Polycyclic amino compounds compounds or their salts, their optically pure isomers, the method of obtaining polycyclic aminecontaining compounds, cyclic amino compounds compounds or their salts, their optically pure isomers and the pharmaceutical composition having an antagonistic activity to the receptor neirokinina

 

(57) Abstract:

Usage: in medicine as receptor antagonists neirokinina. Products: polycyclic amino compounds compounds f-crystals of l, where Ar is phenyl, x is 0 or 1, X is hydrogen, hydroxyl, acetoxy or aceraminophen, m is 2 or 3, Ar' is phenyl or naphthyl, n is 0, 1, 2 or 3, p is 1 or 2, provided that when p = 2, n = 1 and Q is two hydrogen atoms, Q is oxygen or two hydrogen atoms, T is-C(0)- or-CH2-, q = 0 or 1, Z is phenyl. Reagent 1: compound f-crystals 2 : Reagent 2 : HOC(O)-(CH2)qZ or HaI-(CH2)q+1-Z, where HaI - halogen, E is a hydroxyl or O - protected group of the obtained compound 3 otscheplaut protected group process and CH3SO2Cl and secondary amine f-ly lV.

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9 C. and 4 h.p. f-crystals, 8 PL.

The invention relates to polycyclic aminecontaining compounds, to their optically pure enantiomers, the way they are received, to Farmaceutici on their basis, as well as to new intermediate compounds for the synthesis of polycyclic compounds.

New polycyclic compounds can be used in therapeutic purposes, in particular pathological phenomena which affected the system of neurokinins, as, for example, b is the treatment (J. Losay and comp. Substance P, Von Eulez, U. S. Pernow ed. Raven Press, New York, 1977, 287-293), gastrointestinal disorders (D. Regoli and comp. Trend Pharmacol. Sci. 1985, 6, 481-484), respiratory disorders (J. Mizrahi and comp. Pharmacology, 182, 25, 39-50).

Known endogenous ligands to receptors of neurokinins, such as substance P (SP), neurokinin A (NKA) (S. J. Bailey and comp. 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 neurokinins are many drugs and now they are classified into three types: NK1NK2and NK3. The majority of the studied up to the present time preparations are several types of receptors, such as preparations of ileum of the Guinea pig contain NK1NK2and NK3some drugs are only one type of receptor, for example drugs from the carotid artery of the dog contain NK1from devoid of endothelium of the pulmonary artery of the rabbit contains NK2and from the portal vein of the rat contains NK3(D. Regoli et al. Trends 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)11SP, [NIe10]NKA4-10and Me Phe7-NKB possess the selectivity of the time it was discovered, new polycyclic amino compounds compounds have valuable pharmacological properties, in particular antagonistic activity to the receptor of neurokinins, and may be suitable for the treatment of any pathology, dependent on substance P and neirokinina.

Thus, the invention relates to polycyclic aminecontaining compounds of the formula

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where

Y represents a

Ar represents phenyl,

x is 0 or 1,

X represents hydrogen, hydroxyl, acetoxy or allmenalp,

m is 2 or 3,

Ar' represents a phenyl, substituted stands or two halogen atoms, or naphthyl,

n equals 0, 1, 2 or 3,

p is 1 or 2, provided that when p is 2, n is 1 and Q is two hydrogen atoms,

Q represents an oxygen or two hydrogen atom,

T represents a group selected from-C(O)- and-CH2-,

q is 0 or 1,

Z represents phenyl, which may be single - or Disaese C1-C4-alkoxygroup or halogen, or monohalogenated naphthyl, with the proviso that when T is a group-C(O) -,- (CH2)qZ can represent a benzyl group is B> the alkyl and possibly substituted on the aromatic cycle by halogen or C1-C4-alkoxygroup or their salts with mineral or organic acids or Quaternary ammonium salt or N-oxide derived nitrogen (b) of piperidine.

Salts of compounds of formula (l) include salts with mineral or organic acids which allow a suitable separation or crystallization of the compounds of formula (l), such as picric acid or oxalic acid, or optically active acid, for example, almond or campostoma acid, and salts with acids which form pharmaceutically acceptable salts such as hydrochloride, bromohydrin, sulfate, hydrosulfate, dihydrophosphate, methanesulfonate, methylsulfate, maleate, fumarate, 2-naphthalenesulfonate, glycolate, gluconate, citrate, izational.

When the compounds of formula (l) may be in the form of a Quaternary ammonium salt formed with nitrogen (b) of piperidine, or N-oxide derivative, formed with nitrogen (b).

In accordance with another aspect of the invention relates to a method for producing compounds of formula (l) and their salts, characterized in that

a) compound total formyl or perhaps O-protected group, such as, for example, tetrahydropyranyl-2-oxygraph, or group

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in which

Y represents a group in which X is hydroxyl, or protected hydroxyl,

process

or a functional derivative of the acid of General formula

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in which

q and z are as defined above, if you want to obtain the compounds of formula (l), where T is a group-CO-;

or halogenated derivative of General formula

Hal-(CH2)q+1-Z (lV)

in which

q and Z are as defined above, and Hal represents a halogen, preferably a bromine atom or chrome, if you want to obtain the compounds of formula (l), where T is a group-CH2-;

get the compound of General formula

,

b) then, when E is tetrahydropyranyloxy, otscheplaut tetrahydropyranyloxy under action of an acid;

c) thus obtained alcohol of General formula

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treated with methanesulfonamide;

d) received mesilate General formula

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treated with a secondary amine of the formula

,

in which

Y is as defined above;

e) after a possible smola with a mineral or organic acid, or the Quaternary ammonium salt or N-oxide derived nitrogen (in) piperidine.

Salts of Quaternary ammonium get in the reaction of compounds l in the form of free bases, in which other AMINOPHENYL possibly present, are N-protected any N-protecting group, with an excess of alkylating agent of the formula

A Q'

in which A represents a group to delete and is such as chloride, bromide, iodide, methanesulfonate or paratoluenesulfonyl, preferably the chloride or iodide, and Q' is alkyl (C1-C6or benzyl,

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 of one to several hours, to obtain after processing in accordance with conventional methods and after possible removal of the protection of a mixture of axial and Equatorial diastereoisomers Quaternary ammonium salts.

Arepresents preferably iodide, which can be replaced by another anion or a pharmacologically acceptable anion, for example PI is or Duolith A375< / BR>
Diastereoisomer are separated according to conventional methods such as chromatography or recrystallization.

N-oxide derivatives are obtained by the interaction with the peroxide derivative, such as metallocarboranes acid or hydrogen peroxide, in accordance with conventional methods.

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

If the original product is used as a compound of the formula (II), where E represents a group

,

the method according to the invention can be represented and illustrated in detail in figure 1.

Scheme 1.

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In the formula (IIIa) the acid chloride of the acid is considered as a reactive functional derivative of the acid (III). However, you can use a different functional derivative of the acid (III) in the presence of an organic base, such as, for example, triethylamine, in a solvent such as dichloromethane or dimethylformamide, at ambient temperature. The compounds (I) are selected and purified in accordance with conventional methods, such as chromatography or recrystallization.

If the original product is used as a compound of the formula (II), where E is tetrahydropyranyloxy (Tgp-O-), then the method according to the invention can be depicted and illustrated in scheme 2.

The reaction of compound (II) with the reagent (IIIa) and (IV) ions, as described above, with an acid chloride of acid (IIIa) can be replaced by other functional derivatives or free acid is activated, for example, by means of paph.

Thus obtained intermediate compound (V) is subjected to removal of protection by mild acid hydrolysis, which leads to a free hydroxyl-containing compound (VI), which gives mesilate (VII), then processes the secondary amine of formula (VIII) and get the final compound (I) according to the invention.

Scheme 2.

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Thus obtained compounds of formula (I) is isolated in the form of free base or Sol is the first base, the salt formation is carried out as a result of processing the selected acid in an organic solvent. In the treatment of the free base, dissolved, for example, in alcohol, such as isopropanol, a solution of the chosen acid in the same solvent to obtain the corresponding salt, which is allocated using classical methods. Get, for example, hydrochloride, bromohydrin, sulfate, hydrosulfate, dihydrophosphate, methanesulfonate, oxalate, maleate, fumarate, 2-naphthalenesulfonate.

Upon completion of the reaction of compounds of formula (I) can be allocated in the form of one of their salts, for example the hydrochloride or the oxalate; in this case, if necessary, the free base can be obtained by neutralizing the specified salt of a mineral or organic base, such as sodium hydroxide or triethylamine, or a carbonate or bicarbonate of an alkali metal, such as a carbonate or bicarbonate of sodium or potassium.

The parent compound with formula (II) are obtained on the basis of NITRILES, commercial or obtained in accordance with known methods.

The separation of racemic mixtures of (I) allows to distinguish the enantiomers (I*) formula

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in to the of (+) or (-);

Y, m, Az', n, p, Q, T, q and z are as defined above for the derivatives of formula (l); or one of their salts with mineral or organic acids or formed with the nitrogen atom (in) one of the salts of Quaternary ammonium or the N-oxide derivatives.

These salt or N-oxide derivatives are obtained as indicated above for the salts and derivatives, the corresponding derivative of formula (I).

The enantiomers of the formula (l*are new products, which form part of the invention.

You can also be separated by fractional crystallization of racemic mixtures of the products of formula (II) in which m, Z', n and p are as defined for compounds (l), E represents a hydroxyl, and O represents hydrogen, to obtain santomera (l*products of formula (I).

The racemate separation carried out on the intermediate compounds (II), is able to give salts with optically active acids. In this case santomera share using classical methods, such as crystallization or preparative chiral chromatography high pressure.

Thus obtained optically pure aminoplast is the new om, has a specific configuration of (+) or (-).

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

The compound (l) and its 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. Cascieri and comp. j. Biol. Chem. 1983, 258, 5158-5164 and D. D. Paya and comp. j. Immunol. 1984, 133, 3260-3265.

The same compounds and their salts showed antagonistic properties with respect to binding of NKA in experiments carried out on the membranes of the duodenum of rats in accordance with the work of L. Bergstom and comp. Md. Pharmacol. 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 and comp. Br. j. Pharmacol. 1988, 94, 602-608.

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

Compounds in accordance with the invention are antagonists of substance P, neirokinina A or neirokinina B.

Thus, compound 2 from example 2 is antagonism to the binding of substance P in Kiequal to 8.3 molentje 3 of example 3 is antagonism to bind aladina when Kiequal to 200 nmole.

The results of the test compounds in accordance with the specified methods, summarized in table. 8.

Compounds according to the invention is usually given in a single dose in the form of pharmaceutical compositions in which the active ingredient is mixed with a pharmaceutical indifferent substance.

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

Pharmaceutical compositions for oral, sublingual, subcutaneous, intramuscular, transdermal, local or rectal introduction of active ingredients can be in single doses mixed with classical pharmaceutical carriers. Single doses correspond to different forms, such as tablets, altinova capsules, powders, granules for oral administration and oral solutions or suspensions, sublingual forms and cheek introduction, forms for subcutaneous, intramuscular, intravenous, intranasal or intraocular administration and forms for rectal administration.

When purchasing solid composition is starch, lactose, magnesium stearate, talc, gum Arabic or similar. Can be coated tablets with sucrose or other appropriate materials or they can be processed so that they had polarisavenue activity or Vice versa, delayed, 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 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 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, n the form of aqueous suspensions, saline isotonic solutions or sterile and injectable solutions which contain farmacologicas compatible dispersing and/or wetting agents, such as propylenglycol or butyleneglycol.

For administration by inhalation using an aerosol containing, for example, triolein sorbitan or oleic acid, as well as Trichlorofluoromethane, DICHLOROFLUOROMETHANE, dichlorotetrafluoroethane or any biologically compatible gas serving to eject.

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

Examples of formulations of farmcampsite in the form of gelatin capsules.

1. Gelatin capsule weighing 220 mg are presented in table. 1.

2. Gelatin capsule with an oxide weight of 200 mg, mg:

The compound of the formula I (in the form of base) 0,25

Corn starch 70,0

Lactose in the form of extra fine crystals USD 128.0

Magnesium stearate 1,75

When determining the toxicity of new compounds, the following data:

DL50in mouse and rat is more than 2 g/kg

Compounds according to the invention do not have t the

Tests for mutagenesis negative, in particular the Ames test. Therefore, the compounds according to the invention can be attributed to non-toxic or low-toxic.

The following examples illustrate the invention without limiting it.

The melting temperature and decomposition products (TPL) were measured at a heating installation Koffler. The spectra of nuclear magnetic resonance13C were obtained at 50 MHz in dimethyl sulfoxide.

Example 1. Hydrochloride 5-2-4(4-benzyl-1-piperidinyl)-ethyl-5-(3,4-dichlorophenyl)-1-benzylpiperidine

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A/ 3,4-Dichlorotetramethyldisiloxane- -benzoylacetonitrile.

Prepare a suspension of 20 g of sodium hydride, in a liquid oil with a concentration of 55-60% and 200 ml of anhydrous tetrahydrofuran. At 20oC is added drop by drop over 30 minutes a solution containing 85 g of 3,4-dichlorobenzonitrile 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 2-prematureejaculation 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 chloride AMT, 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.

B/ g Tetrahydropyranyloxy g - cyano-3,4-dichlorobenzidine ethyl.

In 100 ml of tetrahydrofuran dissolve 21 g of the nitrile obtained above in stage (A), then added drop by drop in the ambient temperature of the solution containing 0,067 mol diisopropylamide lithium in 100 ml of tetrahydrofuran, and stirred the reaction mixture for 1 h at ambient temperature. Then add 12 g of bromopropionate ethyl and heated at 50oC for 2 hours the Mixture is cooled, it is poured to a saturated solution of ammonium chloride and extracted with ether, washed with water, the ether phase is separated by decantation, dried over Na2SO4and concentrate under vacuum. The residue is purified by chromatography on silica gel, eluent dichloromethane/ethyl acetate 100/1 (V/V). Concentration of the pure fractions gives 13 g of the expected product.

C/ 5-Tetrahydropyranyloxy-5-(3,4-dichlorophenyl)-piperidine.

Dissolve 13 g obtained this compound in 250 ml of ethanol and 40 Austlii of Raney Nickel. When absorbed theoretically calculated amount of hydrogen, the mixture is filtered on celite and concentrate the filtrate under vacuum. The remainder absorb water, extracted with ether, then the ether phase is washed with water, dried over MgSO4and concentrate under vacuum.

m 9,

D/ 5-Tetrahydropyranyloxy-5-(3,4-dichlorophenyl)-1-benzylpiperidine.

Add 2,05 g benzylbromide to a solution containing 4.5 g of the product obtained above in 60 ml of dimethylformamide in the presence of 0.3 g of sodium hydride. The reaction mixture is heated at 40-50oC for 2 h and concentrated under vacuum. The remainder absorb water, extracted with ether, and the ether phase is washed with water, dried over MgSO4and concentrate under vacuum.

The remainder chromatographic on silica gel, eluent of dimethanol 100/1 (V/V).

The fractions of pure product are concentrated under vacuum.

m 2 g

E/ 5-Methanesulfonylaminoethyl-5(3,4-dichlorophenyl)-1-benzylpiperidine.

Dissolve 2 g of the product obtained above in 40 ml of methanol saturated with gaseous chloroethanol acid, and stirred the solution for two hours at ambient temperature. The solvents are concentrated under watermelon and add 0.4 g of triethylamine and 0.45 g of methylchloride, then stir the mixture for half an hour at ambient temperature. Concentrate under vacuum, extract the residue in water, extracted with ether, the ether phase is washed with water, decanted, dried over MgSO4and concentrate under vacuum.

m=1,6,

K/ Connection 1.

Dissolve to 0.68 g of the product obtained above and 0.63 g of 4-benzylpiperidine in 2 ml of dimethylformamide and heated the mixture at 80oC for 2 hours Cooled solution is poured to water, extracted with ethyl acetate, decanted organic phase, dried over MgSO4and concentrate under vacuum. The residue is purified by chromatography on silica gel, eluent dichloromethane/methanol 100/3 (on/about).

The fractions of pure product are concentrated under vacuum, then get hydrochloride, which hardens in a mixture of ether/pentane 50/50.

m 0.25 was

TPL115oC.

Example 2. Hydrochloride 3-[2(4-benzyl-1-piperidinyl)-ethyl]-3-(3,4-dichlorophenyl)-1-phenylacetylamino

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A/ 3-Tetrahydropyranyloxy-3-(3,4-dichlorophenyl)-piperidine.

Dissolved in 50 ml of tetrahydrofuran, 4.5 g of 5-tetrahydropyranyloxy-5-(3,4-dichlorophenyl)-piperidine obtained in accordance with example 1C,th the mixture is heated for 1 h at 60oC, then cooled. Add 1 ml water, 1 ml of 4n sodium hydroxide and 3 ml of water. Separate the mineral precipitate by filtration and concentrate the filtrate under vacuum. The residue is extracted with ether, dried over MgSO4and concentrate under vacuum, giving 3.5 g of the target product.

B/ 3-Tetrahydropyranyloxy-3(3,4-dichlorophenyl)-1 - phenylacetylenes.

Add 0.75 g of the acid chloride phenylacetic acid to the solution containing 1.7 g obtained before this product and 0.9 g of triethylamine in 50 ml dichloromethane. The reaction mixture was stirred for 1 h at ambient temperature and concentrate under vacuum. The residue is extracted with ethyl acetate, then washed with water, the organic phase is dried over MgSO4and concentrate under vacuum. The residue is purified by chromatography on silica gel, eluent dichloromethane/methanol 100/0,5 (V/V).

Concentration of the pure fractions gives 1 g of the target product.

C/ 3-Methanesulfonylaminoethyl-3(3,4-dichlorophenyl)-1 - phenylacetylenes.

Dissolve 0.8 g of product obtained above in 40 ml of methanol, saturated chloroethanol acid, and stirred the mixture for 0.5 h at ambient temperature. Concentrate under W the reaction mixture for 1 h at ambient temperature, then concentrate under vacuum. The residue is extracted with ethyl acetate, washed with water, the organic phase is separated by decantation, dried over MgSO4and concentrate under vacuum.

m 0,71 g

I/ Connection 2.

Within 3 hours, heated at 80oC 0.7 g obtained before this product and 0.52 g of 4-benzylpiperidine dissolved in 2 ml of dimethylformamide. Cool the reaction mixture was poured in water, extracted with ether, the ether phase is washed with water, dried over MgSO4and concentrate under vacuum and then recrystallized hydrochloride in a mixture of dichloromethane/ether.

m=0,12,

TPL210-212oC.

Conducting the synthesis in accordance with example 1, receive connections 3-6, described in table. 2

Conducting the synthesis in accordance with example 2, receive connections 7-15 described in table. 3, below.

Conducting the synthesis in accordance with the above examples 1 and 2, but replacing them 3,4-dichlorobenzonitrile on-naphthylacetamide receive connection 16-19, described in table. 4.

Example 20. Hydrochloride 3-[2-(4-benzyl-1-piperidinyl)-ethyl]- 3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenyl)-acetylserine

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A/ -Tetrahydropyranyloxy (obtained in accordance with stage A of example 1), dissolved in 100 ml of dimethylformamide, are added in small portions to 4.6 g of NaH with a concentration of 60% of the reaction mixture is Stirred for 3 h at ambient temperature, cooled to 0oC, then added to 22.4 g of 4-bromobutyrate ethyl dissolved in 40 ml of dimethylformamide. Stirred the reaction mixture for 3 h at ambient temperature, poured to water, extracted with ether, washed with saturated NaCl solution, dried over Na2SO4and concentrate under vacuum. Purify the resulting residue by chromatography on silica gel, eluent toluene.

m 24,

B/ 6-Tetrahydropyranyloxy-6-(3,4-dichlorophenyl)-azepine.

Hydronaut 8 g obtained before this product under atmospheric pressure and at ambient temperature in the presence of Raney Nickel in a solution formed by 120 ml of ethanol.

When absorbed theoretically calculated amount of hydrogen, the catalyst is filtered off and concentrated under vacuum.

The oil obtained absorb then 20 ml of xylene and the reaction mixture is heated for 48 hours at a temperature of education phlegmy. Evaporate and purify the resulting residue by chromatography on C2">

C/ 3 Tetrahydropyranyloxy-3-(3,4 dichlorophenyl)-azepin.

On the basis of 2 g is received before this product, 0,49 g of lithium aluminum hydride and conducting the synthesis in accordance with stage a of example 2, to obtain 1.7 g of the expected product in the form of liquid oil.

D/ 3-Tetrahydropyranyloxy-3-(3,4-dichlorophenyl)-1 - isopropoxyphenyl)-acetylserine.

On the basis of 1.7 g obtained before this product and resulting synthesis in accordance with stage B of example 2, to obtain 1.7 g of the expected product.

E/ 3-Methanesulfonylaminoethyl-3-(3,4-dichlorophenyl)-1-(3 - isopropoxyphenyl)-acetylserine.

On the basis of 1.7 g obtained before this product and 0.34 g of methylchloride and resulting synthesis in accordance with stage C of example 2, to obtain 1.5 g of the expected product.

K/ Connection 20.

Within 2 h, heated at 80oC 1.5 g obtained before this product and 1.4 g of 4-gasoline piperidine, dissolved in 3 ml of dimethylformamide. Cooled, poured the reaction mixture to water, extracted with ether, washed with limited phase with water, dried over Na2SO4and concentrate under vacuum.

Purify the resulting residue by chromatography on silica gel, eluent CH2Cl2

TPL164oC.

Example 21. Hydrochloride 3-[2-(4-benzene-1-piperidinyl)-ethyl]-3(3, 4-dichlorophenyl)-1-(3-methoxyphenyl)-acetalization

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A/ 3-Tetrahydropyranyloxy-3-(3,4-dichlorophenyl)-1 -(3-methoxyphenyl)-acetalization.

To 1 g of 3-tetrahydropyranyloxy-3-(3,4-dichlorophenyl)- azetidine dissolved in 50 ml dichloromethane in the presence of 1 g of triethylamine and 0.5 g of 3-methoxyphenylacetic acid, add 1.5 g of BOP. Stirred the reaction mixture for 1 h at ambient temperature, evaporated to dryness, extract the residue with ethyl acetate, washed with water, dilute sodium hydroxide, the buffer solution with pH 2 and finally with water, saturated NaCl. Dried the organic phase over MgSO4and evaporated to dryness. Purify by chromatography on silica gel, eluent CH2Cl2/CH3OH 100/0,75 (on/about).

Get that image of 0.50 g of liquid oil.

B/ 3-Methanesulfonylaminoethyl-3-(3,4 - dichlorophenyl)-1-(3-methoxyphenyl)-acetalization.

To 0.50 g is received before this product, dissolved in 50 ml of methanol, add ether, saturated chloroethanol acid to pH 1. Mix a solution of p is a rotary AcOEt, washed with water, dried on MgSO4and evaporated to dryness.

The liquid absorb oil 30 ml of dichloromethane and added 0.20 g of triethylamine and 0.12 g of methylchloride. Stirred the reaction mixture at ambient temperature for 1 h, evaporated to dryness, extract the residue in ethyl acetate, washed with water, dried on MgSO4and evaporated to dryness.

Get that image of 0.50 g of liquid oil.

C/ Connection 21.

Within 3 hours, heated at 80oC 0.50 g described before this product, dissolved in 2 ml of dimethylformamide with 0.40 g of 4-benzylpiperidine. Cool the reaction mixture was poured to water, extracted with ethylcatechol, washed with water, dried over MgSO4and evaporated to dryness.

Purify the resulting residue by the method of chromography on silica gel, eluent CH2Cl2/CH3OH 100/2,5 (V/V).

Concentrated pure fractions under vacuum and get a hydrochloride by adding ether saturated with chloroethanol acid. Extract the residue in dichloromethane and precipitated hydrochloride in ether, filtered, washed with ether and dried under vacuum.

Get so 0,22 g of the expected product.

TPL1 is piperidine

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A/ 4-Methanesulfonylaminoethyl-4-(3-were)-N - cetilpiridini.

To 21 g of 4-(2-hydroxyethyl)-4-(3-were)-N - cetilpiridini dissolved in 200 ml dichloromethane and cooled to 0oC, add one drop of 3.8 ml of methanesulfonanilide. The reaction mixture is left for 0.5 h at ambient temperature, washed twice with water, dried over MgSO4and concentrate under vacuum.

Get so 23,5 g foamy substance.

B/ 4-[2-(4-benzene-1-piperidinyl)-ethyl] -4-4(3-were)-N - cetilpiridini

Within 4 h, heated at 60oC 18,5 g described above nelfinavir and 13.5 g of 4-benzylpiperidine dissolved in 40 ml of dimethylformamide. Making the reaction mixture to 500 ml of ice water, the precipitate is filtered off and washed with water. Absorb residue with ether, washed with dilute NaOH, then with water, dried over MgSO4and concentrate to dryness.

Purify the resulting residue by chromatography on silica gel, eluent CH2Cl2/CH3OH 100/3 (on/about).

Get so 18 g foamy substance.

C/ Dichlorhydrate 4-[2-(4-benzene-1-piperidinyl)-ethyl]-4-(3-were)-piperidine.

Within 30 minutes, heated at 604
and concentrate to dryness.

The base is dissolved in dichloromethane, add ether, saturated chloroethanol acid, and concentrated to dryness. Mix thus obtained the hydrochloride in ether, filtered and dried.

m 12.7 g

TPL160oC.

D/ Connection 22.

To 2 g of the product obtained above, dissolved in 30 ml of dichloromethane from 0.77 3-chlorophenylalanine acid and 2.2 g of triethylamine, was added 2.4 g of BOP. Stirred the reaction mixture for 30 min at ambient temperature, concentrated to dryness, absorb residue with ethyl acetate, washed with water, then with dilute NaOH solution, then with water, saturated NaCl, dried over MgSO4and concentrate under vacuum. Purify the residue by chromatography on silica gel, eluent: CH2Cl2/CH3OH - 100/10 (on/about). Get a hydrochloride by adding ether saturated with chloroethanol acid, and concentrated to dryness. Absorb residue with isopropyl ether, filtered and dried under vacuum.

m 2.1 g

T 106oC.
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A/ 3,4-Dichlorotetramethyldisiloxane- -benzoylacetonitrile

By the way, is identical to stage A of example 1, and according to 37.2 g of 3,4-dichlorobenzonitrile and 44.6 g of 3-bromopropionaldehyde, obtain 35 g of the expected product.

B/ g-Tetrahydropyranyloxy - g-cyano-3,4 - dichlorobenzidine ethyl.

On the basis of 35 g obtained at the stage of A product and 19.2 g of bromopropionate ethyl, conducting the synthesis is identical to stage B of example 1, to obtain 28 g of the expected product.

C/ 5-Tetrahydropyranyloxy-5-(3,4-dichlorophenyl)-piperidone.

Hydronaut 23 g obtained in stage B of the product dissolved in 650 ml of ethanol under atmospheric pressure and at ambient temperature in the presence of Raney Nickel. When absorbed theoretically calculated amount of hydrogen, the catalyst is filtered off, evaporated to dryness, extract the residue with ether, washed with water, buffer solution with pH 2, dried over Na2SO4and evaporated to dryness.

Get so 18 g of the expected product.

D/ 3-Tetrahydropyranyloxy-3-(3,4-dichlorophenyl)-piperidine.

Maintain a temperature of 60oC for 1 h the reaction mixture Cooled down, hydrolyzing by adding 3 ml of water 4n NaOH and 9 ml of water. Separate the mineral residue and the organic phase is evaporated under vacuum.

Get that way 12.4 g of the expected product.

E/ 3-Tetrahydropyranyloxy-3-(3,4-dichlorophenyl)-1-(3 - methoxyphenyl)-acetylpiperidine.

Added to 3.9 g of BOP to the solution containing 3 g obtained in stage 1 product, 2.4 g of triethylamine and 1.3 g of 3-methoxyphenylacetic acid in 50 ml of dichloromethane. Stirred the reaction mixture for 1 h at ambient temperature, evaporated to dryness, absorb AcOEt, washed with water, dried over Na2SO4and evaporated to dryness.

Purify the resulting residue by chromatography on silica gel, eluent CH2Cl2/CH3OH 100/2 (on/about).

The concentration of particles fractions gives 3 g of the expected product.

K/ 3-Methanesulfonylaminoethyl-3-(3,4-dichlorophenyl)-1-(3-methoxyphenyl)- acetylpiperidine.

Based on 3 g obtained in stage E of the product and 0.68 g of methylchloride receive the expected CE, eluent CH2Cl2/CH3OH 100/1,5 (V/V), and concentration of the fractions of pure product is obtained 2 g of the expected product.

L/ Connection 26.

Within 1 h, heated at 70oC 2 g obtained at stage K of the product and 1.6 g of 4-benzylpiperidine dissolved in 3 ml of dimethylformamide. Cool the reaction mixture was poured to water, extracted with ether, washed with water and dried over Na2SO4filter and concentrate under vacuum.

Purify the resulting residue by chromatography on silica gel, eluent CH2Cl2/CH3100/3 (on/about). Pure fractions are concentrated under vacuum, the residue is absorbed with acetone, then get hydrochloride in the addition of ether saturated with chloroethanol acid. Filtered hydrochloride, washed in pentane and dried under vacuum at P2O5.

Get so 1.1 g of the expected product.

TPL=108oC.

Example 27. Hydrochloride 3-[3-(4-phenyl-4-acetamido-1-piperidinyl)-propyl] -3-(3,4-dichlorophenyl)-1 - benzoylpiperidine

< / BR>
< / BR>
A/ 3-Tetrahydropyranyloxy-3-(3,4-dichlorophenyl)-1 - benzoylpiperidine.

Added 1.13 g of benzoyl chloride to 3 g 3-tet is outstay of 1.62 g of triethylamine, dissolved in 50 ml of dichloromethane. Stirred the reaction mixture for 30 min at ambient temperature, evaporated to dryness, absorb residue with ether, washed with water, dried over Na2SO4and evaporated to dryness. Purify the resulting residue by chromatography on silica gel, eluent CH2Cl2/CH3OH 100/1 (V/V).

Get 3 g of liquid oil.

B/ 3 Methanesulfonylaminoethyl-3-(3,4-dichlorophenyl)-1-benzoylpiperidine.

To 3 g obtained at the stage of A product, dissolved in 50 ml of methanol, add ether, saturated chloroethanol acid to pH 1. Stirred the reaction mixture for 30 min at ambient temperature and evaporated to dryness. Remove residue by 50 ml of dichloromethane and 1.07 g of triethylamine, then add 0,72 g methylchloride. Stirred at ambient temperature for 1 h, evaporated to dryness, extract the residue with ethyl acetate, washed with water and dried over Na2SO4filter and concentrate under vacuum. Purify the residue by chromatography on silica gel, eluent CH2Cl2/AcOEt 100/3 (on/about).

Get so 1.6 g of the expected product.

2SO4filter and concentrate under vacuum. Purify the residue by chromatography on silica gel, eluent CH2Cl2/CH3OH 100/5 (on/about). Concentrate the fractions of pure product, extracted with dichloromethane, receive hydrochloride in the addition of ether saturated with chloroethanol acid, evaporated to dryness, absorb residue with ethanol and precipitated in ether. Is filtered off, washed residue in pentane and dried under vacuum.

m=0,60,

TPL=184oC.

Example 28. Hydrochloride 5-[3-(4-hydroxy-4-phenyl-1-piperidinyl)-propyl]-5- (3,4-dichlorophenyl)-1-(3-methoxybenzyl)-piperidone

< / BR>
< / BR>
A/ 5-Tetrahydropyranyloxy-5-(3,4-dichlorophenyl)-1-(3-methoxybenzyl)-piperidin.

Added 0.66 g NaH with a concentration of 60% to a solution containing 6.4 g of 5-tetrahydropyranyloxy-5-(3,4-dichlorophenyl)-piperidine described in stage C of example 26, in 60 ml of dimethylformamide. Stirred the reaction mixture for 30 min at ambient temperature. Then add one drop of 2.5 g of 3-methoxybenzylamine and nagrevayut in dichloromethane, washed with water, dried over Na2SO4and evaporated to dryness.

Purify the resulting residue by chromatography on silica gel, eluent CH2Cl2/AcOEt 100/5 (on/about). Concentrate the fractions of pure product, resulting in a gain of 6 g of liquid oil.

B/ 5-(3-Hydroxypropyl)-5-(3,4-dichlorophenyl)-1-(3-methoxybenzyl)- piperidin.

Mix 6 grams obtained at the stage of A product, dissolved in 50 ml of methanol saturated with chloroethanol acid for 1 h at ambient temperature.

Is evaporated to dryness, resulting in a gain of 4.3 g of liquid oil.

C/ 5-Methanesulfonamido-5-(3,4-dichlorophenyl)-1-(3-methoxybenzyl)-piperidin.

Add to 1.14 g methylchloride to 4.3 g obtained in stage B of the product in the presence of 2 g of triethylamine dissolved in 50 ml of dichloromethane. Stirred the reaction mixture for 1 h at ambient temperature, evaporated to dryness, extract the residue in AcOEt, washed with water, saturated NaCl, dried over Na2SO4and evaporated to dryness.

Purify the resulting residue by chromatography on silica gel, eluent CH2Cl2/CH3OH 100/2 (on/about). The end of the
Within 2 h, heated at 80oC 4 g obtained in stage C of the product and 3.1 g of 4-hydroxy-4-phenylpiperidine dissolved in 5 ml of dimethylformamide. Cooled, poured to water, extracted by AcOEt, washed with water, dried over Na2SO4and evaporated to dryness. Remove the liquid oil ether and receive hydrochloride in the addition of ether saturated with chloroethanol acid. Filtered, washed with ether and dried under vacuum.

m=4,

TPL=110-117oC.

Example 29. Dichlorhydrate 3-[3-(4-hydroxy-4-phenyl-1-piperidinyl)-propyl] -3- (3,4-dichlorophenyl)-1-(3-methoxybenzyl)-piperidine

< / BR>
Add 2 g of 5-[3-(4-hydroxy-4-phenyl-1-piperidinyl)-propyl] -5- (3,4-dichlorophenyl)-1-(3-methoxybenzyl)-piperidone to the suspension containing 0,60 g of lithium aluminum hydride in 50 ml of tetrahydrofuran. Heated the reaction mixture for 1 h at ambient temperature, cooled, gidrolizuut under the action of 5 ml of water, filtered mineral precipitate and evaporated to dryness.

Purify the resulting residue by chromatography on silica gel, eluent CH2Cl2/CH3OH 100/5 (V/V), concentrated fractions of pure product and receive hydrochloride lolitat by filtration, washed with ether and dried under vacuum at P2O5.

m= 1.5,

TPL= 160-175oC.

Example 30. Dichlorhydrate 3-(4-hydroxy-4-phenyl-1-piperidinyl)-ethyl]-3- (3,4-dichlorophenyl)-1-benzylpyrrolidine

< / BR>
< / BR>
Conducting the synthesis in accordance with example 29, but on the basis of the product described in example 5, to obtain the expected product.

TPL= 170oC.

Example 31. Dichlorhydrate 3-[2-(4-benzyl-1-piperidinyl)-ethyl]-3-(1-naphthyl)- 1-benzylpiperidine

< / BR>
Conducting the synthesis in accordance with example 29, but on the basis of the product described in example 17, will receive the above connection.

TPL= 140oC.

Example 32. Hydrochloride 3-[2-(4-benzyl-1-piperidinyl)-ethyl]-3-(3,4-dichlorophenyl)-1- (3-isopropoxyphenyl)-acetylpiperidine (-)

< / BR>
< / BR>
I-obtaining optically pure amerosport.

A/ 3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl)-piperidine.

To 55 g of 3-tetrahydropyranyloxy-3-(3,4-dichlorophenyl)-piperidine, dissolved in 200 ml of methanol, add ether, saturated chloroethanol acid to pH 1. Stirred for 0.5 h at ambient temperature, concentrated to dryness, extract the residue with water, Podlachia>2SO4and evaporated to dryness. Obtain a liquid oil.

Extracted by 200 ml of isopropyl ether/ ether 50/50 (V/V). Stirred, filtered, washed with ether and dried under vacuum at P2O5.

m=45,

TPL=122oC.

B/ 3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl)-piperidine (+)

To 43 g obtained at the stage of A product, dissolved in 250 ml 100oth ethanol at a temperature of education phlegmy, add 23,54 g L-(+)-tartaric acid dissolved in 750 ml 100oon ethanol. Heat the reaction mixture at a temperature of education phlegmy within half an hour, allowed to return to ambient temperature, filtered, the obtained crystals are washed with 100o-m ethanol and dried under vacuum at 50oC at P2O5.

m=31,

Then recrystallized in 540 ml 100oon ethanol, filtered off, washed with ether and dried under vacuum at P2O5.

m=25,

()2D0= +8,5(c=1, H2O)

Then tartrate extracted with water, neutralized with NaOH solution, extracted with dichloromethane, washed with water, dried over Na2SO4and evaporated to dryness. Pollpri 50oC.

m=13,5,

TPL=138oC.

()2D0= +8,2(c=1, CH3OH)

C/ 3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl)-piperidine (-).

Carrying out the synthesis as described above, on the basis of D (-) tartaric acid, receive enantiomer (-).

TPL=139oC.

()2D0= -8,4(c=1, CH3OH)

II the connection 32.

A/ 3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl)-1-butylcarbamoyl.

To 13 g of 3-(2-hydroxy)-3-(3,4-dichlorophenyl)-piperidine (+), dissolved in 100 ml of dioxane, was added 12.4 g dicret. BUTYLCARBAMATE. Then stirred for 1 h at 40oC. Evaporated until dry, remove the residue with ether, washed with water, then buffer solution with pH 2 and finally with water. Dried over Na2SO4, filtered and evaporated to dryness. Purify the residue by chromatography on silica gel, eluent CH2Cl2/CH3OH 100/2) on/about). After concentration of the pure fractions thus receive the 16.7 g of the expected product in the form of butter.

B/ 3-Methanesulfonylaminoethyl-3-(3,4-dichlorophenyl)-1-tert. butylcarbamoyl.

To 16.5 g obtained at the stage of A product, dissolved in 100 poluchasa at ambient temperature, evaporated until dry, remove the residue in ether, washed with water, dried over Na2SO4and concentrate under vacuum. Get so 19 g of liquid oil.

C/ 3-2-(4-Benzyl-1-piperidinyl)-ethyl-3-(3,4-dichlorophenyl)-1-tert. butylcarbamoyl

Within 3 hours, heated at 80oC 18 g obtained in stage B of the product and 14 g of 4-benzylpiperidine dissolved in 40 ml of dimethylformamide. Then the dimethylformamide is evaporated, remove the residue in water, extracted with ether, washed with water, dried over Na2SO4and concentrate under vacuum. Purify the residue by chromatography on silica gel, eluent CH2Cl2/CH3OH 100/3 (on/about). Pure fractions are concentrated under vacuum.

m=15,

D/ Dichlorhydrate 3-[2-(4-benzyl-1-piperidinyl)-ethyl]-3-(3,4 - dichlorophenyl)-piperidine (-).

Mix 15 g obtained in stage C of the product, dissolved in 75 ml of methanol, 60 ml of concentrated chloroethanol acid and 15 ml of water at ambient temperature for 1 h Evaporated until dry, remove the remainder by 100 ml of dichloromethane and precipitated in ether. The precipitate is filtered off, washed with ether and dried under vacuum.

m=11,5,

TPL=1752SO4filter and concentrate under vacuum. Purify the residue by chromatography on silica gel, eluent CH2Cl2/CH3OH 100/5 (on/about). Pure fractions are concentrated under vacuum, the hydrochloride is obtained by processing CH2Cl2after addition of ether saturated with chloroethanol acid, evaporated to dryness, kristallisera in isopropyl ether, filtered, washed with ether and dried under vacuum.

m=11,4,

TPL=105oC.

()2D0= -2,9(c=1, CH3OH)

Example 33. Hydrochloride 3-[2-(4-benzyl-1-piperidinyl)-ethyl]-3-(3,4 - dichlorophenyl)-1-(3-isopropoxyphenyl)-acetylpiperidine (+)

< / BR>
Conducting the synthesis in accordance with example 32 and using as starting compound enantiomer 3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl)-piperidine ( - ) receive the above connection 33 in the form of enantiomer (+).

TPL=105oC.

()2D0= +3.0V(c=1, CH3OH).

Example 34. Hydrochloride 3-[2-(4-hydroxy-4-f who yl)-ethyl]-3-(3,4 - dichlorophenyl)-1-tert.butyl-carbamoylbiphenyl.

Within 2 h, heated at 80oC 0.9 g of 3-methanesulfonylaminoethyl-3-(3,4-dichlorophenyl)-1-tert. butyl-carbamoylbiphenyl obtained in accordance with stage B of example 32, and 0.88 g of 4-hydroxy-4-phenylpiperidine dissolved in 3 ml of dimethylformamide. Evaporated until dry, remove the residue in water, extracted by AcOEt, washed with water, saturated NaCl, dried over MgSO4and evaporated to dryness. Purify the residue by chromatography on silica gel, eluent CH2Cl2/CH3OH 100/2 (on/about). Concentrated pure fractions, resulting in a gain of 0.8 g of oil.

B/ 3-[2-(4-hydroxy-4-phenyl-1-piperidinyl)-ethyl]-3-(3,4 - dichlorophenyl)-piperidine.

Mix 0.8 g obtained at the stage of A product, dissolved in 5 ml of methanol, 4 ml of concentrated chloroethanol acid and 1 ml water for 1 h at ambient temperature. Then is evaporated to dryness and used the rest in this form, as he is in the next stage.

m=0,77,

C/ Connection 34.

To 0,77 g obtained in stage B of the product and 0.3 g of triethylamine dissolved in 30 ml of dichloromethane, was added 0.26 g of benzoyl chloride. Stirred the reaction mixture for 1 h at ambient temperature, viparis is Purified by chromatography on silica gel, eluent CH2Cl2/CH3OH 100/3 (on/about). Concentrated pure fractions, extracted in CH2Cl2and receive hydrochloride in the addition of ether saturated with chloroethanol acid. Is evaporated to dryness, the residue is crystallized in ether, filtered off, washed with ether and dried under vacuum.

m=0,2,

TPL=176oC.

()2D0= -32,0(c=1, CH3OH).

Example 35. Hydrochloride 3-[2-(4-hydroxy-4-phenyl-1-piperidinyl)-ethyl]-3-(3,4 - dichlorophenyl)-1-benzoylpiperidine (+)

< / BR>
Conducting the synthesis in accordance with example 34, from 3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl)-piperidine ( - ) receive the above enantiomer (+).

TPL=175oC.

< / BR>
Example 36. Iodide N(a)-methyl-3-[2-(4-benzyl-1-piperidinyl)-ethyl] -3-(3,4-dichlorophenyl)- 1-(3-isopropoxyphenyl)-acetylpiperidine

< / BR>
Mix 1 g of the product described in example 14 dissolved in 10 ml under the conditions for 24 h at ambient temperature. Then concentrate under vacuum. The remainder chromatographies on silica gel, eluent CH2Cl2/CH3OH 100/3 (on/about). First suirvey product corresponds to the compound, which the methyl on the nitrogen (b) 4-be/BR> Example 37. Iodide N(e)-3-[2-(4-benzyl-1-piperidinyl)-ethyl]-3-(3,4 - dichlorophenyl)-1-(3-isopropoxyphenyl)-acetylpiperidine

< / BR>
Resulting in the synthesis as in example 36, described above, and collecting the fraction loireau secondly, get a product with a methyl on the nitrogen (b) 4-benzylpiperidine is in the Equatorial position.

m=0,15,

An NMR spectrum13C:

< / BR>
Conducting syntheses according to examples 36 and 37 above, receive a Quaternary ammonium salt, described in table. 6.

Example 44. Chloride N (a)-methyl-3-[2-(4-benzyl-1-piperidinyl)-ethyl] -3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenyl)-acetylpiperidine (-)

< / BR>
A/ Obtaining iodide derivative.

Mixing 10 g described in example 32 product dissolved in 50 ml under the conditions, for 2 h at ambient temperature. Is evaporated to dryness and chromatographic the residue on silica gel: CH2Cl2/CH3OH - 100/3 (on/about). Conformer, which eluted first, corresponds to the compound, of which methyl is axial position when the nitrogen (in) 4-benzylpiperidine.

B/ Receiving chloride derivative.

Iodide ion is exchanged then the chloride ion in the elution of the product aqueous ammonium.

TPL103oC.

< / BR>
Example 45. Chloride N(a)-methyl-3-[2-(4-benzyl-1-piperidinyl)-ethyl]- 3-(3,4-dichlorophenyl)-1-(3-isopropoxyphenyl)-acetylpiperidine (+)

< / BR>
Conducting the synthesis method is identical to example 44, on the basis of the product described in example 33, the gain of 8.9 g of the expected salt of Quaternary ammonium.

TPL104oC.

()2D0= + 13,0(c=1, CH3OH)

Example 46. Iodide N(e)-methyl-3-[2-(4-benzyl-1-piperidinyl)-ethyl]-3-(3,4 - dichlorophenyl)-1-(3-isopropoxyphenyl)-acetylpiperidine (-)

< / BR>
< / BR>
Conducting the synthesis in accordance with example 44A and collecting the fraction loireau secondly, get enantiomer, in which the methyl on the nitrogen (in) 4-benzylpiperidine is in the Equatorial position. Get so 2.6 g Quaternary ammonium salt.

TPL110oC.

()2D0= -0,1(c=1, CH3OH)

Example 47. Iodide N(e)-methyl-3-[2-(4-benzyl-1-piperidinyl)-ethyl] - 3-(3,4-dichlorophenyl)-1-(3-isoproterenol)-acetylpiperidine (+)

< / BR>
Conducting the synthesis in accordance with example 46, on the basis of the product described in example 33, to receive the expected compound.

TPL110oC

(-3-(3,4-dichlorophenyl)- 1-(3-isopropoxyphenyl)-acetylpiperidine

< / BR>
Dissolve 2 g of the free base of the compound from example 14 in 20 ml of tetrahydrofuran. Added 1.1 g of metallocarboranes acid and stirred the reaction mixture for 2 h at ambient temperature. Concentrate under vacuum to a volume of size 5 ml and dilute the residue in 10 ml of dichloromethane. Washed twice, this solution is a saturated solution of NaHCO3, decanted, dried over MgSO4and concentrate under vacuum. Chromatografic the residue on silica gel, eluent CH2Cl2/CH3OH 100/5 (on/about). Concentrate the fractions of pure product under vacuum and kristallisera the residue in isopropyl ether.

m 1,47,

TPL135oC.

Example 49. Dichlorhydrate 3-[2-(4-benzyl-1-piperidinyl)-ethyl] -3-(3,4 - dichlorophenyl)-piperidine

Intermediate compound for the synthesis of formula (ll)

< / BR>
A/ 4-(4-benzyl-1-piperidinyl)-2-(3,4-dichlorophenyl)-butyronitrile

To 94 g of 3,4 dichlorobenzonitrile dissolved in 500 ml of anhydrous ether, is added in small portions to 23.5 g of sodium amide. Then stirred for 1 h at ambient temperature, then for 3 hours at a temperature of education phlegmy. Cool the mixture to 0oC and added drop by drop the environment, then heated for 3 hours at a temperature of education phlegmy. Cooled, poured to 600 ml of water, decanted organic phase, washed with water and extravert twice in 500 ml of 15% HCl solution. Mix the aqueous phase and precipitate the product as the hydrochloride. Filtered off, washed with water and dried under vacuum. The residue is recrystallized in 600 ml of isopropanol. Get thus 95,

The product is extracted in water and the solution neutralized with NaOH solution. Extract with ether, washed with water, dried over Na2SO4and evaporated to dryness. Obtain 87 g of oil.

B/ -[2-(4-benzyl-1-piperidinyl)-ethyl] g - cyano-3,4-dichlorobenzidine ethyl

Within 24 h, heated at 80oC 87 g described in stages a product, 28 g of ethyl acrylate and 2.5 ml of Triton B, dissolved in 45 ml of dioxin. Cooled, extracted with ether, washed with water, dried over Na2SO4and evaporated to dryness. Get 109,5 g butter.

C/ 5-[2-(4-benzyl-1-piperidinyl)-ethyl]-5-(3,4-dichlorophenyl)- piperidone.

Hydronaut 100 g obtained in stage B of the product, dissolved in 1.5 l of ethanol at 60oC and under atmospheric pressure in the presence of Raney Nickel. After absorbing the volume of hydrogen hoteltravel the same time, receive hydrochloride, which is recrystallized in 220 ml of isopropanol. Filtered and dried under vacuum. The product is extracted with water, neutralized with NaOH solution, extracted with ether and dried over Na2SO4. Obtain 44 g of oil.

D/ Connection 49.

Add one drop of 44 g obtained in stage C of the product, dissolved in 200 ml of tetrahydrofuran to the suspension containing 9.4 g of lithium aluminum hydride in 250 ml of tetrahydrofuran, which is heated to 60oC. Continue heating at a temperature of education phlegmy within 3 hours is Cooled with ice and add successively with 10 ml water, 10 ml of 4n NaOH and 30 ml of water. Filtered mineral precipitate and the filtrate is evaporated to dryness, extracted in dichloromethane and get harkirat. Evaporation to dryness, precipitated in powder form in pentane, filtered and dried under vacuum.

m 35,

TPL170oC.

Example 50. Hydrochloride 3-[2-(4-benzyl-1-piperidinyl)-3-(3,4-dichlorophenyl) -1-(2-phenyl-2-methoxy)-acetylpiperidine.

The least polar diastereoisomer.

< / BR>
Stirred for 2 h 1.5 g of the diamine obtained in example 49, 1.06 g of triethylamine, 0.55 g ()- methoxyphenylacetic acid and 1.6 g of BOP in 25 ml of dichloromethane. Evaporated douchetastic by chromatography on silica gel, eluent CH2Cl/CH3OH 100/0,5 (V/V). The product, which eluted first, is the expected connection. The fractions are concentrated under vacuum, extracted in CH2Cl2receive hydrochloride, evaporated to dryness, precipitated in powder form in pentane, filtered and dried under vacuum.

m 0,5 g

TPL134oC.

Example 51. Chargedat 3-[2-(4-benzyl-1-piperidinyl)-ethyl]-3 -(3,4-dichlorophenyl)-1-(2-phenyl-2-methoxy)-acetylpiperidine (most polar diastereoisomer).

< / BR>
Spend the synthesis according to example 50 and by elution with a mixture of CH2Cl2/CH3OH 100/2 (on/about), get the most polar diastereoisomer. Hydrochloride get in dichloromethane, evaporated to dryness, extracted in pentane.

m 0,50,

TPL118oC.

Conducting the synthesis in accordance with examples 50 and 51 receive a pair of diastereoisomeric 52, 53, 54, 55, 56, 57, described in table. 7.

Hydroxy-3-isopropoxyphenoxy acid used as a reactant to obtain the compounds of examples 56 and 57, which is a new product, can be obtained as shown below.

a-Hydroxy-3-isopropoxyphenoxy acid.

CO3then 60 ml of 2-iodopropane.

Heat the reaction mixture at 50oC for 18 hours the mixture prilisaetsa 2.5 l of water. Extracted with ether, washed with diluted NaOH solution, then with water. Dried over MgSO4, the solvent is evaporated, resulting in a gain of 53.5 liquid residue.

Stage 2.

Added 53 g of the product obtained in accordance with the previous stage 1, to a solution containing 38 g of sodium bisulfite in 120 ml of water. Stirred for 20 h, then at 20oC was added a solution containing a 44.2 g of potassium cyanide in 90 ml of water.

After 2 h, extracted with ether, washed with water, dried over MgSO4and the solvent is evaporated under vacuum. The remainder chromatographic on silica gel, eluent heptane/ethyl acetate 100/30 (on/about). Allocate 57 g of the product in the form of liquid oil.

Stage 3.

Added 46 g of the product obtained in accordance with the previous stage 2, to 50 ml of water and 50 ml of concentrated HCI. Heated at 110oC for 1 h, After cooling, extracted with ether, washed with water. The acid is extracted with dilute NaOH solution. Acidifying the aqueous phase is extracted with ether, dried over MgSO4that is evaporated Rast 3-[2-(4-benzyl-1-piperidinyl)-ethyl]-3 -(3,4-dichlorophenyl)-1-[2-(3-chlorophenyl)-2-hydroxy]-acetylpiperidine (+)

< / BR>
< / BR>
Stirred for 2 h 0,67 g dichlorhydrate 3-[2-(4-benzyl-1-piperidinyl)-ethyl] -3-(3,4-dichlorophenyl)-piperidine (-), described in stage 1 of example 32, 0.17 g of triethylamine, 0.32 g of S-(+)- alpha-hydroxy-3-chlorophenylalanine acid and 0.82 g of BOP, dissolved in dichloromethane. Evaporated until dry, absorb residue with ethyl acetate, washed with water, dried over Na2SO4concentrate under vacuum. Purify the residue by the method chromatographie on silica gel, eluent CH2Cl2/CH3OH 100/1,5 (V/V). Concentrated pure fractions under vacuum, extracted into dichloromethane, receive hydrochloride, is evaporated to dryness and extracted with pentane. Filtered, washed with ether and dried under vacuum.

m 0,40,

TPL122oC.

< / BR>
Example 59. Hydrochloride 3-[2-(4-benzyl-1-piperidinyl)-ethyl]-3 -(3,4-dichlorophenyl)-1-[2-(3-chlorophenyl)-2-hydroxy]-acetylpiperidine (-)

< / BR>
< / BR>
Conducting the synthesis in accordance with example 58, from 3-[2-4(benzyl-1-piperidinyl)-ethyl] 3-(3,4-dichlorophenyl)-piperidine (+), obtained in accordance with stage I of example 32, from 3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl)-piperidine (-), described in stage C of obtaining optically pure amerosport, when interacting with R (-) -hydroxy.

()2D0= -74 (c =1, CH3OH)

Example 60. Hydrochloride 3-[2-(4-benzyl-1-piperidinyl)-ethyl]-3-(3,4-dichlorophenyl)- 1-[2-(3-chlorophenyl)-2-hydroxy]-acetylpiperidine (-)

< / BR>
Stirred at ambient temperature for 2 h to 0.67 g of 3-[2-(4-benzyl-1-piperidinyl)-ethyl] -3-dichlorophenyl)-piperidine (-), 0.32 g of R (-) -hydroxy-3-chlorophenylalanine acid, 0.17 g of triethylamine and 0.82 g of BOP, dissolved in 50 ml of dichloromethane. Then, carrying out the synthesis as in example 58, you get the expected product.

m=0,40,

TPL=128oC.

< / BR>
Example 61. Hydrochloride 3-[2-(4-benzyl-1-piperidinyl)-ethyl]-3-(3,4 - dichlorophenyl)-1-[2-(3-chlorophenyl)-2-hydroxy]-acetylpiperidine (+)

< / BR>
Conducting the synthesis in accordance with example 58, on the basis of S (+) -hydroxy-3-chlorophenylalanine acid and 3-[2-(4-benzyl-1-piperidinyl)-ethyl] -3-(3,4-dichlorophenyl)-piperidine (+), obtained according to stage D of example 32 and on the basis of 3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl)-piperidine (-), described in stage C of obtaining optically pure amerosport receive the expected product.

m=0,4,

TPL=127oC.

()2D0= +35(c=1, CH3OH)

All examples are given in the table. 8.


m is 2 or 3;

Ar' is phenyl, substituted by stands or two halogen atoms, or naphthyl;

n 0 3 integer;

p is 1 or 2, provided that when p is 2, n is 1 and Q is two hydrogen atoms;

Q is oxygen or two hydrogen atoms;

T group selected from-C(O)- and-CH2-;

q is 0 or 1;

Z is phenyl, which may be single - or Disaese1- C4-alkoxygroup or halogen, or monohalogenated naphthyl, with the proviso that when T is a group-C(O) - (CH2)qZ can represent a benzyl group which is substituted in the aliphatic residue of a hydroxyl,1WITH4-alkoxygroup or1- C4the alkyl and possibly substituted on the aromatic cycle by halogen or C1WITH4-alkoxygroup,

or their salts with mineral or organic acids, or Quaternary ammonium salt or N-oxide derivatives with respect to nitrogen (b)of piperidine.

2. Optically pure polycyclic amino compounds compounds of General formula I*< / BR>
< / BR>
where*the carbon atom having a specific absolute configuration of (+) or (-);

Y, m, Ar', n, p, Q, T, q and Z have the meanings indicated in the e-derived nitrogen (b)of piperidine.

3. Connection under item 1 or 2 of the General formula I or I*where Y group

< / BR>
Ar, x, X, m, Ar', n, p, Q, T, q and Z have values under item 1,

in the form of a Quaternary ammonium salt or N-oxide derived nitrogen (b)of piperidine, where the group

represents a group

< / BR>
where Aanion selected from among chloride, bromide, iodide, acetate, methanesulfonate or paratoluolsulfonata;

Q1C1C6-alkyl or benzyl.

4. The method of obtaining polycyclic aminecontaining compounds of formula I on p. 1, characterized in that a) a compound of General formula II

< / BR>
where m, Ar', n, p and Q defined in paragraph 1;

E. hydroxyl or if necessary On a protected group, such as tetrahydropyranyl-2-oxygraph or group

< / BR>
where Y group

< / BR>
where X is a hydroxyl or protected hydroxyl,

process or functional derivatives of the acid of General formula III

< / BR>
where q and Z are defined in paragraph 1,

to obtain the compounds of formula I, where T is the group-C(O)-, or a halogenated derivative of General formula IV

Hal-(CH2)q+1-Z

where q and Z are defined in paragraph 1;

Hal is halogen, preferably bromine or chlorine,

to obtain the compounds of formula I, where T gruppem tetrahydropyranyloxy under the action of acid, (C) the resulting alcohol of General formula VI

< / BR>
treated with methanesulfonamide, d) the resulting product of General formula VIII

< / BR>
treated with a secondary amine of General formula VIII

< / BR>
where Y is defined in paragraph 1,

e) after, if necessary, remove protection from hydroxyl X transform, if necessary, the resulting product into one of its salts with a mineral or organic acid, or Quaternary ammonium salt or N-oxide derived nitrogen (b)of piperidine.

5. Cyclic amino compounds compounds of General formula II

< / BR>
where m, Ar', n, p and Q defined in paragraph 1;

E. hydroxyl or perhaps On a protected group, such as tetrahydropyranyl-2-oxygraph or group

< / BR>
provided that if E is hydroxyl, m 2, n 1, p 1 and Ar' is 3,4-dichlorophenyl or 4-were, then Q is oxygen.

6. Connection on p. 5, a 5-tetrahydropyranyloxy-5-(3,4-dichlorophenyl)piperidine, 3 - tetrahydropyranyloxy-3-(3,4-dichlorophenyl)piperidine, 3-(2 - hydroxyethyl)-3-(3,4-dichlorophenyl)piperidine.

7. Cyclic amino compounds compounds of General formula V

< / BR>
where E is hydroxyl or a protected group, such as 2-tetrahydropyranyloxy, or suspended or organic acids.

8. Cyclic amino compounds compounds of General formula VI

< / BR>
where m, Ar', Q, n, p, T, q and Z are defined in paragraph 1,

or their salts with mineral or organic acids.

9. Cyclic amino compounds compounds of General formula VII

< / BR>
where m, Ar', n, p, Q, T and Z are defined in paragraph 1,

or their salts with mineral or organic acids.

10. Optical pure cyclic amino compounds compounds of General formula II*< / BR>
< / BR>
where m, Ar', n, and p are defined in paragraph 1;

Q is hydrogen,

C*the carbon atom having the absolute configuration of (+) or (-).

11. Connection on p. 10, predstavlyayushie a (+)- 3-(2-peroxyacyl)-3-(3,4-dichlorophenyl)piperidine or (-)- 3-(2-hydroxyethyl)-3-(3,4-dichlorophenyl)piperidine.

12. Optically pure cyclic amino compounds compounds of General formula V*< / BR>
< / BR>
where G is hydrogen or methanesulfonyl group;

Q is hydrogen;

m, Ar', n, p, q, T, Z and C*have the specified values.

13. Pharmaceutical composition having antagonistic activity to the receptor neirokinina containing the active principle and a pharmaceutically acceptable excipients, characterized in that the active agent it contains polyclonal, or Quaternary salt ammonia or N-oxide derived nitrogen (b)of piperidine in an effective amount.

 

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The invention relates to organic synthesis and relates to new quinoline derivatives and method of production thereof

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, namely, to derive a cyclic amide of the formula I

R1-(CH2)n-Z,

where R1group cyclic amide, such as 2H-3,4-dihydro-1,3-benzoxazin-2-she, 2H-3,4-dihydro-1,3-benzoxazin-2,4-dione, and 1,2,3,4-tetrahydroquinazoline-2,4-dione, and 1,2,3,4-tetrahydroquinazolin-2-it, 1,2,3,4-tetrahydropyrido(3,2-d)-pyrimidine-2,4 - dione, and 1,2,3,4-tetrahydropyrido(3,2-d)pyrimidine-2-it, 1,2,3,4-tetrahydropyrimidine-2,4-dione, pyrrolidin-2-it, 1,2,3,4 - tetrahydropyridine-2-it, 5H-6,7,8,9-tetrahydropyrido(3,2-b)azepin-6-she N-5,6,7,8-tetrahydropyrido(2,3-b)azepin - 8-she, 2H-3,4-dihydropyrido(2,3-e)-1, 3-oxazin-2-thione or 2-she pyrrolidine (3,4-b)-pyrazin-5-she 1H-2,3,4,5-tetrahydrothieno(2,3-b)indol-2-it, 8H-4,5,6,7-tetrahydrothieno(2,3-b)thiophene-7-she 4H-pyrazolo(5,4-f)benzazepin-9-it, isoindoline-1,3-dione, benzoxazolyl-2-it, unsubstituted or substituted lower alkyl, lower alkoxy, halogen, the nitro-group, carboxy, benzoyl or benzyl, n is zero or an integer from 1 to 6, Z is a group of formula (A) or (B):

N-(CH2)mR2(A) or -(CH2)p, dioxolane, furan, tetrahydrofuran, methylfuran or thiophene, m is an integer from 1 to 3; R3is lower alkyl; R4is phenyl or a radical of dioxolane, furan or thiophene, p = 1, provided that when R1radical 1,2,3,4-tetrahydrobenzo-2-or 1,2,3,4-tetrahydroquinazoline-2,4-dione, R2and R4are not phenyl or substituted by a halogen phenyl, or their pharmacologically acceptable salts with antiacetylcholinesterase activity

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)6-cyano-3,4-dihydro-2,2 - dimethyl-trans - 4-(2-oxo-1-pyrrolidinyl) -2h-1-benzopyran-3-ol" target="_blank">

The invention relates to organic synthesis and concerns a method for obtaining derived benzopyran representing () -6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo-pyrrolidinyl)-2H - 1-benzopyran-3-ol of the formula VI

known as Cromakalim (DRL 34 915)

The invention relates to new cyclic imino-derivatives of General formula

In X And Y E (I) where a 2-pyrrolidinone or pyrrolin-2-it, unsubstituted or substituted residues R1and R2where R1means phenyl, unsubstituted or substituted by carboxyla, methoxycarbonyl, aminocarbonyl, methylaminoethanol, ethylaminoethanol, dimetilaminoflavonola, methanesulfonylaminoethyl or acetaminophe, alkyl with 1-4 carbon atoms, substituted by two phenyl groups, cyclohexyl, naptalam or phenyl, unsubstituted or substituted by fluorine, chlorine, bromine, hydroxyl, alkyl with 1-4 carbon atoms, alkoxyl with 1-4 carbon atoms, phenyl, vinylmation, benzyloxypropionic, methylsulfinyl, methylsulfonyl, trifluoromethyl, two chlorine atoms, two metaxylene groups, alkyl with 1-4 carbon atoms, unsubstituted or substituted by hydroxyl, metaxylem or fenoxaprop, moreover, these substituents are not in the position I, if R1linked to the nitrogen atom of the cycle And; methyl, substituted vinyl, carboxyla, methoxycarbonyl, aminocarbonyl, methylaminoethanol, ethylaminoethanol, dimetilaminoflavonola, benzylaminocarbonyl, pyrrolidinecarbonyl, piperidyl, methylaminopropane, arylaminopoly, AMI - nomation, dimethylaminopropoxy, carboxyla, methoxycarbonyl or dimetilaminoflavonola, if R1not linked to the nitrogen atom of the cycle; or sulfonyl, replaced by stands, dimethylaminopropoxy, phenyl or methoxyphenyl, if R1not linked to the carbon atom adjacent to the nitrogen atom of the cycle A, R2alkyl with 1-4 carbon atoms, unsubstituted or substituted phenyl;

In amino, aminomethyl and amidino, unsubstituted or substituted with one nitrogen atom by a benzyl, hydroxyl, methoxy group, cyano, one or two alkyl groups with 1-4 carbon atoms, alkoxycarbonyl with the total number of carbon atoms 2-5, benzyloxycarbonyl, phenoxycarbonyl or benzoyl, or two atoms of nitrogen amidinopropane linked using ethylene group, cyano, trimethylammonio, guanidino or guanidinate;

Y-E nonbranched alkyl with 2-5 carbon atoms, substituted carboxyla, methoxycarbonyl or stands, substituted vinyl, allyl, 1,2-Diocletian, carboxyla, phosphonopropyl, 0-methylphosphono, 0,0-dimethylphosphoric, oximation, alkoxycarbonyl with the total number of 2-7 carbon atoms, dimethylaminocarbonylmethyl is 1-3 carbon atoms in the CNS group, whereby phenyl may be substituted by one or two metaxylene groups, pyridinedicarboxylate, aminocarbonyl, unsubstituted or substituted by alkyl with 1-4 carbon atoms, biphenyloxy, replaced by carboxyla, carboxymethyl or methoxycarbonylmethyl, and the shortest distance between these substituents and the first nitrogen atom of the residue is at least 10 links;

X group of the formula

-X1X2X3X4X5where X1means a bond, methylene or ethylene, and if methylene not linked to the nitrogen atom of the cycle And then between the methylene and related balance X2may contain oxygen atom or sulfur, sulfonyl imino, -N(COCH3)-, -N(SO2CH3)-, -N(benzyl)-, -СОNH-, -NH-CO - or-NH-SO2- or between methylene and related balance X2can be imino, -N(benzyl) -, or-NH-CO-, and X1associated with the remainder of a, And X5with the rest IN;

X2nonbranched alkylen with 2-4 carbon atoms, albaniles with 2 or 3 carbon atoms and the double bond must not be adjacent to the heteroatom, phenylene, unsubstituted or substituted by fluorine, chlorine, bromine, stands, ethyl, trifluoromethyl, nitro-group, acetaminophe, meansville with 4-7 carbon atoms or bicycloalkyl to 7 carbon atoms;

X3bond, -CO-, -CO-NH -, or-NHCO-, if X3not directly followed by a heteroatom or a triple bond balance, and CO -,- CONH - and-NHCO - may not be adjacent to an aliphatic double bond of residue X2or an oxygen atom, sulfenyl, sulfinil, sulfonyl, oxymethylene, imino or sulfonylamino, if X2no aliphatic double bond at the end and for X3not directly followed by a heteroatom or a saturated carbon atom of the residue IN;

X4communication, the unbranched alkylene with 1-5 carbon atoms, phenylene, unsubstituted or substituted by fluorine, chlorine or stands, cycloalkyl with 4-7 carbon atoms;

X2together with X3and X4forms the unbranched alkylene with 3-6 carbon atoms, phenanthrene and naftilan, which may be fully or partially gidrirovanny, fluorenyl, in which the methylene may be replaced by oxymethylene or carbonyl, indaniel, endangerment or serialkiller from 8 to 11 carbon atoms;

X5link

) 6-cyano-3,4-dihydro-2,2 - dimethyl - trans-4- (2 - hydroxy-1 - pyrrolidinyl) -2h-1 - benzopyran-3 - ol" target="_blank">

The invention relates to organic synthesis and concerns a method for obtaining ()-6-cyano-3,4-dihydro-2,2-dimethyl-TRANS-4-(2-oxo - 1-1-pyrrolidinyl)-2H-1-benzopyran-3-ol formula

(I) known as Cromakalim
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