Derivatives of n-alkylenediamine, the method of production thereof, pharmaceutical compositions on their basis, optically pure derivatives of n-alkylenediamine

 

(57) Abstract:

Usage: in medicine as antagonistic means receptor neirokinina. The inventive product: derivatives of N-alkylenediamine formula

< / BR>
where Aris phenyl, pyridyl, 1-methylimidazole-2; Ar is 3,4-dichlorophenyl, naphthyl; X is oxygen, sulfur, -NH-, -N(CH3)-, -N(COCH3); R is hydrogen, methyl; Z is 2,4-dichlorophenyl, 2,4-acid, 3-chlorophenyl, 3-isopropoxyphenyl, 4-fornuft-1-yl, or hydrochloride, dihydrochloride or their Quaternary ammonium salt formed by the nitrogen of the piperidine. Reagent 1: mesilate formula: CH3SO2-O-(CH2)2-CH(Ar') -CH2-N(R0)-C(O)-Z. Reagent 2: secondary amine of the formula . 3 s and 5 C. p. F.-ly, 4 PL.

The invention relates to the field of synthesis of biologically active compounds, more specifically to new derivatives of N-alkylenediamines and their enantiomers, method of production thereof and to pharmaceutical compositions based on them.

The new compounds possess valuable pharmacological properties, enabling their use in pathological conditions involving the system of neurokinins, for example: bole (D. Regoli al. Life Sciences, 1987, 40, 109-117), Allergy and inflammation (J. York, 1977, 287-293), gastrointestinal disorders (D. Regoli al. Trends Pharmacol. Sci. 1987, 6, 481-484), respiratory disorders (J. Mizzahi al. Pharmacology, 1982, 25, 39-50).

Endogenous ligands to receptors of neurokinin have already been described, for example, such as substance P (SP), neurokinin A (NKA) (S. J. Bailey and al. Substance P, P. Skrabanck ed. Boole Press, Dublin, 1983, 16-17) and neurokinin B (NKB) (S. P. Watson, Life Sciences, 1983, 25, 797-808).

Receptors of neurokinin were found in many drugs and is currently classified into three types: NK1NK2and NK3. While the majority of the studied up to the present time preparations are several types of receptors, such as the ileum of the Guinea pig (NK1NK2and NK3), some of them have only one type of receptor, such as the carotid artery of the dog (NK1), devoid of endothelium of the pulmonary artery of the rabbit (NK2) and portal vein of the rat (NK3) (D. Regoli al. Rends Pharmacol. Sci. 1988, 9, 290-295 and Pharmacology, 1989, 38, 1-15).

A more precise description of the different receptors was made possible by the synthesis of selective agonists. So, [Sar9, Met(O2)II]SP,NIe10]NKA4-10and [Me Phe7] -NKB possess selectivity for receptors NK1NKderived N-alkylenediamines possess antagonistic activity to the receptor of neurokinins and are particularly suitable for the treatment of any pathology, depending on substance P and neirokinina.

Thus, the invention relates to derivatives of N-alkylenediamines General formula:

< / BR>
where Azphenyl, pyridyl or 1-methylimidazole-2,

Ar'3,4-dichlorophenyl or naphthyl,

X is an oxygen atom, a sulfur, a group-NH-, -N(CH3)- or-N(COCH3)-,

R is hydrogen or methyl,

Z is 2,4-dichlorophenyl, 2,4-acid, 3-chlorophenyl, 3-isopropoxyphenyl or 4-fornuft-1-yl or their hydrochloridum, dihydrochloride or their Quaternary ammonium salts formed by the nitrogen of piperidine.

The invention relates also to a method for producing derivatives of N-alkylenediamines General formula I, namely, that the free amine of formula II:

< / BR>
where E represents a 2-tetrahydropyranyloxy;

R is hydrogen, methyl;

Ar'have the above values, process, functional derivatives of acids of formula III:

< / BR>
where have the above values, obtaining the compounds of formula IV:

< / BR>
where E, Ar', R and Z above, which is subjected to hydrolysis to obtain substituted alkanolamine formula V:

< / BR>
with its subsequent processing methanesulfonamido getting nelfinavir formula VIBR> where the value of ArX above, followed, if necessary, transfer the compounds obtained in salt.

As a functional derivative of the acid (III) use the acid activated appropriately, for example by cyclohexylcarbodiimide or hexaphosphate benzotriazolyl-N-exitridmasteroffline (BOP), or one of the functional derivatives which react with amines, for example an anhydride, a mixed anhydride, acid chloride or activated ester.

If the original product is used as a compound of the formula (II), where E is tetrahydropyranyloxy, the method can be illustrated by scheme 1.

< / BR>
When using a carboxylic acid as a reactive functional derivative of the acid (III) the reaction is carried out in an inert solvent such as dichloromethane or benzene, in the presence of a base, such as, for example, triethylamine, at ambient temperature.

Thus obtained intermediate compound (IV') is subjected to removal of protection by acid hydrolysis, which leads to a free hydroxyl-containing compound (V).but with the compound (II"). You get a hydroxyl-containing compound (III'), which is introduced into the reaction directly with the reagent (IIIa), resulting in a compound (V). Then get mesilate (VI) with subsequent replacement with a secondary amine of the formula (VII) and get the compound (I) in accordance with the invention.

Removing the 0-protective tetrahydropyranyloxy group can be carried out under mild conditions of hydrolysis using dilute para-toluenesulfonic acid.

The resulting products of formula (I) is isolated in the form of free base or acid in accordance with the classical methods.

If the compounds of formula (I) are obtained in the form of a free base, the translation in salt is carried out in the processing of the chosen acid in an organic solvent, the free base, dissolved, for example, in alcohol, such as isopropanol, treated with acid solution in the same solvent, and obtain the corresponding salt, which emit known methods. Thereby obtaining hydrochloride, bromohydrin, sulfate, hydrosulfate, dihydrophosphate, methanesulfonate, oxalate, maleate, fumarate, 2-naphthalenesulfonate.

If the compounds of formula (I) selected as one of them is tralization specified salt of a mineral or organic base, such as sodium hydroxide or triethylamine, or carbonate, or bicarbonate of an alkali metal, such as a carbonate or bicarbonate of sodium or potassium.

Salts of Quaternary ammonium compounds, formed by the nitrogen of the piperidine is obtained in the reaction of the free base of compound (I), in which other AMINOPHENYL possibly present, are N-protected conventional N-protecting group, with an excess of alkylating agent of the formula:

A Q'

in which A represents a removable group and is the anion of chloride, bromide, iodide, acetate, methanesulfonate, paratoluolsulfonata, preferably chloride or iodide, and Q' is alkyl or benzyl, and then heat the reaction mixture in a solvent chosen among, for example, dichloromethane, chloroform, acetone, or acetonitrile, at a temperature that is between the ambient temperature and the temperature phlegmy, during the time from one to several hours to get after processing in accordance with conventional methods and after possible removal of the protecting mixture exiling and Equatorial conformers Quaternary ammonium salts.

Arepresents preferably iodide, which can be the compounds (I) through ion-exchange resin, for example, Amberlite IPA68 or duolith A375.

The conformers shared by known methods, for example, by chromatography or recrystallization.

Each of exiling or Equatorial conformers of compounds (I) may be in the form of racemates or in the form of optically pure enantiomers P or s

Separating by fractional crystallization of the racemic mixture of products of formula (II), in particular, products of the formula (II') and (II), or their predecessors, you can also obtain the enantiomers of the products of formula (I).

Separation by fractional crystallization products of the formula (II) is carried out in accordance with patent EP-A-428 434.

The initial compounds of the formula (II) receive from NITRILES of the formula:

< / BR>
in which E and Ar' are as defined above, by restoring and possible alkylation of the obtained amine.

If you want to obtain the compounds of formula (II), where R is the stands, then treated free amine obtained by hydrogenation of the nitrile (VIII), using chloroformiate, such as chloroformiate formula

Cl-CO-OAlk

where Alk is alkyl (C1C3preferably the ethyl, to obtain a carbamate of the formula:

as alumalite sodium, alumoweld lithium, or under the action of a hydride of boron, such as dimethyl sulphide of borane. The recovery is carried out in a solvent such as ether or toluene, at a temperature that is between ambient temperature and 60oC. the thus Obtained methylamine of the formula:

< / BR>
allocated in accordance with conventional methods.

Synthesis of NITRILES of formula (VIII) where E is tetrahydropyranyloxy, preferably based on tetrahydropyranyloxy (TIII-O-), obtained by the reaction between alkanol formula

Br-(CH2)-OH

and dihydropyrano that leads to the connection:

< / BR>
which are then injected into the reaction in the presence of a hydride of an alkali metal derived from acetonitrile:

< / BR>
obtaining the target compound VIII:

< / BR>
The invention relates, furthermore, to the enantiomers of the compounds of formula (I) and their salts; moreover, these enantiomers answer the following formula (I*):

< / BR>
in which Ar, Ar', Z, X and R are as defined above, and "*" means that the carbon atom marked with this symbol has a specific absolute configuration of (+) or (-).

The method for obtaining enantiomers of the formula I*
< / BR>
which tarifitsiruetsya in alkanol AlkOH, where Alk is alkyl with 1-4 carbon atoms in the acidic environment, and then processes the received ester of the formula:

< / BR>
in which Alk, Ar' and R are as defined above, functional derivatives of acids of the formula:

HO CO Z

and is the same as defined above, under conditions identical to the conditions for obtaining derivatives (IV) obtaining a complex ester of the formula:

< / BR>
which is then reduced to the corresponding alcohol of the formula:

< / BR>
Alcohol with formula (V*turns into a derivative methansulfonate with the formula:

< / BR>
in accordance with the terms and conditions identical to the conditions for obtaining derivatives (VI).

Substitution of melilite (VI*) an amine of the formula:

< / BR>
in accordance with the conditions described above to obtain (I), allows to obtain derivatives (I*after possible removal of protection, which are then, if necessary, turn in one of their salts in accordance with the classical methods of salt formation or one of their salts, Quaternary ammonium.

Received SS="ptx2">

If the compound of formula (I*) get in the form of a free base, transfer into salt by processing the selected acid in an organic solvent. So, treating the free base, dissolved, for example, in alcohol, in particular isopropanol, a solution of the acid in the same solvent to obtain the corresponding salt, which is allocated by the known methods.

Thus get, for example, hydrochloride, bromohydrin, sulfate, hydrosulfate, dihydrophosphate, methanesulfonate, methyl sulfate, oxalate, maleate, fumarate, 2-naphthalenesulfonate.

If the compounds of formula (I*selected as one of their salts, for example the hydrochloride or oxalate, or one of their salts, Quaternary ammonium, then transfer them into the free base can be made by neutralizing the specified salt of a mineral or organic base.

Compounds according to the invention are the object of biochemical tests.

The compound (I) and (I*) and their salts showed antagonistic properties against binding of substance P in the tests carried out on the membranes of the cerebral cortex of rats and lymphoblastic IM9 cells in accordance with the works of M. A. heavily antagonistic properties with respect to binding of NKA in the experiments, carried out on the membranes of the duodenum of rats in accordance with the work of L. Bergstom et al. Mol. Pharmac. 1987, 32, 764-771.

The same compounds and their salts showed antagonistic properties with respect to binding eledoisin in experiments carried out on the membranes of rats in accordance with A. C. Foster et al. Br.J.Pharmacol. 1988, 94, 602-608.

Eledoisin is a peptide isolated from amphibians, which is equivalent to neirokinina Century

Thus, the compounds according to the invention are antagonists of substance P, neirokinina or neirokinina Century

So the connection 4 is antagonism to the binding of substance P at the Kiequal to 41 nm, compound 8 is antagonism to bind neirokinina And when the value of Ki5.5 nm and the connection 9 is antagonism to bind eledoisin with the value of Kiequal to 400 nm.

It was also examined substances obtained according to examples 12, 15 and 16 describe, in the test for inhibition of binding of the substance In preparations of the cerebral cortex of the rat and lymphoblastic cells IM9 (by the method according to the above documents), and in the test for inhibition of binding of CA in drugs in the membranes of dvenadcataja, presented in table.1

The invention relates also to a pharmaceutical composition having an antagonistic activity against receptors of neurokinins, namely, that as the active agent used, the compound of General formula I or I*in an effective amount and in pharmaceutical additives.

Pharmaceutically acceptable dose can be, in particular from 0.01 to 100 mg per 1 kg body weight of the mammal per day, preferably from 0.1 to 50 mg/kg / day. Human dose may range preferably from 0.5 to 4000 mg per day, in particular from 2.5 to 1000 mg depending on the patient's age, subject to treatment or from treatment to prevention or to recovery.

Pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal injection can be produced in the form of single forms of administration. So forms for oral administration may be tablets, gelatin capsules, powders, granules and oral solutions or suspensions.

If preparing a solid composition in the form of tablets, the active ingredient is mixed with a pharmaceutical carrier, that is Ki sucrose or other appropriate materials or they can be processed so so they have activity extended to the delay or continuously release a predetermined amount of the active component.

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

A preparation in syrup or elixir may contain the active ingredient at the same time with a sweetener, preferably a calorie-free, methylparaben and propyl paraben as antiseptics, as well as giving a taste substance and with an appropriate dye.

Powders or granules, dispersible in water, may contain the active ingredient mixed with dispersing agents or wetting agents or suspendresume agents, for example, 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 and what you for example propylene glycol or butyleneglycol.

For administration by inhalation using an aerosol containing, for example, triolein sorbitan or oleic acid, as well as trichloromethane, dichloromethane, dichlorotetrafluoroethane or any other biologically compatible carrier gas.

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

The following examples illustrate the invention without limiting it.

The melting temperature or decomposition products (TPL) were measured at the facility Koffler. The spectra of nuclear magnetic resonance13Were obtained at 50 MHz in dimethyl sulfoxide.

Example 1. The hydrochloride of N-[4-(4-phenoxy-1-piperidinyl)-2-(3,4-dichlorophenyl)-butyl]2,4-dichlorobenzamide

< / BR>
< / BR>
A/ Obtaining Amin:

< / BR>
Dissolve to 60.6 g of 4-hydroxypiperidine in a mixture containing 320 ml of dioxane and 80 ml of water. Then quickly added 144 g SIDE2O and the reaction mixture is heated at 80oC for one and a half hours after the addition. Concentrate under vacuum, extract the residue in ether, washed three times with water, decanted ether the oil is yellowish in color, which is dissolved in 300 ml of hexane, then crystallizes, which gives 100 g of crystals.

TPL68-70oC.

In 500 ml of dichloromethane was dissolved 100 g obtained before these crystals and of 55.5 g of triethylamine. Then add one drop of 60.1 g of methylchloride, cooling with ice. Upon completion of addition, allowed to return to ambient temperature and the reaction mixture is stored overnight. Dichloromethane is concentrated under vacuum and the residue is extracted with water and extracted with ethyl acetate. The organic phases are washed with water, then 5 th solution of NaHCO3then a saturated solution of NaCl, and then concentrated under vacuum, resulting in the formation of crystals, which precrystallization in 250 ml of ethyl acetate with the addition of 500 ml of hexane.

m 135,28

TPL99oC.

Prepare a suspension of the 0,83 g of sodium hydride, in a liquid oil with a concentration of 55 and 150 ml of dimethylformamide, then rapidly added to 3.67 g of phenol dissolved in 10 ml of dimethylformamide. The mixture was stirred at ambient temperature for 30 min, then added of 8.37 g is received before this product and the reaction mixture is heated at 80oC for 4 h Restoration. The ether phase is successively washed with 5% sodium hydroxide solution, then with saturated NaCl solution, dried on Na2SO4and concentrated under vacuum. The resulting residue is treated is heated to 50-60oC with a solution containing 30 ml of methanol, 10 ml of concentrated chloroethanol acid and 10 ml of water for one hour, then the mixture is concentrated under vacuum and precrystallization in 100 ml of ethyl acetate.

m 3,44,

In/ Get 1-/2,4-dichloraniline/-2-/3,4-dichlorophenyl/-4-methyloxirane.

a/ 3-/3,4-Dichlorophenyl/-1-/2-tetrahydropyranyl/-3-cyanopropyl.

Prepare a suspension of 20 g of sodium hydride, in a liquid oil with a concentration of 55 to 60 and 200 ml of dry tetrahydrofuran. Add drop by drop in the 20oC for 30 min, the solution containing 85 g of 3,4-dichlorophenyl-acetonitrile in 500 ml of tetrahydrofuran, and then the reaction mixture is stirred at ambient temperature for 2 hours the Mixture is cooled to -20oC and add the solution containing 98 g of 1-bromo-2-tetrahydropyranyloxy in 100 ml of tetrahydrofuran, allow the mixture to return to ambient temperature and after 2 h was added a solution containing 50 g of ameriglide 3 l gSO4and concentrate under vacuum.

The remainder chromatographic on silica gel, eluent dichloromethane. The fractions of pure product are concentrated under vacuum, resulting in a gain of 83.6 g of liquid oil.

in/ 1-Amino-2-/3,4-dichlorophenyl/-4-/2-tetrahydropyranyl-hydroxy-butane.

In 100 ml of absolute ethanol was dissolved with 83.6 g obtained before nitrile. Added 350 mg of concentrated ammonia solution, and then injecting nitrogen added Raney Nickel /10 on the number of initial amine/. Then hydronaut in an atmosphere of hydrogen at ambient temperature and under normal pressure.

3 hours is absorbed 11,9 l of hydrogen. The catalyst separated in the filtering on celite, the filtrate is concentrated under vacuum, the residue is extracted in a saturated solution of sodium chloride. After extraction with ether and drying over MgSO4receive 82.5 g of liquid oil.

with/ 1-/2,4-Dichloraniline/-2-/3,4-dichlorophenyl/-4-/2-tetrahydropyranyloxy/ -butane.

800 g of dichloromethane was dissolved 80 g obtained before this amine. Cool the solution to 0oC, add to 38.4 ml of triethylamine, then 55 g of the acid chloride 2,4-dichlorobenzoyl acid. Then the reaction mixture paramashiva is dried on MgSO4and concentrated under vacuum, resulting in a gain of 120 g of liquid oil.

d/ 1-/2,4-Dichloraniline/-2-/3,4-dichlorophenyl/-4-butanol.

Dissolve 120 ml obtained before this product in 1 l of methanol in the presence of 12 g of paratoluenesulfonyl. The reaction mixture was stirred for 18 h at ambient temperature, then concentrated under vacuum. The residue is extracted into dichloromethane and washed with 10% sodium carbonate solution. The organic phase is decanted and dried on MgSO4, resulting in a gain of 106 g of liquid oil.

e/ 1-/2,4-Dichloraniline/-2-/3,4-dichlorophenyl/-4-methyloxiran.

Dissolve 106 g obtained before this alcohol in 2 l of dichloromethane, then add to cooled to 0oC to a solution of 44 ml of triethylamine and 24.2 ml of methylchloride. The reaction mixture was stirred at 0oC for 45 min, washed three times with ice water, decanted, dried on MgSO4and concentrated under vacuum.

The remainder precrystallization in isopropyl ether.

m 95 g

With/ Connection 1.

Prepare a solution containing 3.6 ml of triethylamine in 2 ml of dimethylformamide, then slow the tion under the action of NaOH. Then to this solution was added 2.2 g of methanesulfonate obtained in accordance with stage d stage, the reaction mixture is heated at 60oC for one hour, add 0.1 g of 4-phenoxypyridine and again heated at 60oC for 30 minutes, the Reaction mixture prilisaetsa to water, extracted several times with ether, the ether phase decantered, dried on Na2SO4, filtered and concentrated under vacuum. The remainder chromatographies on silica gel, eluent dichloromethane/methanol 93/3 (on/about), then 95/5 about/about. Concentration of the pure fractions gives 1.9 g of the expected product in the form of a base, then get the hydrochloride in ethyl acetate.

m 1.5 grams

TPL210oC.

Example 2. Hydrochloride N-/4-(4-phenylthio-1-piperidinyl)-2-(3,4-dichlorophenyl)-butyl/-4-fluoro-1-naphthalenamine.

< / BR>
< / BR>
A/ Obtaining Amin:

< / BR>
Dissolve to 20.2 g of 4-hydroxypiperidine in 80 ml of dioxane and 20 ml of water. Quickly add 48g SIDE2O and heated the reaction mixture at a temperature of phlegmy during the night. The solvents are concentrated under vacuum and the residue precrystallization in hexane.

Get 30 g of crystals.

In 60 ml of dichloromethane is dissolved 9.0 g polucen ml of dichloromethane. The reaction mixture was stirred for 2 h at ambient temperature, then the solvents are concentrated under vacuum. The residue is extracted with water and extracted with ethyl acetate. The organic phase is separated and washed successively with 5 th solution of NaHCO3then with a saturated NaCl solution, dried on Na2SO4and concentrated under vacuum. The remainder precrystallization in a mixture of ethyl acetate/hexane.

Obtain 10.4 g of crystals.

Prepare a suspension of 1.5 g of sodium hydride, in a liquid oil with a concentration of 55 and 150 ml of dimethylformamide, are then added at ambient temperature 4,29 g thiophenol. After stirring for 30 min add of 8.37 g is received before this product and the reaction mixture is stored overnight at ambient temperature. Concentrate the solvent under vacuum, extract the residue in sodium hydroxide solution and extracted with ether. The organic phase is separated and washed successively with 5-s ' solution of sodium hydroxide, once with water, then saturated NaCl solution, dried on Na2SO4and concentrated under vacuum.

Get 8,56 g of oily residue.

m 5,42 g

TPL159-161oC

In/ Get 1-/4-fluoro-1-naphthylamine/-2-/3,4-dichlorophenyl/-4-methyloxirane.

a/ 3-/3,4-Dichlorophenyl/-1-/2-tetrahydropyranyloxy/-3-cyanopropyl.

Prepare a suspension of 20 g of sodium hydride, in a liquid oil with a concentration of 55 to 60 and 200 ml of dry tetrahydrofuran. Add drop by drop for 30 min at 20oC solution containing 85 g of 3,4-dichlorophenyl-acetonitrile in 500 ml of tetrahydrofuran, and then the reaction mixture is stirred at ambient temperature for 2 hours the Mixture is cooled to -20oC and add the solution containing 98 g of 1-bromo-2-tetrahydropyranyloxy in 100 ml of tetrahydrofuran, allow the mixture to return to ambient temperature and after 2 h was added a solution containing 50 g of ameriglide 3 l of water. Extracted using 1.5 l of ether, washed with a saturated solution of sodium chloride, decanted, dried on MgSO4and concentrate under vacuum.

The remainder chromatographies on silica gel, eluent: dichloromethane. The fractions of pure product concentrate/-butane.

In 100 ml of absolute ethanol was dissolved with 83.6 g obtained before nitrile. Add 350 ml of concentrated ammonia, and then injecting nitrogen added Raney Nickel /10 on the number of initial amine/. Then hydronaut in an atmosphere of hydrogen at ambient temperature and under normal pressure.

3 hours is absorbed 11,9 l of hydrogen. The catalyst separated in the filtering on celite, the filtrate is concentrated under vacuum, the residue is extracted in a saturated solution of sodium chloride. After extraction with ether and drying over MgSO4receive 82.5 g of liquid oil.

C/ 2-/3,4-Dichlorophenyl/-1-/4-fluoro-1-naphthylamine/-4-/2-tetrahydropyranyloxy/-butane.

In 50 ml of methylene chloride is dissolved 4.8 g obtained before this amine and 3 ml of triethylamine. Then add drop by drop a solution containing 5 g of acid chloride of 4-formatting acid in 10 ml of dichloromethane. After addition, the reaction mixture is heated under irrigation by phlegm for 15 min, then concentrated under vacuum. The residue is extracted with water and extracted with ether. The ether phase is separated and washed successively with 5 th solution of NaHCO3and saturated NaCl solution. After drying over Na2SO4and p is p-1 naphthylamine-/4-butanol.

To a solution containing 13 g obtained in the previous step with/ connections in 80 ml of methanol, was added 4 ml of acid resin Amberlyst Astir the mixture for 1H at ambient temperature and heated at a temperature of phlegmy for 30 minutes to Separate the resin in the filter on celite and concentrate the filtrate under vacuum.

m 10,7,

e/ 2-/3,4-Dichlorophenyl/-1-/4-fluoro-1-naphthylamine/-4-methyloxiran.

To a solution containing 10.5 g is received before this alcohol in 100 ml of dichloromethane, was added 4.3 g of triethylamine, then 3.5 g of methylchloride. Upon completion of addition, washed successively with water, then saturated NaCl. The organic phase is separated by decantation, dried on Na2SO4and concentrated under vacuum. The liquid oil crystallizes in the air.

m, 10,15

With/ Connection 2.

Dissolved in 10 ml of dimethylformamide 2.3 g of 4-phenylthioureido,i.e., the amine obtained above /on the stage/ and released under the action of NaOH, and 1.4 ml of triethylamine, then added 2.8 g obtained before nelfinavir and heat the mixture at 80oC for 45 minutes the Mixture prilisaetsa to water and extracted e is rotiruetsya on silica gel, eluent dichloromethane/methanol 93/7 about/about, then 92/8 about/about. Concentration of the pure fractions gives a liquid oil which is dissolved in ethyl acetate. Addition of ether saturated with chloroethanol acid, allows to obtain a hydrochloride, which crystallizes.

m 1 g

TPL211oC.

Conducting the synthesis in accordance with examples 1 or 2 above, get a connection, described below in table.2.

Example 7. Dichlorhydrate N-/4-(4-aniline-1-piperidinyl)-2-(3,4-dichlorophenyl)-butyl/-2,4-dichlorobenzamide.

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< / BR>
A/ Amin:

< / BR>
is commercial.

In/ Connection 7.

In 1 ml of dimethylformamide is dissolved 1 g 1-/2,4-dichloraniline/-2-/3,4-dichlorophenyl/-4-methyloxirane obtained in accordance with examples 1B, as described above, and 0.8 g of 4-anilinopiperidine /commercial/ and heated the reaction mixture at 60oC for one hour. Then poured the solution to water, extracted with ethyl acetate, separate the organic phase, which is washed with water, dried on Na2SO4and concentrated under vacuum. The residue is purified by chromatography on silica gel, eluent dichloromethane/methanol 97/3 about/about.

koncentrirovannyh">

m 0.25 g

TPL214oC.

Example 8. Hydrochloride N-/4-(N'-4-acetylamino-1-piperidinyl)-2-(3,4-dichlorophenyl) -butyl/N-methylbenzamide.

< / BR>
< / BR>
A/ 3-/3,4-Dichlorophenyl/-1-/2-tetrahydropyranyloxy/-3-cyanopropyl.

Prepare a suspension of 20 g of sodium hydride, in a liquid oil with a concentration of 55 to 60 and 200 ml of dry tetrahydrofuran. Add drop by drop for 30 min at 20oC solution containing 85 g of 3,4-dichlorophenyl-acetonitrile in 500 ml of tetrahydrofuran, and then the reaction mixture is stirred at ambient temperature for 2 hours the Mixture is cooled to -20oC and add the solution containing 98 g of 1-bromo-2-tetrahydropyranyloxy in 100 ml of tetrahydrofuran, allow the mixture to return to ambient temperature and after 2 h was added a solution containing 50 g of ammoniaand in 3 l of water. Extracted using 1.5 l of ether, washed with a saturated solution of sodium chloride, decanted, dried on MgSO4and concentrate under vacuum.

The remainder chromatographies on silica gel, eluent dichloromethane. The fractions of pure product are concentrated under vacuum, giving of 83.6 g of liquid oil.

In/ 1-Amino-2-/3,4-dichlorophenyl/-4-/2-tetrahydropyranyl-oxy/-Butantan ammonia solution, then, while blowing nitrogen added Raney Nickel /10 on the number of initial amine/. Then hydronaut in an atmosphere of hydrogen at ambient temperature and under normal pressure.

3 hours is absorbed 11,9 l of hydrogen. The catalyst separated in the filtering on celite, the filtrate is concentrated under vacuum, the residue is extracted in a saturated solution of sodium chloride. After extraction with ether and drying over MgSO4receive 82.5 g of liquid oil.

With/ 1-Ethoxycarbonyl-2-/3,4-dichlorophenyl/-4-/2-tetrahydropyranyloxy/-butane.

To 31.8 g is received before this product, dissolved in 150 ml of dichloromethane, are added to 10.1 g of triethylamine, and then 10.8 g of ethylchloride. Stirred for half an hour at ambient temperature, washed with water, dried on sodium sulfate and evaporated to dryness.

D/ 1-Methylamino-2-/3,4-dichlorophenyl/-4-/2-tetrahydropyranyloxy/-butane.

Received before this liquid oil, dissolved in 150 ml of tetrahydrofuran, is added to the suspension containing 7.6 g of lithium aluminum hydride in 100 ml of tetrahydrofuran, under irrigation with phlegm. After irrigation with phlegm for two hours, cool, add 30 ml of 5 N. NaOH, the precipitate is filtered off and the issue is SS="ptx2">

Add drop by drop 14,05 g of benzoyl chloride, dissolved in 50 ml of dichloromethane, to the solution containing received before this product and 10.1 g of triethylamine in 150 ml of dichloromethane. Stirred for half an hour at ambient temperature, evaporated to dryness, extract the residue in ether, washed with water, dried on sodium sulfate and evaporated to dryness. Purify by chromatography on silica gel, eluent dichloromethane/ethyl acetate 9/1 about/about.

Obtain 28.5 g of colorless liquid oils.

F/ N-methylbenzylamino-2-/3,4-dichlorophenyl/-4-hydroxybutane.

To a solution containing 21,7 g is received before this product in 150 ml of methanol, add 15 ml of ether, saturated chloroethanol acid, stirred for half an hour at ambient temperature, evaporated to dryness and kristallisera the product in ether.

Get so 16,9,

TPL137-149oC.

G/ N-1 methylbenzylamino-2-/3,4-dichlorophenyl/-4-mesyl-oxybutin.

Add one drop of 4.6 g of methylchloride dissolved in 25 ml of dichloromethane, to 14 g obtained before this product and 4 g of triethylamine dissolved in 100 ml of dichloromethane. Stirred for one hour at those who t thus, 15,4

TPL100-102oC.

H/ Connection 8.

To 2 g of N-4-acetylaminofluorene added 1 g received before this product, then dissolve the mixture in 5 ml of dimethylformamide. The reaction mixture is heated at 80oC for 2 h, then add ice, extracted with ether, the ether phase is washed with water, dried on MgSO4and concentrate under vacuum. The remainder chromatographies on silica gel, eluent dichloromethane/methanol 92/8 about/about.

Concentration of the pure fractions gives a residue which is extracted in dichloromethane, then add ether, saturated chloroethanol acid, and the separated hydrochloride the result of the filter.

m 0,92 g

TPL108oC.

Conducting the synthesis in accordance with the above examples 7 and 8 receive connections 9, 10 and 11, described below in table.3.

Example 12. Dichlorhydrate N-[(4-(2-methyl-2-imidazolidine)-1-piperidinyl)-2-naphthylmethyl] -2,4-dimethoxybenzamide.

< / BR>
< / BR>
A/ Obtaining amine

< / BR>
Conducting the synthesis in accordance with example 1A, but substituting phenol, 1-methyl-2-mercaptoimidazole receive the above amine.

TPL209oC /hydrochloride/.

In/ Connection 12.

oC for 1 h 30 min in the presence of 1.35 g of the amine obtained before this, and 2.02 g of triethylamine in 8 ml of dimethylformamide. Then allow the reaction mixture to cool, then add ice-cold water. The precipitate is separated by filtration and dissolved in dichloromethane. Washed with water, then the organic phase is dried on MgSO4and concentrated under vacuum. The remainder chromatographies on silica gel, eluent dichloromethane/methanol 100/2 about/about.

Concentration of the pure product gives a residue which is extracted in dichloromethane, then add a solution of hydrogen chloride in ether. Hydrochloride is separated in the filter.

m 0.25 g

TPL146-150oC.

Conducting the synthesis in accordance with the above example 12, receive connections described below in table.4.

Example 15. Dichlorhydrate N-methyl-N[4-(4-aniline-1-piperidinyl)-2-(3,4-dichlorophenyl) -butyl/-4-fluoro-1-naphthaleneboronic /-/.

< / BR>
< / BR>
Enantiomer /-/ above compound is obtained from racemic amerosport, which distinguish enantiomers in accordance with the method described in patent application EP-A-428 434, as shown below.

Enantiomer /+/ 1-ADO education phlegmy, added 93 g of racemic amerosport dissolved in 300 ml of methanol. Allowed to return to ambient temperature, filtered, the crystals washed with methanol and dried under vacuum at 50oC at P2O5.

m 64,8 g

()2D0= -5,2/1 in water/.

Then recrystallized in 2,96 l of methanol, filtered off the crystals, wash them in methanol and dried under vacuum at 50oC at P2O5.

m, 45,3

()2D0= -4,5/C= 1 in water/.

D-/-/-tartrate is extracted in 250 ml of water, podslushivaet concentrated sodium hydroxide solution and extracted 3 times with 200 ml dichloromethane, then washed with a saturated solution of sodium chloride, decanted, dried on MgSO4filter and concentrate under vacuum. The residue is extracted into isopropyl ether, the mixture is stirred for one hour at ambient temperature, the crystals are filtered and washed with isopropyl ether.

m 24,7 g

()2D0= +9,0/1 in methanol/.

TPL79-80oC.

Enantiomer /-/ 1-amino-2-/3,4-dichlorophenyl/-4-butanol.

()2D0= 9.2 per/1 in methanol/.

TPL79-80oC.

A/ 1-Amino-2-/3,4-dichlorophenyl/-4-/2-tetrahydropyranyloxy/-butane.

Dissolve 12,50 g of 1-amino-2-/3,4-dichlorophenyl/-4-butanol /+/ in a mixture consisting of 150 ml of dichloromethane and 50 ml of DMF. Add ether, saturated chloroethanol acid up to pH 12, then of 5.39 g tetrahydropyrane and heat the reaction mixture under irrigation by phlegm within one hour. Concentrate the solvent under vacuum, extract the residue in ether and the precipitate is separated by filtration.

m, 15,5

/ 2-/3,4-Dichlorophenyl/-4-/2-tetrahydropyranyloxy/ -4-utanfor-2-naphthaleneboronic.

In 100 ml of dichloromethane is dissolved 15.5 g is received before this product in the presence of 13.3 g of triethylamine. Added 10.6 g of acid chloride of 4-formatting acid, dissolved in 10 ml of dichloromethane, then leave the reaction mixture for 3 h at ambient temperature with stirring. Concentrate the solvent under vacuum, extract the residue in water, extracted with ethyl acetate and washed successively 10% NaOH solution, water, then a saturated solution of NaCI. The organic phases are dried on MgSO4and the end of the Tang/ -4-fluoro-1-naphthaleneboronic.

Prepare a suspension of 1.56 g NaH with a concentration of 55 and 60 ml of DMF, and then slowly added 21,3 g is received before this product, dissolved in 120 ml of DMF. The mixture was stirred for 15 min, then add one drop of 12.3 g of melodica dissolved in 20 ml of DMF. The reaction mixture was stirred at ambient temperature for an hour, then concentrated under vacuum. The residue is extracted in water, washed with water, then with saturated solution of NaCI. The ether phase is dried on MgSO4and concentrated under vacuum.

m 18,6 g

D/ N-methyl-N/2-(3,4-dichlorophenyl)-4-butanol/-4-fluoro-1-naphthaleneboronic.

In 300 ml of methanol is dissolved a 18.57 g is received before this product, then add 2 ml of ether saturated with chloroethanol acid, and heat the reaction mixture under irrigation by phlegm within 5 hours Concentrating the solvent under vacuum, extract the residue in 2n. a solution of HCI, extracted with ether and washed successively with water, 5 th solution of NaHCO3water, then a saturated solution of NaCI. Phase is concentrated under vacuum, and the residue chromatographically on silica gel, eluent CH2CI2/CH3OH 97/3 about/about. The fractions of pure product are concentrated under TPL125-127oC.

Example 16. Iodide 4 - (methylaniline)-N(a)-methyl-[2-(3,4-dichlorophenyl)-4-(4-fluoro-1-naphthaleneamine) -N'-methylbutyl]-piperidine /-/.

< / BR>
< / BR>
Left under stirring for 24 h at ambient temperature to 2.41 g of the compound obtained above in accordance with example 15 in the form of a free base, 24 ml under the conditions and 1 ml of acetone.

The reaction mixture is concentrated under vacuum, and the residue chromatographically on silica gel, eluent CH2CI2/CH3OH 97/3 about/about.

Product suirvey the first corresponds to which methyl on the nitrogen of the piperidine is in axial position. Concentration of the appropriate fractions gives a residue which is deposited on the air.

m 1,11,

TPL152-154oC.

()2D0= -28,3/1 in methanol/.

Example 17. Iodide 4 - (methylaniline)-N(a)-methyl-[2-(3,4-dichlorophenyl) -4-(3-isopropoxypropylamine)-N'-methylbutyl]-piperidine.

< / BR>
< / BR>
Conducting the synthesis in accordance with example 16, but proceeding from the compound described in example 10, in the form of a free base receive the above connection.

>For example, the compound of example 1 exhibits no toxicity after repeated administration by oral rat dose 300 mg/kg for 4 weeks.

Examples of farmakonisi:

1. Gelatin capsules,mg:

Connection 1 (equivalent to 25 mg base 30,3

Unmodified corn starch 79

Crystalline lactose 109

Magnesium stearate 1,70

220

6 Gelatine capsules, mg:

The connection 15 3,03

Unmodified corn starch 19

Crystalline lactose 109

Magnesium stearate 1,97

220 mH

1. Derivatives of N-alkylenediamine General formula I

< / BR>
where Ar is phenyl, pyridyl, 1-methylimidazole-2;

Ar is 3,4-dichlorophenyl, naphthyl;

X is oxygen, sulphur, the group-NH-, -N(CH3)-, -N(COCH3)-;

R is hydrogen, methyl;

Z is 2,4-dichlorophenyl, 2,4-acid, 3-chlorophenyl, 3-isopropoxyphenyl, 4-fornuft-1-yl or hydrochloride, dihydrochloride or their Quaternary ammonium salt formed by the nitrogen of piperidine.

2. Optically pure derivatives of N-alkylenediamines General formula

< / BR>
where * means that the carbon atom marked with this sign has a specific absolute configuration of (+) or (-);

X is-NH or-N(CH3
< / BR>
in this case, represents a group of General formula

< / BR>
where Ar and X above.

4. Connection on p. 1, which is N-[2-(3,4-dichlorophenyl)-4-4(4-(2-pyridylthio)-1-piperidinylmethyl] -2,4-dichlorobenzamide or hydrochloride, dihydrochloride or Quaternary ammonium salt formed by the nitrogen of piperidine.

5. Connection on p. 1, representing N-[4-(N'-4-acetylamino-1-piperidinyl)- 2-(3,4-dichlorophenyl)-butyl] -N-methylbenzamide or hydrochloride, dihydrochloride or its Quaternary ammonium salt formed by the nitrogen of piperidine.

6. Connection on p. 1, representing N-[4-(1-methyl-2-imidazolyl)-4-thio-1-piperidinyl-1-naphthylmethyl] -2,4-dimethoxybenzamide or hydrochloride, dihydrochloride or Quaternary ammonium salt formed by the nitrogen of piperidine.

7. The method of obtaining derivatives of N-alkylenediamines General formula I on p. 1, characterized in that the free amine of General formula

< / BR>
where 2-tetrahydropyranyloxy;

R0hydrogen, methyl;

Ar has the abovementioned meaning,

process functional derivative of the acid of General formula

< / BR>
where Z has the value

< / BR>
with its subsequent processing methanesulfonamido getting nelfinavir General formula

< / BR>
where Ar,RAnd Z have the values

and processing of a secondary amine of General formula

< / BR>
where Ar,X have the specified values

followed, if necessary, transfer the compounds obtained in salt.

8. Pharmaceutical composition having antagonistic activity against receptors neirokinina containing the active principle and pharmaceutical additives, characterized in that the active agent contains a compound of formula I under item 1 in an effective amount.

 

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< / BR>
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< / BR>
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< / BR>
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< / BR>
< / BR>
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