CA1048512A - 1-(imidazol-1-yl)-2-(4-(4-chlorophenyl) phenoxy)-4,4-dimethylpentan-3-one, its salts and a process for their preparation - Google Patents

Abstract

1-(IMIDAZOL-1-YL)-2-[4-(4-CHLOROPHENYL)PHENOXY]-4,4-DIMETHYLPENTAN-3-ONE, ITS SALTS AND A PROCESS
FOR THEIR PREPARATION

Abstract 1-(Imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one of the formula:

Description

Detailed Description The present invention relates to l-(imidazol-l-yl)-

2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one and its salts, to a process for their preparation and to their antimicrobial ùse.
It ~s known that some N-tritylimidazoles exhibit an antimycotic effect; see e.g., Belgian Patent Specification No. 720,801. Antimycotically active imidazolyl-(l)-ether-ketones have also already been disclosed; see e.g., German Offenlegungsschrift 2,105,490 and Belgian Patent No. 804,092.
However, these compounds are not always satisfactory particu-larly when administered orally at very low doses. Furthermore their antimycotic spectrum is not very broad.
The present invention provides an imidazol-l-yl-ether-ketone of the formula:

; Cl~ O-fH-CO-C(CH3)3 fH2 (I) .. ~

a~d to its pharmaceutically acceptable s~lts.
` The compounds of the invention exhibit powerful antimycotic effects.
The compounds of the invention may be prepared by reactin~ a compound of the formula:
, ,, ' .

1~4~S~2 C~- I -CO-c(cH3)3 (Il) OH

with imidazole in the presence of a dehydrating agent, and, optionally converting the resulting base into a salt. The interconversion o~ ~he compound of Formula I and its salts is accomplished by convent~onal techniques.
. Surprisingly, the imidazol-l-yl-ether-ketone accord-ing to the invention, and its salts, exhibit a substantially greater antimycotic effect, particularly on oral administra-tion, and also on parenteral administration and local applica- :

tion, than known antimycotic imidazole derivatives and known and comm~rcially available products such as, for example, griseofulvin, tolnaftate and nystatin.
l-Hydroxy-2-[4-(4-chlorophenyl)pheno~y]-4,4-dimethyl-.. . .
pentan-3-one and imidazole are employed as starting materials and the course of the reaction can be represented by the follow-ing eq~ation: .
- .' ~ ~ ~ O-cu-co-c(cH3)3 ''' ' CH , . . .

-~2 > ~ ~ - O-CH-CO-c(cH3)3 , CH2 ,. I
. ~ .

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~a~48512 The above hydroxy derivative of Formula II has not previously been disclosed but can be prepared according to known processes. For example, it is obtained when 4-(4-chlorophenyl)phenol and a compound of the formula:
Hal-CH2-C0-C(C~3)3 (III) in which Hal is a halogen atom, are condensed to give 1-[4-(4-chlorophenyl)phenoxy1-3,3-dimethylbutan-2-one which is reacted in accordance with conventional techniques, in the presence of alkali, for example of aqueous sodium hydroxide solution, with formaldehyde or form ldehyde donors, for exam-.
ple a 40% strength aqueous formaldehyde solution, in an inertorganic solvent, such as ethanol, at an elevated temperature, for example at the boiling point of the reaction mixture.
In the reaction leading to the free base of the present illvention, diluents ean be used. These include all inert higher-boiling water-immiscible organic solvents, pre-ferably aliphatic and aromatic hydrocarbons which boil from approximately 50C upwards, such as ligroin, benzene and toluene. The reaction is carried out in the presence of a dehydrating agent, such as calcined calcium carbonate or dry sodium sulphate, or using a water separator. The reaction temperature can be varied within a substantial range but in general is carried out at from about 50C to about 180C, preferably from 80C to 140C.
In carrying out thP process according to the in-vention, preferably about l to about 5, especially l to 1.5, mols of imida20le and about 0.5 to about 20, especially l to

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S, mols of the dehydrating agent are employed per mol of the compound of Formula II.
The free base of Formula I can be isolated in accordance with customary methods. For e~xample, the solvent can be removed by distillation in vacuo, the residue taken up w~th methylene chloride and the organic phase separated. After drying as over sodium sulphate, the solvent is removed by dis-tillation in vacuo. The resulting residue is purified by re-crystallization one or more times. One can also prepare the salt after the first distillation of solvent and purify the salt by recrystallization. The compound of Formula I, in the form of the free base, can then be libera~ed from the salt through trea~ment with a base.
The preferred salts of the imidazol-l-yl-ether-.
ketone of Formula I are those of physiologically tolerable acids. Examples of such acids are the hydrogen halide acids, .especially hydrochloric ac~d, phosphorus acids, sulphuric 1 . ~
acit, nitric acid, monofunctional and bifunctional carboxylic scids and hydroxycarboxylic acids such as, for example, acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, Ioltric acid, salicylic acidD sorbic acid ant lactic acid, and l~S-naphthalenedisulphonic acid.
The new compound of Formula I and its salts exhibit very powerful ant~microbial effects. They display a broad 8pectrumiof action, for example against dermatophytes and yeasts and also against biphase fungi and moulds, as well as against staphylococci and trichomonades, and can thus be ;, . .
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successfully employed in combatting fungal infections in man and animals, such as dermatomycoses and systemic mycoses caused by Trichophyton mentagrophytes and other species of Tr~chophY-ton, species of Microsp~ron, EpidermophYton floccosum, blasto-mycetes and biphase fungi as well as moulds The compounds of the present invention are administered parenterally or orally in any of the usual pharmaceutical forms.
These include solid and liquid oral unit dosage forms such as tablets, capsules~ powders, suspensions, solutions, sy,~ps and the like, including sustained release preparations, and fluid in~ecta~le forms such as sterile solutions and suspensions;
The term unit dosage form as used in this specificatlon and the claims refer to physically discrete units to be administered in single or multiple dosage to animals, each unit containing a predetermined quantity of active material in association with i the required diluent, carrier or vehicle. The quantity of active material is that calculated to produce the desired thera-J peutic effect upon administration of one or more of such units.
Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted diluent pharmaceutical carrier such as an edible carbohydrate material as for example, starch. Sweetening, flavoring, pre-servative, dispersing and coloring agents can also be present.
;i Capsules are mad~ by preparing a powder mixture as described above and filling formed gelatin sheaths. A lubricant such as talc, magnesLum stearate and calcium stearate can be :, ~ .

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` 1~)48S12 added to the powder mixture as an adjuvant before the filling operat~on; a glidant such as colloidal silica may be added to improve flow properties; a disintegrating or solubilizing agent may be added to impro~e the availability of the medlcament when the capsule is ingested.

- Tablets are made by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the compound, suitably comminuted, sith a diluent or base such as starch, sucrose, kaolin, dicalcium phosphate and the like. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the resulting imperfectly formed slugs braken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, ' talc or mineral oil. The lubricated mix~ re is then compressed into tablets. The medicaments can also be combined with free flowing inert carriers and compressed into tablets directly without going through the granulating or slugging steps. A
protective coating consisting of a sealing coat of shellac, a coa~ing of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coat~lgs to distinguish different unit dosages.

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Oral fluids such as syrups and elixirs can be prepared in unit dosage form so that a glven quantity, e.g., a teaspoon-ful, contains a predetermined amount of the compound. Syrups can be prepared by dissolving the compound in a suitably flavored aqueous sucrose solution while elixirs are prepared through the use o a non-toxic alcoholic vehicle. Suspensions can be form~-lated by dispersing the compound in a non-toxic vehicle in which it is insoluble.

Fluid unit dosage forms for parenteral administration can be prepared by suspending or dissolving a measured amount of the compound in a non-toxic liquid vehicle suitable for injection such as an aqueous or oleaginous medium and steriliz-ing the suspension or solution. Alternatively a measured amount of the compound is placed in a vial and the vial and its con-tents are sterilized and sealed. An accompanying vial or vehicle can be provided for mixing prior to administration In general it has proved advantageous to administer amounts of fro~ about 10 mg to about 300, preferably from 50 to 20~, mg/kg of body weight per day to achieve effective results. Nevertheless, it is at times necessary to deviate from these dosage ra~es, and in particular to do so as a ;', ' function of the nature and body weight of the human or animal sub~ect being treated, the individual's response, the formu-lation, the stage of the disease, and the interval at which it is administered. Thus in some cases, it suffices to use less than the above-mentioned minimum dosage while in other . :
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cases the upper limit must be exceeded to achieve the desired results. Where lar~er amounts are administered it is often desirable to divide these into several indi.vidual administra-tions over the course of the day.
The microbiological activity of the active com-pounds usable according to the invention can be conveniently observed in vitro and in vivo models. As will be seen from ; these data, the compounds are well-tolerated and very effect- ;
ive antimycotics having a broad spectrum of action on oral, parenteral and local administration. They are superior to clotrimazol, miconazol and all other azole derivatives by virtue of their effectiveness at very low doses on oral ad-ministration, superior to griseofulvin, tolnaftate, nystatin ; and pimaricin by virtue of their very mNch broader spectrum of action, and superior to amphotericin B by virtue of their substantially lower toxicity.
1.) in vitro activity.
The preparations according to the invention show a broad activity, in vitro, against fungi which are pathogenic to humans and animals, Gram positive bacteria and tricho-monades. The table which follows lists MIC values of the preparations in comparison with representative species of fungi, Staph. aureus and Trichomonas va~inalis The activity was tested in the series dilution test on Sabouraud's milieu d'epreuve, meat broth-glucose, bouillon, Fr-ncis blood agar and Kimmig malt extract-peptone medium.

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The incubation temperatures were 28 and 37C and the incubation time wa~ 24, 48 and 96 hours. The inoculum wasr ~n every case S x 103 germs/ml of substrate. The results are summarized in Table A and compared with two commercially available preparations while the effects of some previously known imidazol-l-yl-ether derivatives are shown in Table B.

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The antimyoo~ic type of effect is primarily fungi-static; a fungicidal a~tion, with a reduction of the inoculum by more than 99%, is achievable with 2 to 4 times th~ m~nlmum inhibitory concentrations in vitro and in vivo.
Development of resistance o~ initially sensitive germs could not be found by the passage method and by the Szibalsky technique. This makes it possible to state that development of resistance, if it occurs at all, takes place slowly and ... .
in accordance with the multiple-step schème.
2.) in vivo activitY.

The preparations claimed also have a curative effect in vivo in the case of dermatophytoses and systemic mycoses when administered orally or parenterally or applied locally to the infected test animal, a) Effect on oral administration.

, I) on condidosis in mice.

;~ White mice of the CFlSPF strain are infected with 1-3 x 106 Candida albicans cells intravenously by puncture of the tail vein. Untreated control animals die from the 3rd to the 6th day after infection as a result of the candidosis of the organs which develops. If the preparations claimed are given orally in doses of 2 x 6.25 - 2 x 150 mg/kg of body weight, starting from the day of infection and up to the 5th day after infection, the following survival rates are observed:

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1~48512 The previously known imidazol-l-yl-ether deriva-tives in Table B show, at a dose of SO mg/kg of body weight to 125 mg/kg of body weight, given twice daily, survival rates of approximately 75~ to 85Z on the 6th day after in-fection.
II) On trichophytosis in mice and guinea pigs, caused by Trich. mentagrophytes and Trich. Quinckean~m:
Mice (CFlSPF) and guinea pigs (Pearl brigh~ white) are infected on the back with suspensions of spores of Trich.
ment. or Trich. Quinckeanum. In the case of the untreated control animals, the s~mptoms of a dermatophytosis, typical of the pathogen, developed within 12 days after infection.
Oral doses of 1 x 25 to 1 x 100 mg/kg of body weight administered from the 3rd to the 12th day after infection en-tirely suppress the development of the experimental dermato-phytoses.
b) ~ffect of local application, on trichophytosis in , guinea pigs.
White guinea pigs weighing 400-500 g are infected ~ 20 o~ the back with a suspension of spores of Trich. ment. in `¦ the usual form. For local therapy, the compounds in a 1%
il solution in polyethylene glycol 400 are applied as a thin layer to the infected area, once daily, from the 4th to the 13th day after ~nfection, a~d rubbed in lightly with a horn 8patula. Table D whi~h foll~ws shows the curative effects of the preparations in comparison to the untreated control:
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~ (~485~2 c) Guideline data on the pharmacok~netic~ after oxal administration.
The preparations claimed are resorbed well on oral administration to mice and guinea pigs and after doses of 50 mg/kg of body weight give serwm peak concentrations of

4-6 ~/ml for the case of the hydrochloride.
The elimination half-life is approx. 4.5-5.5 hours;
approx. 20~ of the elimination take~ place renally and ~70%
faecally via the bile.
d) Acute toxicity ~nd toleration.
On oral administration to mice, rats and guinea pig~, the preparation~ mentioned sh~wed an LD50 of between 750 and 1,200 mg~k~ of body weight. The toleration by skin, on local application of l~/o 8trength solutions, wa8 excellent.

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E~am~le 1 o_Cc~-CO-C(CH3)3 - L ~ x HCl , . .
i 30.3 g (0 1 mol) of 1-t~-(4-chlorophenyl)phenoxy]
:3,3-dimethylbutan-2-one were suspended in 200 ml of ethanol.
30 ml of 30% strength formalin solution and 3 ml of 10%
! strength sodium hydroxide solution were added. After heat-ing for 4 hours ~nder reflux, the solvent was distilled off ~n vacuo. The oil wh~ch remained was taken up in 200 ml of . ~ . . , ~
-1 toluene and, after addltion of 10 g tO-15 mol) of ~midazole the mixture was heated overnight under reflux. The solvent .' ' , '. ' .
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~48S12 was then dis~illed off in vacuo, the residue was taken up in ether and the solution was repeatedly washe(d with water The organic phase was dried over sodium sulphate and 30 ml of hydrochloric acid in ether was ~dded; After distilling off the ~olvent in vacuo, 100 ml of diethyl e1:her and 50 ml of ethyl acetate were added. The mixture was stirred until crystallization ~tar~ed. The crystals were filtered off, washed with an ether/ethyl acetate mixture and dried.
13.8 g (33% of theory) of 1-(imidazol-1-yl)-2-¦4-(4-chlorophenyl)phenoxy~-4,4-dimethylpentan-3-one hydro-chloride of melt~ng point 178-180C are obtained.

ExamPle 2 Cl~o-CH-CO-C ( CH3 j 3 - . ~
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The free base oi E~ample 1 was obtained in accordance with the method described there, by adding the calculated amount of triethylamine in ethyl acetate to the hydro- -. . . .
chloride and filtering ofi the triethylamine hydrochloride which had precipitated, and distilling ofi the solvent in vacuo. Th~ melting point was 122-124C.
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Claims (14)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. The process for the preparation of a compound selected from the group consisting of 1-(imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one and the pharmaceutically acceptable nontoxic acid addition salts there-of which comprises reacting imidazole with 1-hydroxy-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one in the pre-sence of a dehydrating agent and, when desired, converting the resultant base into a pharmaceutically acceptable salt through treatment with an acid.

2. A compound selected from the group consisting of 1-(imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one and the pharmaceutically acceptable nontoxic acid addition salts thereof whenever prepared accord-ing to the process of claim 1 or an obvious chemical equivalent thereof.

3. The process for the preparation of 1-(imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one ich comprises reacting imidazole with 1-hydroxy-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one and removing the water thus formed.

4. 1-(Imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one whenever prepared according to the process of claim 3 or an obvious chemical equivalent thereof.

5. The process for the preparation of 1-(imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one hydrochloride which comprises treating 1-(imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxyl]-4,4-dimethylpentan-3-one with hydrogen chloride.

6. 1-(Imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one hydrochloride whenever prepared according to the process of claim 5 or an obvious chemical equivalent thereof.

7. The process for the preparation of 1-(imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxyl-4,4-dimethylpentan-3-one nitrate which comprises treating 1-(imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one with nitric acid.

8. 1-(Imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one nitrate whenever prepared according to the process of claim 7 or an obvious chemical equivalent thereof.

9. The process for the preparation of 1-(imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one phosphate which comprises treating 1-(imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one with phofiphoric acid.

10. 1-(Imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one phosphate whenever prepared according to the process of claim 9 or an obvious chemical equivalent thereof.

11. The process for the preparation of 1-(imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one sulfate which comprises treating 1-(imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one with sulfuric acid.

12. 1-(Imidazol-1-yl)-2-[4-(4-chlorophenyl)phenoxy]-4,4-dimethylpentan-3-one sulfate whenever prepared according to the process of claim 11 or an obvious chemical equivalent thereof.

13. The process as defined in claim 1 wherein said base is converted into a hydrogen halide, phosphoric acid, sulphuric acid, nitric acid, sulphonic acid, monobasic carboxylic acid or dibasic carboxylic acid salt.

14. A salt of 1-(imidazol-1-yl)-2-[4-(4-chlorophenyl) phenoxy]-4,4-dimethylpentan-3-one with a hydrogen halide phosphoric acid, sulphuric acid, nitric acid, sulphonic acid, monobasic carboxy-lic acid or dibasic carboxylic acid whenever prepared according to the process of claim 13 or an obvious chemical equivalent thereof.