18 (d, 1H), 6.05 (tt, 1H), 6.59-6.78 (m, 2H), 6.82 (d, 1H), 6.90

187 237 (d, 2H), 6.91-7.00 (m, 1H), 7.21-7.38 (m, 10H), 7.42 (d, 2H), 7.42 (d, 1H) , 7.79 (s, 1H), 8.28 (s, 1H), 8.39 (s, 1H).

(b) 2- (2,4-difluoro-phosphine] dihydrogen phosphate] -1- {3 - [(E) -4- (2,2,3,3-tetrefluoropropoxy) styryl] -1 H-1,2,4 -triazol-1-yl} -3- (1H-1,2,4-triazol-1-yl) -2-propyl

<img file="PL187237B1_D0021.tif" />

A solution of the compound of step (a) (298 mg, 0.37 mmol) in methylene chloride (5 mL) was cooled to 0 ° C and then treated with bromotrimethylsilane (254 mg, 1.66 mmol) and pyridine (180 mg, 3 , 10 mmol). The resulting mixture was stirred at 0 ° C for 3 hours and then quenched with water (1 mL) containing sodium hydroxide (96 mg, 2.41 mmol). The mixture was then acidified with dilute sulfuric acid and the product was extracted into ethyl acetate. After washing with brine, the acetate phase was dried over magnesium sulfate and the solvent was evaporated to give the title compound as a pale yellow foam (202 mg, 88%).

Example 7

Dihydrogen phosphate (2RS, 3RS) -3- (4- [4-cyanoffnyl] thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl ) -2-butyl (a) Dibfenzyl phosphate- (2RS, 3RS) -3- (4- [4-cyanoffnyl] thiazol-2-yl) -2- (2,4-difluorophenyl) - 1- (1H-1 , 2,4-triazol-1-yl) -2-butyl

<img file="PL187237B1_D0022.tif" />

187 237

Under nitrogen atmosphere 3- [4- (4-cyanophenyl) thiazol-2-yl] -2- (2,4-difluorophenyl) -1- (1H-1,2,4-triazol-1-yl) butan-2 -ol (Example 88, EP 0667346, 900 mg, 2.06 mmol), 1H-tetrazole (432 mg, 6.18 mmol), 4-dimethylaminopyridine (100 mg, 0.82 mmol) and dibenzyloxy (diisopropylamido) phospho - (1.42 g, 4.12 mmol) in methylene chloride (10 mL) was heated to reflux for 20 hours. The mixture was cooled to 0 ° C, and then, while maintaining the temperature below 20 ° C, hydrogen peroxide (2.5 mL, 30% solution in water) was added dropwise. The resulting mixture was stirred at 20 ° C for 30 minutes and then the organic layer was separated, which was washed with water, dried over magnesium sulfate and the solvent was evaporated. The resulting pale yellow oil was purified by column chromatography (silica gel, eluting with ethyl acetate / hexane) to give the title compound as a thick syrup (732 mg, 51%).

NMR (300 MHz, CDClj) δ = 1.40 (d, 3H), 4.38 (q, 1H), 4.81-4.96 (m, 4H), 5.40 (d, 1H), 5 , 43 (d, 1H), 6.52-6.71 (m, 1H), 6.74-6.82 (m, 1H), 7.15-7.37 (m, 10H), 7.58 (s, 1H), 7.62 (d, 2H), 7.73 (s, 1H), 7.97 (d, 2H), 8.48 (s, 1H).

(b) (2RS, 3RS) -hydrogen phosphate -3- (4- [4-cyanophenyl] thiazol-2-yl) -2- (2,4-difluorophenyl) -1- (1H -1,2,4-triazol- 1-yl) -2-butyl

<img file="PL187237B1_D0023.tif" />

A solution of the compound of step (a) (310 mg, 0.44 mmol) in methylene chloride (5 mL) was cooled to 0 ° C and then treated with bromotrimethylsilane (303 mg, 1.98 mmol) and pyridine (215 mg, 3 , 70 mmol). The resulting mixture was stirred at 0 ° C for 3 hours and then quenched with water (1 mL) containing sodium hydroxide (115 mg, 2.87 mmol). The yellow precipitate was filtered off and then partitioned between dilute sulfuric acid and methylene chloride. The organic phase was washed with brine, dried over magnesium sulfate and the solvent was evaporated to give the title compound as a pale yellow solid (80 mg, 35%).

Ή NMR (300 MHz, DMSO) δ = 1.38 (d, 3H), 4.22 (q, 1H), 5.31 (d, 1H), 5.41 (d, 1H), 6.88- 6.97 (m, 1H), 7.09-7.19 (m, 1H), 7.31-7.40 (m, 1H), 7.80 (s, 1H), 7.87 (d, 2H), 8.05 (d, 2H), 8.32 (s, 1H), 8.65 (s, 1H).

Example 8

(2R, 3S) -2- (2,4-difluorophenyl) -3- [4- (1-methylpn'azol-5-yl) phenyl] -1- (1,2,4-triazol-1 phosphate disodium salt yl) -2-butyl

a) O, N-dimethyl-4-iodobenzene hydroxamic acid

To a suspension of 4-iodobenzoyl chloride (251 g, 0.94 mol) and N, O-dimethylhydroxylamine hydrochloride (57 g, 0.94 mol) in dichloromethane (850 ml), a solution of pyridine (104 g, 1, 32 mol) in dichloromethane (150 ml). The mixture was allowed to warm to room temperature and stirred for 18 hours. The solution was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (1 liter) and then washed with dilute hydrochloric acid (2N, 3 x 400 ml), saturated sodium bicarbonate solution (300 ml) and dried over sodium sulfate. This organic extract was evaporated under reduced pressure. The residue was purified by distillation to give the title compound (241 g, 93%) as a yellow oil with a boiling point of 130 ° C (0.1 mm Hg), which was characterized by 'H NMR spectroscopic analysis.

187 237 (b) 2- (2,4-Difluorophenyl) -1- (4-iodophenyl) ethanone

Under a nitrogen atmosphere and while stirring, 2,4-difluorobenzyl bromide (23.7 ml, 0.114 mol) was added dropwise to a mixture of magnesium chips (8.1 g, 0.183 mol) in anhydrous ether (300 ml). The mixture was initially heated until the reaction started, then bromide was added at such a rate that the mixture was kept under gentle reflux. After 1 hour, the resulting Grignard reagent solution was added dropwise at -78 ° C to a solution of O, N-dimethyl-4-iodobenzene hydroxamic acid [see step (a)] (45.7 g, 0.157 mol) in anhydrous ether (300 ml) and allowed that the mixture warms slowly to room temperature overnight. The mixture was partitioned between saturated aqueous ammonium chloride and ethyl acetate, and then the organic solution was separated, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as a white solid, 38.71 g (69%), which characterized by spectroscopic analysis by the 'HNMR method.

(c) 2- (2,4-Difluorophenyl) -1- (4-iodophenyl) prop-2-enone

While stirring, 2- (2,4-difluorophenyl) -1- (4-iodophenyl) ethanone (17.73 g, 0.04595 mol from step (b)) in acetic anhydride (23.1 ml, 0.248 mol) ) bis (dimethylamino) methane (8.78 mL, 0.075 mol) was added dropwise at room temperature. The reaction was exothermic and the temperature of the mixture increased to 60 ° C. After the addition was complete, the mixture was stirred at room temperature for 35 minutes, and then ice-water was added to hydrolyze the excess acetic anhydride. After a further 30 minutes, the product was extracted with ethyl acetate and the extracts were washed with dilute hydrochloric acid and saturated aqueous sodium bicarbonate, dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as a white solid (17.03 g, 93% ), which was characterized by 'H NMR spectroscopic analysis.

(d) 2- (2,4-Difluorophenyl) -1- (4-iodobenzoyl) oxirane

Benzyltrimethylammonium hydroxide (3.44 mL, 40% aqueous solution, 8.2 mmol) was added in one portion, at room temperature, to the 2- (2,4-difluorophenyl) -1- (4-iodophenyl) prop-2- solution enone [37.3 g, 100.8 mmol, from step (c)] and t-butyl hydroperoxide (36.6 mL, 3M solution in trimethylpentane, 109 mmol) in toluene (550 mL). After 2 hours, the mixture was washed with water (2 x 500 mL), dried over magnesium sulfate and concentrated under reduced pressure to give the title compound as a white solid (37.46 g, 96%), which was characterized by spectroscopic analysis Ή NMR.

(e) 2- (2,4-Difluorophenyl) -2- [1- (4-iodophenyl) ethenyl] oxirane

Under a nitrogen atmosphere and while stirring, a suspension of methyl triphenyl phosphonium bromide (45.0 g, 126 mmol) in anhydrous THF (600 mL) was added dropwise at -78 ° C over 10 minutes over 10 minutes n-butyllithium (50 mL, 2.5M solution in hexane) , 125 mmol). The mixture was allowed to warm to -20 ° C over 20 minutes and then a solution of 2- (2,4-difluorophenyl) -2- (4-iodobenzoyl) oxirane (37.46 g, 97 mmol with step (d)) in anhydrous THF (200 ml). The mixture was allowed to warm to room temperature and stirred for 84 hours. A 10% aqueous solution of ammonium chloride (500 ml) was added and the mixture concentrated under reduced pressure. The product was extracted with ethyl acetate and then the combined extracts were dried over magnesium sulfate and concentrated under reduced pressure. The solid residue was treated with boiling hexane (3 x 500 ml) and then the solid residue was discarded. These hexane solutions were combined, filtered through a low bed of silica gel and concentrated under reduced pressure to give the title compound as a yellow oil (34.3 g, 92%), which was characterized by spectroscopic analysis ^!1 H NMR.

(f) 2j (2,4-Difluoro-phenyl) -3- (4-iodophenyl) -1- (1H-1,2,4-triazol-1-yl) -3-butene-2-ol

Under a nitrogen atmosphere at 70 ° C to a solution of (2,4-difluorfenyl) -2- [1- (4-iodophenyl) etoyloyoxirane [34.3 g, 89 mmol from step (e)) in anhydrous DMF (350 mL) 1,2,4-triazole sodium (12.15 g, 133 mmol) was added. The mixture was stirred for 5 hours and then cooled and the solvent removed under reduced pressure. The residue was separated

187 237 between ether (800 ml) and water (2 x 500 ml). This organic solution was dried over magnesium sulfate, filtered and silica gel (60-200 (i, 75 g) was added. The ether was removed under reduced pressure and the solid residue was introduced from above onto a silica gel column (40-60 μ, 300 g). The product was eluted with hexane and increasing amounts of ethyl acetate (0 - 75%). The product was obtained as white foam (23.8 g, 61%), which was characterized by spectroscopic analysis ¹ 1 H NMR.

(g) (+) - (R) -2- (2,4-difluorophenyl) -3- (4-iodophenyl) -1- (1H-1,2,4-triazol-1) (3) bromocamphoro-10-sulfonate -yl) -3-butene-2-ol

A solution of (+) - 3-bromocamphor-10-sulfonic acid (36.3 g, 0.11 mol) in IMS (40 ml) was added to a solution of the product from step (f) (50 g, 0.110 mol) in IMS (300 ml). After seeding, the resulting suspension was granulated at room temperature for 20 hours. After further granulation at low temperature for 1 hour, a white solid (22 g, 0.03 mol) was filtered off. Chiral purity was estimated to be 95% enonciomeric purity by chiral HPLC on a Chiralcel ™ OD column eluting with ethanol / hexane (40:60).

(h) (R) -2- (2,4-Difluorophenyl) -3- (4-iodophenyl) -1- (1H-1,2,4-triazol-1-yl) -3-butene-2-ol

The product of step (g) (206.5 g, 0.27 mol) was added to methylene chloride (620 ml) and basified with 40% NaOH. The mixture was stirred at room temperature for 15 minutes and then separated. The aqueous phase was re-extracted with methylene chloride (310 mL). The organic product solution was washed with water (620 ml) and concentrated to a volume of 245 ml. While stirring, the inoculated concentrate was added at room temperature at a steady rate of hexane (2450 mL). The resulting suspension was granulated at 5 ° C for 1 hour. Filtration afforded a white solid (117.4 g, 0.26 mol), which was characterized by spectroscopic analysis using Ή nMr.

(i) (2R) -2- (2,4-Diflnophenyl) -3- [4- (1-MrSylpyrazol-5-yl) phenyl] -1- (1,2,4-triazol-1-yl) - 3-buten-2-ol

To a solution of 1-methylpyrazole (3.28 g, 0.04 mol) in THF (370 ml) a solution of nBuLi (1.6N, 24.1 ml, 0.04 mol) was added at -70 ° C and kept at below -60 ° C stirred for 30 minutes. To this mixture kept below -40 ° C, zinc chloride solution (0.5N, 77.1 mL, 0.04 mol) was added, followed by tetrakis (triphenylphosphine) palladium (15% w / w, 0.9 g) and then, while still keeping the temperature below -40 ° C, a solution of the product from step (h) (6 g, 0.013 mol) in THF (36 ml) was added at a constant rate. The reaction mixture was allowed to warm to room temperature and then heated to reflux for 2 hours. After cooling to room temperature, the residual stirrer was kept below 25 ° C and treated with acetic acid (12 ml) and water (120 ml). The reaction mixture was evaporated under reduced pressure to remove THF. The product was extracted with methylene chloride (120 mL) and the aqueous phase was further extracted with methylene chloride (50 mL). The combined organic extracts were washed with water (2 x 120 mL) and concentrated to give an oil. While stirring, 5-sulfosalicylic acid (3.3 g, 0.13 mol) in IPA (10 mL) was added to a filtered solution of this oil in ethyl acetate (100 mL). The resulting mixture was stirred at room temperature for 0.5 hours. The filtered solid was again taken up in ethyl acetate (50 ml) and recrystallized from IPA (60 ml) to give a white solid (7.2 g, 0.01 mol). This solid was added to methylene chloride (35 mL) and water (50 mL) and basified with 40% NaOH. The mixture was stirred at room temperature for 15 minutes and then separated. The aqueous phase was re-extracted with methylene chloride (25 ml) and the combined organic extracts washed with water (35 ml). The organic product solution was concentrated to foam and its properties were determined.

[Α]₀ = -25,6°

For C22 H19F2N5O · 0.5 H2O calculated: C, 63.45; H, 4.84; N, 16.82,

Found C, 63.92; H, 4.86; N, 16.64, (j) (2R, 3S) -2- (2,4-Dlflnophenyl) -3- [4- (1-mrtylpyrazol-5-yl) phenyl] -1- (1,2,4 triazol-1-yl) -3-bntrn-2-ol

187 237

<img file="PL187237B1_D0024.tif" />

A solution of the product of step (i) (2.0 g, 5 mmol) in ethanol (50 ml) was hydrogenated at 50 pounds / inch² (333 kPa) at 50 ° C with 5% palladium on charcoal (0.2 g) for 18 hours. A further portion of catalyst (0.2 g) was added and hydrogenation continued for a further 18 hours. The mixture was filtered through Arbocel® and the filtrate evaporated under reduced pressure. The residue was chromatographed on silica eluting with a gradient of ethyl acetate / hexane / diethylamine (from 0: 95: 5 to 65: 33: 2). The fraction containing the desired product was combined and evaporated under reduced pressure. The residue was dissolved and re-evaporated three times from ethyl acetate and then three times from ether to give a colorless solid. This solid was recrystallized from aqueous ethanol to give the title compound (1.25 g, 62%) as a colorless solid.

Tt = 144-145 ° C, [α] ο = -107 ° (c = 0.1%, CH2G2, 25 ° C).

Elemental analysis (%) found: C, 64.26; H, 5.13; N, 17.07 for C22H21F2N5O calculated: C, 64.54; H, 5.17; N, 17.17.

[This compound is also disclosed in example 67 in the pending international patent application No. PCT / EP96 / 02470], (k) Dibenzyl- (2R, 3S) -2- (2,4-difluorophenyl) -3- [4 - (1-methylpyrazol-5-yl) phenyl] -1- (1,2,4-triazol-1-yl) -2-butyl _about

<img file="PL187237B1_D0025.tif" />

Product solution from step (j) (2.0 g, 4.4 mmol), dibenzyloxy (diisopropylamido) phosphorus (2.28 g, 6.6 mmol), tetrazole (0.92 g, 13.2 mmol) and 4 -dimethylaminopyridine (50 mg) in dichloromethane (30 mL) was heated to reflux for 13 hours. The reaction mixture was cooled (0 ° C) and m-chloroperbenzoic acid (1.52 g, 8.8 mmol) was added. The solution was stirred at 0 ° C for an additional hour and the mixture was allowed to warm to room temperature. The reaction mixture was washed with aqueous sodium sulfite (10%, 30 mL), saturated sodium bicarbonate (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate and the solvent was evaporated in vacuo to give an oil. Purification by column chromatography (silica gel, 45 g with a gradient elution with toluene to 3.5% diethioamine in toluene) gave the desired product as a colorless oil (0.8 g, 27%). '

187 237 m / z 671 (M + + 1).

1 H NMR (CDCl3) δ = 1.3 (d, 3H); 3.8 (s, 3H); 3.85 (q, 1H); 4.8 (m, 2H); 4.9 (m, 2H), 5.2 (s, 2H); 6.25 (s, 1H); 6.6 (m, 1H); 6.8 (m, 1H); 7.05 (m, 1H); 7.15 (m, 2H); 7.2-7.35 (m, 12H); 7.5 (s, 1H); 7.8 (s, 1H); 8.23 (s, 1H).

(1) Disodium salt of (2R, 3S) -2- (2,4-difluorophene) -3- [4- (1-m-phenylpyrazol-5-yl) phenyl] -1- (1,2,4-triazol- 1-yl) -2-butyl o

II

<img file="PL187237B1_D0026.tif" />

<img file="PL187237B1_D0027.tif" />

The suspension of the product from step (k) (0.5 g, 0.75 mmol) and sodium acetate (0.14 g, 1.65 mmol) in ethanol (20 ml) was hydrogenated with 5% palladium on carbon (75 mg ) at room temperature at 333 kPa (50 lb / cai) for 24 hours. TLC analysis showed that the reaction was not complete and the catalyst was filtered off through a layer of filtration aid (Arbacel®). Pearlman's catalyst (75 mg) was added and hydrogenation continued for a further 72 hours. The catalyst was filtered off through an Arbacel® bed and the solvent removed in vacuo. The residue was dissolved in dichloromethane (20 mL) and filtered through a layer of filtration aid (Hiflow®) to remove excess sodium acetate. The solvent was evaporated in vacuo and trituration with diethyl ether gave the title compound as a white solid (0.250 g, 68%).

Found: C, 46.66; H, 4.87; N, 11.82; for C22H22F₂N5Nz2C&gt; 4P · 0.09 Et2O calculated: C, 46.62; H, 4.36; N, 12.16%.

1 H NMR (DMSO) δ = 1.2 (d, 3H); 3.75 (q, 1H); 3.8 (s, 3H); 5.1, 5.5 (AB system, 2H); 6.3 (s, 1H); 6.6 (m, 1H); 6.9 (m, 1H); 7.2, 7.4 (AB system, 4H); 7.4 (m, 3H); 7.45 (m, 1H); 7.6 (s, 1H); 9.1 (s, 1H).

Example 9

The water solubility of the compounds of Examples 1, 3 and 8 (in the form of di-sodium salts) was compared with the solubility of the corresponding parent compounds (non-phosphorylated, in the form of the free base). The results are shown in the following table.

<td>Relationship</td><td>Solubility (mg / ml)</td>

<td>Example 1</td><td> &gt;150,0</td>

<td>mother</td><td> 2,0</td>

<td>Example 3</td><td> &gt;150,0</td>

<td>mother</td><td> 0,6</td>

<td>Example 8</td><td> &gt;50,0</td>

<td>mother</td><td> 0,01</td>

187 237

Example 10

An aqueous preparation for intravenous injection

<td>Ingredient</td><td>mg / ml</td>

<td>Compound of Example 1</td><td> 100,00</td>

<td>Sodium hydroxide</td><td> 22,80</td>

<td>Concentrated hydrochloric acid</td><td>qs *</td>

<td>Water for injections</td><td>up to 1.00 ml</td>

* The pH of the resulting solution was adjusted to 8.5-9.5 by the addition of sufficient 5M hydrochloric acid.

187 237

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