DD299176A5 - SUBSTITUTED AMINOALKOXYBENZOLE DERIVATIVES - Google Patents

Abstract

The compounds of formula I, wherein R 1 and R 2 are each hydrogen, lower alkyl or lower alkenyl or together straight-chain alkylene having 2 to 4 carbon atoms, R 3 is hydrogen, halogen or lower alkyl, Q is alkylene or alkenylene having 4 to 11 carbon atoms and at least 4 carbon atoms between the two free valencies and Y and Y 'each represent a direct bond or the group CH 2, CH 2 CH 2, CHCH or CC, the group R 1 R 2 NQO is attached to the 3- or 4-position of the ring designated A and the symbol R denotes z the ring is unsubstituted or mono- or polysubstituted by halogen, trifluoromethyl, cyano, nitro, lower alkyl and / or lower alkoxy, and their pharmaceutically acceptable acid addition salts can be used to control or prevent fungal infections, in particular topical or systemic infections caused by pathogenic Caused by fungi, and used in the preparation of antifungal agents. Not only do the compounds of Formula I possess a pronounced antifungal effect, but they also exhibit synergistic effects in combination with other known antifungal agents which inhibit sterol biosynthesis, such as ketoconazole and terbinafine. Formula I

Description

The present invention relates to the use of compounds of the general formula

Y-CO-Y!

wherein R ¹ and R ^{2 are} each hydrogen, lower alkyl or lower alkenyl or together straight-chain alkylene having 2 to 4 carbon atoms, R ^{3 is} hydrogen, halogen or lower alkyl, Q is alkylene or alkenylene having 4 to 11 carbon atoms and at least 4 carbon atoms between the two free Valencies and Y and Y 'are each a direct bond or the group -CH ₂ -, -CH ₂ CH ₂ -, -CH = CH- or-C = C-, the group R ¹ R ² NQO- to the 3- or 4-position of the ring designated A and the symbol R means that the ring is unsubstituted or mono- or polysubstituted by halogen, trifluoromethyl, cyano, nitro, lower alkyl and / or lower alkoxy, and their pharmaceutically acceptable acid addition salts for controlling or preventing fungal infections, in particular topical or systemic infections caused by pathogenic fungi, and for the production of antifungal agents. Not only do the compounds of formula I possess a pronounced antifungal effect, they also show synergistic effects in combination with other known antifungal agents which inhibit sterol biosynthesis, such as ketoconazole and terbinafine.

In a specific aspect, the present invention relates to the use of 4- [4- (dimethylamino) butyl) oxy] benzophenone for the purposes just mentioned

 Further objects of the present invention are compounds of the general formula

Ν-Q - 0-4- A | [ \ ' υ la

* SV

R ³

wherein Q 'denotes alkylene having 5 to 11 carbon atoms and at least 5 carbon atoms between the two free valencies or alkenyls having 4 to 11 carbon atoms and at least 4 carbon atoms between the two free valencies, and R ¹ , R ² , R ³ , R, A, Y and Y 'have the above meaning, and their pharmaceutically acceptable acid addition salts for use as therapeutic agents, in particular as antifungal agents, corresponding drugs based on these compounds of formula Ia and, if Y and Y' are not simultaneously a direct bond, when Q 'is alkylene having 5 carbon atoms and R ¹ and R ^{2 are} simultaneously lower alkyl having more than 2 carbon atoms, the compounds of formula Ia as such, their preparation and intermediates for their preparation.

Compounds of the formula I in which Q is unbranched alkylene having 4 carbon atoms belong to a class of substances known per se. In U.S. Patent No. 3,864,501, such compounds are described as agents for improving the coloration of fruits and vegetables. In U.S. Patent No. 3,312,696, such compounds are described as coronary dilatants. European Patent Publication No. 115,080 describes such compounds as intermediates for the production of drugs against alcohol intoxication.

Compounds of the formula I in which Y and Y'je are a direct bond, R ¹ and R ² each represent lower alkyl having more than 2 carbon atoms and Q is unbranched alkylene having 5 carbon atoms, likewise belong to a class of substances known per se. European Patent Publication No. 114,410 describes such compounds as intermediates for the preparation of drugs against alcohol intoxication.

The term "lower" refers to radicals and compounds having at most seven, preferably at most four, carbon atoms The term "alkyl" denotes straight-chain or branched, saturated hydrocarbon radicals, such as methyl, ethyl, propyl, isopropyl and tert-butyl. The term "alkenyl" denotes straight-chain or branched hydrocarbon radicals having an olefinic double bond, such as allyl and 2-butenyl The term "alkoxy" denotes alkyl groups bonded via an oxygen atom, such as methoxy and ethoxy. The term "alkylene" denotes straight-chain or branched, saturated hydrocarbon radicals having two free valencies, such as dimethylene, trimethylene or tetramethylene The term "alkenylene" denotes straight-chain or branched hydrocarbon radicals having at least one olefinic double bond and two free valencies, such as 2-butene-1 , 4-diyl. The term "halogen" refers to the four forms fluorine, chlorine,

Bromine and iodine.

The term "leaving group" used below preferably denotes halogen atoms, in particular chlorine, bromine and iodine, and lower alkyl and arylsulfonyloxy groups, such as Mothylsulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy and

p-chlorobenzenesulfonyloxy.

R ¹ and R ² are preferably each C ^ -Alky), C ^ i-alkenyl or together are C ^ ₃ alkylene. Q 'is preferably straight-chain alkylene having 5 to 7 carbon atoms. The group R ¹ R ² N-CT-O- is preferably attached to the 4-position of the ring designated A. Y is preferably a direct bond or the group -CH ₂ -, in particular a direct bond. Y 'preferably denotes a direct bond or the group -CHy ₁ -CHjCH ₂ -OdBr-CH = CH-, in particular a direct bond or the GrUpPe-CH ₂ -. The symbol R preferably means that the ring is unsubstituted or substituted by

Substituted halogen, nitro and / or lower alkyl, preferably mono- or disubstituted.

In the context of the present invention, particularly preferred new compounds of the formula Ia are:

4-l (6- (dimethylamino) hexyl) oxy] -2-phenylacetophenone, 4 - [(6- (dimethylamino) hexyl) oxy) benzophenone, 4 '- [(6- (diethylamino) hexyl) oxyl-3-phenylpropiophenone '4'-l (6- (dimethylamino) hexyl) oxy] -3-phenylpropiophenone, (EM'-l-IDimethylaminohexylloxyl-S-phenylacrylophenone, 4 - [(6-dimethylamino) hexyl) oxylbenzophenone, 4 - [(6- (Dimethylamino) hexyl) oxy] -4'-fluorobenzophenone, 4 - [(6- (1-Acetidinyl) hexyl) oxy] benzophenone, 4 - [(6- (1-Pyrrolidinyl) hexyl) oxy) benzophenone, 2- | 4- [(6- (dimethylamino) hexyl oxy] phenyl] acetophenone, 4 - [(7- (dimethylamino) heptyl) oxy] benzophenone, 4 - [(5- (dimethylamino) pentyl) oxy] benzophenone, 4 - ([6 - (allylmethylamino) hexyl] oxyl-2-phenylacetophenone, 4 - [(6- (allylmethylamino) hexyl] oxy] -4'-fluorobenzophenone, trans-4 - [[4- (allylmethylamino) -2-butenyl] oxy] benzophenone , 4 - [[6- (Allylmethylamino) hexyl] oxy] -3-methylbenzophenone, trans-4- [4- (allylmethylamino) -2-butenylloxy] -2 ', 4'-dichlorobenzophenone, 4- | (Allylmethylamino) hexyl] oxyl-4'-nitrobenzophenone and 4 - [[6- (allylmethylamino) hexyl] oxyl-3-chloro-benzophene on.

The novel compounds of the formula Ia and their pharmaceutically acceptable acid addition salts can be prepared according to the invention by a) a compound of the general formula

, Y-CO-Y X-Q'-O

wherein X is a leaving group, and A, Q ', Y, Y', R ³ and R have the above meaning, with an amine of the general formula HNR ¹ R ² , wherein R ¹ and R ^{2 have the} above meaning, or b ) a compound of the general formula

wherein A, R ¹ , R ² , R ³ , Q ', Y, Y' and R have the above meaning oxidized, or c) a compound of the general formula

Y-COOR ¹

wherein R 'is lower alkyl, and A, R ¹ , R ² , R ³ , Q' and Y have the above meaning, with a compound of the general formula

Μ-Υ ¹ .

wherein M is -MgCI, -MgBr, -MgJ or Li, and Y 'and R have the above meaning, or d) a compound of the general formula

Y-COOH

Vl

wherein A, R ¹ , R ² , R ³ , Q 'and Y have the above meaning, in the form of a reactive derivative in the presence of a Lewis acid with a compound of the general formula

VII

wherein R has the above meaning, or e) a compound of the general formula

Y-CO-CH3

VIII

wherein A, R ¹ , R *, R ³ , Q 'and Y have the above meaning, in the presence of a base with a compound of the general formula

IX

wherein R has the above meaning, or f) a compound of the general formula

wherein A, R ¹ , R ² , R ³ , Q ', Y and R have the above meaning hydrogenated, or g) a compound of the general formula

wherein A, R, R ³ , Y and Y 'have the above meaning, in the presence of triphenylphosphine and a Azodicarbonsäuredi (lower alkyl ester) with a compound of general formula

R ¹ R ² N-CT-OH

xl

wherein R ¹ , R ² and Q 'have the above meaning, and,

h) if desired, converting a compound of formula Ia obtained into a pharmaceutically acceptable acid addition salt. The reaction of a compound of the formula II with an amine of the formula HNR ¹ R ² according to process variant a) can be carried out by methods known per se and familiar to any person skilled in the art. The reaction is preferably carried out as an acid-binding agent in a temperature range of about ⁰ ° C to about 15O ⁰ C in a polar solvent and in the presence of a base. Suitable solvents are, for example, lower alcohols, such as methanol and ethanol, and lower dialkyl ketones, such as acetone.

Suitable bases are, for example, excess amine of the formula HNR ¹ R ² , tertiary amines, such as triethylamine, and inorganic bases, such as alkali metal carbonates, hydroxides and alcoholates.

The oxidation of a compound of the formol III according to process variant b) can be carried out by methods known per se and familiar to any person skilled in the art. The reaction is preferably carried out in an inert solvent and in the presence of an oxidizing agent in a temperature range of about -80 ° C to about room temperature. Suitable solvents are, for example, chlorinated, lower hydrocarbons, such as methylene chloride and chloroform. Suitable oxidizing agents are, for example, manganese dioxide or mixtures of dimethyl sulfoxide with oxalyl chloride, dicyclohexylcarbodiimide or acetic anhydride and a tertiary amine, such as triethylamine.

The reaction of a compound of the formula IV with a compound of the formula V according to process variant c) can be carried out by methods known per se and familiar to any person skilled in the art. The reaction is preferably carried out in an inert solvent and in a temperature range of about -80 ° C to about room temperature. Suitable solvents are, for example, open-chain and cyclic ethers, such as diethyl ether, methyl-t-butyl ether and tetrahydrofuran, and mixtures thereof.

The reaction of a reactive derivative of a compound of the formula VI with a compound of the formula VII according to process variant d) can be carried out by methods known per se and familiar to any person skilled in the art. The reaction is preferably carried out in an inert solvent and in the presence of a Lewis acid in a temperature range of about ⁰ ° C to about 100 ⁰ C. Examples of suitable solvents are halogenated lower hydrocarbons, such as methylene chloride, chloroform and ethylene chloride, nitrobenzene, carbon disulfide and excess compound of the formula VII. The Lewis acid used is preferably aluminum chloride. Suitable reactive derivatives of compounds of the formula VI are, for example, the corresponding carboxylic acid chlorides. The reaction of a compound of the formula VIII with a compound of the formula IX in the presence of a base according to process variant e) can be carried out by methods known per se and familiar to any person skilled in the art. The reaction is preferably carried out in a polar solvent and in a temperature range from about 0 ° C to about 6O ⁰ C. Suitable solvents are, for example, lower alcohols, such as methanol and ethanol, and mixtures thereof with water. The bases used are preferably alkali metal carbonates and hydroxides, such as potassium carbonate and sodium hydroxide.

The hydrogenation of a compound of formula Γ according to process variant f) can be carried out by methods known per se and familiar to any person skilled in the art. The reaction is preferably conducted in a polar solvent with elemental hydrogen in the presence of a suitable hydrogenation catalyst and in a temperature range of from about ⁰ ° C to about room temperature. Suitable solvents are, for example, lower alcohols, such as methanol and ethanol. Suitable catalysts are, for example, palladium or platinum on carbon, platinum oxide or Raney nickel. The reaction of a compound of the formula X with a compound of the formula XI according to process variant g) is likewise a known method, namely the so-called Mitsunobu coupling. It is preferably in an inert organic solvent and in a temperature range of about ^{0 0} C to the boiling temperature of the reaction. performed. Suitable solvents are, for example, chlorinated, lower hydrocarbons, such as methylene chloride and chloroform, and open-chain and cyclic ethers, such as diethyl ether, methyl-t-butyl ether and tetrahydrofuran, and mixtures thereof.

The preparation of pharmaceutically acceptable acid addition salts of compounds of the formula Ia according to process variant h) can be carried out by methods known per se and familiar to any person skilled in the art. In this case, salts with pharmaceutically acceptable inorganic and organic acids come into consideration. Preferred acid addition salts are the hydrochlorides, hydrobromides, sulfates, nitrates, citrates, acetates. Succinates, fumarates, methanesulfonates and the p-toluenesulfonates.

The known compounds of the formula I and their pharmaceutically acceptable acid addition salts can also be prepared according to the above processes a) -h). The corresponding starting materials can be prepared as described below for the starting materials for the novel compounds of the formula Ia.

The compounds of the formulas II, III, IV, VI and VIII used as starting materials are novel and likewise the subject of the present invention. They can be prepared, for example, according to the following Reaction Schemes I-IV and the following descriptions of the various reactions. The other compounds used as starting materials belong to si Ji known classes of substances. In these reaction schemes R ¹ , R ² , R ³ , R, R ', A, M, Q', X, Y and Y 'have the meaning given above for the novel compounds of formula Ia or their preparation.

Reaction scheme I

Reaction scheme II

^ Y-CHO

Ν-Q'-OH

XI

Reaction B

XIV

Reaction C

Y-CHOH-Y '

Reaction B

XI

-Y-COOR '

IV

Reaction D.

Reaction scheme IV

Y-CO-CH3

, N-Q'-O

VI

Y-COOH

Reaction B

Y-C0-CH3

XI

VIII

Reaction A

This reaction can be carried out according to known per se and familiar to any person skilled in methods and is preferably carried out in a polar solvent and in the presence of a base in a temperature range of about ⁰ ° C to about 15O ⁰ C. Suitable solvents are, for example, lower alcohols, such as methanol and ethanol, and lower dialkyl ketones, such as acetone. Suitable bases include, for example, alkali metal carbonates, hydroxides, alcoholates and hydrides. However, the reaction A can also be carried out in a two-phase system in the presence of a phase transfer catalyst, for example a quaternary ammonium salt. The aqueous phase used is preferably an aqueous liquor, such as sodium hydroxide solution, and as the organic phase, a halogenated lower hydrocarbon, such as methylene chloride, or an aromatic hydrocarbon, such as toluene. The compound of formula XII is preferably used in excess, preferably using 2 to 4 molar equivalents of the compound of formula XII.

Reaction B

This reaction is the Mitsunobu coupling described above in connection with process variant g). It is preferably carried out in an inert organic solvent and in a temperature range from about ⁰ ° C. to the boiling point of the reaction mixture. Suitable solvents are, for example, chlorinated, lower hydrocarbons, such as methylene chloride and chloroform, and open-chain and cyclic ethers, such as diethyl ether, methyl-t-butyl ether and tetrahydrofuran, urine mixtures thereof.

Reaction C

The reaction of a compound of the formula XIV with a compound of the formula V can be carried out by methods known per se and familiar to any person skilled in the art. The reaction is preferably carried out in an inert solvent and in a temperature range of about -80 ° C to about room temperature. Suitable solvents are, for example, open-chain and cyclic ethers, such as diethyl ether, methyl-t-butyl ether and tetrahydrofuran, and mixtures

from that.

Reaction D

This reaction is a hydrolysis. This can be carried out by methods known per se and familiar to any person skilled in the art and is preferably carried out by treatment with an alkali metal hydroxide, such as sodium and potassium hydroxide, or with a mineral acid, such as hydrochloric and hydrobromic acid, in a polar solvent and in

a temperature range of about O ⁰ C to about 100 ⁰ C performed. Suitable solvents are, for example, mixtures of lower alcohols, such as methanol and ethanol, and water-miscible open-chain and cyclic ethers, such as tetrahydrofuran, with water.

As already mentioned, the compounds of the formula I and their pharmaceutically acceptable acid addition salts have valuable antifungal properties. They are active against a variety of pathogenic fungi causing topical and systemic infections, such as Candida albicans and Histoplasma capsulatum. The 2,3-epoxysqualene-lanosterol cyclase, an enzyme involved in the sterol biosynthesis of the eucaryotic cell, is an essential enzyme for the fungi. So z. A S. cerevisiae strain in which this enzyme is not viable (F.Karst & F. Lacroute, Molec. Gon. Genet., 154, 269 [19771]. The inhibitory effect of the compounds of the formula I on the abovementioned enzyme from C. albicans was taken as a measure of the antifungal activity. The inhibition can be measured, for example, by the method described below.

Determination of the IC50 value for the inhibition of the 2,3-epoxysqualene-lanosterol cyclase of Candida albicans

The cells of a culture of Candida albicans at the end of the logarithmic growth phase are collected and supplemented with 10 mM phosphate buffer (pH = 6.9), digestion buffer and 50 mM phosphate buffer (pH = 7.4) containing 1M mannitol and 5 mM

DTT contains, washed.

1, Og of these cells are slurried in 5 ml of digestion buffer, treated with 1 mg Zymolase lOOT (Seikagaku Kogyo, Japan) and 12.5μΙ ß-mercaptoethanol and incubated for 30 minutes at 30 ⁰ C. The resulting protoplasts are isolated by centrifugation (10 minutes at 2 500 g) and then by adding 2 ml 10OmM phosphate buffer; (pH - 6.9) burst. Re-centrifugation (10 minutes at 10,000 g) gives a cell-free extract (CFE) as a supernatant.

This is diluted to 10 mg protein per ml and the pH is brought to 6.9.

The activity of 2,3-epoxysqualene-lanosterol cyclase in CFE is measured by the reaction of ¹⁴ C-squalene epoxide in the presence of n-decylpentaoxyethylene as a detergent. Titration with appropriate amounts of the test substance allows the determination of the IC ₆₀ value (concentration of the test substance which reduces the enzyme activity by half).

The experiment is carried out as follows:

Ultrasonication is used to prepare a 250 μΜ solution of ¹⁴ C-squalene epoxide in 100 mM phosphate buffer (pH = 6.9) with the addition of 1% n-decylpentaoxyethylene. 100 μΙ of this solution is mixed with 20 μΙ ejner solution of the test substance in dimethyl sulfoxide (or 20 μΙ pure dimethyl sulfoxide as a control). After addition of 880 μl of CFE, the well-mixed solution is incubated with shaking for 1 hour at 30 °. Then, by adding 500 μΙ 15%

Potassium hydroxide in 90% ethanol stopped the reaction.

The mixture is extracted twice with 1 ml of η-hexane, the hexane is evaporated and the lipid residue is taken up in 200 μΙ diethyl ether. After thin layer chromatography on silica gel with methylene chloride as the eluent, the

Examined plates with a radioactivity thin-layer scanner.

Under the conditions used, only Lanosterol is found as a radioactive product. Its amount is with

compared to the amount of radioactive lanosterol in the control.

The IC _M values are determined graphically and expressed in μ s of test substance per ml. Table I below contains, for representative representatives of the compound class defined by the formula I, the IC _M values determined in the above experiment,

as well as acute toxicity when administered subcutaneously to mice (DL ₅₀ in mg / kg).

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Table I (continued)

-CH ₃ - (CH) - -CH -CH H - (CH ₂ ) ₁₀ - (4) _ H 2.00 1000-2000 I 21 3 -CII H - (CH ₂ ) ₆ - (4) I IO "<o 22 3 -CH -CH H - (CH ₂ ) ₆ - (4) -CH ₂ - - H 0.34 (O «J O 23 3 -CH .3 H H - (C, ₂ ) ₆ - (4) - H 0.19 24 3 -CH -CH -CH ₃ O) - (CH ₂ ) ₆ - (4) - H 0.30 25 3 -CH -CH H - (CH ₂ ) ₆ - (4) - H 0.19 26 3 -CH J -CII H - (CH ₂ ) ₆ - (4) - 2 _T 3-dimethyl 0.42 27 3 -CH "CH ₃ H - (CH ₂ ) ₆ - (4) - 2,4-dichloro 0.26 28 3 -CH-CH = CH ₀ -CH - (CH ₂ ) ₆ - (4) - 3,5-dichloro 1.50 29 2 2 -CH ₀ -CH = CH ₀ O-CH -Cl (3) - (CH ₂ ) ₆ - (4) - 4-nitro 0.28 30 2 ί -CH ₀ -CH = CH 3 -CH ₃ H - (CH ₂ ) ₆ - (4) - 2,4-dichloro 0.10 31 2 c. -CH ₀ -CH = CH ₀ -CH ₃ H - (CH ₂ ) ₆ - (4) - H 0,044 32 2 2 -CH-CH = CH ₀ -CH ₃ H - (CHJ - (4) Z D -CH ₂ - H 0,035 33 2 2 -CH-CH = CH ₀ -CH ₃ -CH (3) - (CH ₂ ) ₆ - (4) - 4-fluoro 0.031 34 2 2 -CH-CH = CH ₀ -CH ₃ • 3 H - (CH ₂ ) ₆ - (4) - H 0.032 35 ?. ί -CH-CH = CH ₀ -CH ₃ H - (CHJ .- (4) 2 D - 2,3-dimethyl 0.085 36 2 £ -CH ₀ -CH = CH ₀ -CH ₃ H - (CH) - (4) O C. - 2,4-dichloro 0,055 37 2 2 -CH ₀ -CH = CH -CH ₃ H - (CH ₀ ) - (4) Z 0 - 3,5-dichloro 0.34 38 2 ί -CH ₀ -CH = CH ₀ -CH ₃ -Cl (3) - (CH ₂ ) ₆ - (4) - 4-nitro 0.04 39 2 2 -CH ₀ -CH = CH ₀ -CH -ClO) - (CH ₂ ) ₆ - (4) - H 0,025 40 Z ί -CH -CH H -CH-CH = CH-CH ₂ - (4) - - 2,4-dichloro 0.026 41 3 -CH ₃ ό - ^CH 3 H -CH-CHRCH-CH - (4) - - H 0.02 42 -CH ₃ H -CH-CH = CH-CH ₂ - {4) - - 2,4-dichloro 0,007 43 -C ₃ H -CH-CH = CH-CH ₀ -W - H 0.22 44 - 2,4-dichloro 0,065

The already mentioned synergistic effect of the compounds of formula I and their pharmaceutically acceptable acid addition salts in combination with other sterol biosynthesis inhibitors, such as ketoconazole and terbinafine, can be demonstrated, for example, by the agar dilution method. Casiton agar and inocula (10 cells / ml) of cultures of Candida albicans are used for 48 hours. The test substances (TS, compounds of formula I) are applied in concentrations of 80 ~ 1.25mg / ml and the sterol biosynthesis inhibitors (SBH) at concentrations of 20 to 0.001 \ ig / m \, wherein the dilution steps in each case 1: 2 amount. The cultures are each incubated for 2 days at 37 ⁰ C. The minimum inhibitory concentrations (MIC) of the different active substances in the sole and in the combined application are then determined and the fractionated inhibitory concentration (FIC) calculated from the MIC values determined according to the following formula:

FIC =

MIC (TSaIIeIn)

₊ MIC (SBH alone)

MIC (TS in combination) MIC (SBH in combination)

A synergistic effect exists when the FIC is <0.5. The data in Table II below for the compound 6 according to Table I, a representative representative of the class of compounds defined by the formula I, in combination with ketoconazole or terbinafine, representative sterol Biosysnthese inhibitors, prove the synergistic effect.

Tables C. albicans

Connection 6 40 40 ketoconazole Connection 6 ketoconazole 1.25 0,155 2.5 6.25 FIC alone 40 40 in combination 10 0.03 10 1.55 H ₁₂ 40 40 5 0.6 0,155 2.5 6.25 0.062 H ₂₉ 40 40 0.25 10 0.31 5 0.75 0,375 H ₄₂ 40 40 10 1.25 0,155 5 0.55 0.032 B ₆ 5 0,125 B ₄ 5 MlCir ^ g / ml 0.062 Connection 6 Connection 6 terbinafine C. albicans alone in combination terbinafine FIC H ₁₂ 100 0,125 H ₂ 9 6.25 0.5 H ₄₂ 100 0,125 B ₅ 6.25 0.25 B ₄ 12.5 0.25

For the combination with compounds of the formula I suitable sterol biosynthesis inhibitors are, for example, the systemic, antifungal effective azoles of the miconazole type, z. Ketoccnazole, itraconazole and fluccnazole, and the systolic, antifungal, allylamines of the naftifine type, e.g. Naftifine and terbinafine.

The compounds of formula I and their pharmaceutically acceptable acid addition salts can be used as medicaments, e.g. B. in the form of pharmaceutical preparations for enteral, parenteral or topical application, find use. You can, for example, orally, z. B. in the form of tablets, coated tablets, Dragries, hard and soft gelatin capsules, solutions, emulsions or suspensions, rectally, z. In the form of suppositories, parenteral, ζ. In the form of injection solutions or infusion solutions, or topically, e.g. In the form of ointments, creams or ointments. The preparation of the pharmaceutical preparations can be carried out in a manner familiar to any person skilled in the art by combining the described compounds of the formula I and their pharmaceutically acceptable acid addition salts, optionally in combination with other therapeutically valuable substances, for example the mentioned sterol biosynthesis inhibitors, together with suitable non-toxic, inert, therapeutically acceptable solid or liquid carrier materials and optionally the usual pharmaceutical excipients in a galenic dosage form brings. Suitable support materials are both inorganic and organic support materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof can be used as carrier materials for tablets, lacquered carrots, dragoes and hard gelatine capsules. For soft gelatine capsules, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols are suitable as carrier materials (depending on the nature of the active ingredient, however, no carriers are required for soft gelatin capsules). For the preparation of solutions and syrups are suitable as carrier materials, for example, water, polyols, sucrose, invert sugar and glucose. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. For suppositories, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols are suitable as carrier orally. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

The dosage of the compounds of formula I, depending on the pathogenic fungi to be controlled, the age and the individual condition of the patient and the mode of administration, vary within wide limits and, of course, must be adapted to individual circumstances in each individual case. For the prevention and control of topical and systemic infections by pathogenic fungi, for the adult patient in the case of monotherapy a daily dose of from about 0.01 g to about 4 g, in particular from about 0.05 g to about 2 flor is considered. Depending on the dosage, it is expedient to administer the daily dose in several dosage units. In the case of combination therapy, a daily dose of from about 0.01 g to about 2 g, more preferably from about 0.02 to about 1 g of a compound of formula I and from about 0.02 g to about 0.2 g of a sterol biosynthesis Hemmers into consideration.

The pharmaceutical monoprocesses expediently contain 10-1000 mg, preferably 50-500 mg of a compound of the formula I. The combination preparations expediently contain about 10-500 mg, preferably 20-250 mg of a compound of the formula I and about 50-100 mg of a sterol. biosynthesis inhibitor.

The following free games serve to further explain the present invention. They should not limit their scope in any way. All temperatures are given in degrees centigrade.

example 1

a) A mixture of 2.5 g of N, N-dimethyl-6-amino-1-hexanol (Bull. Soc. Chim. France 1975, 2315), 3.4 g of 4-hydroxybonzophenone (Beilstein 8 [III], 1263), 4.5 g of triphenylphosphine and 140 ml of tetrahydrofuran is added slowly at 20 ° with a solution of 2.7 ml of diethyl azodicarboxylate in 15 ml of tetrahydrofuran. After the dropwise addition is stirred for 1 hour at room temperature. The reaction mixture is evaporated in a rotary evaporator and the residue is chromatographed on 400 g of alumina neutral (activity grade III) with hexane / ethyl acetate 7: 3. The resulting yellowish oil is dissolved in 25 ml of ether, followed by the addition of 25 ml of a 10% solution of hydrogen chloride in ether. The precipitated colorless crystals are filtered off with suction, washed with ether and recrystallized from acetone. This gives 1.93 g (31%) of 4 - [(6-dimethylamino) hexyl) oxy] benzophenone hydrochloride, mp. 121 °.

In an analogous manner one obtains:

b) from N, N-dimethyl-6-amino-1-hexanol and 4'-hydroxychalcone (Planta Med. 53, 110 (1987)) the (E) -4'- [6- (dimethylamino) hexyl] oxy] 3-phenylacrylophenone as a colorless solid, mp. 43-46 ° (yield 27%);

c) from N, N-dimethyl-6-amino-1-hexanol and 4'-hydroxy-3-phenylpropiophenone-4'-1- [6- (dimethylamino) hexylloxy] -3-phenylpropiophenone as a slightly yellowish solid, mp. 27-28 ° ( Yield 47%);

d) from N, N-dimethyl-6-amino-1-hexanol and 4-fluoro-4'-hydroxybenzophenone (European Patent Publications Nos. 167240 and 128692) the 4 - [[6- (dimethylamino) hexyl] oxy] -4 '-fluorobenzophenone as a colorless solid, mp. 37-38 ° (yield 52%);

e) from N, N-dimethyl-6-amino-1-hexanol and 2- (4-hydroxyphenyl) aceiophenone (Indian J. Pharmacol., 31, 49 [1969]), the 2- [4 - [[6- (dimethylamino ) hexyl] oxy] phenyl] acetophenone of mp. 53-54 ° (yield 30%);

f) from 6- (diethylamino) -1-hexanol (J. Chem. Soc. 1942, 428) and 4-hydroxybenzophenone, the 4- ([6- (diethylamino) hexyl] oxy] benzophenone as a yellowish oil (yield 30%).

Mass spectrum: Tips and others at m / e 353 (M *, 2%), 338 (2.7%), 199 (3%) and 86 (100%);

g) from 6- (diethylamino) -1-hexanol and 3'-hydroxychalcone (reports 32.1924 [1899]) the (E) -3 '- ([6- (dimethylamino) -hexyl] oxyl.3-phenylacrylophenone as same oil (yield 38%).

Mass spectrum: peaks among others at m / e 351 (M ⁺ , 8%), 131 (4%), 103 (5%) and 58 (100%);

h) from 1-oxo-3-phenylm - [4-hydroxyphenyl] propane (Chem. Zentralbett II, 1949 [1927]) and 6- (dimethylamino) -1-hexanol, the 3 '- [[6- (dimethylamino) hexyl ] oxy] -3-phenyl-propiophenone as a yellowish oil (yield 12%). Mass spectrum: peaks among others in m / e353 (M ⁺ , 0.8%), 128 (5.7%), 105 (1.8%) and 58 (100%);

i) from 4-hydroxy-2-phenylacetophenone (J. Org. Chem. 45, 1596 [1980]) and N, N-dimethyl-6-amino-1-hexanol the 4 - [(6-dimethylamino) hexyl) oxy ] -2-phenylacetophenone as a colorless solid in front of mp 69-71 (yield 25%);

j) from 3-hydroxybenzophenone (Beilstein 8 [III], 1262) and N, N-dimethyl-6-amino-1-hexanol, the 3 - ((6- (dimethylamino) hexyloxybenzophenone as a yellowish oil (yield 73%). Mass spectrum: peaks among others in m / e 325 (M ⁺ , 3%), 128 (6%), 105 (6%) and 58 (100%).

Example 2

a) 100 ml of a 10% aqueous sodium hydroxide solution are added to a solution of 34.5 g of 1,5-dibromopentane, 9.9 g of 4-hydroxybenzophenone and 1.6 g of tetrabutylammonium bromide in 100 ml of methylene chloride. The heterogeneous mixture is stirred overnight at room temperature. The organic phase is separated, dried over sodium sulfate and evaporated. Chromatography of the residue on silica gel with hexane / ethyl acetate 7: 3 gives 13.47 g (78%) of 4 - [(5-

Bromopentyl) oxyl] benzophenone as a colorless oil.

A solution of 3.0 g of 4 - [(5-bromopentyl) oxy] benzophenone in 30 ml of ethanol is mixed with 16 ml of a 33% solution of

Dimethylamine in ethanol for 1.5 hours in a pressure tube heated to 90 °. After cooling, the mixture is poured into water and extracted three times with ethyl acetate. The dried over sodium sulfate organic phases are evaporated,

and the residue is chromatographed with hexane / ethyl acetate (7: 3) on alumina neutral (activity level III). This gives 2.69 g (97%) of 4 - [(5- (dimethylamino) -pentyl) oxy] benzophenone as a colorless oil. 1 H-NMR (CDCl ₃ ): 1.6-2.0 (m, 6H): 2.23 (s, 6H); 2.30 (t, J = 7Hz, 2H); 4.05 (t, J = 7Hz, 2H); 6.95 (d, J = 9Hz, 2H); 7.3-7.9 (m, 4H); 7.83 (d, J = 9Hz, 2H) ppm.

In an analogous manner one obtains:

b) from 1,8-dibromoctane and 4-hydroxybenzophenone the 4 - [(8-bromoctyl) oxy] benzophenone as colorless crystals of mp. 59-61 ° C (yield 81%) and therefrom with dimethylamine the 4 - [(8 - (Dimethylamino) octyl) oxy) benzophenone as a yellowish oil (yield 42%).

¹ H-NMR (CDCl ₃ ): 1.3-1.6 (m, 10H); 1.80 (qui, J = 7Hz, 2H); 2.22 (s, 6H); 2.25 (t, J = 7Hz, 2H); 4.03 (t, J = 7Hz, 2H); 6 94 (d, J = 9Hz, 2H); 7.4-7.65 (m, 3H); 7.7-7.9 (m, 4H) ppm;

c) from 1, G-dibromohexane and 4-hydroxybenzophenone, the 4 - [(6-Brcmhexyl) cxy] benzophenone as colorless crystals of mp. 47-49 ⁰ C (yield 77%) and from it with pyrrolidine the 4 - [(6 - (Pyrrolidino) hexyl) oxy] benzophenone as a colorless oil (yield 33%).

¹ H-NMR (CDCl ₃ ): 1.3-2.0 (m, 12H); 2.3-2.65 (m, 6H); 4.05 (t, J = 7Hz, 2H); 6.97 (d, J = 9Hz, 2H); 7.45-8.0 (m, 7H) ppm;

d) from 1,4-dibromobutane and 4-hydroxybenzophenone das4 - [(4-bromobutyl) oxy] benzophenone (yield 86%) and therefrom with dimethylamine, the 4 - [[4- (dimethylamino) butyl] oxy] benzophenone as a yellowish oil (Yield 80%). Mass spectrum: peaks among others at m / e 297 (M ⁺ , 0.5%), 192 (0.5%), 152 (2.5%), 105 (3.5%) and 58 (100%);

e) from 1,6-dibromohexane and 4-hydroxybenzophenone the 4 - ((6-bromohexyljoxy) benzophenone (yield 66%) and from this with Ν, Ν-dipropylamine the 4 - [[6- (dipropylamino) hexyl] oxy] - benzophenone as yellowish oil (yield 94%) Mass spectrum: peaks among others at m / e 381 (M ⁺ , 3%), 352 (60%) and 114 (100%);

f) from 4 - [(6-bromohexyl) oxy] benzophenone and trimethyleneimine give the 4 - [(6- (azetidinyl) hexyl) oxy] benzophenone as a yellowish oil (yield 5%);

Mass spectrum: peaks among others at m / e 337 (M ⁺ , 1%), 140 (19%) and 70 (100%).

g) from 1,7-dibromoheptane and 4-hydroxybenzophenone the 4-t (7-Bromhepty!) oxy] benzophenone (yield 82%) and therefrom with dimethylamine the 4 - ((7- (dimethylamino) heptyl] oxy] benzophenone as yellowish oil (yield 90%) Mass spectrum: peaks, among others, at m / e 339 (M ⁺ , 3%), 121 (2%), 105 (3%) and 58 (100%);

h) from 1,9-dibromonanane and 4-hydroxybenzophenone the 4 - [(9-bromononyl) oxyjbenzophenone (yield 74%) and from it with dimethylamine, the 4 - [[9- (dimethylamino) nonyl] oxy] benzophenone as a colorless solid with a mp. Of 44-45 ° C (yield 77%);

I) from 1,10-dibromodecane and 4-hydroxybenzophenone, the 4-1 (10-bromodecyl) oxy] benzophenone (yield 75%) and therefrom with dimethylamine, the 4- | [10- (dimethylamino) decyl] oxy] benzophenone of the mp . 33-35 ⁰ C (90% yield);

]) from 4 - [(6-bromohexyl) oxy] benzophenone and methylamine the 4 - [[6- (methylamino) hexyl) oxy] benzophenone. By treatment with ethereal hydrochloric acid, the corresponding hydrochloride is obtained in a yield of 13%; Mp 155-157 ° C;

k) from 4 - [(6-bromohexyl) oxy] benzophenone and N-allyl-methylamine, the 4 - [[6- (allylmethylamino) hexyl] oxy] benzophenone as

yellowish oil (yield 55%).

Mass spectrum: peaks among others at m / e 351 (M ⁺ , 5%), 84 (100%);

I) from 1,6-dibromohexane and 4-hydroxy-2-phenylacetophenone, the 4 - [(6-bromo-hexyl) oxy] -2-phenylacetophenon as a yellowish solid with a mp. Of 75-78 ⁰ C (yield 71%) and therefrom with N-allyl-methylamine the 4 - [[6- (allylmethylamino) -hexyl] oxy] -2-phenylacetophenone as a yellowish oil (yield 48%)

Mass spectrum: peaks among others at m / e 365 (M ⁺ , 4%), 274 (4%), 84 (100%);

m) from 4-fluoro-4'-hydroxybenzophenone (European Patent Publication Nos. 167240 and 128692) and 1,6-dibromohexane, the 4-l (6-bromohexyl) oxyl-4'-fluoro-benzophenone as colorless crystals with a mp. of 79 ⁰ C (yield 57%) and therefrom with N-allyl-methylamine, the 4 - [(6- (allylmethylamino) hexyl] -oxy] -4'-fluorobenzophenone, which is converted into the hydrochloride (yield 74%), Mp 84 ^° C;

n) from trans-1,4-dibromobutene and 4-hydroxybenzophenone, the 4 - [(4-bromo-2-butenyl) oxy] benzophenone as a colorless solid with a mp. Of 100 ⁰ C (yield 45%) and therefrom with dimethylamine the trans-4- [4- (dimethylamino) -2-butenyljoxyl benzophenone as a colorless solid with a mp. 48-50 ° C (yield 69%);

o) from 4 - ((4-bromo-2-butenyl) oxy] benzophenone and N-allylmethylamine, the trans-4- [4- (allylmethylamino) -2-butenyl] -oxylbenzophenone, which is converted into the hydrochloride (yield 88%), mp 90-91 "C.

Example 3

a) A mixture of 2.17 g of 6-diethylamino-1-hexanol (J. Chem. Soc. 1942,428), 1.52 g of 4-hydroxybenzaldehyde and 3.3 g of triphenylphosphine in 100 ml of tetrahydrofuran at 20 ⁰ C slowly with a solution of 1.97 g Azodicarbonsäurediäthylester added. After the dropwise addition is stirred for 5 hours at room temperature. The reaction mixture is then in

Rotary evaporator evaporated. The residue is chromatographed on 400 g of alumina neutral (activity grade III) with hexane / ethyl acetate 7: 3. This gives 2.22 g (64%) of 4 - ([6- (diethylamino) hexyl] oxylbenzaldehyde as a yellowish oil.

b) A solution of this aldehyde in 20 ml of ether is added dropwise to a solution of Phenäthylmagnesiumbromid (from 1.47 g of phenethyl bromide and 143 mg magnesium in 20 ml of ether) at 0 ° C under argon. The reaction mixture is stirred at room temperature for 3 hours, then poured onto 100 ml of saturated ammonium chloride solution and extracted three times with 100 ml of dichloromethane. The organic phases are dried over magnesium sulfate and evaporated. The crude 1 - [4 - [[6- (diethylamino) hexyl] oxy] phenyl] -3-phenylpropanol is used in the next step without further purification.

c) To a solution of 0.8 ml of oxalyl chloride in 30 ml of methylene chloride is added dropwise at -60 ⁰ C for 5 minutes, a solution of 1.58ml dimethyl sulfoxide in 10 ml of methylene chloride. After 2 minutes of stirring, are added at -6O ⁰ C a solution of the crude 1-l4 - [[6- (diethylamino) hexyl] oxy] phenyll-3-phenyl-propanol in 20 ml of methylene chloride over 10 minutes thereto. After 15 minutes, add 7.5 ml of triethylamine at -6O ⁰ C thereto, and the reaction mixture is allowed to warm to room temperature After one hour at room temperature, 100 ml of water to the organic phase is separated off and the aqueous phase extracted twice with 100 mL of methylene chloride , The combined organic phases are dried over magnesium sulfate and evaporated. After the residue is chromatographed on 240 g of silica gel with ammonium hydroxide / methanol / methylene chloride 1:10:90, 1.76 g (37%) of 4'-l [6- (diethylamino) hexyl] oxy] -3-phenylpropiophenone are obtained as a yellow oil crystallized on standing; M.p. 83-84 ⁰ C.

In an analogous manner one obtains:

d) from 3 - ([6- (diethylamino) hexyl] oxy) benzaldehyde (prepared from 3-HydroxybenzalcJehyd and 6- (diethylamino) -1-hexanol) and Phenäthylmagnesiumbromid and oxidation of the condensation product with oxalyl chloride / dimethyl sulfoxide the 3'-l [ 6- (diethylamino) hexyl] oxy] -3-phenylpropiophenone as a yellow oil (yield 38%).

Mass spectrum: peaks among others in m / e 381 (M ⁺ , 1%), 366 (4%), 290 (0.8%) and 86 (100%);

e) from 3 - [[6- (diethylamino) hexyl] oxy] benzaldehyde and lithium phenylacetylide, the 3 - [[6- (diethylamino) hexyl] oxy] -a- (phenyläthinyl) benzyl alcohol and from this the 3'-I [6 (Diethylamino) hexyl] oxy) -3-phenylpropiolophenone (yield 85%). Mass spectrum: peaks among others at m / e 377 (M ⁺ , 1.5%), 362 (2%), 318 (3.8%), 129 (4%) and 86 (100%).

Example 4

a) To a solution of 5.52 g of pentafluorobenzene in 50 ml of tetrahydrofuran at -78 ⁰ C under argon is added dropwise 20.75 ml of a 1.6M solution of n-butyllithium in hexane. The reaction mixture is stirred for 30 minutes at -78 ° C. At the same temperature, a solution of 4.47 g of anisaldehyde in 25 ml of tetrahydrofuran is then added dropwise thereto. Ntich 1 hour at -78 ⁰ C is allowed to warm the mixture to room temperature and stirred for a further 1 hour. The reaction mixture is poured onto 100 ml of a saturated ammonium chloride solution and extracted three times with 1 UOmI ethyl acetate. The organic phases are washed with 100 ml of a saturated sodium chloride solution and dried over magnesium sulfate. Evaporation gives 10 g of crude 2,3,4,5,6-pentafluorophenyl-4'-methoxyphenylcarbinol.

b) A solution of this crude carbinol in 60 ml of methylene chloride is added dropwise to a solution of 3.3 ml of oxalyl chloride and 5.6 ml of dimethyl sulfoxide ^: n 130 ml of methylene chloride within 15 minutes at -78 ° C under argon. The mixture is stirred for 15 minutes at -78 ⁰ C. 27.6 ml of triethylamine are then added dropwise at -78 ⁰ C within 15 minutes. The mixture is then allowed to warm to room temperature. The reaction mixture is mixed with 500 ml of water. The organic phase is separated, and the aqueous phase is extracted twice with 200 ml of methylene chloride. The combined organic phases are dried over magnesium sulfate and evaporated in a rotary evaporator. The residue is chromatographed on 920 g of silica gel with methylene chloride. This gives 7.82 g (78%), 2,3,4,5,6-pentafluoro-4'-methoxybenzophenone as a colorless oil.

c) A solution of 5.6 g of 2,3,4,5,6-pentafluoro-4'-methoxybenzophenone in 100 ml of ethylene chloride is added dropwise to a solution of 23.23g Bortribrornid in 100 ml of ethylene chloride at -7 ⁰ C under argon. The reaction mixture is warmed to room temperature and stirred for 5 hours at this temperature. The reaction mixture is poured onto 200 ml of ice-cold water and extracted three times with 150 ml of methylene chloride. The combined extracts are washed with 200 ml of water and dried over magnesium sulfate. After evaporation of the solvent, the residue is chromatographed on 900 g of silica gel with methylene chloride. This gives 3.87 g (72%) of 2,3,4,5,6-pentafluoro-4'-hydroxybenzophenone with a mp. Of 138-14O ⁰ C.

d) in analogy to Example 1 is obtained from 2,3,4,5,6-pentafluoro-4'-hydroxybenzophenone and 6- (dimethylamino) -1-hexanol, the 4 '- (l6- (dimethylamino) hexyl] oxyl- 2,3,4,5,6-pentailuorbenzophenon as a colorless oil (yield 37%) ¹ H-NMR (CDCI _3): 1.3-1.9 (m, 8H), 2.26 (s, 6H). 2,1-2,3 (m, 2H), 4,06 (t J = 7Hz, 2H), 6,96 (d, J = 9Hz, 2H), 7,84 (d, J = 9Hz, 2H) ppm.

Example 5

a) In analogy to Example 3 b) is obtained from 4 - [(6- (diethylamino) hexyl] oxy] benzaldehyde and phenylacetylene / butyllithium crude 4 '- [[6- (diethylamino) hexyl] oxylphenyl-phenyläthinyl-carbinol (yield 50%).

b) A solution of 1.58 g of 4 '- [16- (diethylamino) ,. jxyl] oxy] -phenyl-phenylethyl-carbinol in 60 ml of methylene chloride is added with 2.07 g of activated manganese dioxide. After 20 hours, the reaction mixture is filtered through diatomaceous earth. After evaporating the filtrate, the residue is chromatographed on 100 g of aluminum oxide neutral (activity level III) with hexane / ethyl acetate 2: 1. This gives 1.34 g (50%) of 4 '- [[6- (diethylamino) hexyl] oxy] -3-phenylpropiolophenone as a colorless oil.

Mass spectrum: peaks among others at m / e 377 (M ⁺ , 5%), 362 (4.8%), 194 (3%) and 86 (100%).

Example 6

a) A solution of 24 g of 2-methylanisole, 35 g of N-bromosuccinimide and 1.24 g of dibenzoyl peroxide in 150 ml of carbon tetrachloride is refluxed for 12 hours. After cooling the solution is filtered, and the filtrate is evaporated. The residue is recrystallized from hexane. This gives 18.6 g (47%) of 4-bromo-2-methylanisole as a colorless solid with a mp. From 66-68 ⁰ C.

b) From 10 g of 4-bromo-2-methylanisole and 1.21 g of magnesium turnings in 30 ml of tetrahydrofuran, the corresponding Grignard reagent is prepared dropwise in a pre-cooled to -72 ⁰ C solution of 7 g of benzoyl chloride in 80 ml of tetrahydrofuran. The temperature is kept below -65 ⁰ C. After the dropwise addition is stirred for 0.5 hours at 2O ⁰ C, whereupon hydrolyzed with 400 ml of ice water. The solution acidified with dilute hydrochloric acid is extracted with ether, and the organic phase is dried and evaporated. Chromatography of the residue on silica gel with hexane / ethyl acetate 7: 3 gives 6.17 g (55%) of 4-methoxy-3-methylbenzophenone as a yellowish oil. ¹ H-NMR (CDCl ₃ ): 2.26 (s, 3H); 3.90 (s, 3H); 6.8-8.0 (m, 8H) ppm.

c) A mixture of 6.17 g of 4-methoxy-3-methyl-benzophenone, 65 ml of glacial acetic acid and 103 ml of a 62% hydrobromic acid solution is refluxed for 3 hours. The resulting dark solution is concentrated, extracted with ethyl acetate, and the organic phase is dried and evaporated. The residue is chromatographed on silica gel with hexane / ethyl acetate 7: 3. This gives 2.90 g (50%) of 3-methyl-4-hydroxybenzophenone as a yellowish solid with a mp. Of 170-173 ° C.

d) In analogy to Example 2 is obtained from 1,6-dibromohexane and 3-methyl-4-hydroxybenzophenone, the 4 - [(6-bromohexyl) oxy-3-methyl-benzophenone as a yellowish oil [yield 79%; 'H NMR (CDCl ₃ ): 1.45-2.15 (m, 8H); 2.25 (s, 3H); 3.43 (t, J = 7Hz, 2H); 4.07 (t, J = 7Hz, 2H); 6.8-8.0 (m, 8H) ppm) and therefrom with dimethylamine the 4 - [[6- (dimethylamino) hexyl] oxy] -3-methylbenzophenone, which is converted into the hydrochloride (yield 61%); Mp 162-163 ° C.

Example 7

In analogy to Example 2, 4 - [(6-bromohexyl) oxy] -3-methylbenzophenone and N-allylmethylamine give 4 - [[6- (allylmethylamino) hexyl] oxy] -3-methylbenzophenone , which is converted into the hydrochloride (yield 49%); Mp.

112-113 ⁰ C.

Example 8

a) From the Grignard reagent of 2-bromo-m-xylene and 4-methoxybenzoyl chloride is obtained in analogy to Example 6b), the 4-methoxy-2 ', 3'-dimethylbenzophenone as a yellowish oil (yield 47%).

'H-NMR _(CDCl3): 2.15 (s, 6H); 3.85 (s, 3H); 6.8-7.95 (m, 7H) ppm.

b) In analogy to Example 6c), the 4-hydroxy-2 ', 3'-dimethylbenzophenone is obtained therefrom as yellowish crystals (yield 72%); Mp 155-158 ⁰ C.

c) In analogy to Example 2 is obtained therefrom with 1,6-dibromohexane, the 4 - [(6-bromo-hexyl) oxy] -2 ', 3'-dimethyl-benzophenone as a yellowish oil [yield 78%; Ή-NMR (CDCl ₃ ): 1.35-2.0 (m, 8H); 2.11 (s, 6H); 3.43 (t, J = 7Hz, 2H); 4.03 (t, J = 7Hz, 2H); 6.8-7.9 (m, 7H) ppm] and from this with dimethylamine the 4 - [[6- (dimethylamino) hexyl] oxy] -2 ', 3'-dimethylbenzophenone, which is converted into the hydrochloride ( Yield 81%); M.p. 117-12O ⁰ C.

Example 9

From 4 - [(6-bromo-hexyl) oxy) -2 ', 3'-dimethyl-benzophenone and N-allyl-methylamine, the 4 - [6] is obtained in analogy to Example 2.

(Allylmethylamino) hexyl] oxy] -2 ', 3'-dimethylbenzophenone as a yellowish oil (yield 82%).

Mass spectrum: peaks among others at m / e 379 (M ⁺ , 4%), 350 (6%), 84 (100%). .

Example 10

a) From the Grignard reagent of 4-bromoanisole and 2,4-dichlorobenzoyl chloride is obtained in analogy to Example 6b), the 2,4-dichloro-4'-methoxybenzophenone as a yellow oil (yield 76%). ¹ H-NMR (CDCl ₃ ): 3.56 (s, 3H); 6.9-8.0 (m, 7H).

b) In analogy to Example 6c), the 4-hydroxy-2 ', 4'-dichlorobenzophenone is obtained therefrom as yellowish crystals (yield 63%); M.p. 14O ⁰ C.

c) In analogy to Example 2, 1,6-dibromohexane is used to give 4 - [(6-bromohexyl) oxy) -2 ', 4'-dichlorobenzophenone as a colorless oil (yield 86%; mass spectrum: peaks, inter alia, at m / e430 [M ⁺ , 10%], 266 [19%], 173 [18%], 121 [100%]) and from this with N-allyl-methylamine the 4 - [[6-allylmethylamino) hexyl] oxy] -2 ', 4'-dichlorobenzophenone as a yellowish oil (yield 67%).

Mass spectrum: peaks among others in m / e419 (M ⁺ , 2%), 173 (3%), 84 (100%).

Example 11

From 4-hydroxy-2 ', 4'-dichlorobenzophenone and N, N-dimethyl-6-amino-1-hexanol are obtained in analogy to Example 1, the 4 - [6]

(Dimethylamino) hexyl] oxy] -2 ', 4'-dichlorobenzophenone as a colorless oil (yield 31%).

Mass spectrum: Tips and others at m / e 393 (0.5%), 173 (1.5%), 128 (5%), 58 (100%).

Example 12

From the Grignard compound of 4-bromoanisole and 3,5-dichlorobenzoyl chloride is obtained in analogy to Example 6b) the

S. DichlM'-methoxybenzophenone as a colorless solid (yield 37%).

¹ H-NMR (CDCl ₃ ): 3.92 (s, 3H); 7.0-8.0 (m, 7H) ppm.

In analogy to Example 6c), the 4-hydroxy-3 ', 5'-dichlorobenzophenone is obtained therefrom as brownish crystals (yield 91%);

M.p. 183 ⁰ C.

In analogy to Example 2 is obtained therefrom with 1,6-dibromohexane, the 4 - [(6-bromo-hexyl) oxy] -3 ', 5'-dichlorobenzophenone as

colorless solid (yield 49%) with a mp of 7O ⁰ C and from it with dimethylamine the 4- | [6-

(Dimethylamino) hexyl oxy] -3 ', 5'-dichlorobenzophenone, which is converted to the hydrochloride (yield 66%); Mp.

148-149 ⁰ C.

Example 13

From 4 - [(6-bromohexyl) oxyl-3 ', 5'-dichlorobenzophenone and N-allylylamine, the 4 - [[6- (allylmethylamino) hexyl] oxy] -3', 5 'is obtained in analogy to Example 2. dichlorobenzophenone, which is converted to the hydrochloride (yield 74%); Mp.

111-112 ⁰ C.

Example 14

4-Hydroxy-2 ', 4'-dichlorobenzophenone and trans-1,4-dibromobutene are obtained in analogy to Example 2, 4 - ((4-urom-2-butenyl) oxy] -2', 4'-dichlorobenzophenone as a sticky resin (yield 73%; mass spectrum: peaks among others at m / e 400 [M ⁺ , 2%], 319 [3%], 266136%], 173 [54%], 133 [45%], 121170%] ) and therefrom with dimethylamine, the trans-4 - [(4- (dimethylamino) -2-butenyl] oxy] -2 ', 4'-dichlorobenzophenone, which is converted into the hydrochloride (yield 82%), mp 147 ° C. ,

Example 15

From 4 - [(4-bromo-2-butenyl) oxy] -2 ', 4'-dichlorobenzophenone and N-allyl-methylamine obtained in analogy to Example 2, the trans-4 - [[4- (allylmethylamino) -2 -butenyl] oxy] -2 ', 4'-dichlorobenzophenone, which is converted to the hydrochloride (yield 80%); Mp. 98 ° C.

Example 16

a) 150 ml of nitrobenzene are cooled in an ice bath and treated portionwise with 41 g of aluminum chloride. The temperature is kept below 5 ° C. Subsequently, a solution of 50g4-nitrobenzoyl chloride in 50 ml of nitrobenzene is added dropwise so that the temperature remains below 5 ° C. At the same temperature now 27.8 g anisole are dripped to it. The mixture is then stirred at 2O ⁰ C overnight. The solution is poured into 11 ice-water, extracted with methylene chloride, dried over magnesium sulfate and concentrated. The nitrobenzene is distilled off under high vacuum, and the remaining yellowish crystals are recrystallized from cyclohexane. This gives 36.5 g (52%) of 4-methoxy-4'-nitrobenzophenone as a yellow solid with a mp. Of 124 ° C.

b) From 4-methoxy-4'-nitrobenzophenone and hydrobromic acid is obtained in analogy to Example 6c), the 4-hydroxy-4'-nitrobenzophenone as yellow crystals (yield 75%); Mp. 196 ⁰ C.

c) In analogy to Example 2 is obtained from 4-hydroxy-4'-nitrobenzophenone and 1,6-dibromohexane, the 4 - [(6-bromohexyl) -oxy] -4'-nitrobenzophenone as a yellow solid with a mp of 61 ⁰ C (yield 65%) and from this with dimethylamine the 4 - [[6- (dimethylamino) hexyl] oxy) -4'-nitrobenzophenone, which is converted into the hydrochloride (yield 80%); M.p. 101 ⁰ C.

Example 17

From 4 - [(6-bromohexyl) oxyl] -4'-nitrobenzophenone and N-allylmethylamine, 4 - ([6- (allylmethylamino) hexyl] oxy] -4'-nitrobenzophenone is obtained analogously to Example 2, which is converted into the Hydrochloride is converted (yield 85%), mp 79 ⁰ C.

Example 18

From 2-chloroanisole and benzoyl chloride is obtained in analogy to Example 16a), the 3-chloro-4-methoxybenzophenone as colorless

Solid (yield 72%); Mp 87 ° C.

In analogy to Example 6c), the 3-chloro-4-hydroxybenzophenone is obtained therefrom as a yellowish solid (yield 91%);

Mp. 18O ⁰ C.

In analogy to Example 2 is obtained therefrom with 1,6-dibromohexane, the 4 - [(6-bromo-hexyl) oxy] -3-chloro-benzophenone as a colorless solid with a mp. Of 58 ° C (68% yield) and from it with Dimethylamine the 4 - ([6- (dimethylamino) -hexyl] oxy] -3-

Chloro-benzophenone, which is converted into the hydrochloride (yield 94%); Mp 195 ° C.

Example 19

From 4 - [(6-bromo-hexyl) oxy) -3-chloro-benzophenone and N-allyl-methylamine, in analogy to Example 2, 4- [6- (allylmethylamino) hexyl] oxy] -3-chloro-benzophenone is obtained , which is converted into the hydrochloride (yield 98%); Mp.

Example 20

From 2-chloroanisole and 2,4-dichlorobenzoyl chloride, the 2 ', 3,4'-trichloro-4 is obtained analogously to Example 16a).

methoxybenzophenone as yellowish crystals (yield 87%); Mp 98 ^° C.

This gives in analogy to Example 6c), the 2 ', 3,4'-trichloro-4-hydroxy-benzophenone as yellowish crystals (yield

89%); M.p. 145 ⁰ C.

In analogy to Example 2, there is obtained with 1,6-dibromohexane the 4 - [(6-bromohexyl) oxy] -2 ', 3,4'-trichlorobenzophenone as a yellowish oil (yield 21%) and from this with dimethylamine 4- [[6- (dimethylamino) hexyl] oxy] -2 ', 3,4'-trichloro-benzophenone, which is converted to the hydrochloride (yield 49%); Mp. 91 ° C.

Example 21

From 4 - [(6-bromo-hexyl) oxy] -2 ', 3,4'-trichlorobenzophenone and N-allyl-methylamine, the 4 - [[6- (allylmethylamino) hexyl] oxy] -2 is obtained analogously to Example 2 ', 3,4'-trichlorobenzophenone, which is converted into the hydrochloride (yield 30%); Mp 100 ^° C.

Example 22

In analogy to Example 2 is obtained from 4-hydroxy-4'-nitrobenzophenone and trans-1,4-dibromobutene, the 4 - [(4-bromo-2-butenyl) oxy] -4'-nitrobenzophenone as a yellowish solid (yield 71 Mass spectrum: peaks among others at m / e 375 [M ⁺ , 2%), 296 [8%], 243 (44%), 150 [32%], 133 [62%], 121 [62% D and the like with dimethylamine, the trans-4 - [[4- (dimethylamino) -2-butenyl] oxy] -4'-nitrobenzophonone, which is converted into the hydrochloride (yield 90%); M.p. 144 ⁰ C.

Example 23

From 4 - [(4-bromo-2-butenyl) oxy] -4'-nitrobenzophenone and N-allyl-methylamine, in analogy to Example 2, the trans-4 - [[4- (allylmethylamino) -2-butenyl] oxy] -4'-nitrobenzophenone, which is converted to the hydrochloride (yield 85%); Mp 152 ^° C.

Example 24

From 4-bromobenzoyl chloride and anisole, the 4-bromo-4'-methoxy-benzophenone is obtained in analogy to Example 16a)

colorless solid (yield 65%).

Mass spectrum: peaks among others at m / e 290 (M ⁺ , 18%), 135 (100%).

This gives, in analogy to Example 6c), the 4-bromo-4'-hydroxybenzophenone as a yellowish solid (yield 77%).

Mass spectrum: peaks among others in m / e 276 (M ⁺ , 18%), 121 (100%).

Analogously to Example 2, trans-1,4-dibromobutene is used to give the ^/ 1 - [(4-hromo-2-butenyl) oxyl-4'-bromo-benzophenone as colorless crystals (yield 64%, mass spectrum: peaks, inter alia, at m / e 410 (M ⁺ , 4%), 329 [11%], 276 [32%], 183 [34%], 133 [50%], 121 [100%]) and from this with dimethylamine the trans-4- [(4- (dimethylamino) -2-butenyl] oxy] -4'-bromo-benzophenone,

which is converted into the hydrochloride (yield 85%); Mp 184-185 ° C.

Example 25

From 4 - [(4-bromo-2-butenyl) oxy] -4'-bromobenzophenone and N-allylmethylamine, in analogy to Example 2, the trans-4 - [[4- (allylmethylamino) -2-butenyl] oxy] 4'-bromobenzophenone, which is converted into the hydrochloride (yield 83%); M.p. 116-117 ⁰ C.

Example A

The compound 4 - [(6- (dimethylamino) hexyl) oxy] -2-phenylacetophenone can be prepared as an active ingredient for the preparation of

Tablets are used:

ingredients mg / tablet active substance 200 Milk sugar powder. 100 PovidoneK30 15 Na carboxymethylstarch 10 talc 3 magnesium stearate 2 tablet weight 330

The active substance and the lactose powder are mixed intensively. The resulting mixture is then moistened with an aqueous solution of Povidone K30 and kneaded, after which the resulting mass is granulated, dried and sieved. Mix the granules with the other ingredients and then compressed into tablets of suitable size.

Claims (12)

wherein R ¹ and R ^{2 are} each hydrogen, lower alkyl or lower alkenyl or together straight-chain alkylene having 2 to 4 carbon atoms, R ^{3 is} hydrogen, halogen or lower alkyl, Q is alkylene or alkenylene having 4 to 11 carbon atoms and at least 4 carbon atoms between the two free Valencies and Y and Y 'are each a direct bond or ilie group -CH ₂ -, -CH ₂ CH ₂ -, -CH = CH- or -CsC-, the group R ¹ R ² NQO- to the 3- or 4 Position of the ring designated A and the symbol R means that the ring is unsubstituted or mono- or polysubstituted by halogen, trifluoromethyl, cyano, nitro, lower alkyl and / or lower alkoxy, and their pharmaceutically acceptable acid addition salts, optionally in US Pat Combination with antifungal agents that inhibit sterol biosynthesis for the preparation of antifungal agents. 2. Use of compounds of the general formula Y-CO- ^ i wherein R ¹ and R ^{2 are} each hydrogen, lower alkyl or lower alkenyl or together straight-chain alkylene of 2 to 4 carbon atoms, R ^{3 is} hydrogen, halogen or lower alkyl, Q 'is alkylene of 5 to 11 carbon atoms and at least 5 carbon atoms between the two free valencies or alkenylene having 4 to 11 carbon atoms and at least 4 carbon atoms between the two valences Y and Y 'is each a direct bond or the group -CH ₂ -, -CH ₂ -CH ₂ -, -CH = CH- or -C = C- the group R ¹ R ² N-Cf-O- is attached to the 3- or 4-position of the ring designated A and the symbol R denotes that the ring is unsubstituted or lower by halogen, trifluoromethyl, cyano, nitro Alkyl and / or lower alkoxy monosubstituted or polysubstituted, and their pharmaceutically acceptable acid addition salts, optionally in combination with antifungal substances which inhibit sterol biosynthesis, for the preparation of antifungal agents , 3. Process for the preparation of compounds of the general formula Y-CO-Y ¹ la wherein R ¹ and R ^{2 are} each hydrogen, lower alkyl or lower alkenyl or together straight-chain alkyl of 2 to 4 carbon atoms, R ^{3 is} hydrogen, halogen or lower alkyl, Q 'is alkylene of 5 to 11 carbon atoms and at least 5 carbon atoms between the two free valencies or alkenylene having 4 to 11 carbon atoms and at least 4 carbon atoms between the two free valencies and Y and Y 'are each a direct bond or the group-CH ₂ -, -CH ₂ CH ₂ -, -CH = CH- or-C = C - The group R ¹ R ² N-Q'-O- is bound to the 3- or 4-position of the ring designated A and the symbol R means that the ring is unsubstituted or by Haloc-en, trifluoromethyl, cyano , Nitro, lower alkyl and / or lower alkoxy is monosubstituted or polysubstituted, with the proviso that Y and Y 'are not simultaneously a direct bond, when Q' is alkylene of 5 carbon atoms and R ¹ and R ^{2 are} simultaneously lower alkyl with more as 2 carbon atoms bede uten, and their pharmaceutically acceptable acid addition salts, characterized in that a) a compound of the general formula wherein X is a leaving group, and A, Q ', Y, Y', R ³ and R have the above meaning, with an amine of the general formula HNR ¹ R ² , wherein R ¹ and R "have the above meaning, or
b) a compound of the general formula , N-Q ' Y-CHOH-Y ' Ill wherein A, R ¹ , R ² , R ³ , Q ', Y, Y' and R have the above meaning oxidized, or c) a compound of the general formula -Y-COOR ¹ IV wherein R 'is lower alkyl, and A, R ¹ , R ² , R ³ , Q' and Y have the above meaning, with a compound of the general formula RM- Y ' wherein M is -MgCI ₁ -MgFr ₇ -MgJ or Li, and Y 'and R have the above meaning, or
d) a compound of the general formula Y-COOH Vl wherein A, R ¹ , R ² , R ³ , Q 'and Y have the above meaning, in the form of a reactive derivative in the presence of a Lewis acid with a compound of the general formula .R wherein R is an amine radical, or e) a compound of the general formula , Y-CO-CH ₃ VIII wherein A, R ¹ , R ² , R ³ , Q 'and Y have the above meaning, in the presence of a base with a compound of the general formula IX wherein R has the above meaning, implements, or
a compound of the general formula x-N-Q · - Y-CO-CH = CH wherein A, R ¹ , R ² , R ³ , Q ', Y and R have the above meaning hydrogenated, or
g) a compound of the general formula Y-CO-Y ' wherein A, R, R ³ , Y and Y 'have the above meaning, in the presence of triphenxylphosphine and an azodicarboxylic acid di (lower alkyl ester) with a compound of the general
formula R ¹ R ² N-CT-OH xl wherein R ¹ , R ² and Q 'have the above meaning, and, h) if desired, converting a compound of formula I a obtained into a pharmaceutically acceptable acid addition salt. 4. The method of claim 3, wherein R ¹ and R ^{2 are} each hydrogen or lower alkyl or together
straight-chain Aikylen having 2 to 4 carbon atoms, R ^{3 is} hydrogen and Q 'Aikylen with 5 to 11
Carbon atoms and at least 5 carbon atoms between the two free valencies
and the symbol R means that the ring is unsubstituted or substituted by halogen,
Trifluoromethyl, nitro, lower alkyl or lower alkoxy. 5. The method of claim 3 or 4, wherein Q 'is unbranched Aikylen having 5 to 7 carbon atoms. 6. The method according to claim 3 or 5, wherein R ¹ and R ^{2 are} each C ^ alkyl or C ₃ _4 alkenyl or together C ₃ -4 alkylene. 7. The method according to any one of claims 3 to 6, wherein the group R ¹ R ² N-QMD- is attached to the 4-position of the ring designated A. 8. The method according to any one of claims 3 to 7, wherein Y is a direct bond or the group-CH ₂ means. 9. The method of claim 8, wherein Y represents a direct bond. 10. The method according to any one of claims 3 to 9, wherein Y'eine direct bond or the group-CH ₂ -, -CH ₂ CH-CH ₂ -or-CH = means. 11. The method of claim 10, wherein Y 'is a direct bond or the group -CH ₂ - means. 12. The method according to any one of claims 3 to 11, wherein the symbol R means that the ring
unsubstituted or mono- or disubstituted by halogen, nitro and / or lower alkyl. 13. The method according to claim 3, characterized in that one
4 - [(6- (dimethylamino) hexyl) oxy] -2-phenylacetophenone,
4 - ((6- (dimethylamino) hexyl) oxylbenzophenon,
4 '- [(6- (diethylamino) hexyl) oxy] -3-phenylpropiophenone,
4 - [(6- (dimethylamino) hexyl) oxy] -3-phenylpropiophenone,
4 '- [(6- (dimethylamino) hexyl) oxy] -3-phenylpropiophenone,
4 - [(dimethylamino) hexyl 6- () oxy] benzophenone,
4 - [(6- (dimethylamino) hexyl) oxy] -4'-fluorobenzophenone, 4 - [(6- (1-Acetidinyl) hexyl) oxy] benzophenone, 4 - [(6- (1-pyrrolidinyl) hexyl) oxy] benzophenone, 4- [4 - [(6- (dimethylamino) hexyl) oxy] phenyl] acetophenone _/ 4 - [(7- (dimethylamino) heptyl) oxy] benzophenone or 4 - [(5- (dimethylamino) pentyl) oxy] benzophenone. 14. The method according to claim 3, characterized in that 4 - [[6- (allylmethylamino) hexyl] oxy] -2-phenylacetophenone, 4 - [[6- (allylmethylamino) hexyl] oxy] -4'-fluorobenzophenone, trans 4-l [4- (allylmethylamino) -2-butenyl] oxy] benzophenone, 4 - ([6- (allylmetylamino) hexyl] oxy] -3-methylbenzophenone, trans ^ -IK-1-allylmethylamino ^ -butenylloxyl ^ '^' dichlorobenzophenone, 4 - [[6- (allylmethylamino) hexyl] oxy] -4'-nitrobenzophenone or 4 - [[6- (allylmethylamino) hexyl) oxy] -3-chlorobenzophenone. Use of compounds of the formula Ia defined in claim 3 and of pharmaceutically acceptable acid addition salts thereof, optionally in combination with other antifungal active substances which inhibit sterol biosynthesis, for the preparation of antifungal agents.