DE2633492A1 - DERIVATIVES OF SUBSTITUTED N-ALKYLIMIDAZOLES AND THEIR PRODUCTION AND USE - Google Patents

Description

- .; ■ · ■■ .. ■; ■; ^: 'Patent Attorneys

DipL-lng. P. WIRTH Dr. V. SCHMIED-KOWARZIK DipL-Ing. G. QANNENBERG Dr. P. WEIN HOLD Dr. D. GUDEL

TELEPHONE (OSiI)

281134 287014

6 FRANKFURT / M.

GR. ESCHENHEIMER STR. 39

PA 745/792

wa / ii

Syntex (USA) Inc.

3401 Hillview Avenue Palo Alto, CaI. 94304 / üSA

their_production_and_use

7Q980 8/114 8

The present invention relates to new chemical compounds which are derivatives of substituted N-alkylimidazoles, in particular on compounds the formula

1 ^

R-CH- (CH ₀ ) -NN

²ⁿ

(D

12th

wherein R and R are each phenyl, phenyl straight chain lower Alkyl or phenyl-straight-chain lower alkenyl or in which one of the above-mentioned radicals im Phenyl ring with one or more substituents selected from the group: lower alkyl with 1 - about 4 carbon atoms, Halogen and trifluoromethyl is or are selected, is substituted; X = oxygen or sulfur; and η a is an integer from 1 to about 8, with η, however

-ι

is not the number 1 when R = phenyl or substituted Is phenyl;

and the antimicrobial acid addition salts of these.

The compounds according to the invention are suitable for combating of fungi, bacteria and protozoa by administering the compound or a composition containing them.

In the description and claims, the terms listed below have the following meanings, unless otherwise stated: The term "lower alkyl ^Ir refers to a straight or branched chain monovalent substituent consisting only of carbon and hydrogen, containing no unsaturated bonds and has 1 to about 8 carbon atoms. Examples of lower alkyl groups are: methyl, ethyl, n-propyl, i-propyl, η-butyl, tert-butyl, pentyl, n-hexyl and n-octyl. The term "lower alkenyl "refers to a straight or branched chain monovalent substituent consisting only of carbon or hydrogen,

709808/1148

has a mono-olefin unsaturated bond and which has about 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-enyl, hex-5-enyl, hept-1-enyl, hept-4-enyl, hept-6-enyl, oct-1-enyl, oct-5-enyl and oct-7-enyl. The term "styryl" refers to egg-styryl. The term "halogen" refers to fluorine, chlorine and bromine. "Antimicrobial acid addition salts" of the compounds according to the invention are those salts which preserve the antimicrobial properties of the free bases, which "are undesirable neither biologically nor in other respects 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, salicylic acid will.

All compounds of the formula (I) have at least one ehiral center, ie. the carbon atom to which the radicals R, X, (CHo) _n and H are bonded. The compounds according to the invention can therefore be prepared either in optically active form or as a racemic mixture. Unless otherwise indicated, the compounds described below are all in the racemic form. However, the present invention is not intended to be restricted to this form, but rather also includes the individual optical isomers of the compounds according to the invention. In addition, the compounds which have an optionally substituted phenyl straight-chain lower alkenyl group can also have geometric (cis and trans) isomers in the double bond. Both isomers and mixtures of these are also intended to be encompassed by the present invention. ■ - ".. ·

709808/1 U Β

Optionally, raceric dishes produced according to the invention Intermediate products or end products also according to conventional separation processes known per se into their optical antipodes are broken down, for example by the separation (e.g. fractional crystallization) of the diastereomeric salts; the by reacting, for example, racemic compounds of the formula (I) with an optically active acid are, or by separating the diastereomeric salts or esters obtained by reacting racemic compounds of the Formula (II) have been formed with an optically active acid. Examples of such optically active acids are the optically active forms of camphor-10-sulfonic acid, d-bromo-camphor-tr-sulfonic acid, camphoric acid, menthoxyacetic acid, Tartaric acid, malic acid, diacetyl tartaric acid, pyrrolidone-5-carboxylic acid and the like. The severed ones pure diastereomeric salts or esters can then be cleaved by standard methods to give the corresponding optical isomers of the compounds of formula (i) or (II).

The compounds of formula (I) .a, fungici'de "invention - antibacterial and Intiprotozoen efficacy example, have the compounds of the invention a fungicidal activity against human and animal pathogens, such as.!

EiiLMicrpsporum..audpuini, _ .. _v ;. · _. j. · :. v .._...-.- ..

Yc; -Microsporum; gypseum,:;:.: "._; Γ:: \ ■ '.

lriKicrosporum gypse.um-.canisj ..:; _ .. · _. :;: '.; ;.

£:; -. Ep.idermophyton floccosum,:; · .; ; ■. ::: ...: '. :

i;.:. Trichophyton mentagrophytes.,.

"_. Tri.chophyton.rubrum, · ·· ..: ..... _ ·

;.:. Trichophyton tonsurans, ■ --.- ■

- ^l - Candida albicans and -

Cryptococcus neoformans.

The compounds according to the invention also have a fun-effectiveness against the following fungi, which are mainly of importance in agriculture:

709808 / 1U8

ORIGINAL INSPECTED

.: ■. . '■' ν ■. '> 5 - ■. ". ■■. '" ■■ ■■■■ -. ■■ .'-. -

Aspergillus flavus, Aspergillus longer,

Cladosporiuin herbarum, Penicillium oxalicum,

Fusarium graminearum,. Penicillium spinulosum,

Penicillium notatum and Pithomyces ehartarum ,,

In addition, the compounds according to the invention also have a antibacterial activity against human and animal pathogens, such as

Staphylococcus aureus,
Streptococcus faecalis?

·. Corynebacterium aches,. :

Erysepelothrix insidiosa,; .

Escherichia "coil,
Proteus vulgaris,
Salmonella choleraesuis,
Pasteurella multocida and
Pseudompnas. aeruginosa. . .- '.

The ^Compounds of the invention also have A, ntiprotozoen- efficacy against protozoa, such as Trichomonas vaginalis. ·. :

In general, the compounds according to the invention have. has a low level of toxicity. They also own these Compounds have "good solubility in the stratum corneum. Since dermatophytic (i.e. parasitic-fungal) infections are usually located in the dead tissue of the stratum pornoum, increases the solubility of the fungicide. Means in this Tissues' essentially their effectiveness,

In view of the above efficacies are "in the novel compounds are valuable anti = m4.kr0bis.che agents that are not only suitable for the pharmaceutical, but also for agricultural and industrial applications. *" ^R *

9808/1148

v; .i ί ... «« "il..-si

The present invention also relates to compositions for pharmaceutical, agricultural use and industrial use which comprise the compounds of formula (1) according to the invention in combination with a suitable carrier. The growth of fungi, bacteria and protozoa is inhibited by a yeast infected with or infected by fungi, bacteria or protozoa threatens to be attacked, an effective amount of a compound according to the invention or a suitable containing them Composition is administered.

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 drug carriers normally used for solid compositions are, for example, 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, for example, 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 of the present invention may be subjected to conventional pharmaceutical methods such as sterilization, and may contain conventional pharmaceutical additives such as preservatives, stabilizers, emulsifiers, osmotic pressure adjusting salts and buffers. The compositions can also contain other therapeutically active materials. * _f When used pharmaceutically, the compounds and compositions according to the invention can be administered to humans and animals by conventional methods, for example externally, orally, parenterally or the like. Parenteral administration includes both intramuscular and intramuscular

709808 / 1U8 "'

subcutaneous and intravenous administration. The intravenous injection of "fungieid" compounds of the imidazole type has been shown to be effective in the treatment of systemic mycosis (see, for example, "Drugs", pp. 419-420, 1975-, wherein the intravenous administration of miconazole, i _o 1 - / 2,4-dichloro-β - (2 ', 4' -dichorbenzyloxy) -phenäthylT'-imidazole nitrate, is described in patients with systemic candidiasis). Local application is the preferred form of administration for pharmaceutical use. In this treatment, an area that is already infected with fungi, bacteria or protozoa or is to be protected from attack by fungi, bacteria or protozoa can be treated with the compound or composition according to the invention , namely Z ₀ B. · by dusting, spraying, atomizing, rinsing, brushing, dipping, smearing, coating, impregnating and the like ,, Pharmaceutical compositions for external use, which contain compounds of the invention possess very different concentrations, for example, _{s o} from about 0 _p 1 - 10.0 wt _o - $> the composition, a fungicidal, antibacterial and antiprotozoa: effectiveness. In any case, the composition to be administered contains a sufficient amount of the compound according to the invention to provide relief of a particular condition or to prevent this condition from occurring.

The pharmaceutical compositions according to the invention generally comprise one or more of the inventive Compounds of the formula '(I) and * one pharmaceutical usable, non-toxic carriers and are preferably prepared in dosage units to facilitate administration to facilitate (a dosage unit is the amount of active ingredient that is administered at once).

ώ general, it is the case of systemic administration (e.g. B _0, oral or parenteral) appropriate to the active ingredient in amounts zwisphen about 1 and 100 mg per kg body weight per day and / preferably, between about 5 and 50 mg per kg body weight

- 7 Ö 9 8 0 8/1 U 8

and per day, to be administered, preferably divided into several administrations (e.g. in three separate Doses) in order to achieve the highest possible effect. With localized Administration (e.g. externally) a correspondingly smaller amount of active ingredient is necessary.

The precise regulation of the administration of the compounds and compositions according to the invention depends, of course, on the Needs of the individual treated patient, the type of treatment, for example whether it is preventive or a curative treatment, the type of organism affected and, of course, the judgment of the treating person Doctor.

When used in agriculture, the compounds according to the invention can be applied directly to plants (e.g. seeds, leaves) or applied to the ground. The compounds according to the invention can, for example, alone or mixed with a powdery solid carrier can be applied to the seeds. Typical powdered carriers are the various mineral silicates, e.g. mica, talc, pyrophyllite and ÜDone The compounds according to the invention can also mixed with a conventional surface-active wetting agent and optionally additionally with a solid carrier • The seeds are used. As surface-active wetting agents all conventional anionic, non-ionic and cationic wetting agent types are suitable. For the treatment of the

. The compounds according to the invention can be used against fungi and the like 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 one Means, are applied, or the compounds according to the invention can be used as an aqueous spray, which may optionally contain a surfactant dispersant and a powdery solid carrier can be used. For the Treating foliage, the compounds according to the invention can be in the form of an aqueous spray which has a surface-active Dispersant and optionally a powdery one

709808/1 Ue

contains solid carriers as well as carbon / water solvents, can be applied to growing plants »

In industrial applications, the invention Compounds used to fight bacteria and fungi are known by the pathogen To be brought into contact with the connections in a manner «, Materials that are suitable to serve as breeding grounds for bacteria and fungi can be protected by using them the compounds according to the invention are brought into contact, mixed or impregnated. To increase the effect, the compounds according to the invention can be used with other pesticides, such as fungicides, bactericides, insecticides, Miticides and the like, combined .. A special one important industrial and agricultural application area of the compounds of the invention is for use as a food preservative against bacteria and Fungi that cause food to spoil.

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

^ R-CH- (CH ₀ ) -NN R-GH -. (CH ₉ J _n -NN

I ⁿ V_ / I X = J

12th

where R _s R and η have the meaning given above *

Both groups of compounds can be made from common intermediates that have a free hydroxyl group which is then converted to either the ether or the thioether, and they can be made by many different processes depending on the length of the chain (CH ₂ ) _n , that is, "h ₀ depends on the value n,"

70 98Q8 / 1H;

A preferred subgroup of compounds of the formula (i) are those compounds in which η = 1, 2 or 3 means. When η = 1, the preferred group is compounds where R = phenethyl, styryl or halogen (preferably Chlorine) substituted phenethyl or styryl, preferably 4-chloro, 4-bromine, 4-fluorine, 2,4-dichloro or 3,4-dichloro

2 substituted phenethyl or styryl, and R either phenyl or benzyl or a halogen substituted derivative of these

- where this "derivative denotes the" halogen substituent (s) preferably has the radical R in the same position as above

or, if R = substituted phenylthio, additionally one 2,4,5-trichloro- and 2,3,4,5,6-pentachlor-substituted Derivative is -, or means cinnamyl or 4-halocinnamyl.

When η = 2 or 3, the preferred group is those compounds in which R = phenyl or halogen-substituted Phenyl, preferably 4-chloro, 4-bromo, 4-fluoro, 2,4-dichloro, 2,4-difluoro or 2,4-dibromo-substituted

2
Phenyl, and R = either phenyl or benzyl or a halogen (preferably chlorine) substituted derivative of these

- preferably with the halogen substituents in the same Position like R and, when R. = Substituted phenylthio, additionally the .; 2,4,5-trichloro- and 2,3,4,5,6-pentachloro-substituted Derivatives - ^ - 33, e.deutet.

As already mentioned, the compounds of the formula (I) can be prepared by converting from a suitable alcohol the Formula (II) '

R ^2- CH- (CH ₀ ) -N "N
t 2 η

OH

1
where R and η have the same meaning as above,

an ether or thioether is produced. Connections of

70 9.8 08/1 HS

Formula (II) can be prepared by many different reaction routes, depending on the size of η.

For example, when η = 1, certain compounds of the formula (Ha) can be prepared according to Reaction scheme A below will:

Reaction scheme A

R ¹ CHO · R ^2- -CH-CH ₀ > R ^1- -CH-CH ₀ -N. V

² ■ ' ² A =;

■ Ο ·. · ■. · OH

R ^1- -CH = CH ₀

In this reaction scheme, the imidazole alcohol of formula (Ha) is formed by opening a terminal epoxide of formula (III) with imidazole. This reaction is generally carried out by adding at least 1 mole, and preferably an excess, of imidazole, based on the epoxide, is used The reaction can be carried out either in the absence of solvents or, preferably, in an inert organic solvent such as dimethylformamide, hexamethylphosphoramide, acetonitrile, etc. The temperature normally used for such epoxy openings is between about -20 and 10O ⁰ C, preferably between about 20 and 60 ^{0 C..}

Epoxides of the formula (III) can, if they are not known or are readily available, can be prepared by various known methods, e.g., by epoxidation of a terminal

70 9808/1 14 8

Olefins (e.g. (V)) with, for example, a peracid, or by reacting an aldehyde that is one carbon atom less '(e.g. (IV)), with dem-ylide, that of trimethylsulfoxonium iodide has been prepared and, for example, in J.Am. Chem. Soc, 84, page 867 (1962), and there 87, page 1353 (1965).

Another method for the preparation of certain compounds of formula (Ha) is shown in Reaction Scheme B below shown:

Reaction scheme B

R ¹ COCH ₀ Y · ',. > R ¹ COCH ₂ -N- ^ N- -> R ¹ ^ H-CH ₂ -N ^

Ct . Xl I \. /

evil) -. / _t .

where Y = chlorine or bromine.

In this reaction scheme, the hydroxy compound is the Formula (Ha) produced by reducing the corresponding ketone (VI), which in turn is produced by reacting an 06 halogen ketone (VII) obtained with imidazole.

Ot haloketones are widely available or can be readily prepared, for example, by halogenating the corresponding methyl ketone. When R is styryl or substituted styryl, a particularly suitable bromination process is given in Tetrahedron , 29, p. 1625 (1973), and in Can.J .Chem. 47, 'page 706 (1969).

The · cc-haloketone is dissolved in an inert organic solvent brought into contact with imidazole to obtain the keto-imidazole of the formula (VI). The reaction is using of at least a molar amount, preferably one

709808 / 1U8

Excess of imidazole, based on the halo ketone, was also given. The reaction may be in the absence of solvent or preferably in an inert organic solvent., Eg, dimethylformamide, Hexaraethylphosphoramid, acetonitrile and the like, performed -Be ,, namely, conveniently at an initial temperature of about -10 to 100 ⁰ C, preferably from about 0 to 25 ⁰ C.

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

If η = 2, the compounds of the formula (lib) according to various synthetic processes can be produced. A suitable method for making certain compounds of formula (lib) is in Reaction Scheme C below ■ shown i- "..

- · 'Reaction scheme C

ί'βΓ: Hannich-Sase ^ '
quaternary salt)

"(IX) (VIII)

₀ CH ₀ -NN

^{2 2} W = /

1 -

OH

(lib)

This scheme involves the reaction of imidazole with a vinyl ketone of formula (VIII) (or a quaternary base:, intermediate of a Mannich reaction), followed by

709808/1 UB

the reduction of the resulting ketoimidazole of the formula (IX) to the hydroxyimidazole of the formula (lib).

Vinyl ketones of formula (VIII), if they are not known or generally available, can be prepared by various processes which are well known in the field of synthetic organic chemistry, such as, for example, by the addition of vinyl lithium to the corresponding carboxylic acid; by addition of vinyl lithium to the corresponding: acid aldehyde, followed by the oxidation of the allyl acid alcohol, whereby the vinyl ketone is obtained (see e.g. J.Chem.Soc. (C) _t 1966 _t page 1972; J.Chem.Soc. (London) , 1956 , Page 3070); or by a Mannich reaction of the corresponding 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 carried out by contacting the vinyl ketone (or a quaternary base precursor obtained by a Mannich reaction) with imidazole in an organic solvent is brought. The reaction is expediently carried out by adding 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 example diethyl ether, dichloromethane or dimethylformamide, at a temperature of about 0-40 ^° C., preferably at about room temperature, is used.

The reduction of the ketoimidazole of the formula (IX) ^ u dem Hydroxyimidazole of formula (lib) is made in the same manner as above for the conversion of the compound of Formula (VI) has been described in the compound of formula (Ha).

709808/1 U8

When η = 2 (or a higher number), certain compounds of the formula (II) according to Reaction Scheme D below getting produced:

Reaction scheme D

R ¹ CO (CH ₀ I _n Y -> R ¹ CO (CH) -N. N

\ j

(χ)

1 ^

R ¹ CH (CH ^) - NN

j V ■. /

OH '' -.

where Y = chlorine or bromine.

In this reaction scheme, a uj-halogen (preferably Chlorine) ketone of B'ormel (X) into the corresponding ketoimidazole of formula (Xl) and then in. the hydroxyimidazole of formula (II) converted.

The c ^ -halogen ketones used as starting material can, if they are not known or are generally available, expediently prepared by the known Friedel-Crafts reaction, which uses the aromatic hydrocarbon
is carried out.

Hydrocarbon R H and a ui-haloacyl halide

The conversion of the compound (X) into the compound (Xl) is carried out using imidazole by the same procedure as described above for the conversion of the compound (VII) into the compound (VI). If η = 3 or higher, the reaction temperature is about 0-10O ⁰ C, preferably about ^{25-80 0} C.

70 9808/1 148

The reduction of the Ketoimidazols of formula (XI) _Z u the hydroxy imidazole of formula (II) is carried out in the same manner that has been previously described for the conversion of compound (Vl) to compound. (1Ia).

Certain compounds of the formula (lic) can also after a alternative method can be prepared, which is shown in the following Reaction Scheme E:

i ^ 1 ν ^ 1 ^>

R COCH = CH ₀ -> R- ¹ COCH-CH ₀ -> (X) - ^ R -CH- (CH ₀ ) --NN

\ ' ² \ / ² I ^{2 3} \ —J

'.OH

(VIII) (XII) ' (lic)

In this process, the above-described Viny3.ketone of the formula (VIII) is converted into the corresponding cyclopropyl ketone Formula (XII) converted, after which the conversion into the ^ -halo ketone of the formula (X) - at η = 3 - and then, as described above, into the hydroxyimidazole of the formula (lic) *

The cyclopropanation of the vinyl ketone of the formula (VIII) can be carried out by methods known per se, for example by the method described in J.Am.Chem.Soc. , 87, page 1353 (1965). The cyclopropyl ketone obtained is then opened to obtain the "halo ketone by treatment with a hydrohalic acid, for example hydrobromic acid.

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

70 98 08 / 1U8

R ¹ CHO + CH ₂ = CH-

(IV) _r (XIII)

R ^X CO (CH ") Y -> R CO (CH.) -NN

2 η 2 η

(X) (XI)

R CH (CH _n ) -NN

I ²ⁿ \ = J

OH

(ID

where Y = chlorine or bromine "

This reaction scheme is particularly useful for making compounds where ri = 4 or greater, but it can also be used to make compounds where v / orin is 2 or 3. In this scheme, the aldehyde of the formula (IV) described above is reacted with an alkene of the formula (XIII) which has CJ-halogen end groups and which can easily be prepared, for example, by halogenation of the corresponding alcohol in an addition reaction based on free radicals, in order to obtain the above-described haloketone of the formula (X), which is then converted in the manner described above via the ketoimidazole of the formula (XI) into the hydroxyimidazole of the formula (II). The conversion of the compounds (IV) + (XIII) into the compound (X) is conveniently carried out using a source of free radicals, such as "Diacetylperoxjrd, di-tert _e - = butyl-PjBroxyd, dibenzoyl peroxide, Azobisisobutyronitrilj or photochemically in a temperature between about 50 and 15O ⁰ C, preferably carried out between about 60 and 8O ⁰ Cj using an excess of aldehyde as solvent medium.

709808/1148

Certain compounds of formula (II) can also be prepared according to Reaction Scheme G below:

R ¹ COZ + CH ₉ = CH- (CH ₀ ) ₀ ~ Y. . '■' * '

. (XIV) (XIII). . . "'

J _n Y, ^ _XI

(X)

where Y = chlorine or bromine.

This reaction scheme is expediently used when compounds are desired in which η = 4 or greater.

In this reaction scheme, an acid halide of formula (XIV) is easily prepared from the corresponding carboxylic acid can be, with the previously described, tü-halogen end groups having alkene of the formula (XIIl) reacted in order to obtain the halo ketone of the formula (X), which then, as described above, is converted into the hydroxyimidazole of formula (II). The addition reaction between the compounds of the formulas (XIV) and (XIII) is expediently carried out under conditions such as those described in G. Olah, "Friedel Crafts and Related Reactions", Volume 3, Part 2, Interscience Publishers, New York, (1964).

Certain compounds of the formula (II) in which η = 1 or greater can also be prepared by a different sequence of reactions shown in Reaction Scheme H below will:

Reaction scheme H

R ° -CH = CH _n + YCO (CH-.) Y -> R ¹ CO (CH ₀ ) Y

2. · 2 η α η

709808 / 1U8

wherein R ¹ = R ⁰ CH ₂ CH ₂ and Y = chlorine or bromine.

In this scheme, the above-described to-halo ketone of the formula (X) is prepared by using as starting material a terminal olefin of the formula (XV) and a u> -haloacyl halide of the formula (XVl), the Z ₀ B ₀ easily from the corresponding hydroxy acid can be produced is used. The reaction is carried out under the conditions described above for reaction scheme G »

In the following Reaction Scheme I, alternative processes for the preparation of certain compounds of formula (II), wherein η = 1 is / is shown:

Reaction scheme I.

R ⁰ CHO + 0 ₃ P = CHCOCII ₂ -NN

(XVII)

- (XIX)

R -CH = CH-COCH, -N N

\ J

0 ₃ P-CH ₂ COCH ₂ Y Θ

(XVIII)

R ⁰ CHO

(XVII)

0 ₃ P = CHCOCH ₂ Y. · (XXI)

-> R ^ CK = CHCOCH ₂ Y, (XXII)

where R ¹ »R ° -CH = CH- or R ⁰ CH ₂ CH ₂ - and Y = chlorine or bromine.

In this scheme, an aldehyde of formula (XVII) is in a Wi'tig reaction with an ylid of formula (XIX) or (XXl) reacted to das.entnachende olefin of the formula (XX) or (XXII). The ylid (XXI) is prepared from the corresponding phosphonium salt (XVIII) by methods known per se.

8/1148

forms, which in turn is produced from triphenylphosphine and the corresponding dihaloacetone. In order to form the ylide of formula (XIX), the phosphonium salt in an inert organic solvent such as acetonitrile or dimethylformamide, at a temperature of about 25 to 100 ⁰ C, preferably from about 50 to 8O ⁰ C, with an excess of imidazole reacted to yield the imidazole-substituted ylide of formula (XIX), which is then, by reaction with the aldehyde of formula (XVII) under standard Wittig conditions (for example, in acetonitrile at 80 ⁰ C) the unsaturated Ketoimidazol of formula (XX ) results.

Optionally, by reacting the aldehyde of the formula (XVII) with the ylide of the formula (XXI), this can be carried out in a customary manner obtained from the phosphonium salt (XVIII) by treatment with a base such as an alkali metal carbonate is, the .unsaturated haloicetone of the formula (XXII) is produced will. This compound can then by treatment with imidazole in the above for the conversion of the compound (VII) in the manner described in the compound (VI) are converted into the corresponding imidazole compound of the formula (XX). One Reduction of the keto group of the compound (XX) then leads to the hydroxyimidazole of the formula (Ha). The ones attached to the hydroxy group adjacent double bond can be hydrogenated in order to obtain a compound of the formula (Ha) which, as the radical R is Phenyl lower alkyl or substituted phenyl lower alkyl group having. This hydrogenation can be carried out under standard conditions, for example using a palladium-on-carbon catalyst in a solvent, like 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 dfer formula (i) in which X = O and R = optionally substituted Phenyl straight chain lower alkyl or phenyl straight chain lower alkenyl means converted by

2 an O-alkylation with the corresponding RY, where Y = a

709808/1 U8

separable "" group, such as a halide (chloride, bromide or Iodide), or a sulfonate ester (e.g. p-toluenesulfonate or methanesulfonate) is carried out.

The alkylation is carried out by removing the hydroxyl group of the compound of formula (II) by treatment with a; strong base such as 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 dimethylformamide, hexamethylphosphoramide, tetrahydrofuran and the like alkali metal salt is then contacted with the RY in contact, preferably in the same solvent system and at a temperature of about 0 to 80 ⁰ G, preferably from about 0 to 6O ⁰ C.

Compounds of the formula (I) in which R is optionally sub-. Substituted phenyl (i.e. phenolic ether or thioether) can be selected from the compounds of formula (II) by a Two-step process are produced, which is the conversion the hydroxyl group into a suitable removable group, such as a halide (e.g. a chloride or bromide) or a Sulfonate ester (e.g. methanesulfonate or p-toluenesulfonate) includes, which then with a metal salt of the corresponding

2 2

Phenol R OH or thiophenol R SH are implemented.

The conversion of the alcohol into the halide or the sulfonate ester takes place according to 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 take place in the presence of a molar equivalent of a base (ζ <, Β »pyridine)"

709808/114 8

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

Sulphonate esters can be prepared by a standard process which consists in treating the alcohol with an excess of, for example, methanesulphonyl chloride or p-toluenesulphonyl chloride in the presence of a base, e.g., pyridine or triethylamine. This reaction \ is conducted at a temperature of about -20 to +50 ⁰ C, preferably from about 0 ⁰ C bis'20 performed.

The halide prepared in the manner described above or

sulphonate ester 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 a temperature of about 20 to 8O ⁰ C. Optionally, the metal salt of the phenol or thiophenol can be formed prior to the addition of the halide.

Compounds of the formula (i) in which X = S and R = optionally substituted phenyl straight chain lower alkyl or phenyl-straight-chain-lower-alkenyl can be prepared by using the above halide or the Sulfonate ester with the metal salt, preferably an alkali metal salt, like the sodium or potassium salt, of a thiol

ρ
R SH is implemented. This reaction is carried out in an inert organic solvent such as tetrahydrofuran, diethyl ether, methanol and the like. The salt is treated with a strong base such as sodium hydride, sodium amide,

7098Ö8 / 1U8

Sodium methylate and the like, formed at a temperature i / o «about 20 to -80 ^° C. · - ·

Compounds of the formula (I) in which η = 1, X = S and R = optionally substituted phenyl-straight-chain-lower-alkyl can also be prepared according to Reaction Scheme J shown below

Reaction scheme J

'9

₀ ■ + ■ ■ "K

\ / ■■ ". ·" ■

or R ² SH

(in)

R ¹ ^ CH-CH ₂ -SR ² , and / or

You

κ. :

"R ¹ ^ CH-CH ₀ -N" Ν

-SR

where Y = a split-off group.

In this scheme, the above-described epoxide of the formula (Hl) is opened with a thiol or thiophenol or a metal salt of these to obtain the compound of the formula (XXIII). This reaction is carried out by preferably adding an alkali metal salt of thiol or thiophenol, in particular the sodium salt, in an inert organic solvent, such as tetrahydrofuran or acetone, at a temperature of about 0 to 67 ⁰ C, or by adding the free

709808/1 H8

Thiol or thiophenol in the presence of an acid catalyst, e.g. perchloric acid, is used under similar conditions.

In the next stage, the hydroxyl group of the compound of the 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) converted, by, for example, reacting with a halogenating agent such as thionyl chloride, neat or preferably in an inert solvent such as dichlorinethane, or with, for example, p-toluenesulfonyl chloride in one Solvent such as pyridine is treated. The product of formula (XXIV) can be shown in one or both of the forms exist and can exist via an episulfonium intermediate each be convertible into the other form.

In the final stage, the compound of the formula (XXIV) is converted into the final product of the formula (I) by treatment with imidazole. This reaction is in an inert organic solvent such as acetonitrile, dimethylformamide and the like at a temperature of about O - from 80 ⁰ C.

If appropriate, certain compounds of the formula (I) in a final stage by hydrogenation of a compound of the formula

R ¹ '-CH- (CH,) -NN · "\ - /

2 '

• X-R

1'

or an acid addition salt thereof, wherein R and R are with

12 1 '/

the radicals R and R are identical, but where R and / or

R has an aliphatic olefinically unsaturated bond,

/ ι ρ I

i.e., where R and / or R is an optionally substituted Phenyl-lower-alkenyl group is formed v / ground. This hydrogenation can be carried out under known conditions.

709808/1148

. - - .. ■.: ■ - ■■ "■" ■■ - ■ ■■■■■■ -. -25 - ■■■ .- "ν:. ■ ■ ..- .. ■ ;;

2633Λ92

For example, the hydrogenation at about atmospheric or a higher pressure and at temperatures of about 0 to 100 ⁰ C in the presence of a suitable - optionally supported or soluble - metal catalyst, such as palladium, platinum or tris (triphenylphosphine) chlorrhodium, in one inert solvents, such as benzene * acetone, methanol and the like, can be made for a sufficient length of time to allow the required amount of hydrogen to be taken up.

The compounds according to the invention can be used as free bases severed; however, since many of the connections are in In the form of base oils, it is more convenient to use the compounds separated and determined 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, which are formed with dibasic acids (e.g. oxalic acid), can contain one or two base molecules per acid molecule. All of the oxalates described here contain one molecule of oxalic acid per molecule of imidazole base. Optionally, the salts easily by treatment with alkali, such as potassium carbonate, Sodium carbonate, or sodium or potassium hydroxide, into the free base form can be converted.

The following examples serve to explain the present invention without, however, limiting it.

70 9 808 / 1U8

Procedure 1

This procedure illustrates Reaction Scheme A.

3-phenylpropionaldehyde (26.8 g) method described under nitrogen the ylide so ciety to in Journal of the American Chemic al, Volume 84, page 867 (1962) and Volume 87, page 1353 (1965) of trimethylsulfoxonium iodide was ( 48.4 g) and sodium hydride (55 % dispersion in oil; 9 _} 6 g) in dry dimethyl sulfoxide (200 ml) was added. After 1 hour the solution was poured into 1 liter of water and the product was extracted with ether (3 x 300 ml). The extract was washed with water (2 × 150 ml, dried (MgSO ^) and evaporated to give an oil, 1,2-epoxy-4-phenylbutane, which was used directly in the next step.

The oil obtained above was in 50 ml of dimethylformamide with imidazo! Treated (70 g), and the mixture was stirred overnight at 4O ⁰ C. The resulting solution was poured into a mixture of 700 ml v / water and 200 ml hexane, stirred until crystallization was complete, and the product was then filtered off in the form of buff granules (28.2 g). By recrystallization from ethyl acetate 1- (2-Hydroxy-4-phenylbutyl) -imidazole was obtained in the form of colorless crystals, melting point 106-107 ° C. -

Using the same procedure, but by replacing 3-phenylpropionaldehyde by the corresponding aldehyde, For example, the following compounds of the formula (Ha) can also be prepared:

1- ^ ~ 2-hydroxy-4- (4-chlorophenyl) butyl / imidazole 1 - / ~ '2-Hydroxy-4- (2,4-dichlorophenyl) -butyl / - imidazole 1 - ^ ~~ 2-Hydroxy-4 ~ (4-ter t. -Butylphenyl) -butyl / - imidazole 1- £ "2-Hydroxy-4- (4-fluorophenyl) -butyl / -imidazole and

1 * - / ~ 2-Hydroxy-4- (2,4-dimethylphenyl) -butyl / -imidazole.

709808/1 U 8

Procedure 2

This procedure illustrates the 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-cold solution of imidazole (35 g) in dimethylformamide (25 ml), the temperature rising to less than 13 ⁰ C was kept. The mixture was stirred for 3 "hours at ⁰ ° C. and then overnight at 25 ° C. and then poured into 1 liter of water. The solution was extracted successively with benzene (600 ml) and with ether (600 ml), and the combined Extracts were dried (MgSO 4) and evaporated. Adding benzene to the residue gave lemon yellow granules (12 g). 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 1- (4-phenylbut-3-en-2-onyl) imidazole hydrochloride as a white solid, melting point 208 -. 210 ⁰ C.

The ketone obtained above (5.50 g) in 50 ml of methanol was ^{treated at 0} ° C. by stirring it with an excess of sodium borohydride. When the reaction was complete, the solvent was evaporated and the residue was treated with ice-cold water (10 ml). Filtering and washing with a small amount of ice water gave an off-white powder (5.40 g) which, after recrystallization from benzene, 1- (2-hydroxy-4-phenylbut-3-enyl) imidazole (5.20 g) , melting point 125 -127 ⁰ C, resulted. ■

Using the same procedure, but by replacing the bromomethyl styrylke tons with the corresponding Halogenice ton, For example, the following compounds of the formula (EIa.) can also be prepared;

70 9808/1 U8

1 - (2-Hydroxy-j5-phenylpropyl) -imidazole

1 - / ~ 2-Hydroxy-3- (4-chlorophenyl) propyl / imidazole

1 - / "~ 2-Hydroxy-4- (4-chlorophenyl) -'but-3-enyl7-imidazole.

709808/1 U8

- 29 - ■ ■. .

Procedure 3

This procedure illustrates Reaction Scheme C,

A '. 7.0 g of 2,4-dichlorophenyl vinyl ketone (prepared by a Jones oxidation of 2,4-dichlorophenyl vinyl carbinol using the method described in J. Chem. Soc. (C) , 1-966, page 1972) in 350 ml of anhydrous ether were treated with 3.5 g of imidazole, the solution was stirred overnight and then washed with water (3 x 30 ml). The solution was then dried (MgSO 4) and evaporated to give 2,4-dichloro- / 3- (1-imidazole) propiophenone in the form of an amber rubbery mass (8.65 g). The hydrochloride salt was precipitated from ether and purified by recrystallization from methanol / acetone to obtain a product in the form of colorless rods, melting point 105.5 to 110 ⁰ G.

B. 13.1 g of 2,4-dichlorobenzoylethyl-trimethylammonium3odid (produced in a Mannich reaction of 2,4-dichloroacetophenone 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 × 75 ml) and dried. The hydrochloride of 2,4-dichloro _/ 4 (i-imidazole) propiophenone was prepared by adding ethereal hydrogen chloride precipitated was then recrystallized v / hich from methanol / acetone, mp 105-109 ⁰ C,

C. The prepared in Part A or B can ketone to the corresponding alcohol, 1 - "~ 3-hydroxy-3-2 / | 4-dichlorophenyl) -propylJ-imidazole, melting point 112 to 114.5 ⁰ C can be reduced, using the procedure described above 2.

709808/1148

D. Using the same procedure as above, but using the appropriate vinyl ketone or cLuataten Mannich salt instead of the compounds mentioned in part A or B, the following compounds of the Formula (lib) can be produced:

1- / ~ 3 ~ hydroxy-3- (4-chlorophenyl) imidazol -propyl7 ~ »mp 95-100 ⁰ C.

1 - / "~ 3-hydroxy-3- (4-tert-butylphenyl) propyl / imidazole, Melting point 139.5-140.5 ° C

"1- / ~ 3-hydroxy-3- (4-fluorophenyl) imidazol--propylZ" melting point 104.5 to 110 ⁰ C.

1- / ~ 3-Hydroxy-3- (2> 4-dimethylphenyl) propyl7-imidazole 1- (3-Hydroxy-4-phenylbutyl) -imidazole 1- _J / T "3-Hydroxy-4- (4-chlorophenyl ) -butyl / - imidazole 1- ^ T "3-hydroxy-4- (4-methylphenyl) -butyl / -imidazole 1 -j / 7 * 3-hydroxy ~ 5- (4-chlorophenyl) -pentyl) -imidazole and .

1 - / ~ 3-Hydroxy-3- (2-trifluoromethylphenyl) propyl / imidazole

1 -2C ~ 2-hydroxy-3- (2,4-dibromophenyl) propyl / imidazole 1- ^ ~ 3-hydroxy-3- (2,4-difluorophenyl) propyl / imidazole.

709808/1 U8

Procedure 4

This procedure illustrates Reaction Scheme D.

A. p> -Chlorpropiophenon (16.8 g) 'and imidazole (35 g) in dimethylformamide (25 ml) were ^{stirred for 3 hours at 0} ° C. and then poured into 700 ml of water. The product was filtered off (15.9 g) in the form of buff-colored flakes and then recrystallized from cyclohexane ,, wherein one / V- (i-imidazolyl) propiophenone in the form of colorless flakes, melting point 96 to 99.5 ⁰ C, was .

The material obtained above (5.60 g) in 70 ml of methanol was ^{treated at 0} ° C. with an excess of sodium borohydride. 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 imidazole 1- (3-hydroxy-3-phenylpropyl) in the form of colorless rods, melting point 1O6,5 - 108 ⁰ C.

B. To a slurry of 8.24 g of imidazole in 15 ml of dry dimethylformamide with a temperature of ⁰ ° C. 5 _} 79 g of p-tert-butyl-Y-chlorobutyrophenone were added, and the mixture was left overnight at room temperature and then stirred for one day at 6O ⁰ C. 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, giving 5.25 g of 1- / ~ 4- (4-tert-butylphenyl) -butane-4-onyl7 "imidazole in the form of a golden 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 pooled extracts were

709808 / 1U8

dried over magnesium sulfate and evaporated, and 1 - / ~ "4-hydroxy-4- (4-tert-butylphenyl) butyl / imidazole, which was converted into the oxalate salt and recrystallized from ethyl acetate / ethanol, melting point 205 - 207 ⁰ C (foaming).

Following the same procedure, but using the corresponding one Haloketones instead of the compound specified in Part A or B, for example, can also use the first four compounds of the formula (lib) listed under process 3 and the following compounds of the formula (II) were prepared will:

1- / ~ "4-Hydroxy-4- (4-chlorophenyl) -butyl_ / - iraidazole 1 - ^ f "4-Hydroxy-4- (2,4-dichlorophenyl) -butylZ-imidazpl

1 - ^ ~ "4-hydroxy-4- (4-fluorophenyl) butyl / imidazole, melting point 91.5 to 94 ⁰ 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 "] - £ ~ 'k- Hydroxy-5- (4-chlorophenyl) -pentyl / -imidazole 1 - / ~ 4-Hydroxy-6- (4-chlorophenyl) -hexyl / -imidazole 1- (6-hydroxy-6-phenylhexyl) -imidazole 1 - / "" 6-hydroxy-6- (4-chlorophenyl) -hexyl / - imidazole 1- / ~ 6-hydroxy-7-) 4-chlorophenyl) -heptylZ-imidazole 1- (6-hydroxy-8-phenyloctyl) -imidazole 1- (6-hydroxy-1O-phenyldecyl) -imidazole 1- (9-hydroxy-9-phenylnonyl) -imidazole 1- / "~ 9-Hydroxy-9- (4-chlorophenyl) -nonyl / - imidazole 1 - / ~ 9-Hydroxy-10- (4-chlorophenyl) -decyl / -imidazole 1- (9-Hydroxy-11-phenylundecyl) - iiaidazole and 1- (9-hydroxy-13-phenyltridecyl) imidazole.

709808/1148

Procedure 5 .

This procedure illustrates Reaction Scheme L.

7.3 g of chloroacetylmethyl triphenylphosphine chloride. and 7.3 g of imidazole in acetonitrile (60 ml) were stirred and ^{heated to 80 °} C. for two days. The resulting solution was evaporated and the residue treated with water, extracted with benzene and the extract washed with water, dried (MgSOr) and evaporated. Recrystallization from ethyl acetate / cyclohexane gave 1-imidazolylacetylmethylene triphenylphosphorane in the form of colorless leaves, melting point 154.5; - 158 ⁰ C.

The phosphorane (3.85 g) / and p-tolualdehyde (2.4 g) obtained above were stirred in 30 ml of acetonitrile and refluxed overnight. After evaporation to dryness: the residue was chromatographed on silica gel using acetone / dichloromethane as the eluent to give 1- / ~ 4- (4-methylphenyl) -but-3-en-2-oney2 _i 7-i ^m i ⁽ iazole in the form of a colorless solid.

This material was reduced with sodium borohydride according to the procedure described under 2 to give "1 - / ~ ² ~ ^H ycLr ^ox y ~ 4- (4-methylphenyl) -but-3-enyl7-iniidazole.

By the same method, but under Ven-zendung of benzaldehyde in place of p-tolualdehyde, 1- (2-hydroxy-4-phenylbut-3-enyl) imidazole, m.p. 125-127 ⁰ C ^ produced. . "....'-;

2.5 g of this material in 30 ml of methanol were at room temperature and under normal pressure over a 10 ^ Hydrogenated palladium on carbon catalyst. When the uptake of hydrogen ceased, the solution was filtered and the residue was recrystallized from benzoil / cyclohexane,

70 980 8/1 148

to give 1- (2 ~ hydroxy-4-phenylbutyl) imidazole (2.37 g) as white microcrystals, mp 108 to 109.5 ⁰ C, obtained.

Following the same procedure, but using the corresponding one Aldehydes instead of the above compound, for example, the following compounds of the Formula (Ia) can be produced:

-4- (4-chlorophenyl) ~ but-3-enyl7-imidazole 1- / ~ 2-hydroxy-4- (4-chlorophenyl) -butyl / -imidazole 1-27 "2-hydroxy-4- (2,4 -dichlorophenyl) -but-3-enyl7-imidazole 1 -jT ~ 2-hydroxy-4- (2,4-dichlorophenyl) -butyl / -imidazole 1- / ~ 2-hydroxy-4- (4-tert.- butylphenyl) -but-3-enyl7-imidazole 1 - / "~ 2-hydroxy-4- (4-tert-butylphenyl) -butyl / -imidazole 1- / ~ 2-hydroxy-4- (4-fluorophenyl) -but-3-enyl7-imidazole 1 - / ~ 2-hydroxy-4- (4-fluorophenyl) -butyl / -imidazole 1- £ ~ 2-hydroxy-4- (2,4-dimethylphenyl) -but-3- enyl7-imidazole and
1 - / ~ 2-hydroxy-4- (2,4-dimethylphenyl) butyl / -i ^mid -azol.

7Q9808 / 1 U8

example 1

A. A mixture of 430 mg of 1 = (2-hydroxy-4-phenylbutyl) -imidazole and 96 mg of sodium hydride (56% dispersion in mineral oil) in 3 ml of dry hexamethylphosphoramide was under nitrogen for 1 hour at room temperature and 1 hour at 45 ° C stirred. After the development was terminated by hydrogen, the solution was cooled in an ice bath and a solution of 430 mg of 2,4-dichlorobenzyl chloride was added dropwise in 2 ml. Hexamethylphosphoramide, while the temperature was kept under 1O ⁰ C. The solution was stirred for 1 hour at room temperature and then for 2 hours at 45 ^° C. and left to stand overnight. The mixture obtained was then poured into water, extracted with ether, the ether extracts were washed with water, dried and evaporated. The oil-like product, X- £ ~ 2- {2, 4-Dichloro-benzyloxy) -4-phenylbutyl7 ~ iniidazol was then transformed by treatment of an ethereal solution with concentrated nitric acid in the nitrate salt, which was recrystallized in the form of colorless flakes of ethyl acetate \ Melting point 121 - 124 ⁰ C.

B. Trans-1 / ^- "2-hydroxy-4-phenylbut-3-enyl7-imidazole (430 mg) in 5 ml of dry tetrahydrofuran was treated with 96 mg of sodium hydride (56% dispersion in mineral oil) under nitrogen with stirring , and the mixture was then heated under reflux for 30 minutes. After cooling in an ice bath, the mixture was stirred with 430 mg of 2,4-trichlorotoluene in 5 ml of tetrahydrofuran for 30 minutes at ⁰ ° C. for 1 hour and treated 25 ⁰ C to reflux overnight the mixture was evaporated to dryness, it \ irurde ether (150 ml) was added and the ether extract was washed with water, and evaporated dried over magnesium sulfate to give trans-1 -. £ ~ 2- (2,4-dichlorobenzyloxy) -4-phenylbut-3 • received iaidazol. the nitrate salt precipitated from ether and was utnkristallisiert from ethyl acetate, mp 133.5 134.5 ⁰ C (foaming).

709808/1148

Example 2

A solution of 1.00 g of 1- (2-hydroxy-4-phenylbutyl) imidazole in 40 ml of dichloromethane was stirred with 1 ml of thionyl chloride and the solution was heated to gentle reflux for 1 hour. By evaporating the solution to 1- (2-chloro-4-phenylbutyl) -imidazole hydrochloride was obtained in the form of a white solid.

The free base for use in the subsequent alkylation step can optionally be obtained by dissolving the hydrochloride in dichloromethane with an excess of aqueous Potassium carbonate solution is shaken, the organic phase is washed with water and dried over magnesium sulfate and evaporated to dryness.

Example 3

600 mg of 1- (2-chloro-4-phenylbutyl) imidazole hydrochloride were used a fully reacted mixture of 1.1 g of 3,4-dichlorobenzyl mercaptan and 400 mg of a 56% sodium hydride dispersion added 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 mixture obtained was washed twice with water and the ethereal solution was dried and evaporated to obtain 1 - / ~ 2- (3,4-dichlorobenzylthio) -4-phenylbutyl7-imidazole in Shape of an oil. This material was made by treating an ethereal solution with oxalic acid in ether to completion the precipitate is converted into the oxalate salt, which is then converted from acetone / ethyl acetate in the form of colorless flakes (660 mg) was recrystallized; Melting point 143.5-146 ° C.

709808/114

A mixture of 600 mg of (2-chloro-4-phenylbutyl) imidazoil 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 1 - / "" 2- (3,4-dichlorophenylthio) -4 ~ phenyibutyl7-imidazOl in the form of an oil. This material was converted to the oxalate salt by treatment with oxalic acid in ether, which was then recrystallized from acetone / ethyl acetate as colorless flakes (850 mg); Melting point 145 - 147 ⁰ C.

The free base was also converted into the nitrate salt by treatment with nitric acid in ether Ethyl acetate was recrystallized; Melting point 99-105 ° C (decomposition); LDcq (oral, acute, mice) > 1000 mg / kg.

Example 5 ■. . ".;

1,2-epoxy-4-phenylbutane (1.48 g) in dry tetrahydrofuran (10 ml) was added to the clear solution, which was obtained by reacting of 50 mg of a 56% sodium hydride dispersion in mineral oil with 2.25 g of 5,4-dichlorobenzyl mercaptan 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 treated with water / water and extracted with ether. The ether extract was dried and evaporated to give a color. - "-. iose oil.

70 9 80 87 1148

The oil obtained above in 30 ml of dichloromethane was treated with 2 ml of thionyl chloride for 30 minutes at room temperature and the solution was evaporated to dryness. The residue was treated with 4 g of imidazole and 15 ml of acetonitrile and dried overnight at room temperature and then stirred for one day at 5O ⁰ C. The solvent was then evaporated and, after 50 ml of water had been added, the residue was extracted with ether. The ether extract was washed with water, dried and evaporated to give 1- / ~~ 2- (3,4-dichlorobenzylthio) -4-phenylbutyl7-imidazole as an oil, which was then further converted to its oxalate salt; Melting point 143.5-146 ° C.

Example 6

According to the procedure 1, 2 or 5 and in the examples. 1,2,3,2,4; or 5 and using equivalent amounts of the appropriate starting materials the following connections can be made. If indicated, the compounds can be converted into the corresponding Acid addition salt are identified in more detail.

1 - £ ~ 2- (3> 4-dichlorobenzylthio) -S-phenylpropyl / - imidazole 1- / ~ 2- (4-chlorophenylthio) -3-phenylpropyl7-imidazole 1 -jT ~ 2- (2,4-dichlorophenoxy) - 3 -phenylpropyl / - imidazole 1 - / "~ 2- (3,4,5-trichlorophenylthio) ^ -phenylpropyl / - imidazole 1 - /""2- (2,4-dichlorobenzylthio) -3- (4-chlorophenyl ) -propyl / -imidazole 1 - £ ~ 2- (4-fluorophenylthio) -3- (4-chlorophenyl) -propyl / -imidazole 1- / ~ 2- (4-tert-butylphenoxy) -3- (4- chlorophenyl) propyl / '- iniidazole 1 - / "2- (3ι4-dichlorophenylthio) -3- (4-chlorophenyl) propylT-imidazole 1 1- £ ~ 2- (2,4-dichlorobenzylthio) -4-phenylbutyl7- imidazole 1- £ ~ 2- (3,4-dichlorobenzyloxy) -4-phenylbutyl) -imidazole • 1- £ "2- (3,4-dichlorophenoxy) ^ -phenylbutyl / - imidazole

709808/1148

1 - / ~ 2- (2,3,4,5,6-pentachlorophenylthio) -4-P] IeHyIbUtYl / -imidazo!

1- / ~ 2- (4-bromobenzylthio) -4-phenylbutyl / -imidazo!

1- £ ~ 2- (4-fluorophenoxy) -4-phenylbutyl7 ~ iniidazole 1 - £ ~ 2- (4-methylphenylthio) ^ - phenylbutylZ-imidazole 1- / ~ 2-cinnamyloxy-4-phenylbutyl7-imidazole

1 - £ "2- (4-chlorophenylthio) -4- (4-chlorophenyl) butyl / -imidazolnitratsalz, melting point 116-119 ⁰ C ■ '.

1- / ~ 2- (4-chlorophenoxy) -4- (4-chlorophenyl) butyl / imidazole

Λ- £ ~ 2- (4-chlorobenzylthio) -4- (4-chlorophenyl) butyl / -imidazoloxalatsalz, melting point 143-144 ⁰ C.

1 "£" 2- (4-chlorobenzyloxy) -4- (4-chlorophenyl) -butyl / -imidazole 1 "£ ~ 2- (2,4-dichlorobenzyloxy) -4- (4-chlorophenyl) -butyl / -imidazole 1 - £ ~ 2- (2,4-dichlorobenzylthio) -4- (4-chlorophenyl) -butyl / -imidazole \ - £ ~ 2- (3,4-dichlorobenzylthio) -4- (4-chlorophenyl) -butylZ- imidazole '

1 - / ~ 2 ~ (3,4-dichlorophenylthio) -4- (4-chlorophenyl) -butyl / -imidazole nitrate salt, melting point 84 - 89 ⁰ C (decomposition)

1 - £ ~ 2- (3,4-dichlorobenzylthio) -4- (4-chlorophenyl) -butyl / -imidazole 1 - / ~ 2- (2,4,5-trichlorophenylthio) -4- (4-chlorophenyl) - butyl / imidazole

1 - / '"2-cinnamyloxy-4- (4-chlorophenyl) -butyl / imidazole

1 - £ ~ 2- (2,4-dichlorophenylthio) -4 _r (4-chlorophenyl) butyl / ■ imidazole nitrate salt, m.p. 113.5 to 115 ⁰ C 1 - £ ~ 2- (4-Chlorcinnamyloxy) -4 - (4-chlorophenyl) -butyl / -imidazole 1 - £ ~ 2- { 4-fluorocinnamylthio) -4- (4-chlorophenyl) -butyl / -imidazole 1 - £ ~ 2- (4-trifluoromethylohenylthio) -4- ( 4-chlorophenyl) butyl / imidazole

Γ £ "2- (4-chloro-3-trifluoromethylphenylthio) -4- (4-chlorophenyl) butyl / imidazole.

1 - / ~ 2- (4-trifluoromethylbenzyloxy) -4- (4-chlorophenyl) -butyl / -imidazole ■

709808/1148

1- £ "2.- (Benzyl thio) -4- (2,4-dichlorophenyl) butyl / imidazole - (4-chlorobenzyloxy) -4- (2,4-dichlorophenyl) butyl / imidazole

1 - £ ~ 2- (2,4 ~ dichlorobenzylthio) -4- (2,4-dichlorophenyl) -butylimidazole

-£ ~ 2- (3,4-dichlorobenzylthio) -4- (2,4-dichlorophenyl) -butyljimidazole

1- £ ~ 2- (4-tert-butylbenzyloxy) -4- (2,4-dichlorophenyl) butyl / imidazole

1 -j / ~ "2-Cinnamyloxy-4- (2,4-dichlorophenyl) -butyl / - imidazole 1 - £" 2. " (4-chloro cinnamyl thio) -4- (2,4-dichlorophenyl) butyl7 -imidazole

1 - £ "2- (4-phenylbutylthio) -4- (2,4-dichlorophenyl) -butyl7 ~ imidazole 1 " £ "2- (4-chlorophenylthio) -4- (4-tert-butylphenyl) -butyl / -imidazole

1- £ ^m 2 ~ (2,4-dichlorobenzyloxy) -4- (4-tert-butylphenyl) -butyl7-imidazole

1- £ ~ 2- (3j 4-dichlorophenylthio) -4- (4-fluorophenyl) -butyl7-imidazole 1- / ~ 2- (2,4-dichlorobenzyloxy) -4- (4-fluorophenyl) -butyl7 ~ i ^mid- azole 1- / ~ ^I 2- (3,4-dichlorobenzylthio) -4- (4-fluorophenyl) -butyl7-imidazole

1- £ "2- (3,4-dichlorobenzylthio) -4- (2,4-dimethylphenyl) -butyl7-imidazole

-£ ~ 2- (4-chlorophenoxy) -4- (2,4-dimethylphenyl) butyl / imidazole

i; rans-1 - £ "2- (3,4-Bichlorphenylthio) -4-phenylbut-3-enyl7-imidazol-oxalate salt, m.p. 171.5 to 175.5 ⁰ C (decomposition)

■ fe; rans-1 - £ ~ 2- (3,4-D..ichlorbenzylthio) -4-phenylbut-3-enyl7 ~ imidazole nitrate salt, melting point 138 - 139 ⁰ C (V ■ foaming)

^ rans-1 - £ 2- (2,4-Dichloro-benzyloxy) -4-phenylbut-3-enyl7-imidazole-nitrate salt, Schmelzpunlct 133.5 to 134.5 ⁰ C (i. 'S-chäumung) ■ 1 / ~ 2- (4-chlorobenzylthio) -4-phenylbut-3-enyl7-imidazole 1 - £ ~ 2- (4-chlorophenylthio) -4-phenylbut-3-enyl7-imidazole

709808 / 1U8

1 - £ ~ 2- (4-chlorophenoxy) ^ - phenylbut-S-eny ^ -imidazole 1 - / "~ 2- (4-bromobenzylthio) -4-p] ienylbut-3-enyl7-iiiiidazole. 1 - £" 2- (4-Fluorophenoxy) -4-phenylbut-3- ⁱ -enyl7-iiiiidazole 1 - / "2- (3 --- P] ienylpropyloxy) - 4-phenylbut - 3-enyl7-imidazöl-1- / "2-Cinnamyloxy-4-phenylbut-3-enyl) -imidazole 1 - £ ~ 2- (4-Chlorcinnamyloxy) ^ - phenyrbut ^ -enyl / -imidazo! ■ l- £ "2-C4-phenylbutylthio) -4-phenylbut-3-enyl7-i ^m id.azole ■ ■■ -

1- ^ ^-1 2- (3,4-dichlorophenylthio ^^) -4- (4-chlorophenyl) -but-3 "enyl7-imidazole

1- / ~ 2- (4-Clilorphenoxy) -4- (4-chlorophenyl) -but-3-enyl7-imidazole 1 - / ^ 2- (2,4,5 - trichlorophenylthio) - 4- (4-chlorophenyl) -but-3- "enyl7-: imidazole. :

- (2,3,4,5,6-Pentachlorophenylthio) -4- (4-chlorophenyl) -but-JTidl

1 ^ 2 [ ^r 2 ~ (Cinnamylthlp) -4 - '(4-cbJLorphenyl) -but-3 ^ enyl7-lniidazole "· Λ-JjZ- (4-chlorocinna-diyloxy) -4- (4-chlorophenyl) imldazole

1 - / ^ 2- (4 - chlorophenylthio) -4- (4-chlorophenyl) imidazole

1 ~ - / ~ 2- (4-chlorobenzylthio) ~ 4- (4-chlorophenyl) -but-3-enyl7-imidazole 1- / ~ 2- (4-chlorobenzylthio) -4- (4-chlorophenyl) but -3-enyl7-imidazole- _; , _: . "

1 ~ £ ^ 2- (2,4-dichlorobenzyloxy) -4- (4-chlorophenyl) -but-3-enyl7-iffiidazole

ΐ- / ~ * 2- (2-, 4-dichlorophenylthio) ^ -phenylbuty ^ -imidazo! - (4-chlorobenzylthio) ^ -phenylbutylj-imidazole

- { 4-chlorobenzylthio-4-phenylbiityl7-iiiii ^< i ^azo l 1 -j / j ~ 2- (4-chlorobenzylthio) -4- (4-fluorophenyl) ■ -bu.tyl.7-imidazole ·

1- £ ~ 2 -; (2; 4-Dich3: örbenzylthio) -4- (4-fluorophenyl) -butyi7-;

1 - £ "2- ( 2, 4-dichlorophenylthio) -4- (4-fluorophenyl) -butyl / - imidazol.- : 70 9808/1 1 ^ 4 8 ·; '

Example 7

The following compounds can be prepared using equivalent amounts of the appropriate starting materials according to the procedure described under experiment 3 or 4 and "" in * -den -Bsplen .. X) 2 ', 3 or "2,4. If indicated, the compounds are described in more detail by converting them into the corresponding acid addition salt *

1 - £ ~ 3- (4-chlorophenylthio) -3- (4-chlorophenyl) -propylj-imidazoloxalatsalz, melting point 108-112 ⁰ C.

1- / ~ "3- (4-chlorobenzylthio) -3- (4-chlorophenyl) -propylj-imidazoloxalatsalz, melting point 115-156 ⁰ C.

1- £ ~ 3- (4-chlorobenzyloxy) -3- (4-chlorophenyl) propyl / imidazole oxalate salt, melting point 105-106 ° C

1 - £ "3- (4-bromo-3-methylphenylthio) -3- (4-chlorophenyl) -propyljimidazol nitrate salt, m.p. 107-108 ⁰ C (decomposition)

1 - £ ~ 3- (4-tert-butylphenylthio) -3- (4-chlorophenyl) propyl7-imidazole oxalate salt, melting point 127.5 - 129 ° C (decomposition)

1- £ "3- (4-fluorophenylthio) -3- (4-chlorophenyl) -propylj-imidazole 1 - £" 3- (4-bromobenzyloxy) -3- (4-chlorophenyl) -propylZ-imidazole 1 ~ jT ~ 3- (2,4-dichlorophenylthio) -3- (4-chlorophenyl) propyl / imidazole

1- £ ~ 3- (3,4-dichlorophenylthio) -3 - {- 4-chlorophenyl) propyl7-imidazole. '* - · * ■' - ''. '■■

1- £ ~ 3- (4-trifluoromethylphenylthio) -3- (4-chlorophenyl) propylZ-imidazole

1 - £ "3- (4-trifluoromethylbenzyloxy) -3- (4-chlorophenyl) propyl7-imidazole '

⁴ ] ^L - £ ~ 3- (4-chloro cinnamyloxy) -3- (4-chlorophenyl) -propylj-imidazole 1 - £ "3- (2,4-dichlorocinnamylthio) -3- (4-chlorophenyl) -propylZ- imldazole

709808/1 * 1 48

1 - / "3- (4-phenylbutyloxy) -3- (4-chlorophenyl) propyl / imidazole

1 - / "3- (4-methylbenzylthio) -3- (2,4-dichlorophenyl) propyl / imidazole nitrate salt, melting point 69.5 - 75 ⁰ C (decomposition)

1 - £ "3- (4-chlorobenzylthio 3- (2,4-dichlorophenyl) propyl / -imidazole-nitrate salt, m.p. 63 to 66.5 ⁰ C (decomposition)

1 - £ ~ 3- (4-chlorophenylthio) -3- (2,4-dichlorophenyl) propyl / -imidazole-nitrate salt, m.p. 123.5 to 125.5 ⁰ C (decomposition)

1- £ ~ 3- (2,4-dichlorophenylthio) -3- (2,4-dichlorophenyl) propyl7 ~ imidazole

-£ ~ 3- (3 j 4-dichlorophenylthio) -3- (2,4-dichlorophenyl) propyl / imidazole

1 - / "3- (4-trifluoromethylphenylthio) -3- (2,4-dichlorophenyl) propyl / imidazole 1 - £ ~ 3- (4-T-rifluoromethylbenzyloxy) -3- (2,4-dichlorophenyl) -propylZ-imidazole

1 - £ ~ 3- (4-1ert-butylphenylthio) -3- (2,4-dichlorophenyl) -propyl7-imidazole -

1 - / "" 3- (4-methylbenzyloxy) -3- (2,4-dichlorophenyl) propyl / imidazole 1- £ "3- (4-chlorocinnamyloxy) -3- (2,4-dichlorophenyl) propyl7 -imidazole

1 - / "3 - (^, 4-dichlorobenzyloxy) -3- (2,4-dichlorophenyl) propyl7-imidazole

1 - £ ~ 3- (2,4,5-trichlorophenylthio) -3- (2,4-dichlorophenyl) propyl7 ~ imidazole 1 - £ ~ 3- (4-phenylbutylthio) -3- (2,4-dichlorophenyl) -propyl / -imidazole 1 - £ ~ 3- (4-chlorobenzyloxy) -3- (2,4-dichlorophenyl) propyl / -imidazole 1 - £ "3- (2,4-dichlorobenzyloxy) -3- (2, 4-dichlorophenyl) propyl / -. Imidazole

1- / T3- (4-chlorophenylthio) -3- (4-tert-butylphenyl) propyl / imidazole ·

709808 / 1H

1-3 " (2,4-dichlorobenzylthio) -3- (4-tert-butylphenyl) propyl7-imidazole

1 - £ "3- (2,4,5-Trichiorphenylthio) -3- (4-fluorophenyl) -propyl7-imidazol-oxalate salt melts at 76 ⁰ C, a final melting point of 99 ⁰ C

1 - £ ~ 3- (4-chlorobenzylthio) -3- (4-fluorophenyl) propyl / - imidazole 1 - £ ~ 3- (4-tert-butylphenylthio) -3- (4-fluorophenyl) propyl / -imidazole

1- £ "3- (4-chlorocinnamyloxy) -3- (4-fluorophenyl) propylZ-imidazole 1- £" 3- (4-chlorocinnamyloxy) -3- (2,4-dimethylphenyl) propyl / imidazole

1- £ ~ 3- (2,4-dichlorobenzylthio) -3- (2,4-dimethylphenyl) propyl7-imidazole

1- £ ~ 3- (4-bromophenylthio) -3- (2,4-dimethylphenyl) propylj-imidazole

1 - / ~ 3- (4-methylbenzylthio) -3- (4-tert.-butylphenyl) propyl.7-imidazole nitrate salt, melting point 132 - 134 ⁰ C (decomposition)

1- / ~ 3-Cinnamyloxy-3- (4-tert-butylphenyl) -propylZ-imidazole 1 - £ "3- (4-chlorophenylthio) ^ - phenylbutylZfimidazole 1 - £"ϊ> - (2,4-dichlorobenzylthio) -4-phenylbutyl7- ^im i ⁽ iazole 1 -f ^ 3- (4-tert-butylphenylthio) -4-phenylbutyl) -imidazole 1 - £ ~ 3- (4-chlorocinnamyloxy) -4-phenylbutyl7-imidazole 1- / ~ 3- (2,4-Dichlorophenylthio) -4- (4-chlorophenyl) -butyl7-imidazole 1 - £ "3- (4-Methylbenzylthio) -4- (4-chlorophenyl) -butyl7-imidazole 1 - £ ~ 3 - (4-Chlorobenzylthio) -4- (4-methylphenyl) -butyl7-imidazole 1 - £ "3- (2,4-dichlorophenoxy) -4- (4-methylphenyl) -butyl7-imidazole 1 - £" 3- ( 4-chlorocinnamyloxy) -4- (4-methylphenyl) -butyl.7- imidazole 1- £ ~ 3- (2,4-dichlorobenzylthio) -5- (4-chlorophenyl) -pentyl7-imidazole

1- £ ~ 3- (4-bromobenzylthio) -5- (4-chlorophenyl) -p ent3rl7-imidazole 1- £ ~ 3- (4-chlorobenzylthio) -5- (4-chlorophenyl) pentyl ^ -imidazole

709808/1148

\ ■ - *: ^ - ,. · ■■ ' ^ 45 -' ■■■■■ - .-- ■ ■. ". ■. ■■, ■.

1- £ ~ 3- (2,4,5-TricMorphenylthio) -5- (4-chloroph.enyl) -pentylj-

o) -5- (4-chlorophenyl) - pentyi7- ^!

imidazo! ■. '

propyltrimidazole., _;; : ■■, "...--." , ..-.-. . "- (3,4-Dichlorbenzyltiiio) -3- (2-trifluoromethylphenyl) - ■ '

ylj; liio) ^ - 3- (2j4-dibroraphenyl) -propyl7-imidazpl \ ■

1- £ ~ 3 ^ 4-Chlorptienyithio) -3- (2,4-difluoroplienyl) -propyljimidazole :

1- £ ~ 3-t { 4-fluorophe2iylthio) -3- (2,4-dichlorophenyl) -propylj-; imidazole

1- / ~ "3,4- (Fluorbeazylthlo) -3- (.2,4-di.ehlorphenyl) -propyl / -iraidazole.

709808/114 8

Example 8 - '"

According to the process described under process 4 and in Examples. 1, 2, 3 or 24 and using equivalent amounts of the corresponding starting materials, the following _; Connections are made. If indicated, the compounds can be further characterized by conversion into the corresponding acid addition salts. ■ - · -

1 - £ ~ k- (3,4-dichlorophenylthio) -4- (4-chlorophenyl) butyl / imidazole nitrate salt, melting point 100 - 104.5 ⁰ Cj oxalate salt, melting point 118 - 123 ⁰ C (foaming)

1 - / "" 4- (3,4-dichlorophenoxy) -4- (4-chlorophenyl) -butyl / -imidazole-. nitrate salt, melting point 128-130.5 ° C

1- / ~ 4- (4-chlorobenzylthio) -4- (4-chlorophenyl) -butyl / -imidazolnitrate salt, melting point 123 - 125 ⁰ C (foaming)

1- / ~ 4- (2,4-dichlorobenzyloxy) -4- (4-chlorophenyl) butyl / imidazole nitrate salt, melting point 91 - 114 ⁰ C 1 - / "4- (3 j 4-dichlorobenzyloxy-4- (4-chlorophenyl) -butyl7-imidazole 1 - / "4- (4-bromobenzylthio) -4- (4-chlorophenyl) -butyl / -imidazole 1 - /""4- (4-fluorophenylthio) -4- (4 -chlorophenyl) -butyl7-l ^m icl? 3. ^zo l 1 ~ / ~ "4- (4-methylbenzyloxy) -4- (4-chlorophenyl) -butyl7-imidazole · 1 - £ ~ k- (4-chlorophenyl thio ) -4- (2,4-dichlorophenyl) -butyl7-imidazole oxalate salt, m.p. 69-75 ° C (foaming) 1 - / "4- (4-methylphenylthio) -4- (2,4-dichlorophenyl) butyl7 -imidazole

1 - / "" "4- (4-chlorobenzylthio) -4- (2,4-dichlorophenyl) -butylZ-imidazole oxalate salt, Melting point 62.5 - 65 ° C (foaming)

1- / ~ 4-Benzylthio-4- (2,4-dichlorophenyl) -butyl / -imidazole 1r- / ~ "4- (2,4-dichlorobenzyloxy) -4- (2,4-dichlorophenyl) butyl / imidazole

1 - / "4- (4-chlorobenzyloxy) -4- (2,4-dichlorophenyl) butyl / -imidazolni stepped salt, melts at 98.5 ⁰ C; definitive .g + r ^?

709808/1148

- (4-Phenylbutylthio) -4- (2,4-dichlorophenyl) -butyljimidazole

1- £ "k- (4-Fluorobenzylthio) -4- (2,4-dichlorophenyl) -butyl7-imidazole oxalate salt, melting point 95-101.5 ° C

- (4-tert-Butylphenyithio) -4- (4-fluorophenyl) -butyl7-imidazole

1 -j ["h- (3 s 4-dichlorophenylthio) -4- (4-fluorophenyl) butyl / imidazole

"(4-tert-Butylbenzyloxy) -4- (4-fluorophenyl) -butyl7-imidazol-oxalate salt, Sclimelzpunkt 49.5 to 51 ⁰ C.

1 - _j / ~ 4-Phenylprop3'-lthio-4- (4-f luorphenyl) -butylj-imidazoloxalatsalz, S _c hmelzpunlit 97 "99 ⁰ C. -

1- / ~ ^ phenylthio-4- (4-tert-butylphenyl) -butylj-imidazolnitratsalz, melting point 121.5 to 123.5 ⁰ C (decomposition) 1 -jt "4- (4-chlorophenylthio) -4- (4-tert-butylphenyl) butyl / imidazole

1 - / "4-2,4-dichlorobenzylthio) -4- (4-tert-butylphenyl) -butyl7-imidazole

1 - / "4- (4-fluorophenylthio) -4- (2,4-dimethylphenyl) -butyl7-imidazole

1 - / 7 "4-cinnamyloxy-4- (2,4-dimethylphenyl) -butyl7-imidazole

1 - / ~ 4- (4-methylbenzylthio) -4- (4-bromophenyl) -butyl ^ -imidazole nitrate salt, melting point 93 - 95 ⁰ C (decomposition)

- (4-bromobenzyloxy) -4- (4-bromophenyl) -butylj-imidazole-

nitrate salt, melting point 117 to 123.5 ⁰ C.

- (4-Chloip'henylthio) -5-phenylpentyl7-imidazole 1- / ~ 4- (2,4-dichlorobenzylthio) -5-phenylpenty] _7-imidazole - (4-tert-butylphenoxy) -5-phenylpentyl7-imidazole - (4-chlorocinnamyloxy) -S-phenylpentyl / -imidazole - (2,4 ~ dichlorophenylthio) -5- (4-chlorophenyl) -pentyl7-

7 0 9 80 8 / .1U

imidazole

" (4-Methylbenzylthio) -5- (4-chlorophenyl) -pentyl7 ~ imidazole 1 - / ~ 4- (2,4-dichlorobenzylthio) -6- (4-chlorophenyl) -hexylj-imidazole 1 - / ~ 4- ( 4-bromobenzylthio) -6- (4-chlorophenyl) -hexy.17-imid.azole 1 - / "" 4- (4-chlorobenzylthio) -6- (4-chlorophenyl) -hexylZ-imidazole

1- £ "k- (2,4,5-trichlorophenylthio) -6- (4-chlorophenyl) -hexyl / -imidazole

1- £ ~ k- (4-tert-Butylbenzylthio) -6- (4-chlorophenyl) -hexyl7-iinidazole

1- £ ~ k- (4-Trifluorme thy lphenylthio) -6- (4-chlorophenyl) -hexyl / -iraidazole

1- £ "k- (4-Trifluoromethylbenzyloxy) -6- (4-chlorophenyl) -hexyl / -imidazole

1 - / ~ 6- (2,4-dichlorobenzylthio) -o-phenylhexyl ^ -imidazole 1 - £ "6- (4-chlorobenzylthio) -e-phenylhexy ^ -imidazole 1 - £ ~ 6- (4-methylphenylthio) - o-phenylhexylT'-imidazole 1- / "" 6- (4-chlorophenylthio) -e-phenylhexyl ^ -iniidazole 1- £ ~ 6- (4-chlorobenzyloxy) -6- (4-chlorophenyl) -hexyl7-iniidazole 1 - / ~ 6-Benzylthio-6- (4-chlorophenyl) -hexyl7-imidazole 1 - £ ~ 6- (4-fluorobenzylthio) -6- (4-chlorophenyl) -hexyl ^ -ifflidazole 1 - / "" 6- ( 3,4-dichlorobenzyloxy) -6- (4-chlorophenyl) -hexy ^ -imidazole 1 - / ~ 6-cinnamyloxy-6- (4-chlorophenyl) -hexy ^ -iniidazole 1 - / "" 6- (2,4 -Dichlorbenzyloxy) -7- (4-chlorophenyl) -hepty ^ -imidazole 1 - £ ~ 6- (2,4-dichlorobenzylthio) -S-phenyloctylJ'-imidazole 1 - £ "6- (4-chlorobenzyloxy) -lO- phenyldecy ^ -imidazole 1- (9-Benzyloxy-9-phenylnonyl) -imidazole 1- £ ~ 9- (4-fluorophenylthio) -9-phenylnonyl7-imidazole 1- / 9-phenoxy-9- (4-chlorophenyl) -nony .17-imidazole 1- £ "9- (2,4,5-trichlorobenzylthio) -9- (4-chlorophenyl) -nonyl7-imidazole

709808/1148

■■ "■ - 49 -

1-2f "9-Cinnamyloxy-9- (4-chlorophenyl.) -NonyiJT'-imidazole 1- £ ~ 9- (2,4-Dichlorbenzyloxy) -10- (4-chlorophenyl) -decyl / -imidazoi.

^ - ■ £ "9" (2,4-dichlorobenzylthio) -11-phenylundecyl / -imidazo! 1 ~ / ~~ 9- (4-chlorobenzyloxy) -13-phenyltridecyl7-imidazole 1 ^ "" 4- (4-fluorophenylthio) -4- (2,4-dichlorophenyl) -butyl / -imidazole.

709808/114

Example 9

Nitric acid (70%; density = 1.42) was added dropwise to a stirred solution of 2.0 g of 1- / ~ 2- (2,4-dichlorobenzyloxy) -4-phenylbutyl7-imidazole in 30 ml of anhydrous ether until the precipitation was complete. The product was filtered, washed with ether, air dried and recrystallized from ethyl acetate to give 1- / ~~ 2- (2,4-Dichloro-benzyloxy) -4-phenylbutyl7-imidazolnitrat, melting point 121-124 ⁰ C.

In the same way, all compounds of the formula (I) present in base form can be converted into the corresponding antimicrobial ones Acid addition salts are converted by them with the corresponding 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 will.

Example 10

1- / ~ 2- (2,4-dichlorobenzyloxy) -4-phenylbutyl7-imidazole nitrate (2.0 g) in 100 ml of dichloromethane was shaken with an excess of dilute potassium carbonate solution until the salt was complete was resolved. The organic phase was then separated off, washed twice with water and dried over magnesium sulfate and evaporated to give 1 - / "" 2- (2,4-dichlorobenzyloxy) -4-phenylbuty] -7-imidazole in the form of an oil.

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

709808/1 U8

• - 51 -

Example 11

This example describes the preparation of representative pharmaceutical compositions which are used for
Fighting fungi, bacteria and protozoa can be used and an active ingredient compound, such as a salt of
1 - / 7 * 2- (3,4-dichlorophenylthio) -4-phenylbuty] -7-imidazole.

A. Compositions for external use

Active ingredient compound 0.2-2 Chip 60 2 Tween 60 2 mineral oil 5 vaseline 10 Methyl parabens 0.15 Propyl paraben 0.05 BHA (butylated hydroxyanisole) 0.01 water to 100

All of the above components, with the exception of water,
are combined and heated ^{to 6O 0 C with stirring.}
Then a sufficient amount of water at a temperature of 6O ⁰ C is added with vigorous stirring to 100 g of a
cream-like composition, which is then cooled to room temperature.

B. Composition for intravenous administration

Active ingredient compound 0.5g

Propylene glycol 20.0 g

, Polyethylene glycol 400 20.0 g

Tween 80 1.0g

0.9 saline solution to 100 ml

7.0 98 08/1 14 8

■ - 52 -

The active ingredient is dissolved in propylene glycol, polyethylene glycol and Tween 80. Then a sufficient amount of one is used 0.9% saline solution was added with stirring to obtain 100 ml of the solution for intravenous administration, the then filtered through a 0.2 micron membrane filter and under under sterile conditions.

C. Composition for Oral Administration

Parts by weight

Active ingredient compound 200

Magnesium stearate 3

Strength 30

Lactose 116

PVP (polyvinylpyrrolidone) 3

The ingredients listed are combined and granulated using methanol as the solvent. The composition is then dried and tablets are made therefrom using a suitable tabletting machine shaped (with a content of 200 rag active ingredient).

709808/1 U8

Example 12 ■

The fungicide. Effectiveness of certain compounds according to the invention is proven by the following experiments.

The following test organisms were used:

1. Candida albicans (ATCC 10231) - Ca1

2. Candida: albicans (ATCC 14053) - Ca, 2

3; Epidermophvton floecosum (ATCC 15693) - EVf.

4. Trichophvton liientagr ophytes (ATCC 11481) -Lm ...

5. V 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 would you. sometimes treated differently.

The inliubation of all organisms took place in roll drum

was gläsch.

vial containing 5 ml · medium, incubated at 25 ⁰ C

The test compounds were dissolved in 0.6 ml of dimethyl sulfoxide, Dissolve ethanol or sterile distilled water, and these Solutions were added to 30 ml of sterile Sabouraud dextrose broth, around the first mistaken concentration of the compounds to obtain. Samples of the same amount of these basic solutions were made with sterile Sabouraud dextrose broth (DTfco) in a suitable Way thinned. In general, the dilutions were made in geometric series, e.g. 300, 100, 30, 10, 3 and .1 | ig / ml. Approximately 5 ml of each dilution was made sterile Test tubes added (16 mm), and the tubes vAirden vaccinated with 2 drops of vaccine. The glasses were under en conditions due to movement in a rolling drum

incubated at 25 ^{° C.}

70 98087 1 148

To receive the vaccines, yeasts of Sabouraud dextrose agar (Difco) -schrägkultur s in Sabouraud broth Dextrpse were transferred and incubated at 25 ⁰ C overnight. Two drops of 1/10 dilutions of these 16 hour old cultures were used as vaccine for each vial. Dermatophytic fungi were on Sabouraud dextrose agar or malt extract agar neutral - slants at least - were incubated for 4 weeks at 25 ⁰ C, cultured. Approximately 10 ml of 0.7-6 sodium chloride solution was added to the agar surfaces and suspensions were made by scraping the agar surfaces and vortexing the suspensions. These suspensions were filtered through two layers of sterile stainless steel funnels (40 40 mesh and 100 100 mesh). This procedure separated the agar particles and the particles of fungus mycelium on the agar from the spores required for the test. After microscopic examination of the suitability of the vaccine, two drops of these suspensions were added to various dilutions of the test compounds in Sabouraud dextrose broth.

The fungus arrest, i.e. the concentration at which growth was prevented, was determined visually and recorded as the minimum inhibition concentration (MIC) in μg / ml. In the case of the yeasts, the readings were taken after an incubation of 3 days, the stoppages in the case of the Fungi 4 and 5 were determined after incubation for 5 days, and organism 3 became stagnant after an incubation of 7 days determined.

MIC (iig / ml)

1- £ "3- (4-chlorobenzylthio) -3- (2,4-dichlorophenyl) propyl / inlidazole nitrate

Ef - <0.1
Ca2 1

709808/1 H8

1- £ "3- (4-methylbenzylthio) -3- (2,4-dichlorophenyl) propyl / imidazole _nitrate;

Ef .. ■■■ - < 0.1 C. a. 2nd - 1st

1-Z ~ 3- (4-chlorophenylthio) -3- (2,4-dichlorophenyl) propyl / imidazole nitrate

E.f. - 0.3 C.a.2 ■■ - 1

1 - £ ~ 3- (4-tert-butylphenylthio) -3- (4-chlorophenyl) propyl / imidazole oxalate

T.m. - 1 approx. 1 - 10 C.a.2 - 10

1 - £ "3- (4-Bromo-3-methylphenylthio) -3- (4-chlorophenyl) propyl / - imidazole nitrate -

T.m. ' - 1 Approx. 1 - 10 Approx. 2 - 10

1 - £ "2- (4-chlorobenzylthio) -4- (4-chlorophenyl) -butyl / -imidazole oxalate - ._

M..g. 1 3 E.f. 2 - £ 0.1 Approx. 3 Approx. 3

709808/1 U8

1- £ ~ 2- (3,4-dichlorophenylthio) -4- (4-chlorophenyl) butyl / imidazole nitrate

M.g. - 1 3 E.f. - 2 <0 Approx. 3 Approx. 3

1- £ "2- (4-chlorophenylthio) -4- (4-chlorophenyl) butyl / imidazole nitrate

M.g. - 1 3 E.f. - 2 έθ Approx. 3 Approx. 3

1 - £ ~ 2- (3j 4-dichlorophenylthio) ^ - phenylbutylj-imidazole oxalate

Approx. 1 - 3 C a. 2 - 3

- (3 »4-Dichlorophenylthio) -4- (4-chlorophenyl) -butyl7- imidazole nitrate

M.g. - 3 T.m. - 1

1- £ "k- (4-chlorobenzylthio) -4- (4-chlorophenyl) butyl / imidazole nitrate

Approx. 1 - 10

1 - / "" 4- (2,4-dichlorobenzyloxy) -4- (4-chlorophenyl) -butyl7-imidazole nitrate

709808 / 1U8

4- (4-chlorobenzyloxy) -4- (2,4-dichlorophenyl) -buty ^ Z-imidazole nitrate

- (4-chlorobenzylthio) -4- (2,4-dichlorophenyl) -butylj imidazolnitrat

10

1 - / "4- (4-chlorophenylthio) -4- (2,4-dichlorophenyl) -butylZ- imidazole oxalate

10

7 0 9 80 8 / 1U8

Claims (1)

Claims 1. Compound of the formula 1 2 '■ wherein R and R are each phenyl, phenyl straight-chain. lower-alkyl or phenyl-straight-chain-lower-alkenyl or one of these groups in the phenyl ring with one or more substituents from the group: lower alkyl with 1 to about 4 carbon atoms, halogen and trifluoromethyl is substituted; X = oxygen or sulfur; η = one denotes an integer from 1 to about 8, but η does not denote 1 when R = phenyl or substituted phenyl means; . . . . *. - - as well as the antimicrobial acid addition salts thereof. 2. Vprbombination according to claim 1, characterized in that X = sulfur. "'------ 3. \ ^r connection according to claim "Ί," characterized in that X = oxygen. 4. A compound according to claims 1-3, characterized in that h β is 1. "" - ■■ · --- - - - - ----- 5. Connection according to Ahspruch.1-4, characterized in that R = phenethyl, styryl or halogen-substituted phenethyl . ρ ι or styryl and R = phenyl, benzyl, cinnamyl or halogen-substituted phenyl, benzyl or: is cinnamyl. 6. A compound according to claim 5, characterized in that the halogen substitution on r " ¹ = 4-chlorine, 4-bromine, 4-fluorine, • is 2,4-dichloro or 3,4-dichloro. _s -. - ■ 709808 / 1U8 7. A compound according to claim T-6, characterized in that the halogen substitution.am- R ² = 4-chlorine, 4-bromine, 4-fluorine, 2,4-dichloro or 3> 4-dichloro and - if R = substituted Phenylthio means - additionally 2,4,5-trichlor or Is 2,3,4,5,6-pentachlor. 8. 1 - / "" 2- (3J4-dichlorophenylthio) -4-phenylbutyl7-i ^m idazol and the acid addition salts of this. 9.1 - £ ~ 2 ~ (3, 4-dichlorobenzylthio) -4-phenylbutyl7-imidazole and the acid addition salts of this. 10. 1 - £ ~ 2 ~ ( 2,4-dichlorobenzyloxy) - ^ - phenylbutylj-iniidazole and the acid addition salts thereof; 11. 1 - / "2- (4-chlorophenylthio) -4- (4-chlorophenyl) -but-3-enyljimidazole and the acid addition salts of this, 12. 1 - / "" 2- (4-chlorobenzyloxy) -4- (4-chlorophenyl) -but-3-enyl7-imidazole and the acid addition salts thereof. 13. 1- £ ~ 2- (4 ~ chlorobenzylthio) -4- (4-chlorophenyl) -but-3-enyl7-imidazole and the acid addition salts thereof. 14. 1 - / 7 * 2- (2,4-dichlorobenzyloxy) -4- (4-chlorophenyl) -but-3-enyl7 imidazole and the acid addition salts thereof. 15. 1- _j r "2- (4-chlorophenylthio) -4- (4-chlorophenyl) -butyl7-imidazole and the acid addition salts thereof. 16. 1- £ ~ 2 ~ (2,4-dichlorobenzyloxy) -4- (4-chlorophenyl) -butyl7-imidazole and the acid addition salts thereof. 17. h-Z "2- (4-chlorobenzylthio) -4- (4-chlorophenyl) -butyl7-imidazo! and the acid addition salts' of this. 70 9 808 / 1U8 18. 1 - / "2- (3} 4-dichlorophenylthio) -4- (4-chlorophenyl) -butyl7-imidazole and the acid addition salts thereof. 19. 1 - / "2- (4-chlorobenzyloxy) -4- (4-chlorophenyl) -butyl7-imidazole and the acid addition salts thereof. 20. 1 ~ £ "2- (2,4-dichlorophenylthio) -4- (4-chlorophenyl) -butyl7-imidazole and the acid addition salts thereof. 21. 1- / ~ 2- (3,4-dichlorophenylthio) -4- (4-chlorophenyl) -but-3-enyl7-imidazole and the acid addition salts thereof. 22. 1 - £ "2- (3,4-dichlorophenylthio) -4- (4-fluorophenyl) -butyl7-imidazole and the acid addition salts thereof. 23. 1 - / ~ 2- (2,4-dichlorobenzyloxy) -4- (4-fluorophenyl) -butyl7-imidazole and the acid addition salts thereof. 24. 1 - / "2- (3,4-dichlorobenzylthio) -4- (4-fluorophenyl) -butyl7-imidazole and the acid addition salts thereof. 25. A compound according to claims 1-3, characterized in that n '= 2 or 3. 26. A compound according to claim 25, characterized in that 1 2 R = phenyl or halogen-substituted phenyl and R = phenyl, benzyl or halogen-substituted phenyl or Means benzyl. 27. \ ^r connection according to claim 25, characterized in that the halogen substitution'am R = 4-chlorine, 4-bromine, 4-fluo, 2,4-dichloro, 2,4-difluoro or 2,4-dibromine . 28. Compound according to claim 25-27, "characterized in that the halogen substitution irt R = 4-chlorine, 4-bromine, 4-fluorine. 2,4-dichloro- or 3,4-dichloro and - if R ² = substituted phenylthio - is also 2,4,5-trichlor or 2,3,4,5,6-pentachlor. 709808 / 1U8 29. 1> ^ 3- (4-chlorobenzyl ^ imidazpl and the acid addition salts of this. 30. 1 - / ^ 3- (2,4-Diehlorbenzyloxy) -3- (2,4-dichlPrphenyl) -propyl / • imidaz oil and its acid addition salts. 31. 1- ^ 3- (3i4-Dicnlprbenzyloxy imidaz oil and the acid addition salts thereof. 32. 4 - / ^ 5- (i-Chlprb ^ nzylthio) -3- (2,4-dichlorophenyl) -prppylT "-imidazole and the acid addition salts thereof. 33. i- ^ 3- (4-Chlorophenylthio) -3- (2,4-dichlorophenyl) propyl / imidazole and the acid addition salts thereof. 34. 1-2 ^ 4- (3,4-bichlorophenylthio) -4- (4-chlorophenyl)> - butyl7-imidazoil andv the acid addition salts thereof. 35.1 * £ - ~ 4- ■■ (4-Chi öriäenzyltnio) -4- (4-chlorophenyl) and the acid addition salts of this. 36. i- £ ~ 3- (3> 4-dichlorophenylthio) -3- (2,4-dichlorophenyl) -propyljimidazole and the acid addition salts of this » 37. 1- / ~ 4- (2,4-dichlorobenzyloxy) -4- (4-chlorophenyl) -Mty ^ imidakol and the acid addition salts ^ of this. 38. 1- £ ~ k- (3,4-dichlorobenzyloxy) - ^/ + - (4-chlorophenyl) -butyl7-imidazole and the acid addition salts thereof. 39. 1 j-ipi- (4-chlorophenylthio) -4- (2,4-dichlorophenyl) butyl / imidazole and the acid addition salts of this ^ 1- £ "4-C4-chlorobenzylthao) -4- (2,4-dichlorophenyl) -butylZ-imidazole and the acid addition salts thereof. 0 9808/1 U8 41.1 - £ "k- (3,4-dichlorophenylthio) -4- (4-fluorophenyl) -butyl7-imidazole and the acid addition salts of this..: ' 42.1 - £ ~ k- (4-fluorobenzylthio) -4- (2,4-dichlorophenyl) -butyl7-imidazole and the acid addition salts thereof. 43.1 - / "~ 4-Benzylthio-4- (2,4-dichlorophenyl) -butyl7-imidazole and the acid addition salts thereof. 44. 1 - / "4- (2,4-dichlorobenzyloxy) -4- (2,4-dichlorophenyl} -butyl7 imidazole and the acid addition salts of this. · -. 45.1 - / "4- (4-chlorobenzyloxy) -4- (2,4-dichlorophenyl) -butylimidazole and the acid addition salts thereof. 46. Composition for inhibiting the growth of fungi, Bacteria and protozoa, characterized in that they contain an effective amount of a compound of the formula 1 / V ^R "GH- (CH ₂ J _n -NN (D wherein R, R,. X and η have the same meaning as in Have claim 1, ' or an antimicrobial acid addition salt thereof together with a suitable carrier. 47. Composition according to claim 46, which is suitable for pharmaceutical use, characterized in that the Carrier is a pharmaceutically acceptable, non-toxic one «Carrier is. " 48. Composition according to claim 47 for external use, • characterized in that the compound of formula I reduction% in the cooperation ■ is present - in an amount of about 0.1 to 10.0 wt.. 7Q9808 / 1 U8 .49. I-imidazolylacetylmethylene triphenylphosphorane. 50. Process for the preparation of a compound of the formula 1 ■■ ^ R --CH- (GH ₀ ) -NN I 2 \ - / . XR ^{2 X} ' (D 1 2
wherein R, R:, X and η have the same meaning as in claim 1, characterized by having the following stages includes: a. Converting a compound of the formula R -CH- (CH-) -N N . j W OH
. ,. '. . (II) where R and η have the same meaning as above, into an ether by using a base and RY, p
in which R = optionally substituted phenyl straight-chain lower-alkyl or phenyl-straight-chain lower alkenyl and Y = a group which can be split off, is reacted, or b. Converting a compound of the formula R ^ -CH- (CH ₀ ) --U where R, η and Y have the same meaning as above, ■ 709808/1 U8 or an acid addition salt of this into an ether or thioether by treating with a base and 2-22
R OH or R SH, where R = optionally substituted Denotes phenyl, is reacted, or c. Converting a compound of the formula R-CH- (ClI.,) -N N ²ⁿ W where R, η and Y have the same meaning as above, or an acid addition salt thereof into one ρ ρ Thioethers by reacting with a base and R SH, where R ' optionally substituted phenyl straight-chain lower-alkyl or phenyl-straight-chain lower alkenyl is implemented, or d. Reacting a compound of the formula . ■ R ¹ -CH-CH_-SR ² uird / odej? R ³ -CH-CH ₀ -Y ι 2 ι J. where R = optionally substituted phenyl-straight-chain-lower-alkyl and R = optionally substituted phenyl, phenyl-straight-chain-lower-alkyl or phenyl-straight-chain-lower-alkenyl and Y is the same as above, with imidazole, or e *. Hydrogenating a compound of the formula VC -CH- (CH ₀ ) -N ·· I 2 ¹ X-R 709808 / 1U8 r : - 2623492 - ■■ .- ■ "■■■ ·." ■ - "" - or an acid addition salt thereof, wherein R and R are identical to the radicals R and R defined for the formula (I), but where R and / or R contain unsaturated aliphatic olefinic bonds, and f. optionally converting a free base into an acid addition salt thereof, or ■ "■" "■ - ■ - ig. optionally converting an acid addition salt into the corresponding free base. \ 08/1148