DE2430476A1 - 9-IMIDAZOLYL (1) -9- (2-METHYLPHENYL) -FLUORENE SALTS, THE METHOD FOR THEIR MANUFACTURING AND THEIR USE AS A MEDICINE - Google Patents

Description

Bayer Aktiengesellschaft 2430476

Central area of patents, trademarks and licenses

509 Leverkusen. Bayerwerk la (Pha) _lkm

Salts of 9-imidazolyl (1) -9- (2-methylphenyl) fluorene, process for their manufacture and their use as pharmaceuticals

The present invention relates to the salts of 9-imidazolyl- (1) -9- (2-methylphenyl) fluorene, a process for their production and their use as pharmaceuticals, in particular as antifungal agents with good pharmacokinetic and therapeutic Properties.

It is already known that fluorene derivatives for Regulation of the growth of higher plants can be used / "see French patents 1,455,554 and 1 475 53o, the GDR patent specification 34 214, the Austrian patent specification 241 498_7.

It is also known that azolyl fluorene derivatives are used as drugs can be used /, "see the German Offenlegungsschriften 2 oo4 697 and 2 o53 o8o_7 · The antifungal effect of 9-imidazolyl (i) -9- (2-methylphenyl) fluorene and similar compounds has also already been described / "see British Patent 1,244,798 and Belgian patent 742 389_7.

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However, the effect is not always satisfactory, especially at low concentrations, especially in the case of oral concentrations and parenteral administration. In addition, the range of applications for most of these compounds is very narrow.

It has been found that the new salts of 9-imidazolyl (l) -9- (2-methylphenyl) fluorene the formula:

X ry O

xm H ₂ O (I)

in which

S stands for a physiologically compatible acid,

η stands for an integer from 1 to 8, and m stands for an integer from 0 to 12,

have strong antifungal and particularly favorable pharmacokinetic and thus also good therapeutic properties.

It has also been found that the salts of 9-imidazolyl (l) -9- (2-methylphenyl) fluorene of the formula (i) is obtained if the 9-imidazolyl (l) -9- (2-methylphenyl) fluorene of the formula:

(II)

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with physiologically compatible acids, if necessary in
Reacts the presence of inert solvents.

Surprisingly, the salts according to the invention show des
9-Imidazolyl (l) -9- (2-methylphenyl) fluorene, in addition to a very good antifungal effect, has significantly better pharmacokinetic and therapeutic properties than the free base and the comparable imidazolyl (l) fluorene derivatives known from the prior art . The invention
Substances thus represent an enrichment of the therapy of
Fungal infections.

Using 9-imidazolyl (l) -9- (2-methylphenyl) fluorene
and nitric acid as starting materials, the course of the reaction can be represented by the following equation:

+ ENT ₃

Cooling ^ rNr ^{X m} ° ^{3 xEz} ° ⁶ CH ^ SN Π

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Physiologically acceptable acids that can be used for the implementation according to the invention include, for example: Hydrohalic acids, especially hydrochloric acid and hydrobromic acid, various phosphoric acids, nitric acid, mono- and bifunctional carboxylic acids and hydroxycarboxylic acids, such as acetic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, Sorbic acid, lactic acid, 1,5-naphthalenedisulfonic acid.

All inert organic solvents can be used as diluents. These preferably include aromatic ones Hydrocarbons such as benzene or toluene, ethers such as diethyl ether and tetrahydrofuran, halogenated hydrocarbons such as dichloromethane and chloroform, lower alkyl nitriles such as acetonitrile and ethyl acetate.

The reaction temperatures can be varied over a wide range. In general, the reaction is preferably carried out between about -20 ° and about 80 ⁰ C, between -10 and 6O ⁰ C.

When carrying out the process according to the invention, 1 mole of 9-imidazolyl (1) -9- (2-methylphenyl) fluorene is used slightly more than the stoichiometrically required amount of the corresponding acid.

The salts according to the invention are worked up and isolated by the customary methods (see preparation examples).

The new active ingredients of formula (i) have strong antifungal agents Effects on. They show a broad spectrum of activity, for example against yeasts such as Candida, Cryptococcus; Molds, such as Aspergillusj dermatophytes, such as Trichophyton, microsporon and against biphasic fungi. You can therefore with good success against fungal infections be used in humans and animals.

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As indication areas in human medicine, for example to be named:

Dermatomycoses and systemic mycoses caused by Trichophyton mentagrophytes and other Trichophyton species, microsporon species, Epidermätophyton floccosum, biphasic fungi and molds.

The following areas of indication in veterinary medicine can be listed, for example:

All dermatomycoses and systemic mycoses, especially those caused by the pathogens mentioned above.

The claimed salts of the formula (i) are particularly important because of their favorable pharmacokinetic properties and their good therapeutic effectiveness resulting therefrom. For example, various salts provide serum concentrations when administered orally to mice that are more than 30 % higher than when the base is used. As a result of the better enteral absorption, the salts show better therapeutic effectiveness when administered orally to infected test animals. This effect, observed in mice, of a higher absorption rate and higher active substance concentration in the serum after administration of salts of the formula (i) can be observed in the same way in dogs, monkeys and humans. This widespread use of the spectrum underlines the importance of the salts according to the invention.

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The present invention includes pharmaceutical preparations, In addition to non-toxic, inert pharmaceutically suitable carriers, one or more according to the invention Contain active ingredients or those of one or more according to the invention There are active ingredients and processes for the production of these preparations.

The present invention also includes pharmaceutical preparations in dosage units. This means that the preparations in the form of individual parts, e.g. tablets, coated tablets, capsules, pills, suppositories and ampoules, their Active ingredient content correspond to a fraction or a multiple of a single dose. The dosage units can e.g. 1, 2, 3 or · 4 single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose preferably contains the Amount of active ingredient that is administered in one application, usually a whole, a half or a third or a quarter of a daily dose.

Among non-toxic, inert pharmaceutically acceptable carriers are solid / semi-solid or liquid diluents, fillers and formulation auxiliaries of all kinds to understand.

Preferred pharmaceutical preparations are tablets, coated tablets, capsules, pills, granules, suppositories, solutions, Suspensions and emulsions, pastes, ointments, gels, creams, lotions, powders and sprays.

Tablets, dragees, 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, lactose, cane sugar, glucose, mannitol and silicic acid, (b) binders, e.g. carboxymethyl cellulose, Alginates, gelatin, polyvinylpyrrolidone, (c) humectants, e.g. glycerine, (d) disintegrants, e.g. agar agar, calcium carbonate and sodium bicarbonate, (e) dissolution retarders, e.g. paraffin and (f) absorption accelerators, e.g. quaternary ammonium compounds, (g) wetting agents , e.g. cetyl alcohol, glycerine monostearate, (h) Adsorp-Le A 15 778 - 6 -

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agents, e.g. kaolin and bentonite and (i) lubricants, ζ. B. talc, calcium and magnesium stearate and solid polyethylene glycols or mixtures of the substances listed under (a) to (i).

The tablets, coated tablets, capsules, pills and granules can optionally contain opacifying agents with the usual Coverings and casings can be provided and also be composed in such a way that they only or prefer the active ingredient (s) in a certain part of the intestinal tract, if necessary with a delay, whereby e.g. Polymer substances and waxes can be used.

The active ingredient (s) can optionally with one or several of the above-mentioned carriers are also present in microencapsulated form.

In addition to the active ingredient (s), suppositories can contain the usual water-soluble or water-insoluble carrier substances, for example polyethylene glycols, fats, for example cocoa fat and higher esters (for example C ₁₄ alcohol with C ₁₆ fatty acid) or mixtures of these substances.

Ointments, pastes, creams and gels can contain the usual carrier substances in addition to the active ingredient (s), e.g. animal ones and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, Silicic acid, talc and zinc oxide or mixtures of these substances.

Powders and sprays can be used in addition to the active ingredient or ingredients the usual carriers, e.g. lactose, talc, silica, aluminum hydroxide, calcium silicate and polyamide powder or mixtures of these substances. Sprays can also use the usual propellants, e.g. chlorofluorocarbons, contain.

Solutions and emulsions can be used in addition to the active ingredient or ingredients the usual carriers such as solvents, solubilizers xind emulsifiers, e.g. water, ethyl alcohol, isopropyl alcohol, Le A 15 778 - 7 -

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Ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oil, in particular cottonseed oil, peanut oil, corn oil, olive oil, Castor oil and sesame oil, glycerine, glycerine formal, tetrahydrofurfuryl alcohol, Contain 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. ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and Sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these Contain substances.

The formulation forms mentioned can also contain colorants, preservatives and odor and taste-improving agents Contains additives, e.g. peppermint oil and eucalyptus oil and sweeteners, e.g. saccharine.

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

In addition to the active ingredients according to the invention, the pharmaceutical preparations listed above can also contain other pharmaceutical preparations Contain active ingredients.

The manufacture of the pharmaceutical preparations listed above takes place in the usual way by known methods, e.g. by mixing the active ingredient (s) with the active ingredient (s) Support straps.

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The present invention also includes the use of the invention Active ingredients and pharmaceutical preparations that contain one or more active ingredients according to the invention contained in human and veterinary medicine for the prevention, amelioration and / or healing of the diseases listed above.

The active ingredients or the pharmaceutical preparations can locally, orally, parenterally, intraperitoneally and / or rectally, preferably parenterally, in particular intravenously.

In general, it has been found beneficial in both human and veterinary medicine Active ingredients according to the invention in total amounts of about .3.Q up to about .100, preferably .2Q to .5Q. mg / kg body weight every 24 hours, if necessary in the form of several individual doses to be administered to achieve the desired results.

However, it may be necessary to deviate from the dosages mentioned, depending on the type and the Body weight of the object to be treated, the type and severity of the disease, the type of preparation and application of the drug and the period or interval within which the administration takes place. So it can be in in some cases it may be sufficient to make do with less than the above amount of active ingredient, while in others Cases, the amount of active ingredient listed above is exceeded Got to. The determination of the respectively required optimal dosage and type of application of the active ingredients can be done by anyone A skilled person can easily be done based on his specialist knowledge.

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The good microbiological effectiveness, especially the good pharmacokinetic and therapeutic properties are can be seen from the following in vitro and in vivo tests.

The salts according to the invention show the same good spectrum of activity and the same intensity of activity as the in vitro free base. The MIC values of the salts are (see Table A):

Table A:

Mushroom species 0.5 - MIC values γ / ml Dermatophytes 1 - 1 γ / ml Yeasts 0.5 - 4th γ / ml Cryptococci 0.1 - 2 - 1 γ / ml biphasic mushrooms
(Coccidioides, Histo-
plasma, Sporothrix) 0.1 - 0.5 γ / ml Aspergillus species 1 - 1 γ / ml other mold
mushrooms 4th

But they show compared to the German Offenlegungsschrift 1,811,654 known imidazolyl (l) fluorene derivatives an increase in activity, in particular against yeasts, e.g. Candida and molds, e.g. Aspergillus, which have MIC values up to 100 γ / ml.

Differences between the salts and the base arise in the in vivo effectiveness and in the possible applications.

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The free base is practically insoluble in water. The salts of inorganic acids (e.g. hydrochloric !, phosphate, nitrate) In contrast, they are readily to very well soluble in water. These salts are therefore distinguished - in comparison to the base significantly more favorable pharmacokinetic properties, which translate into better therapeutic results show in animal experiments.

The better pharmacokinetic properties are, briefly summarized:

1) Faster absorption with oral application, recognizable by - compared to the base - occurring much earlier Maxima of the serum concentrations;

2) Greater availability ('bioavailability') from the gastrointestinal tract. The area integrals of the serum concentration curves of the salts are .30 to 50 % greater than those of the base;

3) More even absorption, therefore less inter-individual fluctuations in serum concentrations;

4) Ability to use parenteral therapy Permitted in case of illness and age-related absorption disorders. After intravenous administration of 5 mg or 10 mg of 9-imidazolyl (l) -9- (2-methylphenyl) fluorene diphosphate can be added to the beagle dog 1/4 hour after application Serum concentrations of 3 to 4 / fg / ml or 7 to Achieve ll ^ g / ml (chemical method of determination).

Naphthalene-1,5-disulfonate, which is sparingly soluble in water, leads to long-lasting concentrations of the active substance, as this salt as a result of its poor solubility and thus slow release of active ingredient like a depot of the free base in the gastrointestinal tract works.

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The data given in Tables B to E below were determined using a chemical (densitometric) method, which is absolutely specific for the free base.

Table B:

substance Serum concentration range (/ ig / ml)
in the mouse after oral administration of
100 mg / kg body weight of free base or one of the
Salts in equimolar doses. 1/4 1/2 1 2 4th 6th 8th 10 Hours after application 2-3 3-4 4-5 5-6 5 4th 3 2-3 6th 7-8 6th 5-6 5 4th 3 2-3 free base 7-8 11-12 9-10 8-9 5 4-5 4th 3-4 Hydrochloride 7th 6-7 5-6 6th 5-6 5 4-5 4th phosphate 2-3 4-7 5-6 5-6 4-5 4-5 4-5 4-5 nitrate Naphthalene-1,5-
disufonat

Table C:

substance

Serum concentrations ( JU g / ml) in beagle dogs after oral administration of 25 mg / kg body weight of free base or phosphate in equimolar doses. Mean values (n = 4).

Hours after application 2- 4 6

free base phosphate

0.06 0.13

0.08
0.17

0.07 0.18

0.06 0.12

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Table D:

substance

Serum concentrations (/ 'g / ml) in the rhesus monkey after oral administration of 25 mg free base per kg body weight or phosphate in equimolar dosage (mean values, η = 3)

Hours after application 2 4 6

free base phosphate

0.14
0.16

0.17
1.11

0.15 0.65

0.11 0.41

Table E:

substance Serum concentrations (/ ig / ml) in men
after oral administration of 5 mg
free base per kg body weight or phosphate in
equimolar dosage (mean values, η = 3) 1 2 4th Hours after application 0.32 0.39 0.24 0.36 0.92 0.43 free base phosphate

The known imidazolyl (l) fluorene derivatives do not show this extremely favorable application spectrum.

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As a result of the better enteral absorption, the salts show when administered orally to the infected test animal, a better therapeutic effectiveness than the base. In the following Table F is an example of the survival rates of Candida albicans-infected mice after treatment with some salts and the base with the same dosage on the 5th day p.i. compiled:

Table F:

preparation Survival rates in % on the 5th day pi at
oral doses of 2 χ 25
mg / kg 2 χ 50
mg / kg 2 χ 100
mg / kg 2 χ 12.5
mg / kg 5 % 3 - 5 % 5-6% control 5 % 40 80 100 Base- 30th 90 100 100 Hydrochloride 70 80 100 100 nitrate 70 90 100 100 phosphate 80 70 90 100 Deoxycholate 60 50 75 95 naphthalene
disulf onate 30th

The known imidazolyl (l) fluorene derivatives show, when administered at 50-100 mg / kg body weight on the 5th day, survival rates of a maximum of 80 %,

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Manufacturing examples

example 1

χ ENT,

χ H, O

N '

32.2 g (0.1 mol) of 9-imidazolyl (1) -9- (2-methylphenyl) fluorene are dissolved in 150 ml of chloroform. 7 g of 50 % nitric acid, dissolved in 50 ml of chloroform, are then added dropwise while cooling with ice. The solution is then mixed with 250 ml of absolute ether with further cooling. The nitrate precipitates as a white, crystalline substance. It is suctioned off and washed with ether. This gives 26.5 g (66% of theory) of 9-imidazolyl (l) -9- (2-methylphenyl) fluorene-nitratmonohydrat a melting point of 193 ⁰ C (decomposition).

Starting product

105 g (0.36 mol) are added in portions to a solution of 81.6 g (1.2 mol) of imidazole in 400 ml of absolute • acetonitrile 9-chloro-9- (2-methylphenyl) fluorene. Then stir under reflux. The reaction is complete after about 2 hours (checked by TLC). Then one carries in 3 l of water

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and stir overnight. A white solid product is obtained which is filtered off with suction, washed well with water and dried. For purification, it is recrystallized from toluene. This gives 109 g (94% of theory) of 9-imidazolyl (l) -9- (2-methylphenyl) fluorene, melting point 167-170 ⁰ C.

Preparation of 9-chloro-9- (2-methylphenyl) fluorene:

108 g (0.4 mol) of 9- (2-methylphenyl) -fluorenol-9 are dissolved in 200 ml of methylene chloride. 53.5 g (0.45 mol) of thionyl chloride are slowly added dropwise at room temperature. The mixture is then stirred under reflux until the evolution of gas has ceased (about 2 hours). It is concentrated by distilling off the solvent. The residue is taken up in acetone and concentrated again. A solid product is obtained which, after being triturated with acetonitrile, can be filtered off with suction and washed off. This gives 105 g (90% of theory) of 9-chloro-9- (2-methylphenyl) fluorene, melting point 112-113 ⁰ C.

Preparation of 9- (2-methylphenyl) -fluorenol-9:

24.3 g (l mol) of magnesium shavings are dried in approx. 250 ml Submitted ether, mixed with about 0.5 ml of methyl iodide and heated to the boil. The boiling solution is slowly mixed with 171 g (1 mol) of o-bromotoluene, so that the reflux rate corresponds approximately to the dripping speed. The mixture is then allowed to stir for 2 to 3 hours. 90 g (0.5 Mol) fluorenone is placed in 1.5 l of ether and the Grignard solution is added dropwise at room temperature to reflux temperature. The mixture is left to stir at room temperature overnight. A white dispersion is obtained which is poured onto ice / water. Hydrochloric acid is added until the aqueous phase has a pH of 6. Then you shake the ether phase like this

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often with water until the aqueous phase remains neutral. The ether phase is dried over sodium sulfate, concentrated and triturated with petroleum ether. The white crystals obtained are filtered off with suction and washed. 105 g (78 % of theory) of 9- (2-methylphenyl) -fluorenol-9 with a melting point of 115-118 ° C. are obtained.

Example 2

2 H, PO,

966.0 g (3.0 mol) of 9-imidazolyl (1) -9- (2-methylphenyl) fluorene are dissolved in 3 liters of methylene chloride. 691.8 g (6.0 mol) of 85.0 % ± ge phosphoric acid (p> a.) Are allowed to flow into the filtered solution at room temperature with stirring. The phosphoric acid initially dissolves without any noticeable exothermicity until about 1/3 of the total amount has been added. Then crystallization begins after inoculation. The heat of crystallization released causes the solution to boil. When all the phosphoric acid has been added, the mixture is stirred for 1/2 hour, filtered off with suction and washed with methylene chloride. The crystalline product is dried in a vacuum drying cabinet for 24 hours first at 6O ⁰ C, then the temperature is increased to 105 ⁰ C.

1517 g (97.6 % of theory) of 9-imidazolyl (1) -9 -, (2-methylphenyl) fluorene diphosphate with a melting point of 164-166 ° C. are obtained.

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Example 3

χ HCl χ H, O

32.2 g (0.1 mol) of 9-imidazolyl (l) -9- (2-methylphenyl) fluorene are dissolved in 350 ml of dry ethyl acetate. Hydrogen chloride is passed in until saturation, then the precipitated salt is suctioned off, washed with ethyl acetate and dried over potassium hydroxide in a vacuum desiccator. 29.0 g (77 % of theory) of 9-imidazolyl (I) -9- (2-methylphenyl) fluorene hydrochloride monohydrate with a melting point of 214-216 ° C. are obtained.

According to Examples 1 to 3, the salts listed in Table 1 are obtained.

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Table 1:

χ Ζ

example Z SO ₃ H Fp ( ⁰ C) ^1/2 CO 4th I.
SO ₃ H 235-237 H ₄ P ₂ O ₇ χ H ₂ O VJl 3α, 12a-dihydroxy
5ß-cholanic acid 6th COOH • 70 ' CHOH "" _n
ι X n ₂ U
CHOH 7th COOH 90-98 OH OH JtTl ^xHz ° 8th OH 94 (Zer

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Continuation of table 1:

example Z Fp ( > ^e c) 9 CH ₂ COOH
HO-C-COOH χ H ₂ O
CH ₂ COOH 110 (Decomp.) 10 CH ₂ COOH
CH ₂ COOH 150 (Decomp.)

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Claims (4)

Claims 1.) Salts of 9-'imidazolyl (i) -9- (2-methylphenyl) fluorene the formula χ 2 S χ m (D in which S for a physiologically acceptable acid, η for an integer from 1 to 8 and m is an integer from 0 to 12. 2.) Process for the preparation of salts of 9-imidazolyl (i) ■ 9- (2-methylphenyl) fluorene of the formula XjS χ m in which S for a physiologically acceptable acid, η for an integer from 1 to 8 and j m stands for an integer from 0 to 12, characterized in that 9-imidazolyl (1) -9- (2-methylphenyl) fluorene is used with physiologically compatible Le A 15 778. - 21 - 509883/0951 Acids, optionally in the presence of inert ones
Reacts solvents. 3.) Medicines, characterized by a content of
at least one salt according to claim 1. 4.) Process for the preparation of antifungal agents, characterized in that salts according to claim 1 with inert, non-toxic, pharmaceutically suitable Mixed carriers. Le A 15 778 - 22 - 509883/0951