JPS5817466B2 - Process for producing [1-imidazolyl-(1)]-[2-(4'-(4''-chlorophenyl)phenoxy]-4,4-dimethyl-pentan-3-one and its salts) - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides certain novel [1-imidazolyl-(1)
] -C2-(4'-(4/I-chlorophenyl)-phenoxy)-4,4-dimethyl-pentan-3-ono and its salts, its production method, and its drugs, especially antifungal agents (
antimycotics).

It has already been disclosed that some N-trityl-imidazoles have an antifungal effect (see Belgian Patent No. 720,801).

Imidazolyl-(1)-ether-ketones with antifungal activity have also been previously disclosed (West German Published Application No. 21054).
90 and Belgian Patent No. 804092).

However, these known compounds do not always show satisfactory effects, especially when administered orally at very low doses.

Moreover, their activity spectrum is often not very broad.

According to the present invention, imidazolyl-(1)-ether-ketones of formula (1) and salts thereof are provided.

The compounds of the invention (ie compounds of formula CI and salts thereof) exhibit strong antifungal effects.

ν Among the compounds of the invention that are salts, therefore, those that are pharmaceutically acceptable are of particular interest and preference.

The compounds of the present invention are prepared by reacting the compound of formula (II) with imidazole in the presence of a dehydrating agent, and then optionally converting the resulting base into a salt.

Artificial) compounds and their salts can be converted into each other by means known per se.

Surprisingly, the imidazolyl-(1)-ether-keto/and salts thereof of formula CI) are substantially more effective than known imidazole derivatives, especially when administered orally and also when applied parenterally and topically. Shows great antifungal effect,
It is often used as a commercially available product, such as griseofulvin, tolnaftat (T
olnaftat) and Nystatin
) thicker.

When [1-hydroxy)-C2-(4'-(4//-chlorophenyl)-phe7noxy]-4,4-dimethyl-pentan-2-one and imidazole are used as starting materials, the reaction process is as follows: It can be represented by the following equation: Suitable salts of the imidazolyl-(1)-ether-ketone of formula (I) are salts with physiologically acceptable acids.

Examples of such acids are hydrohalic acids, especially hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, monofunctional and difunctional carboxylic acids and hydroxycarboxylic acids such as acetic acid, maleic acid, succinic acid, fumaric acid, citric acid and tartrate. acids, salicylic acid and lactic acid, and 1,5-naphthalene disulfonic acid.

The hydroxy derivatives of formula (II) that can be used as starting materials have not been previously disclosed, but can be prepared according to known methods.

For example, it is possible to prepare an ether-ketone of formula (V) by condensing the compound (■: and (IV) [in the above formula, Hal represents a halogen atom], and then using an inert organic solvent according to a conventional method. For example, increasing the temperature in ethanol,
For example, it is produced when formaldehyde or a formaldehyde donor, such as a 40% aqueous formaldehyde solution, is reacted in the presence of an alkali, such as an aqueous sodium hydroxide solution, below the boiling point of the reaction mixture.

Diluents that can be used are all high-boiling water-immiscible organic solvents.

These preferably include aliphatic and aromatic hydrocarbons boiling above about 50°C, such as ligroin, benzene or toluene.

The reaction is preferably carried out in the presence of a dehydrating agent, such as calcined calcium carbonate or anhydrous sulfuric acid, or by using a water separation device.

The reaction temperature can be varied within a substantial range.

Generally the reaction is carried out at about 50°C to about 180°C, preferably at 80°C to about 180°C.
It is carried out at 40°C.

When carrying out the process according to the invention, compounds 1 of formula (II)
Preferably from 1 to 5, especially from 1 to 1.5, mol of imidazole and suitably from 0.5 to 20, especially from 1 to 5 mol of dehydrating agent are used per mole.

Compounds of formula (I) can be separated according to generally known conventional methods.

For example, the solvent is distilled off under vacuum and the residue is captured in methylene chloride.

The organic phase is then separated.

After drying over sodium sulfate, the solvent is distilled off under vacuum.

The resulting residue is purified by recrystallization.

If purification by recrystallization is not sufficient, it is possible to prepare the salt after distilling off the initial solvent and purify the salt by recrystallization.

The basic form of the compound of formula (I) can be liberated from the salt with the aid of a base according to known methods.

The new compounds of formula (I) and their salts exhibit very strong antifungal effects.

They have a wide spectrum of effects, such as skin fungi and yeasts, as well as against biphasic fungi and yeasts.
ungi) and molds, as well as against staphylococci and trichomonates.

Therefore, they are effective against bacterial infections in humans and animals.
Can be used successfully.

The following may be mentioned as examples of use in human medicine: Trichophytonm
e tagrophytes) and other species of trichomites, Microsporon, Epidermophyton ftoec.
osum), Blastomycstes
and cutaneous and systemic mycoses caused by diphasic fungi and molds.

The following may be mentioned as examples of use in veterinary medicine: all dermatomycoses and systemic mycoses caused by the pathogens mentioned above.

According to the invention, the compound of the invention can be used as an active ingredient in a solid or as a mixture with a liquefied gas diluent or in a liquid diluent other than a solvent with a molecular weight of less than 200 (preferably less than 350), unless a surfactant is present. A pharmaceutical composition is provided containing the agent in admixture with the agent.

Further according to the invention there is provided a pharmaceutical composition containing a compound of the invention as an active ingredient in the form of a sterile or isotonic aqueous solution.

Further according to the invention there is provided a medicament in dosage unit form containing a compound of the invention alone or in a mixture with a diluent.

The present invention further provides medicaments in the form of tablets (including sweeteners and granules), dragees, capsules, pills, ampoules or suppositories containing a compound of the invention alone or in a mixture with a diluent.

The term "drug" herein refers to a physically distinguishable mass suitable for administering a drug.

"Drug in dosage unit form" means the daily dosage of a compound of the invention or a multiple (up to 4 times) or a submultiple (up to 4 times) of the daily dosage of a compound of the invention.
means a physically distinguishable mass suitable for the administration of the drug it contains (up to 10 times less).

If the drug is a daily dose or e.g.
Whether the pharmaceutical composition according to the invention contains 3 or 1/4 will depend on whether the drug is administered once or, for example, 2, 3 or 4 times per day. They may, for example, take the form of soft powders, gels, pastes, creams, propellants (including aerosols), lotions, suspensions of the active ingredient in aqueous or non-aqueous diluents, solutions and emulsions, syrups, granules or powders. .

Diluents that may be used in pharmaceutical compositions suitable for forming tablets, dragees, capsules and pills (e.g. granules) include: (a) fillers and extenders, such as starches; , sugars, mannitol, and silicic acids; (b) binders, such as carboxymethyl cellulose and other cellulose derivatives, alginates, gelatin and polyvinylpyrrolid; (c) wetting agents, such as glycerol; (d) disintegrants, such as Agar - agar, calcium carbonate and sodium bicarbonate = (e) dissolution retardant, e.g. paraffin; resorption enhancer, e.g.
Ammonium compound = (g) surfactant, e.g. cetyl alcohol, glycerol moa/stearate); (h)
Adsorption carriers such as kaolin and bentonite): (i) Lubricants such as talc, calcium and magnesium stearate and solid polyethylene chloride.

Tablets, dragees, capsules, and pills formed from the pharmaceutical compositions of the present invention may have conventional coatings, wrappers, and protectors that may contain opacifying agents.

They can be shaped so as to release the active ingredient, preferably in a particular part of the gastrointestinal tract, preferably over a period of time.

Coatings, wrappers and protectors may be made from polymeric substances or waxes, for example.

The ingredients may be in the form of microcapsules together with one or more of the diluents mentioned above.

Diluents used in pharmaceutical compositions suitable for forming into suppositories include, for example, common water-soluble or water-insoluble diluents such as polyethylene glycols and fats such as cocoa oil and C14 alcohols and Cta fatty acids. higher esters) or mixtures of these diluents.

Pharmaceutical compositions which are pastes, creams and gels can be prepared, for example, by using the usual diluents such as animal and vegetable fats, waxes, paraffin, starches, gum tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites,
It may contain silicic acid, talc and zinc oxide or mixtures of these substances.

Pharmaceutical compositions which are powders and propellants can be prepared, for example, by using common diluents such as lactose, talc, silicic acid, aluminum hydroxide,
It contains calcium silicate, and polyamide powder or a mixture of these substances.

Aerosol propellants include, for example, common propellants, such as chlorofluorohydrocarbons.

Pharmaceutical compositions that are solvents and emulsions contain, for example, the usual diluents (excluding, as mentioned above, solvents with a molecular weight of less than 200, unless of course a surfactant is present), e.g. a solvent that dissolves the drug and an emulsifier. I can do it.

Special examples of such dilutions are water, ethyl alcohol,
Isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g. ground nut oil), glycols, tetrahydrofurfuryl alcohol, polyethylene glycol and It is a fatty acid ester of sorbitol or a mixture thereof.

For parenteral administration, solutions and emulsions should be sterile and suitably isotonic with blood.

Pharmaceutical compositions that are suspensions can be prepared using conventional diluents such as liquid diluents such as water, ethyl alcohol, propylene glycol, surfactants such as ethoxylated instearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microorganisms, etc. It may contain microcrystalline cellulose, aluminum methyhydroxide, bentonite, agar and tragacanth, and mixtures thereof.

All pharmaceutical compositions according to the invention may also contain colorants and preservatives, as well as perfumes and flavoring agents (eg pepper oil and eucalyptus oil) and sweetening agents (eg saccharin).

The pharmaceutical composition according to the invention has a total composition of about o,i to 99
．． 5, preferably about 0.5 to 95% by weight of active ingredient.

In addition to the present compounds, pharmaceutical compositions and medicaments according to the invention include:
It may also contain other pharmacologically active compounds.

Furthermore, they may contain more than one compound of the invention.

The diluent in the medicament of the invention may be any of those described above with respect to the pharmaceutical composition of the invention.

Such agents may also contain a solvent having a molecular weight of less than 200 as the sole diluent.

The distinct bulk portions (either in dosage unit form or otherwise) constituting the medicament of the invention may be, for example, any of the following: tablets (including sweetened tablets and granules); Pills, dragees, capsules, suppositories and ampoules.

Some of these forms are designed to retard the release of the active ingredient.

Such capsules contain a protective enclosure that makes the portions of the drug physically distinct and agglomerated.

Suitable daily doses for human administration of the drug are 0.5 to 509 parts of active ingredient.

The manufacture of the above-mentioned pharmaceutical compositions and medicaments may be carried out according to methods known in the art, for example by mixing the active ingredient with a diluent to produce a pharmaceutical composition (e.g. granules) and then converting the composition into a medicament (e.g. tablet). This is done by K-molding.

It will be understood that the active compound may be administered orally, parenterally (for example intramuscularly, intraperitoneally or intravenously), rectally or topically, preferably orally or topically.

Suitable pharmaceutical compositions and medicaments are therefore those suitable for oral or topical administration such as tablets, pills, dragees, capsules, lozenges, gels, creams, sprays or lotions.

Administration in this method is preferably oral administration.

Generally, for effective results, 10 to 3
001n9/9 body weight, preferably 5O-200In9
It has proven advantageous to administer in an amount of 7 to 9 body weight.

nevertheless deviating from these dosage proportions;
In particular, doing so as a function of the nature and body weight of the human being or animal to be treated, the individual response of that being treated, the type of formulation and mode of administration in which the active ingredient is administered, and the course of the disease or the interval at which it is administered. is especially necessary.

That is, in some cases it may be sufficient to use less than the above-mentioned minimum dosage proportions, while in other cases more than the above-mentioned upper limit will give desirable results.

When administering large amounts, it is expedient to divide these into several doses over the course of the day.

) The microbiological activity of the active compounds which can be used according to the invention can be demonstrated in the following in vitro and in vivo experiments.

According to these documents, the preparation can be described as a highly effective antifungal agent that is well tolerated and has a broad spectrum of action for oral and parenteral administration and for topical application.

They are superior to clotrimazole and miconazole (all other azole derivatives) because of their efficacy at very low doses after oral administration, and because of their great potential for action. It is superior to griseofulvin, tolnafat, nystatin and pimaricin because of its broad spectrum, and is superior to amphotericin (Amphoter) because of its substantially lower toxicity.
i-c 1n) was found to be superior to B.

(1) Activity in vitro The preparation according to the invention exhibits a wide range of activity in vitro against bacteria, Gram-positive bacteria and trichomonades, which are pathogens of humans and animals.

The table below shows representative bacterial species, Staphylococcus aureus (Staphy
loccocus aureus and Trichomonas vaginalis (
MIC values of the preparations are shown in comparison to Trichomonas vaginalis).

The activity is based on the Sabrou-MiIJ Au-Debroub (Sab
Ouraud's m111ieud'epre
uve), gravy-glucose, bouillon, Francis blood sugar and Kimmitsuhi malt extract-peptone medium.

The culture temperature was 28 and 37℃, and the culture time was 24.4℃.
8 and 96 hours.

The inoculum was in each case 5 x 103 spores/substrate rni.

The experimental results are summarized in Table A and compared with two commercial preparations.

Table B shows the effects of some conventionally known imidazolyl-(1)-ether derivatives.

These results show that the compounds of the invention have activity against skin fungi and yeasts, and against biphasic fungi and molds, and also against staphylococci and trichomonates.

The antifungal effect is mainly due to fungi
c); bactericidal action can be achieved at 2 to 4 times the minimum inhibitory concentration in vitro and in vivo, with a reduction in inoculum of more than 99%.

The development of resistance in initially susceptible spores is achieved by the passage method and by the Szibalsky technique.
ue) was not found.

This means that even if the development of resistance occurs, it will occur gradually and through a multipie-step process.
scheme ) K Therefore, it can be said that it occurs.

→(2) Activity in vivo This preparation is effective when administered orally or parenterally to infected test animals, or when applied locally, in vivo in cases of dermatomycoses and systemic mycoses. It also has therapeutic effects.

(a) Effects upon oral administration (I) For mouse cassidosis, CF18PF white mice were infected intravenously with 1 to 3 x 106 Candida cells by puncturing the tail vein. Ta.

Untreated control animals died on days 3-6 post-infection as a result of intraluminal development of candidiasis.

When the preparation was orally administered at a dose of 2 x 6.25 to 2 x 1100 Ir1/unit body weight, the following survival rates were found starting from the day of infection and up to the 5th day (Table C).

The already known imidazolyl-(1)-ether derivatives of Table B show a survival rate of about 75-85% at 6 days post-infection when administered twice daily at a dose of 50-125rn9/body weight. Ta.

Wholesale Hair Healing Bacteria and Trichophyton Fin Care '5'
= A (For mouth disease in mice and guinea pigs caused by Trichophyton quinckeanum%; Mice (CF18PF) and guinea pigs (pearly white) were given a suspension of spores of Trichophyton quinckeanum and Trichophyton quinckeanum on their backs. was infected.

In untreated comparison animals, symptoms of dermatomycosis, typically caused by the pathogen, developed within 12 days after infection.

Oral doses of the preparation according to the invention from 1x25 to 1x100/day per body weight on days 3 to 12 after infection suppressed the development of experimental dermatomycoses.

The already known imidazolyl-(1)-ether derivatives of Table B did not exhibit this overall effect.

(b) Effect of topical application on guinea pig palatiasis.

The backs of animals weighing 400-5009 kg were infected with a suspension of spores of the common form of the white mole mono MC1.

For topical treatment, polyethylene glycol 1 in 400
The preparation as a % solution was applied as a thin layer to the infected area once a day from day 4 to day 13 after infection and rubbed in lightly with a corner spatula.

The table below shows the therapeutic efficacy of the preparation compared to untreated control animals (Table D).

(e) Guideline data on pharmacodynamics after oral administration.

This preparation is well absorbed when administered orally to mice and guinea pigs, with 4 to 6
Serum peak concentration of γ/stile.

The elimination half-life is approximately 4.5-5.5 hours; approximately 20% elimination occurs in the kidneys, with ~70% being excreted in bile and feces.

(d) Acute Toxicity and Tolerability When administered orally to mice, rats and guinea pigs, the above-mentioned preparations exhibited an LD5o of 750-1200~/unit body weight.

The 1% solution was well tolerated by the skin when applied topically.

Production Example Example 1 (1-(4'-(4//-chlorophenyl)-phenoxy)-3,3-dimethyl-butan-2-one 30.39
(0.1 mol) was suspended in ethanol 200 rILAK.

30 ml of formalin solution and 30 ml of 10 ml of sodium hydroxide solution were added.

After heating under reflux for 4 hours, the solvent was removed under vacuum.

The remaining oil was captured in 200 g of toluene and after addition of imidazole 11 (0.15 mol) the mixture was heated under reflux overnight.

The solvent was then removed in vacuo, the residue was taken up in ether and the solution was washed repeatedly with water.

The organic phase was dried over sodium sulfate and diluted with 30% hydrochloric acid in ether.
rnA was added.

After distilling off the solvent under vacuum, diethyl ether 100-
and ethyl acetate 50I72A were added.

The mixture was stirred until crystallization began.

The crystals were separated, washed with an ether/ethyl acetate mixture,
Dry.

[1-imidazolyl-(1)] with a melting point of 178-180°C
)-C2-(4'-(4//-chlorophenyl)-phenoxy)-4,4-dimethyl-pe/tan-3-one hydrochloride 13.8 p (theoretical amount of 33 p) were obtained.

Example 2 The free base of Example 1 was obtained by adding a calculated amount of triethylamine in ethyl acetate to the hydrochloride salt according to the method described above, separating the precipitated triethylamine hydrochloride with P and distilling off the solvent under vacuum. Ta.

Its melting point was 122-124°C.

The following compounds were obtained in the same manner: The embodiments of the present invention and related matters are summarized as follows: 1. Formula %(4-chlorophenyl)-fair/xy)-4, 4-dimethyl-pentacy-3-one or a salt thereof.

2. The compound according to 1 above, which is a salt of hydrohalic acid, nitric acid, mono- or difunctional carboxylic acid or hydroxycarboxylic acid.

3. The compound according to 1 above, which is a salt of hydrochloric acid.

4. A compound according to any of Examples 3 to 5 as specifically described, other than the compound according to 3 above.

5. [1-imidazolyl-m)-CZ-(4
'-(4/-chlorophenyl)-phenoxy)-4,4
- A method for producing dimethyl-pentan-3-one or a salt thereof.

6. The method of 5 above, wherein the dehydrating agent is calcined calcium carbonate or anhydrous sodium sulfate.

7. The above 5 or 6 in which the reaction is carried out at a temperature of 50 to 180°C
method.

8. The above 5-- using 1 to 5 mol of imidazole and 0.5 to 20 mol of dehydrating agent per mol of compound of formula (ID7)
Method according to any of 7.

9. A process for preparing a compound according to 1 above, substantially as described above in Example 1 or 2.

10. A compound according to 1 above, produced by a method according to any one of 5 to 9 above.

11. A compound according to any of 1 to 4 and 10 above as an active ingredient, as a solid or as a mixture with a liquefied gas diluent, or with a molecular weight of 2 unless a surfactant is present.
1. A straw manufacturing composition characterized in that it is contained in a mixture with a liquid diluent other than a solvent of 0.00 or less.

12. A pharmaceutical composition containing a compound according to any of 1 to 4 and 10 above as an active ingredient in the form of a sterile or isotonic aqueous solution.

13. The composition according to 11 or 12 above, containing the active ingredient in an amount of 0.5 to 95% by weight.

14. A medicament in dosage unit form containing a compound according to any of 1 to 4 and 10 above, alone or in admixture with a diluent.

15. A medicament in the form of a tablet, pill, dragee, capsule, ampoule, or suppository containing a compound according to any of 1 to 4 and 10 above, alone or mixed with a diluent.

16. An active compound according to any of 1 to 4 and 10 above, alone or in a mixture with a diluent, or 1 above.
A method for controlling fungal diseases in humans and non-human animals, which method comprises administering to the animal in the form of a drug according to No. 4 or No. 15.

17. The method according to 16 above, wherein the active compound is administered in an amount of 10 to 300 WU9/body weight per day.

18. The method according to 16 or 17 above, wherein the active compound is orally administered.

19. Compounds according to 1 above as described in any of Examples 3-5.

20. 11 above, wherein the active ingredient is a compound according to 19 above.
A composition according to any one of 13 to 13.

21, 14 above, wherein the compound is the compound according to 19 above;
or a drug according to 15.

22, 1 above, wherein the active compound is a compound according to 19 above;
The method according to any one of 6 to 18.

Claims (1)

[Scope of Claims] [1-Imidazolyl-(1) ] -C2
-(4'-(4//-chlorophenyl)-phenoxy)
A method for producing -4,4-dimethyl-pentan-3-ono or a salt thereof.