HRP930437A2 - Substituted aminoaloxy-benzene-derivatives - Google Patents

Description

This invention relates to the use of compounds of the general formula

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in which R1 and R2 are each individually hydrogen, lower alkyl and lower alkenyl or together are straight-chain alkylene with 2 to 4 carbon atoms, R3 is hydrogen, halogen or lower alkyl, Q is alkylene or alkenylene with 4 to 11 carbon atoms and at least 4 carbon atoms between the two free valences and Y and Y' each denote a particularly direct bond or group -CH2-, -CH2CH2-, -CH=CH- or -C=C-, wherein the group R1R2N-Q-O-bonded in position 3 or 4 of the ring marked with A and the symbol R indicates that the respective ring is not substituted or is substituted once or more by halogen, trifluoromethylene, cyano-, nitro-group, lower alkyl and/or lower alkoxy-group, and their pharmaceutically acceptable acid addition salts for suppression or prevention of fungal infections, especially topical or systemic infections caused by pathogenic fungi and to obtain agents with anti-fungal activity. The compounds of formula I not only have pronounced antifungal activity, but also show synergistic effects in combination with other known, antifungally effective substances, which prevent and hinder the biosynthesis of sterols, such as ketoconazole and terbinafine.

In a special aspect, this invention relates to the use of 4-(4-(dimethylamino)butyl)oxy/benzophenone for the purposes mentioned above.

Further objects of this invention are compounds of the general formula

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in which Q' denotes alkylene with 5 to 11 carbon atoms and at least 5 carbon atoms between two free valences or alkylene with 4 to 11 carbon atoms and at least 4 carbon atoms between two free valences, and R1, R2, R3, R, A, Y and Y' have the meaning given above,

and their pharmaceutically acceptable acid addition salts for use as therapeutically active substances, especially as antifungal active substances, then corresponding drugs based on compounds of formula Ia and, if Y and Y' do not simultaneously denote a direct bond, when Q' denotes alkylene with 5 carbon atoms and R1 and R2 simultaneously denote lower alkyl with more than 2 carbon atoms, the compounds of formula Ia as such, then their preparation and intermediates for their preparation.

Compounds of formula I, in which Q stands for unbranched alkylene with 4 carbon atoms, belong to a known group of compounds (substances). In the USA, patent list no. 3 864 501 such compounds are described as agents for improving the coloring of fruits and vegetables. In the USA, patent list no. 3,312,696 describes such compounds as coronary dilators. In the European patent publication no. 115 080 such compounds are described as intermediates for obtaining active substances against alcohol poisoning.

The term "lower" means residues and compounds with up to 7, preferably up to 4 carbon atoms. The term "alkyl" refers to straight or branched chain saturated hydrocarbon radicals, such as methyl, ethyl, propyl, isopropyl and t-butyl. The term "alkenyl" refers to straight or branched chain hydrocarbon radicals with one olefinic double bond, such as allyl or 2-butenyl. "Alkoxy" refers to alkyl groups bonded through one oxygen atom, such as methoxy and ethoxy. The term "alkylene" means straight-chain or branched saturated hydrocarbon residues with 2 free valences, such as dimethylene, trimethylene and tetramethylene. The term "alkenylene" refers to straight or branched chain hydrocarbon radicals having at least one olefinic double bond and two free valencies, such as 2-butyl-1,4-diyl. The term "halogen" refers to the four forms of halogen: fluorine, chlorine, bromine and iodine.

Furthermore, the term "leaving group" refers primarily to halogen atoms, especially chlorine, bromine and iodine, and lower alkyl and arylsulfonyloxy groups, such as methylsulfonyloxy, benzenesulfonyloxy, p-toluenesulfonyloxy and p-chlorobenzenesulfonyloxy.

R 1 and R 2 denote preferably individually C 1-4 -alkyl, C 3-4 , alkenyl, or together denote C 3-4 -alkylene. Q' denotes primarily unbranched alkylene with 5 to 7 carbon atoms. The group R1R2N-Q'-O- is primarily attached in position 4 of the ring marked with A. Y primarily denotes a direct bond or the group -CH2-, especially a direct bond. Y' denotes primarily a direct bond or group -CH2-, -CH2CH2- or -CH=CH-, especially a direct bond or group -CH2-. The symbol R indicates primarily that the ring to which it is attached is not substituted or is substituted primarily mono- or disubstituted by halogen, nitro-group, and/or lower alkyl.

Within the framework of this invention, especially favorable new compounds of formula Ia are:

4-(6-dimethylamino)hexyl)oxy/-2-phenylacetophenone,

4-(6-dimethylamino)hexyl)oxo/benzophenone,

4'-(6-dimethylamino)hexyl)oxo/-3-phenylpropiophenone,

4'-(6-dimethylamino)hexyl)oxy/-3-phenylpropiophenone,

(E)-4'-//6-(dimethylamino)hexyl/oxy/-3-phenylacrylophenone,

4-(6-dimethylamino)hexyl)oxy/benzophenone,

4-[(6-dimethylamino)hexyl)oxy]-4'-fluorobenzophenone,

4-(6-1-azetidinyl)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/oxy/-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-butenyl/oxy/-2',4'-dichlorobenzophenone,

4-//6-(allylmethylamino)hexyl/oxy/-4'-nitrobenzophenone i

4-//6-(allylmethylamino)hexyl/oxy/-3-chlorobenzophenone.

The new compounds of formula Ia and their pharmaceutically acceptable acid addition salts can be obtained according to the present invention by

a) a compound of the general formula

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in which X is a leaving group and A, Q', Y, X', R3 and R are as defined above, reacts with an amine of the general formula NHR1R2, in which R1 and R2 are as defined above, or which

b) oxidizes a compound of the general formula

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wherein A, R1, R2, R3, Q', Y, Y' and R are as defined above,

or what

c) a compound of the general formula

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in which R' denotes lower alkyl and A, R1, R2, R3, Q' and Y have the meaning given above, reacts with a compound of the general formula

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in which M denotes -MgBr, -MgJ or -Li and Y' and R have the meaning given above,

or what

d) a compound of the general formula

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in which A, R1, R2, R3, Q' and Y have the meaning given above,

reacts in the form of a reactive product in the presence of a Lewis acid with a compound of the general formula

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in which R has the meaning given above

or what

e) a compound of the general formula

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in which A, R1, R2, R3, Q' and Y have the meaning given above,

reacts in the presence of a base with a compound of the general formula

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in which R has the meaning given above

or what

f) hydrogenates a compound of the general formula

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wherein A, R1, R2, R3, Q', Y and R are as defined above

or whatever

g) a compound of the general formula

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in which A, R, R3, Y and Y have the meaning given above, in the presence of triphenylphosphine and di-(lower alkyl ester) nitrous acid, reacts with a compound of the general formula

R1R2N-Q ́-OH XI

in which R1, R2 and Q ́ have the meaning given above

and what

h) if desired, the resulting compound of formula I is converted into a pharmaceutically acceptable acid addition salt.

The reaction of the compound of the formula II with the amine of the formula HNR1R2 according to variant a) of this procedure can be carried out according to methods known per se and accessible to any expert in this field. The reaction is primarily carried out in a polar solvent and in the presence of a base as an acid binder in the temperature range of about 0°C to about 150°C. Suitable solvents are, for example, lower alcohols, such as methanol and ethanol, lower dialkyl ketones, such as acetone. Suitable bases are, for example, the amine itself of the formula HNR1R2 taken in excess. then tertiary amines, such as triethylamine and inorganic bases, such as alkali metal carbonates, -hydroxides and -alcoholates.

Oxidation of compounds of formula III according to variant b) of this procedure can be carried out according to methods known per se and accessible to any expert in this field. The reaction is primarily carried out in an inert solvent and in the presence of oxidizing agents in the temperature range from 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 dimethylsulfoxide with oxalyl chloride, dicyclohexylcarbodiimide or acetic anhydride and some tertiary amine, such as triethylamine.

The reaction of the compound of formula IV with the compound of formula V according to variant c) of this procedure can be performed according to methods known per se and accessible to any expert. The reaction is primarily carried out in an inert solvent and in the temperature range from about -80°C to about room temperature. Suitable solvents are, for example, aliphatic (open chain) and cyclic ethers, such as diethyl ether, methyl-t-butyl ether and tetrahydrofuran and mixtures thereof.

The reaction of the reactive product of the compound of formula VI with the compound of formula VII according to variant d) of this procedure can be carried out by methods known to oneself and accessible to any expert in this field. The reaction is primarily carried out in an inert solvent and in the presence of a Lewis acid at a temperature of about 0°C.

Suitable solvents are, for example, halogenated lower hydrocarbons such as methylene chloride, chloroform and ethylene chloride, then nitrobenzene, carbon disulphide and the compound of formula VII taken in excess. Aluminum chloride is primarily used as a Lewis acid. Suitable reaction products of the compounds of formula VI are, for example, the corresponding carboxylic acid chlorides.

Reaction of the compound of formula VIII. with a compound of formula IX. in the presence of a base according to variant e) of this procedure can be carried out according to methods known per se and accessible to any expert. The reaction is primarily carried out in a polar solvent in the temperature range from about 0°C to about 60°C. Suitable solvents are, for example, lower alcohols, such as methanol and ethanol, and their mixtures with water. Alkali metal carbonates and hydroxides, such as potassium carbonate and sodium hydroxide, are primarily used as bases.

Hydrogenation of the compound of formula I ́ according to variant f) of this procedure can be carried out according to methods known per se and accessible to any expert. The reaction is primarily carried out in a polar solvent with elemental hydrogen and in the presence of a suitable catalyst for hydrogenation and in the temperature range 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.

During the reaction of compound of formula X with compound of formula XI. according to variant g) of this procedure, it is also a known method, namely, the so-called Mitsunobu-merger. It is primarily carried out in an inert organic solvent and in the temperature range from about 0°C to the boiling temperature of the reaction mixture. Suitable solvents are, for example, chlorinated, lower hydrocarbons such as methylene chloride and chloroform and aliphatic (open chain) and cyclic ethers such as diethyl ether, methyl-t-butyl ether and tetrahydrofuran and mixtures thereof.

Obtaining pharmaceutically acceptable acid addition salts of compounds of formula Ia according to variant h) of this procedure can be carried out according to methods known per se. This includes salts with pharmaceutically acceptable inorganic and organic acids. Suitable acid addition salts are hydrochlorides, hydrobromides, sulfates, nitrates, citrates, acetates, succinates, fumarates, methanesulfonates and p-toluenesulfonates.

The known compounds of formula I and their pharmaceutically acceptable acid addition salts can also be prepared according to the above-mentioned variants a) - h) of this procedure. Suitable starting materials can be obtained, as given below for the starting materials for the new compounds of formula Ia.

The compounds of formulas II, III, IV and VIII used as starting substances are new and can also be treated as the subject of this invention. They can be obtained according to the following reaction schemes I-IV. and according to the following descriptions of the various reactions. Compounds that were also used as starting substances and do not belong to this group belong to known groups of substances.

In these reaction schemes, R1, R2, R3, R, R ́, A, M, Q ́, X, Y and Y ́ have the meaning given above for the new compounds of formula Ia, respectively in their preparation.

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Reaction A

This reaction can be carried out according to methods known per se and accessible to any expert in this field and is primarily carried out in a polar solvent and in the presence of a base in the temperature range from about 0°C to about 150°C. Suitable solvents are, for example, lower alcohols such as methanol and ethanol, and lower ketones such as acetone. Suitable bases are, for example, alkali metal carbonates, -hydroxides, -alcoholates and -hydrides.

However, reaction A can also be carried out in a two-phase system in the presence of a phase transfer catalyst, for example, in the presence of some quaternary ammonia salt. As an aqueous phase, an aqueous alkali solution, such as an aqueous solution of sodium hydroxide, is primarily used, and as an organic phase, some halogenated lower hydrocarbon, such as methylene chloride or an aromatic hydrocarbon, such as toluene. Compound of formula XII. it is primarily applied in excess, whereby 2 to 4 molar equivalents of compounds of formula XII are primarily applied.

Reaction B

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

Reaction C

The reaction of the compounds of the formula XIV with the compound of the formula V can be carried out according to methods known per se and accessible to any expert. The reaction is primarily carried out in an inert solvent and at a temperature in the range from about -80°C to about room temperature. Suitable solvents are, for example, aliphatic (open chain) and cyclic ethers such as diethylether, methyl-t-butylether and tetrahydrofuran and mixtures thereof.

Reaction D

This reaction is hydrolysis. It can be carried out according to methods known per se and known to every expert in the field and is primarily carried out by treatment with an alkali metal hydroxide, such as sodium or potassium hydroxide or with a mineral acid, such as hydrochloric and hydrobromic acid, in a polar solvent and in the temperature range from about 0°C to about 100°C. Suitable solvents are, for example, mixtures of lower alcohols, such as methanol and ethanol, and aliphatic (open chain) ethers and cyclic ethers, such as tetrahydrofuran, with water.

As mentioned above, the compounds of formula I and their pharmaceutically acceptable acid addition salts have valuable antifungal properties. They are active against a large number of pathogenic fungi, which cause topical and systemic infections, such as Candida albicans and Histoplasma capsulatum. 2,3-Epoxysqualene-lanosterol-cykase, an enzyme implicated in sterol biosynthesis in eukaryotic cells, is an essential enzyme for these fungi. Thus, for example, the genus S. cerevisiae, which lacks this enzyme, is not capable of life (F. Karst & F. Lacroute, Molec. Gen. Genet., 154, 269 (1977)). The inhibitory effect of the compound of formula I on the above-mentioned enzyme from C. albicans was taken as a measure of antifungal activity. This inhibition can, for example, be measured using the methods described below.

Determination of the IC 50 value for prevention (suppression)

2,3-epoxysqualene-lanosterol-cyclase from Candida albicans

Cells from a Candida albicans culture (at the end of the logarithmic phase of development) were harvested and washed with 100 mM phosphate buffer (pH=6.9) containing 1 M mannitol and 5 mM DTT.

1.0 g of these cells was suspended in 5 ml of digestion buffer, mixed with 1 mg of zymolase (Zymolase) 100 T (Seikagaku Kogyn, Japan) and 12.5 μl of β-mercaptoethanol and incubated for 30 minutes at 30°C. The resulting protoplasts were isolated by centrifugation (10 minutes at 2500 g) and then by the addition of 2 ml of 100 mM phosphate buffer (pH - 6.9) they were brought to rupture. After repeated centrifugation (10 minutes at 10,000 g), it is obtained as the upper layer in the form of cell-free extract (CFE). This layer is diluted with 10 mg of protein per 1 ml and the pH value is brought to 6.9.

The cyclase activity of 2,3-epoxysqualene-lanosterol in CFE is measured by the reaction of 14C-squalene-epoxide in the presence of n-decylpentaoxyethylene as a detergent. Titration with measured amounts of the tested substance enables determination of the IC50 value (concentration of the tested substance, which lowers enzyme activity by half).

The experiment was performed as follows:

By ultrasound treatment, a 250 μm solution of 14C-squalene-epoxide is prepared in 100 mM phosphate buffer (pH=6.9) with the addition of 1% n-decylpentaoxyethylene. 100 μl of this solution is mixed with 20 μl of a solution of the tested substance in dimethylsulfoxide (that is, 20 μl of pure dimethylsulfoxide as a control sample). After adding 880 μl of CFE, the well-mixed solution is incubated for one hour at 30°C with shaking. Then the reaction was stopped by adding 500 μl of a 15% solution of potassium hydroxide in 90% ethanol.

The mixture is extracted twice with 1 ml of n-hexane, the hexane is evaporated and the lipid residue is taken up in 200 μl of diethyl ether. After thin-layer chromatography on silica gel using methylene chloride as eluent, these plates are examined using a thin-layer scanner for radioactivity.

Under the applied conditions, only lanosteriol was found as a radioactive product. Its amount was compared with the amount of radioactive lanosterol in the control sample.

IC50 values are determined graphically and given in μg of tested substance per 1 ml. The following Table I contains the IC50 values determined in the above experiment for representative representatives of the group of compounds defined by formula I, as well as data on acute toxicity when administered subcutaneously to mice (DL50 in mg/kg).

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The aforementioned synergistic action 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 means of the agar dilution method. Castioagar and inocula (10 cells/ml) of Candida albicans cultures that are 48 hours old are used for this. Tested substances (TS, compounds of formula I.) were applied in concentrations of 80-1.25 /μg/ml, and sterol biosynthesis inhibitors (SBH) were applied in concentrations of 20-0.001 /μg/ml, whereby the degrees of dilution are each time 1:2. Cultures were incubated each time for 2 days at 37°C. Then, the minimum inhibitory concentrations (MIC) of the various active substances are determined for individual and combined applications, and from the determined MIC values, the fractional inhibitory concentration (FIC) is calculated according to the following formula:

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Synergistic action exists when FIC < 0.5. The values given for compound 6 according to table II, which represents a representative representative of the class of compounds defined by formula I, in combination with katoconazole or terbinafine (representative representatives of sterol biosynthesis inhibitors), support the existence of a synergistic effect.

Table II.

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For combination with the compound of formula I, suitable suppressors (inhibitors) of sterol biosynthesis are, for example, systemically, antifungally acting (active) azoles of the miconazole type, e.g. ketozole, itraconazole and fluconazole, and systemically, antifungally active allylamines of the type, e.g. naftifine and terbinafine .

The compounds of formula I and their pharmaceutically acceptable acid addition salts can be used as drugs, for example in the form of pharmaceutical preparations for enteral, parenteral or topical application. They can be administered, e.g. perorally, e.g. in the form of tablets, light tablets, dragees, capsules with hard and soft jelly, solution, emulsion or suspension, then rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions or infusion solutions, or topically, eg in the form of ointments, creams or oils.

Obtaining pharmaceutical preparations can be done in a way that is accessible to any expert in the field by bringing the described compounds of formula I and their pharmaceutically acceptable acid addition salts into galenic form of administration, in a given case in combination with other therapeutically valuable substances, e.g. with the above-mentioned inhibitors of sterol biosynthesis, together with suitable non-toxic, inert, therapeutically tolerable solid and liquid carrier materials and, in a given case, together with other pharmaceutical auxiliary materials.

Both inorganic and organic carrier materials are suitable as carrier materials. For example, lactose, corn starch or its derivatives, talc, stearic acid or its salts can be used for tablets, light tablets, dragees and hard jelly capsules. For capsules with hard jelly, they are suitable as carrier materials, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the quality of the active substance, however, with capsules with soft jelly sometimes carriers are not even necessary).

For obtaining solutions and syrups, e.g. water, polyols, sucrose, invert sugar and glucose are suitable as carrier materials. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerin and vegetable oils. For suppositories, they are suitable as carrier materials, for example natural and hardened oils, waxes, fats and semi-liquid or liquid polyols. Glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid alacate (fatty) alcohols, sterols, polyethylene glycols and cellulose products are suitable as carrier materials for topical preparations.

As pharmaceutical auxiliary substances, the usual agents for stabilization, preservation, storage, moistening and emulsification, then agents for improving the consistency, agents for improving the taste, salts for changing the osmotic pressure, buffer substances, solvent carriers, coloring and coating agents and antioxidants come into consideration. .

The dosage of the compound of formula I can vary, depending on the fungus to be controlled, then on the age and individual condition of the treated patient and on the method of application, and this can vary within wide limits and of course in each individual case it must be adapted to individual and individual circumstances. For the prevention of topical and systemic infections caused by pathogenic fungi, daily doses of about 0.01 to about 4 g, especially about 0.05 to about 2 g, are considered for adult patients (in the case of monotherapy). that the daily dose is given in several dosage units. In the case of combined therapy, a daily dose of about 0.01 g to about 2 g, especially about 0.02 to about 1 g of the compound of formula I and about 0.02 g to about 0.2 g of the biosynthesis suppressor (inhibitor) comes into consideration. sterols.

Pharmaceutical mono-preparations expediently contain about 10-1000 mg, preferably 50-500 mg of compound of formula I. Combined preparations expediently contain about 10-500 mg, preferably 20-250 mg of compound of formula I about 50-100 mg of sterol biosynthesis inhibitor.

The following examples serve for a closer explanation of the attached invention. However, they should in no way limit the scope of this invention. All temperatures are given in degrees Celsius.

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-hydroxybenzophenone (Beilstein 8 (III), 1263) , 4.5 g of triphenylphosphine and 140 ml of tetrahydrofuran were mixed slowly at 20°C with a solution of 2.7 ml of diethyl ester of azodicarboxylic acid in 15 ml of tetrahydrofuran. After instillation, it is stirred for another 1 hour at room temperature. The reaction mixture is evaporated in a rotary vacuum evaporator and the residue is chromatographed on a column of 400 g of neutral aluminum oxide (activity level III) using a 7:3 hexane/ethyl acetate mixture. The obtained yellowish oil is dissolved in 25 ml of ether, after which it is treated with 25 ml of a 10% solution of HCl in ether. The precipitated colorless crystals are filtered through a sieve, washed with ether and recrystallized from acetone. 1.93 g (31%) of 4-(6-dimethylamino)hexyl)oxy/benzophenone hydrochloride with a melting point of 121°C is obtained.

In an analogous way, the following are obtained:

b) (E)-4 ́-//6-(dimethylamino)hexyl/oxy/ is obtained from N,N-dimethyl-6-amino-1-hexanol and 4-hydroxychalcone (Planta Med., 53,110 (1987)) -3-phenylacrylophenone in the form of a colorless solid with m.p. 43 - 46°C (yield 27%).

c) from N,N-dimethyl-6-amino-1-hexanol and 4'-hydroxy-3-phenylpropiphenone, 4'-/(6-(dimethylamino)hexyl/oxy/-3-phenylpropiophenone is obtained as a light yellowish solid with m.p. 27-28°C (yield 47%);

d) from N,N-dimethyl-6-amino-1-hexanol and 4-fluoro-4'-hydroxybenzophenone (European patent publications no. 167240 and 128692) 4-//6-(dimethylamino)hexyl/oxy/ is obtained -4'-fluorobenzophenone in the form of a colorless solid with m.p. 37-38°C (yield 52%);

e) 2-/4-//6- (dimethylamino)hexyl/oxy/phenyl/acetophenone with m.p. 53-54°C (yield 30%);

f) from 6-(dimethylamino)-1-hexanol (J. Chem. Soc. 1942, 428) and 4-hydroxybenzophenone, 4'-//6-(diethylamino)-hexyl/-oxy/benzophenone is obtained in the form of a yellowish oil (yield 30%); mass spectrum: peaks, among others, m/e 353 (M+, 2%), 338 (2.7%), 199 (3%) and 86 (100%);

g) from 6-(diethylamino)-1-hexanol and 3'-hydroxychalcone (Berichte 32, 1924 (1899)) (E)-3'-//6-(dimethyl-amino)hexyl/oxy/-3 -phenylacrylophenone as a yellow oil (yield 38%); mass spectrum: peaks, among others, at m/e 351 (M+, 8%), 131 (4%), 103 (5%) and 58 (100%);

h) 3'-//6(dimethylamino )hexyl/oxy/-3-phenyl-propiophenone in the form of a yellowish oil (yield 42%); mass spectrum: peaks among others at m/e 353 (M+, 0.8%), 128 (5.7%), 105 (1.8%) and 58 (100%);

i) 4-/(6-dimethylamino) hexyl/oxy -2-phenylacetophenone as a colorless solid with m.p. 69-71°C (yield 25%);

j) from 3-hydroxybenzophenone (Beilstein 8 (III), 1262) and N,N-dimethyl-6-amino-1-hexanol, 3-/(6-(dimethyl-amino)hexyl /oxy/ benzophenone is obtained as a yellow oil (yield 73%); mass spectrum: peaks, among others, at m/e 325 (M+, 3%), 128 (6%), 105 (6%) and 58 (100%);

Example 2

a) 100 ml of 10% aqueous sodium hydroxide solution is added to a solution of 34.5 g of 1,5-dibromopentate, 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 obtained residue on a silica gel column using a mixture of hexane/ethyl acetate 7:3 yielded 13.47 g (78%) of 4-(5-bromopentyl)oxy/benzophenone as a colorless oil.

A solution of 3.0 g of 4-/(5-bromopentyl)oxy/benzophenone in 30 ml of ethanol is heated in 16 ml of a 33% solution of dimethylamine in ethanol for 1.5 hours in a pressure tube (test tube) at 90 °C. After cooling, the mixture is poured into water and extracted three times with ethyl acetate. The organic phases, which are dried over sodium sulfate, are evaporated and the resulting residue is chromatographed on an aluminum oxide column (activity level III) (which is neutral) using a hexane/ethyl acetate mixture as eluent 7:3. 2.69 g (97%) of 4-(5-dimethylamino)pentyl)oxy/benzophenone is obtained as a colorless oil.

1H-NMR (CDCl3): 1.6-2.0 (m,2H), 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 way, the following are obtained:

b) 4-/(8-bromoxyl)oxy/benzophenone is obtained from 1,8-dibromooctane and 4-hydroxybenzophenone in the form of colorless crystals with m.p. 59 - 61°C (yield 81%) and 4-/(8-(dimethylamino)octyl/oxy/-benzophenone is obtained from it in the reaction with dimethylamine in the form of a yellowish oil (yield 42%).

1H-NMR (CDCl3): 1.3-1.6 (m,10H), 1.80 (qui,J=7Hz,1H), 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) 4-/(6-bromohexyl)oxy/benzophenone is obtained from 1,6-dibromohexane and 4-hydroxybenzophenone as colorless crystals with m.p. 47-49° (yield 77%), and from this, in the reaction with pyrrolidine, 4-/(6-(pyrrolidino)hexyl)oxy/benzophenone is obtained as a colorless oil (yield 33%).

1H-NMR (CDCl3): 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-dibromooctane and 4-hydroxybenzophenone, 4-/(4-bromobutyl)oxy/benzophenone is obtained (yield 86%), and from it in the reaction with dimethylamine, 4-//4-(dimethylamino)- butyl/oxy/benzophenone as a yellowish oil (yield 80%).

Mass spectrum: peaks before 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, 4-/(6-bromohexyl)oxy/benzophenone is obtained (yield 66%), and from it in the reaction with N,N-dipropylalamine, 4-//6- (dipropylamino)hexyl/oxy/benzophenone in the form of a yellowish oil (yield 94%).

Mass spectrum: peaks with others at m/e 385 (M+, 3%), 352 (60%) and 114 (100%).

f) from 4-/(6-bromohexyl)oxy/benzophenone and trimethylamine, 4-/((6-azetidinyl)hexyl)oxy/benzophenone is obtained 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, 4-/(7-bromoheptyl)oxy/benzophenone is obtained (yield 82%), and from it in the reaction with dimethylamine, 4-//(7-dimethylamino)heptyl is obtained /oxy/benzophenone in the form of a yellowish oil (yield 90%).

Mass spectrum: peaks with other m/e 339 (M+, 3%), 121 (2%), 105 (3%) and 58 (100%).

h) from 1,9-dibromnonane and 4-hydroxybenzophenone, 4-/(9-bromnonyl)oxy/benzophenone is obtained (yield 74%), and from it in the reaction with dimethylamine, 4-//(9-dimethylamino)nonyl is obtained /oxy/benzophenone as a colorless solid with m.p. 44-45°C (yield 77%).

i) 4-/(10-bromodecyl)oxy/benzophenone is obtained from 1,10-dibromodecane and 4-hydroxybenzophenone (75% yield), and 4-//(10-dimethylamino) is obtained from it in the reaction with dimethylamine -decyloxy/benzophenone with m.p. 33-35°C (yield 90%);

j) from 4-/(6-bromohexyl)-oxy/benzophenone and methylamine, 4-//6-(methylamino)hexyl/oxy/benzophenone is obtained. By treating with an ester solution of hydrochloric acid, the corresponding hydrochloride is obtained in a yield of 13%; d.p. 155-157°C;

k) from 4-/(6-bromohexyl)-oxy/benzophenone and N-allyl-methylamine, 4-//6-(allylmethylamino)hexyl/oxy/benzophenone is obtained in the form of a yellowish oil (yield 55%).

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

l) 4-/(6-bromohexyl)oxy/-2-phenylacetophenone is obtained from 1,6-dibromohexane and 4-hydroxy-2-phenylacetophenone as a yellowish solid with m.p. 75-78°C (yield 71%) and from it with N-allylmethylamine 4-//6-(allylmethylamino)hexyl/oxy/-2-phenylacetophenone is obtained in the form of 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 no. 167240 and 128692) and 1,6-dibromohexane, 4-/(6-bromohexyl)oxy/-4 ́-fluorobenzophenone is obtained in the form of a colorless crystal with m.p. 79°C (yield 57%) and from it, in the reaction with N-allyl-methylamine, 4-//6-(allylmethyl-amino)hexyl/oxy/4 ́-fluorobenzophenone is obtained, which is converted into the hydrochloride (yield 74% ), m.p. 84°C;

n) 4-/(4-bromo-2-butenyl)oxy/benzophenone is obtained from trans-1,4-dibromobutene and 4-hydroxybenzophenone in the form of colorless hard crystals with m.p. 100°C (yield 45%) and from it, in the reaction with dimethylamine, trans-4-//4-(dimethylamino)-2-butenyl/oxy/benzophenone is obtained as a colorless solid with m.p. 48-50°C (yield 69%);

o) from 4-/(4-bromo-2-butenyl)oxy/benzophenone and N-allyl-methylamine, trans-4-//4-(allylmethylamino)-2-butenyl/-oxy/benzophenone is obtained, which converts to hydrochloride (yield 88%), m.p. 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 triphenyl-phosphine in 100 ml of tetrahydrofuran at 20°C it is slowly mixed (treated) with a solution of 1.97 g of diethyl ester of nitrous carbonic acid. After instillation, it is stirred for another 5 hours at room temperature. The reaction mixture is then evaporated in a rotary evaporator. The residue is chromatographed on 400 g of neutral aluminum oxide (activity level III) using a mixture of hexane/ethyl acetate 7:3. 2.22 g (64%) of 4-//6-(diethylamino)hexyl/oxy/benzaldehyde are obtained as a yellowish oil.

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

c) In a solution of 0.8 ml of oxalyl chloride in 30 ml of methylene chloride, a solution of 1.58 ml of dimethylsulfoxide in 10 ml of methylene chloride is added dropwise at 60°C for 5 minutes. After 2 minutes of mixing, a solution of 1-/4-//6-(dimethylamino)-hexyl/oxy/phenyl-3-phenylpropanol in 20 ml of methylene chloride is added at -60°C over a period of 10 minutes. After 15 minutes, 75 ml of triethylamine was added at -60°C and the reaction mixture was allowed to warm to room temperature. After standing at room temperature for 1 hour, 100 ml of water is added to it, the organic phase is separated and the aqueous phase is extracted twice with 100 ml of methylene chloride. The combined organic phases are dried over magnesium sulfate and evaporated. After chromatography of the obtained residue on 240 g of silica gel using a mixture of ammonium hydroxy/methanol/methylene chloride 1 : 10 : 90, 1.76 g (37%) of 4 ́-//6-(diethylamino)hexyl/oxy-3-phenylpropiophenone is obtained as a yellow oils, which crystallize on standing; d.p. 83-84°C.

In an analogous way, the following are obtained:

d) from 3-//6-(diethylamino)hexyl/oxy/benzaldehyde (which was obtained from 3-hydroxybenzaldehyde and 6-(diethylamino)-1-hexanol) and phenethylmagnesium bromide, and then by oxidation of the condensation product with a mixture of oxalyl chloride/dimethyl- sulfoxide gives 3 ́//6-(dimethylamino)hexyl/oxy/-3-phenylpropiophenone as a yellow oil yield 38%).

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

e) from 3-//6-(dimethylamino)hexyl/oxy/benzaldehyde and lithium phenyl-acetylide, 3-//6-(diethylamino)hexyl/oxy/-a-(phenylethynyl)benzylalcohol is obtained, and from it 3 is then obtained ́-//6-(dimethylamino)hexyl/oxy/-3-phenylpropiolphenone (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) In a solution of 5.52 g of pentafluorobenzene in 50 ml of tetrahydrofuran at –78°C under argon, 20.75 ml of a 1.6 M solution of n-butyllithium in hexane is added dropwise. 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 added dropwise. After one hour at -78°C, the mixture is left at room temperature to warm up to that temperature and then stirred for another hour. The reaction mixture is placed on 100 ml of saturated aqueous ammonium chloride solution and extracted three times with 100 ml of ethyl acetate. The organic phases are washed with 100 ml of saturated aqueous sodium chloride solution and dried over magnesium sulfate. After evaporation, 10 g of crude 2,3,4,5,6-pentafluorophenyl-4 ́-methoxyphenylcarbonyl is obtained.

b) A solution of this crude carbonyl in 60 ml of methylene chloride is added dropwise to a solution of 3.3 ml of oxalyl chloride and 5.6 ml of dimethylsulfoxide in 130 ml of methylene chloride over a period of 15 minutes at -78°C under argon. The mixture is stirred for 15 minutes at –78°C. To this is then added 27.6 ml of triethylamine at -78°C over a period of 15 minutes. The mixture is allowed to warm to room temperature. The reaction mixture is then mixed with 500 ml of water. The organic phase is separated, and the aqueous phase is extracted twice with 200 ml of methylene chloride each. The combined organic phases are dried over magnesium sulfate and evaporated in a rotary vacuum evaporator. The residue is chromatographed on 920 g of silica gel using methylene chloride as eluent. 7.82 g (78%) of 2,3,4,5,6-pentafluoro-4 ́-methoxy-benzophenone is obtained as a colorless oil.

c) A solution of 5.6 g of 2,3,4,5,6-pentafluoro-4 ́-benzophenone in 100 ml of ethylene chloride is added dropwise to a solution of 23.23 g of boron tribromide in 100 ml of ethylene chloride at –7°C under argon. The reaction mixture was warmed to room temperature and then stirred for 5 hours at that temperature. The reaction mixture is then placed in 200 ml of ice-cooled water and extracted three times with 150 ml of methylene chloride. The combined extracts are washed with 200 ml of water and then dried over magnesium sulfate. After evaporation of the solvent, the resulting residue is chromatographed on 900 g of silica gel using methylene chloride as eluent. 3.87 g (72%) of 2,3,4,5,6-pentafluoro-4 ́-hydroxybenzophenone with m.p. 138-140°C.

d) Analogously to example 1, 4 ́-//6-(dimethylamino) hexyl/oxy/ is obtained from 2,3,4,5,6-pentafluoro-4 ́-hydroxy-benzophenone and 6-(dimethylamino)-1-hexanol -2,3,4,5,6-pentafluoro-benzophenone as a colorless oil (yield 37%).

1H-NMR (CDCl3): 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) Analogously to example 3b) from 4-//6-(dimethylamino)hexyl/oxy/-benzaldehyde and phenylacetylene/butyllithium, crude 4 ́-//6-(diethylamino)hexyl/oxy/phenyl-phenylethynyl-carbonyl is obtained (yield 50%).

b) A solution of 1.58 g of 4 ́-//6-(diethylamino)hexyl/oxy/-phenyl-feylethynyl-carbonyl in 60 ml of methylene chloride is mixed with 2.07 g of activated manganese dioxide. After 20 hours, the reaction mixture is filtered through kieselguhr. After evaporation of the filtrate, the residue is chromatographed on a column of 100 g of neutral aluminum oxide (activity level III) using a mixture of hexane/ethyl acetate 2:1. 1.34 g (50%) of 4 ́-//6-(diethylamino)hexyl/oxy/-3-phenylpropiolphenone is obtained 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 (carbon tetrachloride) is heated for 12 hours under reflux until boiling. After cooling this solution, it is filtered, and the resulting filtrate is evaporated. The residue is recrystallized from hexane. 18.6 g (47%) of 4-bromo-2-methylanisole is obtained as a colorless solid with m.p. 66 – 68°C.

b) From 10 g of 4-bromo-2-methylanisole and 1.21 g of magnesium pilotine in 30 ml of tetrahydrofuran, the appropriate Grinjar reagent is made, which is added dropwise to a solution of 7 g of benzoyl chloride in 80 ml of tetrahydrofuran that has previously been cooled to -72 °C. The temperature is kept below –65°C. After instillation, it is stirred for half an hour at 2°C, after which it is 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 obtained residue on silica gel using a mixture of hexane/ethyl acetate 7:3 gives 6.17 g (55%) of 4-methoxy-3-methylenebenzophenone as a yellowish oil.

1H-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-methylbenzophenone, 65 ml of acetic acid and 103 ml of a 62% hydrobromic acid solution is heated for 3 hours under reflux until boiling. The resulting dark solution is concentrated, extracted with ethyl acetate, and the organic phase is dried and evaporated. The residue is chromatographed using a mixture of hexane/ethyl acetate 7:3 as eluent on a silica gel column. 2.90 g (50%) of 3-methyl-4-hydroxybenzophenone is obtained as a yellowish solid (substance) with m.p. 170 – 173°C.

d) Analogously to example 2, 4-(6-bromohexyl)oxy-3-methyl-benzophenone is obtained from 1,6-dibromohexane and 3-methyl-4-hydroxybenzophenone as a yellowish oil (yield 78%; 1H-NMR (CDCl3) : 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 from this, in the reaction with dimethylamine, 4-//6-(dimethylamino)hexyl/-oxy/-3-methylenebenzophenone is obtained, which is converted into the hydrochloride (yield 61% ); d.p. 162 – 163°C.

Example 7

Analogously to example 2, from 4-/(6-bromohexyl)oxy/-3-methyl-benzophenone and N-allylmethylamine, 4-//6-(allylmethylamino)hexyl/oxy/-3-methylbenzophenone is obtained, which is converted into the hydrochloride (yield 49%); d.p. 112-113°C.

Example 8

a) From Grinjar's reagent (which is obtained from 2-bromo-m-xylene and 4-methoxybenzochloride), working analogously to example 6b), 4-methoxy-2 ́,3 ́-dimethylbenzophenone is obtained as a yellowish oil (yield 47%) .

1H-NMR (CDCl 3 ): 2.15 (s,6H), 3.85 (s,3H), 6.8-7.95 (m,7H) ppm.

b) Analogously to example 6c), 4-hydroxy-2 ́,3 ́-dimethylbenzophenone is obtained as yellowish crystals (yield 72%); d.p. 155 – 158°C.

c) Working analogously to example 2, from this, in the reaction with 1,6-dibromohexane, 4-/(6-bromohexyl)oxy/-2 ́,3 ́-dimethylbenzophenone is obtained as a yellowish oil (yield 78%; 1H-NMR (CDCl3) : 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, in the reaction with dimethylamine, 4-//6-(dimethylamino)hexyl/oxy/-2 ́,3 ́-dimethylbenzophenone is obtained, which is converted into hydrochloride (yield 81%); d.p. 117 – 120°C.

Example 9

From 4-/(6-bromohexyl)-2 ́,3 ́-dimethylbenzophenone and N-allylmethylamine, working analogously to example 2, 4-//6-(allylmethylamino)hexyl/oxy/-2 ́,3 ́-dimethyl is obtained -benzophenone as a yellowish oil (yield 82%).

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

Example 10

a) Starting from Grinjar's reagent (which is obtained from 4-bromoanisole and 2,4-dichlorobenzoyl chloride), working analogously to example 6b), 2,4-dichloro-4 ́-methoxybenzophenone is obtained as a yellowish oil (yield 76%); 1H-NMR (CDCl 3 ): 3.56 (3.3H), 6.9-8.0 (m, 7H).

b) Working analogously to example 6c), 4-hydroxy-2 ́,4 ́-dichlorobenzophenone is obtained from this in the form of yellowish crystals (yield 63%); d.p. 140°C.

c) Working analogously to example 2, 4-/(6-bromohexyl)oxy/-2 ́,4 ́-dichlorobenzophenone is obtained from this in the reaction with 1,6-dibromohexane as a colorless oil (yield 86%; mass spectrum: peaks next to the rest at m/e 430 (M+, 10%), 266 (19%), 173 (18%), 121 (100%), and from this, in the reaction with N-allylmethylamine, 4-//6-allylmethylamino is obtained) hexyl/oxy/-2 ́,4 ́-dichlorobenzophenone in the form of a yellowish oil (yield 67%).

Mass spectrum: peaks, among others, at m/e 419 (M+, 2%), 173 (3%), 84 (100%).

Example 11

From 4-hydroxy-2 ́,4 ́-dichlorobenzophenone and N,N-dimethyl-6-amino-1-hexanol, working analogously to example 1, 4-//6-(dimethylamino)hexyl/oxy/-2 ́ is obtained ,4 ́-dichlorobenzophenone as a colorless oil (yield 31%).

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

Example 12

Starting from Grinjar's reagent (which was obtained from 4-bromoanisole and 3,5-dichlorobenzoyl chloride), working analogously to example 6b), 3,5-dichloro-4 ́-methoxybenzophenone is obtained in the form of a colorless solid (yield 37%).

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

Working analogously to example 6c), 4-hydroxy-3 ́,5 ́-dichlorobenzophenone is obtained from this in the form of brown crystals (yield 91%); d.p. 183°C.

Working analogously to example 2, 4-/(6-bromohexyl)oxy/-3 ́,5 ́-dichlorobenzophenone is obtained from this in the reaction with 1,6-dibromohexane as a colorless solid (yield 49%) with m.p. 70°C, and 4-//6-(dimethylamino)hexyl/oxy/-3 ́,5 ́-dichlorobenzo-phenone is obtained from this in the reaction with dimethylamine, which is converted into the hydrochloride (yield 66%); d.p. 148 – 149°C.

Example 13

From 4-/(6-bromohexyl)oxy/-3 ́,5 ́-dichlorobenzophenone and N-allylethylamine, working analogously to example 2, 4-//6-(allylmethylamino)hexyl/oxy-3 ́,5 ́- dichlorobenzophenone, which is converted to the hydrochloride (yield 74%), m.p. 111-112°C.

Example 14

From 4-hydroxy-2 ́,4 ́-dichlorobenzophenone and trans-1,4-dibromobutene, working analogously to example 2, 4-/(4-bromo-2-butenyl)oxy/-2 ́,4 ́-dichlorobenzophenone is obtained , as a sticky resin (yield 73%; mass spectrum: peaks, among others, at m/e 400 (M+, 2%), 319 (3%), 173 (54%), 133 (45%), 121 (70%) and from this, in the reaction with dimethylamine, trans-4-//4-(dimethylamino)-2-butenyl/oxy/-2 ́,4 ́-dichloro-benzophenone is obtained, which is converted into the hydrochloride (yield 82%); m.p. 147°C.

Example 15

Starting from 4-/(4-bromo-2-butenyl)oxy/-2 ́,4 ́-dichlorobenzo-phenone and N-allylmethylamine, working analogously to example 2, one obtains trans-4-//4-(allylmethylamino)- 2-butenyl/oxy/-2 ́,4 ́-dichlorobenzophenone, which is then converted to the hydrochloride (yield 80%); d.p. 98°C.

Example 16

a) 150 ml of nitrobenzene is cooled in a cold bath and treated in portions with 41 g of ammonium chloride. The temperature is maintained below 5°C. Then a solution of 50 g of 4-nitrobenzoyl chloride in 50 ml of nitrobenzene is added dropwise, in such a way that the temperature is maintained below 5°C. At the same temperature, 27.8 g of anisole are dropped into it. It is then stirred overnight at 20°C. The solution is placed in one liter of cold water, extracted with methylene chloride, dried over magnesium sulfate and concentrated. Nitrobenzene is distilled off under high vacuum, and the remaining yellowish crystals are recrystallized from cyclohexane. 36.5 g (52%) of 5-methoxy-4 ́-nitrobenzophenone is obtained as a yellow solid with m.p. 124°C.

b) Starting from 4-methoxy-4 ́-nitrobenzophenone and hydrobromic acid, working analogously to example 6c), 4-hydroxy-4 ́-nitrobenzophenone is obtained in the form of yellow crystals (yield 75%); d.p. 196°C.

c) Working analogously to example 2 and starting from 4-hydroxy-4 ́-nitrobenzophenone and 1,6-dibromohexane, 4-/(6-bromohexyl)-oxy-4 ́-nitrobenzophenone is obtained in the form of a yellow solid with m.p. 61°C (yield 65%), and from this, in the reaction with dimethylamine, 4-//6-(dimethylamino)hexyl/oxy/-4 ́-nitrobenzophenone is obtained, which is converted into the hydrochloride (yield 80%), m.p. 101°C.

Example 17

Starting from 4-/(6-bromohexyl)oxy/-4 ́-nitrobenzophenone and N-allylmethylamine, working analogously to example 2, 4-//6-(alimethyl)amino)hexyl/oxy/-4 ́-nitrobenzophenone is obtained, which is converted into the hydrochloride (yield 85%); d.p. 79°C.

Example 18

Starting from 2-chloroanisole and benzoyl chloride, working analogously to example 16a), 3-chloro-4-methoxybenzophenone is obtained, in the form of a colorless solid (yield 72%); d.p. 87°C.

Working analogously to example 6c), 3-chloro-4-hydroxybenzophenone is obtained from this in the form of a yellowish solid (yield 91%); d.p. 180°C.

Working analogously to example 2, 4-/(6-bromohexyl)oxy/-3-chloro-benzophenone is obtained from this in the reaction with 1,6-dibromohexane in the form of a colorless solid, with m.p. 58°C (yield 68%), and from this, in the reaction with dimethylamine, 4-//6-(dimethylamino)hexyl/oxy/-3-chlorobenzophenone is obtained, which is converted into the hydrochloride (yield 94%); d.p. 195°C.

Example 19

Starting from 4-/(6-bromohexyl)oxy/-3-chlorobenzophenone and N-allylmethylamine, working analogously to example 2, 4-//6-(allylmethylamino)hexyl/oxy/-3-chlorobenzophenone is obtained, which is converted into hydrohydride (hydrochloride) (yield 98%); d.p. 133°C.

Example 20

From 2-chloroanisole and 2,4-dichlorobenzoyl chloride, working analogously to example 16b), 2 ́,3 ́,4 ́-trichloro-4-methoxybenzophenone is obtained, as yellowish crystals (yield 87%); d.p. 98°C.

Working analogously to example 6c), 2 ́,3 ́,4 ́-trichloro-4-hydroxybenzophenone is obtained from this in the form of yellowish crystals (yield 89%); d.p. 145°C.

Working analogously to example 2, 4-/(6-bromohexyl)oxy/-2 ́,3 ́,4 ́-trichlorobenzophenone is obtained from this in the reaction with 1,6-dibromohexane in the form of a yellow oil (yield 21%), and from this, in the reaction with dimethylamine, 4-//6-(dimethylamino)hexyl/oxy/-2 ́,3 ́,4 ́-trichlorobenzophenone is obtained, which is converted into the hydrochloride (yield 49%); d.p. 91°C.

Example 21

From 4-/(6-bromohexyl)oxy/-2 ́,3 ́,4 ́-trichlorobenzophenone from N-allylmethylamine, 4-//6-(allylmethylamino)hexyl/oxy/-2 ́,3 ́,4 ́-trichlorobenzophenone, which is converted into hydrochloride (yield 38%); d.p. 100°C.

Example 22

Working analogously to example 2, starting from 4-hydroxy-4 ́-nitrobenzophenone and trans-1,4-dibromobutane, 4-/(4-bromo-2-butenyl)oxy/-4 ́-nitrobenzophenone is obtained, in the form of a yellowish solid substance (yield 71%; and from this, in the reaction with dimethylamine, trans-4-//4-(dimethylamino)-2-butenyl/oxy/-4 ́-nitrobenzophenone is obtained, which is converted into hydrochloride (yield 90%); mp 144°C.

Example 23

From 4-/(4-bromo-2-butenyl)oxy/-4 ́-nitrobenzophenone and N-allylmethylamine, working analogously to example 2, trans-4-//4-(allylmethylamino)-2-butenyl/oxy/ is obtained -4 ́-nitrobenzophenone, which is converted into hydrochloride (yield 85%); d.p. 152°C.

Example 24

From 4-bromobenzoyl chloride and anisole, working analogously to example 16a), 4-bromo-4 ́-methoxybenzophenone is obtained as a colorless solid (yield 65%).

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

Working analogously to example 6c), 4-bromo-4 ́-hydroxybenzophenone is obtained from this in the form of a yellowish solid (yield 77%).

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

Working analogously to example 2, from this is obtained in the reaction with trans-1,4-dibromobutene, 4-/(4-bromo-2-butenyl)oxy/-4 ́-bromobenzophenone in the form of colorless crystals (yield 64%; mass spectrum : peaks among others at m/e 410 (M+, 4%), 329 (11%), 276 (32%), 183 (34%), 133 (50%), 121 (100%)), and from this in the reaction with dimethylamine, trans-4-//4-(dimethylamino)-2-butenyl/oxy/-4 ́-bromobenzophenone is obtained, which is converted into hydrochloride (yield 85%); d.p. 184 – 185°C.

Example 25

Working analogously to example 2 and starting from 4-/(4-bromo-2-butenyl)oxy/-4 ́-bromobenzophenone and N-allylmethylamine, trans-4-//4-(allylmethylamino)-2-butenyl/oxy /-4 ́-bromobenzophenone, which is converted into hydrochloride (yield 83%); d.p. 116 – 117°C.

Example A

The compound 4-/6-(dimethylamino)hexyl/oxy/-2-phenyl-acetophenone can be used as an active substance to obtain tablets in the following way:

[image]

The active substance and milk sugar powder are intensively mixed. The obtained mixture is then moistened with an aqueous solution of povidone K 30 and kneaded (kneaded), after which the granulated mass is obtained by granulating the obtained mass, then drying and screening of the mass is carried out. The granulate is mixed with other ingredients and pressed into tablets of the required size.

Claims (16)

1. Application of the compound of the general formula [image] in which R 1 and R 2 are each individually hydrogen, lower alkyl or lower alkenyl or together are straight-chain alkylene with 2 to 4 carbon atoms, R 3 is hydrogen, halogen or lower alkyl, Q is alkylene with 4 to 11 carbon atoms and at least 4 carbon atoms between the two valences and Y and Y' each denote a particularly direct bond or group -CH2-, -CH2CH2-, -CH=CH- or -C=C-, wherein the group R1R2N-Q-O- is attached in position 3 or 4 of the ring which is marked with the symbol A, and the symbol R means that this ring is not substituted or that it is substituted one or more times by halogen, trifluoromethyl, cyano group, nitro group, lower alkyl and/or lower alkoxy group, and their pharmaceutically acceptable acid addition salt, indicated by the fact that in combination with antifungal active substances that prevent and suppress the biosynthesis of sterols, to obtain antifungal active agents. 2. Application of a compound of the general formula [image] In which R1 and R2 are each individually hydrogen, lower alkyl or lower alkenyl or together are straight-chain alkylene with 2 to 4 carbon atoms, R3 is hydrogen, halogen or lower alkyl, Q' is alkylene with 5 to 11 carbon atoms and at least 5 atoms of carbon between two free valences or alkenylene with 4 to 11 carbon atoms and at least 4 carbon atoms between two valences and Y and Y' each stand for one a direct bond or a group -CH2-, -CH2CH2-, -CH=CH- or -C=C-, where the group R1R2N-Q'-O- is attached in position 3 or 4 of the ring marked with the symbol A, and the symbol R means that this ring is not substituted or is substituted one or more times by halogen, trifluoromethyl, cyano group, nitro group, lower alkyl and/or lower alkoxy group, and their pharmaceutically acceptable acid addition salts, indicated that in combination with antifungal active substances, which suppress and prevent the biosynthesis of sterols, to obtain antifungal active agents. 3. Procedure for obtaining a compound of the general formula [image] In which R1 and R2 are each individually hydrogen, lower alkyl or lower alkenyl or together are straight-chain alkylene with 2 to 4 carbon atoms, R3 is hydrogen, halogen or lower alkyl, Q' is alkylene with 5 to 11 carbon atoms and at least 5 atoms of carbon between two free valences or alkenylene with 4 to 11 carbon atoms and at least 4 carbon atoms between two free valences and Y and Y' each individually denote a direct bond or group -CH2-, -CH2CH2-, -CH=CH- or -C =C-, where the group R1R2N-Q'-O- is attached in position 3 or 4 of the ring marked with A, and the symbol R means that this ring is not substituted or that it is substituted one or more times by trifluoromethyl, a cyano group, lower by an alkyl and/or lower alkoxy group, provided that Y and Y' simultaneously do not denote a direct bond, when Q' denotes an alkylene with 5 carbon atoms and R1 and R2 simultaneously denote a lower alkyl with more than 2 carbon atoms and their pharmaceutically acceptable acid addition salts, characterized in that a) a compound of the general formula [image] in which X represents a leaving group and A, Q', Y, Y', R3 and R have the meaning given above, reacts with an amine of the general formula HNR1, in which R1 and R2 have the meaning given above, or which b) oxidizes a compound of the general formula [image] in which A, R1, R2, R3, Q', Y, Y' and R have the meaning given above,, or what c) a compound of the general formula [image] in which R' denotes lower alkyl, and A, R1, R2, R3, Q' and Y have the meanings given above, reacts with a compound of the general formula [image] in which M denotes -MgCl, -MgBr, -MgJ or -Li, and Y' and R have the meaning given above, or what d) a compound of the general formula [image] in which A, R1, R2, R3, Q' and Y have the meaning given above, reacts in the form of a reactive derivative in the presence of a Lewis acid with a compound of the general formula [image] in which R has the meaning given above, or what e) a compound of the general formula [image] in which A, R1, R2, R3, Q' and Y have the meaning given above,, reacts in the presence of a base with a compound of the general formula [image] in which R has the meaning given above,, or what f) hydrogenates a compound of the general formula [image] wherein A, R1, R2, R3, Q', Y and R are as defined above, or what g) a compound of the general formula [image] in which A, R, R3, Y and Y' have the meaning given above,, reacts in the presence of triphenylphosphine and di-(lower alkyl)ester of azodicarboxylic acid with a compound of the general formula R1 R2NQ' –OH in which R1, R2 and Q' have the meaning given above, and what h) if desired, the resulting compound of formula Ia is converted into a pharmaceutically acceptable acid addition salt. 4. The method according to claim 3, characterized in that R1 and R2 denote each individually hydrogen or lower alkyl or together denote straight-chain alkylene with 2 to 4 carbon atoms, R3 denotes hydrogen and Q' denotes alkylene with 5 to 11 carbon atoms and at least 5 carbon atom between two free valences, and the symbol R means that this ring is not substituted or is substituted by trifluoromethyl, lower alkyl or lower alkoxy group. 5. The method according to claim 3 or 4, characterized in that Q' denotes unbranched alkylene with 5 to 7 carbon atoms. 6. The method according to claim 3 or 5, characterized in that R1 and R2 denote each individual C1-4-alkyl or C3-4-alkylene. 7. The method according to one of claims 3 to 6, characterized in that the group R1 R2 N-Q'-O- is attached in position 4 of the ring marked with A. 8. The method according to one of claims 3 to 7, characterized in that Y denotes a direct bond or group –CH2-. 9. The method according to claim 8, characterized in that Y denotes a direct connection. 10. The method according to one of claims 3 to 9, characterized in that Y' denotes a direct bond or group -CH2-, -CH2CH2- or -CH=CH-. 11. The method according to claim 10, characterized in that Y' denotes a direct bond or the group -CH2-. 12. The method according to one of claims 3 to 11, characterized in that the symbol R means that this ring is unsubstituted or substituted by lower alkyl, once or twice. 13. The method according to claim 3, characterized in that what is obtained 4-[(6-(dimethylamino)hexyl)oxy]-2-phenylacetophenone, 4-[(6-(dimethylamino)hexyl)oxy]benzophenone, 4'-[(6-(dimethylamino)hexyl)oxy]-3-phenylpropiophenone, 4-[6-(dimethylamino)hexyl)oxy]-3-phenylpropiophenone, 4'-[(6-(dimethylamino)hexyl)oxy]-3-phenylacrylophenone 4-[(6-(dimethylamino)hexyl)oxy]benzophenone, 4-[(6-(1-azetidinyl)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 what is obtained 4-{[6-(allylmethylamino)hexyl]oxy}-2-phenylacetophenone, trans-4{- [4-(allylmethylamino)-2 butenyl]oxy} benzophenone, 4-{1 6-(allylmethylamino)hexyloxy}-3-methylbenzophenone, 4-{[6-(allylmethylamino)hexyl]oxy}-3-chlorobenzophenone. 15. Process for obtaining medicines, especially antifungal agents, indicated by the fact that a compound whose formula is defined in claim 2 or 3 (namely formula Ia) or one of its pharmaceutically acceptable acid addition salts is introduced into the galenic administration form and in the given case some other antifungally active substance that suppresses sterol biosynthesis, together with some therapeutically inert carrier. 16. Application of the compounds of formula Ia defined in claim 3 and its pharmaceutically acceptable acid addition salts in a given case in combination with other antifungal active substances that suppress the biosynthesis of sterols, indicated by this, to obtain antifungal agents.