Substituted derivatives of 2-dialkylaminoalkylbiphenyl

FIELD: organic chemistry, medicine.

SUBSTANCE: invention reports about preparing new substituted derivatives of 2-dialkylaminoalkylbiphenyl of the general formula (I):

wherein n = 1 or 2; R1 means cyano-group (CN), nitro-group (NO2), SO2CH3, SO2CF3, NR6aR7a, acetyl or acetamidyl; R2 means hydrogen atom (H), fluorine atom (F), chlorine atom (Cl), bromine atom (Br), cyano-group (CN), nitro-group (NO2), CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; or R1 and R mean in common group -OCH2O, -OCH2CH2O, CH=CHO, CH=C(CH3)O or CH=CHNH; R3 means H, F, Cl, Br, CN, NO2, CHO, SO2CH3, SO2CF3, OR6, NR6R7, (C1-C6)-alkyl, acetyl or acetamidyl being alkyl can comprise one or more similar or different substitutes taken among halogen atom or hydroxy-group; R4 and R5 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6 and R7 have similar or different values and mean hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R6a means hydrogen atom (H) or unsubstituted (C1-C6)-alkyl; R7a means unsubstituted (C1-C6)-alkyl as their bases and/or salts of physiologically acceptable acids, with exception of compound representing 4-chloro-2'-dimethylaminomethylbiphenyl-2-carbonitrile and to a method for their preparing. Derivatives of 2-dialkylaminoalkylbiphenyl can be used in medicine for treatment or prophylaxis of pains, inflammatory and allergic responses, depressions, narcomania, alcoholism, gastritis, diarrhea, enuresis, cardiovascular diseases, respiratory ways diseases, cough, psychiatry disorders and/or epilepsy.

EFFECT: valuable medicinal properties of compounds.

13 cl, 2 tbl, 43 ex

 

The present invention relates to substituted derivatives of 2-dialkylaminoalkyl, to the way they are received, to medicines containing these compounds and to the use of these compounds to obtain drugs.

Treatment of chronic and nechanicky painful States plays in medicine critical role. Despite the progress made throughout remains an urgent need for a highly effective pain management. An urgent need to develop targeted, taking into account the individual characteristics of patients the treatment of chronic and nechanicky painful conditions, with mean successful and satisfactory for patients analgesic treatment, reflected in numerous recently published scientific papers in the field of applied analgesics, respectively fundamental studies of nociception.

Classical opioids, such as morphine, have a high efficiency in the treatment of strong, including the most severe pain. Their use, however, limit known caused by side effects such as respiratory depression, vomiting, sedation sedatives, constipation, irresistible craving, dependence, and addiction. This item is icine their use is permissible only with the observance of special precautions such as, in particular, as special provisions in cases of prolonged treatment period or at higher dosages (Goodman, Gilman, The Pharmacological Basis of Therapeutics, published by Pergamon Press, New York (1990)). In addition, certain medical conditions, above all if neuropathic pain, their effectiveness is reduced.

Given the above, one of the underlying the present invention tasks consisted in obtaining effective analgesic substances suitable for use in pain management. In addition, it was envisaged that these substances must show a minimum of the side effects inherent to opioid analgesics, such as nausea, vomiting, dependence, respiratory depression and constipation. Other tasks consisted in obtaining such active substances that could be used for the treatment of inflammatory and allergic reactions, depression, drug and/or alcohol abuse, gastritis, diarrhoea, urinary incontinence, cardiovascular diseases, respiratory tract diseases, coughing, mental disorders and/or epilepsy.

According to the invention these problems are solved with the help of new substituted derivatives of 2-dialkylaminoalkyl suitable for the treatment of inflammatory and allergic reactions, depression, drug and/or alcohol abuse, gastritis, diarrhoea, urinary incontinence, genial, OEM is-vascular diseases, respiratory tract diseases, coughing, mental disorders and/or epilepsy and possessing, moreover, a pronounced analgesic effect.

The object of the invention in accordance with this are substituted derivatives of 2-dialkylaminoalkyl General formula I

in which

n denotes 1 or 2,

R1, R2, R3have identical or different meanings and denote H, F, Cl, Br, CN,

NO2, SNO, SO2CH3, SO2CF3, OR6, NR6R7C1-C6alkyl, preferably C1-C3alkyl, aryl, acetyl, acetamido, benzoyl or linked via C1-C6alkylenes group, preferably via C1-C3alkylenes group, aryl, or

R1and R2together denote respectively the group base2Oh, och2CH2Oh, CH=Cho, CH=C(CH3)O or CH=CHNH,

R4, R5have identical or different meanings and represent N or C1-C6alkyl, preferably C1-C3alkyl,

R6, R7have identical or different meanings and represent N or C1-C6alkyl, preferably C1-C3alkyl, aryl, or linked via C1-C6alkylenes group, preferably via C1-C3alkylenes aryl group,

in the form and the bases and/or salts of physiologically acceptable acids, with the exception of the group of compounds including

2'-dimethylaminomethylphenol-2-carbaldehyde, biphenyl-2-ilmatieteen,

2'-dimethylaminomethylphenol-2-ol, as well as the corresponding hydrochloride

(2',3'-dimethoxybiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride and the corresponding hydrobromide,

(4'-methylbiphenyl-2-ylmethyl)dimethylamine,

(2'-methylbiphenyl-2-ylmethyl)dimethylamine,

4-chloro-2'-dimethylaminomethylphenol-2-carbonitril,

(2'-dimethylaminomethylphenol-2-yl)methanol,

2'-dimethylaminomethylphenol-2,3-diol and the corresponding hydrobromide,

[2-(3',4'-dimethoxybiphenyl-2-yl)ethyl]dimethylamine and the corresponding hydrochloride

[2-(2',3'-dimethoxy-6'-methylbiphenyl-2-yl)ethyl) - dimethylamine and the corresponding hydrobromide and biphenyl-2-latertimetimes.

Under alkyl radicals includes at least one-deputizing, preferably by halogen and/or hydroxy-group, particularly preferably fluorine and/or hydroxy-group, the hydrocarbon. If hydrocarbons contain more than one substituent, the latter can be identical or different. Preferred alkyl radicals are methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl, 1-metalpa the Tyl, CHF2, CF3or CH2HE.

Under the aryl moiety includes at least one-deputizing HE, halogen, preferably F and/or Cl, CF3C1-C6the alkyl, C1-C6alkoxygroup, C1-C7cycloalexie, C3-C7cycloalkyl, C2-C6alkylene or phenyl group family or nattily. The phenyl radicals can also be condensed with other rings.

Particularly preferred are the following substituted derivatives of 2-dimethylaminoacetonitrile:

(3'-methoxybiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(4'-chlorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

2'-dimethylaminomethylphenol-3-ol and the corresponding hydrochloride

(2'-methoxybiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(3'-chlorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(2'-forbiden-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(3'-forbiden-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(4'-forbiden-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(3'-chloro-4'-forbiden-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(3'-methoxybiphenyl-2-retil)dimethylamine and the corresponding hydrochloride

dimethyl-[2-(2-m is diversiform-4-yl)benzyl]amine and the corresponding hydrochloride

2'-dimethylaminomethylphenol-2-carbaldehyde and the corresponding hydrochloride

(3'-diverseylever-2-ylmethyl)dimethylamine and the corresponding hydrochloride

2'-dimethylaminomethylphenol-3-carbaldehyde and the corresponding hydrochloride

biphenyl-2-ilmatieteen and the corresponding hydrochloride

(3',4'-dichlorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(3',5'-dichlorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

dimethyl-(4'-nitro-3'-triptorelin-2-ylmethyl)amine and the corresponding hydrochloride

(3',4'-diferuloyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(4'-fluoro-3'-triptorelin-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(4'-chloro-3'-methoxybiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

N-(2'-dimethylaminomethyl-3-cryptomaterial-4-yl)ndimethylacetamide and the corresponding hydrochloride

(3'-isopropoxyphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

2'-(2-dimethylaminoethyl)biphenyl-3-ol and the corresponding hydrochloride

4-chloro-2'-dimethylaminomethylphenol-3-ol and the corresponding hydrochloride

[2-(1H-indol-5-yl)benzyl]dimethylamine and the corresponding hydrochloride

(4'-methysulfonylmethane-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(2',4'-dichlorobiphenyl-2-ylmethyl)dimethylamine the corresponding hydrochloride

(2',3'-diferuloyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(2',5'-diferuloyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(2-benzo[1,3]dioxol-5-ylbenzyl)dimethylamine and the corresponding hydrochloride

1-[2'-(2-dimethylaminoethyl)biphenyl-3-yl]Etalon and the corresponding hydrochloride

[2-(3',4'-dimethoxybiphenyl-2-ileti]dimethylamine and the corresponding hydrochloride

[2-(3'-isopropoxyphenyl-2-yl)ethyl]dimethylamine and the corresponding hydrochloride

[2-(4'-chloro-3'-methoxybiphenyl-2-yl)ethyl]dimethylamine and the corresponding hydrochloride

4-chloro-2'-(2-dimethylaminoethyl)biphenyl-3-ol and the corresponding hydrochloride

dimethyl-(3'-nitrobiphenyl-2-ylmethyl)amine and the corresponding hydrochloride

4-amino-2'-dimethylaminomethylphenol-3-ol and the corresponding dihydrochloride,

(3',5'-diferuloyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(2',5'-dimethoxybiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

2'-dimethylaminomethyl-5-cryptomaterial-2-ylamine and the corresponding dihydrochloride,

N-(2'-dimethylaminomethyl-5-cryptomaterial-2-yl)ndimethylacetamide and the corresponding hydrochloride

3,5-dichloro-2'-dimethylaminomethylphenol-4-ylamine and the corresponding hydrochloride.

Another object of the invention are methods of obtaining substituted derivatives of 2-dialkylamino is Albufera General formula I, which are characterized in that compounds of General formula II where Y denotes Cl, Br or I, a m denotes 0 or 1,

dissolved restore using an appropriate reducing agent, preferably lithium aluminum hydride and/or diisobutylaluminium, to compounds of General formula III, where n denotes 1 or 2,

and the compounds obtained by the usual methods cleanse and release.

Compounds of General formula III in the presence of an appropriate reducing agent, preferably formic acid and/or sodium borohydride, is subjected to the interaction with aliphatic C1-C6aldehydes with obtaining compounds of General formula IV

where R4and R5have the meanings mentioned for the General formula I and the compounds obtained by the usual methods cleanse and release.

Compounds of General formula IV by exchanging the halogen-metal, preferably with magnesium and/or utility, and the subsequent interaction with the ester of boric acid, preferably trialkylborane and particularly preferably trimethylboron, at temperatures of ≤0°converted into compounds of General formula V, where R is a C1-C6alkyl,

and the obtained compound is of the usual methods cleanse and release.

Compounds of General formula V by contact with an aqueous acid, preferably with hydrochloric acid, can be converted into compounds of General formula VI

and these compounds by conventional methods to clean and to allocate.

Compounds of General formula V or VI by reaction catalyzed transition metal, preferably with compounds of palladium(0) or salts of palladium(II), particularly preferably tetrakis(triphenylphosphine)palladium, bis(dibenzylideneacetone)palladium, elemental palladium on charcoal, palladium chloride (II) and/or palladium (II)acetate, in a simple aliphatic ether, preferably 1,4-dioxane and tetrahydrofuran, or a hydrocarbon, preferably toluene or hexane, in alcohol, preferably ethanol or isopropanol, in a chlorinated hydrocarbon, preferably chloroform or dichloromethane, in water or in mixtures of these solvents at temperatures in the range from 20 to 150°subjected to interaction with compounds of General formula VII

where X denotes Cl, Br, I or OSO2CpF(2p+1), a R1-R3have the meanings mentioned for the General formula I, to obtain the compounds of General formula I, which on conventional methods to cleanse and release.

In another embodiment, link the General formula VIII or IX

where R1-R3have the meanings mentioned for the General formula I, and R represents C1-C6alkyl, by the reaction, catalyzed transition metal, preferably with compounds of palladium(0) or salts of palladium(II), particularly preferably tetrakis(triphenylphosphine)palladium, bis(dibenzylideneacetone)palladium, elemental palladium on charcoal, palladium chloride (II) and/or palladium (II)acetate, in a simple aliphatic ether, preferably 1,4-dioxane and tetrahydrofuran, or a hydrocarbon, preferably toluene or hexane, in alcohol, preferably ethanol or isopropanol, in a chlorinated hydrocarbon, preferably chloroform or dichloromethane, in water or in mixtures of these solvents at temperatures in the range from 20 to 150°subjected to interaction with compounds of General formula III or IV with the obtained compounds of General formula I, which on conventional methods to cleanse and release.

Compounds of General formula I with physiologically acceptable acids, for example hydrochloric acid, Hydrobromic acid, sulfuric acid, methanesulfonate, formic acid, acetic acid, oxalic acid, succinic acid, tartaric acid, almond acid, fumaric sour is s, lactic acid, citric acid, glutamic acid and/or aspartic acid, can be translated in the usual way in their salts. The formation of salts is preferably carried out in an appropriate solvent, such as diethyl ether, diisopropyl ether, alkilany ether acetic acid, acetone and/or 2-butanone. To obtain hydrochloride suitable, in addition, trimethylchlorosilane in aqueous solution.

Proposed in the invention substituted derivatives of 2-dialkylaminoalkyl General formula I toxicologically safe and are therefore suitable for use in pharmaceuticals, biologically active substances.

Another object of the invention is in accordance with these drugs, containing as active substance at least one substituted derivative 2-dialkylaminoalkyl General formula I in the form of its bases and/or salts of physiologically acceptable acids and optionally other active and auxiliary substances.

Preferably these medicines are used for the treatment or prevention of pain, inflammation or allergic reactions, depression, drug and alcohol abuse, gastritis, diarrhoea, urinary incontinence, cardiovascular diseases, respiratory diseases, cough, crazy the mental disorders and/or epilepsy.

Another object of the invention in accordance with this is the use of at least one substituted derivative 2-dialkylaminoalkyl General formula I in the form of its bases and/or salts of physiologically acceptable acids for obtaining a medicinal product intended for treating or preventing pain, inflammation or allergic reactions, depression, drug and alcohol abuse, gastritis, diarrhoea, urinary incontinence, cardiovascular diseases, respiratory tract diseases, coughing, mental disorders and/or epilepsy.

For the preparation of corresponding pharmaceutical compositions, along with at least one substituted derivatives of 2-dimethylaminoacetonitrile General formula I using carriers, fillers, solvents, diluents, dyes and/or binders. The choice of auxiliary substances, as well as their applicable amount depend on the purpose and methodology introduction the medicinal product, i.e. whether it is assigned for oral, intravenous, intraperitoneal, percutaneous, intramuscular, nasal, buccal or topical application, for example, skin infections, infections of the mucous membranes or eye infections. For oral administration suitable compositions are in the form of tablets, pills, capsules, granules, drops, mixed doubles and syrups, for parenteral, local and inhalation apply solutions, suspensions, easily reconstructed dry compositions, as well as aerosols. For percutaneous introduction of the compounds of General formula I according to the invention may be administered in depot, in dissolved form or embedded in a plaster, optionally with the addition of tools to facilitate penetration. Used for oral or percutaneous administration of medicinal forms can be prolonged action, i.e. to release the compounds of General formula I according to the invention gradually slowed down.

Assigned to a particular patient, the amount of the active substance varies depending on body weight, methods of administration, indications and severity of the disease. Normally, applying at least one derivative of 2-dialkylaminoalkyl General formula I it is prescribed in a dosage of from 0.5 to 500 mg/kg

Examples

Below the invention is explained in more detail by way of examples, which in no way limit its scope.

The output of the obtained compounds is not optimal.

All temperatures are listed without adjustments.

Under the concept of "simple ether" refers to diethyl ether.

As stationary (stationary phase in chromatography columns used silica gel 60 (0,040-0,063 mm) of the firm E. Merck. Darmstadt.

And the repetition by thin-layer chromatography was performed using ready GHUR-plates, silica gel 60 F 254 company K. Merck, Darmstadt.

Ratio in mixtures of eluents in chromatographic studies indicated in all cases in a volume ratio.

Example 1

(3'-methoxybiphenyl-2-ylmethyl)dimethylamine, hydrochloride

Stage 1

3-methoxybenzeneboronic acid

41,3 g (220 mmol) of 3-bromoanisole was dissolved in 880 ml of tetrahydrofuran and cooled to -70°in a bath of coolant mixture (ethanol/dry ice). Then in an atmosphere of nitrogen was added dropwise 160 ml (250 mmol) of a solution of utility (1.6 M in hexane) in such a way that the temperature did not exceed -60°C. after stirring for 1.5 h at -70°With added dropwise 75 ml (660 mmol) of triethylborane also so that the temperature did not exceed -60°C. After a further hour of stirring in the cold the mixture for 2 h was heated to 25°C, then added to 720 ml of hydrochloric acid (1 M) and was stirred for 15 h at 25°C.

For further processing the mixture was extracted three times with simple ether portions 300 ml), the organic phases were combined, washed with water 100 ml and saturated solution of sodium chloride, dried over anhydrous solution of magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). Thus scored 30.8 g of 3-methoxybenzeneboronic acid (92.1 per cent of theory).

(2-bromobenzyl)dimethylamine

of 25.1 g (113 mmol) of 2-bromobenzylamine, hydrochloride was dissolved in 26 ml (678 mmol) of formic acid and 52 ml (678 mmol) of a solution of formaldehyde (36 wt.%-tion in water) and with stirring, they were heated to 95°aged at this temperature for 6 hours Then the solution was cooled in an ice bath to 0°and added 90 grams of potassium hydroxide solution (50 wt.%-nogo).

Next three times were extracted by a simple ether in 100 ml, the organic phases were combined, mixed with a small amount of activated charcoal, dried over magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received of 22.2 g (2-bromobenzyl)dimethylamine (91,9% of theory).

Stage 3

(3'-methoxybiphenyl-2-ylmethyl)dimethylamine, hydrochloride

1.13 g (7,43 mmole) 3-methoxybenzeneboronic acid, 1,67 g (7,78 mmole) (2-bromobenzyl)dimethylamine and 2,62 g (24.7 mmole) of sodium carbonate was dissolved in a mixture of 50 ml of toluene, 20 ml of water and 10 ml ethanol. Then in an atmosphere of nitrogen was added 175 mg of tetrakis(triphenylphosphine)palladium(0) and with stirring, they were heated to 110°aged at this temperature for 16 hours

For further processing was added 75 ml of simple ether and was extracted three times with a solution of potassium hydroxide (0.5 M) portions of 75 ml of the combined aqueous solutions extragere is whether 30 ml of a simple ester, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received 2,12 g of crude base (118% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:1 (vol./about.) got 0,61 g base, which was dissolved in 6.0 ml of 2-butanone and successively mixed with 25 μl (1,39 mmole) of water and 350 μl (2,78 mmole) of chlorotrimethylsilane. During the next 15 h the mixture was stirred at 25°appearing in the precipitate solid was filtered off, washed with small portions of simple ether and dried in the generated oil pump vacuum to obtain a constant weight. The result was obtained 0.56 g (27.2% of theory) of (3'-methoxybiphenyl-2-ylmethyl)dimethylamine, hydrochloride with tPL144°C.

Example 2

(4'-chlorobiphenyl-2-ylmethyl)dimethylamine, hydrochloride

0.88 g (5,65 mmole) 4-chlorobenzylamino acid, 1.27 g (5,93 mmole) was obtained analogously to example 1 (stage 2) (2-bromobenzyl)dimethylamine and 2.00 g (18,8 mmole) of sodium carbonate was dissolved in a mixture of 39 ml of toluene, 16 ml of water and 8 ml of ethanol. Next, in an atmosphere of nitrogen was added 133 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

To further the processing was added 65 ml of simple ether and was extracted three times with a solution of potassium hydroxide (0.5 M) portions 65 ml. The combined aqueous was extracted again with 20 ml simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using relacionado evaporator (500-10 mbar). In this way received of 1.30 g of crude base (93.8% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:3 (vol/about.) got 0,61 g base, which was separated for further purification by GHWR. Conditions of separation: eluent acetonitrile/water (80:20 (vol./about.) + 0,5% vol. Isopropylamine), flow rate 10 ml/min, wavelength 254 nm, column type Eurogel PRP 100 (manufactured by Knauer, $ 250×16 mm, with precolonial). Thus obtained 0.31 g of crude base from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone was obtained 0.33 g (20,7% of theory) of (4'-chlorobiphenyl-2-ylmethyl)dimethylamine, hydrochloride with tPL232°C.

Example 3

2'-dimethylaminomethylphenol-3-ol, hydrochloride

0,70 g (2,52 mmole) was obtained analogously to example 1 (stage 3) (3'-methoxybiphenyl-2-ylmethyl)dimethylamine, hydrochloride was dissolved in 10 ml of water, then with 10 ml of water and 2 ml of sodium hydroxide solution (32 wt.%-tion) released Foundation, was extracted three times with simple ether in 20 ml, the volume of the United organic extracts were dried over anhydrous magnesium sulfate, was filtered and concentrated using rotary evaporator (500-10 mbar). Then 0,59 g (2,44 mmole) this Foundation for 2 h was heated under reflux (bath temperature 145° (C) with 55 ml of a solution of HBR (48 wt.%-tion in water).

For further processing the mixture was poured into 600 ml of a solution of sodium bicarbonate (1 M) (pH 7-8), was extracted three times with ethyl ether, acetic acid, 100 ml, the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated using a rotary evaporator (500-10 mbar). In this way received and 0.61 g of crude base (109% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution using a simple ester was obtained 0.51 g of base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone was obtained 0.51 g (79,7% of theory) of 2'-dimethylaminomethylphenol-3-ol, hydrochloride with tPL180°C.

Example 4

(2'-methoxybiphenyl-2-ylmethyl)dimethylamine, hydrochloride

to 1.00 g (to 6.58 mmole) 2-methoxybenzeneboronic acid, 1.48 g (6,91 mmole) 20 obtained analogously to example 1 (stage 2) (2-bromobenzyl)dimethylamine and 2,32 g (of 21.9 mmole) of sodium carbonate was dissolved in a mixture of 45 ml of toluene, 18 ml of water and 9 ml of ethanol. Next, in an atmosphere of nitrogen was added 160 mg of Tetra is IP(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110° C).

For further processing to the mixture was added 75 ml of simple ether and was extracted three times with a solution of potassium hydroxide (0.5 M) portions of 75 ml of the combined aqueous solutions were extracted with 20 ml of simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received of 1.62 g of crude base (102% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution using a mixture of simple ether/n-hexane in the ratio of 1:2 (vol./about.) obtained 0.64 g of base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone was obtained 0.31 g (17.1% of theory) of (2'-methoxybiphenyl-2-ylmethyl)dimethylamine, hydrochloride c tPL163°C.

Example 5

(3'-chlorobiphenyl-2-ylmethyl)dimethylamine, hydrochloride

to 1.00 g (6,39 mmole) 3-chlorobenzylamino acid, 1.44 g (of 6.71 mmole) was obtained analogously to example 1 (stage 2) (2-bromobenzyl)dimethylamine and 2.26 g (21.3 mmole) of sodium carbonate was dissolved in a mixture of 44 ml of toluene and 17 ml of water and 9 ml of ethanol. Then in an atmosphere of nitrogen was added 160 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 75 ml of simple generous garden light with the ether and was extracted three times with a solution of potassium hydroxide (0.5 M) portions 75 ml. The combined aqueous re-extracted with 20 ml simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received 1,49 g of crude base (94.7% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:1 (vol./about.) got to 0.62 g of base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone got hydrochloride. Forth from it with 10 ml of water and 2 ml of sodium hydroxide solution (32 wt.%-tion) released Foundation, was extracted three times with simple ether in 20 ml combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). The resulting crude base was purified by GHWR. Conditions of separation: eluent acetonitrile/water (80:20 (vol./about.) +0,5% vol. Isopropylamine), flow rate 10 ml/min, wavelength 254 them, column type Eurogel PRP 100 (manufactured by Knauer, $ 250×16 mm, with precolonial). Thus obtained 0.32 g of crude base from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone got to 0.29 g (16.3% of earie) (3'-chlorobiphenyl-2-ylmethyl)dimethylamine, hydrochloride with tPL169°C.

Example 6

(2'-forbiden-2-ylmethyl)dimethylamine, hydrochloride

1,02 g (7,27 mmole) 2-ferbinteanu acid, 1.63 g (to 7.61 mmole) was obtained analogously to example 1 (stage 2) (2-bromobenzyl)dimethylamine and 2.57 g (or 24.2 mmole) of sodium carbonate was dissolved in a mixture of 50 ml of toluene, 20 ml of water and 10 ml ethanol. Next, in an atmosphere of nitrogen was added 172 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 80 ml of a simple ether and was extracted three times with a solution of potassium hydroxide (0.5 M) portions of 80 ml combined aqueous re-extracted with 20 ml simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received 1.73 g of crude base (104% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:3 (vol/about.) received of 0.13 g of base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone was obtained 0.10 g (4.7% of theory) of (2'-forbiden-2-ylmethyl)dimethylamine, hydrochloride with tPL184°C.

Example 7

(3'-forbiden-2-metil)dimethylamine, hydrochloride

1,03 g (7,39 mmole) 3-ferbinteanu acid, of 1.05 g (is 4.93 mmole) was obtained analogously to example 1 (stage 2) (2-bromobenzyl)dimethylamine and 2,61 g (of 24.6 mmole) of sodium carbonate was dissolved in a mixture of 50 ml of toluene, 20 ml of water and 10 ml ethanol. Next, in an atmosphere of nitrogen was added 175 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 80 ml of a simple ether and was extracted three times with a solution of potassium hydroxide (0.5 M) portions of 80 ml combined aqueous re-extracted with 20 ml simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way got to 1.38 g of crude base (122% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:3 (vol/about.) got 0,57 g base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone received of 0.53 g (41.9% of theory) of (3'-forbiden-2-ylmethyl)dimethylamine, hydrochloride with tPL183°C.

Example 8

(4'-forbiden-2-ylmethyl)dimethylamine, hydrochloride

to 1.00 g (7,15 mmole) 4-ferbinteanu acid, of 1.02 g(4,76 mmole) was obtained analogously to example 1 (stage 2) (2-bromobenzyl)dimethylamine and 2.52 g (of 23.8 mmole) of sodium carbonate was dissolved in a mixture of 50 ml of toluene, 20 ml of water and 10 ml ethanol. Next, in an atmosphere of nitrogen was added 170 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 80 ml of a simple ether and was extracted three times with a solution of potassium hydroxide (0.5 M) portions of 80 ml combined aqueous re-extracted with 20 ml simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way got to 1.21 g of crude base (111% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:3 (vol/about.) obtained 0.56 g of base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone was obtained 0.56 g (44.0% of theory) of (4'-forbiden-2-ylmethyl)dimethylamine, hydrochloride with tPL222°C.

Example 9

(3'-chloro-4'-forbiden-2-ylmethyl)dimethylamine, hydrochloride

1.12 g (6,41 mmole) of 3-chloro-4-ferbinteanu acid, 1.44 g (6.73 x mmole) was obtained analogously to example 1 (stage 2) (2-bromobenzyl)dimethylamine and 2.26 g (21,4 mmole) of sodium carbonate was dissolved in a mixture of 44 ml of toluene, 18 ml of water and 9 ml of ethanol. Next, in a nitrogen atmosphere add the Yali 151 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110° C).

For further processing was added 70 ml of a simple ether and was extracted three times with a solution of potassium hydroxide (0.5 M) portions 70 ml. combined aqueous re-extracted with 20 ml simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received 1.66 g of crude base (98.2% of theory), which was introduced into the column size h cm, filled with silica gel. In the elution with a mixture of simple ether/n-gsxr in the ratio of 1:1 (vol./about.) got to 0.66 g of the base, which was purified by GHWR. Conditions of separation: eluent acetonitrile/water (80:20 (vol./about.) +0,5% vol. isopropylamino) flow rate 10 ml/min, wavelength 254 nm, column type Eurogel PRP 100 (manufactured by Knauer, $ 250×4.6 mm, with precolonial). In this way got to 0.37 g of crude base from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone obtained 0.34 g (17.6% of theory) of (3'-chloro-4'-forbiden-2-ylmethyl)dimethylamine, hydrochloride with tPL205°C.

Example 10

(3'-methoxybiphenyl-2-ylmethyl)dimethylamine, hydrochloride

Stage 1

2-(2-bromophenyl)ethylamine

10.0 g (51 mmol) of 2-bromophenylacetonitrile was dissolved in 80 ml of simple ether was added dropwise to of 5.81 g (153 mmole) of aluminum hydride whether the Oia in 230 ml of a simple ester. Then for 3 h with stirring, was heated under reflux and after cooling under vigorous stirring slowly was added dropwise 80 ml of potassium hydroxide solution.

After stirring overnight the supernatant decantation, the precipitate twice washed by a simple ether in 100 ml, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). The result was 9,48 g 2-(2-bromophenyl)ethylamine (93% of theory).

Stage 2

[2-(2-bromophenyl)ethyl]dimethylamine

9,42 g (47,3 mmole) of 2-(2-bromophenyl)ethylamine was dissolved in 18 ml (473 mmole) of formic acid and 36 ml (473 mmole) of formaldehyde solution (36 wt.%-tion in water) and for 6 h with stirring, was heated under reflux to 95°C. Then the solution was cooled in an ice bath to 0°and added 61 grams of potassium hydroxide solution (50 wt.%-nogo). Then at 25°thrice was extracted with simple ether portions 40 ml), combined organic phase was mixed with a small amount of activated charcoal, dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). The result was obtained 11.3 g that contains a number of impurities [2-(2-bromophenyl)ethyl]dimethylamine (105% from Theo the AI).

Stage 3

(3'-methoxybiphenyl-2-retil)dimethylamine, hydrochloride

2.0 g (13.2 mmole) was obtained analogously to example 1 (stage 1) 3-methoxybenzeneboronic acid and 3.15 g (to 13.8 mmole) of [2-(2-bromophenyl)ethyl]amine, obtained in stage 1, and of 4.66 g (43,8 mmole) of sodium carbonate was dissolved in a mixture of 90 ml of toluene and 36 ml of water and 18 ml of ethanol. Then in an atmosphere of nitrogen was added 312 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 150 ml of a simple ether and was extracted three times with a solution of potassium hydroxide (0.5 M) portions 150 ml. combined aqueous re-extracted with 50 ml of simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way got to 3.52 g of crude base (104% of theory), which was introduced into the column size 4,5×33 cm, filled with silica gel. After elution using a mixture of simple ether/n-hexane in the ratio of 1:1 (vol./about.) received 2.24 g of the base, which was purified by GHWR. Conditions of separation: eluent acetonitrile/water (70:30 (vol./about.) +0,05% vol. Isopropylamine), flow rate 10 ml/min, wavelength 254 them, column type Eurogel PRP 100 (manufactured by Knauer, $ 250×16 mm, with precolonial). This PU is eaten obtained 0.96 g of crude base, of which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone was obtained 0.65 g (3'-methoxybiphenyl-2-retil)amine, hydrochloride (17.3% of theory) with tPL143°C.

Example 11

Dimethyl-[2-(2-methylbenzofuran-4-yl)benzyl]amine, hydrochloride

Stage 1

2-(dimethylaminomethyl)bentlebanonrola acid

23.3 g (109 mmol) obtained analogously to example 1 (stage 2) (2-bromobenzyl)amine was dissolved in 400 ml of tetrahydrofuran and in the bath of the cooling mixture (ethanol/dry ice) was cooled to -70°C. and Then in an atmosphere of nitrogen was added dropwise 78 ml (125 mmol) of a solution of utility (1.6 M in hexane) in such a way that the temperature did not exceed -65°C. After stirring for 1.5 h at -70°was added dropwise 37 ml trimethylborane thus that the temperature did not exceed -60°C. After a further hour of stirring in the cold was heated to 25°aged at this temperature for 2 h, was added 350 ml of hydrochloric acid (1 M) and for 15 h and was stirred at 25°C.

For further processing the mixture was neutralized with 10 ml of sodium hydroxide solution (32 wt.%-tion), podslushivaet with 3.5 g of sodium carbonate (pH about 9), were extracted three times by a simple ether portions 150 ml), the organic phases were combined, dried over anhydrous Sul is an atom of magnesium, was filtered and concentrated using rotary evaporator (500-10 mbar). In this way received 9,29 g of 2-(dimethylaminomethyl)benthivorous acid (47,7% of theory).

Stage 2

Dimethyl[2-(2-methylbenzofuran-4-yl)benzyl]amine, hydrochloride

to 1.00 g (5,59 mmole) of 2-(dimethylaminomethyl)benthivorous acid, obtained in stage 1, 1.24 g (5,86 mmole) of 4-bromo-2-methylbenzofuran and 1.97 g (to 18.6 mmole) of sodium carbonate was dissolved in a mixture of 38 ml of toluene, 15 ml of water and 8 ml of ethanol. Next, in an atmosphere of nitrogen was added 132 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing to the mixture was added 75 ml of simple ether and was extracted three times with a solution of potassium hydroxide (0.5 M) portions 75 ml. Then the combined aqueous re-extracted with 20 ml of a simple ester. The combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received a 1.75 g of crude base (124% of theory), which was introduced into the column size 3×25 cm filled with silica gel. After elution using a mixture of simple ether/n-hexane in the ratio of 1:3 (vol/about.) got 0,78 g base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-b is tanone obtained 0.64 g (39,5% of theory) of dimethyl-[2-(2-methylbenzofuran-4-yl)benzyl]amine, hydrochloride with tPL217°C.

Example 12

2'-dimethylaminomethylphenol-2-carbaldehyde, hydrochloride

1.20 g (7,97 mmole) 2-formylbenzeneboronic acid, 1.63 g (to 7.59 mmole) was obtained analogously to example 1 (stage 2) (2-bromobenzyl)dimethylamine and $ 2.68 g (to 25.3 mmole) of sodium carbonate was dissolved in a mixture of 52 ml of toluene, 21 ml of water and 10 ml ethanol. Then in an atmosphere of nitrogen was added 180 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 85 ml of simple ether and was extracted three times with portions 85 ml of a solution of potassium hydroxide (0.5 M). The combined aqueous re-extracted with 20 ml simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way got to 1.87 g of crude base (98.2% of theory). Then, this base was dissolved in 50 ml of simple ether was extracted three times with portions of 25 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet with 15 ml of sodium hydroxide solution (32 wt.%-tion) (pH approximately 11). Next was extracted three times with portions of 25 ml of simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtrowanie concentrated using a rotary evaporator (500-10 mbar). In this way received 1.28 g of crude base (70,3% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:1 (vol./about.) got 0,42 g base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water butanone got 0,43 g (20.5% of theory) of 2'-dimethylaminomethylphenol-2-carbaldehyde with tPL230°C.

Example 13

(3'-diverseylever-2-ylmethyl)dimethylamine, hydrochloride

0,98 g (5,46 mmole) was obtained analogously to example 11 (stage 1) 2-(dimethylaminomethyl)benthivorous acid, 1.19 g (5,73 mmole) 1-bromo-3-deformational and of 1.93 g (18.2 mmole) of sodium carbonate was dissolved in a mixture of 37 ml of toluene, 15 ml of water and 8 ml of ethanol. Then in an atmosphere of nitrogen was added 130 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing to the mixture was added 60 ml of a simple ether and was extracted three times with portions of 60 ml of a solution of potassium hydroxide (0.5 M). The combined aqueous re-extracted with 20 ml simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received a 1.46 g of crude base (13% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution using a mixture of simple ether/n-hexane in the ratio of 1:3 (vol/about.) got 0,79 g base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone got to 0.67 g (40,9% of theory) of (3'-diverseylever-2-ylmethyl)dimethylamine, hydrochloride with tPL147°C.

Example 14

2'-dimethylaminomethylphenol-3-carbaldehyde, hydrochloride

1,03 g (6,89 mmole) 3-formylbenzeneboronic acid, 1.40 g (6,56 mmole) was obtained analogously to example 1 (stage 2) (2-bromobenzyl)dimethylamine and 2,32 g (to 21.8 mmole) of sodium carbonate was dissolved in a mixture of 45 ml of toluene, 18 ml of water and 9 ml of ethanol. Then in an atmosphere of nitrogen was added 156 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing to the mixture was added 75 ml of simple ether and was extracted three times with a solution of potassium hydroxide (0.5 M) portions 75 ml. combined aqueous re-extracted with 20 ml simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received 1.66 g of crude base (100% of theory). Then, this base was dissolved in 50ml of simple ether, three times were extracted portions of 25 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet with 15 ml of sodium hydroxide solution (pH approximately 11). Then was extracted three times with portions of 25 ml of simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way got a 1.08 g of crude base (68.7% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution using a mixture of simple ether/n-hexane in the ratio of 1:3 (vol/about.) received 0.40 g of base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone was obtained 0.31 g (17.3% of theory) of 2'-dimethylaminomethylphenol-3-carbaldehyde, hydrochloride with tPL185°C.

Example 15

Biphenyl-2-ilmatieteen, hydrochloride

1.01 g (8,30 mmole) of benthivorous acid, 1,69 g (of 7.90 mmole) was obtained analogously to example 1 (stage 2) (2-bromobenzyl)dimethylamine and 2,79 g (to 26.3 mmole) of sodium carbonate was dissolved in a mixture of 54 ml of toluene, 22 ml of water and 11 ml of ethanol. Then in an atmosphere of nitrogen was added 187 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For far is it processing was added 90 ml of simple ether and was extracted three times with portions 90 ml of a solution of potassium hydroxide (0.5 M). The combined aqueous re-extracted with 20 ml simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received 1.64 g of crude base (93.3% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:3 (vol/about.) obtained 0.26 g of base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone obtained 0.28 g (14.2% of theory) biphenyl-2-ylmethylamino, hydrochloride with tPL189°C.

Example 16

(3',4'-dichlorobiphenyl-2-ylmethyl)dimethylamine, hydrochloride

1.01 g (from 5.29 mmole) of 3,4-dichlorobenzophenone acid, 1.19 g (5,56 mmole) was obtained analogously to example 1 (stage 2) (2-bromobenzyl)dimethylamine and of 1.87 g (to 17.6 mmole) of sodium carbonate was dissolved in a mixture of 36 ml of toluene, 15 ml of water and 7 ml of ethanol. Then in an atmosphere of nitrogen was added 125 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 60 ml of a simple ether and was extracted three times with portions of 60 ml of a solution of potassium hydroxide (0.5 M). The combined aqueous re-extracted with 20 ml of simply what about the ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received 1,43 g of crude base (96.5% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:3 (vol/about.) received 0.52 g of the base, which was separated for further purification by GHWR. Conditions of separation: eluent acetonitrile/water (90:10 (vol./about.) + 0,05% vol. Isopropylamine), flow rate 10 ml/min, wavelength 254 nm, column type Eurogel PRP 100 (manufactured by Knauer, $ 250×16 mm, with precolonial). Thus obtained 0.20 g of crude base from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone got to 0.19 g (11.4% of theory) of (3',4'-dichlorobiphenyl-2-ylmethyl)dimethylamine, hydrochloride with tPL219°C.

Example 17

(3',5'-dichlorobiphenyl-2-ylmethyl)dimethylamine, hydrochloride

0,89 g (4,66 mmole) of 3,5-dichlorobenzophenone acid, 0.95 g (of 4.44 mmole) was obtained analogously to example 1 (stage 2) (2-bromobenzyl)dimethylamine and 1.57 g (of 14.8 mmole) of sodium carbonate was dissolved in a mixture of 30 ml of toluene, 12 ml of water and 6 ml of ethanol. Then in an atmosphere of nitrogen was added 106 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux bath temperature 110° C).

For further processing was added 50 ml of a simple ether and was extracted three times with 50 ml of a solution of potassium hydroxide (0.5 M). The combined aqueous re-extracted with 20 ml simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received a 1.25 g of crude base (95.5% of theory). This base was dissolved in 50 ml of simple ether was extracted three times with portions of 25 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet with 15 ml of sodium hydroxide solution (32 wt.%-tion) (pH approximately 11). Next was extracted three times with portions of 25 ml of simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received and 0.46 g of crude base (37,3% of theory), which was introduced into the column size 3×15 cm, filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:3 (vol/about.) got to 0.23 g of base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone was obtained 0.20 g (14.9% of theory) of (3',5'-dichlorobiphenyl-2-ylmethyl)dimethylamine, hydrochloride with t 198°C.

Example 18

Dimethyl(4'-nitro-3'-triptorelin-2-ylmethyl)amine, hydrochloride

Stage 1

Dimethyl-2-(dimethylaminomethyl)benovolent

20.2 g (94,2 mmole) was obtained analogously to example 1 (stage 2) (2-bromobenzyl)amine was dissolved in 350 ml of tetrahydrofuran and in the bath of the cooling mixture (isopropanol/dry ice) was cooled to -70°C. Next, in a nitrogen atmosphere was added dropwise 68 ml (108 mmole) of a mixture of utility (1.6 M in hexane) in such a way that the temperature did not exceed -60°C. After stirring for 2 h at -70°was added dropwise 32 ml (282 mmole) trimethylborane also so that the temperature did not exceed -60°C. Next, the mixture was heated to 25°aged at this temperature for 15 h and then concentrated solution using a rotary evaporator (500-10 mbar) without the supply of heat. The residue was dissolved in 200 ml n-hexane, stirred for 1 h, was filtered in a nitrogen atmosphere through a Frit with protective gas and the filtrate was concentrated using a rotary evaporator (500-10 mbar) without the supply of heat. Thus obtained 12.0 g of dimethyl-2-(dimethylaminomethyl)benovolent (61.5% of theory).

Stage 2

Dimethyl-(4'-nitro-3'-triptorelin-2-ylmethyl)amine, hydrochloride

1.84 g (8,89 mmole) obtained in stage 1 dimethyl-2-(dimethylaminomethyl)benovolent, 1.20 g (of 4.44 mmole) -bromo-2-nitrobenzotrifluoride and 1.57 g (of 14.8 mmole) of sodium carbonate was dissolved in a mixture of 30 ml of toluene, 12 ml of water and 6 ml of ethanol. Then in an atmosphere of nitrogen was added 105 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 45 ml of a simple ether and washed three times with portions 45 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions of 17 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet with 10 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next three times were extracted by a simple ether in 20 ml combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received 1.29 g of crude base (89.4% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:10 (vol./about.) received of 1.05 g of base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone got 1,02 g (66,1% of theory) of dimethyl-(4'-nitro-3'-triptorelin-2-ylmethyl)amine, hydrochloride with tPL240°C.

Example 19

(3',4'-diferuloyl-2-ylmethyl)dimethylamine, hydrochloride

1.01 g (4,87 mmole) obtained an is logically example 18 (stage 1)of dimethyl-2-(dimethylaminomethyl)benovolent, 1.88 g (9,75 mmole) of 3,4-diversamente and 1,72 g (16.2 mmole) of sodium carbonate was dissolved in a mixture of 33 ml of toluene, 13 ml of water and 7 ml of ethanol. Then in an atmosphere of nitrogen was added 116 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 55 ml of simple ether and washed three times with portions 55 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions of 22 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet using 13 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next three times were extracted by a simple ether in 20 ml combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way got to 0.67 g of crude base (55.3% of theory), which was introduced into the column size 3×15 cm, filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:10 (vol./about.) got to 0.47 g of base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone obtained 0.52 g (37.6 per cent of theory) of (3',4'-diferuloyl-2-ylmethyl)dimethylamine, hydrochloride with tPL222°C.

Example 20

(4'-fluoro-3'-triptorelin-2-ylmethyl)dimethylamine, hydrochloride

1,02 g (4,91 mmole) was obtained analogously to example 18 (stage 1) of dimethyl-2-(dimethylaminomethyl)benovolent, of 2.38 g (9,81 mmole) of 5-bromo-2-fermentatively and 1.73 g (16.3 mmole) of sodium carbonate was dissolved in a mixture of 34 ml of toluene, 14 ml of water and 7 ml of ethanol. Then in an atmosphere of nitrogen was added 117 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 55 ml of simple ether and washed three times with portions 55 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions of 22 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet using 13 ml of sodium hydroxide (32 wt.%-tion) (pH about 12). Next three times were extracted by a simple ether in 20 ml combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). Thus obtained 0.55 g of crude base (37.5% of theory), which was introduced into the column size 3×15 cm, filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:10 (vol./about.) received 0.39 g of base, from which analogously to example 1 (step 3) use the reattaching the mixture chlorotrimethylsilane/water in 2-butanone got 0,37 g (22,8% of theory) of (4'-fluoro-3'-triptorelin-2-ylmethyl)dimethylamine, hydrochloride with tPL180°C.

Example 21

(4'-chloro-3'-methoxybiphenyl-2-ylmethyl)dimethylamine, hydrochloride

1.52 g (4,87 mmole) was obtained analogously to example 18 (stage 1) of dimethyl-2-(dimethylaminomethyl)benovolent, 1.08 g (4,88 mmole) of 5-bromo-2-chlorothioxanthone and 1,72 g (16.3 mmole) of sodium carbonate was dissolved in a mixture of 33 ml of toluene, 13 ml of water and 7 ml of ethanol. Then in an atmosphere of nitrogen was added 116 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 55 ml of simple ether and washed three times with portions 55 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions of 22 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet using 13 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next three times were extracted by a simple ether in 20 ml combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). Thus obtained 1.26 g of crude base (93.3% of theory), which was introduced into the column size 3×15 cm, filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:20 (vol./about.) got 0,44 g the basis of the Oia, of which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone got 0,46 g (29.9% of theory) of (4'-chloro-3'-methoxybiphenyl-2-ylmethyl)dimethylamine, hydrochloride with tPL218°C.

Example 22

N-(2'-dimethylaminomethyl-3-cryptomaterial-4-yl)acetamide", she hydrochloride

1.55 g (of 7.48 mmole) was obtained analogously to example 18 (stage 1) of dimethyl-2-(dimethylaminomethyl)benovolent, 1,49 g (4.99 mmole) of 4-bromo-2-(triptoreline)acetanilide and 1.76 g (of 16.6 mmole) of sodium carbonate was dissolved in a mixture of 34 ml of toluene, 14 ml of water and 7 ml of ethanol. Then in an atmosphere of nitrogen was added 118 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 55 ml of simple ether and washed three times with portions 55 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions of 22 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet using 13 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next three times were extracted by a simple ether in 20 ml combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received 1,72 g wet basis of the project (97.6% of theory), which was introduced into the column size 3×15 cm, filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:10 (vol./about.) got 0,91 g Foundation. Of 0.40 g of this base analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone received 0.39 g (45.5% of theory) of N-(2'-dimethylaminomethyl-3-cryptomaterial-4-yl)acetamide", she hydrochloride with tPL182°C.

Example 23

(3'-isopropoxyphenyl-2-ylmethyl)dimethylamine, hydrochloride

1.51 g (7,31 mmole) was obtained analogously to example 18 (stage 1) of dimethyl-2-(dimethylaminomethyl)benovolent, of 1.05 g (4,87 mmole) 1-bromo-3-isopropoxybenzoic and 1,72 g (16.2 mmole) of sodium carbonate was dissolved in a mixture of 33 ml of toluene, 13 ml of water and 7 ml of ethanol. Then in an atmosphere of nitrogen was added 116 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 55 ml of simple ether and washed three times with portions 55 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions of 22 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet using 13 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next three times were extracted by a simple ether portions 20 m is, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received a 1.25 g of crude base (94.8% of theory), which was introduced into the column size 3×15 cm, filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:20 (vol./about.) obtained 0.65 g of base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone was obtained 0.36 g (24,0% of theory) of (3'-isopropoxyphenyl-2-ylmethyl)dimethylamine, hydrochloride.

Example 24

2'-(2-dimethylaminoethyl)biphenyl-3-ol, hydrochloride

0,89 g (3,49 mmole) was obtained analogously to example 10 (stage 2) base (3' -methoxybiphenyl-2-retil)amine, hydrochloride (10) for 2 h was heated under reflux with 89 ml of a solution of HBR (48 wt.%-tion in water) (bath temperature 145°).

For further processing the mixture was poured into 1000 ml of a solution of sodium bicarbonate (1 M) (pH 7-8), four times were extracted by a simple ether in 100 ml combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). Thus obtained 0.32 g of crude base (38.5% of theory), which analogously to example 1 (stage 3) and with the use of a mixture of chlorotrimethylsilane/water in 2-butanone was obtained 0.26 g (27,9% of theory) of 2'-(2-dimethylaminoethyl)biphenyl-3-ol, hydrochloride with tPL161°C.

Example 25

4-chloro-2'-dimethylaminomethylphenol-3-ol, hydrochloride

0,59 g (2,15 mmole) was obtained analogously to example 21 of the base (4'-chloro-3'-methoxybiphenyl-2-ylmethyl)amine, hydrochloride (21) for 2 h was heated under reflux with 60 ml of a solution of HBR (48 wt.%-tion in water) (bath temperature 145°).

For further processing the mixture was poured into 140 ml of water and by adding solid sodium bicarbonate was established pH value of 7-8, were extracted three times by a simple ether portions 50 ml), the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). Thus obtained 0.55 g of crude base (98,1% of theory), of which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone was obtained 0.56 g (88,0% of theory) of 4-chloro-2'-dimethylaminomethylphenol-3-ol, hydrochloride with tPL194°C.

Example 26

[2-(1H-indol-5-yl)benzyl]dimethylamine

4.77 g (23 mmole) was obtained analogously to example 18 (stage 1) of dimethyl-2-(dimethylaminomethyl)benovolent, 3,01 g (15.4 mmole) of 5-bromoindole and 5.42 g (51,1 mmole) of sodium carbonate was dissolved in a mixture of 105 ml of toluene, 42 ml of water and 21 ml of ethanol. Then in an atmosphere of nitrogen was added 364 mg of tetrakis(triphenylphospine(0) and for 16 h was heated under reflux (bath temperature 110° C).

For further processing was added 100 ml of a simple ether and washed three times with a solution of potassium hydroxide (0.5 M) in portions of 100 ml of the Organic solution was extracted three times with hydrochloric acid (5 wt.%-Noah portions 45 ml, the combined acidic phases were washed with 20 ml of simple ether, and podslushivaet with 25 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next three times were extracted portions 45 ml simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received of 2.23 g of crude base (58,1% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:1 (vol./about.) obtained 0.33 g (37.6 per cent of theory) of [2-(1H-indol-5-yl)benzyl]amine.

Example 27

(4'-methysulfonylmethane-2-ylmethyl)dimethylamine, hydrochloride

1,59 g (7,69 mmole) was obtained analogously to example 18 (stage 1)of dimethyl-2-(dimethylaminomethyl)benovolent, 1,21 g (5,13 mmole) 4-bromophenylacetate and of 1.81 g (17.1 mmole) of sodium carbonate was dissolved in a mixture of 35 ml of toluene, 14 ml of water and 7 ml of ethanol. Then in an atmosphere of nitrogen was added 122 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (temperature b is either 110° C).

For further processing was added 55 ml of simple ether and washed three times with portions 55 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions of 22 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet using 13 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next three times were extracted by a simple ether in 20 ml combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way got to 0.67 g of crude base (55.3% of theory), which was introduced into the column size 3×15 cm, filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:1 (vol./about.) obtained 0.65 g of base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone got to 0.62 g (37.2% of theory) of (4'-methysulfonylmethane-2-ylmethyl)dimethylamine, hydrochloride with tPL173°C.

Example 28

(2',4'-dichlorobiphenyl-2-ylmethyl)dimethylamine, hydrochloride

1,69 g (8,17 mmole) was obtained analogously to example 18 (stage 1) of dimethyl-2-(dimethylaminomethyl)benovolent, 1,23 g (5,44 mmole) of 2,4-dichlorobenzamide and 1.92 g (18,1 mmole) of sodium carbonate was dissolved in a mixture of 37 ml of toluene, 15 the l of water and 8 ml of ethanol. Then in an atmosphere of nitrogen was added 129 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 60 ml of a simple ether and washed three times with portions of 60 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions of 24 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet using 14 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next was extracted three times with portions of 25 ml of simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way got to 0.62 g of crude base (40.3% of theory), which was introduced into the column size 3×15 cm, filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:3 (vol/about.) received 0.39 g of base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone was obtained 0.25 g (15.2% of theory) of (2',4'-dichlorobiphenyl-2-ylmethyl)dimethylamine, hydrochloride with tPL170-171°C.

Example 29

(2',3'-diferuloyl-2-ylmethyl)dimethylamine, hydrochloride

of 1.97 g (at 9.53 mmole) was obtained analogously to example 18 (stage 1) dimate is-2-(dimethylaminomethyl)benovolent, of 1.23 g (6,35 mmole) of 2,3-differentialblood and 2.24 g (of 21.2 mmole) of sodium carbonate was dissolved in a mixture of 43 ml of toluene and 17 ml of water and 9 ml of ethanol. Then in an atmosphere of nitrogen was added 151 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 70 ml of a simple ether and washed three times with a solution of potassium hydroxide (0.5 M) portions 70 ml Organic solution was extracted three times with portions of 27 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet using 16 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next was extracted three times with 30 ml of simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received 0,99 g of crude base (63.2% of theory), which was introduced into the column size 3×15 cm, filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:3 (vol/about.) received and 0.61 g of base, from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone was obtained 0.55 g (34.3% of theory) of (2',3'-diferuloyl-2-ylmethyl)dimethylamine, hydrochloride with tPL214°C.

Example 0

(2',5'-diferuloyl-2-ylmethyl)dimethylamine, hydrochloride

1.86 g (8,98 mmole) was obtained analogously to example 18 (stage 1) of dimethyl-2-(dimethylaminomethyl)benovolent, of 1.16 g (5,99 mmole) of 2,5-differentialblood and 2,11 g (to 19.9 mmole) of sodium carbonate was dissolved in a mixture of 41 ml of toluene and 17 ml of water and 8 ml of ethanol. Then in an atmosphere of nitrogen was added 142 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 65 ml of simple ether and washed three times with portions 65 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions 26 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet with 15 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next was extracted three times with portions of 25 ml of simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way got to 0.66 g of crude base (44.4% of theory), which was introduced into the column size h cm, filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:3 (vol/about.) received 0.40 g of base, from which analogously to example 1 (stage 3) with ispolzovaniem chlorotrimethylsilane/water in 2-butanone was obtained 0.36 g (23.4% of theory) of (2',5'-diferuloyl-2-ylmethyl)dimethylamine, hydrochloride with tPL165°C.

Example 31

(2-benzol[1,3]dioxol-5-ylbenzyl)dimethylamine, hydrochloride

1,71 g (8,24 mmole) was obtained analogously to example 18 (stage 1) of dimethyl-2-(dimethylaminomethyl)benovolent, 1.10 g (5,49 mmole) of 4-bromo-1,2-(methylenedioxy)benzene and of 1.94 g (to 18.3 mmole) of sodium carbonate was dissolved in a mixture of 38 ml of toluene, 15 ml of water and 8 ml of ethanol. Then in an atmosphere of nitrogen was added 130 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 55 ml of simple ether and washed three times with portions 55 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions of 22 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet using 13 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next three times were extracted by a simple ether in 20 ml combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received a 1.46 g of crude base (104% of theory), which was introduced into the column size 3×15 cm, filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:1 (vol./about.) got 1,17 g based what I of which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone obtained 1.20 g (74.8% of theory) of (2-benzol[1,3]dioxol-5-ylbenzyl)dimethylamine, hydrochloride with tPL181°C.

Example 32

1-[2'-(2-dimethylaminoethyl)biphenyl-3-yl]alanon, hydrochloride

2,13 g (13.0 mmol) 3-acetylanthranilic acid, 1.98 g (8,68 mmole) was obtained analogously to example 10 [2-(2-bromophenyl)ethyl]dimethylamine and 3.06 g (of 28.9 mmole) of sodium carbonate was dissolved in a mixture of 60 ml of toluene, 23 ml of water and 12 ml of ethanol. Then in an atmosphere of nitrogen was added 206 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 90 ml of simple ether and washed three times with portions 90 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions of 35 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 20 ml of simple ether, and podslushivaet with 20 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next was extracted three times with 40 ml of simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received of 2.08 g of crude base (89.5% of theory), which is similar PR is a measure 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone received of 1.57 g (59.6% of theory) 1-[2'-(2-dimethylaminoethyl)biphenyl-3-yl]ethanone, hydrochloride with tPL141°C.

Example 33

[2-(3',4'-dimethoxybiphenyl-2-ileti]dimethylamine, hydrochloride

2,22 g (12.2 mmole) of 3,4-dimethoxybenzophenone acid, 1.86 g (8,14 mmole) was obtained analogously to example 10 [2-(2-bromophenyl)ethyl]dimethylamine are 2.87 g (27,1 mmole) of sodium carbonate was dissolved in a mixture of 55 ml of toluene, 22 ml of water and 11 ml of ethanol. Then in an atmosphere of nitrogen was added 193 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 90 ml of simple ether and washed three times with portions 90 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions of 35 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 20 ml of simple ether, and podslushivaet with 20 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next three times were extracted portions 35 ml simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way got to 1.82 g of crude base (78,0% of theory), of which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone got 2,02 g (76.8% of theory) of [2-(3',4'-dimethoxybiphenyl-2-retil)dimethylamine, hydrochloride with t 179°C.

Example 34

[2-(3'-isopropoxyphenyl-2-ileti]dimethylamine, hydrochloride

Stage 1

Dimethyl-2-(2-dimethylaminoethyl)benovolent

19,0 g (83,2 mmole) was obtained analogously to example 10 (stage 2) [2-(2-bromophenyl)ethyl]amine was dissolved in 300 ml of tetrahydrofuran in a bath of coolant mixture (isopropanol/dry ice) was cooled to -70°C. and Then in an atmosphere of nitrogen was added dropwise 60 ml (95,7 mmole) of a mixture of utility (1.6 M in hexane) in such a way that the temperature did not exceed -60°C. After stirring for 2 h at -70°was added dropwise 28 ml (250 mmole) of trimethylborane also so that the temperature did not exceed -60°C. Next, the mixture was heated to 25°aged at this temperature for 1 to 5 h and the solution was concentrated using a rotary evaporator (500-10 mbar) without the supply of heat. The residue was dissolved in 200 ml n-hexane, stirred for 1 h, was filtered in a nitrogen atmosphere through a Frit with protective gas and the filtrate was concentrated using a rotary evaporator (500-10 mbar) without the supply of heat. In this way received 14.1 g of dimethyl-2-(2-dimethylaminoethyl)benovolent (76,5% of theory).

Stage 2

[2-(3'-isopropoxyphenyl-2-yl)ethyl]dimethylamine, hydrochloride

1.20 g (5,43 mmole) of dimethyl-2-(2-dimethylaminoethyl)benovolent obtained in stage 1, about 1.75 g (8,14 mmole) 3-bromazepam is xianzai and 1.92 g (18,1 mmole) of sodium carbonate was dissolved in a mixture of 37 ml of toluene, 15 ml of water and 8 ml of ethanol. Then in an atmosphere of nitrogen was added 129 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 60 ml of a simple ether and was extracted three times with portions of 60 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions of 23 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet using 14 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next was extracted three times with portions of 25 ml of simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way got to 1.32 g of crude base (86,0% of theory), of which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone got 1,11 g (63.9% of theory) of [2-(3'-isopropoxyphenyl-2-yl)ethyl]amine, hydrochloride with tPL164°C.

Example 35

[2-(4'-chloro-3'-methoxybiphenyl-2-yl)ethyl]dimethylamine, hydrochloride

1.20 g (5,43 mmole) was obtained analogously to example 34 stage (stage 1) of dimethyl-2-(2-dimethylaminoethyl)benovolent, of 1.80 g (8,14 mmole) of 5-bromo-2-chloroanisole and 1.92 g (18,1 mmole) of sodium carbonate was dissolved in a mixture of 37 ml of toluene, 15 ml of the odes and 8 ml of ethanol. Then in an atmosphere of nitrogen was added 129 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 60 ml of a simple ether and washed three times with portions of 60 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions of 23 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet using 14 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next was extracted three times with portions of 25 ml of simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received 1,43 g of crude base (90,7% of theory), of which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone received of 1.34 g (75.6% of theory) of [2-(4'-chloro-3'-methoxybiphenyl-2-yl)ethyl]amine, hydrochloride with tPL227°C.

Example 36

4-chloro-2'-(2-dimethylaminoethyl)biphenyl-3-ol, hydrochloride

of 0.58 g (2.01 mmole) of the base obtained analogously to example 35 [2-(4'-chloro-3'-methoxybiphenyl-2-yl)ethyl]amine, hydrochloride for 2 h was heated under reflux with a solution of HBR (48 wt.%-tion in water) (bath temperature 145° C).

For further processing the mixture was poured into 700 ml of a solution of sodium bicarbonate (1 M) (pH 7-8), was extracted three times with simple ether in 100 ml combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received of 0.54 g of crude base (98,0% of theory), of which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in butanone was obtained 0.51 g (93,5% of theory) of 4-chloro-2'-(2-dimethylaminoethyl)biphenyl-3-ol, hydrochloride c tPL164°C.

Example 37

Dimethyl(3'-nitrobiphenyl-2-ylmethyl)amine, hydrochloride

1.04 g (6,20 mmole) 3-nitrobenzeneboronic acid, 1,21 g (5,64 mmole) was obtained analogously to example 1 (stage 2) (2-bromobenzyl)dimethylamine and 1.99 g (18,8 mmole) of sodium carbonate was dissolved in a mixture of 40 ml of toluene, 16 ml of water and 8 ml of ethanol. Then in an atmosphere of nitrogen was added 134 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 65 ml of simple ether and washed three times with portions 65 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions of 25 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet by the th 15 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next was extracted three times with portions of 25 ml of simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received 714 mg of crude base (49,3% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:3 (vol/about.) got 330 mg base from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone received 262 mg (15,9% of theory) of dimethyl-(3'-nitrobiphenyl-2-ylmethyl)amine, hydrochloride with tPL147°C.

Example 38

4-amino-2'-dimethylaminomethylphenol-3-ol, dihydrochloride

2,40 g (6,17 mmole) of the base obtained analogously to example 22 N-(2'-dimethylaminomethyl-3-cryptomaterial-4-yl)acetamide", she hydrochloride (22) for 6 h was heated under reflux with 110 ml of a solution of HBR (33 wt.%-acetate in glacial acetic acid) (bath temperature 160°).

For further processing the mixture was poured into 1000 ml of simple ether and the supernatant decantation. The residue was dissolved in water, washed three times with simple ether in 20 ml, with a solution of sodium bicarbonate (1 M) were established pH value of 7-8, were extracted three times porci the mi 40 ml of a simple ester, the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received of 1.94 g of crude base (130% of theory), which was introduced into the column size 3×30 cm filled with silica gel. In the elution using a mixture of simple ether/n-hexane in the ratio 2:1 (vol./vol.), in addition 1,72 g virtually unchanged educt, got 178 mg of crude base from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone received 177 mg (7.5% of theory) of 4-amino-2'-dimethylaminomethylphenol-3-ol, dihydrochloride, which decomposes when heated above 120°C.

Example 39

(3',5'-diferuloyl-2-ylmethyl)dimethylamine, hydrochloride

1,71 g (compared to 8.26 mmole) was obtained analogously to example 18 (stage 1) of dimethyl-2-(dimethylaminomethyl)benovolent, 1.06 g (5,51 mmole) bromo-3,5-diferently and of 1.94 g (to 18.3 mmole) of sodium carbonate was dissolved in a mixture of 38 ml of toluene, 15 ml of water and 7.5 ml of ethanol. Then in an atmosphere of nitrogen was added 131 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 60 ml of a simple ether and washed three times with portions of 60 ml of a solution of potassium hydroxide (0.5 M). The organic solution three times uh what was strayaway portions 24 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 25 ml of simple ether, and podslushivaet using 14 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next was extracted three times with portions of 25 ml of simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). Thus obtained 1.19 g of crude base (87.6% of theory), which was introduced into the column size 3×25 cm filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:3 (vol/about.) received 990 mg base from which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone obtained 1.06 g (37.2% of theory) of (3',5'-diferuloyl-2-ylmethyl)dimethylamine, hydrochloride, which decomposes when heated above 190°C.

Example 40

(2',5'-dimethoxybiphenyl-2-ylmethyl)dimethylamine, hydrochloride

of 1.61 g (7,79 mmole) was obtained analogously to example 18 (stage 1) of dimethyl-2-(dimethylaminomethyl)benovolent, 1.13 g (5,20 mmole) of 2-bromo-1,4-dimethoxybenzene and 1.83 g (a 17.3 mmole) of sodium carbonate was dissolved in a mixture of 35 ml of toluene, 14 ml of water and 7 ml of ethanol. Then in an atmosphere of nitrogen was added 123 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For far is it processing was added 55 ml of simple ether and washed three times with portions 55 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions of 22 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 10 ml of simple ether, and podslushivaet using 13 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next three times were extracted by a simple ether in 20 ml combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received 770 mg of crude base (61,0% of theory), of which analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone received 777 mg (49,7% of theory) of (2',5'-dimethoxybiphenyl-2-ylmethyl)dimethylamine, hydrochloride with tPL169°C.

Example 41

2'-dimethylaminomethyl-5-cryptomaterial-2-ylamine, dihydrochloride

6,24 g (to 30.1 mmole) was obtained analogously to example 18 (stage 1) of dimethyl-2-(dimethylaminomethyl)benovolent, 5,14 g (20.1 mmole) of 2-bromo-4-triphtalocyaninine and to 7.09 g (66,9 mmole) of sodium carbonate was dissolved in a mixture of 140 ml of toluene, 55 ml of water and 27 ml of ethanol. Then in an atmosphere of nitrogen was added 476 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 220 ml of simple ether and washed three times with portions 220 ml hydroxy is and potassium (0.5 M). The organic solution was extracted three times with portions 90 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 90 ml of simple ether, and podslushivaet with 52 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next three times were extracted portions 90 ml simple ether, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received of 3.46 g of crude base (55,5% of theory), which was introduced into the column size 4×30 cm filled with silica gel. In the elution with a mixture of simple ether/n-hexane in the ratio of 1:1 (vol./about.) received 1.73 g of the base (27,8% of theory). Of 316 mg of the base analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone received 389 mg of 2'-dimethylaminomethyl-5-cryptomaterial-2-ylamine, hydrochloride, with tPL, 125°C.

Example 42

N-(2'-dimethylaminomethyl-5-cryptomaterial-2-yl)acetamide", she hydrochloride

1.42 g (4,56 mmole) of the base obtained analogously to example 41 2'-dimethylaminomethyl-5-cryptomaterial-2-ylamine within 24 h was heated with 80 ml of a solution of HBR (33 wt.%-acetate in glacial acetic acid) (bath temperature 140°).

For further processing the mixture was poured into 800 ml of a simple e the Ira and the supernatant decantation. The residue was dissolved in water, washed three times with 50 ml of a simple ester, podslushivaet with a solution of potassium hydroxide (1 M) (pH>12), was extracted three times with 50 ml of simple ether, the combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way received of 1.94 g of crude base (130% of theory), which was introduced into the column size 3×30 cm filled with silica gel. In the elution using a simple broadcast received 940 mg base (85.1% of theory). From 303 mg this reason analogously to example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone received 274 mg of N-(2'-dimethylaminomethyl-5-cryptomaterial-yl)ndimethylacetamide, hydrochloride with tPL115°C.

Example 43

3,5-dichloro-2'-dimethylaminomethylphenol-4-ylamine, hydrochloride

6,14 g (29,7 mmole) was obtained analogously to example 18 (stage 1) of dimethyl-2-(dimethylaminomethyl)benovolent, 10.0 g (41.5 mmole) of 4-bromo-2,6-dichloraniline and 10.5 g (98,7 mmole) of sodium carbonate was dissolved in a mixture of 100 ml of toluene, 40 ml of water and 20 ml ethanol. Then in an atmosphere of nitrogen was added 354 mg of tetrakis(triphenylphosphine)palladium(0) and for 16 h was heated under reflux (bath temperature 110°).

For further processing was added 200 ml ol the buffer of net ether and washed three times with portions 130 ml of a solution of potassium hydroxide (0.5 M). The organic solution was extracted three times with portions 90 ml of hydrochloric acid (5 wt.%-Noah), the combined acidic phases were washed with 50 ml of simple ether, and podslushivaet with 45 ml of sodium hydroxide solution (32 wt.%-tion) (pH about 12). Next three times were extracted by a simple ether in 100 ml, the combined organic phases were dried over anhydrous magnesium sulfate, filtered and concentrated using rotary evaporator (500-10 mbar). In this way got to 6.88 g of crude base (78,7% of theory). Of 765 mg of this crude product as in example 1 (stage 3) using a mixture of chlorotrimethylsilane/water in 2-butanone received 470 mg (54.8% of theory) of 3,5-dichloro-2'-dimethylaminomethylphenol-4-ylamine, hydrochloride.

Pharmacological studies

Research analgesia in mice in the test for pain

Study of the analgesic efficacy was performed on mice, studying their behavioural response in the test on pain induced by familienaam (modified method according to I.C. Hendershot, described in Journ. Pharmacol. Exp. Ther. 125, str-240 (1959)). For these purposes, as experimental animals used male NMRI mice weighing 25-30 g Groups of 10 animals each, were selected for testing one dose of the test substance in 10 min after intravenous injection of the investigated substances, inyati is ovali intraperitoneally at a dose of 0.3 ml/mouse of a 0.02%aqueous solution of finishinga (phenylbenzophenone, the company Sigma, Deisenhofen; this solution is prepared by adding 5% ethanol with extract in a water bath at 45°). Animals in order to monitor them individually placed in special cells and in the time intervals from 5 to 20 min after injection of finishinga using a push-button counter counting the number of induced pain extensor movements (so-called behavioral response to pain, i.e. in this case, the bowing of the body with stretching of the hind limbs). As control served as the animals, which were injected only with saline salt. All substances were tested in a standard dose of 10 mg/kg Expressed as a percentage degree of suppression (% suppression) reaction to pain induced by the respective substance was calculated by the following formula:

For some substances, based on dependent on their dosage reducing the number of reactions to pain in comparison with studied in parallel experiments, control groups, which were introduced only finishined, using regression analysis (processing program Martens EDV Service, Eckental) was calculated ED50-values for these reactions to pain with trust region 95%.

All past experimental validation of the is possible according to the invention showed a pronounced analgesic efficacy. The results are presented in the following table 1.

Table 1

Test pain syndrome in mice
Example% reduction reactions pain at 10 mg/kg intravenousED50(mg/kg intravenously)
(1)53
(2)894,55
(3)1000,24
(4)753,95
(5)68or 4.31
(6)884.26 deaths
(7)902,55
(8)677,15
(9)892,32
(10)1001,70
(11)74
(12)891,74
(13)81and 5.30
(14)1002,28
(15)523,66
(16)894,59
(17)90
(18)83
(19)86
(20)834,99
(21)53of 6.78
(22)766,05
(23)97
(24)992,27
(25)74
(26)1000,75
(27)89
(28)90
(29)835,71
(30)89
(31)94
(32)98
(33)89
(34)80
(35)88
(36)93
(37)60
(38)65
(39)80
(40)57
(41)56
(42)44
(43)99

Pharmacological method of determining inhibition of binding of norepinephrine and 5-HT receptor

For tests in vitro allocated synaptosome from the brain of the rat, as described in article E.G.Gray and V.P.Whitaker, "The isolation of nerve ending from brain, J. Anatomy", 96, s-88 (1962), which is specified in the description of the application as references.

Tissue (hypothalamus for determining inhibition of binding of norepinephrine and internal fabric and varolii bridge for determining inhibition of binding NT) homogenized in of 0.32 M sucrose solution, cooled with ice, homogenizer with a Teflon pestle, and used 5 full vertical oscillations of the pistil and the rotation speed of 840 rpm/min

The homogenate was centrifuged at 4°C for 10 min at 1000 g. After the final stage of centrifugation at 17000 g for 55 min received synaptosome (fraction R2), which again suspended in 0,32 M glucose solution (0.5 ml/100 mg initial weight). The corresponding binding was measured in 96-well microtiter tablet. The final volume was 250 μl, incubation was carried out at room temperature (approximately 20-25° (C) in the atmosphere O2. When the binding of [3H]-NA incubation time was 7.5 min, when the binding of [3 H]-5-HT incubation time was 5 minutes At the conclusion of the 96 samples were filtered through a microplate with unifilter GF/B, Packard) and washed with 200 ml of incubation buffer solution using the collector cells (Brabdel Cell-Harvester MPXRI-96T). The plate unifilter GF/B were dried at 55°C for 1 h In conclusion, closed Back plate seal®(Packard company) and to each well was placed in 35 μl of scintillation fluid (Ultima Gold®the firm Packard). Then covered with a film (Packard), was kept for 5 for equilibrium and measured the radioactivity in the pulse counter Trilux 1450 Microbeta, Wallac).

Carrier ligand has the following characteristics:

BindingKm=0,32±0,11 mcm
Linking NTKm=0,084±0,011 mcm

The amount of protein used in the above analysis corresponds to the literature data, for example, see Lowry and others, "Protein measurement with the folin phenol reagent", J. Biol. Chem., 193, 265-275 (1951). Detailed description of the methodology can also be found in the literature, for example, see M.Ch. Frink, H.-H. Hennies, W. Engelberger, M. Haurand and B. Wilffert, Arzneim.-Forsch./Drug Res., 46 (III),11, 1029-1036(1996).

Table 2

The results of pharmacological tests
Connection with the ERU No. Binding of NA rats, 10 μm % inhibitionThe binding of 5-HT rats, 10 μm % inhibition
283
34768
445
58288
63471
78479
857
99679
108969
116080
1376
169545
1790
1986
2068
2186
2341
2473
2563
268921
2869
3050
31 55
3240
3365
3467
3592
3679
3990
4162
4377

1. Substituted derivatives of 2-dialkylaminoalkyl General formula I

in which n denotes 1 or 2;

R1denotes CN, NO2, SO2CH3, SO2CF3, NR6aR7a, acetyl or acetamide;

R2denotes H, F, Cl, Br, CN, NO2CHO, SO2CH3, SO2CF3, OR6, NR6R7C1-C6alkyl, acetyl or acetamide, and the alkyl may contain one or more identical or different substituents selected from halogen and hydroxy-group,

or R1and R2together denote respectively the group base2Oh, och2CH2Oh, CH=Cho, CH=C(CH3)Oh or CH=CHNH;

R3denotes H, F, Cl, Br, CN, NO2CHO, SO2CH3, SO2CF3, OR6, NR6R7C1-C 6alkyl, acetyl or acetamide, and the alkyl may contain one or more identical or different substituents selected from halogen and hydroxy-group;

R4, R5have identical or different meanings and represent H or unsubstituted C1-C6alkyl;

R6, R7have identical or different meanings and represent H or unsubstituted C1-C6alkyl;

R6adenotes H or unsubstituted C1-C6alkyl;

R7adenotes unsubstituted C1-C6alkyl,

in the form of their bases and/or salts of physiologically acceptable acids, except for the connection, a 4-chloro-2'-dimethylaminomethylphenol-2-carbonitrile.

2. Substituted derivatives of 2-dialkylaminoalkyl according to claim 1, wherein R2and/or R3denote C1-C3alkyl, which may contain one or more identical or different substituents selected from halogen and hydroxy-group and the remaining substituents and n have the meanings mentioned for the General formula I.

3. Substituted derivatives of 2-dialkylaminoalkyl according to claim 1 or 2, wherein R4and/or R5denote C1-C3alkyl and the other substituents and n have the meanings mentioned for the General formula I.

4. Substituted proizvodnye-dialkylaminoalkyl according to claim 1 or 2, wherein R6and/or R7denote C1-C3alkyl and the other substituents and n have the meanings mentioned for the General formula I.

5. Substituted derivatives of 2-dialkylaminoalkyl according to claim 1, selected from the group including

dimethyl-[2-(2-methylbenzofuran-4-yl)benzyl]amine and the corresponding hydrochloride

dimethyl-(4'-nitro-3'-triptorelin-2-ylmethyl)amine and the corresponding hydrochloride

N-(2'-dimethylaminomethyl-3-cryptomaterial-4-yl)ndimethylacetamide and the corresponding hydrochloride

[2-(1 H-indol-5-yl)benzyl]dimethylamine and the corresponding hydrochloride

(2-benzo[1,3]dioxol-5-ylbenzyl)dimethylamine and the corresponding hydrochloride

1-[2'-(2-dimethylaminoethyl)biphenyl-3-yl]Etalon and the corresponding hydrochloride

dimethyl-(3'-nitrobiphenyl-2-ylmethyl)amine and the corresponding hydrochloride

N-(2'-dimethylaminomethyl-5-cryptomaterial-2-yl)ndimethylacetamide and the corresponding hydrochloride

(4'-methysulfonylmethane-2-ylmethyl)diamine and its corresponding hydrochloride.

6. The method of obtaining substituted derivatives of 2-dimethylaminoacetonitrile General formula I according to any one of claims 1 to 5, characterized in that compounds of General formula VIII or IX

where R1- R3 have the meanings mentioned for the General formula I according to claim 1, and R represents C1-C6alkyl, catalyzed by transition metal reactions in simple aliphatic ether, a hydrocarbon, an alcohol, a chlorinated hydrocarbon, water or in mixtures of these solvents at temperatures in the range from 20 to 150°subjected to interaction with compounds of General formula IV

where Y denotes Cl, Br or I, and n denotes 1 or 2, and R4and R5have the meanings mentioned for the General formula I according to claim 1, which preferably are compounds of General formula III (R4and R5denote hydrogen),

where Y denotes Cl, Br or I, and n denotes 1 or 2, with the obtained compounds of General formula I, which on conventional methods to cleanse and release.

7. The method according to claim 6, characterized in that compounds of General formula VIII or IX is subjected to transformation by a reaction catalyzed by compounds of palladium(0) or salts of palladium(II), preferably tetrakis(triphenylphosphine)palladium, bis(dibenzylideneacetone)palladium, elemental palladium on charcoal, palladium (II) chloride and/or palladium(II)acetate.

8. The method according to claim 6 or 7, characterized in that the transition metal catalyzed reactions carried the t in 1,4-dioxane, tetrahydrofuran, toluene, hexane, ethanol, isopropanol, chloroform, dichloromethane, water or in mixtures of these solvents.

9. Drug, possess inhibitory effect on NA and 5-HT containing the pharmaceutical active substance is at least one substituted derivative 2-dialkylaminoalkyl General formula I

in which n denotes 1 or 2;

R1denotes H, F, Cl, Br, CN, NO2CHO, SO2CH3, SO2CF3, OR6, NR6R7C1-C6alkyl, acetyl or acetamide, and the alkyl may contain one or more identical or different substituents selected from halogen and hydroxy-group;

R2denotes H, F, Cl, Br, CN, NO2CHO, SO2CH3, SO2CF3, OR6, NR6R7C1-C6alkyl, acetyl or acetamide, and the alkyl may contain one or more identical or different substituents selected from halogen and hydroxy-group,

or R1and R2together denote respectively the group base2Oh, och2CH2Oh, CH=Cho, CH=C(CH3)Oh or CH=CHNH;

R3denotes H, F, Cl, Br, CN, NO2CHO, SO2CH3, SO2CF3, OR6, NR6R7C1-C6alkyl, acetyl or are amidi, moreover, the alkyl may contain one or more identical or different substituents selected from halogen and hydroxy-group;

R4, R5have identical or different meanings and represent H or unsubstituted C1-C6alkyl;

R6, R7have identical or different meanings and represent H or unsubstituted C1-C6alkyl,

in the form of its base and/or salts of physiologically acceptable acids and, optionally, other active ingredients and/or excipients.

10. The drug according to claim 9, containing a pharmaceutical active substance, at least one substituted derivative 2-dialkylaminoalkyl General formula I, selected from the group including

(3'-methoxybiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(4'-chlorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

2'-dimethylaminomethylphenol-3-ol and the corresponding hydrochloride

(2'-methoxybiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(3'-chlorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(2'-forbiden-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(3'-forbiden-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(4'-forbiden the l-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(3'-chloro-4'-forbiden-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(3'-methoxybiphenyl-2-retil)dimethylamine and the corresponding hydrochloride

dimethyl-[2-(2-methylbenzofuran-4-yl)benzyl]amine and the corresponding hydrochloride

2'-dimethylaminomethylphenol-2-carbaldehyde and the corresponding hydrochloride

(3'-diverseylever-2-ylmethyl)dimethylamine and the corresponding hydrochloride

2'-dimethylaminomethylphenol-3-carbaldehyde and the corresponding hydrochloride

(3',4'-dichlorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(3',5'-dichlorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

dimethyl-(4'-nitro-3'-triptorelin-2-ylmethyl)amine and the corresponding hydrochloride

(3',4'-diferuloyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(4'-fluoro-3'-triptorelin-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(4'-chloro-3'-methoxybiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

N-(2'-dimethylaminomethyl-3-cryptomaterial-4-yl)ndimethylacetamide and the corresponding hydrochloride

(3'-isopropoxycarbonyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

2'-(2-dimethylaminoethyl)biphenyl-3-ol and the corresponding hydrochloride

4-chloro-2'-d is methylaminomethyl-3-ol corresponding hydrochloride

[2-(1H-indol-5-yl)benzyl]dimethylamine and the corresponding hydrochloride

(4'-methysulfonylmethane-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(2',4'-dichlorobiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(2',3'-diferuloyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(2',5'-diferuloyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(2-benzo[1,3]dioxol-5-ylbenzyl)dimethylamine and the corresponding hydrochloride

1-[2'-(2-dimethylaminoethyl)biphenyl-3-yl]Etalon and the corresponding hydrochloride

[2-(3'-isopropoxyphenyl-2-yl)ethyl]dimethylamine and the corresponding hydrochloride

[2-(4'-chloro-3'-methoxybiphenyl-2-yl)ethyl]dimethylamine and the corresponding hydrochloride

4-chloro-2'-(2-dimethylaminoethyl)biphenyl-3-ol and the corresponding hydrochloride

dimethyl-(3'-nitrobiphenyl-2-ylmethyl)amine and the corresponding hydrochloride

4-amino-2'-dimethylaminomethylphenol-3-ol and the corresponding dihydrochloride,

(3',5'-diferuloyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

(2',5'-dimethoxybiphenyl-2-ylmethyl)dimethylamine and the corresponding hydrochloride

2'-dimethylaminomethyl-5-cryptomaterial-2-ylamine and the corresponding dihydrochloride,

N-(2'-dimethylaminomethyl-5-triptoreline the Nile-2-yl)ndimethylacetamide and the corresponding hydrochloride

3,5-dichloro-2'-dimethylaminomethylphenol-4-ylamine and the corresponding hydrochloride.

11. The drug according to claim 9 or 10, intended for the treatment or prevention of pain, inflammation and allergic reactions, depression, drug and alcohol abuse, gastritis, diarrhoea, urinary incontinence, cardiovascular diseases, respiratory tract diseases, coughing, mental disorders and/or epilepsy.

12. Substituted derivatives of 2-dialkylaminoalkyl General formula I according to claim 1 in the form of their bases and/or salts of physiologically acceptable acids to obtain drugs for the treatment of painful conditions selected from the group comprising inflammatory reactions, allergic reactions, depression, drug addiction, alcohol abuse, gastritis, diarrhoea, urinary incontinence, cardiovascular diseases, respiratory diseases, coughing, mental disorders, epilepsy.

13. Substituted derivatives of 2-dialkylaminoalkyl General formula I indicated in paragraph 12, selected from the group including

dimethyl-[2-(2-methylbenzofuran-4-yl)benzyl]amine and the corresponding hydrochloride

dimethyl-(4'-nitro-3'-triptorelin-2-ylmethyl)amine and the corresponding hydrochloride

N-(2'-dimethylaminomethyl-3-cryptomaterial-4-yl)ndimethylacetamide and the corresponding hydrochloride

[-(1 H-indol-5-yl)benzyl]dimethylamine and the corresponding hydrochloride

(2-benzo[1,3]dioxol-5-ylbenzyl)dimethylamine and the corresponding hydrochloride

1-[2'-(2-dimethylaminoethyl)biphenyl-3-yl]Etalon and the corresponding hydrochloride

dimethyl-(3'-nitrobiphenyl-2-ylmethyl)amine and the corresponding hydrochloride

N-(2'-dimethylaminomethyl-5-cryptomaterial-2-yl)ndimethylacetamide and the corresponding hydrochloride

to obtain drugs for the treatment of painful conditions selected from the group comprising inflammatory reactions, allergic reactions, depression, drug addiction, alcohol abuse, gastritis, diarrhoea, urinary incontinence, cardiovascular diseases, respiratory diseases, coughing, mental disorders, epilepsy.



 

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< / BR>
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FIELD: polymers, chemical technology.

SUBSTANCE: invention relates to polymeric composition materials used in construction members in aviation and cosmic technique. Amino-derivatives of C60-fullerene combine functions of polyamine hardening agent, electron-active nanomodifying agent of permolecular structure of matrix, function of plasticizer reducing fragility of matrix, function of microcrack stopper and function of reinforcing members. Invention provides preparing amino-derivatives of C60-fullerene - products of chemical interaction of C60-fullerene with benzylamine (BA) of the empirical formula C60(BA)n wherein n = 4-6, and the composition material made from epoxy-base polymeric binding agent and fibrous filling agent wherein polymeric binding agent comprises additionally indicated amino-derivatives of C60-fullerene in the amount 10.2-60.6 mas. p. p. per 100 mas. p. p. of epoxy base.

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3 cl, 2 tbl, 5 ex

FIELD: medicine, neurology.

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EFFECT: higher efficiency.

55 cl, 29 ex, 11 tbl

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