CH617682A5 - Process for the preparation of novel 1-imidazol-1-yl-2-(4'-(4''-chlorophenyl)phenoxy-4,4-dimethylpentan-3-on e and its salts - Google Patents

Description

617682

2nd

PATENT CLAIM Process for the preparation of new [l-imidazolyl- (l)] - {2- [4 '- (4 "-chlorophenyl) -phenoxy]} - 4,4-dimethylpentan-3-one of the formula ol ^ t ^ / ^ -o-ch-qq-0 (chj) ^

Gift, not always a satisfactory effect. In addition, their range of effects is often not very broad.

It was found that the new imidazolyl (l) ether ke-clay of the formula (I)

!! _ // \\ _ /> v chr

(I)

ù

and its salts, characterized in that the compound of the formula

C ° "C (GH5) 3

Oh"

I 2

oh reacted with imidazole in the presence of dehydrating agents and optionally produces salts from the base obtained.

10th

-oh-co-c (ch5) 5

ch «

I 2

n

(I)

O

15

and its salts have strong antifungal effects.

20 It was further found that the imidazolyl (l) ether ketone of the formula (I) according to the invention is obtained if the compound of the formula (II)

25th

30th

Cl - ^^ ~ ^^ - 0-CH-C0-C (CH3) 3

CHr

I '

OH

(II)

The present invention relates to a process for the preparation of new [l-imidazolyl- (l)] - {2- [4 '- (4 "-chlorophenyl) -phenoxy]} -4,4-dimethyl-pentane-3- on and its salts, which can be used as medicines, especially as antifungals.

It has already become known that some N-trityl-imidazoles have an antifungal effect [see Belgian patent specification 720 801].

Antimycotically active imidazolyl (1) ether ketones are also already known [compare German Offenlegungsschrift 2 105 490 and Belgian patent 804 092]. However, these show, especially at very low doses, after oral treatment with imidazole in the presence of dehydrating agents and, if appropriate, produce a salt 35 from the base obtained.

Surprisingly, the imidazolyl (l) ether ketone obtained according to the invention and its salts have a considerably higher antifungal activity, especially when administered orally, but also when administered parenterally and locally, than the imidazole derivatives known from the prior art and also as the known commercial products, such as Griseo-fulvin, Tolnaftat and Nystatin. The substances mentioned thus enrich the pharmaceutical industry.

If [1-hydroxy] {2- [4 '- (4 "-45-chlorophenyl) phenoxy]} -4,4-dimethyl-pentan-2-one and imidazole are used as starting materials according to the invention, the course of the reaction can be carried out by the following formula scheme is shown:

01-

V / \

0-CH-C0-C (0H,),

I 3 3

CHp

I.

0h

-h2o

3rd

617682

Preferred salts of the imidazolyl (l) ether ketone of the formula (I) are those with physiologically tolerated acids. Examples of such acids are the hydrohalic acids, in particular hydrochloric acid, phosphoric acid, nitric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, e.g. Acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, sorbic acid, lactic acid, 1,5-naphthalenedisulfonic acid.

The hydroxy derivative of the formula (II) to be used as the starting material is not yet known, but can be prepared by known processes. It is obtained, for example, if this is obtained from the compounds (III) and (IV)

> \ V // \\ - 0h

(Iii)

(IV)

ci

Hal-CH2-CO-C (CH3) s in which

Shark represents halogen,

condensed ether ketones of formula (V)

ai - ^^ - ^) - o-CH2-oo-G (aH5) 3 (V)

by conventional methods in the presence of alkali, e.g. aqueous sodium hydroxide solution, with formaldehyde or formaldehyde-releasing agents, e.g. a 40% aqueous formaldehyde solution in an inert organic solvent, e.g. Ethanol, at elevated temperature, e.g. Reacting boiling temperature of the reaction mixture.

All inert, higher-boiling, water-immiscible organic solvents are particularly suitable as diluents. These preferably include aliphatic and aromatic hydrocarbons, such as ligroin, benzene or toluene, boiling from about 50 ° C.

The reaction is preferably carried out in the presence of a dehydrating agent, such as baked calcium carbonate or dry sodium sulfate, or using a water separator.

The reaction temperature can be varied over a wide range. Generally one works between about 50 ° C to about 180 ° C, preferably at 80 ° C to 140 ° C.

When carrying out the process according to the invention, e.g. to 1 mol of the compound of formula (II) preferably 1 to 5, in particular I to 1.5 mol of imidazole and optionally 0.5 to 20, in particular 1 to 5 mol of the dehydrating agent.

The compound of formula (I) can be isolated by generally known, customary methods. For example, the solvent can be distilled off in vacuo and the residue taken up with methylene chloride. The organic phase is then generally separated off. After drying over sodium sulfate, the solvent can be distilled off in vacuo. The residue obtained is e.g. purified by recrystallization. If the purification by recrystallization is not sufficient, the salt can be prepared after the solvent has been distilled off for the first time and this can be purified by recrystallization. The compound of the formula (I) can be liberated from the salt in the form of the base in a known manner using a base.

The new compound of formula (I) and its salts have very strong antifungal effects. They show a broad spectrum of activity, for example, against dermatophytes and yeasts, as well as against biphasic fungi and molds, as well as against staphylococci and trichomonas. They can therefore be used with good success against fungal infections in humans and animals.

Indications for use in human medicine include:

Dermatomycoses and system mycoses caused by Trichophyton mentagrophytes and other Trichophyton species, micro-lo sporon species, Epidermophyton floccosum, shoots and biphasic fungi, as well as molds.

Indications in veterinary medicine can include the following:

All dermatomycoses and systemic mycoses, in particular 15 those caused by the pathogens mentioned above.

In addition to non-toxic, inert, pharmaceutically suitable excipients, pharmaceutical preparations contain the compound of formula I and / or their salts, or only 20 the compound of formula I and / or their salts.

Dosage units include preparations in the form of individual parts, e.g. Tablets, dragées, capsules, pills, suppositories and ampoules are present, the active ingredient content of which corresponds to a fraction or a multiple of a single dose. The dosage units can e.g. Contain 1, 2, 3 or 4 single doses or Y, or Y of a single dose. A single dose preferably contains the amount of active ingredient which is administered in one application and which usually corresponds to a whole, a half or a third or a quarter of a daily dose.

Non-toxic, inert, pharmaceutically suitable carriers are solid, semi-solid or liquid diluents of any kind. Tablets, dragees, capsules, pills, granules, suppositories, solutions, suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays may be mentioned as preferred pharmaceutical preparations.

Tablets, dragées, capsules, pills and granules can contain the active ingredient (s) in addition to the usual carriers, such as (a) fillers and extenders, e.g. Starches, milk sugar, cane sugar, glucose, mannitol and silica, (b) binders, e.g. Carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidine, (c) humectants, e.g. Glycerin, 45 (d) disintegrant, e.g. Agar-agar, calcium carbonate and sodium arbonate, (e) solution retarders, e.g. Paraffin, and (f) absorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents, e.g. Cetyl alcohol, glycerol monostearate, (h) adsorbent e.g. Kaolin and bentonite, and so (i) lubricants, e.g. Talc, calcium and magnesium stearate and solid polyethylene glycols, or mixtures of the substances listed under (a) to (i).

The tablets, dragées, capsules, pills and granules can be provided with the customary coatings and casings, optionally containing opacifying agents, and can also be composed in such a way that they release the active ingredient or the active ingredients only or preferably in a certain part of the investment tract, if necessary with a delay , where as embedding compounds, for example Polymer substances and 60 waxes can be used.

The active ingredient (s) can, if appropriate, also be present in microencapsulated form with one or more of the above-mentioned excipients.

In addition to the active ingredient (s) 65, suppositories can contain the usual water-soluble or water-insoluble excipients, e.g. Polyethylene glycols, fats, e.g. Cocoa fat, and higher esters (e.g. Cl4 alcohol with C10 fatty acid) or mixtures of these substances.

617682

4th

In addition to the active ingredient (s), ointments, pastes, creams and gels can contain the usual carriers, e.g. animal or vegetable fats, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, concrete, silica, talc and zinc oxide or mixtures of these substances.

Powders and sprays can contain the usual excipients in addition to the active ingredient (s), e.g. Milk sugar, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances, sprays can additionally use the usual blowing agents, e.g. Chlorofluorocarbons.

In addition to the active ingredient (s), solutions and emulsions can contain the usual carriers, such as solvents, solubilizers and emulsifiers, e.g. Water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, especially cottonseed oil, peanut oil, corn oil, olive oil, castor oil and sesame oil, glycerol, tetra-alcohol form, glycerol formin , Polyethylene glycols and fatty acid esters of sorbitan or mixtures of these substances.

For parenteral administration, the solutions and emulsions can also be in sterile and blood isotonic form. In addition to the active ingredient (s), suspensions can contain the usual carriers, such as liquid diluents, e.g. Water, ethyl alcohol, propylene glycol, suspending agents e.g. contain ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar agar and tragacanth or mixtures of these substances.

The formulation forms mentioned can also colorants, preservatives and use u. flavor-enhancing additives such as Peppermint oil u. Eucalyptus oil and sweeteners, e.g. Saccharin.

The therapeutically active compounds should be present in the pharmaceutical preparations listed above, preferably in a concentration of about 0.1 to 99.5, preferably about 0.5 to 95 percent by weight of the total mixture.

In addition to the compound of the formula I and / or the salts thereof, the pharmaceutical preparations listed above can also contain other active pharmaceutical ingredients.

The pharmaceutical preparations listed above can be prepared in a customary manner by known methods, e.g. by mixing the active substance or substances with the carrier substance or substances.

The active substances or the pharmaceutical preparations can be applied locally, orally, parenterally, intraperitoneally and / or rectally, preferably orally or locally.

In general, it has proven to be advantageous in both human and veterinary medicine to achieve the active ingredient (s) in amounts of about 10 to 300, preferably 50 to 200 mg / kg body weight per 24 hours, preferably in the form of several individual doses to deliver the desired results. However, it may be necessary to deviate from the doses mentioned, depending on the type and severity of the disease, the type of preparation and administration of the medicament, and the period or interval within which the administration takes place. In some cases it may be sufficient to manage with less than the above-mentioned amount of active ingredient, while in other cases the above-mentioned amount of active ingredient is exceeded. The determination of the respectively required optimal dosage and type of application of the active substances can easily be made by any specialist on the basis of his specialist knowledge.

The good microbiological effectiveness of the active compounds obtained according to the invention can be demonstrated by the following in vitro and in vivo tests.

According to this information, the claimed preparations can be described as well tolerated and very effective antifungal agents with a broad spectrum of activity both for oral and for parenteral and local application. Compared to the prior art, they proved to be superior to clotrimazole, miconazole and all other azole derivatives due to their effectiveness at very low doses after oral administration, to criseofulvin, tolnaftate, nystatin and pimaricin due to their much broader spectrum of activity and to amphotericin B due to their significantly lower toxicity.

1. In vitro effectiveness

The preparations according to the invention show a broad activity in vitro against human and animal pathogenic fungi, gram-positive bacteria and trichomonads. The following table shows the MIC values of the preparations compared to representative fungal species, Staph. aureus and Trichomonas vaginalis compiled: The efficacy tests were carried out in a serial dilution test on Saboraud's Milieu d'épreuve, meat water and glucose broth, blood agar according to Francis and malt extract peptone medium according to Kimmig. Incubation temperatures were 28 and 37 ° C, incubation time 24-48-96 hours. The inoculum was uniformly 5 X 103 germs / ml substrate.

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

The effects of some already known imidazolyl (l) ether derivatives are shown in Table B.

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

5

TABLE A: In Vitro Efficacy

617682

MIC values in y / ml nutrient medium

5 H

• 2. ° o W

Ó «

O

Germ species

A nF / = *

o r — 1

O

Griseofulvin

Nystatin

Trich. ment.

1

5-10

20th

Microsporon canis

1

5-10

20-40

Candida albicans

2-4

100

5

Torulopsis glab.

4th

100

5

Cryptococcus neof.

1-2

100

4-10

Aspergillus spec.

1

40-100

40-100

Sporothrix Schenckii

0.1

100

40

Coccidioides immitis

0.1

100

40

Pityrosporum oval

1

100

1

Staph. aureus

4th

100

100

Trichomonas vaginalis

100

1000

1000

TABLE B

In vitro effectiveness of known imidazolyl (l) ether derivatives

connection

MIC values in y / ml nutrient medium in Trichophyton Candida Mikrosporon Aspergillus ment. albicans felinum spec.

I Ii x HCl

40

100

40

40

617682

6

TABLE B (continued)

connection

MIC values in y / ml nutrient medium in Trichophyton Candida Mikrosporon Aspergillus ment. albicans felinum spec.

0 -C 0- ^ y

N

O

10 10 40 10

PO-CH-CO - ^ / ^

à "

10 40

40

Cl-Z ^ -O ^ H-CO-C (CH3) 3

? H2

Ù

(GH3) 3

GH0 l ^

, N

rì

1 N

x HCl

0-G (GH3) 3

JL? H2

X HCl

8 4

0- (j! H-C0-0 (GH3) 3

OH,

A

1 N

7

617682

According to these results, the compounds claimed act both against dermatophytes and yeasts and against biphasic fungi and molds and against staphylococci and trichomonads.

The type of antifungal activity is primarily fungistatic; Fungicides with a reduction in the inoculum of more than 99% can be achieved with the 2-4-fold minimum inhibitory concentrations in vitro and in vivo.

A resistance development of primarily sensitive germs could not be found in the passage method and in the Szibalsky technique. This makes it possible to state that resistance developments - if at all - occur slowly and according to the multiplestep scheme.

2. In vivo effectiveness

The claimed preparations are also curatively effective in vivo on infected test animals with oral, parenteral and local application for dermatophytoses and systemic mycoses.

a) Effect with oral application

I) on the model of the experimental candidiasis of the mouse. White mice of the CFjSPF strain are treated with 1-3 X 106 Candida albicans cells i.v. infected by puncture of the tail vein. Untreated control animals die from the developing organ candidiasis from 3rd to 6th Day p.i. If the claimed preparations are given orally in doses of 2 X 6.25 - 2 X 150 mg / kg body weight, starting from the day of the infection up to the 5th day p.i., the following survival rates result (Table C):

TABLE C

Effect with oral application on the model of the experimental candidiasis of the mouse

The already known imidazolyl (l) ether derivatives in Table B show survival rates of approx. 75% to 85% on the 6th day p.i. at a dose of 50 mg / kg body weight to 125 mg / kg body weight twice a day.

s

II) On the model of experimental mouse and guinea pig trichophytia by Trich. mentagrophytes and trich. Quinckeanum:

Mice (CFjSPF) and guinea pigs (Pearl-bright-io white) are on their backs with spore suspensions from Trich. ment, or trich. Quinckeanum infected. In the untreated control animals, p.i. the pathogen-typical clinical pictures of dermatophytosis. 15 With oral doses of 1 X 25 to 1 X 100 mg / kg body weight from 3rd to 12th Day p.i. when applied, the preparations according to the invention completely suppress the development of experimental dermatophytoses.

The already known imidazolyl (l) ether derivatives in Table B 20 do not show this total effect.

b) Effect with local application on the model of experimental guinea pig trichophytia.

White guinea pigs weighing 400-500 g are placed on the back with a spore suspension from Trich. 25 ment, infected in the usual form. For local therapy, the claimed preparations - 1% dissolved in polyethylene glycol 400 from 4th to 13th Day p.i. applied thinly to the infection site once a day and lightly rubbed with a horn spatula. The following table 30 shows the curative effects of the preparations compared to the untreated control (Table D):

TABLE D

Effect with local application on the model of experimental guinea pig trichophytia

35

Survival rates on day 6 p.i. in '

1 at

Dose in mg / kg body weight

Nystatin 40

Preparation o W

M

Intensity of the curative effect with local application on day 13 p.i.

45

(CH3 h

CH,

n q

x HCl

50 control

-1-I-h / H-I-I-h strong

Dermatophytosis o

2nd

X

6.25

85

2nd

X

12.5

85

2nd

X

25th

90

2nd

X

50

100

2nd

X

100

100

2nd

X

150

100

<10

<10

<10

<10

30 50

+ + + = good effect, i.e. only slight signs of infection + + + + = very good effect, i.e. no signs of infection 55 found.

c) Orientative information on pharmacokinetics after oral administration.

After oral administration 60, the claimed preparations are well absorbed in mice and guinea pigs and, after doses of 50 mg / kg body weight, provide peak serum concentrations of

65

Controls 3-5% on average

617682

8th

4-6 y / ml at

G 1- ^ 2 ^ - ^) "° - ° H" c 0-0 ^ CH3 H

CH «..

I 2

ü

x HCl

The elimination half-life is approximately 4.5-5.5 hours; Elimination is about 20% renal and • —70% faecal via bile.

d) Acute toxicity and tolerability.

After oral administration, the preparations mentioned showed an LD50 of between 750 and 1200 mg / kg body weight in mice, rats and guinea pigs. The skin tolerance with local application of 1% solutions was excellent.

10th

15

Phase is dried over sodium sulfate and mixed with 30 ml of ethereal hydrochloric acid. After the solvent has been distilled off in vacuo, 100 ml of diethyl ether and 50 ml of ethyl acetate are added. The mixture is stirred until crystallization begins. The crystals are filtered off, washed with an ether / ethyl acetate mixture and dried.

13.8 g (33% of theory) [l-imidazolyl- (l)] - {2- [4 '- (4' '-chlorophenyl) -phenoxy]} -4,4-dimethyl-pentane are obtained 3-one - hydrochloride with a melting point of 178-180 ° C.

Example 2

G1O ^) - ° 1H-G0-c (ch3 b

ÇH2 N.

20th

O

Production Examples Example 1

Cl - ^^ - ^^ - O-CH-CO-C (CH ,;)

)He

A Lü

x HCl

The free base of Example 1 is obtained by the route described there, by adding the calculated amount of triethylamine in ethyl acetate to the hydrochloride and suctioning off the precipitated triethylamine hydrochloride and distilling off the solvent in vacuo. The melting point is 115-116 ° C.

30 In an analogous way one obtains

Example No.

structure

35

30.3 g (0.1 mol) of {l- [4 '- (4 "-chlorophenyl) -phenoxy]} - 3,3-dimethyl-butan-2-one are suspended in 200 ml of ethanol. 30 ml of 30% formalin solution and 3 ml of 10% sodium hydroxide solution. After heating for 4 hours under reflux, the solvent is distilled off in vacuo. The remaining oil is taken up in 200 ml of toluene and after the addition of 10 g (0.15 mol) of imidazole The solvent is distilled off in vacuo, the residue is taken up in ether and washed several times with water

x hno,

40

45

q x H, P04 x H2S04

Melting point

3 ci - <^ <Q-o-ch-S-c (ch3) 3 170 ° dec.

196 ° C 153 ° C

v