RU2033991C1 - Aminoalkylbenzene derivatives or their pharmaceutically acceptable salts with acids - Google Patents

Abstract

FIELD: organic chemistry. SUBSTANCE: product: derivatives of aminoalkylbenzene of the formula (I)

where R₁ and R₂ and C_2-4 - hydrogen, lower alkyl or together - unbranched C_4-11-alkylene; Q - CF₃-alkylene with two carbon atoms as minimum between two free valences; Y - simple bond; R - hydrogen, Cl, NO₂, lower alkyl, or pharmaceutically acceptable salt with acid. Synthesized compounds were used in medicine. EFFECT: improved method of synthesis. 3 tbl

Description

N-Q-CH

CO

(I) где R₁ и R₂ каждый означают водород, низший алкил или вместе образуют неразветвленный алкилен С_2-4;
Q алкилен С_4-11 минимум с двумя атомами С между двумя свободными валентностями;
R означает, что кольцо не замещено или замещено галогеном, трифторметилом, нитрогруппой или низшим алкилом, а также к приемлемым для фармацевтических целей солям этих соединений с кислотами. Эти соединения обладают ценными фармакологическими свойствами, в частности имеют выраженные противогрибковое и синергическое действия в комбинации с известными противогрибковыми веществами, подавляющими биосинтез таких стеролов, как кетоцоназол и тербинафин. Поэтому соединения формулы (I) можно использовать в качестве лекарств, в частности для борьбы с топическими или системными заражениями, вызываемыми патогенными грибками, или для предупреждения подобного рода заражений.The invention relates to compounds of the general formula

NQ-CH

CO

(I) where R ₁ and R _{2 are} each hydrogen, lower alkyl, or together form straight chain C _2-4 alkylene;
Q alkylene C _4-11 with at least two C atoms between two free valencies;
R means that the ring is not substituted or substituted by halogen, trifluoromethyl, nitro or lower alkyl, as well as pharmaceutically acceptable salts of these compounds with acids. These compounds have valuable pharmacological properties, in particular, they have pronounced antifungal and synergistic effects in combination with known antifungal substances that inhibit the biosynthesis of sterols such as ketoconazole and terbinafine. Therefore, the compounds of formula (I) can be used as drugs, in particular for combating topical or systemic infections caused by pathogenic fungi, or for preventing such infections.

 The expression "lower" means residues and compounds with the number of C atoms not more than seven, preferably not more than four.

 The term “alkyl” means straight or branched chain saturated hydrocarbon residues, for example methyl, ethyl, propyl, isopropyl, tert.-butyl.

 The term “alkoxy” refers to alkyls attached via an oxygen atom, such as methoxy and ethoxy.

 The term “alkylene” means straight or branched saturated hydrocarbon residues with two free valencies, such as dimethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene.

 The expression "halogen" refers to four types of halogen fluorine, chlorine, bromine, iodine.

Within the scope of this aspect of the invention, the following compounds of formula (I) are preferred:
3- (4-chlorophenyl) -4 '- [3- (dimethylamino) propyl] propiophenone;
3- (2-methylphenyl) -4 '- [3- (dimethylamino) propyl] propiophenone;
(E) -3-phenyl-4 '- [3- (1-pyrrolidinyl) propyl] acrylophenone.

(II) где Х отщепляемая группа;
R³, Q, R имеют вышеуказанное значение, подвергают реакции взаимодействия с амином общей формулы
HNR¹R², где R¹ и R² имеют вышеуказанное значение,
б) соединение общей формулы

N-Q-CH

(III) где R¹, R², R³, Q и R имеют вышеуказанное значение, окисляют, или
в) соединение общей формулы

N-Q-CH

(IV) где R¹ низший алкил;
R¹, R², R³, Q имеют вышеуказанное значение, подвергают реакции взаимодействия с соединением общей формулы

(V) где М -MgCl, -MgBr, -MgJ или -Li;
R имеет вышеуказанное значение, или
г) соединение общей формулы

N-Q-CH

(VI) где R'' и R''' каждый означают низший алкил или вместе образуют диметилен или триметилен;
R¹, R², R³, Q и R имеют вышеуказанное значение, обрабатывают водной кислотой, или
д) соединение общей формулы

N-Q-CH

(VIIа)
или

(VIIб) в виде реакционноспособного производного в присутствии кислоты Льюиса подвергают реакции взаимодействия с соединением общей формулы

(VIIIа)
или

N-Q-CH

(VIIIб) где R¹, R², R³, Q и R имеют вышеуказанное значение, или
е) соединение общей формулы

N-Q-CH

(IX) где R¹, R², R³, Q имеют вышеуказанное значение, в присутствии основания подвергают реакции взаимодействия с соединением общей формулы

(X) где R имеет вышеуказанное значение, или
ж) соединение общей формулы

N-Q-CH

или

N-Q′‗‗ CH

(XI) где Q' группа Q, уменьшенная на атом водорода;
R¹, R², R³, Q и R имеют вышеуказанное значение, гидрируют и
з) полученное соединение формулы (I) при необходимости переводят в приемлемую для фармацевтических целей соль с кислотой.The novel compounds of formula (I) and their pharmaceutically acceptable acid salts according to the invention are obtained in that
a) a compound of the general formula
XQ CH

(II) where X is a leaving group;
R ³ , Q, R have the above meaning, are reacted with an amine of the general formula
HNR ¹ R ² where R ¹ and R ² have the above meaning,
b) a compound of the general formula

NQ-CH

(III) where R ¹ , R ² , R ³ , Q and R are as defined above, oxidize, or
c) a compound of the general formula

NQ-CH

(IV) where R ¹ lower alkyl;
R ¹ , R ² , R ³ , Q have the above meaning, are reacted with a compound of the general formula

(V) where M is MgCl, MgBr, MgJ or Li;
R has the above meaning, or
g) a compound of General formula

NQ-CH

(VI) where R ″ and R ″ ″ each are lower alkyl or together form dimethylene or trimethylene;
R ¹ , R ² , R ³ , Q and R are as defined above, treated with aqueous acid, or
d) a compound of the general formula

NQ-CH

(VIIa)
or

(VIIb) in the form of a reactive derivative in the presence of a Lewis acid is reacted with a compound of the general formula

(VIIIa)
or

NQ-CH

(VIIIb) where R ¹ , R ² , R ³ , Q and R have the above meaning, or
e) a compound of the general formula

NQ-CH

(IX) where R ¹ , R ² , R ³ , Q have the above meaning, in the presence of a base, they react with a compound of the general formula

(X) where R has the above meaning, or
g) a compound of the general formula

NQ-CH

or

NQ′‗‗ CH

(XI) where Q 'is a Q group reduced by a hydrogen atom;
R ¹ , R ² , R ³ , Q and R are as defined above, hydrogenated and
h) the resulting compound of formula (I) is, if necessary, converted into an acid salt suitable for pharmaceutical purposes.

The reaction of the compound of formula (II) with an amine HNR ¹ R ² according to process variant a) is carried out by methods known to the skilled person. It is in particular carried out in a polar solvent and in the presence of a base as an acid acceptor in a temperature range of about 0-150 ° ^C. In this case suitable solvents are, for example, lower alcohols such as methanol and ethanol and lower dialkyl ketones such as acetone. Suitable bases are, for example, an excess of the amine of the formula NHR ¹ R ² , tertiary amines, for example triethylamine, and inorganic bases such as alkali metal carbonates, hydroxides and alkoxides.

The oxidation reaction the compound (III) according to process variant b) is also carried out by methods known to those skilled in particular in the presence of an inert solvent and in the presence of an oxidant in the approximate temperature range from 80 ^C to room temperature. Suitable solvents are, for example, chlorinated lower hydrocarbons, for example, methylene chloride and chloroform. Suitable oxidizing agents are, for example, manganese dioxide or a mixture of DMSO with oxalyl chloride, dicyclohexylcarbodiimide or acetanhydride and a tertiary amine, for example triethylamine.

The reaction of the compound (IV) with the compound (V) according to variant c) is also carried out by methods known to those skilled in particular in an inert solvent and in the approximate temperature range from 80 ^C to room temperature. Suitable solvents are, for example, non-cyclic and cyclic ethers such as diethyl ether, methyl tert-butyl ether and tetrahydrofuran, and mixtures of these compounds.

For treating the compound of formula VI with an aqueous acid according to variant d) is used preferably dilute aqueous mineral acid, such as dilute hydrochloric acid, and reacted at a temperature ranging from about 0 ° ^C to room temperature.

The reaction of a reactive derivative of a compound of formula (VIIa) with a compound of formula (VIIIa) or a reactive compound of formula (VIIb) with a compound of formula (VIIIb) according to process variant e) is carried out by methods known to those 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 from about 0 ° C to ^about 100 ^C. Suitable solvents are, for example, halogenated lower hydrocarbons such as methylene chloride, chloroform and ethylene chloride, nitrobenzene, carbon disulfide and an excess of the compound of formula (VIIIa). As the Lewis acid, aluminum chloride is preferably used. Suitable reactive derivatives of the compounds of formula (VIIa) or (VIIb) are, for example, carboxylic acid chlorides.

The reaction of a compound of formula (IX) with a compound of formula (X) in the presence of a base according to process variant e) is carried out by methods known to the skilled person. The reaction is preferably carried out in a polar solvent and in a temperature range of about 0-60 ° ^C. Suitable solvents are, for example, lower alcohols such as methanol and ethanol, and mixtures of these compounds with water. Preferably, alkali metal carbonates and hydroxides such as potassium carbonate and sodium hydroxide are used as bases.

The hydrogenation reaction the compound of formula (I) or (XI) according to an embodiment w) of the process is carried out by methods known to those skilled in particular in a polar solvent with elemental hydrogen in the presence of a suitable hydrogenation catalyst and in the approximate temperature range of from 0 ° ^C to room temperature. Suitable solvents are also lower alcohols, such as methanol and ethanol. Suitable catalysts are, for example, palladium or platinum on carbon, platinum oxide or Raney nickel.

 The preparation of pharmaceutically acceptable salts of the compounds of formula (I) with acids according to Process Option h) is carried out by methods known to those skilled in the art. This refers to salts with pharmaceutically acceptable inorganic or organic acids. Preferred acid salts are hydrochlorides, hydrobromides, sulfates, nitrates, citrates, acetates, succinates, fumarates, methanesulfonates, p-toluenesulfonates.

 The compounds of formula (I) and their pharmaceutically acceptable acid salts have valuable antifungal properties. They are effective in controlling many pathogenic fungi that cause topical and systemic infections, such as fungi such as Candida albicans and Histoplasma capsulatum. An indispensable enzyme in the life of fungi participating in the biosynthesis of sterol in a eukaryotic cell is 2,3-epoxysqualene-lanosterol cyclase. Thus, strains of S. cerevisiae lacking this enzyme are not viable (see F. Karst and F. Lacroute, Molec. Gen. Genet. 154, 269 (1977). The inhibitory effect of the compounds of formula (I) on the above enzyme contained in fungus C. albicans was chosen as a criterion for antifungal action, and inhibition can be measured, for example, by the method described below.

 Establishment of inhibition of the activity of 2,3-epoxysqualene-lanosterol cyclase of Candida albicans fungus by determining the IC50 value. First, Candida albicans culture cells are harvested at the end of the logarithmic growth phase and washed with 100 mM phosphate buffer (pH 6.9) for digestion buffer, and 50 mM phosphate buffer (pH 7.4) containing 1 M mannitol and 5 mM DTT.

1.0 g of cells was weighed in 5 ml of digestion buffer added to the slurry and 1 mg zimolazy 100T (f-we Seikagaku Kogyo, Japan) and 12.5 l of β-mercaptoethanol after which it was allowed to stand for 30 minutes at 30 ^C. The protoplasts formed during this time are separated by centrifugation (10 min at 2500 g), followed by their rupture by adding 2 ml of 100 mM phosphate buffer (pH 6.9). As a result of repeated centrifugation (10 min at 10,000 g), a supernatant is obtained, which is a cell-free extract (CFE). The latter is diluted to 10 mg protein / ml, after which the pH is adjusted to 6.9.

The activity of 2,3-epoxy-squalene-lanosterol cyclase in CFE is measured by treating squalene-C ¹⁴ epoxide with n-decylpentaoxyethylene as a detergent. By titration of suitable amounts of the test substance, IC ₅₀ values are determined, i.e. the concentration of the test substance, reducing the activity of the enzyme by half.

This experiment is carried out as follows. By sonication, a 250 μM solution of squalene-C ¹⁴ epoxide in 100 mM phosphate buffer (pH 6.9) containing 1% n-decylpentaoxyethylene is first prepared. To 100 μl of this solution, 20 μl of a test substance solution (or 20 μl of pure dimethyl sulfoxide as a control) is added. After addition of 880 .mu.l of CFE well-mixed solution is maintained with shaking for 1 hour at 30 ^C. Then, the addition of 500 .mu.l of 15% potassium hydroxide in 90% ethanol stopped the reaction.

 The resulting mixture was extracted twice with 1 ml of n-hexane, after which hexane was evaporated and the resulting lipid residue was mixed with 200 μl of diethyl ether. After thin-layer chromatography of the product on silica gel with methylene chloride as a solvent, TLC plates were examined using a scanning device to determine the presence of radioactive substances.

 Under the above conditions, only lanosterol is detected as a radioactive product. The amount of the latter is compared with the amount of radioactive lanosterol in the control substance.

IC ₅₀ values are determined graphically and are indicated in μg of test substance per ml. Table 1 shows the IC ₅₀ values for representative representatives of the compounds of formula (I), as well as acute toxicity data for subcutaneous administration of test compounds to mice (LD ₅₀ in mg / kg).

+

Соединения формулы (I) имеют синергическое действие при том условии, что значение ФИК < 0,5. Приведенные в табл.2 и 3 данные для соединения (I) по табл. 1, представляющего собой показательный представитель определенного формулой (I) класса соединений, в комбинации с кетоконазолом, представляющим собой показательный ингибитор биосинтеза стерола, являются доказательством синергического действия соединений.The above synergistic effect of the compounds of formula (I) and their pharmaceutically acceptable salts with acids in combination with sterol biosynthesis inhibitors, for example, ketoconazole, can, for example, be demonstrated by agar serial dilution. For this purpose, casein agar of the Casitonagar type and inoculum (10 cells / ml) two-day cultures of Candida albicans are used. Test substances (compounds of formula (I), TB) are applied at concentrations of 80-1.25 μg / ml, and sterol biosynthesis inhibitors (IHD) at a concentration of 20-0.001 μg / ml) with a dilution ratio of 1: 2. Culture incubated for 2 days at 37 ^C. The minimal inhibitory concentration (MIC) of the individual active ingredients in pure form or in combination with other substances. Based on the MIC values, the fractionated inhibitory concentration (FIC) is calculated by the following formula:
FIC

+

The compounds of formula (I) have a synergistic effect provided that the FIC value is <0.5. The data in tables 2 and 3 for compound (I) in table. 1, which is an indicative representative of a class of compounds defined by formula (I), in combination with ketoconazole, which is an indicative inhibitor of sterol biosynthesis, is evidence of the synergistic effect of the compounds.

 The compounds of formula (I) and their pharmaceutically acceptable acid salts can be used as medicaments, for example in the form of pharmaceutical preparations for enteral or parenteral administration or for topical administration. They can be administered orally, for example in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, for example in the form of suppositories, parenterally, for example in the form of solutions for injection or infusion, or topically for example in the form of ointments, creams or oils.

 The preparation of pharmaceutical preparations is carried out by a sample known to the skilled person, i.e. the fact that the described compounds of formula (I) and their pharmaceutically acceptable salts, if necessary, in combination with other therapeutically valuable substances, for example with the indicated sterol biosynthesis inhibitors, together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carriers and if necessary, with conventional pharmaceutical excipients is processed into a galenic preparation.

 Sterol biosynthesis inhibitors suitable for combination with the compounds of formula (I) include, for example, systemically active antifungal azoles of the miconazole type, such as ketoconazole, itraconazole and fluconazole, as well as systemically active antifungal allylamines of the naphthifin type, such as naphthifin and terbine.

 Carriers can be both inorganic and organic carriers. As such carriers for coated and uncoated tablets, as well as dragees and hard gelatine capsules, for example, lactose, corn starch or its derivatives, talc, stearic acid or its salts can be used. Suitable carriers for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc. (Depending on the nature of the active principle, the use of carriers for soft gelatin capsules may be unnecessary). Carriers such as water, polyols, sucrose, invert sugar, glucose, and the like are suitable for preparing solutions and syrups. Suitable carriers for injectable solutions are, for example, water, alcohols, polyols, glycerin, vegetable oils, and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carriers for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, fatty alcohols, sterols, polyethylene glycols, cellulose derivatives.

 As auxiliary pharmaceutical substances, conventional stabilizers, preservatives, wetting agents, emulsifiers, consistency enhancing agents, sweetening and flavoring agents, salts for varying the osmotic pressure, buffers, dissolution agents, colorants, coating agents and antioxidants can be used.

 Depending on the type of pathogenic fungi, age and state of health of the patient, as well as on the method of administration of drugs, their dosage can vary widely. It should be adapted to the individual needs of the patient. In order to prevent tonic and systemic infections caused by pathogenic fungi, as well as to combat such infections during patient monotherapy, a daily dose of about 0.01-4 g, in particular about 0.05-2 g, is suitable. Depending on the dosage, it is advisable to introduce a daily dose in the form of several single doses. A suitable daily dose for combination therapy is about 0.01-2 g, in particular about 0.02-1 g of the compound of formula (I) and about 0.02-0.2 g of a sterol biosynthesis inhibitor.

 Pharmaceutical monopreparations usually contain about 10-1000 mg, preferably 50-500 mg of the compound of formula (I), and combined preparations of about 10-500 mg, preferably 20-250 mg of the compound of formula (I) and about 50-100 mg of a sterol biosynthesis inhibitor.

The superiority of the new compounds compared with the closest prototype follows from the above report on the experiments. However, the progressivity of new compounds in comparison with the known fungicide cannot be judged only on the basis of a comparison of the numerical values of the concentrations that have an inhibitory effect. New compounds are valuable primarily because they have a different mechanism of action than the known antimycotic agents. Known antimycotic agents are either 4.4 ', 14-trimethylsterol demethylation inhibitors (these include azoles and similar compounds), or Δ ⁸ - Δ ⁷ sterol isomerase inhibitors (e.g. phenpropidine and fenpropimorph) or squalene epoxidase inhibitors (c these include alkyl amines and similar compounds). In contrast, the novel compounds are 2,3-epoxysqualene-lanosterol cyclase inhibitors. To solve the problems of resistance, it is necessary to have available compounds that have an effect in other places of fungal metabolism than the compounds used so far. Thus, the new compounds enrich the range of available antimycotic agents.

EXAMPLES EXAMPLE 1 a) 9.3 g of 1,6-dibromohexane and 5 g of triphenylphosphine is stirred in an argon atmosphere at ¹⁰⁰ ° C for 1 hour. The reaction mixture was then cooled and chromatographed on 90 g of silica gel with a mixture of methylene chloride and methanol (95: 5). To the obtained 6-bromohexylphosphonium bromide (6.37 g, 65%) was added 35 ml of a 33% solution of dimethylamine in ethanol and stirred for 1 day at room temperature under argon atmosphere. The solution was evaporated and the resulting residue was completely dried under high vacuum. The thus obtained hydrobromide 6- (dimethylamino) hexyl-trifenilfosfoniy- bromide is weighed into a 50 ml THF, then at ⁰ ° C was added portionwise 2.09 g of potassium tert-butoxide. The resulting mixture was stirred for 15 min at 0 ^C. Then, at ⁰ ° C was added a solution of 1.86 g of 4-benzoyl-benzaldehyde [Tetrahed. Let. 24, 4287 (1983)] in 10 ml of THF, after which the resulting mixture was stirred at room temperature for 18 hours. Then the reaction mixture was evaporated. The residue is mixed with 100 ml of 1 N. hydrochloric acid and extracted three times with 100 ml of diethyl ether. The aqueous phase is cooled with ice using 2 N. The sodium hydroxide solution is adjusted to an alkaline reaction and extracted three times with methylene chloride. The organic phases are dried with magnesium sulfate and evaporated. The resulting crude product is chromatographed over 100 g of neutral alumina (activity grade III) with a mixture of methylene chloride and ethyl acetate (95: 5). Evaporation gave 1.98 g (31%) of 4 - [(Z) -7- (dimethylamino) -1-heptenyl] benzophenone as a colorless oil.

Data ¹ H-NMR analysis (CDCl ₃ ): 1.3-1.8 (m, 6H); 2.22 (s, 6H); 2.29 (t, J 8 Hz, 2H); 2.35 (m, 2H); 5.80 (dht, J 12 Hz, J 7 Hz, 1 H); 6.48 (dht, J 12 Hz, J 2 Hz, 1 H); 7.39 (d, J 8 Hz, 2 H); 7.4-7.8 (m, 7H) ppm.

 b) 1.12 g of 4 - [(Z) -7- (dimethylamino) -1-heptenyl] benzophenone is dissolved in 30 ml of methanol. 20 mg of 5% palladium-carbon was added to the solution and the suspension was stirred under a hydrogen atmosphere under normal pressure at room temperature for 2.5 hours. The reaction mixture was filtered through silica gel and the filtrate was evaporated. 1.10 g (98%) of 4- [7- (dimethylamino) heptyl] benzophenone are obtained as a colorless oil.

Data ¹ H-NMR analysis (CDCl ₃ ): 1.3-1.6 (m, 8H); 1.67 (q, J, 7.5 Hz, 2 H); 2.23 (s, 6H); 2.29 (t, J 8 Hz, 2); 2.69 (t, J 7.5 Hz, 2 H); 7.3-7.9 (m, 9H) ppm.

Example Example 2 a) To a suspension of 5.06 g of 6- (dimethylamino) geksiltrifenilfosfoniybromida (see. Example 1a) in 50 ml THF at ⁰ ° C under argon was added 2.47 g of potassium tert-butoxide . To this suspension, a solution of 1.64 g of p-formylbenzoic acid methyl ester in 20 ml of THF was added dropwise over 15 minutes. The reaction mass is stirred for 18 hours at room temperature, and then evaporated. The residue is dissolved in 100 ml of 1 N. of hydrochloric acid. The aqueous phase is washed three times with 100 ml of diethyl ether, then with solid potassium carbonate it is brought to an alkaline reaction and extracted three times with 100 ml of diethyl ether. The ether phases are dried with magnesium sulfate and evaporated. The residue is chromatographed over 100 g of silica gel with a mixture of methylene chloride, methanol and ammonium hydroxide (100: 10: 1). 880 mg (32%) of 4 - [(Z) -7- (dimethylamino) -1-heptenyl] benzoic acid methyl ester is obtained as a colorless oil.

 b) 0.88 g of (4 - [(Z) -7- (dimethylamino) -1-heptenyl] benzoic acid methyl ester is dissolved in 20 ml of ethanol, 20 mg of 5% palladium on carbon are added to the solution, and the resulting mixture is stirred suspension in a hydrogen atmosphere under normal pressure at room temperature for 2 hours. The reaction mixture is filtered through diatomaceous earth and the filtrate is evaporated to give 0.85 g (95%) of methyl 4- [7- (dimethylamino) heptyl] benzoic acid in a colorless oil.

c) To a solution of 0.85 g of methyl 4- [7- (dimethylamino) heptyl] -benzoic acid in 20 ml of THF at ^-78 ° C under argon was added dropwise a solution of benzylmagnesium bromide (prepared from 74 mg of magnesium and 524 mg of benzyl bromide) in 20 ml of diethyl ether for 30 minutes The reaction mixture was stirred at ^-78 ° C for 2 hours, then poured onto 50 ml of a saturated aluminum chloride solution and extracted three times with 50 ml of ethyl acetate. The collected organic phases are washed with 100 ml of a saturated solution of sodium chloride, dried with magnesium sulfate and evaporated. Chromatography of the residue per 100 g of silica gel with a mixture of methylene chloride, methanol and aluminum hydroxide (100: 10: 1) gives 340 mg (35%) of 4 '- [7- (dimethylamino) heptyl] -2-phenylacetophenone as a yellowish oil.

Data ¹ H-NMR analysis (CDCl ₃ ): 1.3-1.7 (m, 10 H); 2.40 (s, 6H); 2.52 (t, J 8 Hz, 2H); 2.64 (t, J 7 Hz, 2H); 4.26 (s, 2H); 7.3-7.4 (m, 7H); 7.93 (d, J 8 Hz, 2 N) ppm.

 Example 3. Analogously to example 2c), 4'- [7- (dimethylamino) heptyl] -3-phenylpropiophenone is obtained from 4- [7- (dimethylamino) heptyl] benzoic acid methyl ester and a) phenethylmagnesium bromide in the form of a colorless oil (yield 35%).

Data ¹ H-NMR analysis (CDCl ₃ ): 1.3-1.7 (m, 10H); 2.20 (s, 6H); 2.1-2.3 (m, 2H); 2.64 (t, J 8 Hz, 2H); 3.0-3.4 (m, 4H); 7.2-7.4 (m, 7H); 7.88 (d, J 8 Hz, 2H) ppm.

 b) p- (trifluoromethyl) phenyl magnesium bromide 4- [7- (dimethylamino) heptyl] -4 '- (trifluoromethyl) benzophenone as a colorless oil (yield 40%).

Data ¹ H-NMR analysis (CDCl ₃ ): 1.3-1.7 (m, 10H); 2.24 (s, 6H); 2.28 (t, J 8 Hz, 2H); 2.69 (t, J 8 Hz, 2H); 7.29 (d, J 9 Hz, 2H); 7.7-7.9 (m, 6H) ppm.

 MS analysis data: 391 (1.5% M +); 372 (1%); 235 (2.5%); 173 (3.8%); 145 (4.5%); 58 (100%).

PRI me R 4. a) To 1.2 g of methyl ester of 4- [7- (dimethylamino) heptyl] benzoic acid add 25 ml of methanol and 10 ml of a 20% solution of sodium hydroxide in water, after which the resulting the mixture is heated at reflux for 2 hours. After cooling to 0 ^C the pH of the solution was adjusted with acetic acid to 5. The resulting precipitated material is suctioned off on a suction filter, and dried under high vacuum at a pressure of about 6.7 Pa overnight. The result is 0.97 g (85%) of 4- [7- (dimethylamino) heptyl] benzoic acid.

b) The resulting substance is weighed in 20 ml of methylene chloride, 1.2 ml of oxalyl chloride is added to the resulting suspension, and the resulting reaction mass is stirred at room temperature for 2 hours and evaporated. The crude acid chloride was dried under high vacuum, dissolved in 3 ml of fluorobenzene, and the solution was cooled to 0 ° ^C. To this solution was added 760 mg of aluminum chloride. The resulting mixture was stirred for 30 min at 0 ^C and then for 2 hours at room temperature. The reaction mass is diluted with 50 ml of methylene chloride and washed twice with 50 ml of 2 N. caustic soda solution. The methylene chloride phase is dried with magnesium sulfate and evaporated. The crude product is purified by chromatography on 100 g of silica gel with a mixture of methylene chloride, methanol and aluminum hydroxide (90: 10: 1). 0.5 g (40%) of 4- [7- (dimethylamino) heptyl] -4'-fluorobenzophenone is obtained in the form of a colorless oil.

Data ¹ H-NMR analysis (CDCl ₃ ): 1.3-1.7 (m, 10H); 2.23 (s, 6H); 2.26 (t, J 7.5 Hz, 2H); 2.68 (t, J 7.5 Hz, 2H); 7.1-7.2 (m, 2H); 7.28 (d, J 8 Hz, 2H); 7.70 (d, J 8 Hz, 2H); 7.7-7.9 (m, 2H) ppm.

 PRI me R 5. Analogously to example 4B) from 4- [7- (dimethylamino) heptyl] benzoic acid and 1,3 difluorobenzene receive 2,4-difluoro-4 '- [7- (dimethylamino) heptyl] benzo -phenone in the form of a colorless oil (yield 32%).

Data ¹ H-NMR analysis (CDCl ₃ ): 1.3-1.7 (m, 10H); 2.25 (s, 6H); 2.28 (t, J 7 Hz, 2H); 2.67 (t, J 8 Hz, 2H); 6.8-7.8 (m, 7H) ppm.

PRI me R 6. To a suspension of 486 mg of magnesium chips in 10 ml in an argon atmosphere over a period of 30 minutes add a solution of 6.1 g of 2- (r-bromophenyl) -2-phenyl-1,3-dioxolane ( on the calculation of Germany N 2509474) in 50 ml of THF. The resulting brown solution was stirred at room temperature for 1 h, then cooled ^to 0 ° C and for 1 h at ⁰ ° C was dropwise added to a solution of 5.12 g of dibromohexane and 0.1 mmol dilitiytetrahlorkuprata (Synthesis, 1971, 303 ) in 10 ml THF. The mass is stirred for 18 hours at room temperature, then it is evaporated. To the residue was added 100 ml of a saturated solution of ammonium chloride, after which it was extracted three times with 100 ml of diethyl ether. The organic phases are dried with magnesium sulfate and evaporated. To the residue containing 2- [4- (6-bromohexyl) phenyl] -2-phenyl-1,3-dioxolane, 25 ml of a 33% solution of dimethylamine in ethanol was added. The resulting mass was stirred for 24 hours at room temperature. The solution was concentrated, the obtained residue containing 2- [4- [6- (dimethylamino) hexyl] phenyl] -2-phenyl-1,3-dioxolane was dissolved in 100 ml of 1N. hydrochloric acid and washed three times with 100 ml of diethyl ether. The aqueous phase, cooling it with ice, using 2 N. The sodium hydroxide solution is adjusted to an alkaline reaction and extracted three times with 100 ml of diethyl ether.

The organic phases are dried with magnesium sulfate and evaporated. The crude product was purified by distillation in a furnace provided with a bulb tube at 180-190 ^{° C} and a pressure of about 6.7 Pa. 2.55 g (41%) of 4- [6- (dimethylamino) hexyl] benzophenone are obtained in the form of a yellowish oil.

This oil is dissolved in 5 ml of ethanol and 0.956 g of fumaric acid in 20 ml of ethanol is added to a hot solution. After adding 50 ml of diethyl ether and cooling ^to 0 ° C, colorless crystals were filtered on a Nutsche filter, washed with diethyl ether and dried. Get 3 g (85%) of 4- [6- (dimethylamino) hexyl] benzophenone fumarate (1: 1) with a melting point of 87-89 ^about C.

PRI me R 7. a) 15 g of 4- (3-bromopropyl) acetophenone and 10.8 ml of pyrrolidine are dissolved in 60 ml of ethanol and heated to 40 ^° C for 24 hours. The reaction mass is then evaporated and the residue is removed add 250 ml of ethyl acetate and 150 ml of a semi-saturated solution of sodium chloride, and then shake the mass. The aqueous phase is again extracted with 250 ml of ethyl acetate, and the organic phases are washed once again with 150 ml of a semi-saturated solution of sodium chloride. The collected organic extracts were dried with magnesium sulfate and evaporated. 13.8 g (96%) of 4 '- [3- (1-pyrrolidinyl) propyl] acetophenone are obtained in the form of a brownish liquid; m / e mass spectrum analysis data: M ⁺ 431 (6.4), 84 (100), 42 (10.9).

b) 4 g of 4 '- [3- (1-pyrrolidinyl) propyl] acetophenone and 2 g of benzaldehyde are dissolved in 80 ml of methanol and, cooling the solution with ice, a solution of 9.55 g of potassium carbonate in 38 ml is added over 15 minutes water. Then the batch was allowed to react for 18 hours at room temperature and for another 18 hours at about 40 ^C. The reaction mixture was dissolved in 200 ml of ethyl acetate and shaken with 100 ml of water. The aqueous phase is again extracted with 200 ml of ethyl acetate, and the organic phases are again 100 ml of a semi-saturated solution of sodium chloride. The collected organic phases are dried with magnesium sulfate and evaporated. The residue is chromatographed on silica gel with acetone. 4.5 g (81%) of (E) -3-phenyl-4 '- [3- (1-pyrrolidinyl) propyl] acrylophenone are obtained in the form of a yellow oil; m / e mass spectrum analysis data: M ⁺ 319 (7.1), 131 (1.4), 84 (100), 42 (7.5). In order to obtain hydrochloride, the free amine is dissolved in a small amount of ethanol, and then 10 M ethanolic hydrochloric acid solution is added to it. After recrystallization from isopropanol, pure hydrochloride is obtained; t _pl 211-213 ^about S.

Example 8. 4.1 g of 4- [3- (dimethylamino) propyl] acetophenone and 3.1 g of 4-chlorobenzaldehyde are dissolved in 80 ml of methanol. To the resulting solution, a solution of 6.4 g of sodium hydroxide in 32 ml of water is added over 15 minutes at room temperature. The mass is stirred for 48 hours. For further processing of the mass, it is poured into 150 ml of ice water. The precipitated crystals were filtered on a suction filter, washed three times with 30 ml of water and dried ^at 40 ° C under reduced pressure. 6.36 g (97%) of (E) -3- (4-chlorophenyl) -4 '- [3- (dimethylamino) propyl] acrylphenone are obtained; T _PL 83-86 ^about C.

 4- [3- (dimethylamino) prip] acetophenone can be obtained analogously to example 7a).

PRI me R 9. 3 g of (E) -3- (4-chlorophenyl) -4 '- [3- (dimethylamino) propyl] -acrylophenone is dissolved in 100 ml of ethanol. After adding 300 mg of 5% palladium-carbon, the solution is hydrogenated. After absorbing a theoretical amount of water, the catalyst is filtered off and the filtrate is evaporated. The residue was dissolved in ethanol. Then, using a 10 M solution of hydrochloric acid in ethanol, it is converted into hydrochloride, which precipitates after the addition of hexane. Recrystallization from a mixture of ethyl acetate and ethanol (5: 1) gives 1.44 g (43%) of 3- (4-chlorophenyl) -4 '- [3- (dimethylamino) propyl] propiophenone hydrochloride; _mp 161-164 ° ^C.

Example 10. Similarly to examples 7b and 8, the following compounds can be obtained: a) (E) -3- (4-methylphenyl) -4 '- [3- (dimethylamino] propyl] -acrylophenone; _mp 76, 5-77.5 ^about C;
b) (E) -3- (4-isopropylphenyl) -4 '- [3- (dimethylamino) propyl] acrylophenone; _mp 44-45 ^{° C;}
c) (E) -3- (4-methoxyphenyl) -4 '- [3- (dimethylamino) propyl] acrylophenone in the form of an oil; ¹ H-NMR (CDCl ₃ , 400 MHz): 2.24 (s, 6H); 3.86 (s, 3H) ppm;
d) (E) -3 - [(4-trifluoromethyl) phenyl] -4 '- [3- (dimethylamino) propyl] acrylophenone; _mp = 71,5-73,5 ^{° C;}
d) (E) -3- (3-methylphenyl) -4 '- [3- (dimethylamino) propyl] acrylophenone in the form of an oil; ¹ H-NMR (CDCl ₃ , 400 MHz): 2.25 (s, 6H); 2.40 (s, 3H) ppm;
e) (E) -3- (4-nitrophenyl) -4 '- [3- (dimethylamino] propyl] -akrilofenon; _mp 97-99 ^C;
g) (E) -3- (3-chlorophenyl) -4 '- [3- (dimethylamino] propyl] -acrylophenone in the form of a wax;
mass spectrum m / e: M ⁺ 327 (1.1), 205 (0.8), 143 (0.9), 58 (100);
h) (E) -3-phenyl-4 '- [3- (ethylmethylamino] propyl] -acrylophenone in the form of an oil; mass spectrum m / e: M ⁺ 307 (4), 72 (100) (used as the starting substances 4- [3- (ethylmethylamino) propyl] acetophenone are obtained analogously to example 7a);
u) hydrochloride (E) -3- (4-tret.butilfenil-4 '- [3- (dimethylamino] propyl] nona akrilofe-; _m.p. = 217-219 ^o C (from ethanol);
Q) Hydrochloride of (E) -3- (3,5-dichlorophenyl) -4 '- [3- (dimethylamino] propyl] akrilofenona; _mp> ²³⁰ ° C (dec.);
k) hydrochloride (E) -3- (4-fluorophenyl) -4 '- [3- (dimethylamino] propyl] akrilofenona; _m.p. = 219-220,5 ^{° C} (from ethanol);
l) hydrochloride (E) -3- (2-methylphenyl) -4 '- [3- (dimethylamino] propyl] akrilofenona; _mp 150,5-152 ^{° C} (from a mixture of ethanol and toluene).

PRI me R 11. Analogously to example 9, you can get the following compounds: a) 3- (4-methylphenyl) -4 '- [3- (dimethylamino) propyl] propiophenone in the form of oil; ¹ H-NMR (CDCl ₃ , 400 MHz): 2.22 (s, 6H); 2.32 (s, 3H) ppm;
b) 3- (4-isopropylphenyl) -4 '- [3- (dimethylamino) propyl] propiophenone in the form of an oil; mass spectrum m / e: M ⁺ 337 (5), 133 (4), 58 (100);
c) 3- (4-methoxyphenyl) -4 '- [3- (dimethylamino (propyl) propiophenone in the form of a syrup; mass spectrum m / e: M ⁺ 325 (4), 121 (9), 58 (100);
d) 3- (4-trifluoromethylphenyl) -4 '- [3- (dimethylamino) propyl] propiophenone in the form of an oil; mass spectrum m / e: M ⁺ 363 (2), 159 (3), 58 (100);
d) 3- (4-methylphenyl) -4 '- [3- (dimethylamino) propyl] propiophenone in the form of an oil; mass spectrum m / e: M ⁺ 309 (10.4), 145 (3.8), 105 (7.0), 58 (100);
e) 3- (3-chlorophenyl) -4 '- [3- (dimethylamino) propyl] propiophenone in the form of an oil; mass spectrum m / e: M ⁺ 329 (1.0), 125 (2.5), 58 (100);
g) 3-phenyl-4 '- [3- (ethylmethylamino) propyl] propiophenone in the form of a syrup; mass spectrum m / e: M ⁺ 309 (6), 294 (1), 91 (6), 72 (100);
h) 3- (4-tert. butylphenyl) -4 '- [3- (dimethylamino) propyl] propiophenone in the form of an oil; mass spectrum m / e: M ⁺ 351 (34.7), 131 (32.8), 91 (34.5), 58 (100);
i) 3- (4-fluorophenyl) -4 '- [3- (dimethylamino) propyl] propiophenone in the form of a syrup; mass spectrum m / e: M ⁺ 313 (3), 109 (11), 58 (100);
i) 3- (2-methylphenyl) -4 '- [3- (dimethylamino) propyl] propiophenone; _mp 145-147 ^{° C} (from THF);
j) 3-phenyl-4 '- [3- (1-pyrrolidinyl) propyl] propiophenone in the form of a syrup; mass spectrum m / e: M ⁺ 321 (7), 91 (6), 84 (100).

 PRI me R 12. Analogously to example 1, you can obtain, for example, the following compounds: a) 4- [5- (dimethylamino) pentyl] benzophenone in the form of a colorless oil (yield 96%).

Mass spectrum m / e: M ⁺ 295 (2% M ⁺ ), 100 (3%), 58 (100%).

 b) 4- [8- (dimethylamino) octyl] benzophenone as a colorless oil (88% yield).

Mass spectrum m / e: M ⁺ 337 (2% M ⁺ ), 149 (2.8%), 105 (3.3%), 58 (100%).

PRI me R 13. a) To a solution of 10 g of 7-chlorheptanol [Rec. Trav. Chim. Pays-Bas, 99, 87 (1980)] and 18.7 ml of triethylamine in 100 ml of methylene chloride under argon at ⁰ ° C for 1 hour, a solution of 13.3 g of p-toluenesulfonyl chloride in 100 ml of methylene chloride. The reaction mass is stirred for 6 hours at room temperature, after which it is washed twice with 200 ml of 2 N. hydrochloric acid, two times with 200 ml of a saturated solution of sodium bicarbonate and once with 200 ml of a saturated solution of sodium chloride. Then, the organic phase is dried with magnesium sulfate and concentrated. The resulting crude 7-chloro-heptyl-p-toluenesulfonate (19.5 g, 96%) was dissolved in 40 ml of THF with 0.6 mmol of dilithium tetrachlorocuprate. This solution was cooled ^to 0 ° C under argon. Then, a solution of phenylmagnesium obtained from 3.1 g of magnesium chips and 20 g of bromobenzene in 80 ml of THF is added dropwise over 2 hours. The resulting reaction mass was stirred for 18 hours at room temperature and evaporated.

200 ml of a saturated solution of ammonium chloride are added to the residue and extracted three times with diethyl ether (200 ml each). The organic phases are dried with magnesium sulfate and evaporated. The residue was distilled under high vacuum at 100-110 ^{° C} and a pressure of about 13.4 Pa. The result is 13 g (86%) of 7-chlorheptylbenzene as a colorless liquid.

b) 1.07 g of 7-chlorheptylbenzene and 0.89 g of 4-chlorobenzoyl chloride are dissolved in 10 ml of nitrobenzene, after which 0.82 g of aluminum chloride is added in an ice-cooled argon atmosphere. The resulting mixture was stirred for 18 h at room temperature, after which the mixture was mixed with 100 ml of ice-cold 2 N. hydrochloric acid solution and extracted three times with diethyl ether (50 ml each). The organic phases are washed first with 50 ml of a 10% sodium bicarbonate solution and then with 50 ml of a saturated sodium chloride solution, after which they are dried with magnesium sulfate and concentrated. Then nitrobenzene was removed, driving the mass at 80-100 ^{° C} under a pressure of 20 Pa. Distillation at 240-250 ^{° C} and a pressure of about 13.4 Pa obtained 1.32 g (74%) of 4-chloro-4 '- (7-hlorgeptil) benzophenone as a yellowish oil.

Data of ¹ H-NMR analysis (CDCl ₃ ): 1.2-1.9 (m, 9H), 1.71 (t, J 7.5 Hz, 2H), 3.53 (t, J 7.2 Hz, 2H), 7.2-7.9 (m, 8H) ppm.

 c) 1.32 g of 4-chloro-4 '- (7-chlorheptyl) benzophenone and 0.85 g of sodium iodide are heated at reflux in 20 ml of ethyl methyl ketone. After 24 hours, the reaction mass is evaporated. The residue was weighed into 50 ml of water and extracted three times with ethyl acetate (50 ml each). The collected organic phases are washed with 50 ml of a saturated sodium chloride solution, dried with magnesium sulfate and evaporated. 1.5 g (90%) of crude 4-chloro-4 '- (7-iodoheptyl) benzophenone are obtained in the form of a yellowish oil, which is used without further purification in the next step of the process.

d) To this crude oil is added 10 ml of a 33% solution of dimethylamine in ethanol. The mass is stirred for 24 hours at room temperature, then it is evaporated. The residue is dissolved in 50 ml of 1 N. hydrochloric acid and washed three times with diethyl ether (50 ml each). Cooling the aqueous phase with ice, it is brought to an alkaline reaction using 2 N. caustic soda solution. After that, it is extracted three times with diethyl ether (50 ml each). The organic phases are dried with magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (100 g) with a mixture of methylene chloride, methanol and ammonium chloride (90: 10: 1). 0.6 g (51%) of 4-chloro-4 '- [7- (dimethylamino) heptyl] benzophenone are obtained in the form of a colorless oil. Mass spectrum m / e: 357 (0.6% M ⁺ ), 128 (4%), 58 (100%).

PRI me R 14. Analogously to example 13, you can get the following compounds: a) 4-bromo-4 '- [7- (dimethylamino) heptyl] benzophenone in the form of a colorless oil (yield 38%). After addition of ethereal hydrochloric acid gave the corresponding hydrochloride, _mp 122-123 ^{° C} (yield 85%).

 b) 2,4-dichloro-4 '- [7- (dimethylamino) heptyl] benzophenone as a colorless oil (yield 73%).

Mass spectrum m / e: 391 (0.3% M ⁺ ), 173 (1.3%), 128 (4.2%), 58 (100%).

 c) 4- [4- (dimethylamino) heptyl] benzoyl] benzonitrile as a colorless oil (yield 68%).

Mass spectrum m / e: 348 (0.6% M ⁺ ), 128 (2.7%), 58 (100%).

 d) 4- [7- (allylmethylamino) heptyl] benzophenone (66% yield) as a colorless oil.

Mass spectrum m / e: 349 (1.5% M ⁺ ), 167 (4.3%), 84 (100%).

 d) 4- [7- (allylmethylamino) heptyl] -4'-bromobenzophenone as a yellowish oil (yield 62%).

Mass spectrum m / e: 427 (0.7% M ⁺ ), 400 (3.3%), 84 (100%).

 e) 4- [4 '- [7- (allylmethylamino) heptyl] benzoyl] benzonitrile as a yellow oil (46% yield).

Mass spectrum m / e: 374 (2% M ⁺ ), 345 (8%), 84 (100%).

g) Hydrochloride of 4-bromo-4 '- [6- (dimethylamino) hexyl] benzophenone (yield 72%) as colorless crystals with _mp 115-117 ° ^C.

 h) 4- [6- (allylmethylamino) hexyl] -4'-bromobenzophenone (yield 77%) as a colorless oil.

Mass spectrum m / e: 415 (0.8% M ⁺ ), 413 (0.8%), 386 (2%), 84 (100%).

 i) 3-bromo-4 '- [6- (dimethylamino) hexyl] benzophenone (48% yield) as a yellowish oil.

Mass spectrum m / e: 387 (0.3% M ⁺ ), 114 (7%), 58 (100%).

 i) 4- [6-dimethylamino) hexyl] -2'-methylbenzophenone (36% yield) as a yellowish oil.

Mass spectrum m / e: 325 (0.9% M ⁺ ), 114 (8%), 58 (100%).

 j) 4- [6- (dimethylamino) hexyl] -4'-nitrobenzophenone (80% yield) as a yellow oil.

Mass spectrum m / e: 354 (0.4% M ⁺ ), 114 (6%), 58 (100%).

k) 2-chloro-4 '- [6- (dimethylamino) hexyl] benzophenone (yield 59%). Treating the compound of ethereal hydrochloric acid gave the corresponding hydrochloride, _mp 176-178 ^{° C} (yield 86%).

 m) 4- [7- (dimethylamino) heptyl] -2-methylbenzophenone as a colorless oil.

Mass spectrum m / e: 337 (1.5% M ⁺ ), 128 (6%), 105 (4%), 77 (3%), 58 (100%).

PRI me R 15. The connection 4- [7- (dimethylamino) heptyl] benzophenone is used as an active principle to obtain tablets in the following ratios of components, mg / tablet:
Acting start 200
Milk Sugar
powdered 100 Povidone K 30 15 Carboxy- starch
methyl sodium 10 Talc 3 Magnesium stearate 2
The weight of the tablet is 330 mg. The active principle is well mixed with powdered milk sugar. The resulting mass is moistened with an aqueous solution of Povidone K 30 and kneaded. The resulting mass is granulated, dried and passed through a sieve. The granulate is mixed with the remaining components, and the resulting mass is compressed into tablets of a suitable size.

Claims (1)

Aminoalkylbenzene derivatives of the general formula

where R ₁ and R _{2 are} each hydrogen, lower alkyl, or together form an unbranched C ₂ C ₄ alkylene;
QC ₄ C _{1 1} -alkylene with at least two carbon atoms between two free valencies;
Y is a simple bond;
R means that the ring is unsubstituted or substituted by halogen, trifluoromethyl, nitro or lower alkyl,
or their pharmaceutically acceptable salts with acids.

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