FI84176C - FORM OF THERAPEUTIC ACTIVATION OF 2- (4-CHLOROPHENYL) -3-CYCLOPROPYL-1- (1H-1,2,4-TRIAZOLE-1-YL) BUTAN-2-OLDERIVAT. - Google Patents

Description

1 84176

Process for the preparation of therapeutically active 2- (4-chlorophenyl) -3-cyclopropyl-1- (1H-1,2,4-triazol-1-yl) butan-2-ol derivatives Separated from patent application 840 824

The invention relates to a process for the treatment of therapeutically active 2- (4-chlorophenyl) -3-cyclopropyl-1- (1H-

For the preparation of 1,2,4-triazol-1-yl) butan-2-ol derivatives of formula I

fi 3 R6 f Vr \ is - | \ i_y — C1 u> CH, —C-R? k 20 wherein R 2 is H or CH 3 and R 6 is H or Cl, and for the preparation of these ethers and esters in free form or in the form of acid addition salts.

GB patent application 2,064,520 A describes 25 α-phenyl-α- (C 3-8 cycloalkyl-C 1-3 alkyl) -1H-1,2,4-triazole-1-ethanols which have fungicidal effects. According to said patent application, cycloalkylalkyl primarily means C 3-6 cycloalkylmethyl; specific significant examples are α-cyclohex-30-methylmethyl and α-cyclopentylmethyl.

It has now been found that certain α-aryl-α- (cycloalkylalkyl) -1H-azole-1-ethanols having an substituent or side chain on the carbon atom adjacent to the C (OH) group attached to the ethanol group of the cycloalkyl group have surprisingly advantageous pharmacological properties when its cycloalkyl is cyclopropyl.

When the hydroxy group of the compounds of formula I is etherified, such ethers include, for example, C 1-5 alkyl, C 3-5 alkenyl, C 3-5 alkynyl or aralkyl ethers such as methyl, allyl, propargyl or benzyl ethers; when such a hydroxy group is esterified, esters include, for example, esters of aliphatic carboxylic acids such as acetate.

The compounds of formula 1 have one or more chiral centers. Such compounds are usually obtained as racemic, diastereomeric and / or cis / trans mixtures. However, such mixtures may, if desired, be separated either in whole or in part into the individual compounds or the desired mixtures of isomers by methods known in the art.

The compounds of formula I may exist in the form of the free base or in the form of a salt, such as an acid addition salt formed with an organic or inorganic acid, such as hydrogen chloride, or an alcoholate, e.g. Na ethanolate, and a metal complex, e.g. Ib, Ha, Hb, VIb, VIIIb and VIII with a metal such as copper and zinc, and with anions such as chloride, sulphate and nitrate.

The compounds of formula I and their ethers and esters are prepared according to the invention in such a way that

a compound of formula II

en N

! ’J] (ii>

NT

30 M

wherein M is H, a metal or a trialkylsilyl group, is reacted with a compound of formula III

35 3 84176

Rj .CH7 \ / 'φτ "'

Cl 10 wherein R 2 and R 6 are as defined above in formula I, or a reactive functional derivative thereof, followed, if desired, by etherification or esterification of the ethanol compound thus obtained, and recovery of the compound thus obtained in free form or by addition of an acid addition salt. in terms of.

The process according to the invention can be carried out under similar conditions known for the preparation of azole-1-ethanols by reactions between azole and oxirane.

When M in formula II is H, the reaction with the oxirane compound is suitably carried out in the presence of a base.

When the metal in formula II M is a metal, it is primarily an alkali metal, e.g. Na.

When M in formula II is trialkylsilyl, e.g. trimethylsilyl, the reaction is conveniently carried out in the presence of a base such as NaH.

The process of the invention is conveniently carried out in a solvent which is inert under the reaction conditions, e.g.

30 in dimethylformamide. A suitable reaction temperature is between ambient temperature and the reflux temperature of the reaction mixture; when in formula II M is trialkylsilyl, the temperature is most conveniently above ambient temperature, e.g. between 70 and 90 ° C.

The term "reactive functional derivative" used in connection with the aforementioned oxiranes of formula III is intended to include any oxirane derivative which, when reacted with an azole of formula II, forms ethanol compounds of formula I5. Various examples of such reactive derivatives are known to those skilled in the art; suitable examples are the corresponding halohydrins (where halogen is e.g. Cl or Br).

The conditions under which the ferrous compounds of the formula II can be reacted with the reactive derivatives of the oxiranes of the formula III defined above are also known per se. The reaction of a compound of formula II with a halohydrin derivative of a compound of formula III may be carried out under the conditions set forth for the reaction with oxirane compounds, suitably, however, in the presence of an added base equivalent.

Ester and ether derivatives of the ethanol compounds of formula I can be obtained according to known esterification-20 or etherification methods starting from the corresponding ethanes.

The compounds of formula I are obtained in the form of the free base or in the form of a salt (in the form of an acid addition salt or an alcoholate) or in the form of a metal complex. Salt or me-25 stable complexes can be obtained from the corresponding free form in the usual manner and vice versa.

The compounds of formula I can be isolated from the reaction mixture and purified by methods known per se.

To the extent that the preparation of starting materials has not been described, they are known or can be obtained by methods analogous or analogous to those described herein or by known methods.

The compounds of formula I have interesting biological, in particular antifungal, properties and are therefore said to be suitable for use as a medicament in the treatment of fungal diseases of humans and other living beings. The fungal growth inhibitory effect can be demonstrated by in vitro experiments, e.g. by applying an in vitro serial dilution test to various fungal genera and species, such as yeasts, molds and dermatophytes at concentrations of about 0.05 to about 50 pg / ml and also in vivo. by administration, e.g., by systemic oral administration of about 3 to 100 mg per kilogram of body weight to mice infected intravaginally with Candida Albi-10 cans.

The dosage to be administered for the above use will, of course, vary with the compound employed, the mode of administration and the treatment desired. In general, however, satisfactory results are obtained when administered in a daily dose of 1 to 100 mg per kilogram of animal body weight, which is administered in conveniently divided doses two to four times daily, or in a sustained-release form. For larger mammals weighing about 70 kg, the corresponding daily dose is, for example, in the range of 70-2000 mg; dosage forms suitable, for example, for oral administration, thus contain 17.5 to 1000 mg of active ingredient.

The compounds of the formula I can be prepared and used in free base form or in the form of pharmaceutically acceptable salts (acid addition salts or alcoholates) or metal complexes. In general, the activity of the salt forms is of the same order of magnitude as that of the free base forms. Acids that can be used to prepare acid addition salt forms include, by way of illustration, hydrochloric, hydrobromic, sulfuric, nitric, fumaric, and naphthalene-1,5-disulfonic acids.

The compounds of the formula I can be mixed with customary pharmaceutically (in veterinary medicine) inert carriers and, optionally, with other additives. They may be administered in such unit dosage forms as tablets or capsules, or alternatively they may be administered topically in the usual forms such as creams or ointments or parenterally. The concentrations of the active ingredient vary, of course, depending on the compound used, the treatment desired and the type of form, etc. In general, however, satisfactory results are obtained, for example, for topical administration at concentrations of 0.05 to 5, in particular 0.1 to 1% by weight. %. The compounds of formula I can be used in analogy to analogues known to be used with standard compounds such as ketoconazole.

The appropriate daily dose of a particular compound of formula I will depend on various factors, e.g. its relative activity. This is shown e.g.

For 2- (4-chlorophenyl) -3-cyclopropyl-3-methyl-1- (1H-1,2,4-triazol-1-yl) butan-2-ol in a mouse vaginal candida fungal model and resulted in improvement after oral administration of 4 x 50 mg 20 and even only 4 x 5 mg per kilogram of body weight. The compounds of formula I can therefore be used in similar doses to the commonly used ketoconazole.

The following examples further illustrate this invention. All temperatures are in degrees Celsius. Rf values of 25 are obtained on silica gel.

The finished products

Example 1: 2- (4-Chloro-phenyl) -3-cyclopropyl-1- (1H-1,2,4-triazol-1-yl) -butan-2-ol Step 1 7.6 g of 1- (4- chlorophenyl) -2-cyclopropylpropane-1 is dissolved in 120 ml of dry toluene, this is added to 28.6 g of dodecyldimethylsulfonium methylsulphate at ambient temperature and the suspension is stirred for 15 to 35 minutes. To this is added 6.3 g of ground KOH and the reaction mixture is stirred for 18 hours at 35 °. The reaction mixture is cooled, poured onto ice and, after some addition of dimethylformamide, extracted with diethyl ether. The organic extracts are washed three times with water and then with saturated aqueous NaCl, dried

MgSO 4 and evaporated to dryness in vacuo. The oily residue thus obtained contains 2- (4-chlorophenyl) -2- (1-cyclopropylethyl) oxirane (along with dodecylmethyl sulfide and dodecene-1).

10 Step 2

The crude oxirane reaction product of step 1 is added dropwise to a mixture of 4.2 g of 1,2,4-triazole and 15.4 g of K 2 CO 3 in 80 ml of dry dimethylformamide (DMF) at 90 ° and the mixture is stirred at 90 °: in 2 hours. After cooling, the reaction mixture is poured onto ice and extracted with diethyl ether, the organic extracts are washed with water and saturated aqueous NaCl solution, dried over MgSO4 and the solvent is removed in vacuo. Chromatography of the residue on silica gel with hexane / ethyl acetate gives an oil, a colorless syrup (diastereomeric mixture) which crystallizes slowly. Recrystallization from hexane / CH 2 Cl 2 gives the title compound as a diastereomeric mixture as colorless crystals of m.p. is 100-101 °.

The Rf values on a thin layer chromatographic plate (on a silica gel plate using ethyl acetate as eluent) are: diastereomer A: Rf value 0.30 diastereomer B: Rf value 0.38.

Repeating the chromatography on silica gel using diethyl ether / acetate (99: 1) and diethyl ether / ethyl acetate 99: 1-90: 10 and then crystallizing from hexane / CH 2 Cl 2, the diastereomeric mixture is separated into pure diastereomers:

Example IA: diastereomer A: m.p. 109-110 °.

Example IB: Diastereomer B: m.p. 125-127 °.

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Example 1C

A mixture of 2.0 g of p-toluenesulfonic acid monohydrate in 50 ml of toluene is concentrated to a volume of 5 ml. A solution of 2.9 g of 2- (4-chlorophenyl) -3-cyclopropyl-1- (1H-1,2,4-triazol-1-yl) butan-2 is added dropwise with stirring at room temperature. -ol (diastereomeric mixture) in 35 ml of absolute toluene. The reaction mixture is allowed to stand until crystallization. After adding 20 ml of diethyl ether to the crystallization formed in toluene, the mixture is stirred for 30 minutes, filtered off, washed with diethyl ether and dried at 60 ° C under high vacuum, m.p. 170-171 °.

By a method similar to Example 1C, the following salts of the diastereomeric mixture of the title compound of Example 1 are obtained.

Example ID: hydrogen oxalate, m.p. 180-182 ° IE: hydrochlorides, m.p. 190-200 °.

Example 2: 2- (4-chlorophenyl) -3-cyclopropyl-3-methyl-1-20 (1H-1,2,4-triazol-1-yl) butan-2-ol 1- (4-chlorophenyl) - 2-Cyclopropyl-2-methylpropan-1-one is reacted according to the procedure of Example 1 (Steps 1 and 2). Purification of the title compound is accomplished by crystallization from hexane to give colorless crystals of m.p. is 88-90 ° (= racemate of the title compound).

Example 3

According to the procedure of Example 1 (Step 2), reacting an azole with the desired oxirane provides the following compounds of formula I wherein R 2 and R 6 are as defined in Table A:

Table A

Ex._R2_R6_sp._ 35 3.1 H Cl 113-117 ° 3.2 CH3 Cl 141-142 ° 9 84176

Example 4; 2- (4-chlorophenyl) -3-cyclopropyl-2-methoxy-3-methyl-1- (1H-1,2,4-triazol-1-yl) butane

To a suspension of 0.8 g of 80% NaH in 25 mL of DMF is added dropwise, at room temperature, a solution of 7.64 g of 2- (4-chlorophenyl) -3-cyclo -propyl-3-methyl-1- (1H-1,2,4-triazol-1-yl) butan-2-ol in 50 ml of DMF. The reaction mixture is stirred for 30 minutes at 40 °. 3.76 g of CH 3 I are then added dropwise at 50. The mixture is stirred for 18 hours at 20 °, then poured into one liter of water and extracted with CH 2 Cl 2. The organic phases are washed with water, dried over MgSO 4 and concentrated by continuous evaporation in a flask. Chromatography of the residue on silica gel (eluent phase diethyl ether / triethylamine 10: 2) then gives the title compound as white crystals, m.p. 87-89 °.

Example 5: 2- (4-Chlorophenyl) -3-cyclopropyl-2-allyloxy-3-methyl-1- (1H-1,2,4-triazol-1-yl) butane The title compound is otherwise obtained according to Example 4. by the method except that allyl bromide is used instead of CH 3 I and the reaction mixture is stirred for 18 hours at 70 ° and not at 20 °; mp. 58-60 °. (white crystals).

Example 6: 2- (4-Chloro-phenyl) -3-cyclopropyl-2-benzyloxy-1S-3-methyl-1- (1H-1,2,4-triazol-1-yl) butane

The title compound is otherwise obtained by the method of Example 5, except that benzyl bromide is used instead of allyl bromide, m.p. 130-132 ° (white crystals).

Example 7: 2- (4-Chlorophenyl) -3-cyclopropyl-2-acetoxy-3-methyl-1H- (1H-1,2,4, triazol-1-yl) -butane The title compound is obtained otherwise than in Example 4. 10 841 76, except that acetyl chloride (instead of CH 3 I) is used and the reaction mixture is stirred for 24 hours at 70 °. It crystallizes from diethyl ether; mp. 117-119 ° (yellow crystals).

5 Intermediates

Example 8: 1- (4-Chlorophenyl) -2-cyclopropylpropanone-15 g of 4-chlorophenylcyclopropylmethyl ketone dissolved in 80 ml of dry DMF are added dropwise to a suspension of 2.6 g of 80% NaH in 30 ml of DMF under the protection of the N 2 layer, and the mixture is stirred for 2 hours at 25-35 °. 15.3 g of CH3I are added dropwise, over a period of 15 minutes at room temperature and under cooling, the mixture is stirred for 15 minutes at 25-30 ° and, after the addition of cold water, is extracted with ether. The organic extracts are washed with water and saturated aqueous NaCl, dried over MgSO 4, evaporated to dryness to give the crude title compound which is purified by chromatography on silica gel with hexane / ethyl acetate-98: 2.

4-Chlorophenyl- (cyclopropylmethyl) -ketone is obtained by oxidizing the corresponding alcohol with CrO 3 in aqueous H 2 SO 4 / acetone solution by the Jones method.

Example 9: 1- (4-Chlorophenyl) -2-cyclopropyl-2-methylpropan-1

Proceed according to Example 8, but using 2.4 equivalents of NaH and 3 equivalents of CH 3 I per equivalent of 4-chlorophenylcyclopropylmethyl-ketone. The title compound is chromatographed on silica gel with a hexane fraction / ethyl acetate mixture (99: 1), n * ° = 1.5390.

Example 10 1-4-Chlorophenyl) -2-cyclopropyl-propanone-35 The title compound of Example 8 can also be obtained by starting from 4-chlorobenzylamide by reacting it with cyclopropylmethyl ketone in the presence of NaH, reducing the formed 1- ( 4-chlorophenyl) -1-cyano-2-cyclopropylpropene-1 Mg / CH 3 OH / NH 4 Cl to 1- (4-chlorophenyl) -1-cyano-2-cyclopropylpropane, followed by oxidation of said cyano compound 02 under temporal conditions in the presence of a phase transfer catalyst. Depending on the circumstances (price, environment, etc.), the method of this example may be preferred.

10

Claims (2)

A process for the preparation of therapeutically active 2- (4-chlorophenyl) -3-cyclopropyl-1- (1H-1,2,4-triazol-5-yl) butane-2-parent derivatives of the formula I ( Wherein R 2 is H or CH 3 and R 6 is H or Cl, and ethers and esters thereof, in free form or in acid addition salt form, characterized therefrom a compound of formula II which M is H, a metal or a trialkylsilyl group, reacting with a compound of formula III R 9, CH R 2 and R 6 represent the same as above, or a reactive functional derivative thereof, followed where desired by esterification or esterification of the thus obtained ethanol compound and recovery of the thus obtained compound in free form or in the form of an acid addition salt. 2. A process according to claim 1, characterized in that R 2 is methyl and R 6 is hydrogen.