CH621117A5 - Process for the preparation of substituted N-alkylamidazoles - Google Patents

Description

The present invention relates to processes for the preparation of new chemical compounds, which are derivatives of substituted N-alkylimidazoles. These compounds have the formula:

R1-CH- (CH_)

I? 2 "\ / U

wherein R1 and R2 each represent phenyl, phenyl straight-chain Ci-Cs-alkyl or phenyl straight-chain C2-Cs-alkenyl or in which one of the abovementioned radicals in the phenyl ring with one or more substituents selected from the group: lower alkyl with 1 to 4 carbon atoms, fluorine, chlorine, bromine and trifluoromethyl is or are substituted; X = oxygen or sulfur; and n is an integer from 1 to 8, but n is not the number 1 when R1 = phenyl or substituted phenyl.

The invention also relates to the preparation of the antimicrobial acid addition salts of these compounds.

The compounds obtainable according to the invention are suitable for combating fungi, bacteria and protozoa; for this purpose the compound or a composition containing it is administered.

Unless otherwise stated, the terms used have the following meaning: The term “lower alkyl” refers to a straight-chain or branched-chain monovalent substituent which consists only of carbon and hydrogen, contains no unsaturated bonds and contains 1 to 8 carbon atoms having. Examples of lower alkyl groups are: methyl, ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, pentyl, n-hexyl and n-octyl. The term "lower alkenyl" refers to a straight or branched chain monovalent substituent that consists only of carbon or hydrogen, has an unsaturated mono-olefin bond and has 2-8 carbon atoms. Examples of lower alkenyl groups are ethenyl, prop-1-enyl, prop-2-enyl, but-1-enyl, but-2-enyl, pent-1-enyl, pent-3-enyl, hex-1-enyl, hex -3-enyI, hex-5-enyI, hept-l-enyl, hept-4-enyl, hept-6-enyl, oct-l-enyl, oct-5-enyI and oct-7-enyl. The term «halogen» refers to fluorine, chlorine and bromine. «Anti-

crobial acid addition salts of the compounds are those salts which preserve the antimicrobial properties of the free bases, which are neither biologically nor in any other way undesirable and which, for example, with inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid or phosphoric acid, or with 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, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

All compounds of formula I have at least one chiral center, i. H. the carbon atom to which the radicals R1, X, (CH2) n and H are bonded. The compounds can therefore be prepared either in optically active form or as a racemic mixture. Unless otherwise stated, the compounds described below are all in racemic form. However, the present invention is not intended to be limited to this form, but also includes the preparation of the individual optical isomers of the compounds. In addition, the compounds which have an optionally substituted phenyl straight-chain C2-Cs-alkenyl group can also have geometric (ice and trans) isomers in the double bond. Both isomers and mixtures of these are also intended to be encompassed by the present invention.

If appropriate, racemic intermediates or end products produced according to the invention can also be broken down into their optical antipodes by conventional separation processes known per se, for example by separating (e.g. fractional crystallization) the diastereomeric salts which are obtained by reacting, for example, racemic compounds of the formula I with a optically active acid have been formed, or by separating the diastereomeric salts or esters which have been formed by reacting racemic compounds of the formula II with an optically active acid. Examples of such optically active acids are the optically active forms of camphor-10-sulfonic acid, a-bromo-camphor-jt-sulfonic acid, camphoric acid, menthoxyacetic acid, tartaric acid, malic acid, diacetyltartaric acid, pyrrolidone-5-carboxylic acid and the like. The separated pure diastereomeric salts or esters can then be cleaved by standard methods in order to obtain the corresponding optical isomers of the compounds of the formula I or II.

The compounds of formula I have a fungicidal antibacterial and antiprotozoal activity. For example, the compounds have a fungicidal activity against human and animal pathogens, such as Microsporum audouini,

Microsporum gypseum,

Microsporum gypseum-canis,

Epidermophyton floccosum,

Trichophyton mentagrophytes,

Trichophyton rubrum,

Trichophyton tonsurans,

Candida albicans and Cryptococcus neoformans.

The compounds also have a fungicidal activity against the following fungi, which are mainly of importance in agriculture:

Aspergillus flavus,

Cladosporium herbarum,

Fusarium graminearum,

Pénicillium notatum and s

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Aspergillus niger,

Pénicillium oxalicum,

Penicillium spinulosum,

Pithomyces chartarum.

In addition, the compounds also have an antibacterial activity against human and animal pathogens, such as Staphylococcus aureus,

Strepotococcus faecalis,

Corynebacterium acnes,

Erysepelothrix insidiosa,

Escherichia coli,

Proteus vulgaris,

Salmonella choleraesuis,

Pasteurella multocida and Pseudomonas aeruginosa.

The compounds also have antiprotozoal activity against protozoa such as Trichomonas vaginalis.

In general, the compounds have a low level of toxicity. In addition, these compounds have good solubility in the stratum corneum. Since dermatophytic (i.e. parasitic-fungus) infections are usually found in the dead tissue of the stratum corneum, the solubility of the fungicidal agents in this tissue significantly increases their effectiveness.

In view of the above-mentioned effectiveness, the compounds are valuable antimicrobial agents which are suitable not only for pharmaceutical but also for agricultural and industrial use.

The compounds can also be found in the form of compositions for pharmaceutical, agricultural and industrial use which comprise the compounds of formula I in combination with a suitable carrier. The growth of fungi, bacteria and protozoa is inhibited by administering an effective amount of a compound or a suitable composition containing it to a host which is infected or is threatened by fungi, bacteria or protozoa.

For pharmaceutical use, the compositions can be used in solid, semi-solid or liquid form, such as tablets, capsules, powders, suppositories, liquid solutions, suspensions, creams, lotions and the like. Pharmaceutically acceptable, non-toxic carriers or excipients normally used for solid compositions are e.g. B. tricalcium phosphate, calcium carbonate, kaolin, bentonite, talc, gelatin, lactose, starch and the like; for semi-solid compositions, for example, polyalkylene glycols, petroleum jelly and other cream bases can be used; for liquid compositions are e.g. B. water, oils of vegetable origin and low-boiling solvents such as isopropanol, hydrogenated naphthalenes and the like, are suitable. The pharmaceutical compositions containing the compounds can be conventional pharmaceutical methods, such as. Sterilization, and they may contain conventional pharmaceutical additives such as preservatives, stabilizers, emulsifiers, salts for adjusting the osmotic pressure and buffers. The compositions can also contain other therapeutically active materials. When used pharmaceutically, the compounds and compositions can be administered to humans and animals by conventional methods, for example externally, orally, parenterally or the like. Parenteral administration includes both intramuscular, subcutaneous and intravenous administration. Intravenous injection of fungicides

Imidazole type compounds have been shown to be effective in the treatment of systemic mycosis (see, e.g., "Drugs", 9, pages 419-420, 1975, in which the intravenous administration of miconazole, ie l- [2,4-dichloro- β- (2 ', 4'-diehlorbenzyloxy) phenethyl] imidazole nitrate, in patients with systemic candidiasis is described). Local application is the preferred mode of administration for pharmaceutical use. With this treatment, an area which is already infected with fungi, bacteria or protozoa or which is to be protected against infection by fungi, bacteria or protozoa can be treated with the compound or the composition, for. B. by dusting, spraying, spraying, rinsing, brushing, dipping, lubricating, brushing, impregnating and the like. Pharmaceutical compositions for external use, which contain the compounds, have in very different concentrations, e.g. B. from about 0.1-10.0% by weight of the composition, fungicidal, antibacterial and antiprotozoal activity. In any event, the composition to be administered contains a sufficient amount of the compound to provide relief from a particular condition or to prevent that condition from occurring.

The pharmaceutical compositions generally comprise one or more of the compounds of formula (I) and a pharmaceutically acceptable, non-toxic carrier and are preferably prepared in dosage units to facilitate administration (a dosage unit is the amount of active ingredient administered at one time becomes).

In the case of systemic administration (for example orally or parenterally), it is generally expedient to add the active compound in amounts of between about 1 and 100 mg per kg of body weight and per day, preferably between about 5 and 50 mg per kg of body weight and per day Administer, preferably divided over several administrations (z. B. in three individual doses), in order to achieve the maximum possible effect. With localized administration (e.g. externally), a correspondingly smaller amount of active substance is necessary.

The exact regulation of the administration of the compounds and composition depends, of course, on the needs of the individual patient being treated, the type of treatment, for example whether it is preventive or curative treatment, the type of organism concerned and, of course, also on the judgment of the treating person Doctor.

When used in agriculture, the compounds can be applied directly to plants (e.g. seeds, leaves) or to the soil. The compounds can be applied to the seeds, for example, alone or mixed with a powdery solid carrier. Typical powdery carriers are the various mineral silicates, e.g. B. mica, talc, pyrophyllite and clays. The compounds can also be mixed with a conventional surfactant and, if appropriate, additionally applied to the seeds with a solid carrier. All conventional anionic, nonionic and cationic types of wetting agents are suitable as surface-active wetting agents. For the treatment of the soil against fungi and the like, the compounds can be used in the form of a dust mixed with sand, earth or a powdery solid carrier such as a mineral silicate, optionally together with a surface-active agent, or the compounds can be used as an aqueous spray , which optionally contains a surface-active dispersing agent and a powdery solid carrier. For the treatment of leaves, the compounds can be in the form of an aqueous spray, which is a surface-active dispersion.

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Containing agents and optionally a powdery solid carrier and hydrocarbon solvents can be applied to growing plants.

In industrial applications, the compounds can be used to control bacteria and fungi by bringing the pathogens into contact with the compounds in a known manner. Materials that are suitable as a breeding ground for bacteria and fungi can be protected by being brought into contact with the compounds, mixed or impregnated. To increase the effectiveness, the compounds can be combined with other pesticides such as fungicides, bactericides, insecticides, miticides and the like. A particularly important industrial and agricultural area of application of the compounds is the use as a food preservative against bacteria and fungi, which cause food spoilage.

The compounds of the formula (I) can be divided into two subclasses, namely those of the formulas (Ia) and (Ib):

x ^

R -CH- (CH0) -N N

I 2 W.

0-R

(Ia)

1

R -CH- (CHj -N N

2 2nw

S-IC

(Ib)

Chlorine-) substituted derivative of these - preferably with the halogen substituents in the same position as R1 and, if R2 is substituted phenylthio, additionally the 2,4,5-trichloro and 2,3,4,5,6-pentachloro-substituted Derivatives - means.

The method according to the invention is characterized in that it consists of the following stage:

a. Etherification of a compound of the formula:

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R -CH- (CH-) -N 2 n •

15

OH

/ X

* N

W

(II)

wherein R1 and n have the same meaning as above, with a base and R2Y, in which R2 represents optionally substituted phenyl straight-chain-Ci-Cs-alkyl or phenyl-straight-chain-Cz-C8-alkenyl and Y is a cleavable group, or b. Etherification or thioetherification of a compound of the formula:

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R -CH- (CH_) -N I 2 n

N

w in which R1, n and Y have the same meaning as above, or an acid addition salt thereof with a base and R2OH or R2SH, in which R2 is optionally substituted phenyl, or 35 c. Thioetherification of a compound of the formula:

40 R -CH- (CHL) -N N

i 2n W

wherein R1, R2 and n have the meaning given above.

Both groups of compounds are made from common intermediates that have a free hydroxyl group, which is then converted to either the ether or the thioether.

A preferred subgroup comprises compounds of the formula I in which n = 1, 2 or 3. If n = 1, the preferred group is a compound in which R1 is phenethyl, styryl or fluorine, chlorine or bromine (preferably chlorine) substituted phenethyl or styryl, preferably 4-chloro, 4-bromo , 4-fluoro, 2,4-dichloro or 3,4-dichloro-substituted phenethyl or styryl, and R2 either phenyl or benzyl or a fluorine, chlorine or bromine-substituted derivative of these - this derivative being the ( which) has fluorine, chlorine or bromine substituents, preferably in the same position as the above radical R1, or

if R2 is substituted phenylthio, is additionally a 2,4,5-trichloro and 2,3,4,5,6-pentachloro-substituted derivative - or cinnamyl or 4-fluoro, 4-chloro or 4-bromocinnamyl means.

If n is 2 or 3, the more preferred group is one in which R1 is phenyl or phenyl or fluorine, chlorine or bromine-substituted phenyl, preferably 4-chloro, 4-bromo, 4-fluoro-2, 4-dichloro, 2,4-difluoro or 2,4-dibromo substituted phenyl, and R2 either phenyl or benzyl or a fluorine, chlorine or bromine (preferably

45 wherein R1, n and Y have the same meaning as above,

or an acid addition salt thereof with a base and R2SH, wherein R2 is optionally substituted phenyl straight chain C 1 -C 4 alkyl or phenyl straight chain C 2 Cs alkenyl.

As already mentioned, suitable alcohols of the formula serve as starting products:

55 F ^ -CH-CCH ^ -N * N

OH

/ X

N N

W

(II)

where R1 and n have the same meaning as above. Compounds of formula (II) can be prepared according to many different reaction procedures, which depends on the size of 65 n.

If, for example, n = 1, certain compounds of the formula (IIa) can be prepared according to the following reaction scheme A:

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Reaction scheme A

RICHO »R1-CH-CH2> R! -CH-CH2- N N

T V in W

(IV) / (m) (Ha)

RI_CH = CH2

(V)

In this reaction scheme, the imidazole alcohol of the formula (Ha) is formed by opening a terminal epoxide of the formula (III) with imidazole. This reaction is generally carried out using at least 1 mole - and preferably an excess - of imidazole, based on the epoxide. The reaction can be carried out either in the absence of solvents or, preferably, in an inert organic solvent, e.g. As dimethylformamide, hexamethylphosphoramide, acetonitrile and the like can be performed. The temperature normally used for such epoxy openings is between about -20 and 100 ° C, preferably between about 20 and 60 ° C.

Epoxides of formula (HI), if not known or readily available, can be prepared by various known methods, e.g. B. epoxidation of a terminal olefin (e.g. (V)) with, for example, a peracid, or by reacting an aldehyde which has one carbon atom less (e.g. (IV)) with which the ylide is made from trimethylsulfoxonium iodide and is described, for example, in J.Am.Chem.Soc., 84, page 867 (1962) and exactly there 87, page 1353 (1965).

Another process for preparing certain compounds of formula (Ha) is shown in Reaction Scheme B below:

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Reaction scheme B

R1COCH2Y J- R1COCH2- N N »R1-CH-CH2- N N

\ / OH \ z = J

(VII) (VI) (Ha)

where Y = chlorine or bromine.

In this reaction scheme, the hydroxy compound of the formula (IIa) is prepared by reducing the corresponding ketone (VI), which in turn has been obtained by reacting an a-halo-ketone (VII) with imidazole.

a-Halogen ketones are widely available or can be easily prepared by halogenating, for example, the corresponding methyl ketone. When R1 is styryl or substituted styryl, a particularly suitable brominating process is described in Tetrahedron, 29, page 1625 (1973) and in Can. J. Chem. 47, page 706 (1969).

The α-haloketone is contacted with imidazole in an inert organic solvent to obtain the ketoimidazole of formula (VI). The reaction is carried out using at least a molar amount, preferably an excess, of imidazole, based on the halogeneketone. The reaction can be carried out in the absence of solvents or, preferably, in an inert organic solvent, such as. As dimethylformamide, hexamethylphosphoramide, acetonitrile and the like, can be carried out, conveniently at an initial temperature of about -10 to 100 ° C, preferably from about 0 to 25 ° C.

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

If n = 2, the compounds of formula (üb) can be prepared by various synthetic methods. A suitable process for the preparation of certain compounds of the formula (üb) is shown in reaction scheme C below:

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Reaction scheme C

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R1-COCH = CH2-

.R1-COCHZCH2-N

M

(or Mannich base, quaternary salt)

(vm)

W

(IX)

R1CHCH2CH2-N N

w

OH (IIb)

This scheme involves the reaction of imidazole with a vinyl ketone of formula (Vm) (or a quaternary base, intermediate of a Mannich reaction), followed by reduction of the resulting ketoimidazole of formula (IX) to the hydroxyimidazole of formula (ü). 25th

Vinyl ketones of formula (VIII), if not known or generally available, can be prepared by various methods well known in the art of synthetic organic chemistry, such as e.g. B. by adding vinyl lithium to the corresponding carboxylic acids; by adding vinyl lithium to the corresponding acid aldehyde, followed by oxidation of the allylic acid alcohol to give the vinyl ketone (see e.g. BJChem.-Soc. (C), 1966, page 1972; J.Chem.Soc. (London ), 1956, page 3070); or by a Mannich reaction of the corresponding 3s methyl ketone, quaternization and elimination.

The first stage of the conversion, the reaction of the vinyl ketone of the formula (VIII) to the ketoimidazole of the formula (IX),

is done by contacting the vinyl ketone (or a quaternary base precursor obtained by a Mannich reaction) with imidazole in an organic solvent. The reaction is conveniently carried out by at least a molar amount, preferably an excess, of imidazole, based on the vinyl ketone or the quaternary “Mannich” base, in an inert organic solvent, for. As diethyl ether, dichloromethane or dimethylformamide, at a temperature of about 0-40 ° C, preferably at about room temperature, is used.

The reduction of the ketomidazole of formula (IX) to the hydroxyimidazole of formula (üb) is carried out in the same manner as described above for the conversion of the compound of formula (VI) into the compound of formula (IIa).

If n = 2 (or a higher number), certain compounds of the formula (II) can be prepared according to the following reaction scheme D:

Reaction scheme D

R1CO (CH2) nY- (X)

. R1CO (CH2) n-N • N

Lw ^

UrìCH ^ HìJo-N N

W

(XI)

OH

(II)

where Y = chlorine or bromine.

In this reaction scheme, an m-halo (preferably chloro) ketone of formula (X) is converted into the corresponding ketoimidazole of formula (XI) and then into the hydroxyimidazole of formula (II).

If they are not known or generally available, the co-haloketones used as starting material can expediently be prepared by the known Friedel-Crafts reaction, which is carried out using the aromatic hydrocarbon R! H and a co-haloacyl halide.

The conversion of compound (X) to compound (XI) is carried out using imidazole according to the same procedure described above for the conversion of compound (VII) to compound (VI). When n = 3 or higher, the reaction temperature is about 0-100 ° C, preferably about 25-80 ° C.

The reduction of the ketoimidazole of formula (XI) to the hydroxyimidazole of formula (II) is carried out in the same manner as that previously described for the conversion of compound (VI) to compound (IIa).

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Certain compounds of formula (He) can also be prepared by an alternative process, which is shown in Reaction Scheme E below:

R1COCH = CH2-

(VIII)

-> R1COCH-CH2> (X) -

V

CHz

(xn)

- »R1-CH- (CH2) 3- N N

\ = /

OH

(nc)

In this process, the vinyl ketone of the formula (VIII) described above is converted into the corresponding cyclopropyl ketone of the formula (XII), after which the conversion into the Y-halo ketone of the formula (X) - at n = 3 - and then, as described above, in the hydroxyimidazole of the formula (Ile).

The cyclopropanation of the vinyl ketone of the formula (VIII) can be carried out by processes known per se

ls the, e.g. B. by the method described in J.Am.Chem.Soc., 87, page 1353 (1965). The cyclopropyl ketone obtained is then opened to obtain the y-halo ketone by treatment with a hydrohalic acid, for example hydrobromic acid.

20 Certain compounds of the formula (II) can also be prepared according to the following reaction scheme F:

Reaction scheme F

R1CHO + CH2 = CH- (CH2) n-2Y

(IV) (Xin)

R1CO (CH2) nY- (X)

RKXXOfe). * - N N

\ = J

(XI)

-> R1CH (CH2) n— N N

\ = J

OH

(H)

where Y = chlorine or bromine.

This reaction scheme is particularly suitable for the preparation of compounds in which n = 4 or greater, but it can also be used to prepare compounds in which n = 2 or 3. In this scheme, the aldehyde of the formula (VI) described above is reacted with an alkene of the formula (XIII) which has ro-halogen end groups and which can easily be prepared, for example, by halogenating the corresponding alcohol in an addition reaction based on free radicals to obtain the halogen ketone of formula (X) described above, which is then converted in the manner described above via the ketoimidazole of formula (XI) into the hydroxyimidazole of formula (II). The conversion of compounds (IV) + (Xni) into the compound (X) is conveniently obtained using a source of free radicals, such as, for example, diacetyl peroxide, di-tert-butyl peroxide, dibenzoyl peroxide, azobisisobutyronitrile; or by photochemical means at a temperature between about 50 and 150 ° C. preferably between about 60 and 80 ° C, using an excess of aldehyde as the solvent medium.

Certain compounds of formula (II) can also be prepared according to the following reaction scheme G:

R1COY + CH2 = CH- (CH2) n-2-Y

(XIV) (xni)

1> R1CO (CH2) nY> XI »II

50 (X)

where Y = chlorine or bromine.

55 This reaction scheme is conveniently used when compounds are desired in which n = 4 or greater.

In this reaction scheme, an acid halide of the formula (XIV), which can be easily prepared from the corresponding carboxylic acid 60, is reacted with the alkene of the formula (XIII) having (o-halo gene end groups) described above to give the halogen ketone of the formula (X), which is then, as described above, converted into the hydroxyimidazole of the formula (II). The addition reaction between the compounds of the formulas (XIV and (XIII) is conveniently carried out under the conditions described in G Olah, “Friedel Grafts and Related Reactions”, Volume 3, Part 2, Interscience Publishers, New York,

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(1964). sequence produced by the following reaction

Certain compounds of the formula (II), in which n = 1 or scheme H is represented:

is larger, you can also use another reaction

Reaction scheme H

R ° -CH = CH2 + YCO (CH2) "Y- (XV) (XVI)

. R1CO (CH2) nY

(X)

(II)

In this scheme, the co-halo-ketone of formula (X) described above is prepared by starting with a terminal olefin of formula (XV) and a co-halo-acyl halide of formula (XVI), e.g. B. can be easily prepared from the corresponding hydroxy acid is used. The reaction is carried out under the conditions described for Reaction Scheme G above.

The following reaction scheme I shows alternative processes for the preparation of certain compounds of the formula (II) in which n = 1:

Reaction scheme I

R ° CHO + 03P = CHCOCH2-N N.

\ ~ J R ° -CH = CH-COCH2- N N

(XVII) \ (XIX) ^!

► II a

(XX)

T

03P-CH2COCH2Y

xe (xvm) \

R ° CHO + 03P = CHCOCH2Y

(xvn) (xxi)

.R ° CH = CHCOCH2Y, (XXII)

where R1 = R ° -CH = CH- or R ° CH2CH2- and Y = chlorine or bromine

In this scheme, an aldehyde of formula (XVII) is reacted in 4g of a Wittig reaction with a ylide of formula (XIX) or (XXI) to obtain the corresponding olefin of formula (XX) or (XXII). The ylide (XXI) is formed by processes known per se from the corresponding phosphonium salt (XVIII), which in turn is prepared from triphenyl-50 phosphine and the corresponding dihaloacetone. In order to form the ylide of the formula (XEX), the phosphonium salt is in an inert organic solvent, such as acetonitrile or dimethylformamide, at a temperature of about 25 to 100 ° C, preferably of about 50 to 80 ° C, with an SS Excess imidazole reacted to give the imidazole-substituted ylide of the formula (XIX), which is then reacted with the aldehyde of the formula (XVII)

under standard Wittig conditions (e.g. in acetonitrile at 80 ° C) gives the unsaturated ketoimidazole of the formula (XX). 60

If appropriate, also by reacting the aldehyde of the formula (XVII) with the ylide of the formula (XXI), which can be obtained in the usual manner by treatment with a base, such as an alkali metal carbonate, from the phosphonium salt (XVIII)

has been obtained, the unsaturated halogen ketone of the formula 6s (XII) can be prepared. This compound can then be converted to the corresponding imidazole compound of formula (XX) by treatment with imidazole in the manner described above for converting compound (VII) to compound (VI). A reduction in the keto group of the compound (XX) then leads to the hydroxyimidazole of the formula (IIa). The double bond adjacent to the hydroxyl group can be hydrogenated in order to obtain a compound of the formula (IIa) which has a phenyl-lower alkyl or substituted phenyl-lower alkyl group as the radical R1. This hydrogenation can be carried out under standard conditions, for example using a palladium-on-carbon catalyst in a solvent such as methanol. The hydrogenation can optionally also be carried out before the reduction of the ketone.

The compounds of the formula (II) are converted into the end products of the formula (I), in which X = O and R2 = optionally substituted phenyl straight-chain-Ci-Cs-alkyl or phenyl-straight-chain-C2-C8-alkenyl, by O-alkylation with the corresponding R2Y, where Y = a removable group, such as a halide (chloride, bromide or iodide), or a sulfonate ester (e.g. p-toluenesulfonate or methanesulfonate) is carried out.

The alkylation can be carried out by treating the hydroxy group of the compound of formula (II) by treatment with a strong base such as e.g. An alkali metal hydride such as sodium hydride, an alkali metal amide such as sodium amide or potassium amide, and the like, is converted into the alkali metal salt. This treatment is preferably carried out in an inert organic solvent, such as

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e.g. B. dimethylformamide, hexamethylphosphoramide, tetrahydrofuran and the like. The alkali metal salt is then contacted with the R2Y, preferably in the same solvent system and at a temperature of about 0 to 80 ° C, preferably about 0 to 60 ° C.

Compounds of formula (I) in which R2 is optionally substituted phenyl (i.e. phenolic ether or thioether) are prepared from the compounds of formula (II) in two stages; First, the hydroxyl group is converted into a suitable cleavable group, such as a halide (e.g. a chloride or bromide) or a sulfonate ester (e.g. methanesulfonate or p-toluenesulfonate), which then comprises a metal salt of the corresponding phenol R2OH or thiophenol R2SH can be implemented.

The alcohol is converted into the halide or the sulfonate ester by known processes. For example, the alcohol can be halogenated using a halogenating agent such as thionyl chloride or thionyl bromide, optionally in an inert organic solvent such as dichloromethane or chloroform, at a temperature of about 0-80 ° C, preferably about 20-80 ° C. The halogenation reaction can optionally be carried out in the presence of a molar equivalent of a base (e.g. pyridine).

In other halogenation processes, for example, triphenylphosphine is used together with carbon tetrachloride, carbon tetrabromide or N-chloro- (or N-bromo-) succinidium. If thionyl chloride or thionyl bromide is used without an additional base, the hydrochloride or hydrobromide salt of the corresponding halogen compound is obtained. This salt can be neutralized (e.g. with potassium carbonate) prior to use in the alkylation step, or it can be used directly when an excess of phenol or thiophenol salt is used.

Sulfonate esters can be prepared by a standard procedure which consists in that the alcohol with an excess of, for example, methanesulfonyl chloride or p-toluenesulfonyl chloride in the presence of a base, e.g. As pyridine or triethylamine, is treated. This reaction is carried out at a temperature of about -20 to + 50 ° C, preferably from about 0 to 20 ° C.

The halide or sulfonate ester prepared in the manner described above is then reacted with a metal salt, preferably an alkali metal salt such as the sodium or potassium salt, of the corresponding phenol or thiophenol in the presence of an inert organic solvent such as acetone, methanol and the like at one temperature treated from about 20 to 80 ° C. The metal salt of the phenol or thiophenol can optionally be formed before the addition of the halogenide.

Compounds of formula (I) in which X = S and R2 = optionally substituted phenyl straight-chain Ci-Cs-alkyl or phenyl straight-chain-C2-C8-alkenyl means are also prepared by the above-mentioned halide or the sulfonate ester with the Metal salt, preferably an alkali metal salt, such as the sodium or potassium salt, of a thiol R2SH is reacted. This reaction is usually carried out in an inert organic solvent, such as. B. tetrahydrofuran, diethyl ether, methanol and the like. The salt can be mixed with a strong base, e.g. As sodium hydride, sodium amide, sodium methylate and the like, are formed at a temperature of about 20 to 80 ° C.

The resulting compounds can be separated off as free bases; however, since many of the compounds are oils in the form of bases, it is more expedient to separate and determine the compounds in the form of acid addition salts. These salts are prepared in the usual way, i.e. by reacting the basic compound with one of the suitable inorganic or organic acids described above. Salts formed with dibasic acids (e.g. oxalic acid) can contain one or two base molecules per acid molecule. All oxalates described here contain one molecule of oxalic acid per molecule of imidazole base. Optionally, the salts can be easily converted to the free base form by treatment with alkali such as potassium carbonate, sodium carbonate or sodium or potassium hydroxide.

The following examples serve to explain the present invention in more detail.

Procedure 1

This procedure illustrates Reaction Scheme A.

3-Phenylpropionaldehyde (26.8 g) under nitrogen was the ylide, which according to the procedure described in Journal of the American Chemical Society, volume 84, page 867 (1962) and volume 87, page 1353 (1965) from Trimethylsulfoxonium iodide ( 48.4 g) and sodium hydride (55% dispersion in oil; 9.6 g) in dry dimethyl sulfoxide (200 ml) were added. After 1 hour the solution was poured into 1 liter of water and the product was extracted with ether (3 X300 ml). The extract was washed with water (2 X150 ml), dried (MgSÛ4) and evaporated to give an oil, 1,2-epoxy-4-phenylbutane, which was used directly in the next step.

The oil obtained above was treated in 50 ml of dimethylformamide with imidazole (70 g) and the mixture was stirred at 40 ° C overnight. The resulting solution was poured into a mixture of 700 ml of water and 200 ml of hexane, stirred until crystallization was complete, and the product was then filtered off in the form of leather-colored granules (28.2 g). Recrystallization from ethyl acetate gave l- (2-hydroxy-4-phenylbutyl) imidazole in the form of colorless crystals, melting point 106-107 ° C.

The following process of the formula (IIa) can also be prepared, for example, by the same process, but by replacing 3-phenylpropionaldehyde with the corresponding aldehyde:

1- [2-hydroxy-4- (4-chlorophenyl) butyl] imidazole 1- [2-hydroxy-4- (2,4-dichlorophenyl) butyl] imidazole 1- [2-hydroxy-4- ( 4-tert-butylphenyl) butyl] imidazole 1- [2-hydroxy-4- (4-fluorophenyl) butyl] imidazole and

1- [2-Hydroxy-4- (2,4-dimethylphenyl) butyl] imidazole.

Procedure 2

This procedure illustrates Reaction Scheme B.

Bromomethyl styryl ketone (22.5 g; see Tetrahedron, Volume 29, pages 1625-28, 1973) in a few ml of dimethylformamide was added dropwise to a well-stirred, ice-cooled solution of imidazole (35 g) in dimethylformamide (25 ml), with the temperature on was kept below 13 ° C. The mixture was stirred at 00 ° C for 3 hours and then at 25 ° C overnight and then poured into 11 water. The solution was extracted sequentially with benzene (600 ml) and ether (600 ml) and the combined extracts were dried (MgSO4) and evaporated. Lemon yellow granules (12 g) were obtained by adding benzene to the residue. Treatment of a solution of this product in methanol with ethereal hydrogen chloride, removal of the solvent and trituration of the residue with ethyl acetate (100 ml) gave 5.75 g of l- (4-phenylbut-3-en-

2-onyl) imidazole hydrochloride in the form of a white solid, melting point 208-210 ° C.

The ketone obtained above (5.50 g) in 50 ml of methanol was treated at 0 ° C by stirring with an excess of sodium borohydride. When the reaction was over

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the solvent was evaporated and the residue was treated with ice cold water (10 ml). Filtration and washing with a small amount of ice water gave a whitish powder (5.40 g) which, after recrystallization from benzene, l- (2-hydroxy-4-phenylbut-3-enyl) imidazole (5.20 g) , Melting point 125-127 ° C.

The following compounds of the formula (IIa) can also be prepared, for example, by the same process, but by replacing the bromomethylstyryl ketone with the corresponding halogen ketone:

l- (2-Hydroxy-3-phenylpropyl) imidazole l- [2-Hydroxy-3- (4-cWorphenyl) propyl] imidazole and l [2-Hydroxy-4- (4-chlorophenyl) but-3 -3nyl] imidazoI.

Procedure 3

This procedure illustrates Reaction Scheme C.

A. 7.0 g of 2,4-dichlorophenyl vinyl ketone (prepared by Jones oxidation of 2,4-dichlorophenyl vinyl carbinol using the method described in J. Chem. Soc. (C), 1966, page 1972) in 350 ml of anhydrous ether were treated with 3.5 g imidazole, the solution was stirred overnight and then washed with water (3 X 30 ml). The solution was then dried (MgS04) and evaporated to give 2,4-dichloro-β- (l-imidazole) propiophenone in the form of an amber-colored rubber-like mass. (8.65 g.) The hydrochloride salt could be precipitated from ether, and recrystallization from methanol / acetone gave a product in the form of colorless rods, melting point 105.5-110 ° C.

B. 13.1 g of 2,4-dichlorobenzoylethyl-trimethylammonium iodide (prepared in a Mannich reaction of 2,4-dichloroaceto-phenone with paraformaldehyde and dimethylamine hydrochloride, followed by quaternization with methyl iodide in ether) and 12 g of imidazole in dimethylformamide (50 ml)

were stirred overnight at room temperature and then poured into 500 ml of water. The product was extracted with ether (3 × 300 ml), the extracts washed with water

(3 X 75 ml) and dried. By adding ethereal hydrogen chloride, the hydrochloride of 2,4-dichloro-β- (l-imidazole) propiophenone was precipitated, which was then recrystallized from methanol / acetone, melting point 105-109 ° C.

C. The ketone prepared in Part A or B can be reduced to the corresponding alcohol, l- [3-hydroxy-3-2,4-dichlorophenyl) propyl] imidazole, melting point 112-114.5 ° C, and according to the procedure described above 2.

D. Using the same process as above, but using the appropriate vinyl ketone or quaternary Mannich salt instead of the compounds mentioned in Part A or B, the following compounds of the formula (ü) can also be prepared, for example:

1- [3-Hydroxy-3- (4-chlorophenyl) propyl] imidazole, melting point 95-100 ° C

l- [3-Hydroxy-3- (4-tert-butylphenyl) propyl] imidazole, melting point 139.5-140.5 ° C. l- [3-Hydroxy-3- (4-fluorophenyl) propyl] -imidazole, melting point 104.5-110 ° C

1- [3-hydroxy-3- (2,4-dimethylphenyl) propyl] imidazole 1- (3-hydroxy-4-phenylbutyl) imidazole 1- [3-hydroxy-4-) 4-chlorophenyl) butyl ] imidazole 1- [3-hydroxy-4- (4-methylphenyl) butyl] imidazole 1- [3-hydroxy-5- (4-chlorophenyl) pentyl) imidazole and 1- [3-hydroxy-3 - (2-trifuluormethylphenyl) propylj imidazole

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l- [2-Hydroxy-3- (2,4-dibromophenyl) propyl] imidazole l- [3-Hydroxy-3- (2,4-difluorophenyl) propyl] imidazole.

Procedure 4

This procedure illustrates Reaction Scheme D.

A. β-chloropropiophenone (16.8 g) and imidazole (35 g) in dimethylformamide (25 ml) were stirred at 0 ° C for 3 hours and then poured into 700 ml of water. The product was filtered off in the form of leather-colored flakes (15.9 g) and then recrystallized from cyclohexane to give β- (l-imidazolyl) propiophenone in the form of colorless flakes, melting point 96-99.5 ° C.

The material obtained above (5.60 g) in 70 ml of methanol was treated with an excess of sodium borohydride at 0 ° C. When the reaction was complete, the solvent was evaporated, 100 ml of water was added and the product (4.90 g) was filtered off. Recrystallization from ethyl acetate gave 1- (3-hydroxy-3-phenylpropyl) imidazole in the form of colorless rods, melting point 106.5-108 ° C.

B. To a slurry of 8.24 g of imidazole in 15 ml of dry dimethylformamide at a temperature of 0 ° C was added 5.79 g of p-tert-butyl-y-chlorobutyrophenone and the mixture was left overnight at room temperature and then another Stirred at 60 ° C day. This solution was poured into 400 ml of water and extracted three times with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and the solvent evaporated to give 5.25 g of l- [4- (4-tert-butylphenyl) butan-4-onyl] imidazole in the form of a gold-colored oil .

An excess of borohydride was added to a solution of 5.0 g of the above ketone in 150 ml of anhydrous methanol at a temperature of 0 ° C and the mixture was stirred for 1 hour. After removing the solvent, a small amount of water was added and the mixture was extracted with ethyl acetate. The combined extracts were dried over magnesium sulfate and evaporated to give 1- [4-hydroxy-4- (4-tert-butylphenyl) butyl] imidazole, which was converted to the oxalate salt and recrystallized from ethyl acetate / ethanol, melting point 205-207 ° C (foaming).

The first four compounds of the formula (IIb) and the following compounds of the formula (II), for example, can also be prepared by the same process, but using the corresponding halogen ketone instead of the compound indicated in Part A or B:

1- [4-hydroxy-4- (4-chlorophenyl) butyl] imidazole 1- [4-hydroxy-4- (2,4-dichlorophenyl) butyl] imidazole 1- [4-hydroxy-4- ( 4-fluorophenyl) butyl] imidazole,

Melting point 91.5-94 ° C

1- [4-hydroxy-4- (2,4-dimethylphenyl) butyl] imidazole 1- [4-hydroxy-4- (4-bromophenyl) butyl] imidazole,

Melting point 113.5-115 ° C

1- (4-Hydroxy-5-phenylpentyl) imidazole 1- [4-Hydroxy-5- (4-chlorophenyl) pentyl] imidazole

1- [4-hydroxy-6- (4-chlorophenyl) pentyl] imidazole 1- (6-hydroxy-6-phenylhexyl) imidazole 1- [6-hydroxy-6- (4-chlorophenyl) hexyl] - imidazole 1- [6-hydroxy-7- (4-chlorophenyl) heptyl] imidazole 1- (6-hydroxy-8-phenyloctyl) imidazole 1- (6-hydroxy-10-phenyldecyl) imidazole

1 - (9-Hydroxy-9-phenylnonyl) imidazole l- [9-Hydroxy-9- (4-chlorophenyl) -nonyI] imidazole l- [9-Hydroxy-10- (4-chlorophenyl) decyl] - imidazole l- (9-hydroxy-l l-phenylundecyl) imidazole and

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1- (9-hydroxy-13-phenyltridecyl) imidazole.

Procedure 5

This procedure illustrates Reaction Scheme I.

7.3 g of chloroacetylmethyl triphenylphosphonium chloride and 7.3 g of imidazole in acetonitrile (60 ml) were stirred for two days and heated to 80 ° C. The resulting solution was evaporated and the residue treated with water, extracted with benzene and the extract washed with water, dried (MgSO-t) and evaporated. By recrystallization from ethyl acetate / cyclohexane, 1-imidazolylacetylmethylene triphenylphosphorane was obtained in the form of colorless leaves, melting point 154.5-158 ° C.

The phosphorane (3.85 g) and p-tolualdehyde (2.4 g) obtained above were stirred in 30 ml of acetonitrile and heated under reflux overnight. After evaporating to dryness, the residue was chromatographed on silica gel using acetone / dichloromethane as the eluent to give 1- [4- (4-methylphenyl) but-3-3n-2-onyl] imidazole in the form a colorless solid.

This material was reduced with sodium borohydride using the procedure described in 2 to give l- [2-hydroxy-4- (4-methylphenyl) but-3-enyl] imidazole.

Using the same procedure, but using benzaldehyde instead of p-tolualdehyde, 1- (2-hydroxy-4-phenylbut-3-enyl) imidazole, melting point 125-127 ° C., was produced.

2.5 g of this material in 30 ml of methanol were hydrogenated at room temperature and under normal pressure over a 10% palladium-on-carbon catalyst. When the hydrogen uptake ceased, the solution was filtered and the residue was recrystallized from benzene / cyclohexane to give l- (2-hydroxy-4-phenylbutyl) imidazole (2.37 g) as white microcrystals, melting point 108 -109.5 ° C.

The following compounds of the formula (Ia) can also be prepared, for example, by the same process, but using the appropriate aldehyde instead of the compound indicated above:

1- [2-hydroxy-4- (4-chlorophenyl) but-3-enyl] imidazole 1- [2-hydroxy-4- (4-chlorophenyl) butyl] imidazole 1- [2-hydroxy-4 - (2,4-dichlorophenyl) but-3-enyl] imidazole 1- [2-hydroxy-4- (2,4-dichlorophenyl) butyl] imidazole 1- [2-hydroxy-4- (4- tert-butylphenyl) but-3-enyl] imidazole l- [2-hydroxy-4- (4-tert-butylphenyl) butyl] imidazole l- [2-hydroxy-4- (4-fluorophenyl) -but-3-enyl] imidazole 1- [2-hydroxy-4- (4-fluorophenyl) butyl] imidazole 1- [2-hydroxy-4- (2,4-dimethylphenyl) but-3-enyl ] imidazole and l- [2-hydroxy-4- (2,4-dimethylphenyl) butyl] imidazole.

example 1

A. A mixture of 430 mg of l- (2-hydroxy-4-phenylbu-tyl) imidazole and 96 mg of sodium hydride (56% dispersion in mineral oil) in 3 ml of dry hexamethylphosphoramide was taken under nitrogen for 1 hour at room temperature and 1 hour stirred at 45 ° C for a long time. After the evolution of hydrogen was stopped, the solution was cooled in an ice bath and a solution of 430 mg of 2,4-dichlorobenzyl chloride in 2 ml of hexamethylphosphoramide was added dropwise while the temperature was kept below 10 ° C. The solution was stirred at room temperature for 1 hour and then at 45 ° C for 2 hours and left overnight. The resulting mixture was then poured into water, extracted with ether, the ether extracts were with

Washed water, dried and evaporated. The oily product, l- [2- (2,4-dichlorobenzyloxy) -4-phenylbutyl] imidazole, was then converted to the nitrate by treating an ethereal solution with concentrated nitric acid, which recrystallized in the form of colorless flakes from ethyl acetate has been; Melting point 121-124 ° C.

B. Trans-l- [2-hydroxy-4-phenylbut-3-enyl] imidazole (430 mg) in 5 ml of dry tetrahydrofuran was treated under nitrogen with stirring with 96 mg of sodium hydride (56% dispersion in mineral oil) and the The mixture was then heated under reflux for 30 minutes. After cooling in an ice bath, the mixture was treated with 430 mg of a, 2,4-trichlorotoluene in 5 ml of tetrahydrofuran with stirring for 30 minutes at 0 ° C., for 1 hour at 25 ° C. and under reflux overnight. The resulting mixture was evaporated to dryness, ether (150 ml) was added and the ether extract was washed with water, dried over magnesium sulfate and evaporated to give Trans-l- [2- (2,4-dichlorobenzyloxy) -4- phenylbut-3-enyl] imidazole. The nitrate precipitated from the ether and was recrystallized from ethyl acetate, melting point 133.5-134.5 ° C (foaming).

Example 2

A solution of 1.00 g of l- (2-hydroxy-4-phenylbutyl) imidazole in 40 ml of dichloromethane was treated with 1 ml of thionyl chloride with stirring and the solution was heated under gentle reflux for 1 hour. Evaporation of the solution to dryness gave l- (2-chloro-4-phenylbutyl) imidazole hydrochloride in the form of a white solid.

The free base for use in the subsequent alkylation step can optionally be obtained by shaking the hydrochloride in dichloromethane with an excess of aqueous potassium carbonate solution, washing the organic phase with water, drying over magnesium sulfate and evaporating to dryness.

Example 3

600 mg of l- (2-chloro-4-phenylbutyl) imidazole hydrochloride were added to a fully reacted mixture of 1.1 g of 3,4-dichlorobenzyl mercaptan and 400 mg of a 56% sodium hydride dispersion in mineral oil in 30 ml of tetrahydrofuran. After the mixture was stirred under reflux for 12 hours, the solvent was evaporated in vacuo and 150 ml of ether was added. The resulting mixture was washed twice with water and the ethereal solution was dried and evaporated to give l- [2- (3,4-dichlorobenzylthio) -4-phenylbutyl] imidazole in the form of an oil. This material was converted into the oxalate by treating an ethereal solution with oxalic acid in ether until the precipitation was complete, which was then recrystallized from acetone / ethyl acetate in the form of colorless flakes (660 mg); Melting point 143.4-146 ° C.

Example 4

A mixture of 600 mg of l- (2-chloro-4-phenylbutyl) imidazole hydrochloride, 1.2 g of 3,4-dichlorothiophenol and 800 mg of potassium carbonate in 40 ml of acetone was stirred under reflux for 4 hours. Then the solvent was evaporated in vacuo and 50 ml of water was added. The resulting mixture was extracted with ether and the ether extract was washed with a saturated sodium chloride solution, dried and evaporated to give l- [2- (3,4-dichlorophenylthio) -4-phenylbutyl] imidazole in the form of an oil. This material was converted into ether by treatment with oxalic acid in the oxalate, which was then extracted from acetone / ethyl acetate in the form of color

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loose flakes (850 mg) was recrystallized; Melting point 145-147 ° C.

The free base was also converted to the nitrate by treatment with nitric acid in ether, which was then recrystallized from ethyl acetate; Melting point 99-105 ° C (decomposition); LDso (oral, acute, mice)> 1000 mg / kg.

Example 5

According to the procedure 1, 2 or 5 and in Examples 1,2,3; 2, 4 described methods and using equivalent amounts of the corresponding starting materials, the following compounds can be prepared. If indicated, the compounds can be identified by conversion to the corresponding acid addition salt.

1- [2- (3,4-dichlorobenzylthio) -3-phenylpropyl] imidazole 1- [2- (4-chlorophenylthio) -3-phenylpropyl] imidazole 1- [2- (2,4-dichlorophenoxy) -3 -phenylpropyl] -imidazole l- [2- (3,4,5-trichlorophenylthio) -3-phenylpropylj-imidazole l- [2- (2,4-dichlorobenzylthio) -3- (4-chloro

phenyl) propyl] imidazole l- [2- (4-fluorophenylthio) -3- (4-chloro

phenyl) propyl] imidazole l- [2- (4-tert-butylphenoxy) -3- (4-chloro

phenyl) propyl] imidazole l- [2- (3,4-dichlorophenylthio) -3- (4-chloro

phenyl) propyl] imidazole l- [2- (2,4-dichlorobenzylthio) -4-phenylbutyl] imidazole l- [2- (3,4-dichlorobenzyloxy) -4-phenylbutyl) imidazole l- [2- (3,4-dichlorophenoxy) -4-phenylbutyl] imidazole l- [2- (2,3,4,5,6-pentachlorophenylthio) -4-phenylbutyl] imidazole l- [2- (4-bromobenzylthio) -4-phenylbutyl] imidazole l- [2- (4-fluorophenoxy) -4-phenylbutyl] imidazole l- [2- (4-methylphenylthio) -4-phenyIbutyl] imidazole l- [2-cinnamyloxy ~ 4- phenylbutyl] imidazole l- [2- (4-chlorophenylthio) -4- (4-chlorophenyl) butyl] -

imidazole nitrate salt, melting point 116-119 ° C

1- [2- (4-chlorophenoxy) -4- (4-chlorophenyl) butyl] imidazole 1- [2- (4-chlorobenzylthio) -4- (4-chlorophenyl) butyl] -

imidazole oxalate salt, melting point 143-144 ° C

1- [2- (4-chlorobenzyloxy) -4- (4-chlorophenyl) butyl] imidazole 1- [2- (2,4-dichlorobenzyloxy) -4- (4-chloro-

phenyl) butyl] imidazole l- [2- (2,4-dichlorobenzylthio) -4- (4-chloro

phenyl) butyl] imidazole l- [2- (3,4-dichlorobenzyloxy) -4- (4-chloro

phenyl) butyl] imidazole l- [2- (3,4-dichlorophenylthio) -4- (4-chlorophenyl) -

butyl] imidazole nitrate salt,

Melting point 84-89 ° C (decomposition)

l- [2- (3,4-dichlorobenzylthio) -4- (4-chloro

phenyl) butyl] imidazole l- [2- (2,4,5-trichlorophenylthio) -4- (4-chloro

phenyl) butyl] imidazole l- [2-cinnamyloxy-4- (4-chlorophenyl) butyl] imidazole l- [2- (2,4-dichlorophenylthio) -4- (4-chlorophenyl) butyl] -

imidazole nitrate, melting point 113.5-115 ° C

l- [2- (4-Qilorcinnamyloxy) -4- (4-chloro

phenyl) butyl] imidazole l- [2- (4-fluorocinnamylthio) -4- (4-ch] or-

phenyl) butyl] imidazole 1- [2- (4-trifluoromethylohenylthio) -4- (4-chlorophenyl) butyl] imidazole 1- [2- (4-chloro-3-trifluoromethylphenylthio) -4- ( 4-chlorophenyl) butyl] imidazole

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l- [2- (4-trifluoromethylbenzyloxy) -4- (4-chlorophenyl) butyl] imidazole l- [2- (benzylthio) -4- (2,4-dichlorophenyl) butyl] imidazole l- [2- (4-chlorobenzyloxy) -4- (2,4-dichloro-

phenyl) butyl] imidazole l- [2- (2,4-dichlorobenzylthio) -4- (2,4-dichloro-

phenyl) butyl imidazole l- [2- (3,4-dichlorobenzylthio) -4- (2,4-dichloro-

phenyl) butyl] imidazole 1- [2- (4-tert-butylbenzyloxy) -4- (2,4-dichloro-

phenyl) butyl] imidazole l- [2-cinnamyloxy-4- (2,4-dichlorophenyl) butyl] imidazole l- [2- (4-qilorcinnamylthio) -4- (2,4-dichloro-

phenyl) butyl] imidazole 1- [2- (4-phenylbutylthio) -4- (2,4-dichloro-

phenyl) butyl] imidazole 1- [2- (4-chlorophenylthio) ~ 4- (4-tert-butyl-

phenyl) butyl] imidazole l- [2- (2,4-dichlorobenzyloxy) -4- (4-tert-butyl-

phenyl) butyl] imidazole l- [2- (3,4-dichlorophenylthio) -4- (4-fluoro-

phenyl) butyl] imidazole l- [2- (2,4-dichlorobenzyloxy) -4- (4-fluoro-

phenyl) butyl] imidazole l- [2- (3,4-dichlorobenzylthio) -4- (4-fluoro-

phenyl) butyl] imidazole l- [2- (3,4-dichlorobenzylthio) -4- (2,4-dimethyl-

phenyl) butyl] imidazole l- [2- (4-chlorophenoxy) -4- (2,4-dimethylphenyl) butyl] imidazole trans- l- [2- (3,4-dichlorophenyl-

thio) -4-phenylbut-3-enyl] imidazole oxalate,

Melting point 171.5-175.5 ° C (decomposition)

trans-l- [2- (3,4-dichlorobenzylthio) -4-phenyl-

but-3-enyl] imidazole nitrate,

Melting point 138-139 ° C (foaming)

trans-l- [2- (2,4-dichlorobenzyloxy) -4-phenylbut-3-enyl] imidazole nitrate,

Melting point 133.5-134.5 ° C (foaming)

1- [2- (4-Chlorobenzylthio) -4-phenylbut-3-enyl] imidazole 1- [2- (4-Qilorphenylthio) -4-phenylbut-3-enyl] imidazole

l- [2- (4-chlorophenoxy) -4-phenylbut-3-enyl] imidazole l- [2- (4-bromobenzylthio) -4-phenylbut-3-enyl] imidazole l- [2- (4- Fluorophenoxy) -4-phenylbut-3-enyl] imidazole l- [2- (3-phenylpropyloxy) -4-phenylbut-3-enyl] imidazole l- [2-cinnamyloxy-4-phenylbut-3-enyl] - imidazole 1- [2- (4-QilorcinnamyIoxy) -4-phenylbut-3-enyl] imidazole

1- [2- (4-phenylbutylthio) -4-phenylbut-3-enyl] imidazole 1- [2- (3,4-dichlorophenylthio) -4- (4-chloro-

phenyl) but-3-enyl] imidazole l- [2- (4-qilorphenoxy) -4- (4-chlorophenyl) -

but-3-enyl] imidazole l- [2- (2,4,5-trichlorophenylthio) -4- (4-chloro

phenyl) but-3-enyl] imidazole l- [2- (2,3,4,5,6-pentachlorophenylthio) -4- (4-chloro

phenyl) but-3-enyl] imidazole l- [2- (cinnamylthio) -4- (4-chlorophenyl) -

but-3-enyl] imidazole l- [2- (4-CMorcinnamyloxy) -4- (4-chlorophenyl) but-3-enyl] imidazole l- [2- (4-C-Worphenylthio) -4- (4th -chlorophenyl) but-3-enyl] -imidazole l- [2- (4-chlorobenzyloxy) -4- (4-chlorophenyl) -but-3-enyl] -imidazole l- [2- (4-chlorobenzylthio) - 4- (4-chlorophenyl) but-3-enyl] imidazole 1- [2- (2,4-dichlorobenzyloxy) -4- (4-chlorophenyl) but-3-enyl] imidazole

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l- [2- (2,4-dichlorophenylthio) -4-phenylbutyl] imidazole l- [2- (4-chlorobenzylthio) -4-phenylbutyl] imidazole l- [2- (4-chlorobenzyloxy-4-phenylbutyl] -imidazole l- [2- (4-chlorobenzylthio) -4- (4-fluoro-

phenyl) -buty 1] -imide azole l- [2- (2,4-dichlorobenzylthio) -4- (4-fluoro-

phenyl) butyl] imidazole l- [2- (2,4-dichlorophenylthio) -4- (4-fluoro-

phenyl) butyl] imidazole

Example 6

After experiment 3 or 4 and in Examples 1; The methods described in 2, 3 or 2,4 can be prepared using equivalent amounts of the corresponding starting materials, the following compounds. If indicated, the compounds can be described in more detail by conversion into the corresponding acid addition salt.

1- [3- (4-chlorophenylthio) -3- (4-chlorophenyl) propyl] imidazole oxalate, melting point 108-112 ° C. 1- [3- (4-chlorophenylthio) -3- (4-chlorophenyl) -propyI] -imidazole-oxalate, melting point 115-156 ° C l- [3- (4-chlorobenzyloxy) -3- (4-chlorophenyl) -propyl] -imidazole-oxalate, melting point 105-106 ° C l- [3 - (4-bromo-3-methylphenylthio) -3- (4-chlorophenyl) propyl] imidazole nitrate,

Melting point 107-108 ° C (decomposition)

l- [3- (4-tert-butylphenylthio) -3- (4-chloro

phenyl) propyl] imidazole oxalate,

Melting point 127.5-129 ° C (decomposition)

l- [3- (4-fluorophenylthio) -3- (4-chloro

phenyl) propyl] imidazole

l- [3- (4-bromobenzyloxy) -3- (4-chloro

phenyl) propyl] imidazole l- [3- (2,4-dichlorophenylthio) -3- (4-chloro

phenyl) propyl] imidazole l- [3- (3,4-dichlorophenylthio) -3- (4-chloro-

phenyl) propyl] imidazole

1 - [3 - (4-Trifluoromethylphenylthio) -3 - (4-chloro-

phenyl) propyl] imidazole l- [3- (4-trifluoromethylbenzyloxy) -3- (4-chloro

phenyl) propyl] imidazole l- [3- (4-chlorocinnamyloxy) -3- (4-chloro

phenyl) propyl] imidazole l- [3- (2,4-dichlorocinnamylthio) -3- (4-chloro

phenyl) propyl] imidazole l- [3- (4-phenylbutyloxy) -3- (4-chloro

phenyl) propyl] imidazole l- [3- (4-methylbenzylthio) -3- (2,4-dichloro-

phenyl) propyl] imidazole nitrate,

Melting point 69.5-75 ° C (decomposition)

l- [3- (4-Chlorobenzylthio-3- (2,4-dichloro-

phenyl) propyl] imidazole nitrate,

Melting point 63-66.5 ° C (decomposition)

l- [3- (4-chlorophenylthio) -3- (2,4-dichloro-

phenyl) propyl] imidazole nitrate

Melting point 123.5-125.5 ° C (decomposition)

l- [3- (2,4-dichlorophenylthio) -3- (2,4-dichloro-

phenyl) propyl] imidazole l- [3- (3,4-dichlorophenylthio) -3- (2,4-dichloro-

phenyl) propyl] imidazole 1- [3- (4-trifluoromethylphenylthio) -3- (2,4-dichlorophenyl) propyl] imidazole

1 - [3- (4-Trifluoromethylbenzyloxy) -3- (2,4-dichloro-

phenyl) propyl] imidazole l- [3- (4-tert-butylphenylthio) -3- (2,4-dichloro-

phenyl) propyl] imidazole l- [3- (4-methylbenzyloxy) -3- (2,4-dichloro-

phenyl) propyl] imidazole l- [3- (4-chlorocinnamyloxy) -3- (2,4-dichloro-

phenyl) propyl] imidazole l-f3- (3,4-dichlorobenzyloxy) -3- (2,4-dicMor-

phenyl) propyl] imidazole l- [3- (2,4,5-trichlorophenylthio) -3- (2,4-dicblor-

phenyl) propyl] imidazole l- [3- (4-phenylbutylthio) -3- (2,4-dichloro-

phenyl) propyl] imidazole l- [3- (4-chlorobenzyloxy) -3- (2,4-dichloro-

phenyl) propyl] imidazole l- [3- (2,4-dichlorobenzyloxy) -3- (2,4-dichloro-

phenyl) propyl] imidazole l- [3- (4-chlorophenylthio) -3- (4-tert-butyl-

phenyl) propyl] imidazole l- [3- (2,4-dichlorobenzylthio) -3- (4-tert-butyl-

phenyl) propyl] imidazole l- [3- (2,4,5-trichlorophenylthio) -3- (4-fluoro-

phenyl) propyl] imidazole oxalate,

melts at 76 ° C, final melting point 99 ° C

l- [3- (4-chlorobenzylthio) -3- (4-fluoro-

phenyl) propyl] imidazole l- [3- (4-tert-butylphenylthio) -3- (4-fluoro-

phenyl) propyl] imidazole l- [3- (4-chlorocinnamyloxy) -3- (4-fluoro-

phenyl) propyl] imidazole l- [3- (4-Qilorcirmamyloxy) -3- (2,4-dimethyl-

phenyl) propyl] imidazole l- [3- (2,4-dichlorobenzylthio) -3- (2,4-dimethyl-

phenyl) propyl] imidazole l- [3- (4-bromophenyltbio) -3- (2,4-dimethyl-

phenyl) propyl] imidazole 1- [3- (4-methylbenzylthio) -3- (4-tert-butyl-

phenyl) propyl] imidazole nitrate,

Melting point 132-134 ° C (decomposition)

l- [3-cinnamyloxy-3- (4-tert-butyl-

phenyl) propyl] imidazole l- [3- (4-chlorophenylthio) -4-phenylbutyl] imidazole l- [3- (2,4-dichlorobenzylthio) -4-phenylbutyl] imidazole l- [3- (4th -tert.-butylphenylthio) -4-phenylbutyl) imidazole l- [3- (4-chlorocimamyloxy) -4-phenylbutyl] imidazole l- [3- (2,4-dichlorophenylthio) -4- (4-chloro

phenyl) butyl] imidazole l- [3- (4-methylbenzylthio) -4- (4-chloro

phenyl) butyl] imidazole l- [3- (4-chlorobenzylthio) -4- (4-methyl-

phenyl) butyl] imidazole l- [3- (2,4-dichlorophenoxy) -4- (4-methyl-

phenyl) butyl] imidazole l- [3- (4-chlorocinnamyloxy) -4- (4-methyl-

phenyl) butyl] imidazole l- [3- (2,4-dichlorobenzylthio) -5- (4-chloro-

phenyl) pentyl] imidazole l- [3- (4-bromobenzyloxy) -5- (4-chlorophenyl) pentyl] imidazole l- [3- (4-chlorobenzylthio) -5- (4-chloro

phenyl) pentyl] imidazole l- [3- (2,4,5-trichlorophenylthio) -5- (4-chloro-

phenyl) pentyl] imidazole l- [3- (4-tert-butylbenzylthio) -5- (4-chloro-

phenyl) pentyl] imidazole l- [3- (3,4-dichlorophenylthio) -3- (2-trifluoro-

methylphenyl) propyl] imidazole l- [3- (3,4-dichlorobenzylthio) -3- (2-trifluoro-

methylphenyl) propyl] imidazole l- [3- (4-chlorophenylthio) -3- (2,4-dibromo-

phenyl) propyl] imidazole

14

s

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

l- [3- (4-chlorophenylthio) -3- (2,4-difluoro-

phenyl) propyl] imidazole l- [3- (4-morphenylthio) -3- (2,4-dichloro-

phenyl) propyl] imidazole l- [3,4- (fluorobenzylthio) -3- (2,4-dichloro-

phenyl) propyl] imidazole

Example 7

According to the method 4 and in Examples 1; 2, 3 or 2.4 and using equivalent amounts of the appropriate starting materials, the following compounds can be prepared. If indicated, the compounds can be identified by conversion to the corresponding acid addition salts.

l- [4- (3,4-dichlorophenylthio) -4- (4-chlorophenyl)

butyl] imidazole nitrate, melting point 100-104.5 ° C;

Oxalate, melting point 118-123 ° C (foaming)

l- [4- (3,4-dichlorophenoxy) -4- (4-chlorophenyl) butyl-

imidazole nitrate, melting point 128-130.5 ° C

1- [4- (4-chlorobenzylthio) -4- (4-chlorophenyl) butyl] -

imidazole nitrate, melting point 123-125 ° C (foaming)

l- [4- (2,4-dichlorobenzyloxy) -4- (4-chlorophenyl) butyl] -

imidazole nitrate, melting point 91-114 ° C

l- [4- (3,4-dichlorobenzyloxy-4- (4-chloro

phenyl) butyl] imidazole l- [4- (4-bromobenzylthio) -4- (4-chloro

phenyl) butyl] imidazole l- [4- (4-fluorophenylthio) -4- (4-chloro-

phenyl) butyl] imidazole l- [4- (4-methylbenzyloxy) -4- (4-chloro

phenyl) butyl] imidazole l- [4- (4-chlorophenylthio) -4- (2,4-dichlorophenyl) butyl] -

imidazole oxalate, melting point 69-75 ° C (foaming)

1 - [4 - (4-Methylphenylthio) -4- (2,4-dichloro-

phenyl) butyl] imidazole l- [4- (4-chlorobenzylthio) -4- (2,4-dichloro-

phenyl) butyl] imidazole oxalate,

Melting point 62.5-65 ° C (foaming)

l- [4-Benzylthio-4- (2,4-dichlorophenyl) butyl] imidazole l- [4- (2,4-dichlorobenzyloxy) -4- (2,4-dichloro-

phenyl) butyl] imidazole 1- [4- (4-chlorobenzyloxy) -4- (2,4-dichlorophenyl) butyl] imidazole nitrate, fuses at 98.5 ° C .;

final melting point 108 ° C l- [4- (4-phenylbutylthio) -4- (2,4-dichlorophenyl) butyl] imidazole l- [4- (4-fluorobenzylthio) -4- (2,4- dichlorophenyl) -

butyl] imidazole oxalate, melting point 95-101.5 ° C

l- [4- (4-tert-butylphenylthio) -4- (4-fluoro-

phenyl) butyl] imidazole l- [4- (3,4-dichlorophenylthio) -4- (4-fluorine)

phenyl) butyl] imidazole 1- [4- (4-tert-butylbenzyloxy) -4- (4-fluorophenyl) -

butyl] imidazole oxalate, melting point 49.5-51 ° C

l- [4-phenylpropylthio-4- (4-fluorophenyl) butyl] -

imidazole oxalate, melting point 97-99 ° C

1- [4-phenylthio-4- (4-tert-butylphenyl) -

butylj-imidazole nitrate,

Melting point 121.5-123.5 ° C (decomposition)

l- [4- (4-chlorophenylthio) -4- (4-tert.-

butylphenyl) butyl] imidazole l- [4- (2,4-dichlorobenzylthio) -4- (4-tert.-

butylphenyl) butyl] imidazole 1- [4- (4-fluorophenylthio) -4- (2,4-dimethyl-

phenyl) butyl] imidazole

15 621117

l- [4-Cinnamyloxy-4- (2,4-dimethylphenyl) butyl] imidazole l- [4- (4-Methylbenzylthio) -4- (4-bromophenyl) butyl] imidazole nitrate, melting point 93-95 ° C (decomposition) s l- [4- (4-bromobenzyloxy) -4- (4-bromophenyl) butyl] imidazole nitrate, melting point 117-123.5 ° C l- [4- (4th -Chlorphenylthio) -5-phenylpentyl] imidazole l- [4- (2,4-dichlorobenzylthio) -5-phenylpentyl] imidazole l- [4- (4-tert-butylphenoxy) -5-phenylpentyl] imidazole Io 1- [4- (4-chlorocinnamyloxy) -5-phenylpentyl] imidazole 1- [4- (2,4-dichlorophenylthio) -5- (4-chlorophenyl) pentyl] imidazole 1- [4- ( 4-methylbenzylthio) -5- (4-chlorophenyl) pentyl] imidazole 15 l- [4- (2,4-dichlorobenzylthio) -6- (4-chlorophenyl) hexyl] imidazole l- [ 4- (4-bromobenzyloxy) -6- (4-chlorophenyl) hexyl] imidazole l- [4- (4-chlorobenzylthio) -6- (4-chloro-20 phenyl) hexyl] imidazole l- [4- (2,4,5-trichlorophenylthio) -6- (4-chlorophenyl) hexyl] imidazole 1- [4- (4-tert-butylbenzylthio) -6- (4-chlorophenyl) -hexyl] imidazole 25 l- [4- (4-trifluoromethylphenylthio) -6- (4-chlorophenyl) hexyl] imidazole l- [4- (4-trifluorometh ylbenzyloxy) -6- (4-chlorophenyl) hexyl] imidazole l- [6- (2,4-dichlorobenzyloxy) -6-phenylhexyl] imidazole so l- [6- (4-chlorobenzylthio) -6- phenylhexyl] imidazole I- [6- (4-melthylphenylthio) -6-phenylhexyl] imidazole l- [6- (4-chlorophenylthio) -6-phenylhexyl] imidazole l- [6- (4-chlorobenzyloxy) -6 - (4-chlorophenyl) hexyl] imidazole 35 l- [6-benzylthio-6- (4-chlorophenyl) hexyl] imidazole l- [6- (4-fluorobenzylthio) -6- (4-chloro -phenyl) hexyl] imidazole l- [6- (3,4-dichlorobenzyloxy) -6- (4-chlorophenyl) hexyI] imidazole 40 l- [6-cinnamyloxy-6- (4-chlorophenyl) -hexyl] -imidazole l- [6- (2,4-dichlorobenzyloxy) -7- (4-chlorophenyl) heptyl] -midazole l- [6- (2,4-dichlorobenzylthio) -8-phenyloctyl] - imidazole l-t6- (4-chlorobenzyloxy) -10-phenyldecyl] imidazole 45 l- (9-benzyloxy-9-phenylnonyl) imidazole l- [9- (4-fluorophenylthio) -9-phenylnonyl] imidazole l- [9-phenoxy-9- (4-chlorophenyl) nonyl] imidazole l- [9- (2,4,5-trichlorobenzylthio) -9- (4-chlorophenyl) nonyl] imidazole so l- [ 9-cinnamyloxy-9- (4-chlorophenyl) nonyl] imidazole l- [9- (2,4-dichlorobenzyloxy) -10- (4- chlorophenyl) decyl] imidazole l- [9- (2,4-dichlorobenzylthio) -ll-phenyl-undecyl] imidazole 55 l- [9- (4-chlorobenzyloxy) -13-phenyltridecyl] imidazole l- [4- (4-fluorophenylthio) -4- (2,4-dichlorophenyl) butyl] imidazole.

Example 8

60 To a stirred solution of 2.0 g of l- [2- (2,4-dichlorobenzyloxy) -4-phenylbutyl] imidazole in 30 ml of anhydrous ether, nitric acid (70%; density = 1.42) was added dropwise until precipitation was complete. The product was filtered off, washed with ether, air dried 65 and recrystallized from ethyl acetate, and there was obtained 1- [2- (2,4-dichlorobenzyloxy) -4-phenylbutyl] imidazole nitrate, melting point 121-124 ° C.

In the same way, all of them can be in base form

621117

16

the compounds of formula (I) are converted to the corresponding antimicrobial acid addition salts by reacting with the appropriate acid, e.g. 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, are treated.

Example 9

1- [2- (2,4-dichlorobenzyloxy) -4-phenylbutyl] imidazole nitrate (2.0 g) in 100 ml dichloromethane was shaken with an excess of dilute potassium carbonate solution until the salt was completely dissolved. The organic phase was then separated, washed twice with water, dried over magnesium sulfate and evaporated to give 1- [2- (2,4-dichlorobenzyloxy) -4-phenylbutyl] imidazole in the form of an oil.

In the same way, the antimicrobial acid addition salts of all compounds of formula (I) can be converted into the corresponding compounds in base form.

The following tests demonstrate the fungicidal activity of certain compounds.

The following were used as test organisms:

1. Candida albicans (ATCC10231) - C.a.l

2. Candida albicans (ATCC 14053) - C.a.2

3. Epidermophyton floccosum (ATCC 15693) - E.f.

4. Trichophyton mentagrophytes (ATCC 11481) - T.m.

5. Microsporum gypseum (ATCC 14683) - M.g.

Organisms 1 and 2 are generally classified as yeast-like organisms, while organisms 3, 4 and 5 are dermatophytes. Because of their different properties, some of them were treated differently.

The incubation of all organisms was carried out in roller drum glass containing 5 ml of medium which was incubated at 25 ° C.

The test compounds were dissolved in 0.6 ml of dimethyl sulfoxide, ethanol or sterile distilled water and 30 ml of sterile Sabouraud dextrose broth were added to these solutions to give the first desired concentration of the compounds. Samples of these basic solutions in equal quantities were appropriately diluted with sterile Sabouraud dextrose broth (Difco). In general, the dilutions were made in geometric order, e.g. 300, 100, 30, 10, 3 and 1 [ig / ml. About 5 ml of each dilution was added to the sterile test tubes (16 mm) and the glasses were vaccinated with 2 drops of vaccine. The vials were incubated under aerobic conditions by agitation in a roller drum at 25 ° C.

To obtain the vaccines, yeasts from Sabou-raud dextrose agar (Difco) slant cultures were transferred to Sabouraud dextrose broth and incubated at 25 ° C overnight. Two drops of Vio dilutions from these 16 hour cultures were used as vaccines for each vial. Dermatophytic fungi were grown on Sabouraud dextrose agar or neutral malt extract agar slants, which had been incubated at 25 ° C for at least 4 weeks. About 10 ml of a 0.7% sodium chloride solution was added to the agar areas and suspensions were prepared by scraping the agar surfaces and swirling the suspensions. These suspensions were filtered through two layers of sterile stainless steel funnels (40 X 40 mesh and 100 X100 mesh). This procedure separated the agar and fungus mycelium particles on the agar from the spores needed for the test. After microscopic examination of the suitability of the vaccine, two drops of these suspensions were added to different dilutions of the test compounds in Sabouraud dextrose broth.

The fungus standstill, i.e. the concentration at which growth was prevented was determined visually and recorded as the minimum inhibitory concentration (MIC) in (xg / ml. For the yeasts, the readings were taken after a 3-day incubation, and the fungi 4 and 5 stopped after an incubation of 5 days, and in the case of organism 3, the standstill after an incubation of 7 days was determined.

MIC (fig / ml) 1- [3- (4-chlorobenzylthio) -3- (2,4-dichlorophenyl) propyl] imidazole nitrate egg. - <0.1 C.a. 2-1

1- [3- (4-Methylbenzylthio) -3- (2,4-dichlorophenyl) propyl] imidazole nitrate E.f. - <0.1 C.a.2 - 1

1- [3- (4-chlorophenylthio) -3- (2,4-dichlorophenyl) propyl] imidazole nitrate E.f. -0.3 C.a. 2-1

l- [3- (4-tert-butylphenylthio) -3- (4-chloro ~

phenyl) propyl] imidazole oxalate

T.m. - 1

C.a. 1 -10

C.a. 2-10

l- [3- (4-bromo-3-methylphenylthio) -3- (4-chloro

phenyl) propyl] imidazole nitrate

T.m. - 1

Approx. 1 -10

C.a.2 -10 -

l- [2- (4-chlorobenzylthio) -4- (4-chlorophenyl) -

butyl] imidazole oxalate

M.g. - 3rd

E.f. - <0.1

C.a. 1-3

Approx. 2-3

l- [2- (3,4-dichlorophenylthio) -4- (4-chloro

phenyl) butyl] imidazole nitrate

M.g. - 3rd

E.f. - <0.1

Approx. 1-3

C.a.2 - 3

l- [2- (4-chlorophenylthio) -4- (4-chlorophenyl) -

butyI] imidazole nitrate

M.g. - 3rd

E.f. - <0.1

Approx. 1 - 3

Approx. 2-3

l- [2- (3,4-dichlorophenylthio) -4-phenyl-

butylj-imidazole oxalate

C.a. 1 -3.

C.a.2 -3

s

10th

IS

20th

25th

30th

35

40

45

50

55

60

65

1- [4- (3,4-dichlorophenylthio) -4- (4-chlorophenyl) butyl] imidazole nitrate M.g. -3 T.m. -1

1- [4- (4-chlorobenzylthio) -4- (4-chlorophenyl) butyl] imidazole nitrate C.a. 1 -10

l- [4- (2,4-dichlorobenzyloxy) -4- (4-chloro

phenyl) butyl] imidazole nitrate

T.m. - 3rd

17 621117

l- [4- (4-chlorobenzyloxy) -4- (2,4-dichloro-

phenyl) butyl] imidazole nitrate

T.m. -1

l- [4- (4-chlorobenzylthio) -4- (2,4-dichloro-

phenyl) butyl] imidazole nitrate

C.a. 2 -10

io l- [4- (4-chlorophenylthio) -4- (2,4-dichlorophenyl) butyl] imidazole oxalate C.a. 2 -10

B

Claims (25)

621117 1 ' R -CH- (CII_) -N • N 2n w :: where R1, n and Y have the same meaning as above, or an acid addition salt thereof with a base and R2SH, where R2 is optionally substituted phenyl straight chain Ci-Cs alkyl or phenyl straight chain C2 Cs alkenyl. 1 / V R -CH- (CH0) -N N i ^ n. . Y wherein R1, n and Y have the same meaning as above, or an acid addition salt thereof with a base and R2OH or R2SH, wherein R2 is optionally substituted phenyl, or c. Thioetherification of a compound of the formula: 1 R -CH- (CH-) -N N I 2n w OH (XX) wherein R1 and n have the same meaning as above, with a base and R2Y, in which R2 represents optionally substituted phenyl straight-chain-Ci-Cs-alkyl or phenyl-straight-chain-C2-Cs-alkenyl and Y is a cleavable group, or b. Etherification or thioetherification of a compound of the formula: 1 / R -CH- (CH ^) -N N I 2 * n V— / X-R> ' (I) wherein R1 and R2 are each phenyl, phenyl-straight-chain-Ci-Cs-alkyl or phenyl-straight-chain-C2-Cs-alkenyl or one of these groups which are in the phenyl ring with one or more substituents from the group: lower alkyl having 1 to 4 carbon atoms , Fluorine, chlorine, bromine and trifluoromethyl is substituted; X oxygen or sulfur; n is an integer from 1 to 8, but n is not 1 if R1 is phenyl or substituted phenyl, and their salts, characterized in that it consists of the following step: a. Etherification of a connection of the formula: 2. The method according to claim 1, characterized in that one converts a free base obtained into a salt. 2nd PATENT CLAIMS 1. Process for the preparation of a compound of the formula: 3rd 621117 shows that one produces l- [2- (3,4-dichlorobenzylthio) -4- (4-fluorophenyl) butyl] imidazole and its acid addition salts. 3. The method according to claim 1, characterized in that one converts a salt obtained into the free base. 4. The method according to claim 1, characterized in that one produces a compound of formula I in which X is sulfur. 5. The method according to claim 1, characterized in that one produces a compound of formula I in which X is oxygen. 6. The method according to claim 1, characterized in that one produces a compound of formula I, in which n is 1. Process according to Claim 1, characterized in that a compound of the formula I is prepared in which R1 is phenethyl, styryl or fluorine, chlorine or bromine-substituted phenethyl or styryl and R2 is phenyl, benzyl, cinnamyl or fluorine, Is chlorine or bromine substituted phenyl, benzyl or cinnamyl. 8. The method according to claim 1, characterized in that one produces a compound of formula I in which the substituent on R14 is chlorine, 4-bromo, 4-fluorine, 2,4-dichloro or 3,4-dichloro 9. The method according to claim 1, characterized in that one produces a compound of formula I in which the substituent on R2 4-chlorine, 4-bromo, 4-fluorine, 2,4-dichloro or 3,4-dichloro and - if R2 is substituted phenylthio - is additionally 2,4,5-trichlor or 2,3,4,5,6-pentachlor. 10th IS 10. The method according to claims 1 and 2, characterized in that l- [2- (3,4-dichlorophenylthio) -4-phenylbu-tyl] imidazole and its acid addition salts are prepared. 11. The method according to claims 1 and 2, characterized in that l- [2- (3,4-dichlorobenzylthio) -4-phenylbu-tyl] imidazole and its acid addition salts are prepared. 12. The method according to claims 1 and 2, characterized in that l- [2- (2,4-dichlorobenzyloxy) -4-phenylbu-tyl] imidazole and its acid addition salts are prepared. 13. Process according to Claims 1 and 2, characterized in that l- [2- (4-chlorophenyltbio) -4- (4-chlorophenyl) butyl] imidazole and its acid addition salts are prepared. 14. The method according to claims 1 and 2, characterized in that l- [2- (2,4-dichlorobenzyloxy) -4- (4-chlorophenyl) butyl] imidazole and its acid addition salts are prepared. 15. Process according to Claims 1 and 2, characterized in that l- [2- (4-chlorobenzylthio) -4- (4-chlorophenyl) butyl] imidazole and its acid addition salts are prepared. 16. The method according to claims 1 and 2, characterized in that l- [2- (3,4-dichlorophenylthio) -4- (4-chlorophenyl) butyl] imidazole and its acid addition salts are prepared. 17. The method according to claims 1 and 2, characterized in that l- [2- (4-chlorobenzyloxy) -4- (4-chlorophenyl) butyl] imidazole and its acid addition salts are prepared. 18. Process according to Claims 1 and 2, characterized in that l- [2- (2,4-dichlorophenylthio) -4- (4-chlorophenyl) butyl] imidazole and its acid addition salts are prepared. 19. The method according to claims 1 and 2, characterized in that l- [2- (3,4-dichlorophenylthio) -4- (4-fluorophenyl) butyl] imidazole and its acid addition salts are prepared. 20th 25th 30th 35 40 45 50 55 60 65 20. The method according to claims 1 and 2, characterized in that l- [2- (2,4-dichlorobenzyloxy) -4- (4-fluorophenyl) butyl] imidazole and its acid addition salts are prepared. 21. The method according to claims 1 and 2, characterized gekenn5 22. The method according to claim 1, characterized in that one produces a compound of formula I, in which n is 2 or 3. 23. The method according to claim 22, characterized in that a compound of the formula I is prepared in which R1 is phenyl or fluorine, chlorine or bromine-substituted phenyl and R2 is phenyl, benzyl or fluorine, chlorine or bromine-substituted phenyl or benzyl. 24. The method according to claim 22, characterized in that a compound of formula I is prepared in which the substituent on R1 4-chloro, 4-bromo, 4-fluorine, 2,4-dichloro, 2,4-difluoro or 2nd , 4-dibromo is. 25. The method according to claim 22, characterized in that a compound of formula I is prepared in which the substituent in R2 4-chlorine, 4-bromo, 4-fluorine, 2,4-dichloro or 3,4-dichloro and - if R2 is substituted phenylthio -also is 2,4,5-trichlor or 2,3,4,5,6-pentachlor.