CH623040A5 - Process for the preparation of substituted N-alkylimidazoles - Google Patents

Abstract

The compounds correspond to the formula: <IMAGE> in which R<1> denotes phenyl-straight chain-C1-C8-alkyl and R<2> denotes phenyl, phenyl-straight chain-C1-C8-alkyl or phenyl-straight chain-C2-C8-alkenyl, it being possible for the phenyl ring to be substituted by one or more substituents from the group consisting of: lower alkyl having 1 to 4 carbon atoms, fluorine, chlorine, bromine and trifluoromethyl. They are prepared by reaction of corresponding compounds of the formula: <IMAGE> in which Y represents a removable group, with imidazole. The compounds and their salts are distinguished by fungicidal, antibacterial and antiprotozoal action; they can be used in the corresponding therapeutic indications.

Description

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

15

R

CH-CH2 ~ N

S-R

(I)

R ^ CH-CHo-SR2 or R ^ CH-CH.-Y

SR2

(XXIV)

wherein R1 and R2 have the meanings given above and Y represents a cleavable group, reacted with imidazole.

2. The method according to claim 1, characterized in that one converts a free base obtained into a salt.

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 a compound of formula I is prepared in which R1 is phenethyl or fluorine, chlorine or bromine substituted phenethyl and R2 is phenyl, benzyl, cinnamyl or fluorine, chlorine or bromine substituted phenyl, benzyl or cinnamyl.

5. The method according to claim 1, characterized in that a compound of formula I is prepared in which the substituent on R1 is 4-chloro, 4-bromo, 4-fluorine, 2,4-dichloro or 3,4-dichloro.

6. 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.

7. Process according to Claims 1 and 2, characterized in that l- [2- (3,4-dichlorophenylthio) -4-phe-nylbutyl] imidazole and its acid addition salts are prepared.

8. Process 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.

9. The method according to claims 1 and 2, characterized in that l- [2- (4-chlorophenylthio) -4- (4-chlorophenyl) butyl] imidazole and its acid addition salts are prepared.

10. 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.

11. 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.

12. The method according to claims 1 and 2, characterized in that l- [2- (2,4-dich! Orphenylthio) -4- (4 - chlorophenyl) butyl] imidazole and its acid addition salts are prepared

13. 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.

in which R1 denotes phenyl straight-chain-Ci-Cg-alkyl and R2 phenyl, 20 phenyl-straight-chain-Ci-Cg-alkyl or phenyl-straight-chain - C2-C8-alkenyl, where the phenyl rings with one or more substituents from the group: lower alkyl with 1 to 4 carbon atoms, fluorine, chlorine, bromine and trifluoromethyl may be substituted.

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; 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 1 to 8 Has carbon atoms. 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-40-chain monovalent substituent which 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, 45 hex-1-enyl , Hex-3-enyl, hex-5-enyl, hept-l-enyl, hept-4-enyl, hept-6-enyl, oct-l-enyl, oct-5-enyl and oct-7-enyl. The term «halogen» refers to fluorine, chlorine and bromine. "Antimicrobial acid addition salts" of the compounds are those salts which retain the antimicrobial properties of the 50 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 and the like, be formed 6o.

All compounds of formula I have at least one chiral center, i.e. the carbon atom to which the radical R1 is attached. 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

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the preparation of the individual optical isomers of the compounds. In addition, the compounds which have an optionally substituted phenyl straight-chain-C2-C8-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 (for example fractional crystallization) the diastereomeric salts which are obtained by reacting, for example, racemic compounds of the formula I with an optically active acid or by separating the diastereomeric salts or esters formed by reacting racemic precursors R1-CH (OH) CH2-Y (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-Tt-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, Aspergillus niger,

Cladosporium herbarum, Pénicillium oxalicum,

Fusarium graminearum, Pénicillium spinulosum,

Pénicillium notatum and Pithomyces chartarum.

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

Staphylococcus aureus,

Streptococcus 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 effects, 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 who 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. Tri-calcium 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 e.g. Water, oils of vegetable origin and low-boiling solvents such as isopropanol, hydrogenated naphthalenes and the like are suitable. 30 The pharmaceutical compositions containing the compounds can be conventional pharmaceutical methods such as e.g. sterilization, and they may contain conventional pharmaceutical additives such as preservatives, stabilizers, emulsifiers, salts for adjusting the osmotic pressure and buffers. The compositions may 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. The intravenous injection of imidazole-type fungicidal compounds has been shown to be effective in the treatment of systemic mycosis (see, for example, “Drugs”, 9, pages 419-420, 1975, in which the intravenous administration of miconazole, ie 1- [2.4 -Dichlor - ß- (2 ', 4'-dichlorobenzyloxy) -phenethyl] -imidazoI-nitrate, in patients with systemic Candidiase is described). The local application is the preferred form of administration for pharmaceutical use. In 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, e.g. by dusting, spraying, spraying, rinsing, brushing, dipping, lubricating, brushing, impregnating and the like. Pharmaceutical compositions for external use containing the compounds have very different concentrations in 6o, e.g. from about 0.1 to 10.0% by weight of the composition, fungicide, 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 the formula I.

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4th

and a pharmaceutically acceptable, non-toxic carrier and are preferably made in unit doses to facilitate administration (one unit dose is the amount of active ingredient administered at a time).

In general, when administered systemically (for example orally or parenterally), it is expedient to administer the active compound in amounts 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, and preferably distributed over several administrations (eg 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 precise regulation of the administration of the compounds and compositions naturally depends 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 doctor from.

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. Mica, talc, pyrophyllite and clays. The compounds can also be mixed with a conventional surface-active wetting agent and, if appropriate, additionally with a solid carrier on the seeds. 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 applied to growing plants in the form of an aqueous spray which contains a surface-active dispersant and, if appropriate, a powdery solid carrier and hydrocarbon solvent. 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. In order to increase the activity, 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.

A preferred subgroup comprises compounds of the formula I in which R1 is phenethyl or fluorine, chlorine or bromine (preferably chlorine) substituted phenethyl, preferably 4-chloro, 4-bromo, 4-fluoro, 2,4-dichloro - or 3,4-dichloro-substituted phenethyl, and R2 are either phenyl or benzyl or a fluorine, chlorine or bromine-substituted derivative of these - this derivative being the fluorine,. Chlorine or bromine substituents preferably have the radical R1 in the same position as above or, if R2 denotes substituted phenyl, is additionally a 2,4,5-trichloro and 30 2,3,4,5,6-pentachloro-substituted derivative , or cinnamyl or 4-fluoro, 4-chloro or 4-bromocinnamyl

The process according to the invention is characterized in that a compound of the formula:

35 R1-CH-CH2-SR2 or R ^ CH-CH ^ Y (XXIV)

I I

Y SR2

wherein R1 and R2 have the meanings given above and Y represents a group which can be split off, with imidazole.

The process and the preparation of the starting products can be illustrated by the following scheme:

Reaction scheme J

1 2 0 \ R -CH-CH ,, + RS - - ^

V 2

0 or R SH

(III)

R ^ -CH-CH ^ -SR2 ^ R1-CH-CH2-SR2 and / 6àér R ^ CH-CH ^ Y

ÓH t SR2

(XXIII) (XXIV)

X

R -CH - CKL-N N

1 2 X \ = J

SR2 (I)

5

623040

where Y = a cleavable group.

Epoxides of formula III, if not known or readily available, can be made by various known methods, e.g. by epoxidation of a terminal olefin, e.g. of the formula:

R1-CH = CH2 (V)

with, for example, a peracid, or by reacting an aldehyde that has one carbon atom less, e.g. of the formula:

R1CHO (IV)

with the ylide, which has been prepared from trimethylsulfoxonium iodide and is described, for example, in J. Am. Chem. Soc., 84, page 867 (1962), and 87, page 1353 (1965).

In this scheme, the epoxide of Formula III is opened with a thiol or thiophenol or a metal salt thereof to obtain the compound of Formula XXIII. This reaction is carried out by preferably using an alkali metal salt of thiol or thiophenol, especially the sodium salt, in an inert organic solvent, e.g. Tetrahydrofuran or acetone, at a temperature of about 0 to 67 ° C, or by free thiol or thiophenol in the presence of an acid catalyst, e.g. Perchloric acid, used under similar conditions.

In the next step, the hydroxy group of the compound of formula XXIII is converted into a cleavable group, such as a halide (e.g. chloride or bromide), or a sulfonate ester (e.g. p-toluenesulfonate or methanesulfonate) by, for example, using a halogenating agent , such as Thionyl chloride, in pure form or preferably in an inert solvent, such as dichloromethane, or with, for example, p-toluenesulfonyl chloride in a solvent, such as pyridine, is treated. The product of formula XXIV can exist in one or both of the forms shown and can be convertible to the other form in each case via an episulfonium intermediate.

In the process according to the invention, the compound of formula XXIV is converted into the end product of formula I by treatment with imidazole. This reaction is preferably carried out in an inert organic solvent, e.g. Acetonitrile, dimethylformamide and the like, at a temperature of about 0-80 ° 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 acid 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 imide azole 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.

example 1

1,2-Epoxy-4-phenylbutane (1.48 g) in dry tetrahydrofuran (10 ml) was added to the clear solution which was prepared by converting 50 mg of a 56% sodium hydride dispersion in mineral oil with 2.25 g of 3.4- DichIorbenzylmercap-tan in 50 ml of dry tetrahydrofuran was obtained.

After the mixture was stirred at 60 ° C for 4 hours, the solvent was removed, the residue was treated with water and extracted with ether. The ether extract was dried and evaporated to give a colorless oil.

The oil obtained above in 30 ml of dichloromethane was treated with 2 ml of thionyl chloride at room temperature for 30 minutes and the solution was evaporated to dryness. The residue was treated with 4 g of imidazole and 15 ml of acetonitrile and stirred at room temperature overnight and then at 50 ° C. for a further day. Then the solvent was evaporated and, after adding 50 ml of water, the residue was extracted with ether. The ether extract was washed with water, dried and evaporated to give l- [2- (3,4-dichlorobenzylthio) -4-phenylbutyl] imidazole in the form of an oil which was then further converted to its oxalate; Melting point 143.5-146 ° C.

Example 2

The following compounds can be prepared according to the procedure described in Example 1 and using equivalent amounts of the corresponding starting materials. If indicated, the compounds can be identified by conversion to the corresponding acid addition salt. l- [2- (3,4-dichlorobenzylthio) -3-phenylpropyl] imidazole 1 -f 2- (4-chlorophenylthio) -3-phenylpropyl] imidazole l- [2- (3,4,5-trichlorophenylthio) -3-phenylpropyl] imidazole I- [2- (2,4-dichlorobenzylthio) -3- (4-chlorophenyl) propyl] - imidazole l- [2- (4-fluorophenylthio) -3- (4-chlorophenyl ) -propyl] imidazole l- [2- (3,4-dichlorophenylthio) -3- (4-chlorophenyl) propyl] - imidazole l- [2- (2,4-dichlorobenzylthio) -4-phenylbutyl] - imidazole l- [2- (2,3,4,5,6-pentachirophenylthio) -4-phenyIbutyI] imidazole I- [2- (4-bromobenzylthio) -4-phenylbutyl] imidazole l- [2- (4th -Methylphenylthio) -4-phenyIbutyl] imidazole 1 - r 2- (4-Chloroph enylthio) -4- (4-chlorophenyl) butyl J -imidazole nitrate, melting point 116-119 ° C

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

oxalate, melting point 143-144 ° C l-f2- (2,4-dichlorobenzylthio) -4- (4-chlorophenyl) butyl] imide azoi

1 - [2- (3,4-dichlorophenylthio) -4- (4-chlorophenyl) butyl] imide -

azole nitrate, melting point 84-89 ° C (decomposition) l- [2- (3,4-dichlorobenzylthio) -4- (4-chlorophenyl) -butyl] imide-azole l- [2- (2,4, 5-trichlorophenylthio) -4- (4-chlorophenyl) butyl] - imidazole l- [2- (2,4-dichlorophenylthio) -4- (4-chlorophenyl) -butyI] imide-

azole nitrate, melting point 113.5-115 ° C l- [2- (4-fluorocinnamylthio) -4- (4-chlorophenyl) butyl] imidazole l- [2- (4-trifluoromethylphenylthio) -4- (4th -chlorophenyl) -butyl] - imidazole

1 - [2- (4-Chloro-3-trifluoromethyIphenylthio) -4- (4-chlorophenyl) -

-butyl] imidazole 1 - [2- (benzylthio) -4- (2,4-dichlorophenyl) butyl] imidazole l- [2- (2,4-dichlorobenzylthio) -4- (2,4-dichlorophenyl) -butyl - imidazole l- [2- (3,4-dichlorobenzylthio) -4- (2,4-dichlorophenyl (-butyl) - imidazole l- [2- (4-chlorocinnamylthio) -4- (2.4 -dichlorophenyl) butyl] imidazole 1- [2- (4-phenylbutylthio) -4- (2,4-dichlorophenyl) butyl] imidazole

5

10th

15

20th

25th

30th

35

40

4S.

50

55

60

65

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6

1- [2- (4-chlorophenylthio) -4- (4-tert-butylphenyl) butyl] - imidazole 1- [2- (3,4-dichlorophenylthio) -4- (4-fluorophenyl) butyl] -imid-azole l- [2- (3,4-dichlorobenzylthio) -4- (4-fluorophenyl) butyl] -imidazole l- [2- (3,4-dichlorobenzylthio) -4- (2,4-dimethylphenyl ) -butyl] - imidazole trans-l- [2- (3,4-dichlorophenylthio) -4-phenylbut-3-enyl] imide-

azole oxalate, melting point 171.5-175.5 ° C (decomposition) trans-l-f2- (3,4-dichlorobenzylthio) -4-phenylbut-3 -enyl] imide-

azole nitrate, melting point 138-139 ° C (foaming) l-f2- (4-chlorobenzylthio) -4-phenylbut-3-enyl] imidazole l- [2- (4-chlorophenylthio) -4-phenylbut-3- enyl] -iinidazole 1 - [2- (4-bromobenzylthio) -4-phenylbut-3-enyl] imidazole l- [2- (4-phenylbutylthio) -4-phenylbut-3-enyl] imidazole I- [2 - (3,4-dichlorophenylthio) -4- (4-chlorophenyl) but-3-enyl] - imidazole 1- [2- (2,4,5-trichlorophenylthio) -4- (4-chlorophenyl) but -3-enyl] - imidazole l- [2- (2,3,4,5,6-pentachlorophenylthio) -4- (4-chlorophenyl) but-

-3-enyl] imidazole l- [2- (cinnamylthio) -4- (4-chlorophenyl) but-3-enyl] imidazole l- [2- (4-chlorophenylthio) -4- (4-chlorophenyl) -but-3-enyl] - imidazole l- [2- (4-chlorobenzylthio) -4- (4-chlorophenyl) -but-3-enyl] - imidazole l- [2- (2,4-dichlorophenylthio) -4-phenylbutyl] imidazole l- [2- (4-chlorobenzylthio) -4-phenylIbutyl] imidazole I- [2- (4-chlorobenzylthio) -4- (4-fluorophenyl) butyl] imidazole l- [ 2- (2,4-dichlorobenzylthio) -4- (4-fluorophenyl) butyl] imidazole 1- [2- (2,4-dichlorophenylthio) -4- (4-fluorophenyl) butyl] imide azole.

Example 3

The following compounds can be prepared by the procedure described in Example 1 and using equivalent amounts of the appropriate starting materials. If indicated, the compounds can be described in more detail by conversion into the corresponding acid addition salt.

l- [3- (4-chlorophenylthio) -3- (4-chlorophenyl) propyl] imidazole-

-oxalate, melting point 108-112 ° C l- [3- (4-chlorobenzylthio) -3- (4-chlorophenyl) -propyl] -imidazoI-

-oxalate, melting point 115-156 ° 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-chlorophenyl) propyl] -

-imidazole oxalate, melting point 127.5-129 ° C (decomposition) l- [3- (4-fluorophenylthio) -3- (4-chlorophenyl) propyl] imidazole l- [3- (2,4-dichlorophenylthio ) -3- (4-chlorophenyl) propyl] imide azole l- [3- (3,4-dichlorophenylthio) -3- (4-chlorophenyl) propyl] - imidazole l- [3- (4- Trifluoromethylphenylthio) -3- (4-chlorophenyl) propyl] - imidazole l- [3- (2,4-dichlorocinnamylthio) -3- (4-chlorophenyl) propyl] - imidazole l- [3- (4- Methylbenzylthio) -3- (2,4-dichlorophenyl) propyl] -

-imidazole nitrate, melting point 69.5-75 ° C (decomposition) l- [3- (4-chlorobenzylthio-3- (2,4-dichlorophenyl) propyl] imide-

azole nitrate, melting point 63-66.5 ° C (decomposition) l- [3- (4-chlorophenylthio) -3- (2,4-dichlorophenyl) propyl] imide azole nitrate, melting point 123.5-125 , 5 ° C (decomposition) l- [3- (2,4-dichlorophenylthio) -3- (2,4-dichlorophenyl) propyl] - imidazole l- [3- (3,4-dichlorophenylthio) -3- (2,4-dichlorophenyl) propyl] imidazole l- [3- (4-trifluoromethylphenylthio) -3- (2,4-dichlorophenyl) propyl] imidazole l- [3- (4-tert. -Butylphenylthio) -3- (2,4-dichlorophenyI) propyl] - imidazole l- [3- (2,4,5-trichlorophenylthio) -3- (2,4-dichlorophenyl) propyl] - imidazole l - [3- (4-Phenylbutylthio) -3- (2,4-dichlorophenyl) propyl] - imidazole

1- [3- (4-Chlorophenylthio) -3- (4-tert-butylphenyl) propyl] imidazole 1- [3- (2,4-dichlorobenzylthio) -3- (4-tert-butylphenyl) -propyl] - imidazole l- [3- (2,4,5-trichlorophenylIthio) -3- (4-fluorophenyl) propyl] - imidazole oxalate, melts at 76 ° C, final melting point 99 ° C l- [3- (4-chlorobenzylthio) -3- (4-fluorophenyl) propyl] imidazole l- [3- (4-tert-butylphenylthio) -3- (4-fluorophenyl) propyl] - imidazole l- [3- (2,4-dichlorobenzylthio) -3- (2,4-dimethylphenyl) propyl] - imidazole l- [3- (4-bromophenyIthio) -3- (2,4-dimethylphenyl) propyl] - -imidazole

1 - [3- (4-Methylbenzylthio) -3- (4-tert-butylphenyl) propyl] -

-imidazole nitrate, melting point 132-134 ° C (decomposition) l- [3- (4-chlorophenylthio) -4-phenylbutyl] imidazole l- [3- (2,4-dichlorobenzylthio) -4-phenylbutyl] imidazole l- [3- (4-tert-Butylphenylthio) -4-phenylbutyl) imidazole 1- [3- (2,4-dichlorophenylthio) -4- (4-chlorophenyl) butyl] imidazole l- [3- (4-Methylbenzylthio) -4- (4-chlorophenyl) butyl] imidazole l- [3- (4-chlorobenzylthio) -4- (4-methylphenyl) butyl] imidazole l- [3- (2.4 -Dichorborbylthio) -5- (4-chlorophenyl) pentyl] - imidazole l- [3- (4-chlorobenzylthio) -5- (4-chlorophenyl) pentyl] imidazole l- [3- (2,4, 5-trichlorophenylthio) -5- (4-chlorophenyl) pentyl] imidazole 1- [3- (4-tert-butylbenzylthio) -5- (4-chlorophenyl) pentyl] imidazole

1 - [3 - (3,4-dichlorophenylthio) -3 - (2-trif luormethylphenyl) -

-propyl] i-imidazole l- [3- (3,4-dichlorobenzylthio) -3- (2-trifluoromethylphenyl) -

-propyl] -imidazole l- [3- (4-chlorophenylthio) -3- (2,4-dibromophenyl) -propyl] - imidazole l- [3- (4-chlorophenylIthio) -3- (2,4-difluorophenyl ) -propyl] - imidazole l- [3- (4-fluorophenylthio) -3- (2,4-dichlorophenyl) propyl] - imidazole l- [3,4- (fluorobenzylthio) -3- (2,4 -dichlorophenyl) -propyl] - imidazole.

Example 4

The following compounds can be prepared according to the procedure described in Example 1 and using equivalent amounts of the corresponding starting materials. If indicated, the compounds can be described in more detail by conversion into the corresponding acid addition salt.

1- [4- (3,4-dichlorophenylthio) -4- (4-chlorophenyl) butyl] imide azole nitrate, melting point 100-104.5 ° C; Oxalate, melting point 118-123 ° C (foaming) l- [4- (4-chlorobenzylthio) -4- (4-chlorophenyl) butyl] imidazole-

nitrate, melting point 123-125 ° C (foaming) l- [4- (4-bromobenzylthio) -4- (4-chlorophenyl) butyl] imidazole 1- [4- (4-fluorophenylthio) -4- (4th -chlorophenyl) -butyl] -imidazole l- [4- (4-chlorophenylthio) -4- (2,4-dichlorophenyl) -butyl] -imide-

azole oxalate, melting point 69-75 ° C. (foaming) l- [4- (4-methylphenylthio) -4- (2,4-dichlorophenyl) butyl] - imidazole l- [4- (4-chlorobenzylthio) - 4- (2,4-dichlorophenyl) butyl] imide azole oxalate, melting point 62.5-65 ° C (foaming)

5

10th

15

20th

25th

30th

35

40

45

50

55

60

65

7

623 040

l- [4-Benzylthio-4- (2,4-dichlorophenyl) butyl] imidazole 1- [4- (4-phenylbutylthio) -4- (2,4-dichlorophenyl) butyl] imidazole l- [4 - (4-Fluorobenzylthio) -4- (2,4-dichlorophenyl) butyl] imide azole oxalate, melting point 95-101.5 ° C

l- [4- (4-tert-butylphenylthio) -4- (4-fluorophenyl) butyl] -

-imidazole l- [4- (3,4-dichlorophenylthio) -4- (4-fluorophenyl) butyl] imidazole 1- [4-phenylpropylthio-4- (4-f luorphenyl) butyl] imidazole

oxalate, melting point 97-99 ° C. 1- [4-phenylthio-4- (4-tert-butylphenyl) butyl] imidazole nitrate,

Melting point 121.5-123.5 ° C (decomposed) 1 - [4- (4-chlorophenylthio) -4- (4-tert-butylphenyl) butyl] imidazole

1- [4- (2,4-dichlorobenzylthio) -4- (4-tert-butylphenyl) -butyI] --imidazole 1- [4- (4-fluorophenylthio) -4- (2,4-dimethylphenyl) - butyl] - imidazole 1- [4- (4-methylbenzylthio) -4- (4-bromophenyl) butyl] imidazole-

-nitrate, melting point 93-95 ° C (decomposition) l- [4- (4-chlorophenylthio) -5-phenylpentyl] imidazole l- [4- (2,4-dichlorobenzylthio) -5-phenylpentyl] imidazole l- [4- (2,4-dichlorophenylthio) -5- (4-chlorophenyl) pentyl] - imidazole l- [4- (4-methylbenzylthio) -5- (4-chlorophenyl) pentyl] imidazole l- [ 4- (2,4-dichlorobenzylthio) -6- (4-chlorophenyl) hexyl] imidazole 1- [4- (4-chlorobenzylthio) -6- (4-chlorophenylI) hexyI] imidazole l- [4- (2,4,5-trichlorophenylthio) -6- (4-chlorophenyl) hexyl] imidazole

1- [4- (4-tert-Butylbenzylthio) -6- (4-chlorophenyl) hexyl] imidazole 1- [4- (4-trifluoromethylphenylthio) -6- (4-chlorophenyl) hexyl] - imidazole l- [6- (4-chlorobenzylthio) -6-phenylhexyl] imidazole l- [6- (4-methylphenylthio) -6-phenylhexyl] imidazole l- [6- (4-chlorophenylthio) -6-phenylhexyl] -imidazole l- [6-benzylthio-6- (4-chlorophenyl) hexyl] imidazole 1- [6- (4-fluorobenzylthio) -6- (4-chlorophenyl) hexyl] imidazole l- [6- ( 2,4-dichlorobenzylthio) -8-phenyloctyl] imidazole 1 - [9- (4-fluorophenylthio) -9-phenylnonyl] imidazole l- [9- (2,4,5-trichlorobenzylthio) -9- (4- chlorphenyl) nonyl] - imidazole

1 - [9- (2,4-Dichlorobenzylthio) -1 1-phenylundecyl] imidazole 1- [4- (4-fluorophenyIthio) -4- (2,4-dichlorophenyl) butyI] imidazole.

Example 5

Nitric acid (70%; density = 1.42) was added dropwise to a stirred solution of 2.0 g of l- [2- (2,4-dichlorobenzylthio) -4-phenylbutyl] imidazole in 30 ml of anhydrous ether. until the precipitation was completed. The product was filtered off, washed with ether, air dried and recrystallized from ethyl acetate to give l- [2- (2,4-dichlorobenzylthio) -4-phenylbutyl] imidazole nitrate.

In the same way, all the base compounds of formula (I) can be 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, methane-sulfonic acid, ethanesulfonic acid, p- Toluenesulfonic acid or salicylic acid can be treated.

Example 6

l- [2- (2,4-dichlorobenzylthio) -4-phenylbutyl] imidazole nitrate (2.0 g) in 100 ml dichloromethane was treated with a

Shaken excess dilute potassium carbonate solution until the salt was completely dissolved. Then the organic phase was separated, washed twice with water,

Dried over magnesium sulfate and evaporated to give 5 l- [2- (2,4-dichlorobenzylthio) -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:

ls 1. Candida albicans (ATCC 10231) - C.a. 1

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

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

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

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

20 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.

All organisms were incubated in roller drums containing 25 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 30 broth was 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. 35 300, 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. 40 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 1/10 dilutions of these 16 hour cultures were used as vaccine 45 for each vial. Dermatophytic fungi were grown on Sabouraud dextrose agar or neutral malt extract agar slant cultures that 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 50 suspensions were made 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 x 100 mesh). This procedure separated the agar particles and the 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-60 dextrose broth.

Fungus arrest, that is, the concentration at which growth was prevented, was determined visually and recorded as the minimum inhibitory concentration (MIC) in (ig / ml). The yeasts were read after 65 days of incubation for 3 days In the case of fungi 4 and 5, stoppages were determined after a 5-day incubation, and in organism 3, the stoppage was determined after a 7-day incubation.

623040

8th

MIC (\ xg / ml) l- [3- (4-chlorobenzylthio) -3- (2,4-dichlorophenyl) propyl] - imidazolni joined E. f. - <0.1 C. a. 2 - 1

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

l- [3- (4-Chlorophenylthio) -3- (2,4-dichlorophenyl) propylJ - imidazole nitrate E. f. - 0.3 C. a. 2 - 1

I- [3- (4-tert-butylphenylthio) -3- (4-chlorophenyl) propyl] -

-imidazole oxalate

T. m. - 1

C. a. 1 - 10

C. a. 2 - 10

1- [3- (4-bromo-3-methylphenylthio) -3- (4-chlorophenyl) propyl] -

-imidazole nitrate

T. m. - 1

C. a. 1 - 10

C. a. 2 - 10

1 - [2- (4-Ch! Orbenzylthio) -4- (4-chlorophenyl) butyl] imidazole oxalate

M. g. - 3 E. f. - <0.1 C. a. 1 - 3 C. a. 2-3

l- [2,3 (3 (4-dichlorophenylthio) -4- (4-chlorophenyl) butyl] - imidazole nitrate M. g. - 3 E. f. - <0.1 s C. a. 1 - 3 C. a. 2-3

l ~ [2- (4-chlorophenylthio) -4- (4-chlorophenyl) butyl] imidazole nitrate io M. g. - 3 E. f. - <0.1 C. a. 1 - 3 C. a. 2-3

is l- [2- (3,4-dichlorophenylthio) -4-phenylbutyl] imidazole oxalate C.a. 1 - 3 C. a. 2-3

l- [4- (3,4-dichlorophenylthio) -4- (4-chlorophenyl) butyl] -20 imidazole nitrate M. g. - 3 T. m. - 1

1- [4- (4-Chlorobenzylthio) -4- (4-chlorophenyl) butyl] imidazole-25 nitrate

C. a. 1 - 10

1- [4- (4-Chlorobenzylthio) -4- (2,4-dichlorophenyl) butyl] imide azole nitrate 30 C. a. 2 - 10

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

azoloxalate

C. a. 2 - 10

Claims (2)

623040 2nd PATENT CLAIMS 1. Process for the preparation of a compound of the formula: 14. The method according to claims 1 and 2, characterized in that l- [2- (3,4-dichlorobenzylthio) -4- (4-fluorophenyl) butyl] imidazole and its acid addition salts. poses. R "-CII-CH2-N N s-R w (I) wherein R1 denotes phenyl straight-chain-C-Cg-alkyl and R2 phenyl, phenyl-straight-chain-Cj-Cg-alkyl or phenyl-straight-chain - C2-C8-alkenyl, the phenyl rings having one or more substituents from the group: lower Alkyl with 1 to 4 carbon atoms, fluorine, chlorine, bromine and trifluoromethyl, and their salts, characterized in that a compound of the formula: