Arylalkylamine and pharmaceutical composition based on them

 

(57) Abstract:

Usage: in medicine as receptor antagonists neirokinina A. the inventive Products arylalkylamine f-ly, where Y is a group in which Cyis phenyl, unsubstituted or substituted by hydroxyl, alkoxygroup1-C4cycloalkyl3-C6pyrimidyl, AG'- unsubstituted or substituted phenyl, R is hydrogen, C1-C3-alkyl, T is a group-CO - or-NH, m=2 or 3, Z is M or OM, where M - C1-C4-alkyl. Reagent 1: Compound f-crystals 2. Reagent 2: NSO-Z or O=C=N-z 3 s and 8 C.p. f-crystals, 13 PL.

Connection 1

Connection 2

The invention relates to new derivatives of arylalkylamines, as well as containing their farbkomposition, which can find application in pathological conditions involving the system of neurokinins.

Receptors of neurokinin found in many drugs, and is currently classified into three types: NK1NC2and NK3. In most of the studied drugs there are several types of receptors, for example, in the ileum of the Guinea pig (NK1NC2and NK3), but some of the drugs have only one type of receptor, such as the carotid ar is

Known endogenous ligands to receptors such neurokinin as substance P (SP), neurokinin A (NKA) and neurokinin B (NKB).

It is also known that the receptor NK2and neurokinin And participate for example, if neurogenic inflammation of the respiratory tract (P. J. Barnes, Arch. Int. Pharmacodyn. 1990, , 67 and 82, and G. F. Joos et al. Arch. Int. Pharmacodyn. 1990, , 132 146).

Currently, the only known peptide receptor antagonists NK2. For example, the publication of C. A. Maggi and other Br.J.Pharmacol. 1990, , 588 592 describes peptides that are selective antagonists of receptors NK2.

In the application for the European patent 0347802 described derivative peptide antagonists neirokinina And recommended as immunosuppressants in the treatment of arthritis, asthma, inflammatory pain, gastrointestinal hypermotility, Huntington's disease, psychosis, hypertension, migraine, urticaria, etc.

The application for the European patent 0336230 also describes derivatives of peptide antagonists of substance P and neirokinina And used in the treatment and prevention of asthma.

The applicant developed a new class derived arylalkylamines, which are the ones receptor antagonists neirokinina and can be used for the recalculation General formula I:

< / BR>
where:

Y means a group in which:

Cymeans phenyl, unsubstituted or substituted by hydroxyl or alkoxygroup C1-C4cycloalkyl C3-C6pyrimidyl or group:

< / BR>
in which Ar denotes phenyl, unsubstituted or substituted one or more times by one of the substituents selected from the group of halogen atom, hydroxyl, alkoxy WITH1-C4, trifluoromethyl, alkyl WITH1- C4and these substituents can be identical or different, pyridyl or thienyl, n=0 or 1,

X means a hydroxyl, alkoxygroup1-C4hydroxyalkyl, in which the alkyl is a remnant of the1-C4alloctype1-C4carboxypropyl, generatioxi, carbalkoxy1-C4, cyano, aminoalkyl in which alkylene is a remnant of the1-C3the group-NH-CO-ALK, where ALK means C1- C4-alkyl, a group ALK1-NH-CO-ALK2where ALK1means1-C3-alkylen and Ala2means1-C4-alkyl, acyl, C1-C4or X forms together with the carbon atom to which it is linked in the heterocycle, a double bond,

m=2 or 3,

Ar' denotes phenyl, neslin or indolyl N-substituted by alkyl WITH1-C3,

R denotes hydrogen, alkyl WITH1-C3,

T means With-O - or-CO-NH-,

Z means M or OM, where M denotes alkyl WITH1-C4, phenyl which can be substituted one or more times by halogen, alkyl WITH1-C4or alkoxy group WITH1-C4, naphthyl which may be substituted with halogen, phenylalkyl, in which the alkyl part means the residue FROM1-C3and which may be substituted on the aromatic nucleus by halogen, alkyl WITH1-C4or alkoxyl1- C4thienyl, furyl, pyrrolyl, thiadiazolyl, as well as their salts with organic or mineral acids.

In the present description, the alkyl group or alkoxygroup are linear or branched.

Salts of the compounds with formula (I) in accordance with the present invention include salts with mineral or organic acids, which provide the division or the appropriate crystallization of compounds with formula (I), such as picric acid or oxalic acid or an optically active acid, such as almond or campostoma acid and salts which are pharmaceutically acceptable, such as hydrochloride, Bromid the glycolate, gluconate, citrate, izational.

A particularly preferred compound is N-methyl-N-/4-(4-phenyl-4-acetylaminophenol)-2- (3,4-dichlorophenyl)-butyl/-benzamide in the form of the racemate or one of its enantiomers (+) or (-), as well as salts thereof with mineral or organic acids.

Compounds according to the invention and their salts can be obtained by the way, who is that

a) the free amine of the formula:

< / BR>
in which m, Ar' and R are as defined above, and E represents O-protective group, such, for example, 2-tetrahydropyranyloxy, or group

< / BR>
in which Y has the abovementioned meaning, and, if Y represents a group

< / BR>
where X is hydroxyl, the hydroxyl can be protected:

process

or a functional derivative of an acid of the formula:

HO-CO-Z (III)

in which Z has the above values, when it is necessary to obtain the compound of formula (I), where T is a group-CO-,

any isocyanate of the formula:

O=C=N-Z (III')

in which Z has the above values, when you need to get a connection with formula (I), where T is a group-CO-NH-,

obtaining the compounds of formula:

(IV)

C) process the thus obtained N-substituted alkanolamine formula:

(V)

methanesulfonamido,

g) communicate the received nelfinavir formula:

(VI)

with a secondary amine of the formula:

(VII)

in which Y has the abovementioned meanings, and the resulting product, after possible removal of protection from hydroxyl, translated if necessary into one of its salts.

As a functional derivative of the acid (III) use the acid activated in a suitable manner, for example, using cyclohexylcarbodiimide or using hexaphosphate benzotriazolyl-N-exitridmasteroffline (BOP), or one of the functional derivatives which react with amines, for example, anhydride, mixed anhydride, acid chloride or activated ester. When Z is a group of Ω, the corresponding acid is carbonic acid, and as a functional derivative use monochloride, namely: chloroformiate CI-CO-OM.

When source product used compound of formula (II), where E represents a group

Scheme I

< / BR>
In the above formula (IIIa) consider chloramide is to be more functional derivative or you can start from the free acid (III), through the interaction of the compound (II') with BOP (hexaphosphate benzotriazolyl-N-exitlistener-aminophosphine), then adding the acid (III) in the presence of organic bases, such as, for example, triethylamine, in a solvent such as dichloromethane or dimethylformamide, at room temperature, the resulting compounds (I) are isolated and purified in accordance with conventional methods, such as chromatography or recrystallization.

You can also perform the reaction of compound (II') with the isocyanate O=C=N-Z (III') in an anhydrous inert solvent such as, for example, benzene, over night at room temperature, followed by treating the reaction mixture according to conventional methods.

When the starting compound is used as a compound of the formula (II), where E represents tetrahydropyranyloxy, the method according to the present invention can be presented and illustrated by scheme 2.

The reaction of compound (II") with reagents (IIIa) and (III') proceed as described above for scheme I, and the acid chloride of acid (IIIa) can be replaced by other functional derivatives or free acid is activated, for example, in the mild acid hydrolysis to form a free gidrauxilirovannogo of compound (V). Removing a hydrolysis group tetrahydropyranyloxy can be made directly with the compound (II)". Get so gidrauxilirovanne connection II', which is subjected to reaction directly with reagents IIIA and III', as described in scheme 2 to obtain compound V

On the basis of the connection V get mesylates VI, replace it with a secondary amine of the formula VII and obtain the compounds of formula I.

Thus obtained products with the formula (I) are isolated in the form of free base or salt according to classical methods.

Compounds of the present invention are of low toxicity: in particular, their low toxicity is compatible with their use as medicaments. For such applications, enter the mammal an effective amount of a compound with formula (I) or one of its salts which are pharmaceutically acceptable.

The present invention relates also to pharmaceutical compositions containing as an active ingredient a compound of the formula (I) or one of its pharmaceutically acceptable salts.

Pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, TX forms of introducing mixed with classical pharmaceutical carriers. The appropriate unit forms of introduction include forms for oral administration such as tablets, gelatin capsules, powders, granules and oral solutions or suspensions, forms for sublingual and cheek reception, forms for subcutaneous, intramuscular, intravenous, intranasal or intraocular administration, the forms for rectal administration, forms for administration by inhalation and by processing the mucosa, for example, nose, throat or bronchial tubes, for example, by means of an aerosol spray containing the active ingredient in the form of a liquid for atomization or dry powder.

The dose of active ingredient may vary between 0.25 and 1000 mg per day, preferably between 2 and 250 mg.

Each unit dose can contain from 0.25 to 250 mg of active ingredient, preferably from 1 to 125 mg, in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 4 times a day.

When you prepare a solid composition in tablet form, then mix the active ingredient with pharmaceutical carrier, such as gelatin, starch, lactose, magnesium stearate, talc, gum Arabic. On tablets, you can apply a coating of sucrose or other suitable substances or Majesty and that they continuously release a predetermined amount of the active component.

The drug in gelatin capsules get by mixing the active ingredient with a diluent and Prilepa the resulting mixture into soft or hard gelatin capsules.

A preparation in syrup or elixir may contain the active ingredient together with a sweetener, preferably low-calorie, methyl paraben and propyl paraben as an antiseptic, as well as giving a taste of the agent with a suitable dye.

Powders and granules, dispersible in water, may contain the active ingredient mixed with dispersing agents or wetting agents, or agents for translation in suspension, such as polyvinylpyrrolidone, as well as with sweeteners or taste correctors.

For rectal use of candles, which are prepared with binders, melting at rectal temperature, for example cocoa butter or polyethylene glycols.

For parenteral, intranasal or intraocular injection using aqueous suspensions, isotonic saline solutions or sterile solutions intended for injection, which contain dispersing agents and/or wetting agents, and pharmacologically compatible, for example, profiling the R, trioleate sorbitan or oleic acid, as well as Trichlorofluoromethane, DICHLORODIFLUOROMETHANE, dichlorotetrafluoroethane or any other biologically compatible eject the gas.

The active ingredient may also be administered in the form of microcapsules, if necessary, with one or more carriers or additives.

The above compositions can also contain other active compounds, such as, for example, bronchodilatory, antitussive or antihistamines.

The following examples illustrate the invention, without limiting it.

In the examples below we used the following abbreviations:

AC: acetyl,

ASO: acetoxygroup,

TPL: instantaneous melting point, expressed in degrees Celsius.

NMR spectra were obtained at 200 MG in deuterated dimethyl sulfoxide:

m: array

s: singlet,

RS: advanced singlet,

t: triplet,

M: multiplet.

Example 1.

The hydrochloride of N-(2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidine) -butyl)-2,4-dichlorobenzamide.

< / BR>
m=2; R=H;

(a) -(2-tetrahydropyranyloxy)-3,4-dichlorobenzonitrile.

The remainder chromatographies Nar silica gel, eluent: dichloromethane, then dichloromethane-ethyl acetate 95 5 (V/V). The fractions of pure product are concentrated under vacuum, resulting in a gain of 118 g of liquid oil.

C) b -(2-tetrahydropyranyloxy)-3,4-dichlorobenzonitrile.

Dissolve 118 g of the nitrile obtained above in 700 ml of absolute ethanol. Add 300 ml of concentrated ammonium hydroxide, then injecting nitrogen added Raney Nickel (10% of the original nitrile). Then gidrogenit in an atmosphere of hydrogen at room tempera is e filtering on celite, the filtrate is concentrated under vacuum, the residue absorb a saturated solution of sodium chloride. After extraction with ether and drying over MgSO4obtain 112 g of liquid oil.

C) N-/2-(3,4-dichlorophenyl)-4-(2-tetrahydropyranyloxy)-butyl/ -2,4-dichlorobenzamide.

Dissolve 80 g of the amine obtained above in 800 ml of dichloromethane. The solution is cooled to a temperature of 0oC, add to 38.4 ml of triethylamine, then 55 g of the acid chloride 2,4-di chlorbenzoyl acid. Then the reaction mixture was stirred at room temperature for one hour, then washed with water. The organic phase is decanted, dried over MgSO4and concentrate under vacuum, resulting in a gain of 120 g of liquid oil.

d) N-/2-(3,4-dichlorophenyl)-4-hydroxybutyl/-2,4-dichlorobenzamide.

Dissolve 120 g of the product obtained above in 1 liter of methanol in the presence of 12 g of para-toluensulfonate acid. The reaction mixture is stirred for 18 hours at room temperature, then concentrated under vacuum. The residue is extracted in dichloromethane and washed with 10% sodium carbonate solution. The organic phase is decanted and dried over MgSO4, resulting in a gain of 106 g of liquid oil.

e) N-/4-methysulfonylmethane, then add to cooled to a temperature of 0oTo a solution of 44 ml of triethylamine and 24.2 ml of methanesulfonanilide. The reaction mixture is stirred at a temperature of 0oC for 45 minutes, washed 3 times with ice water, decanted, dried over MgSO4and concentrate under vacuum.

The residue is recrystallized from isopropyl ether.

m=95 g

TPL=93oWITH

f) Connection 1.

A mixture consisting of 1 g of the product obtained above, 0.8 g of 4-hydroxy-4-phenylpiperidine and 1 ml of dimethylformamide is heated at a temperature of 60oC for 2 hours. After cooling, diluted with ether, washed with diluted sodium hydroxide solution, then with water. After drying over MgSO4evaporated solvents and chromatographic balance on 40 g of silica; elution: dichloromethane, then dichloromethane/ methanol 90/10 (V/V). Concentration of the pure fractions yields a 0.9 g of product, which is converted into the hydrochloride in dichloromethane, adding a solution of hydrogen chloride in ether to pH=1. The precipitate was separated by filtration, and then condense in the air.

m=0.95 g

NMR: is 8.75 (t,1H), 7,7 7 (M,11N), 5,4 (s,1H), 3,6 2,6 (m,N), 2,6 - 1,6 (m,6N).

Example 2.

Hydrochloride N-/2-(3,4-dichlorophenyl)-4-methyloxindole/-ndimethylacetamide, by doing as described in example 1 to stages a), b) C) d) and e), but replacing in stage C), the acid chloride 2,4-dichlorobenzoyl acid on acetylchloride.

Connection 2.

Heated to a temperature of 60oWith a mixture of 6.5 g of the product obtained above, 6.8 g of 4-hydroxy-4-phenyl-piperidine and 10 ml of dimethylformamide.

After one hour the reaction mixture was poured to water and extracted with ethyl acetate. The organic phase is decanted, dried over Na2SO4filter and concentrate under vacuum. The residue is purified by chromatography on silica gel; eluent: methanol/dichloromethane 10/90 (V/V). Concentration of pure fractions of product leads to the residue, which is transformed into a salt with a solution of hydrogen chloride in ether, the result is 6 g of the hydrochloride.

NMR: of 7.95 (t,1H), 7,7 7,0 (m,8H), 3,6 2,6 (m,N), 2,6 1,3 (m, N).

Example 3.

The hydrochloride of N-ethyl-N-/2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-vinylpyridine)- butyl/-2-thiophencarboxylic.

< / BR>
m=2, R=-CH2CH3, T-Z=

a) Hydrochloride of N-ethyl/4-hydroxy-4-phenylpiperidine/- -ethyl-3,4-dichlorobenzonitrile.

To a suspension consisting of 0.96 g of lithium aluminum hydride in 10 ml of tetrahydrofuran, are added to the solution, with the ri temperature phlegmy within 2 hours. Then cool and hydrolyzing using 4 ml of 4 n sodium hydroxide solution. Filtered from alumina, washed with tetrahydrofuran and evaporated. After the formation of the salt with a solution of hydrogen chloride in ether hydrochloride condense in a mixture of isopropanol/isopropyl ether, to obtain 4.7 g of product.

in the Connection 3.

At a temperature of 0oTo a solution of 2.45 g of the product obtained above in dichloromethane, added to 2.75 ml of triethylamine, and then 0.8 g of 2-trailhead. After hydrolysis using 0.1 n sodium hydroxide solution and extraction into dichloromethane, the product was then purified by chromatography on silica H, eluent: methanol/dichloromethane 2,5/97,5 (on/about). Pure product was transferred to salt under the action of a solution of hydrogen chloride in ether and obtain 1.0 g of the hydrochloride.

NMR: 7,75 of 6.9 (m,11N), to 5.35 (s, 1H), 3,9 to 2.55 (m,11N), of 1.5 to 2.55 (m,6N), of 0.95 (t,3H).

Example 4.

The hydrochloride of N-ethyl-N-/2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidine)- butyl/-4-methoxybenzamide.

Acting in accordance with example 3, stage b), based on the compound obtained in stage a), and substituting 2-trailhead to the acid chloride with 4-methoxybenzoic acid, receive connection 4.

So pl. 165oC.

Example Sumida.

< / BR>
m=2, R=H, T-Z=

a) N-[2-(3,4-dichlorophenyl)-4-(4,4-ethylenedioxythiophene)- butyl]-2,4-dichlorobenzamide.

Heated at a temperature of 100oWith over 15 minutes to a mixture of 12.1 g nelfinavir obtained in example 1, stage e), and 8.6 g of 4,4-ethylenedioxythiophene. The mixture is cooled, absorb dichloromethane, washed with water. The organic phase is decanted, dried over Na2SO4filter and concentrate under vacuum. The remainder chromatographic on silica gel; eluent: methanol/dichloromethane 2/98 (on/about).

Concentration of the pure fractions yields a 12,15 g of the expected product.

in) N-/2-(3,4-dichlorophenyl)-4-(4-oxopiperidine)- butyl/-2,4-dichlorobenzamide.

Dissolving the above product in 100 ml of acetone, then add 100 ml of 6 n chloroethanol acid. After 2 hours add 1 liter of water and 1 liter of ether and extract the aqueous phase. The latter is then brought to pH 10 in the result of the addition of sodium hydroxide, then extracted with one liter of ether. After drying and evaporating the organic phase, obtain 9.7 g of pure product.

C) Connection 5.

At a temperature of 25oC in nitrogen atmosphere to a solution of 1 g of the product obtained above in 5 ml of Tetrism. Synthesis, page 43, 1974). After hydrolysis and extraction of the ether the residue chromatographic on silica gel: eluent: methanol/dichloromethane 15/85 (V/V). After evaporation of the pure fractions and translation in salt balance under the action of a solution of hydrogen chloride in ether, receive 400 mg foamy substance of white color.

NMR: 8,8 to 7.15 (m,11N), 5,3 (wide C. 1H), 4 to 2.55 (m,11N), 2,35 - 1,4 (m,6N).

Example 6.

The hydrochloride of N-[4-(4-benzyl-4-hydroxypiperidine)-2-(3,4-dichlorophenyl) -butyl]-N'-naphthas-1-rocephine.

< / BR>
m=2, R=H, T-Z=

a) N-[4-(2-tetrahydropyranyloxy)-2-(3,4-dichlorophenyl)- butyl]-N'-naphthas-1-rocephine.

To a solution of 7.6 g of naphthas-1-Iglesiente in 50 ml of toluene was added 12 g -/2-tetrahydropyranyloxy/-3,4-dichlorobenzonitrile in 50 ml of toluene. Stir the reaction mixture for 10 minutes, add 50 ml of methanol and concentrated under vacuum.

C) N-[4-hydroxy-2-(3,4-dichlorophenyl)-butyl]-N'-naphthas-1-rocephine.

To the solution obtained above product was added 2 g of p-toluensulfonate acid and heat the mixture to a temperature of phlegmy within 10 minutes the Solution is washed with sodium bicarbonate and concentrated to dryness. After purification of the residue by chromatography on silica gel with elution of ethylacetate.

To a solution of 13.1 g of the product obtained above in 100 ml of dichloromethane, are added at a temperature of 0oWith lower than the 5.37 ml of triethylamine, then 2,77 ml methylchloride. Then the solution is washed 3 times using 100 ml of ice water, then the organic phase is dried and evaporated. Then the residue is recrystallized from isopropanol, filtered and washed with isopropyl ether.

m=8 g

So pl. 120oC.

d) Connection 6.

Heated at a temperature of 100oC for 20 minutes, the mixture consisting of 4 g of the product obtained above, 4 g of 4-hydroxy-4-benzylpiperidine and 4 ml of dimethylformamide. This is then poured to water and extracted with dichloromethane. Then the residue is purified by chromatography on silica gel with elution with a mixture of methanol/dichloromethane 4/96 (on/about). After translation in the salt solution of hydrogen chloride in ether to obtain 1.0 g of pure hydrochloride.

NMR: 8,7 (s,1H), 8,2 6,8 (m,N), 3,5 2,5 (m,11N), 2,3 1,3 (m,6N).

The compounds described below in tables 1, 2 and 3 were synthesized in the same manner as in examples 1 to 5. All these compounds are chlorhydrate.

Example 14.

The hydrochloride of N-methyl-N-[2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidine) -butyl]-benzamide.

/P> To a cooled to a temperature of -20oWith a solution of 80 g of the amine obtained in example 1, stage C), and 39 ml of triethylamine in 800 ml of dichloromethane is added drop by drop of 26.4 ml ethylchloride. After 30 minutes, washed twice with water, then buffer solution with pH=2. Decanted organic phase and dried over MgSO4, then concentrate under vacuum, resulting in a gain of 98 g of the product in the form of liquid oil.

in) N-/methyl/-/2-tetrahydropyranyloxy/- -ethyl-3,4-dichlorobenzonitrile.

In a three-neck flask with a volume of 2 liters, nitrogen purged, enter 20 g of lithium aluminum hydride in suspension in 200 ml of tetrahydrofuran. At a temperature of 20oTo add a solution of 98 g of carbamate obtained above in 800 ml of tetrahydrofuran.

Gently heated to a temperature of phlegmy and support it within 18 hours.

Cooled to a temperature of 0oAnd hydrolyzing using 35 ml of water and then a mixture of 17 ml of concentrated sodium hydroxide solution and 150 ml of water. Separate the solids by filtration, and then concentrated under vacuum, resulting in a gain of an 80.5 g of the product in the form of liquid oil.

(C) the Hydrochloride of N-methyl - b-hydroxyethyl-3,4-dichlorobenzene-economynarrowband chloroethanol acid. After 2 hours 30 minutes, concentrated under vacuum, dissolve the residue in 200 ml of acetonitrile, then slowly add 350 ml of ether. Stirred for one hour, filtered, the crystals washed with ether.

m=32,8 g

So pl. 152oWITH

d) N-methyl-N-[2-(3,4-dichlorophenyl)-4-hydroxybutyl]-tert-BUTYLCARBAMATE.

It is 32.8 g of the hydrochloride obtained above product is dissolved in 300 ml of dioxane and 30 ml of water, add 20 ml of triethylamine. Then add 27 g Vos2O (di-tert-butyl-dicarbonate), then stirred at room temperature for 15 minutes. Heated at a temperature of 60oC for 30 minutes. After concentration to dryness extracted with ether, washed with water, then buffer solution with pH=2, then again with water. Dried over MgSO4concentrate under vacuum, resulting in a gain of 40 g of liquid oil.

e) N-methyl-N-[2-(3,4-dichlorophenyl)-4-methanesulfonylaminoethyl] - tert-BUTYLCARBAMATE.

To 40 g of the alcohol obtained above, dissolved in 400 ml of dichloromethane, was added 17 ml of triethylamine. Cooled to a temperature of 0oAnd add one drop of 9.3 ml of methylchloride. After 15 minutes, washed 2 times with water, dried over MgSO4concentrate to dryness, the result is nil)- butyl]-tert-BUTYLCARBAMATE.

Heat the mixture consisting of 20 g of product obtained above and 18 g of 4-hydroxy-4-phenylpiperidine in 40 ml of dimethylformamide, at a temperature of 70oC for 1 hour and 30 minutes. Then poured the solution to 300 ml of ice water, the precipitate is filtered off and rinsed with water. The solid is then extracted with ether, dried over MgSO4and evaporated. The crude product is purified by chromatography on silica gel with elution with a gradient of methanol in dichloromethane (5%). Get 22 grams of pure product.

g) Dichlorhydrate N-methyl-or 4-hydroxy-4-phenylpiperidine/- b-ethyl-3,4-dichlorobenzaldehyde.

To a solution of 22 g of the derivative obtained above in 100 ml of methanol was added 100 ml of concentrated chloroethanol acid and 20 ml of water. After one hour the reaction mixture is concentrated under vacuum. Get foamy substance that is converted into a powder in ether, then dried.

m=20.7 g

h) Connection 14

To a solution of 2 g of the product obtained above and 2 ml of triethylamine in 20 ml dichloromethane, at a temperature of -78oC in an atmosphere of nitrogen was added 0.51 ml of benzoyl chloride and left with stirring for 10 minutes. After hydrolysis using 0.1 n sodium hydroxide solution and extracti is. what are square so of 1.37 g of pure product, which was converted into hydrochloride by adding a solution of hydrogen chloride in ether to pH= 1. Get in the end of 1.40 g of the hydrochloride in the form of a foamy substance.

NMR: 7,7 6,6 (m,13H), to 5.35 (s,1H), 3,8 2,5 (m, N), 2,5 1,5 (m,6N).

Example 15.

The hydrochloride of N-methyl-N-/2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidine)- butyl/-N'-benzyladenine.

< / BR>
m=2, R=CH3,

At a temperature of 0oC in nitrogen atmosphere to a solution containing 2 g of the product obtained in accordance with example 14 in stage g), and 1.2 ml of triethylamine in 20 ml of dichloromethane, are added to 0.60 ml benzylisothiocyanate and leave the mixture under stirring for 1 hour. After washing with 0.1 n sodium hydroxide solution, the product is purified by chromatography on silica gel, eluent: methanol/dichloromethane - 6/94 (on/about). Then form a salt of the product under the action of a solution of hydrogen chloride in ether and obtain 1.8 g of the hydrochloride.

NMR: 7,7 6,9 (m,13H), to 6.75 (t,1H), 5,4 (broad s,1H), 4,1 (s,2H), 3,7 2,5 (m,N), 2,5 1,4 (m,6N).

Example 16.

The hydrochloride of N-methyl-N-[2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidine)- butyl]-ethylcarbamate.

< / BR>
m=2, R=-CH3, T-Z=

At a temperature of -78oIn lamina in 20 ml of dichloromethane, gain of 0.44 ml ethylchloride. After 5 minutes hydralicious using 0.1 n sodium hydroxide solution and extracted in dichloromethane. Then the product is purified by chromatography on silica gel; eluent methanol/dichloromethane 8/92 (on/about). Pure fractions are concentrated under vacuum and the addition of a solution of hydrogen chloride in ether to obtain 1.1 g of the hydrochloride in the form of a foamy substance of white color.

NMR: 7,7 7,1 (m,8H), of 5.45 (s,1H), 4,1 to 2.6 (m,14N), 2,6 1,6 (m,6N), 1,1 (t,3H).

The compounds described in tables 4 and 5, obtained according to examples 14 to 16. These compounds are chlorhydrate.

Example 33.

The hydrochloride of N-[2-(3,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidine)- butyl]-N-methyl-2-thiophencarboxylic.

< / BR>
m=2, R=CH3, T-Z=

a) N-[2-(3,4-dichlorophenyl)-4-(2-tetrahydropyranyloxy)- butyl] -2-thiophencarboxylic.

At room temperature, stirred mixture consisting of 4.77 g amine, obtained in accordance with example 1, stage C), and 1.7 g of triethylamine in 50 ml dichloromethane. Then add drop by drop at room temperature 2,19 g of 2-trailhead dissolved in 20 ml of dichloromethane, and leave at room temperature the reaction mixture during the night. RA is carbonate sodium, then a saturated solution of sodium chloride, the organic phase is decanted, dried over Na2SO4filter and concentrate under vacuum. The remainder chromatographic on silica gel, eluent: methanol/dichloromethane 98/2 (V/V). Pure fractions are collected and concentrated under vacuum. The residue was washed with 5% sodium hydroxide solution, extracted with ether and dried. Obtain 4.6 g of colorless liquid oils.

C) N-[2-(3,4-dichlorophenyl)-4-(2-tetrahydropyranyloxy)- butyl]-N-methyl-2-thiophencarboxylic.

At room temperature, stirred mixture consisting of 3,4 amide obtained above and 0.45 g of sodium hydride content of 55% in 10 ml of tetrahydrofuran. The reaction mixture becomes a clear liquid orange. Then add 1,23 g iodomethane in 10 ml of tetrahydrofuran and then stirred for 1 hour at room temperature and heated at a temperature of phlegmy for 1 hour. Concentrate tetrahydrofuran, extract the residue with water, extracted into ether, washed a second time in water with sodium chloride solution and concentrated under vacuum.

m=3.4 g

c) N-[2-(3,4-dichlorophenyl)-4-hydroxybutyl]-N-methyl-2 - thiophencarboxylic.

Dissolve 3.5 g product obtained above at a temperature of phlegmy for 1 hour and 30 minutes.

The mixture is filtered on celite, the filtrate is concentrated under vacuum, the residue is washed in hexane and then extracted with a mixture of ether/hexane. Obtain 2.6 g of white crystals.

So pl. 107 109oC.

d) N-[2-(3,4-dichlorophenyl)-4-methanesulfonylaminoethyl] - N-methyl-2-thiophencarboxylic.

At room temperature, stirred for 2 g of the above alcohol and 0.65 g of triethylamine in 30 ml of dichloromethane.

Then add drop by drop a solution 0,69 g methylchloride in 10 ml of dichloromethane. Upon completion of addition, is heated at a temperature of phlegmy within 30 minutes. Evaporate dichloromethane under vacuum, extract the residue with water, extracted with ethyl acetate, washed with 5% sodium bicarbonate solution, then with saturated sodium chloride solution, dried over Na2SO4, the solvent is evaporated.

m=1.2 g

e) Connection 33

A mixture of 1 g of the product obtained above, 1 g of 4-hydroxy-4-phenylpiperidine and 2 ml of dimethylformamide is heated at 60oC for 2 hours.

After cooling, diluted with ether, washed with water, then with dilute sodium hydroxide solution. Dried over MgSO4then evaporate the solvents. The remainder chromatographies on silica gel; eluent: who; the donkey dissolved in dichloromethane was added a solution of hydrogen chloride in ether to pH=1, then concentrate under vacuum. Hydrochloride is condensed in the air.

m=0.74 g

NMR: 7,8 6,8 (m,11N), 5,3 (s,1H), 3,8 2,5 (m,N), 2,5 1,4 (m,6N).

Example 34.

The hydrochloride of N-methyl-N-[2-(3,4-dichlorophenyl)-4-[4-hydroxy-4-(4-hydroxyphenyl)- piperidinyl]-butyl]-2-thiophenecarboxylate.

< / BR>
m=2, R=-CH3, T-Z=

a) Obtaining amine: 4-hydroxy-4-/4-hydroxyphenyl/-piperidine.

Stage 1.

4-benzyloxyphenol.

Mix of 32.6 g of 4-bromophenol, 34,2 g benzylbromide and 42 g of potassium carbonate in 150 ml of dimethylformamide at a temperature of 40oC for two hours.

The solution is concentrated under vacuum, the residue is extracted with water, then extracted with ether, washed with water, decanted, dried over MgSO4and concentrate under vacuum.

The remainder precrystallization in isopropanol.

m=30 g

So pl. 61oC.

Stage 2.

1-benzyl-4-/4-benzyloxyphenyl/-4-hydroxypiperidine.

Dissolve 14 g of the product obtained above in 100 ml of tetrahydrofuran and added to 1.2 g of magnesium in 20 ml of tetrahydrofuran, at temperatures to a temperature of -10oC. Then add drop by drop a solution of 10 g of 4-benzylpiperidine and give back the mixture to room temperature. The mixture is poured to a saturated solution of ammonium chloride, extracted with ether, washed with water, decanted, dried over MggSO4and concentrate under vacuum. The remainder chromatographies on silica gel, eluent: dichloromethane/methanol 97,5/a 2.5 (on/about). Concentration of the pure fractions gives 9 g of the target product.

So pl. 104 107oC.

Stage 3.

4-hydroxy-4-/4-hydroxyphenyl/-piperidine.

At room temperature and atmospheric pressure 6 g of product obtained above, dissolved in 200 ml of ethanol, hydrogenized in the presence of 10% palladium on coal. When theoretical amount of hydrogen is absorbed, the catalyst is filtered off, concentrate the filtrate under vacuum, extract the residue with ether and filtered off the crystals.

m=1.1 g

So pl. 232 235oC.

The connection 34.

Dissolve 2.1 g of the product obtained above in accordance with example 33 in stage d), 1 g of the amine obtained above in stage 3, and 1.1 g of triethylamine in 5 ml of dimethylformamide and heated at a temperature of 80oC for 2 hours. Concentrate the mixture under vacuum, izvlekaemom, decanted, dried over MgSO4and concentrate under vacuum.

The residue is extracted with acetone and thicken in the air.

m=0.7 g

NMR: 9,3 (s,1H), 6,6 8 (m,10H), and 5.2 (s,1H), 2,6 4 (m,N), 1,6 2,4 (m, 6N).

The compounds described in table 6, obtained according to example 33. These compounds are all chlorhydrate.

Example 42.

The hydrochloride of N-[4-(4-benzyl-4-acetylcytidine)-2-(3,4-dichlorophenyl)- butyl]-2,4-dichlorobenzamide.

< / BR>
m=2, R=H, T-Z=

To 0.4 g of the hydrochloride of N-[4-(4-benzyl-4-hydroxypiperidine)-2-(3,4-dichlorophenyl)- butyl]-2,4-dichlorobenzamide (compound 7 obtained in accordance with example 1), dissolved in 10 ml dichloromethane in the presence of two equivalents of triethylamine, was added 0.12 g acetylchloride.

After stirring for 1 hour at room temperature, washed with water, decanted organic phase, dried over MgSO4and concentrate under vacuum. The remainder chromatographic on silica gel, eluent dichloromethane, then dichloromethane/methanol 95/5 (V/V). The fractions of pure product are concentrated under vacuum, then add a solution of hydrogen chloride in ether to pH=1 and concentrate the ether under vacuum.

Hydrochloride is condensed in the air.

Add one drop of 260 ml of 95% sulfuric acid to 69 g of 1-benzyl-4-hydroxy-4-phenylpiperidine, forming a suspension with 300 ml of acetonitrile, keeping the temperature between 25 and 30oC. Then the reaction mixture was stirred at room temperature for 4 hours, then gradually poured to ice and neutralized using 30% sodium hydroxide solution.

The precipitate was separated by filtration, washed with water, then dried in acetone.

m=58 g

So pl. 180,6 182oWITH

b) Hydrochloride of 4-acetamido-4-phenylpiperidine.

To 58 g of product obtained above, dissolved in 600 ml of methanol, add ether, saturated chloroethanol acid until pH=1. Then gidrogenit at atmospheric pressure and room temperature in the presence of 10% palladium on coal. When absorbed by theoretical volume of hydrogen, separating the catalyst by filtration, concentrate the filtrate under vacuum and the residue is recrystallized in ethanol.

m=45 grams

So pl. 286,5 288oC.

B) Receiving connection 71.

a) N-[4-methanesulfonamide-2-(3,4-dichlorophenyl)-butyl]-N-methylbenzamide.

This connection"ptx2">

At a temperature of 80oC for 2 hours, heated to 1.4 g of 4-acetamido-4-phenylpiperidine and 1.4 g obtained above nelfinavir in 3 ml of DMF. Add ice and extracted with dichloromethane. The organic phase is decanted and washed subsequently with water, then saturated NaCl solution and dried over MgSO4. Concentrate under vacuum and the residue chromatographic on silica gel, eluent: dichloromethane/methanol 97/3 (V/V).

Concentration of the fractions of pure product gives a residue which is extracted with methanol. Addition of ether saturated with chloroethanol acid, gives hydrochloride.

m=0.8 g

NMR: 3H 2 (C ) 18 H between 2,10 and 3,90 (m,N-CH3all SN2CH-C6H5): 13 H between 7.00 and 7,80 (m,H aromatic), 1 H at to 8.20 (s, )

Example 72.

The hydrochloride of N-methyl-N-[4-(4-phenyl-4-acetylaminophenol)-2-(3,4-dichlorophenyl)- butyl]-benzamide (-).

Stage 1.

Alpha/2-tetrahydropyranyloxy/3,4-dichlorobenzonitrile.

This compound is obtained in accordance with example 1, stage a).

Stage 2.

Beta/2-tetrahydropyranyloxy/-3,4-dichlorobenzene-atanamir.

This compound is obtained in accordance with example 1, stage b).

Add 80 ml of ether saturated with chloroform, keeping the temperature between 20 and 25oC. Stirred for 30 minutes at room temperature, then concentrated to dryness. Dissolve the residue in 250 ml of water, washed 2 times with ether, alkalinized with NaOH solution, extracted with dichloromethane. After drying over MgSO4concentrate to dryness, extracted with 800 ml of isopropyl ether, separating the insoluble portion by filtration on celite, concentrate under vacuum to 300 ml of injected seed for crystallization using crystals amerosport, stirred over night.

Filter, rinse with isopropyl alcohol, then with pentane. Get 30,2 g of the expected product.

So pl. 90 91oC.

Stage 4.

Beta-hydroxyethyl-3,4-dichlorobenzonitrile (+).

To the boiling solution containing 29 g of D (-) tartaric acid in 800 ml of methanol is added a solution of 44.7 g of the product obtained in accordance with the previous stage 3, 300 ml of methanol.

Allow to return to room temperature and stirred for 4 hours. Filter, rinse with ethanol, then ether. Get to 34.1 g of tartrate.

Precrystallization>O).

Tartrate absorb 120 ml of water. Alkalinized with NaOH solution, extracted 2 times with dichloromethane, dried over MgSO4concentrate to dryness. Extract in a small amount of isopropyl ether was added pentane, filtered, resulting in a gain of 15.4 g of the product.

So pl. 79 80oC.

()2D5+9,4 (C=10 Meon).

Stage 5.

N-/4-hydroxy-2-(3,4-dichlorophenyl)-butyl/-ethylcarbamate.

Dissolve 15 g of the product obtained in accordance with the previous stage 4 in 200 ml of dichloromethane. Added to 9.9 ml of triethylamine.

Cooled to a temperature of 0oWith and added drop by drop at this temperature, a solution containing 6.3 ml of ethylchloride in 30 ml of dichloromethane. After 15 minutes, washed with water, then dilute HCl, then saturated aqueous NaHCO3. After drying over MgSO4concentrate to dryness, resulting in a gain of 20 g of the product in the form of liquid oil.

Stage 6.

Hydrochloride N-methyl - N-hydroxyethyl-3,4-dichlorobenzonitrile (+).

To 5,1 g of lithium aluminum hydride forming a suspension in 60 ml of anhydrous THF, was added a solution of 20 g of the product obtained in accordance with the previous ODI, filtered the solid, concentrated to dryness. The liquid oil is dissolved in 100 ml of acetone. Add ether, saturated chloroethanol acid until pH= 1, then ether to education Muti. Stirred for 1 hour, filtered off the crystals are rinsed with a small amount of acetone, then ether, resulting in a gain of 11 g of the target product.

So pl. 129oC.

()2D5+8,4 (c=1, MeOH).

Stage 7.

N-[4-hydroxy-2-(3,4-dichlorophenyl)-butyl]-N-methylbenzamide (-).

To of 8.1 g of the product obtained in accordance with the previous stage 6, forming a suspension in 120 ml of dichloromethane, are added to 8.4 ml of triethylamine. Cooled to a temperature of 0oWith and add drop by drop a solution containing 3.4 ml of benzoyl chloride in 35 ml of dichloromethane. After 15 minutes, washed with water, then dilute HCl, then water solution of NaHCO3. Dried over MgSO4concentrate to dryness. Get a solid substance, which is extracted with ether, and filtered.

m=9.0 g

So pl. 129oC.

()2D5-19 (c=1, MeOH).

Stage 8.

N-[4-methanesulfonamide-2-(3,4-dichlorophenyl)- butyl]-N-methylbenzamide (-).

billaut 4.8 ml of triethylamine. Cooled to a temperature of 0oAnd add one drop of 2.7 ml of methanesulfonanilide. After 15 minutes, washed 2 times with water, then saturated aqueous NaCl. Dried over MgSO4concentrate to dryness, resulting in a gain foamy substance.

()2D5-2,3 (c=1, CHCl3).

Stage 9.

The connection 72.

Dissolve to 22.7 g of the hydrochloride of 4-phenyl-4-acetylaminofluorene in 20 ml of water. Add 10 ml of concentrated sodium hydroxide solution. Extracted 2 times with dichloromethane, dried over MgSO4. The resulting solution was added to the product obtained in stage 8. Concentrate to dryness, add 30 ml of DMF and heated at a temperature of 70oC for 1 hour and 30 minutes. Very slowly poured the solution to 30 ml of a mixture water + ice. The precipitate is filtered off, remove it for several times with water and dehydrate it. Purify by chromatography on silica, elution of pure dichloromethane, then dichloromethane with the addition of methanol to 10%

Hydrochloride: the base is dissolved in acetone. Add ether, saturated chloroethanol acid until pH=1. Poured a solution to isopropyl ether, filtered and dried.

m=11 grams

()2H5), 13 H between 6,80 and of 7.70 (m,H aromatic), 1 H at 8,10 (C ).

Example 73.

The hydrochloride of N-methyl-N-[4-(4-phenyl-4-acetylaminophenol)-2-(3,4-dichlorophenyl)- butyl]-benzamide (+).

The enantiomer (+) is obtained in accordance with the same method as that for the enantiomer (-), described above in example 41, substituting in stage 4 of D-tartaric acid, ( - ) L-tartaric acid (+).

()2D5+30,6 (c=1, MeOH).

NMR: 3 H at 1,85 18 H between 2,00 and 3.75 (m,N-CH3all SN2CH-C6H5), 13 H between 6,80 and of 7.70 (m, H aromatic), 1 H at 8,10 .

Example 74.

The hydrochloride of N-[2-(2,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidine)- butyl]-N-methyl-2-thiophenecarboxylate (-).

This compound is obtained by carrying out synthesis according to example 72, above.

()2D5-51,0 (c=1, MeOH).

Example 75.

Hydrochloride N-/2-(2,4-dichlorophenyl)-4-(4-hydroxy-4-phenylpiperidine)- butyl/N-methyl-2-thiophencarboxylic (+).

This compound is obtained by carrying out the synthesis in accordance with examples 72 and 73 above.

()2D5+52,7 (c=1, MeOH).

Example 76.

Hydrochloride of 1-[4-(benzoylmethyl the background acid 4-phenylpiperidine-4-carboxylic acid is stirred in the presence of 1.8 g /2 equivalent/ tert. butanoate potassium in 50 ml of DMF at 80oC for 15 minutes. Then add 1,72 g of N-[4-methanesulfonate-3-(3,4-dichlorophenyl)butyl] -N-methylbenzamide obtained in the conditions of example 1, stage e/, and the reaction mixture is heated at 80oWith over four hours. Concentrate the mixture under vacuum, absorb the remainder water, add a buffer with pH=7, separating the aqueous phase, process resinous residue with ethyl acetate and washed sequentially with buffer solution with pH=7, water and saturated NaCl solution, decanted organic phase, dried over Na2SO4filter and concentrate under vacuum. Obtain 1.8 g of oil, which is purified by chromatography on silica gel; eluent: CH2Cl2/CH3OH (about 80/20. ).

Concentration of pure fractions of product leads to 1 g of the oily desired product, which was transferred to the hydrochloride by introducing ethereal solution saturated with gaseous chlorotalonil acid.

m=0.9 g, so pl. 131oC.

Below are the results of biological and pharmacological testing of new compounds.

1. Pharmacological studies "in vitro"

A. Affinity products to the receptors of neurokinin different membrane preparato/BR> inhibition communication of substance P to its receptor on the membranes of the cerebral cortex of the rat using125I-substance P as a ligand according to the method Kacheri etc. J. Biol.Chem. 258, 5158 5164 (1983) and by the method Pana and other J. Immunol. 133, 3260 3265 (1984).

inhibition due neirokinina a to its receptor on the membrane of the duodenum of the rat using125I neurokinin-And as a ligand according to the method of Berg the lookout and other Molecular Pharmacol. 32, 764 - 771 (1987).

inhibition due neirokinina-In with its receptor on the membrane feed the brain when using125I eledoisin as a ligand according to the method Kacheri and other J. Biol.Chem. 260, 1501 1507 (1985).

Product activity is expressed in Ki(nm), and calculated using software of the device DA (Ligand).

In table 11 the value Ki(nm) presents investigated for different products. Tabular data show that the products have an affinity for the receptors of neurokinin primarily to the receptor neirokinina and to a lesser extent to the receptor for substance P and neirokinina Century

B. Antagonistic activity products to the receptors of neurokinin various isolated organs.

Receptors of neurokinins, antagonistically activity of the products was evaluated by the method of Regoli and other Trends Pharmacol. Sci. 9, 290 295 (1988) and Pharmacology, 38, 1 15 (1989), using drugs and agonists, are shown in table 12.

Antagonistic activity of the products was characterized by the quantities pA2. These values were calculated by the method of van Rossum, Arch. Int. Pharmacodym. Trer. 143, 299 330 (1963).

Table 13 shows the values of pA2for various tested products. The results show that these products are antagonists of neurokinin, primarily at the level of receptor and NK2and at least at the level of the receptor of NK.

II. Pharmacological studies "in vitro" on the preparations of isolated organs of the human body.

Annular strips of human bronchi, bladder and colon were prepared in the form of medication to register their isometric tension of the saturated oxygen solution of Krebs-Henseleit at 37oC. the Reduction was caused by the antagonist (beta Ala8)-NKA (4-1.0). The compound N 72 caused an antagonism with the value of pA2between 9.2 and 9.5 V with respect to the various isolated human organs.

III. Pharmacological studies "in vivo"

In Guinea pigs (I) caused bronchospasm using substances (N, moreover, animals were pretreated with atropine (0.5 mg/kg), diphenhydramine (1 mg/kg) and indomethacin (2 mg/kg) as an intravenous injection. Substance (NIe10)-NKA(4-10) was administered intravenous dose of 5 mg/kg after 5, 15, 30, 45 and 60 minutes after administration of the compound N 72, which was administered either intravenously or through the duodenum increasing doses. In the control experiments repeated injections (NIe10)-NKA(4-10) caused a reproducible bronchospasm, which was estimated by the method of Konzett-Wrestler.

Study "in vivo"

Study "in vivo" pharmacological activity of the compounds N 72 was carried out on the model of bronchospasm caused by agent NKA shot in Guinea pigs (1). The compound N 72 were injected either intravenously or through a 12-duodenum to the injection of a substance (NIe10)-NKA(4-10). In these cases, the compound N 72 caused inhibition of the bronchoconstriction induced by injection (NIe10)-NKA(4-10), and the degree of suppression of the spasm was dose dependent connection N 72. One hour after the introduction of the estimated average dose suppression (ID50) was equal to 37 mg/kg (intravenous) or 350 mg/kg (12-duodenum). By itself, the connection 72 did not change the tone of the rest of the bronchus by donosti. These results suggest that the junction 72 is receptor antagonist NK2"in vivo when administered intravenously or through a 12-duodenum.

The results show the following:

1. Proposed connection find affinity with receptors of neurokinins, in particular, to the NKA receptor.

2. The proposed compounds are antagonists of the effect of neurokinins, particularly at the level of the receptor, which preferably binds neurokinin A.

3. The proposed compounds exhibit pharmacological activity "in vivo" models of pathologies dependent neirokinina A.

4. The proposed compounds are antagonists of the reductions caused by neirokinina And in isolated human bodies, and can be used for therapeutic purposes.

1. Arylalkylamine General formula

< / BR>
where Y group CyN', where Cyphenyl, unsubstituted or substituted by hydroxyl, C1C4-alkoxygroup, C3- C6-cycloalkyl, pyrimidyl or group

< / BR>
where Ar is phenyl, unsubstituted or substituted one or more times by one of the substituents selected from the group of halogen atom, hydroxyl, C1- tion, pyridyl or thienyl;

x is 0 or 1;

X is hydroxyl, C1C4-alkoxygroup, hydroxyalkyl, in which the alkyl is a remnant of the C1C4C1- C4-acyloxy, carboxy, C1C4-carbalkoxy, a cyano group, aminoalkyl with C1C3-alkylene, the group-NH-CO-Alk, where Alk - C1C4-alkyl, a group Alk1-NH-CO-Alk2where Alk1C1C3-alkylen and Alk2C1C4-alkyl, C1C4-acyl; or X forms together with the carbon atom to which they relate in the heterocycle, the double bond;

m is 2 or 3;

Ar' is phenyl, unsubstituted or substituted one or more times by halogen, preferably chlorine, benzothiazyl, naphthyl, indolyl or indolyl, N-substituted C1C3-alkyl;

R is hydrogen, C1C3-alkyl;

T-CO - or-CO-NH-;

Z M or OM, where M C1C4-alkyl, phenyl which can be substituted one or more times by halogen, C1C4-alkyl or C1C4-alkoxy; naphthyl which may be substituted with halogen; phenylalkyl, in which the alkyl part means the remainder of the C1- C3and which can be substituted in the aromatic nucleus by halogen, C1C4-alkyl or C1C4is otami.

2. Connection on p. 1, in which Ar' 3,4-dichloraniline group, or one of its salts with a mineral or organic acid.

3. Connection PP. 1 and 2, in which X is hydroxyl, acetyloxy or group

< / BR>
where Alk C1C4-alkyl,

or one of its salts with a mineral or organic acid.

4. Connection PP. 1 to 3, in which R is methyl, or one of its salts with a mineral or organic acid.

5. Connection PP. 1 to 4, where T is the group-CO-, or one of its salts with a mineral or organic acid.

6. Connection PP. 1 to 5, where T is the group-CO - and Z thienyl, or one of its salts with a mineral or organic acid.

7. Connection PP. 1 6, in which Z is phenyl, possibly substituted by two Halogens, such as chlorine, or one of its salts with a mineral or organic acid.

8. Connection PP. 1 7, which is N-methyl-N-[4-(4-phenyl-4-acetylaminophenol-1)-2-(3,4-dichlorophenyl) butyl]-benzamide in the form of the racemate or one of its salts with organic or mineral acid.

9. Connection PP. 1 7, which is (-)-N-methyl-N-[4-(4-phenyl-4-acetylaminophenol-1)-2- (3,4-dichlorophenyl)butyl] benzamide yl)-N - methyl-N-[4-(4-phenyl-4-acetylaminophenol-1)-2-(3,4-dichlorophenyl) butyl]benzamide or its salt with a mineral or organic acid.

11. Pharmaceutical composition having antagonistic activity to the receptor neirokinina A, containing the active principle and a pharmaceutically acceptable additive, characterized in that the active agent it contains one of arylalkylamines General formula I

< / BR>
where Y is either Cy-N'where Cyphenyl, unsubstituted or substituted by hydroxyl, C1-C4-alkoxygroup, C3- C6-cycloalkyl, pyrimidyl, or group

< / BR>
where Ar is phenyl, unsubstituted or substituted one or more times by one of the substituents selected from the group of halogen atom, hydroxyl, C1- C4-alkoxy, trifluoromethyl, C1C4-alkyl, and the substituents may be the same or different, pyridyl or thienyl;

x is 0 or 1;

X is hydroxyl, C1C4-alkoxy, hydroxyalkyl, in which the alkyl is a remnant of the C1C4C1C4-acyloxy, carboxy, C1C4-carbalkoxy, cyano, aminoalkyl with C1C3-alkylene, the group-NH-CO-Alk, where Alk is C1- C4-alkyl, a group Alk1-NH-CO-Alk2where Alk1C1C3-alkylen, Alk2C1C4-alkyl, C1- C4-acyl, or X forms instead of the config or substituted one or more times by halogen, preferably chlorine, benzothiazyl, naphthyl, indolyl or indolyl, N-substituted C1C3-alkyl;

R is hydrogen, C1C3-alkyl;

T-CO - or-CO-NH-;

Z M or OM, where M C1C4-alkyl; phenyl which may be substituted one or more times by halogen, C1C4-alkyl or C1C4-alkoxyl; naphthyl which can be substituted with halogen, phenylalkyl, in which the alkyl part means the remainder of the C1C3and which may be substituted on the aromatic nucleus by halogen, C1- C4-alkyl or C1C4-alkoxyl; thienyl, furyl, pyrrolyl, thiadiazolyl,

and their salts with mineral or organic acid, in a quantity of 0.25 250 mg single dose.

 

Same patents:

The invention relates to a method for producing derivatives of General formula (I), which allows to improve the yield of these products

The invention relates to the field of organic synthesis and the way to obtain new derivatives of N-oilpipe - rationalcanada
The invention relates to a method of allocation of 2-alkyl-4-amino-5-alkoxystyrene (aminopyrimidine), which is an intermediate in the synthesis of vitamin b1and other biologically active compounds, and may find application in the medical industry

The invention relates to new derivatives of 2-anilinopyrimidines having biological activity

The invention relates to a method of combating fungi on plants by practicing their new derivatives of 2-aniline-pyrimidine of the General formula I

NNwhere R1hydrogen, halogen; C1-C3-alkyl, C1-C2-halogenated,1-C3-alkoxy;

R2hydrogen, halogen;

R3WITH1-C4-alkyl, C1-C3-halogenated, cyclopropyl;

R4unsubstituted or substituted with halogen, methyl cyclopropyl

The invention relates to methods of producing derivatives of 2-anilinopyrimidines or acid additive salts of novel biologically active compounds, which can find application in agriculture

The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

The invention relates to new biologically active compounds derived pyrimidine-4-or their pharmaceutically acceptable salts with serotoninergicheskoi, dopaminergically, antihistaminic activity, and compositions on their basis

The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

Anti-leukemia drug // 2068262
The invention relates to medicinal drug on the basis of biologically active substances and can be used in medical practice for the treatment of cancer, in particular, in the treatment of leukemia
The invention relates to medicine, more specifically to Oncology and can be used in the treatment of cancer hepato-pancreato-duodenal region

The invention relates to organic chemistry, specifically to new chemical compound 5-hydroxy-3,6-dimethyluracil formula

< / BR>
showing membrane and antiradical activity

The invention relates to medicine, namely to the treatment of senile, diabetic, radial long-term healing of wounds

The invention relates to medicine, in particular, to pulmonology pulmonology, immunology, and can be used for stimulation of local immunity in the pathology of respiratory organs

The invention relates to 3-(mercaptoethyl)-hinzelin-2,4-(1H,3H)-diones of General formula I, where R1denotes hydrogen, 6-methyl, 6-fluoro, 6-chloro, 6-bromo or 6,7-dimethoxy; R2denotes hydrogen or methyl and n is 1 or 2, or their tautomers, method for their production and pharmaceutical compositions, in particular for the treatment of immune diseases and/or viral infections in humans and animals
Up!