CH636089A5 - Antimicrobial 1-(2-(halophenylthio)-4-(p-chloro- or -fluorophenyl)-n-butyl)imidazoles and their preparation - Google Patents

Description

The present invention relates to antimicrobial l- [2-halophenylthio) -4- (p-chloro- or -fluorophenyl) -n-butyl] -imidazoles and to processes for their preparation. These compounds are useful as antifungal, antibacterial and antiprotozoal agents.

DE-OS 26 33 492 describes certain substituted N-alkylimidazole compounds of the general formula (A):

and or

O ch2-ch2-ch-ch2-y '20

r-ch- (ch0) 2

x-r

(A)

IXB

where X, Y, Y 'and n have the above meaning, implemented with imi-dazol. 30th

29. Process for the preparation of antimicrobial acid addition salts of compounds of the formula:

> -ch ^ -ch0-ch-ch - n

\ = t 2 2 i 2 \

in which X is chlorine or fluorine, Y is bromine, chlorine or fluorine, where at least one Y is in the 2'-position, n has a value from 1 to 5 if Y is chlorine and n is a value of 1 or 2, if Y has a meaning other than chlorine, characterized in that an antimicrobial free base of the formula (I) is treated with an inorganic or organic acid.

30. Process for the preparation of antimicrobial compounds of the formula:

X-y '\ vch.-ch, -ch-ch, -n n

\ = / 2 2 i 2 w in which R1 and R2 independently of one another each represent phenyl, a phen-yl-lower-alkyl or -lower-alkenyl-25 group (the alkyl or alkenyl group being straight-chain), or one of the substituents R1 and R2 is substituted in the phenyl ring with one or more substituents from the group of Cj_4 lower alkyl, halogen or trifluoromethyl; X represents oxygen or sulfur; n is an integer from 1 to 8 with the condition that when Rj is phenyl or substituted phenyl, n is not = 1; furthermore, the antimicrobial acid addition salts of the compounds are described in the said application. The class of compounds of the above formula and their salts show antifungal, antibacterial and antiprotozoal activity.

(I) It has now been found that a group of the above class of compounds is particularly active. This group of compounds is an extremely active class of compounds which differs from the 40 compounds of the formula (A) described above and is characterized by the following formula:

45

50

• o ch

) -ch0-ch-ch - n n

! 2 i 2 w

(i)

(i)

in which X is chlorine or fluorine, Y is bromine, chlorine or fluorine, where at least one Y is in the 2'-position, n has a value from 1 to 5 if Y is chlorine and n is a value of 1 or 2, if Y has a meaning other than chlorine, characterized in that an antimicrobial acid addition salt of the compound of the formula I is treated with a base.

in which X represents chlorine or fluorine, Y in each case means bromine, chlorine or fluorine, at least one Y in the

55 2 'position, n has a value from 1 to 5 if Y is chlorine and n has a value of 1 or 2 if Y has a meaning other than chlorine; the antimicrobial acid addition salts of the above compounds are also included.

60 A preferred group of compounds corresponds to the formulas:

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* / "V CH ^ -CH ^ -CH-CH.-N ^ N

\ = / 2 2 | 2 w p.

(la)

* fy x _ // \\ _ CH ^ -CH ^ -CH-CH ^ -N ^ iî

v = / 2 2 i 2 w s. e.g.

(Ib)

and their antimicrobial acid addition salts, in which X represents chlorine or fluorine, W each means bromine, chlorine or fluorine, where at least one W is in the 2 'position, m has a value from 1 to 4 if W is chlorine , m has a value of 1 or 2 if W has a meaning other than chlorine, Z each represents bromine, chlorine or fluorine, p has a value of 0 to 3 if Z represents chlorine, and p has a value of 0 if Z has a meaning other than chlorine.

Compounds of the formulas (I), (Ia) and (Ib) and their antimicrobial acid addition salts are particularly preferred, in which n has a value from 1 to 3 or m has a value from 1 to 3 or p has a value of 0 or 1 (Y or W or Z are chlorine if n = 1-3, m = 1-3 or p = I and have a different meaning than chlorine,

if n = 1 or 2, m = 1 or 2 or p = 0), or in which X represents chlorine, or - if X = fluorine - Y (or W or Z) represents chlorine.

Compounds in which X and Y (or W or Z) represent chlorine are further preferred. Particularly preferred, the latter compounds are those in which n = 2, m = 2 or p = 0 and those in which the two (Y or W or Z) chlorine atoms are in the 2 ', 6' position of the phenyl ring. Therefore, the compound 1- [2- (2,6-dichlorophenylthio) -4- (4-chlorophenyl) -n-butyl] imidazole and its antimicrobial acid addition salts are particularly preferred.

The compounds of the formulas (I), (Ia) and (Ib) according to the invention and the salts mentioned1 are characterized by certain special molecular features which result in a highly active class of compounds. These are:

1) a 1,4-butylene chain connecting the imidazole radical and a p-chloro or -fluorophenyl radical, 2) a bromine, chlorine or fluorophenylthio radical which is bonded to the C-2 carbon atom of the 1,4-butylene chain is, counting from the imidazole radical, and in particular 3) at least one bromine, chlorine or fluorine atom in the 2'-position of the phenyl ring in the bromine, chlorine or fluorophenylthio radical. This combination of features results in a surprisingly highly active, new class of compounds.

Unless otherwise stated, the following terms in the present invention have the following meanings. “Halogen” refers to bromine, chlorine and fluorine. "Antimicrobial acid addition salts" of the basic compounds according to the invention relate to sake that preserve the antimicrobial properties of the free bases and are neither biologically nor otherwise undesirable and e.g. with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or organic acids, such as acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzene acid , Mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc., are formed.

All compounds of formula (I) have at least one chiral center, d'.h. the carbon atom to which S, io H and two CH2 groups are attached. The compounds according to the invention can therefore be prepared in any optically active form or as a racemic mixture. Unless otherwise stated, all of the compounds described here are in the racemic form. However, the present invention is not limited to the racemic form, but also encompasses the individual optical isomers of the compounds according to the invention and the various mixtures thereof.

Optionally, the racemic 20 intermediates or end products produced here can be separated into their optical isomers by conventional known separation methods, e.g. by separation (e.g. fractional crystallization) of the diastereomeric salts formed by reacting e.g. racemic compounds of the formula (I) with an optically active acid, or by separating the diastereomeric salts or esters, formed by reacting the racemic compounds of the following formula (II) with an optically active acid. Such optically active acids are e.g. the optically active forms of camphor-10-sulfone-30 acid, a-bromocampfer-it-sulfonic acid, camphor acid, menthoxy oxyacetic acid, tartaric acid, malic acid, diacetyl tartaric acid, pyrrolidone-5-carboxylic acid etc.

The compounds of the formula (I) according to the invention exhibit antifungal, antibacterial and antiprotozoal activity. They show e.g. antifungal activity against pathogens in humans and animals, e.g.

Microsporum audouini,

Microsporum gypseum,

Microsporum gypseum - canis,

40 epidermophyton floccosum,

Trichophyton mentagrophytes,

Trichophyton rubrum,

Trichophyton tonsurans,

Candida albicans, and 45 Cryptococcus neoformans.

Furthermore, the compounds according to the invention show antifungal activity against the following, essentially agricultural fungi Aspergillus flavus,

so Cladosporium herbarum,

Fusarium graminearum,

Pénicillium notatum, and Aspergillus niger,

Pénicillium oxalicum,

55 Pénicillium spinulosum,

Pithomyces chartarum.

Furthermore, the compounds according to the invention show antibacterial activity against pathogens in humans and animals, such as e.g.

60 Staphylococcus aureus,

Streptococcus faecalis,

Corynebacterium acnes,

Erysipelothrix insidiosa,

Escherichia coli,

65 Proteus vulgaris,

Salmonella choleraesius,

Pasteurella multocida, and Pseudomonas aeruginosa.

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In addition, the compounds according to the invention show antiprotozoal activity against protozoa, such as Trichomonas vaginalis and Trichomonas foetus.

The compounds according to the invention generally show low toxicity and good solubility in the stratum corneum. Since dermatophyte infections (i.e. parasitic fungal) are usually localized in the dead tissue of the stratum corneum, the solubility of the antifungal agents in this tissue significantly improves their effectiveness.

Because of the above-mentioned effects, the compounds according to the invention are valuable antimicrobial agents, not only for pharmaceutical but also for agricultural and industrial purposes.

The antimicrobial agents according to the invention are defined in claim 31.

For pharmaceutical purposes, the preparations can be solid, semi-solid or liquid, e.g. in the form of tablets, capsules, powders, suppositories, liquid solutions, suspensions, creams, lotions, ointments, etc. Pharmaceutically acceptable, non-toxic carriers or the excipients normally used for solid formulations include tricalcium phosphate, calcium carbonate, kaolin, bentonite, talc, gelatin , Lactose, starch, etc .; for semi-solid formulations e.g. use polyalkylene glycols, petroleum jelly and other cream bases; for liquid formulations e.g. Water, oils of vegetable origin and low-boiling solvents such as isopropanol, hydrogenated naphthalenes etc. are suitable. The pharmaceutical preparations containing the compounds according to the invention can be prepared in a conventional manner, e.g. are treated by sterilization and contain conventional pharmaceutical agents, such as preservatives, stabilizers, emulsifiers, salts for adjusting the osmotic pressure and buffers. They can also contain other therapeutically active materials. For pharmaceutical purposes, the compounds and preparations according to the invention can be administered to humans and animals in a customary manner, e.g. topically, orally, parenterally, etc. Parenteral administration includes intramuscular, subcutaneous and intravenous administration. The intravenous injection of imidazole-like antifungal agents has been shown to be effective in the treatment of systemic mycoses (see, for example, Drugs 9, page 419-420, (1975), where the intravenous administration of miconazole, ie 1- [2,4- Dichloro-β- (2 ', 4'-dichloro-benzyloxy) phenethyl] imidazole nitrate, in patients with systemic candidiasis is described). Local application is preferred for administration for pharmaceutical purposes. An area with existing fungal, bacterial or protozoal growth or which is to be protected against infection by fungi, bacteria or protozoa can be treated with a compound according to the invention or a preparation, e.g. by dusting, spraying, spraying, washing, brushing, dipping, rubbing, coating, impregnating, etc. Local pharmaceutical preparations with the compounds according to the invention show antifungal, antibacterial and antiprotozoal activity over a wide range of concentrations, e.g. from about 0.1-10.0% by weight of the preparation. In any case, the preparation to be administered should contain an amount of the compound according to the invention which is effective for curing or preventing the particular disease to be treated.

The pharmaceutical preparations according to the invention usually comprise one or more compounds of formula (I) and a pharmaceutically acceptable, non-toxic carrier, and are conveniently formulated in dosage form for ease of administration. (Here is the

Dosage unit the amount of active ingredient administered at one time).

For systemic (e.g. oral or parenteral) administration, it is usually expedient to appropriately distribute the active ingredient in amounts between about 1-100 mg / kg body weight per day, preferably between about 5-50 mg / kg body weight per day, over several applications ( eg in 3 single doses), to achieve the most effective results. However, proportionally less active ingredient is required for localized (e.g. local) administration.

The exact pharmaceutical mode of administration of the compounds and preparations according to the invention necessarily depends on the needs of the individual patient to be treated, the type of treatment, i.e. preventive or curative, the type of organism in question and, of course, the doctor's judgment.

For agricultural purposes, the compounds according to the invention can be applied directly to plants (e.g. seeds, foliage) or to the soil. Thus the compounds according to the invention can e.g. applied alone or in admixture with a powdered solid carrier to seeds. Typical powdered carriers are the various mineral silicates, such as mica, talc, pyrophyllite and clays. Furthermore, the compounds according to the invention can be applied to seeds in a mixture with customary, surface-active wetting agents with or without an additional solid carrier. All conventional anionic, non-ionic or cationic compounds are suitable as surface-active wetting agents. For soil treatment against fungi etc., the compounds according to the invention can be applied as dust in a mixture with sand, earth or a pulverized solid carrier, such as mineral silicates, with or without additional surface-active agents; or they can be used as an aqueous spray, optionally with a surfactant and a powdered solid carrier. For the treatment of foliage, the compounds according to the invention can be used on growing plants as an aqueous spray which contains a surface-active dispersant with or without pulverized solid carrier and hydrocarbon solvent.

For industrial purposes, the compounds according to the invention can be used to control bacteria and fungi by contacting the pathogens with the compounds in a known manner. Materials which are possible carriers of bacteria and fungi can be protected by contact, mixing or impregnation with the compounds according to the invention. For increased effectiveness, the compounds according to the invention can be combined with other pesticides, such as fungicides, bactericides, insecticides, miticides, etc. A particularly important industrial / agricultural use of the compounds according to the invention is as a food preservative against bacteria and fungi which spoil the food.

The methods according to the invention are defined in claims 28, 29 and 30.

The starting materials for process a) can be prepared by forming a suitable alcohol of formula (II) in which X has the meaning given above.

X - // vwH, -CH, -CH-CH

■ \ _y- 2 2, 2 w oh

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The compounds of formula (II) can be prepared according to various reaction sequences, e.g. the following reaction scheme A, in which X has the above meaning.

-Q-

Reaction scheme A

ch_-ch ~ - * ch0

(iv)

x \ xvhv

ch2-ch = ch.

(v)

ch2-ch2-ch-ch2 \ /

(iii)

x

2 ch2-ch-ch

(ii)

Olì

The imidazole alcohol of the formula (II) is formed by opening a terminal epoxide of the formula (III) with imidazole. This reaction is usually carried out using at least 1 mole, preferably an excess of imidazole with respect to the epoxide, optionally in the presence of a salt (preferably an alkali metal salt) of the imidazole. The reaction can be carried out in the absence of a solvent or, preferably, in an inert organic solvent such as dimethylformamide, hexamethylphosphoramide, acetonitrile, etc. The temperature normally used for this epoxy opening is between about -20 to about 100 ° C, especially between about 20-60 ° C.

If not known, the epoxides of formula (III) can be prepared by various known methods, such as e.g. by epoxidation of a terminal olefin, e.g. (V), with a peracid, or by reacting an aldehyde with one less C atom, such as (IV), with the ylide, prepared from trimethylsulfoxonium iodide or trimethylsulfonium iodide (see, for example, J. Am. Chem. Soc., 84, page 867 (1962); ibid, 87, page 1353 (1965).

The compounds of formula (II) can also be prepared as follows:

Reaction scheme B

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(VII)

(vi)

<- ^^) - ch2-ch2-ch-ch2-

Oh

(II)

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in which X has the meaning given above and Y "stands for chlorine or bromine.

The hydroxy compound of the formula (II) is prepared by reducing the corresponding ketone (VI), which in turn is prepared by reacting an a-haloketone (VII) with imidazole.

The a-haloketones can easily be obtained by well known procedures, e.g. from the corresponding dihydrocinnamic acid by reaction of the acid chloride or bromide with diazomethane and subsequent treatment of the diazoketone obtained with HY ".

The a-haloketone is contacted with imidazole in an inert organic solvent and provides the ketoimidazole of the formula (VI). The reaction is carried out using at least a molar amount and preferably an excess of imidazole with respect to the halogen ketone; furthermore, it is carried out in the absence of a solvent or, preferably, in an inert organic solvent, such as dimethylformamide, hexamethylphosphoramide, acetonitrile, etc. The reaction is conveniently carried out initially at a temperature between about -10 and 100 ° C., in particular between about 25-80 ° C. .

In the next step, the ketoimidazole of the formula (VI) is reduced to the hydroxyimidazole of the formula (II) using a conventional metal hydride reducing agent, such as sodium borohydride. The reaction is conveniently carried out in an alcoholic solvent such as methanol or ethanol at a reduced temperature, e.g. between about -10 and + 25 ° C, especially at about 0 ° C.

The compounds of formula (I) can be removed from the compounds of formula (II) in two steps by converting the hydroxyl group into a suitable, removable group Y ', e.g. a halide, such as chloride or bromide,

or a sulfonate ester, e.g. Methanesulfonate or p-toluenesulfonate. The reaction of the compound of the formula thus obtained:

x- <0hh2-ch2-çh-c „2-0 (na)

Y '

wherein X and Y 'have the above meaning, with the corresponding thiophenol, wherein Y and n have the above meaning, is preferably carried out in the presence of a base such as potassium carbonate, or by using a metal salt of thiophenol.

The alcohol can be converted into the halide or the sulfonate ester in a known manner. The alcohol can e.g. halogenated with a halogenating agent such as thionyl chloride or bromide, alone or in an inert organic solvent such as dichloromethane or chloroform, at a temperature between about 0-80 ° C, preferably between about 20-80aC. The halogenation can optionally be carried out in the presence of a molar equivalent of a base such as pyridine. Other halogenation processes include e.g. the use of triphenylphosphine with carbon tetrachloride, carbon tetrabromide or N-chloro- (or N-bromo-) succinimide. If thionyl chloride or bromide is used without added base, the hydrochloride or hydrobromide salt of the corresponding halogen compound is obtained. This salt can be used e.g. in the alkylation e.g. neutralized with potassium carbonate or used directly when excess thiophenol salt is used.

The sulfonate esters can be prepared by treating the alcohol with an excess, e.g. of methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a base such as pyridine or triethylamine. This reaction takes place at a temperature of about -20 to + 50 ° C, preferably between about 0-20 ° C.

Then the halide or sulfonate ester as prepared above may be reacted with the thiophenol, preferably in the presence of a base, or with a salt, preferably an alkali metal salt such as the sodium * or potassium salt, of the corresponding thiophenol in the presence of an inert organic solvent such as Acetone, methanol, etc., are treated at a temperature of about 20-80 ° C. If necessary, a metal salt of the thiophenol can be formed before the addition of the halide.

The compounds of the formula (I) can also be prepared according to the following scheme:

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Reaction scheme C

ch ~ -ch0-ch-ch0 +

\ / Y

0

(III)

. ©

"n

H ^ -CH2-CH2-ÇH-CH2-S- ^ y * Q.

or

(VIIIA)

•O

I.

OH

and / or ch ~ -ch ~ -ch-ch-oh

'2 w "2

(VIIIB)

xh

(IXA)

o ch2-ch2-ch-ch2

and or

--Q,

n ch2-ch2-ch-ch2-y1

(IXB)

O

n ch9-ch -, - ch-ch - n n I \ —7

(I)

where X, Y, Y 'and n have the above meaning.

The epoxide of formula (III) described above is opened with a thiophenol or its metal salt to form the compound of formula (VIII). This reaction is preferably carried out with an alkali metal salt of thiophenol, especially the sodium salt, in an inert organic solvent such as tetrahydrofuran or acetone at a temperature between about 0-67QC or using the free thiophenol in the presence of an acid catalyst such as perchloric acid under similar conditions .

In the next step the hydroxy group of the compound of formula (VIII) is converted into a removable group, e.g. converted a halide (e.g. chlorine or bromine) or a sulfonate ester (e.g. p-toluenesulfonate or methanesulfonate) by reacting with a halogenating agent such as thionyl chloride alone or preferably in an inert solvent such as dichloromethane or e.g. with p-toluenesulfonyl chloride in a solvent such as pyridine. The product of formula (IX) can be in one or both of the forms shown, which are mutually convertible into one another via an episulfonium intermediate.

According to the invention, the compound of formula (IX) is converted into the end product of formula (I) by treatment with imidazole. This reaction can be carried out in an inert organic solvent such as acetonitrile, dimethylformamide, etc. at a temperature of about 0-100 ° C.

The thiophenol reactants can be prepared from the corresponding phenols by known methods [see e.g. J. Org. Chem. Vol. 31, page 3980 (1973)].

The compounds according to the invention can be isolated as free bases; however, since some of the compounds are oils in their basic form, it is more convenient to isolate and label the compounds as acid addition salts. These salts are obtained in the usual way, i.e. 45 by reacting the basic compound with a suitable inorganic or organic acid described above. The salts formed with dibasic acids such as oxalic acid can contain 1 or 2 molecules of base per molecule of acid. All oxalates described here contain 50 1 molecule of oxalic acid per molecule of imidazole base. Optionally, the salts can be easily converted to the free base by treatment with alkali such as chewing carbonate, sodium carbonate or sodium or potassium hydroxide.

The following experiments and examples illustrate the present invention without restricting it.

Trial 1

34 g of 3- (4-fluorophenyl) -l-propanol in 200 cc of anhydrous methylene chloride were added directly to a suspension of 71.5 g of pyridinium chlorochromate in 400 ccm of methylene chloride with thorough stirring. After 2 hours at room temperature, ether was added to precipitate the reagent, the reaction mixture was decanted, and the residue was washed with ether. The combined 65 organic extracts were filtered through Florisil, evaporated and the product distilled under reduced pressure; this gave 3- (4-fluorophenyl) propionaldehyde as a colorless oil.

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Similarly, 3- (4-chlorophenyl) propional dehyde was prepared as an oil.

Trial 2

This experiment shows the procedure of Reaction Scheme A. 20.6 g of 3- (4-fluorophenyl) propionaldehyde were converted to ylide under nitrogen, prepared from 31.8 g of trimethylsulfonium iodide and 7.48 g of sodium hydride (55% dispersion in oil) in 100 cc dry dimethyl sulfoxide by the method of J. Am. Chem. Soc., Vol. 87, page 1353 (1965). After 1 hour at -10 ° C the solution was allowed to come to 0 ° C, poured into 500 cc of ice water and the product extracted 3 times with 300 cc of ether each. The extract was washed thoroughly with water, dried (MgS04) and evaporated to provide 1,2-epoxy - 4- (4-fluorophenyl) butane as an oil, which was used directly in the next step.

The above oil in a few cc of tetrahydrofuran was added to a mixture made by reacting 9.18 g of imidazole and 3.24 g of sodium hydride (50% dispersion in mineral oil) in 200 cc of tetrahydrofuran until hydrogen evolution ceased. The mixture was heated to reflux overnight, evaporated to dryness and the residue extracted with a small volume of di-chloromethane. This solution was filtered and chromatographed on silica gel eluting with 10% methanol in dichloromethane. After trituration with ethyl acetate / hexane, l- [2-hydroxy-4- (4-fluorophenyl) - n-butyl] imidazole was obtained as colorless crystals with a melting point of 120.5-122.5 ° C.

If 3- (4-chlorophenyl) propionaldehyde was used in the above process instead of 3- (4-fluorophenyl) propionaldehyde, 1- [2-hydroxy-4 (4-chlorophenyl) -n-butyl] was obtained. -imidazole with a melting point of 105-109 ° C.

Trial 3

A solution of 6.0 g of l- [2-hydroxy-4- (4-chlorophenyl) -n-butyl] imidazole in 30 cc of thionyl chloride was heated to 65 70 ° C. for 1 hour. After evaporation to dryness, 1 - [2-chloro-4- (4-chlorophenylene) -n-butyl] imidazole hydrochloride was obtained.

Similarly, l- [2-chloro-4- (4-fluorophenyl) - n-butyl] imidazole hydrochloride was prepared.

The free base for use in the subsequent alkylation step can be obtained by e.g. shake the hydrochloride in dichloromethane with excess aqueous potassium carbonate solution, wash the organic layer with water, dry over magnesium sulfate and evaporate to dryness under vacuum to remove all traces of dichloromethane.

example 1

A mixture of 6.46 g of l- [2-chloro-4- (4-chlorophenyl) - n-butyl] imidazole, 8.5 g of 2,6-dichlorothiophenol and 6.4 g of anhydrous potassium carbonate in 100 cc of acetone was heated to reflux with stirring for 18 hours. The solvent was evaporated under reduced pressure and 100 cc of water was added. The mixture obtained was extracted with 300 cc of ether and the ether extract was washed twice with water and dried with MgSO 4 to a solution which was 1- [2- (2,6-dichlorophenylthio) -4- (4-chlorophenyl) -n- contained butyl] imidazole.

The nitrate salt was obtained by dropwise addition of 70% nitric acid (d = 1.42) to the ethereal solution until the precipitation had ended. The salt obtained was recrystallized from acetone / ethyl acetate as a colorless plate with a melting point of 162-163 ° C. (foaming).

Similarly, l- [2- (2,6-dichlorophenylthio) -4 - (4-fluorophenyl) -n-butyl] imidazole nitrate salt having a melting point of 131.5-132.5 ° C was prepared.

Example 2

A mixture of 3.65 g of 2-epoxy-4- (4-chlorophenyl) butane, 4.0 g of 2,6-dichloro-thiophenol and 200 mg of anhydrous potassium carbonate in 60 cc of acetone was stirred for about 4 hours Nitrogen heated to reflux. After removal of the solvent, 150 cc of ether were added and the extract was washed with water, dried (MgS04) and evaporated.

The above material in 100 cc dichloromethane was treated with 6 cc thionyl chloride, gently heated to reflux for 1 hour and the solution evaporated to dryness and evacuated to remove traces of thionyl chloride. The residue was treated with 7 g imidazole and 30 cc acetonitrile and stirred overnight at 55 ° C and 1 day at 85aC. The solvent was evaporated and, after adding 50 cc of water, the residue was extracted with ether. The ether extract was washed thoroughly with water and dried (MgS04) to provide a solution containing 1- [2- (2,6-dichlorophenylthio) -4- (4-chlorophenyl) - n-butyl] imidazole, which was used as its nitrate salt precipitated and cleaned at a melting point of 162.5-164.5 ° C.

Similarly, the l- [2- (2,6-dichlorophenyl-thio) -4- (4-fluorophenyl) -n-butyl] imidazole nitrate salt having a melting point of 131.5-132.5 ° C produced.

Example 3

According to the procedures of Experiments 1, 2 and 3 and Examples 1 or 2, the following compounds were obtained by using equivalent amounts of the corresponding starting materials. Where indicated, the compounds can be further characterized by conversion into the acid addition salts mentioned:

1 - [2- (2,5-dichlorophenylthio) -4- (4-chlorophenyl) -n-butyl] -

-imidazole nitrate salt; F. lSSjS-lS? ^ L- [2- (2,3-dichlorophenylthio) -4- (4-chlorophenyl-n-butyl] imide-

azole nitrate salt; M.p. 136-139.5 ° C l- [2- (2-'ChIorphenylthio) -4- (4-chlorophenyl) -n-butyl] -imide-

azole nitrate salt; M.p. 136-136.5 ° C 1 - [2- (2-bromophenylthio) -4- (4-chlorophenyl) -n-butyl] imidazole nitrate salt; M.p. 137-138 ° C 1 - [2- (2,6-dibromophenylthio) -4-chlorophenyl) -n-butyl] imidazole

1 - [2- (2,4-dibromophenylthio) -4- (4-chlorophenyl) -n-butyl] imidazole

1 - [2- (2,4,6-T richlorophenylthio) -4- (4-chlorophenyl) -n-butyl] -

-imidazole; F. 136-137aC; Nitrate salt; Mp 165-166 ° C l- [2- (2,5-dichlorophenylthio) -4-4-fluorophenyl) -n-butyl] -

-imidazole nitrate salt; M. 128.5-131 ° C l- [2- (2,3-dichlorophenylthio) -4- (4-fIuorphenyl) -n-butyl] - imidazole l- [2- (2-chlorophenylthio) -4- (4-fluorophenyl) -n-butyl] imide

azole nitrate salt; F. 123-124 ° C l- [2- (2-bromophenylthio) -4-fluorophenyl) butyl] imidazole l- [2- (2,6-dibromophenylthio) -4- (4-fluorophenyl) -n- butyl] imidazole

1 - [2- (2,4-dibromophenylthio) -4- (4-fluorophenyl) -n-butyl] --imidazole 1- [2- (2,4,6-trichlorophenylthio) -4- (4-fluorophenyl) -n-butyl] imidazole nitrate salt; Mp 163-164 ° C

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l- [2- (2,3,6-trichlorophenylthio) -4- (4-chlorophenyl) -n-butyl] -

-imidazole nitrate salt; M. 138-142 ° C. (Foaming) l- [2- (2,3,4-trichlorophenylthio) -4- (4-chlorophenyl) -n-butyl] - imidazole l- [2- (2,3,5-trichlorophenylthio) -4- (4-chlorophenyl) -n-butyl] - imidazole l- [2- (2,3,4,5-tetrachlorophenylthio) -4- (4-chlorophenyl) -n-butyl] imidazole l- [2 - (2,3,4,6-tetrachlorophenylthio) -4- (4-chlorophenyl) -n-butyl] imidazole l- [2- (2,3,5,6-tetrachlorophenylthio) -4- (4th -chlorophenyl) -n-butyl] -imidazole l- [2- (2,3-dibromophenylthio) -4- (4-chlorophenyl) -n-butyl] - imidazole l- [2- (2,5- Dibromophenylthio) -4- (4-chlorophenyl) -n-butyl] - imidazole l- [2- (2,6-difluorophenylthio) -4- (4-chlorophenyl) -n-butyl] - imidazole l- [2 - (2,5-DifluorophenyIthio) -4- (4-chlorophenyl) -n-butyl] - imidazole

1 - [2- (2,4-Difluorophenylthio) -4- (4-chlorophenyl) -n-butyl] --imidazole 1- [2- (2-fluorophenylthio) -4- (4-chlorophenyl) -n-butyl ] -imidazole l- [2- (2,3-difluorophenylthio) -4- (4-chlorophenyl) -n-butyl] - imidazole l- [2- (2,3,4-trichlorophenylthio) -4- (4th -fluorophenyl) -n-butyl] - imidazole l- [2- (2,3,6-trichlorophenylthio) -4- (4-fluorophenyl) -n-butyl] - imidazole l- [2- (2,3 , 5-trichlorophenylthio) -4- (4-fluorophenyl) -n-butyl] imidazole

1 - [2- (2,3,4,6-Tetrachlorophenylthio) -4- (4-f Iuorphenyl) -n-butyl] imidazole l- [2- (2,3,5,6-Tetrachlorophenylthio ) -4- (4-fluorophenyl) -n-butyl] imidazole

1 - [2- (2,3,4,5-tetrachlorophenylthio) -4- (4-f luorphenyl) -n-butyl] imidazole l- [2- (2,3-dibromophenylthio) -4- ( 4-fluorophenyl) -n-butyl] - imidazole 1- [2- (2,5-dibromophenylthio) -4- (4-fluorophenyl) -n-butyl] - imidazole

1 - [2- (2-Fluorophenylthio) -4- (4-f luorphenyl) -n-butyl] imidazole 1- [2- (2,3-difluorophenylIthio) -4- (4-fluorophenyl) -n-butyl I ] - imidazole l- [2- (2,4-difluorophenylthio) -4- (4-fluorophenyl) -n-butyl] - imidazole l- [2- (2,5-difluorophenylthio) -4- (4- fluorophenyl) -n-butyl] - imidazole and l- [2- (2,6-difluorophenylthio) -4- (4-fluorophenyl) -n-butyl] - imidazole.

Example 4

70% nitric acid (d = 1.42) was added dropwise with stirring to a solution of 2.0 g of l- [2- (2-chlorophenylthio) -4- (4-chlorophenyl) -n-butyl] -imidazole added in 30 cc anhydrous ether until the precipitation was complete. The product was filtered off, washed with ether, air dried and extracted from ethyl acetate to give 1- [2- (2-chlorophenylthio) -4- (4-chlorophenyl) -n-butyl] imidazole nitrate with an F. of 136-136.5 ° C recrystallized.

Similarly, all of the compounds of formula (I) in base form can be converted to their antimicrobial acid addition salts by combining them with the appropriate acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, propionic acid, glycolic acid, lactic acid , Pyruvic acid, oxalic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid or salicylic acid.

Example 5

2.0 g of l- [2- (2,6-dichlorophenylthio) -4- (4-chlorophenyl) -n-butyl] imidazole nitrate in 100 cc ether were stirred with excess dilute potassium carbonate solution until the salt was completely dissolved. The organic layer was then separated, washed twice with water, dried over magnesium sulfate and evaporated; This gave l- [2- (2,6-dichlorophenylthio) -4- (4-chlorophenyl) -n-butyl] imidazole with a melting point of 68-70.5 ° C. (foaming) after recrystallization from cyclohexane .

Similarly, the antimicrobial acid addition salts of all compounds of formula (I) can be converted to the corresponding basic form.

Example 6

This example describes the preparation of representative pharmaceutical formulations that can be used to control fungi, bacteria and protozoa using an active compound, e.g. a salt of l- [2- (2,6-di-chlorophenylthio) -4- (4-chlorophenyl) -n-butyl] imidazole is used.

A. Formulations for topical use g

active connection

0.2-2

"Span 60"

2nd

"Tween 60"

2nd

mineral oil

5

Petrolatum

10th

Methyl paraben

0.15

Propyl paraben

0.05

BHA (butylated hydroxyanisole)

0.01

Water qs 100

All of the above ingredients except water were combined and heated to 60 ° C with stirring. A sufficient amount of water was then added at 60 ° C with vigorous stirring to give 100 g of the cream formulation, which was then cooled to room temperature.

B. I.V. Wording g

Active connection 0.5

Propylene glycol 20

Polyethylene glycol 400 20

"Tween 80" 1

0.9% saline solution qs 100

The active compound was dissolved in propylene glycol, polyethylene glycol 400 and Tween 80. Then one became

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sufficient 0.9% saline solution was added with stirring to make 100 cc of I.V. To give solution, which was then filtered through a 0.2 micron membrane filter and packaged under sterile conditions.

C. Oral formulation

Parts by weight

Active connection

200

Magnesium stearate

3rd

Strength

30th

Lactose

116

Polyvinyl pyrrolidone

3rd

The above ingredients were combined and granulated using methanol as a solvent. The formulation was then dried and shaped into tablets using an appropriate tablet machine (with 200 mg of active compound).

Example 7

The antifungal activity of certain compounds according to the invention was illustrated by the following test procedure:

A. A Trichophyton mentagrophytes fungus culture for infection was grown on inclined agar plates made from Sabouraud dextrose for 4 weeks at room temperature. A 2% corn starch solution was obtained by heating the starch in sterile dist. Water. About 7 cc of cornstarch solution was added to 8 sloping culture plates each. The suspension of the organism was accompanied by violent pipetting and swirling of the plates.

Guinea pigs weighing 250-350 g were divided into 10 test groups of 10 animals each (5 female, 5 male). One day before irritation, all guinea pigs in the interscapular region were circumcised and shaved, avoiding any grazes or tears.

The animals were irritated over a shaved area of 1.5 cm X 1.5 cm by rubbing with a toothbrush immersed in the fungal suspension. Rubbing continued until there was a slight reddening.

Treatment with the test compound started 3 days after the irritation and was repeated once a day for 5 consecutive days. With each treatment, about 1 cc of formulation was applied to the infected area using a spatula (tongue de-pressor). 10 animals were not treated and served as an untreated infection control.

In each guinea pig, hair was torn from 10-20 places in the infected area. The hair was vaccinated on plates containing Mycosel Agar. One plate was used per animal at each culture time (3, 7 and 14 days after infection). The plates were incubated at room temperature (about 21 ° C) and read 7 days after vaccination.

Summary of cultural results

Test connection 3 * 4 7 14

untreated

Controls 10/10 ** 10/10 10/10 8/10 0.5% «Miconazole»,

in cream 10/10 3/10 2/10 9/10

{1- [2,4-dichloro-ß- (2,4-dichlorobenzyloxy) phenethyl] imidazole nitrate}

0.5% l- [2- (2-chlorophenylthio) -4- (4-chlorophenyl) -n-butyl] imide-

azole nitrate; in cream 10/10 0/10 0/10 0/10

untreated

Controls 10/10 10/10 10/10 10/10 0.3% «Miconazole»,

in cream 10/10 3/10 0/10 3/10

0.1% l- [2- (2,5-chlorophenylthio) -4 - (4-chlorophenyl) -n-butyl] imidazole nitrate,

in cream 10/10 0/10 0/10 0/10

untreated

Controls 10/10 10/10 10/10 10/10 0.3% miconazole,

in cream 10/10 3/10 0/10 3/10

0.1% l- [2- (2-bromo-phenylthio) -4- (4-chlorophenyl) -n ~ butyl] imidazole nitrate, in cream 10/10 2/10 0/10 0/10

* Pretreatment culture

** Animals with positive culture / whole animals in the group

B. Female Swiss / Webster mice of 17-20 g received 0.25 mg of ß-estradiol suspension in a volume of 0.2 cc subcutaneously on days 1, 3 and 5 to induce estrus. This was maintained every 7 days by means of a β-estadiol injection.

A clinical isolate from human sputum was used. The organism to be injected was grown for 72 hours on inclined Sabouraud Dextrose Agar (SDA) plates at 30 ° C. On the day of irritation, 2-3 cc of Sabouraud Dextrose Broth (SDB) was added to each plate of the organism and mixed by pipetting to achieve a homogeneous suspension. The concentration of the organisms for injection was approximately 1010 org / ccm (2-3 cc SDB was added to the organism culture growing on the SDA plates). 7 days after the first injection of estradiol, about 25 ml of culture suspension was injected into the vagina of each mouse using a 20 mm animal feeding needle with a ball point.

The mice were initially treated 6 hours after irritation and then twice daily at 6 hour intervals using the ball point feeding needle for cream or liquid formulations. The flowable formulations were up to

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Injected into the vagina. The treatment was carried out on 5 consecutive days. All animals received only one treatment on the 5th day, so that they could be kept 6 hours after treatment during the working hours. Mice were sampled on day 4 after irritation (6 hours after treatment) and day 7 after irritation (72 hours after treatment). Cultures were obtained by vaginal washing with 0.1 cc sterile distilled water using an 18-20 gauge 2 The ball was placed in an SDB tube containing 10% oxytetracycline / ccm. The cultures were incubated at 30aC for 48-72 hours and then examined microscopically. Candida albicans was found in sheep serum at 37 in 2-3 hours ° C detected by nucleation in the tube.

Cultural results

Test connection

6 hours after treatment% negative

72 hours after treatment% negatively untreated

0

0

2% econazole, in cream

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0

l- [2,4-dichloro-ß- (4-chloro-benzyloxy) phenethyl] imidazole nitrate

2% l- [2- (2,4,6-trichlorophenylthio) -4- (4-fluorophenyl) n-butyl] imidazole nitrate; in cream

80

56

untreated

0

0

2% «Miconazole», in cream

80

20th

2% l- [2- (2,6-dichlorophenylthio) -4- (4-chlorophenyl) - n-butyl] imidazole nitrate, in cream

100

100

Example 8 Acute Oral Toxicity in Mice (LDS0)

The test material was suspended in a 0.5%, low-viscosity sodium carboxymethyl cellulose carrier. The concentrations were adjusted so that the doses could be administered in volumes of 0.1 ccm / 10 g body weight. 6 groups (from 5 male and 5 female mice in each group) were used. The mouse was given a single oral dose of 100 mg, 200 mg, 400 mg, 800 mg, 1600 mg or 3200 mg per kg body weight of l- [2- (2,6-dichlorophenylthio) -4- (4-chlorophenyl) -n- butyl] imide azole nitrate administered. The mice were then observed for 2 weeks.

According to the above procedure, the acute oral LDS0 of l- [2- (2,6-dichlorophenylthio) -4- (4-chlorophenyl) -n-butyl] imidazole nitrate was estimated to be> 3200 mg / kg.

Three mice showed signs of toxicity at a dose of 3200 mg / kg, whereas no other mouse showed signs of toxicity in this study.

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Claims (15)

636089 \ = / 2 21 2 \ (II) (Ib) 50 and their antimicrobial acid addition salts, in which X is chlorine or fluorine, Y is bromine, chlorine or fluorine 55, where at least one Y is in the 2'-position, n has a value from 1 to 5 if Y is chlorine and n has a value of 1 or 2 if Y has a meaning other than chlorine, characterized in that a. a compound of the formula <• '-0- ch2-ch2-ch-ch2-n s = J (IIa) 65 and their antimicrobial acid addition salts, in which X stands for chlorine or fluorine, each Z bromine, chlorine or in which X has the meaning given above and Y 'stands for a cleavable group, or their acid addition salt by reaction with 2. Compounds according to claim 1, characterized in that n has a value from 1 to 3. 2nd PATENT CLAIMS 1. Antimicrobial compounds of the formula: k2-ch2-ch-ch2-n and their antimicrobial acid addition salts, in which X represents chlorine or fluorine, each Y represents bromine, chlorine or fluorine, at least one Y being in the 2 'position and n having a value from 1 to 5 when Y is chlorine and n has a value of 1 or 2 if Y has a meaning other than chlorine. 3rd 636 089 Yn ^ O "EK or a salt thereof, where Y and n have the meaning given above, converts into a thioether of the formula I; or b. a compound of the formula: X - ^ "~ ^ -ch2-CH2-CH-CH2-S- ^ ~ ^ n 31. Antimicrobial agent containing a compound according to claim 1. 32. Antifungal agent according to claim 31. 33. Agent according to claim 31 or 32, containing a compound according to one of claims 2 to 27. 3. Compounds according to claim 2, characterized in that X represents chlorine. 4. Compounds according to claim 3, characterized in that Y represents chlorine. 5 shows that p is 0 or 1. 15. Compounds according to claim 14, characterized (I) characterized in that X represents chlorine. 16. Compounds according to claim 15, characterized in that Z represents chlorine. 17. Compounds according to claim 14, characterized in that X is fluorine and Z is chlorine. 18. Compounds according to claim 16, characterized in that p stands for 0. 19. The compound l- [2- (2,6-dichlorophenylthio) -4- (4-15-chlorophenyl) -n-butyl] imidazole and its antimicrobial Acid addition salts according to claim 1. 20. The compound 1- [2- (2,5-dichlorophenylthio) -4- (4-chlorophenyl) -n-butyl] imidazole and its antimicrobial acid addition salts according to approach 1. 20 21. The compound l- [2- (2-chlorophenylthio) -4- (4-chlorophenyl) n-butyl] imidazole and its antimicrobial acid addition salts according to claim 1. 22. The compound l- [2- (2,3-dichlorophenylthio) -4- (4-chlorophenyl) -n-butyl] imidazole and its antimicrobial 25 acid addition salts according to claim 1. 23. The compound 1- [2- (2-bromophenylthio) -4- (4-chlorophenyl) n-butyl] imidazole and its antimicrobial acid addition salts according to claim 1. 24. The compound 1- [2- (2,6-dichlorophenylthio) -4- (4- 30-fluorophenyl) -n-butyl] imidazole and their antimicrobial Acid addition salts according to approach 1. 25. The compound 1- [2- (2,4,6-trichlorophenylthio) -4 - (4-chlorophenyl) -n-butyl] imidazole and its antimicrobial (yes) acid addition salts according to claim 1. 35 26. The compound l- [2- (2,5-dichlorophenylthio) -4- (4 - fluorophenyl) -n-butyl] imidazole and its antimicrobial acid addition salts according to approach 1. 27. The compound l- [2- (2,4,6-trichlorophenylthio) -4 - (4-fluorophenyl) -n-butyl] imidazole and its antimicrobial 40 acid addition salts according to claim 1. 28. Process for the preparation of antimicrobial compounds of the formula: 45x_a x \ -ch0-ch, -ch-ch0-n 5. Compounds according to claim 2, characterized in that X is fluorine and Y is chlorine. 6. Compounds according to claim 4, characterized in that n has a value of 2. 7. Compounds according to claim 1 of the formula: x "ok H2-CH2-ÇH-CH2-NN and their antimicrobial acid addition salts, in which X is chlorine or fluorine, each W is bromine, chlorine or fluorine, at least one W being in the 2'-position, and m being 1 to 4 when W is Chlorine, and m has a value of 1 or 2 if W has a meaning other than chlorine. 8. Compounds according to claim 7, characterized in that m has a value from 1 to 3. 9. Compounds according to claim 8, characterized in that X represents chlorine. 10th 10. Compounds according to spoke 9, characterized in that W represents chlorine. 11. Compounds according to claim 8, characterized in that X is fluorine and W is chlorine. 12. Compounds according to claim 10, characterized in that m stands for 2. 13. Compounds according to claim 1 of the formula: Fluorine means, p has a value of 0 to 3 if Z is chlorine, and p is 0 if Z has a meaning other than chlorine. 14. Compounds according to claim 13, characterized in 15 IXA