JPS6030290B2 - Pharmaceutical compositions and uses - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel 1-
It relates to the use of acyloxy-2-imidazolyl-1-phenyluethanes. For example, 1-[8-butoxy-8-(4'-chlorophenyl)-ethyl]-imidazole,
It is already known that -aryru-8-(R-oxy)-ethyl]-imidazoles exhibit good antifungal activity (see German Patent Application No. 2063857). However, the action of these compounds is not always completely satisfactory, especially against dermatophytes. In the present invention, R represents a halogen, a phenyl group optionally substituted with a halogen, or a phenoxy group optionally substituted with a halogen, and R represents a lower alkyl group or a phenyl substituted with a halogen. and n represents an integer of 1 to 5, and the present invention provides an antibacterial agent characterized by containing 1-acyloxy-2-imidazolyl-1-phenylethane or a salt thereof as an active ingredient. Surprisingly, the 1-acyloxy-2-imidazolyl-1-phenyluethanes of the formula '1} which can be used according to the invention are the most closely related chemically and in terms of their action known from the past, the 1-[ It exhibits antifungal activity that can be used as a therapeutic agent superior to that of 8-butoxy-8-(4-chlorophenyl)-ethyl]-imidazole. The active compounds that can be used according to the invention thus represent an advance in the pharmaceutical field. In this formula {1), R preferably represents halogen, particularly fluorine, chlorine and bromine; mention may be made of phenyl or phenoxy groups which may be substituted with such halogens. It is preferable that n represents 0 or an integer of 1 to 3. Furthermore, in formula 01, R represents a straight-chain or branched lower alkyl group having 1 to 6, in particular 1 to 4 carbon atoms, or a phenyl group substituted with halogen. As examples of active compounds that can be used according to the invention, mention may be made of the following: 1-(4-chlorobenzoyloxy)-1-(2,4-dicoophenyl)-2-(imidazole- 1-il)-ethane, 1
-acetoxy-1-(2,4-dichlorophenyl)-2
-(imidazol-1-yl)-ethane, 1-acetoxy-1-(4-chlorophenyl)-2-(imidazol-1-yl)-ethane, 1-(4-chlorobenzoyloxy)-11-(4-chlorophenyl)-2-(imidazole) -1-yl)-ethane, 1-acetoxy1-(4
-biphenylyl)-2-(imidazol-1-yl)-
Ethane, 1-(4-chlorobenzoyloxy)-1-(
4-biphenylyl)-121 (imidazole-1-yl)
-ethane, 1-acetoxyl-[4-(4-chlorobiphenylyl)]-2-(imidazol-1-yl)-ethane, 1-(4-chlorobenzoyloxy)-1-[4
-(4'-chloropiphenylyl)]-2-(imidazo-
(1-yl)-ethane, 1-acetoxy1-[4-
(2,4-dichlorobiphenylyl)]-121(imidazol-1-yl)-ethane), 1-(4-chlorobenzoyloxy)-111[4-(2',4'-dichlorobiphenylyl)] 1-2-(imidazol-1-yl)-ethane, 1-acetoxy-1-[2-chloro-4-(4'-chlorobiphenylyl)]-2-(imidazol-1-yl)-ethane, 1-(4-chlorobenzoyloxy) )−
11 [2-chloro41 (4'-chlorobifurenyl)
]-2-(imidazol-1-yl)-ethane, 1-acetoxy-1-[4-(4'-chlorophenoxy)-phenyl]-2-(imidazol-1-yl)-ethane,
11 (4-chlorobenzoyloxy)111 [41 (4
'-chlorophenoxy)-phenyl]121(imidazol-1-yl)-ethane, 1-acetoxy-11(4
-phenoxyphenyl)121(imidazol-1-yl)-ethane, 1-(4-chlorobenzoyloxy)111(4-phenoxyphenyl)121(imidazol-1-yl)-ethane, 1-ethyl Carbonyloxy-1-(2,4-dichlorophenyl)-2-(imidazol-1-yl)-ethane, 1-isopropylcarbonyloxy-1-(2,4-dichlorophenyl)-2-
(imidazol-1-yl)-ethane, 1-t-butylcarbonyloxy-1-(2,4-dichlorophenyl)
-2-(imidazol-1-yl)-ethane, 1-(2
・4-dichlorophenylcarbonyloxy)-1-(2
・4-dichlorophenyl)-2-(imidazole-1-
yl)-ethane, 1-acetoxyl-[4-(2'・
4'-dichlorobiphenylyl)]121(imidazol-1-yl)-ethane, 1-acetoxy1-[41(
2',4'-dichlorophenoxy)-phenyl]-2-
(imidazol-1-yl)-ethane, 1-acetoxy-1-phenyl-2-(imidazol-1-yl)-ethane, 1-acetoxy-1-(4-fluorophenyl)
1-2-(imidazol-1-yl)-ethane, 1-(2
・4-dichlorobenzoyloxy)-1-1-(4-chlorophenyl)-2-(imidazol-1-yl)-ethane, 1-(2,4-dichlorobenzoyloxy)-1-(
2,4-dichlorophenyl)-12-(imidazole-1
-yl)-ethane, 1-(2,4-dichlorobenzoyloxy)-1-(4-biphenylyl)-2-(imidazol-1-yl)-ethane, 1-(2,4-dichlorobenzoyloxy)-1-1 (2-biphenylyl)-2-(
imidazol-1-yl)-ethane, 1-(2,4-dichlorobenzoyloxy)-1-[4-(4-chlorobiphenylyl)]-2-(imidazol-1-yl)-ethane, 1-(2,4 -dichloro-penzoyloxy)-11-(4-phenoxyphenyl)-2-(imidazol-1-yl)-ethane, 1-(2,4-dichlorobenzoyloxy)-11-[4-(4'-chlorophenyl)-2-(imidazol-1-yl)-ethane, enoxy)
-phenyl]-2-(imidazol-1-yl)-ethane and 1-(2,4-dichlorobenzoyloxy)-
1-[4-(2,4-dichlorophenoxy)-phenyl]-2-(imidazol-1-yl)-ethane, or a salt of any of the above compounds. Compounds of the invention have the formula

[21 where R and n have the above-mentioned meanings, 1-hydroxy-2-imidazolyl-1-phenyl-ethane of (a' formula {3-HPI-CO-R''3' where R' has the above meaning and the ratio 1 represents a halogen, in particular chlorine or bromine, in the presence of an inert organic solvent, such as ethyl acetate, and from 0 to 1
It can be produced by reacting at a temperature of 20°C. The compound of formula '1} is obtained in the form of the hydrochloride salt, but it can be obtained in that form by precipitating it by adding an organic solvent, for example hexane, purifying it by furnace separation and optionally by recrystallization. can be isolated. The compound of formula {1} can also be isolated in the free base form by adding an aqueous solution of sodium bicarbonate to the reaction mixture to form the free base and separating it according to conventional methods. In a preferred embodiment, a hydroxy compound of formula {2) in a suitable organic solvent, such as chloroform, is converted to an alkali metal alkanolate using an alkali metal amide or alkali metal hydride;
and, without isolating the latter, react immediately with the halide of formula [3-] to obtain the compound of formula m according to the invention in one operation with removal of the alkali metal halide. The compound of the present invention is a compound of formula (2).
b] Formula [4} R'-CO-○-CO-R' (4-where R' has the above-mentioned meaning) and an inert organic solvent, e.g. Reacting in the presence of acetone or with an excess of acid anhydride and in the presence of an acid or basic catalyst, such as sodium acetate, at a temperature of 0 to 150°C and isolating the compounds of the invention according to conventional methods. or 'C} Formula ■ ○=C=CH-R'' [5) Here R
' represents hydrogen, alkyl, alkenyl, alkynyl or halogenomethyl with ketene, for example in equimolar amounts, in the presence of an inert organic solvent, such as ethyl acetate, and of an acid or base catalyst, such as sodium acetate. or by reacting at a temperature of -10 to 7,000 °C and isolating the compound of the invention by conventional methods, or 'd} with the formula {6-○=C=N-R''' [6}Z here isocyanate, in which R''' represents alkyl or optionally substituted phenyl, for example in equimolar amounts, in the presence of an inert organic solvent, such as benzene, and in the presence of a catalyst, such as dibutyltin dilaurate. It can also be produced by reacting at a temperature of 0 to 100°C and isolating the compound of the present invention according to a conventional method.
1-Hydroxy-2-imidazolyl-1-phenyluethanes of formula 2 (2} are known (see German Patent Application No. 2063857) or can be easily prepared by the methods described in this specification. can be obtained, for example, by reduction of the corresponding imida 2zo IJ ralcanone. Suitable salts of compounds of formula '1} are those of physiologically acceptable acids. These are preferably salts of halogen Hydrochloric acids, such as hydrochloric acid and hydrobromic acid, especially hydrochloric acid, and phosphoric acid, nitric acid,
Monofunctional and difunctional carboxylic and hydroxycarboxylic acids, such as acetic acid, maleic acid, succinic acid,
Includes fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid and 1,5-naphthalenedisulfonic acid. The salt of the compound of formula {1} can be prepared by conventional methods, e.g. by dissolving the base in an ether, e.g. diethyl ether, and adding an acid, e.g. nitric acid, and the salt is isolated by known methods, e.g. by heating. Moreover, it can be easily obtained by purification if necessary. The compounds of formula [1}, and their salts, which can be used according to the invention exhibit antibacterial, in particular strong, antifungal action. These are particularly effective against species of the genus Candida, such as dermatophytes and dermatophytes, as well as diphasic fungi, such as species of the genus Candida, such as dermatophytes, eg Aspergillus niger, eg Aspergillus niger. Species of the genus Asbergillus such as Black mold, species of the genus Acrobacterium such as M. feline, species of the genus Microsporomycota such as Microsporum feli, and species of the genus Microsporum such as M. feli. It has a very broad spectrum of antifungal action against Nicilium species. This table of microorganisms is not intended to limit the types of cells that can be combated, but is merely an example.
Fields of application in human medicine that may be mentioned are, for example, the following fields: P. alba and other species of the genus M. microsporum, species of the genus Microsporum, epidermophytes, fungi. Dermatomycoses and systemic mycoses caused by genera and diphasic fungi and molds. Fields of application in veterinary medicine that may be mentioned are, for example, the following fields: dermatomycoses and systemic mycoses, especially those caused by the pathogens mentioned above. The invention further provides pharmaceutical compositions containing as active ingredient a compound of the invention in the form of a sterile or isotonic aqueous solution. The present invention also provides a medicament in dosage unit form containing a compound of the invention, either alone or as a mixture with a diluent. Furthermore, the present invention provides tablets (including lozenges and tablets), bran, capsules, pills, ampoules containing a compound of the present invention, either alone or as a mixture with a diluent. Yes, they also offer suppositories. "Drug" as used herein refers to physically separate, associated moieties suitable for medical administration. As used herein, "drug in dosage unit form" refers to a daily dosage or daily dosage, respectively, of a compound of the invention mixed with a carrier and/or encapsulated within a coating. Several times (up to 4 times) or a fraction of the amount (
1'40). The drug is the appropriate amount for one day or one
For example, half, 1/3 or 1/4 of the daily amount
depending on whether the drug is to be taken once or, for example, twice, three or four times a day, respectively. The pharmaceutical composition according to the invention can be prepared using an aqueous or non-aqueous diluent, a syrup,
The active compounds in granules or powders can take the form of, for example, ointments, gels, tubes, creams, sprays (including aerosols), washes, suspensions, solutions and emulsions. Diluents to be used in pharmaceutical compositions (e.g. granules) suitable for shaping as tablets, bran, capsules and pills include: {a' fillers and extenders; For example starches, sugars, mannitol and silicic acid; 'b' binders such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin and polyvinylpylene. Ridone;'c} Moisturizers, such as glycerin: {d}
Disintegrants, such as agar, calcium carbonate and sodium bicarbonate; [e} Dissolution retardants, such as paraffin; '0 Absorption enhancers, such as quaternary ammonium compounds; Bee) Surfactants, such as cetyl alcohol, glycerin monostearate; (i) Lubricants such as talc, calcium and magnesium stearate and solid polyethylene glycols. Tablets, pastes, capsules and pills formed from the pharmaceutical compositions of the present invention may contain opacifying agents. It can have conventional coatings, envelopes and protective matrices. These may be configured to release the active ingredient only or preferentially in certain parts of the intestinal tract, preferably over a period of time. Coatings, envelopes and protective matrices can for example consist of polymeric substances or waxes. The active ingredient, together with one or more of the diluents mentioned above,
It can also be made into micro-encapsulated form. Diluents to be used in pharmaceutical compositions adapted to form suppositories include, for example, polyethylene glycols and fatty acids such as cocoa oil and higher esters [such as esters of C,4-alcohols and C.6-fatty acids]. ), or mixtures of these diluents. Pharmaceutical compositions, which are ointments, lipsticks, creams and gels, are prepared, for example, by the usual diluents such as animal and vegetable fats, waxes, paraffin, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, It can contain silicic acid, talc and zinc oxide or mixtures of these substances. Pharmaceutical compositions that are powders and sprays can, for example, contain the usual diluents such as lactose, talc, oxic acid, aluminum hydroxide, calcium silicates, and polyamide powder or mixtures of these substances. Aerosol propellants can, for example, contain conventional propellants, such as chlorofluorohydrocarbons. Pharmaceutical compositions that are solutions and emulsions (subject to the above exclusion of solvents having a molecular weight lower than 200, of course, except in the presence of surfactants), include, for example, solvents, solubilizers and It may contain conventional diluents such as emulsifiers; specific examples of such diluents are water, ethyl alcohol, inpropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, pendyl benzoate, propylene glycol. , 1,3-butylene glycol, dimethylformamide, oils (eg peanut oil), glycerin, tetrahydrofurfuryl alcohol, polyethylene glycol and sorbitol, or mixtures thereof. For parenteral administration, solutions and emulsions must be sterile;
In addition, if necessary, the blood must be isotonic. Pharmaceutical compositions that are suspensions may be prepared using conventional diluents such as liquid diluents such as water, ethyl alcohol, propylene glycol, surfactants such as ethoxylated isostearyl alcohol, polyoxyethylene sorbate, etc. and sorbitan esters), microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, or mixtures thereof. All of the pharmaceutical compositions according to the invention may also contain colorants and preservatives and flavorings and flavorings (eg oil of mint and eucalyptus) and sweetening agents (eg saccharin). Pharmaceutical compositions according to the invention generally have between 0.1 and 0.1 of the total composition.
99. Furthermore, it usually contains 0.5 to 99.5% by weight of active ingredient. In addition to the compounds of the invention, the pharmaceutical compositions and medicaments according to the invention can contain other therapeutically active compounds. They can also contain more than one compound of the invention. All diluents in the medicament of the invention may be any of those mentioned above with respect to the pharmaceutical compositions of the invention. Such agents can contain a solvent of molecular weight less than 200 as the sole diluent when a surfactant is present. The separate joined parts 2 constituting the medicament according to the invention are generally adapted for pharmaceutical administration by their shape or packaging and can be, for example, any of the following: tablets (lozenges and jaws). (including granules), pills, bran, capsules, suppositories and ampoules. Some of these shapes can be tailored to provide delayed release of the active ingredient. Some, such as capsules, include a protective envelope that physically separates and brings together the portions of the drug. A suitable daily dose for administration of the medicament of the invention is 0.5 to 30 minutes of active ingredient. The manufacture of the above pharmaceutical compositions and medicaments can be carried out by any known method, for example by adding the active substance(s) to the diluent(s).
and forming a pharmaceutical composition (eg, granules) and then forming the composition into a medicament (eg, a tablet). Furthermore, the present invention provides a method for combating (preventing, mitigating and (including treatment). These active compounds can be considered for administration orally, parenterally (for example intramuscularly, intraenterically and intravenously), rectally or topically, preferably parenterally, especially intravenously. . In general, both in human medicine and in veterinary medicine, to obtain the desired results, the active compound or active compounds according to the invention must be used at a dose of 2/9 kg of body weight.
For each unique period, the total amount is about 10 to about 300, preferably 5
It has been found advantageous to administer in amounts of 0 to 20, optionally in divided dosage form. However, deviations from the above dosages may be necessary, in particular with regard to the nature and weight of the subject to be treated, the type and severity of the disease, the nature of the formulation and drug administration and the time or interval at which the administration is carried out. and such a thing may be necessary. Thus, in some cases it may be sufficient to treat with less than the above-mentioned amounts of active compound, whereas in other cases higher amounts of active compound are required.
The optimal dosage and method of administration of the active compound required in a particular case can be readily determined by those skilled in the art, based on their expertise. The LD5o of the active compounds according to the invention is between 200 and 1500 9/kg body weight. Examples AC below illustrate the antifungal activity of the compounds used in this invention. In addition, in Examples A to C, the compound numbers correspond to the manufacturing example numbers described later. EXAMPLE A Description of In Vitro Antifungal Activity Experiment In vitro testing was carried out by a type of dilution test using a bacterial inoculum with an average of 5 x 1 bacteria per heart of substrate. The nutrient medium used was {a'Milieud' Milieud for Dermatophytes and Molds.
epresive) as well as 'b} Sensites from oxoid for yeast.
tBroth). The culture temperature was 28qo;
The incubation time was 2 hours for yeasts and 9 hours for dermatophytes and molds. Table A: Test tube example B In vivo antifungal activity against candidiasis in 20-day-old mice (
Experimental description: GF, strain white mice weighing 20-22 days were injected with 2 x 1 Candida cells (injection) in physiological saline by puncture of the tail vein. Infection was carried out intravenously with a dose of 0.2'). 6 days or more after infection. Within 90% of untreated animals died from this infection. The mortality rates for infected mice and mice treated orally twice a day with different doses of the active compound according to the invention and the comparison substance starting from the day of infection are summarized in Table B. Twenty animals were used per dose group and control group. Table B: Survival rate after oral treatment of Candida-infected 20-day-old mice 2 x 50 females/kg 2 Description: The shaved, unscarred backs of Purbright-white guinea pigs were infected with microspore and macrospore suspensions of P. aeruginosa. In untreated animals, a typical 18/2 dermatophytosis occurs within 12 days after infection, with redness, shoulder drop, and hair loss up to total integument loss at the point of infection.
0 14/20 10/2020/20 17/20
15/20 *Clinical diagram develops. Infected animals were treated with formulation '7 starting 3 days after infection.
) and (9} were treated topically once a day with a 1% concentration polyethylene glycol solution.
After 4 days, the untreated control animals showed the typical clinical picture of dermatophytosis, but both test formulations completely inhibited the course of the infection, ie had therapeutic activity. The following Preparation Examples illustrate the preparation of the active compounds and related compounds of the invention. Production Example 1 (Method a) 25.8 mol (0.1 mol) of 11(2,4-dichlorophenyl)111(hydroxy-21(imidazole-1)
-yl)-ethane is dissolved in 200 °C of chloroform and the solution is added dropwise into a mixture of 60% pure sodium hydride and 100 °C of chloroform. The reaction mixture is then heated under reflux for about 1 hour. After cooling, the sodium salt thus obtained was added at room temperature to 3
5.4 hours (0.2 mol) of 4-chlorobenzoyl chloride are added dropwise. The mixture is allowed to stand overnight at room temperature, concentrated somewhat, and then washed with water. After drying over sodium sulfate, the mixture is further concentrated by distilling off the solvent. Add naphthalene disulfonic acid to the residue. The resulting crystalline salt is separated in an oven and dried. 1-(4-
Chlorobenzoyloxy)-1-(2,4-dichlorophenyl)-2-(imidazol-1-yl)-ethanenaphthalenedisulfonate is obtained. Preparation of Precursor 25.5 molar (0.1 mol) imidazole-1-
After dissolving 12,4-dichloroacetophenone in 300 methanol, 4 min (0.1 mol)
of sodium borohydride was placed between 5 and 10 am,
Add little by little while worshiping the lights. The mixture is then allowed to stand at room temperature for an additional hour and then heated for one hour until weaving. After distilling off the solvent, the residue is briefly heated with 200 °C of water and 40 °C of concentrated hydrochloric acid. After making the reaction mixture alkaline using sodium hydroxide solution, the solid reaction product is filtered off. 1-(2,4-dichlorophenyl)-1-hydroxy-2-(imidazol-1-yl)-ethane, mp 90oo, after recrystallization from ligroin/isopropanol, 21.3 nights (82% of theory); get. Preparation of Starting Materials 269 molar (1 mol) of -bromo-2,4-dichloroacetophenone is dissolved in 250 molar of acetonitrile. This solution is added dropwise into a suspension of 69 ml (1 mol) of imidazole and 150 mol of potassium carbonate in acetonitrile and it is boiled under reflux. After heating for 2 hours under reflux, the cooled suspension is placed in an oven, the solvent is removed from the oven liquid, the afterglow is dissolved in ethyl acetate, and after drying over sodium sulfate, the solvent is removed. The retentate from ethyl acetate crystallizes on addition of isopropanol. Melting point 11,700 after recrystallization from ligroin/isopropanol
154 units of -(imidazol-1-yl)-2,4-dichloroacetophenone (60% of theory) are obtained. Production Example 2 (Method b) 24.5 mol (0.088 mol) of 1-hydroxy-2-(imidazol-1-yl)-1-(4-phenoxyphenyl)-ethane is mixed with enough acetic acid to cover the tip of a spatula. in 87.5' acetic anhydride with sodium,
Heat at 100 qo for 1 hour. Next, after cooling this solution, 1000
Add the water above. The sticky crystalline material that precipitates is dissolved in chloroform. The chloroform solution is washed with sodium bicarbonate and water, then dried over sodium sulfate and concentrated by evaporating the solvent under vacuum. Add naphthalene disulfonic acid to the residue. The resulting crystalline salt is separated in a furnace and dried. 1-acetoxy-2-(imidazol-1-yl)-11-(4-phenoxyphenyl)-ethanenaphthalenedisulfonate having a melting point of 193 DEG C. and a strength of 28.8 degrees (70% of theory) is obtained. Preparation Example 3 5.7 ml (0.1 mol) of methyl isocyanate and a few drops of dibutyltin dilaurate are dissolved in 25.8 ml (0.1 mol) of 1-(2,4-dichlorofluoride) in 250 m' of benzene. (enyl)-1-hydroxy-2-(imidazolyl-1-yl)-ethane while stirring. Light this mixture at 60-65 oo overnight. It is then allowed to cool, and the crystalline precipitate is filtered out and washed with ether. 25.5 pm (
1-(2,4-dichlorophenyl)-2-(imidazol-1-yl)-1-methylcarbamoyloxyethane (81% of theory) is obtained. Production Examples 4 to 10 The following production examples for general formulas are carried out in the same manner as the above production examples.

Claims (1)

[Claims] 1 Formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ where R represents a halogen, a phenyl group optionally substituted with a halogen, or a phenoxy group optionally substituted with a halogen, and R' represents a lower alkyl group or a halogen-substituted phenyl group, and n represents 0 or an integer of 1 to 5, contained as an active ingredient in 1-acyloxy-2-imizolyl-1-phenyl-ethane or a salt thereof. An antibacterial agent characterized by: 2. The antibacterial agent according to claim 1, which is in the form of a composition mixed with a liquid diluent other than a solvent having a molecular weight of less than 200, except in the presence of a surfactant. 3. The antibacterial agent according to claim 1 or 2, wherein n represents 0 or an integer of 1 to 3. 4. The antibacterial agent according to any one of claims 1 to 3, which is in the form of a sterile or isotonic aqueous solution as an active ingredient. 5. The antibacterial agent according to any one of claims 1 to 4, containing 0.5 to 95% by weight of the active ingredient. 6. The antibacterial agent according to any one of claims 1 to 4, which is in the form of a suitable dosage unit. 7. The antibacterial agent according to any one of claims 1 to 4, which is in the form of a tablet, pill, sugar coating, capsule, or suppository.