FI66851B - FOERFARANDE FOER FRAMSTAELLNING AV ANTIMYKOTISKA 2,4-DICHLORPHENYLIMIDAZOLYLETANONER (OLER) - Google Patents

Description

R3FH M / m KU RELEASE PUBLICATION // jSft lJ '1 UTLÄGGNI NGSSKAIFT 0000 1 C Patent issued on 12 12 1934

Patents oeddelat ^ '^ (51) K * J? / Fc »ta.3 C 07 D 233/60 FINLAND — FINLAND (ϊΐ) 780431 (22) H> hM * piM — A-atoiimrfii 09.02.78 (Fl) f ? T) λβγμ ^ βτι nnmtiriit »! 09.02.78 (41) Tutut— tttvkeffwidi 12.08.78

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Patana · och I eilltarit / ralaan 'Ambkm mk§ »odi ucLtfcrlton piMfcarad (32X33X31) W * ^ ewo * w-l ^ lrdFrlertw 11.02.77

The Federal Republic of Germany-Förbundsrepubliken

Germany (DE) P 2705677.5 (71) Bayer Aktiengesel1schaft, Leverkusen, Federal Republic of Germany1-Förbundsrepubl iken Germany (OE) (72) Wolfgang Krämer, Wuppertal, Karl Heinz Buchel, Wuppertal,

Manfred Plempel, Wuppertal, Federal Republic of Germany Förbundsrepubl iken Tyskland (DE) (74) Oy Kolster Ab (54) Method for the preparation of antifungal 2,4-dichlorophenylimidazolyl-ethanones (o) The present invention relates to a process for the preparation of novel 2,4-dichlorophenylimidazolylethanones (oles) which are useful as medicaments, in particular as antifungal agents.

It has already become known that phenoxyimidazolyl derivatives have a good antifungal activity (cf. DE-A-2 105 490 and 2 333 355. However, their activity is not always completely satisfactory, especially against ciliates and in vivo Candida species. .

It has been found that novel 2,4-dichlorophenylimidazolylethanones (olees) having the general formula _ - Γ 2 66851

Cl €> ° -iH-A-0 ~ ci u)

. OF

"o wherein A is a keto group or a CH (OH) group, X is halogen, C 1-4 alkyl or when n is 1 also phenyl in the 4-position which may be substituted by chlorine in the para-position and n is an integer 0 -2, and their physiologically acceptable salts have potent antifungal properties.

The compounds of formula (I) in which A is a CH (OH) group have two asymmetric carbon atoms and can therefore exist in the form of both geometric isomers (erythro and threo forms) which can be formed in different proportions. In either case, they are optical isomers. All isomers are within the scope of the invention.

The invention is characterized in that 1-bromo-2- (2,4-dichlorophenyl) -1-phenoxyethan-2-one of the formula

Cl \ ~ ch ”co —'— ci (ii) xÄ_y ir v_ / n 3 66851 wherein X and n have the same meaning as above, is reacted with imidazole in the presence of a diluent and an acid scavenger and, if desired, reduced with a borohydride complex, optionally known per se, in the presence of a diluent, and that the compound obtained is, if desired, converted into a physiologically acceptable salt.

The active ingredients according to the invention surprisingly have a better antifungal, therapeutically useful effect than the phenoxyimidazolyl derivatives known from the prior art, which are chemically and in their effect the closest compounds. The substances according to the invention thus enrich medicine.

If 1-bromo-1- (4-chlorophenoxy) -2- (2,4-dichlorophenyl) ethan-2-one and imidazole are used as starting materials, the reaction procedure can be shown by the following reaction scheme:

Cl ci - @ - ° -fr-c ° -Q / -ci + 1) h

Cl ci-O ^ ° 'iH'c0' <y ^ ci o n_! L

If 1- (4-chlorophenoxy) -2- (2,4-dichlorophenyl) -1-imidazol-1-yl) ethan-2-one and sodium borohydride are used as starting materials, the reaction procedure can be shown by the following reaction scheme: - 4 66851 C1 '_ H? CL ·

Cl-®-O-CH-CO-Q-Cl + NaBH, -> Cl- <Q> -0-CH-CH- <Q) -Cl

, ώι 'Q

Formula (II) generally defines 1-bromo-2- (2,4-dichlorophenyl) -1-phenoxyethan-2-ones as starting materials. In this formula, X mainly corresponds to halogens fluorine, chlorine, bromine and iodine, straight-chain or side-chain alkyl having 1 to 4 carbon atoms and optionally phenyl containing a halogen substituent, in particular a chlorine substituent. The index n mainly corresponds to integers 0-2.

The 1-bromo-2- (2,4-dichlorophenyl) -1-phenoxyethan-2-ones of formula (II) are not yet known compounds, but can be prepared by known methods by administering known phenols of formula jq) oh (iii) xn wherein X and n have the above meanings, react with bromoacetophenone of formula

Cl

Br - CH2 - CO - ~ C1 (IV)

The remaining active hydrogen atom is then converted to bromine in the usual manner.

5 66851

Suitable salts of the compounds of the formula (I) are the salts of physiologically acceptable acids. These are mainly hydrohalic acids, such as hydrochloric acid and hydrobromic acid, in particular hydrochloric acid, phosphoric acid, nitric acid, mono- and difunctional carboxylic acids and hydroxycarboxylic acids, such as acetic acid, citric acid, disulphonic acid, sorbic acid, lactic acid, lactic acid, lactic acid,

Suitable diluents for the reaction are mainly neutral organic solvents. These are mainly ketones such as diethyl ketone, especially acetone and methyl ethyl ketone; nitriles such as propionitrile, especially acetonitrile; alcohols such as ethanol or isopropanol; ethers such as tetrahydrofuran or dioxane? aromatic hydrocarbons such as toluene and 1,3-dichlorobenzene, benzene; formamides, such as in particular dimethylformamide; and halogenated hydrocarbons such as methylene chloride, tetrachloromethane or chloroform.

The reaction is performed in the presence of an acid scavenger. For this purpose, all customary inorganic or organic acid-binding agents can be used, such as alkali metal carbonates, for example sodium carbonate, potassium carbonate and sodium hydrogen carbonate, or, for example, lower tertiary alkylamines, disylethylamines, cycloalkylamines or aralkylamines, for example triethylamine; Ν, Ν-dimethylbenzylamine, further pyridine and diazabicyclooctane. The corresponding excess of imidazole is mainly used.

Reaction temperatures can be varied within wide limits. In general, the reaction is carried out at temperatures between about 0 ° C and about 150 ° C, most preferably between 60 ° C and 120 ° C, in the presence of a solvent such as acetone or methyl ethyl ketone.

In carrying out the process, 1 * · 2 moles of azole and 1-2 moles of acid scavenger are used per mole of the compounds of formula (II). To isolate the compound of formula (I), the solvent is distilled off, the residue is dissolved in an organic solvent and washed with water. The organic phase is dried over sodium sulfate and the solvent is removed in vacuo. The residue is purified by distillation or recrystallization.

In the reduction, polar organic solvents are suitable as diluents β for the cow reaction of the invention. These are mainly alcohols such as methanol, ethanol, butanol, 66661 isopropanol and ethers such as diethyl ether or tetrahydrofuran. The reaction is generally carried out at 0 to 20 ° C. To this end, about one mole of a borohydride such as sodium borohydride or lithium borohydride is added per mole of the compound of formula (II). Thus, to isolate the compounds of formula (I), the residue is dissolved, for example, in dilute hydrochloric acid, then the solution is made alkaline and extracted as an organic solvent or water is added and fed with an organic solvent. Further processing takes place in the usual way. ·

The compounds of formula (I) and their salts prepared according to the invention have antimicrobial properties, in particular potent antifungal properties. They have a very broad spectrum of antifungal activity, especially fungal fungi and branch fungi as well as biphasic fungi, e.g. Candida species such as Candida albicans, grouse species such as Epi-dermophyton floccosum, Aspergillus species such as -lus niger and Aspergillus fumigatus, Trichophyton species such as Trichophyton mentagrophytes, microsporia fungal species such as Microsporon felineum and Penicillium species such as Penicillium commune.

Examples within the scope of the human medical indication include: Dermatomycoses and systemic mycoses caused by Trichophyton mentagrophytes and other Trichophyton species, Microsporum species, Epidermophyton floccosum, branch fungi and biphasic fungi as well as

Example A

In vitro in vitro fungal growth inhibitory effect

Test description:

The in vitro study was performed as a serial dilution experiment with 4 spore implants using 5 x 10 spores / ml substrate. The medium was: (a) for bristles and molds:

Sabouraud's milieu d'epreuve (b) for yeasts: luha extract-grape sugar broth.

The incubation temperature was 28 ° C, the incubation time was 24-96 hours.

Il 7 S 66851 88 '11 § 3

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aa

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0 QUO A

CVHQJ, V

: td o> HO <tn <Ubtn tn n <f <1- Φ H 0) 0 U yQ yo Φ -H CO o, tn o 3 <hf * ΑΛ ί> ι Ή S g λ: c3g <UH oca, -η υ s, * tn - +

tn ro td C o Q rl S

3 -P Ό td O -ί VO ^

4J 4-1 -H O H A

3 0) M C CJ3 H -H td H td td u td> tn I 3

0 -P M td P H

• H (1) | ) -l> oc ov-, o ® D! 1 H J30 ^

C g O-P -P

Ή \ · Η>, C W WI1) sd · παε> -P: td O -P> tn p m „Φ td -3

1 -P

td «K -P

^ 3 g 3 W1 "^ 3 V -3 a 3 3 5 | si-r lv V 3 I i / = *, G ό OV ~ V“ T- • H .. V Γζ o V - SK o N- wo »K / I 3 33 3 ° ~ 9 ~ .. -S V- ^ l § sT V-zvJ si / = * p

<td o ^ = - 1 2 3 S -e o h '—1 s 9 - S

tn i Suio § d \ - '1 p 1 W 1 O ~ 2 H H 1 | 33 3 3 ~ £> o "^ - 8 66851 in

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C i + ί K 4-) I in S a x 2 4-> I -h .¾ 3 g x d) I ^; 9> - .Q. II! O S V o-o-o I # 3 3 X / = i! *> p P υ-ζ υ-ζ I® H M I \ - I I jj CM fo

pH HO - O N-! £ h cm f ° \ H H

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I! 9 66851

Example B

In-vivo fungal growth inhibitory effect (oral) in candle dose in mice_

Experimental Description: SPP-CF1 type mice were infected intravenously with 1-2 x 10 6 logarithmically propagating Candida cells suspended in physiological saline. One hour before infection and seven hours thereafter, the animals were each orally administered 100 mg of the preparations per kilogram of body weight.

Untreated animals died 3-6 days after infection. On the sixth day after infection, the number of untreated surviving control animals was about 5%.

Explanation of symbols: +++++ = very good effect = 90% alive on day 6 after day i ++++ = good effect - 80% alive on day 6 after day i +++ = has effect = 60% alive on day 6 after i ++ = weak effect - 40% alive on day 6 after i + = traces of effect in kW = no effect.

__ "Γ .... ________ 10 66851

Table Β: In-vivo fungal growth inhibitory effect (oral) in mouse candidiasis

Effect Effect Q-Q-0-CH-CC-C (CHs), k.w.

[_(known)

OH

K.W.

Ö (Compounds from Example No. :) 1 +++++ 2 ++++ 12 ++ 11 66851

comparison Tests

The compounds according to the present invention were compared with three compounds known from DE 2 105 490, 1- (4-chlorophenoxy) -1- (1H-imidazol-1-yl) -3,3-dimethylbutanone (Compound A), 1- (4-chlorophenyl) -2- (2,4-dichlorophenoxy) -2- (1H-imidazol-1-yl) ethanone (Compound B) and 2- (4-chlorophenoxy) -2- (1H-imidazol-1- yl) -1-phenyl hydrate (Compound C) to determine the minimum antifungal concentration MHK. The results are shown in the following table.

MHC value ^ / ml medium:

Effect of the substance___Microsporum fel. Penicillium comm.

Cl - ^^ - O-CH-CO-C (CH3) 3 4 4 0 0 (A) (known) / C1

CtO) '° "? H-C0- <0) ^ Cl 100 100 ώ (B) (known)

OH

x HC1 40 40

/ N \ OH

O

(C) (known) j

Prepared according to the invention from example No. ___________ 1 4 32 2 32 32 3 32 8 6 4 8 7 1 4 8 4 4 9 44 12 32 8 i 66851 12

Valmistuseslmerkkejä

Example 1

Cl

S

ci-δ-O-fH-co-Q-ci J_In x hci

103 g (0.26 mol) of 1-bromo-1- (4-chlorophenoxy) -2- (2,4-dichlorophenyl) -ethane are added dropwise to a mixture of 65 g (1 mol) of imidazole in 650 ml of acetonitrile at reflux temperature. 2-one. Heat to reflux for 40 hours. The solvent is then distilled off in vacuo, the residue is dissolved in 500 g of methylene chloride and shaken four times with 250 ml of water. The organic phase is dried over naphthium sulfate and evaporated to dryness by distilling off the solvent in vacuo. The residue is dissolved in 1000 ml of acetone and 47 g (0.26 mol) of 1,5-naphthalenedisulfonic acid in 100 ml of acetone are added. The precipitate formed is filtered off with suction and boiled with 100 ml of acetone. To the residue are added 200 ml of sodium hydrogen carbonate solution and 500 ml of methylene chloride. The organic phase is separated, washed with 200 ml of water and evaporated to dryness by distilling off the solvent in vacuo. The residue is dissolved in 200 g of any ether and an excess of dry hydrogen chloride is added. After distilling off the ether in vacuo, the oily residue is recrystallized from acetone. 31.6 g (29% of theory) of 1- (4-chlorophenoxy) -2- (2,4-dichlorophenyl) -1-imidazol-1-yl-ethan-2-one hydrochloride with a melting point of 146 are obtained. -148 ° C.

Il 13 66851

Example 2

Cl ci-O 0 '““' O 'C1

N OH

There are 45.5 g (0.108 mol) of 1- (4-chlorophenoxy) -2- (2,4-dichlorophenyl) -1-imidazol-1-yl-ethan-2-one hydrochloride (from Example 1) dissolved in 100 to 1 ml of methanol and 4.32 g (0.108 mol) of sodium hydroxide are added. At 0-5 ° C, 4.5 g (0.12 mol) of sodium borohydride are added portionwise and the mixture is stirred for 15 hours at room temperature. 60 ml of concentrated hydrochloric acid are then added dropwise at 0 [deg.] C. and the mixture is stirred again for 15 hours at room temperature. The reaction mixture is then mixed with 800 ml of saturated sodium hydrogen carbonate solution and shaken with 500 ml of methylene chloride. The organic phase is dried over sodium sulfate and evaporated to dryness by distilling off the solvent in vacuo. The residue is recrystallized from ether. 30 g (72.5% of theory) of 1- (4-chlorophenoxy) -2- (2,4-dichlorophenyl) -1-imidazol-1-yl-ethan-2-ol are obtained as a mixture of isomers with a melting point of 108-110 ° C.

According to the above examples, the following compounds of Table 1 are obtained.

14 66851

table 1

Cl δ - ° - fH - a -0 -ci

G

E.g.

n: ° Δ Melting point (0 ^) 3 2,4-Cl2 CC 205-215 (x HCl) 4 ^ -0 “C] L C0 145-148 (x HCl) 5 4 ^ Q> C0 160-162 (x HCl) 6 4-F CO 160 (x HCl) 7 CO 162-168 (x HCl) 8 2,6-Cl2 CO 180 (x HCl) 9 3-C1 CO 168-171 (x HCl) 10 4-CH3 CO 110 (x HCl) 11 4-C1,2-CH 2 CO 177-178 (x HCl) 12 2,4-Cl 2 CH (OH) 208-218 (isomeric mixture) \ x HCl / 13 4 - »^^) CH ( OH) 158-170 (isane mixture) (x HCl) 14 - CH (OH) I56-I59 (isane mixture) (x HCl) 15 3-C1 CH (OH) 165-167 (isane mixture) (x HCl)

Il "''

Claims (1)

A process for the preparation of antifungal 2,4-dichlorophenylimidazolylethanones (oles) having the general formula (i) X "Λ wherein A is a keto group or a CH (OH) group, X is halogen, C 1-4 alkyl or when n is 1 also phenyl in the 4-position, which may be substituted by chlorine in the para-position and n is an integer from 0 to 2, and for the preparation of their physiologically tolerable salts, characterized in that 1-bromo-2- (2,4-dichlorophenyl ) - 1-phenoxy-ethan-2-one of the formula Cl \ (Jj) -O-CH-CO-j \ -Cl (II) Br n where X and n are as defined above, is reacted with imidazole in a diluent and in the presence of an acid scavenger and, if desired, the resulting imidazolylethanone is reduced in a manner known per se with a borohydride complex, optionally in the presence of a diluent, and that the compound obtained is, if desired, converted into a physiologically acceptable salt.