Peralkaline derivatives of nitrogen-containing heterocycles, pharmaceutical composition, method of inhibiting the action of substance p in a mammal

 

(57) Abstract:

The invention relates to new pcoralcalciumonline derived nitrogen-containing heterocyclic compounds, in particular compounds of formula I listed in the description. These new compounds are used for the treatment of inflammatory diseases and disorders of the Central nervous system and other disorders. 3 C. and 25 C.p. f-crystals, tabl.

The invention relates to new pcoralcalciumonline derived nitrogen-containing heterocycles, pharmaceutical compositions containing such compounds and for using such compounds for the treatment and prevention of inflammatory processes and the disorder of the Central nervous system and other disorders. Pharmaceutically active compounds according to the invention are antagonists of the receptors for substance P. the Invention relates to new intermediate compounds used in the synthesis of such receptor antagonists R.

Substance P is a natural undecapeptide belonging to the family of tachykinin peptides, the name of which reflects their stimulating effect on tissue smooth muscle. More specifically, substance P is farmakologicheski characteristic amino acid sequence, as described in the work of D. F. Weber and others, U.S. Patent N 4680283. The active role of substance P and other tachykinins in the pathophysiology of various diseases is well known. For example, substance P, as shown by recent research, is involved in transmitting pain or migraine (B. E. B. Sandberg and others, "Journal of Medical Chemistry, 25, 1009, 1982), and also plays a role in such disorders of the Central nervous system, as anxiety and schizophrenia, in respiratory and inflammatory processes, such as asthma and rheumatoid arthritis, rheumatic diseases, such as fibrosis and gastrointestinal disorders and diseases of the gastrointestinal tract, such like ulcerative colitis and Crohn's disease, etc., (D. Regoli, "Trends in Cluster Headache". Ed. by F. Security and others, "Elsevier saintifik publishers, Amsterdam, S. 85 - 95, 1987).

Recently, attempts were made to obtain antagonists of substance P and other tachykinins peptides that would better treat various disorders and diseases listed above. Some of these antagonists described in the literature have, in General, the nature of the peptides and therefore from the point of view of metabolism, are too unstable to be used in quality is Tim lack, being much more stable from the point of view of metabolism than the above-mentioned agents.

Derivatives of hinoklidina and related compounds active as antagonists of the receptor for substance P, described in the patent Application PCT/US89/05338, registered on 20 November 1989 and in the Application for U.S. patent ser. N 557442, registered on 23 July 1990, Both applications are related to this application.

Similar compounds mentioned in the patent Applications PCT /US91/ 02853 and N PCT /US91/03363, registered on April 25, 1991 may 15, 1991, respectively. These applications also are related to this application.

Derivatives of piperidine derivatives and related heterocyclic nitrogen-containing compounds used as antagonists of substance P, referred to in the Application for U.S. patent ser. N 619361, registered on November 28, 1990, and in the Application for U.S. patent ser. N 590423 registered on September 28, 1990 Both applications are related to this application.

The invention relates to compounds of the formula I

< / BR>
where

X1represents hydrogen, C1-C10-alkoxy, possibly substituted by one to three fluorine atoms, or C1-C10-alkyl, possibly substituted SUB>10-alkyl, possibly substituted by one to three fluorine atoms, C1-C10-alkoxy, possibly substituted by one to three fluorine atoms, trifloromethyl, hydroxy, phenyl, cyano, amino, C1-C6-alkylamino, di-C1-C6-alkylamino, - -NH-C1-C6-alkyl, C1-C6-alkyl-NH-C1-C6-alkyl, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkyl, and-C1-C6-alkyl;

Q represents a group of formulae II-VIII

< / BR>
where

R1represents a radical selected from the group comprising furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl, possibly substituted by one or two substituents, independently selected from halogen, C1-C10-alkyl, possibly substituted by one to three fluorine atoms, C1-C10-alkoxy, possibly substituted by one to three fluorine atoms, carboxy, benzyloxycarbonyl and C1-C3-alkoxycarbonyl;

R13choose from branched C3-C4-alkyl, branched C5-C6-alkenyl, C5-C7-cycloalkyl and radicals listed in R1;

R2represents hydrogen or C1-C6-alkyl;

RZamestitelyami, independently selected from halogen, C1-C10-alkyl, possibly substituted by one to three fluorine atoms, and C1-C10-alkoxy, possibly substituted by one to three fluorine atoms;

Y - (CH2)lwhere l is an integer from one to three, or Y represents a group of formula IX

< / BR>
Z is oxygen, sulfur, amino, C1-C3-alkylamino or (CH2)nwhere n is an integer of 0,1 or 2;

O = two or three;

p = 0 or 1;

R4represents furyl, thienyl, pyridyl, indolyl, biphenyl or phenyl, possibly substituted by one to three substituents, independently selected from halogen, C1-C10-alkyl, possibly substituted by one to three fluorine atoms, C1-C10-alkoxy, possibly substituted by one to three fluorine atoms, carboxy, C1-C3-alkoxycarbonyl and benzyloxycarbonyl;

R5- thienyl, biphenyl or phenyl, possibly substituted by one to three substituents, independently selected from halogen, C1-C10-alkyl, possibly substituted by one to three fluorine atoms, and C1-C10-alkoxy, possibly substituted by one to three fluorine atoms;

each of the two dotted lines in formula I and dotted linstaller a group of formula II;

X represents (CH2)qwhere q is an integer 1 to 6, and where any one of the simple relations of the carbon-carbon bonds in the specified (CH2)qmay be substituted on the double bond carbon-carbon, and where one of the carbon atoms in the specified (CH2)qcan be substituted for R8and where any of the carbon atoms in the specified (CH2)qcan be substituted for R9;

m is an integer of 0 to 8, and any of the simple relations of the carbon-carbon (CH2)mcan be replaced with a double bond of carbon-carbon or carbon triple bond, and any one of carbon atoms in (CH2)mcan be substituted for R11;

R6represents a radical selected from hydrogen, C1-C6-alkyl straight or branched chain, C3-C7-cycloalkyl, where one of the carbon atoms may be replaced by nitrogen, oxygen or sulfur, aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from tanila, furil, pyridyl, thiazolyl, isothiazoline, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and chinoline; phenyl-C2-C6-alkyl, benzhydryl and benzyl, where each of these analnyj and heteroaryl groups and the phenyl fragments of these Benito selected from halogen, nitro, C1-C10-alkyl, possibly substituted by one to three fluorine atoms, C1-C10-alkoxy, possibly substituted by one to three fluorine atoms, amino, hydroxy, C1-C6-alkyl, C1-C6-alkoxy, C1-C6-alkyl, C1-C6-alkylamino, C1-C6-alkyl-O -, C1-C6-alkyl-O - C1-C6-alkyl, C1-C6-alkyl-O, C1-C6-alkyl, C1-C6-alkyl, C1-C6-alkyl-O, C1-C6-alkyl, C1-C6-alkyl- -C1-C6-alkyl-, CI-C1-C6-alkylamino, - -C1-C6-alkyl, C1-C6-alkyl-NH-C1-C6-alkyl, -C1-C6-alkyl; and where one of the phenyl fragments specified benzhydryl can be replaced by naphthyl, teinila, fullam or pyridium;

R7represents hydrogen, phenyl or C1-C6-alkyl; or R6and R7together with the carbon to which they are attached, form a saturated carbocyclic ring having 3 to 7 carbon atoms, where one of the carbon atoms may be replaced by oxygen, nitrogen or sulfur;

R8and R9each independently selected from hydrogen, hydroxy, halogen, amino, oxo (=O) -alkylamino, di-C1-C6-alkylamino, C1-C6-alkoxy, C1-C6- -, C1-C6- alkyl-O- -C1-C6-alkyl, C1-C6-alkyl-O-, C1-C6-alkyl- -C1-C6-alkyl-O-, C1-C6-alkyl, C1-C6-alkyl- -C1-C6-alkyl-, and the radicals listed in R6;

R10represents the NHCR12, NHCH2R12, NHSO2R12or one of the radicals listed in any of the R6, R8and R9;

R11- oximino (=NOH) or one of the radicals listed in any of the R6, R8and R9;

R12- C1-C6is alkyl, hydrogen, phenyl-C1-C6-alkyl or phenyl, possibly substituted C1-C6-alkyl; provided that (a) when m is 0, R11no, b) none of the R8, R9, R10and R11may not form together with the carbon to which it is attached, a ring with R7c) when Q represents a group of formula VIII, R8and R9can not be attached to the same carbon atom, d) when R8and R9attached to the same carbon atom, any one of the radicals R8and R9chosen independently from bodoro is 6-alkyl, or R8and R9together with the carbon atom to which they are attached, form a C3-C6-saturated carbocyclic ring that forms spirochaetaceae with the nitrogen ring to which they are attached, (e) the nitrogen of formula I cannot be connected by a double bond with Q and a substituted benzyl group, to which it is attached, f) when Q represents a group of formula VII and q) is 2 and any R8and R9represents 5-hydroxy-C1-C6-alkyl or 5-C1-C6-alkoxy-C1-C6-alkyl, the other of the radicals R8and R9is either 5-C1-C6is alkyl or hydrogen, g) when Q represents a group of formula VII, and q is 2, then none of R8and R9is not 4-hydroxy-C1-C6-alkyl or 4-C1-C6-alkoxy-C1-C6-alkyl, h) when none of X1X2or X3is not fluorinated CNS group, at least one of R1, R3, R4, R5, R6, R7and R13represents an aryl group, a substituted fluorinated CNS group.

The invention also relates to pharmaceutically acceptable mimih salts of the basic compounds according to the invention using the acid, which form non-toxic salts, i.e. salts containing pharmaceutically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, skalnat, maleate, fumarate, gluconate, saharat, benzoate, methanesulfonate, aconsultant, bansilalpet, p-toluensulfonate and pamoat /i.e., 1,1'-methylene-bis-(2-hydroxy-3-aftout)/.

The term "halogen" in the text refers to chlorine, fluorine, bromine and iodine.

The term "alkyl" in the text refers to saturated monovalent hydrocarbon radicals with a straight or branched chain or cyclic fragments, or combinations thereof.

The term "one or more substituents" in the text means from one to the maximum possible number of substituents, which depends on the number of available binding sites.

Preferred compounds of formula I are compounds where R1, R4, R5and R7represent phenyl, R2is hydrogen, R3represents phenyl, possibly substituted by chlorine, fluorine, C1-C6-alkyl, possibly substituted by one to three fluorine atoms, or C1-C6-alkoxy, perhaps samewe the formula I are the following:

(2S, 3S)-3-(5-tert-butyl-2-methoxybenzyl)amino-2-(3-triptoreline-phenyl)piperidine;

(2S,3S)-3-(2-isopropoxy-5-cryptomaterial)amino-2-phenyl-piperidine;

(2S,3S)-3-(2-ethoxy-5-cryptomaterial)amino-2-phenyl-piperidine;

(2S,3S)-3-(2-methoxy-5-cryptomaterial)-amino-2-phenyl-piperidine;

(2S,3S)-3(5-tert-butyl-2-cryptomaterial)amino-2-phenyl-piperidine;

2-(diphenylmethyl)-N-(2-methoxy-5-trifloromethyl)methyl-1-azabicyclo [2.2.2]Octan-3-amine;

(2S, 3S)-3-[5-chloro-2-(2,2,2-triptoreline)-benzyl] amino-2-phenyl-piperidine;

(2S,3S)-3-(5-tert-butyl-2-cryptomaterial)amino-2-phenyl-piperidine;

(2S,3S)-3-(2-isopropoxy-5-cryptomaterial)amino-2-phenyl-piperidine;

(2S, 3S)-3-(2-deformedarse-5-cryptomaterial)-amino-2-phenylpiperidine;

(2S,3S)-2-phenyl-3-[2-(2,2,2-triptracker)aminopiperidin;

(2S,3S)-2-phenyl-3-(2-cryptomaterial)]aminopiperidin.

Other compounds of formula I include:

3-[N-(2-methoxy-5-cryptomaterial)amino] -5,5-dimethyl-2-phenylpyrrolidine;

3-[N-(2-methoxy-5-cryptomaterial)amino] -4,5-dimethyl-2-phenylpyrrolidine;

3-(2-cyclopropylamino-5-cryptomaterial)amino-2-phenyl-piperidine;

3-(2-cyclopropylmethoxy-5-cryptomaterial)aminodiphenylamine)amino-2-phenylpiperidine;

3-(2-methoxybenzyl)amino-2-(3-trifloromethyl)-piperidine;

3-(2-methoxy-5-cryptomaterial)amino-2-(3-trifloromethyl)piperidine;

2-phenyl-3-(5-n-propyl-2-triptoreline)aminopiperidin;

3-(5-isopropyl-2-cryptomaterial)amino-2-phenylpiperidine;

3-(5-ethyl-2-cryptomaterial)amino-2-phenylpiperidine;

3-(5-sec-butyl-2-cryptomaterial)amino-2-phenylpiperidine;

3-(5-deformedarse-2-methoxybenzyl)amino-2-phenylpiperidine;

3-(2-methoxy-5-cryptomaterial)amino-2-phenylpyrrolidine;

3-(2-methoxy-5-cryptomaterial)amino-2-vanillaoption;

2-benzhydryl-3-(2-methoxy-5-cryptomaterial)aminopyrrolidine;

2-benzhydryl-3-(2-methoxy-5-cryptomaterial)aminoguanidine;

3-[2,5-bis-(2,2,2-triptoreline)benzyl]amino-2-phenylpiperidine;

2-phenyl-3-(3-cryptomaterial)aminopiperidin;

2-benzhydryl-3-(2-methoxy-5-cryptomaterial)aminopiperidin;

1-(5,6-divergences)-3-(2-methoxy-5-cryptomaterial)amino-2-phenylpiperidine;

1-(6-hydroxyhexyl)-3-(2-methoxy-5-cryptomaterial)amino-2-phenylpiperidine;

3-phenyl-4-(2-methoxy-5-cryptomaterial)amino-2-azabicyclo[3.3.0] octane;

4-benzhydryl-5-(2-methoxy-sabillo[4.4.0] decane;

2-phenyl-3-(2-methoxy-5-cryptomaterial)aminoquinuclidine;

8-benzhydryl-N-(2-methoxy-5-cryptomaterial)-9-azatricyclo [4.3.1.04,9]decane-7-amine;

9-benzhydryl-N - (2-methoxy-5-cryptomaterial)-10-azatricyclo [4.4.1.05,10]undecane-8-amine;

9-benzhydryl-N-(2-methoxy-5-cryptomaterial)-3-thia-10-azatricyclo[4.4.05,10]undecane-8-amine;

8-benzhydryl-N-(2-methoxy-5-cryptomaterial)-9-azatricyclo [4.3.1.04,9]decane-7-amine;

5,6-pentamethylene-2-benzhydryl-3-(2-methoxy-5-cryptomaterial) aminoquinuclidine;

5,6-trimethylene-2-benzhydryl-3-(2-methoxy-5-cryptomaterial)- aminoquinuclidine;

9-benzhydryl-N-((2-methoxy-5-trifloromethyl)-methyl)-3-oxa-10 - azatricyclo[4.4.05,10]undecan-3-amine;

8-benzhydryl-N-((2-methoxy-5-trifloromethyl)-methyl)-7-azatricyclo [4.4.1.05,10]undecane-9-amine;

2-benzhydryl-N-((2-methoxy-5-trifloromethyl)methyl)-1-azabicyclo [3.2.2]nonan-3-amine.

The invention relates also to the compound of the formula

< / BR>
where

R14represents triptoreline or deformedarse;

R15represents a C1-C4-alkyl;

R16- deformedarse or C1-C4-alkyl;

R17- Tr is worn also to pharmaceutical compositions for the treatment or prevention of inflammation, (for example, arthritis, psoriasis, asthma and inflammatory bowel disease), States of anxiety, depression or estimatesa disorders, colitis, psychosis, pain, gastroesophageal reflux, allergies such as eczema and rhinitis, chronic airway obstruction, hypersensitivity, vasospastic diseases such as angina, migraine and Raynaud's disease, fibrosis and collagen diseases such as sclerodermataceae and eosinophilic fascioliasis, degeneration of sympathetic reflexes, such as the brachial syndrome, alcoholism, somatic disorders caused by stress, peripheral neuropathy, neuralgia, neurotic diseases disorders such as Alzheimer's disease, dementia caused by AIDS, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or weakening, such as systemic lupus erythematosus, and rheumatic diseases such as fibrosis in mammals, including humans, including a certain number of compounds of formula I or pharmaceutically acceptable salt of this compound, sufficient for effective treatment or prevention of such diseases, and pharmaceutically-acceptable carrier.

Izobretena, arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depressive or estimatesa disorders, colitis, psychosis, pain, gastroesophageal reflux, allergies such as eczema and rhinitis, chronic airway obstruction, hypersensitivity, vasospastic diseases such as angina, migraine and Raynaud's disease, fibrosis and collagen diseases, such as sclerodermataceae and eosinophilic fascioliasis, degeneration of sympathetic reflexes, such as the brachial syndrome, alcoholism, somatic disorders caused by stress, peripheral neuropathy, neuralgia, neurotic diseases disorders such as Alzheimer's disease, dementia, caused by AIDS, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement and weakening, such as systemic lupus erythematosus, and rheumatic diseases such as fibrosis in mammals, including humans, which is that specified mammal appoint a certain number of compounds of formula I, or pharmaceutically acceptable salt of this compound, sufficient for effective treatment or prevention of a pathological state.

The invention relates also to a method of providing antagonism of the effects of substance P in the body of a mammal, including humans, which includes the purpose specified mammal the compounds of formula I in an amount to provide the antagonism of substance P, or a pharmaceutically acceptable salt of this compound.

The invention relates also to pharmaceutical compositions for the treatment or prevention of disorders in mammals, including humans, resulting from an excess of substance P, which includes a compound of formula I or pharmaceutically acceptable salt of this compound in an amount to provide the antagonism of substance P, as well as pharmaceutically acceptable carrier.

The invention relates also to a method of treatment or prevention of disorders in mammals, including humans, resulting from an excess of substance P, which is that specified mammal appoint a compound of formula I or pharmaceutically acceptable salt e to pharmaceutical compositions for the treatment or prevention of disease States, caused by inflammation (such as arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or estimatesa disorders, colitis, psychosis, pain, gastroesophageal reflux, allergies such as eczema and rhinitis, chronic airway obstruction, hypersensitivity, vasospastic diseases such as angina, migraine and Raynaud's disease, fibrosis and collagen diseases such as sclerodermataceae and eosinophilic fascioliasis, degeneration of sympathetic reflexes, such as the brachial syndrome, alcoholism, somatic disorders caused by stress, peripheral neuropathy, neuralgia, neurotic diseases disorders such as Alzheimer's disease, dementia caused by AIDS, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement and weakening, such as systemic lupus erythematosus, and rheumatic diseases such as fibrosis in mammals, including humans, which comprises a compound of formula I or pharmaceutical acceptable salt of this compound in an amount to provide the antagonism of the effects of substance P on the stretch receptor of this substance, as well as farmacevticheskih condition, caused by inflammation (such as arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or estimatesa disorders, colitis, psychosis, pain, gastroesophageal reflux, allergies such as eczema and rhinitis, chronic airway obstruction, hypersensitivity, vasospastic diseases such as angina, migraine and Raynaud's disease, fibrosis and collagen diseases such as sclerodermataceae and eosinophilic fascioliasis, degeneration of sympathetic reflexes, such as the brachial syndrome, alcoholism, somatic disorders caused by stress, peripheral neuropathy, neuralgia, neurotic diseases disorders such as Alzheimer's disease, dementia caused by AIDS, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement and weakening, such as systemic lupus erythematosus, and rheumatic diseases such as fibrosis in mammals, including humans, including the appointment of the specified mammal the compounds of formula I or pharmaceutically acceptable salt of this compound in an amount to provide the antagonism of the effects of substance P on the plot of receptor Atagi of such disorders in mammals, including a human, the treatment or prevention of which conduct or accelerate through the reduction of neurotransmission by substance P, which composition comprises a compound of formula I or pharmaceutical acceptable salt of this compound in an amount to provide the antagonism of the effects of substance P on the stretch receptor of this substance, as well as pharmaceutically acceptable carrier.

The invention relates also to a method of treatment or prevention of such disorders in a mammal, including a human, the treatment or prevention of which conduct or facilitate through reduced neurotransmission through substance P, which method comprises assigning a specified mammal the compounds of formula I or pharmaceutically acceptable salt of this compound in an amount to provide the antagonism of the effects of substance P on the stretch receptor of this substance.

The invention relates also to pharmaceutical compositions for the treatment or prevention of such disorders in a mammal, including a human, the treatment or prevention of which conduct or accelerate through reduced neurotransmission, through substance P, kucove, providing effective treatment or prevention of such disorders, and a pharmaceutically acceptable carrier.

The invention relates also to a method of treatment or prevention of such disorders in a mammal, including a human, the treatment or prevention of which conduct or facilitate through reduced neurotransmission, through substance P, which method comprises assigning the specified mammal the compounds of formula I or pharmaceutically acceptable salt of this compound in an amount to provide effective treatment or prevention.

The compounds of formula I have chiral centers and therefore exist in different enantiomeric forms. The invention relates to all optical isomers and all stereoisomers of the compound of formula I and mixtures of these isomers and stereoisomers.

Formula 1 include compounds that are identical to the compounds represented in the diagram, as well as such compounds, where one or more hydrogen atoms are replaced by a radioactive isotope. Such radiometersonde compounds used in research and diagnostic studies related to pharmokinetic of metabasite and related problems. Similar researched the project for in vivo and in the diagnosis of these substances used in the studies linking in vivo substance P receptors in the corresponding tissues of the human brain that helps to diagnose inflammation, for example, helps to identify immune cells or cells that are directly involved in the disorders associated with inflammatory bowel disease. Among radiomaterialah forms of the compounds of the formula I compounds containing tritium and isotopes of C14.

The compounds of formula I can be obtained by reactions represented by the following scheme. Except where otherwise noted, the radicals R1- R13, X, Z, O, Y, m, n, o, p, q, k, y, and z in the diagram and the description have the above values.

The compounds of formula I can be obtained by methods illustrated in the end of the description in schemes 1 and 2.

In scheme 1 the compounds of formula X are subjected to hydrolysis to remove methoxybenzyloxy groups, which use a strong mineral acid, such as hydrochloric, Hydrobromic or itestosterone acid, at a temperature from room temperature up to the temperature of the distillation of acid. Preferably the reaction is carried out in Hydrobromic acid at a temperature of negotiations 2 hours

For those compounds of formula X, where Q represents a group of formula VII or VIII, it is preferable to remove methoxybenzyloxy group by treatment with hydrogen in the presence of a catalyst containing a metal, such as platinum or palladium. Typically this reaction is carried out in an inert solvent, such as acetic acid or lower alkanol, at a temperature of 0 - 50oC. (In another embodiment, these compounds are treated with a solvent metal, such as lithium or sodium, ammonia at from -30 to about -78oC, or formate (salt) in the presence of palladium or cyclohexane in the presence of palladium). It is preferable to treat such compounds with hydrogen in the presence of palladium on coal in a mixture of methanol/ethanol in water or in hydrochloric acid containing a mixture of methanol/ethanol, at a temperature of approximately 25oC.

The compounds of the formula XI is converted into the corresponding compounds of formula I by reaction with the appropriate compound of formula XII (as shown in figure 1). This reaction is usually carried out in the presence of a reducing agent, such as cyanoborohydride sodium, triacetoxyborohydride sodium, borghild sodium, hydrogen and a metal catalyst, zinc and hydrochloric acid, b is x inert solvents, used in this reaction, lower alkanols (e.g. methanol, ethanol and isopropanol), acetic acid and tetrahydrofuran (THF). Preferably the solvent to use acetic acid as reductant triacetoxyborohydride sodium and perform the reaction at a temperature of approximately 25oC.

According to alternative interaction of the compounds of formula XI with the compound of the formula XII can be carried out in the presence of a desiccant or using a device intended for azeotropic removal of the water formed, to obtain the imine of the formula

< / BR>
which then react with the reducing agent, as described above, preferably with triacetoxyborohydride sodium at room temperature. Getting imine is usually carried out in an inert solvent, such as benzene, xylene or toluene, preferably toluene, at a temperature of about 25 - 110oC, preferably at a temperature of distillation of the solvent. Proper dryer/solvent include titanium tetrachloride/dichloromethane, licenseprefix/dichloromethane and molecular sieves THF. The preferred system is z titanium/dichloromethane.

The compounds of formula XI can the receiving formula

< / BR>
where

L represents a leaving group such as chlorine-, bromine-, iodine-, tosylate or mesilate.

This reaction is usually carried out in an inert solvent such as dichloromethane or THF, preferably in dichloromethane, at a temperature of 0 - 60oC, preferably at about 25oC.

The compounds of formula XI can also be converted into the corresponding compounds of formula I by reacting with an appropriate compound of the formula

< / BR>
where

L have the above values, or represents an imidazole,

and then the reaction mixture is reduced to obtain the amide. This reaction is usually carried out in an inert solvent, such as THF, or dichloromethane, at temperatures from -20 to 60oC, preferably in dichloromethane at a temperature of about 0oC. Recovering the obtained amide is carried out by treatment with reducing agent such as borane-dimethylsulfide complex, alumoweld lithium or diisobutylaluminium, in an inert solvent, such as ethyl ether or THF. The reaction temperature may vary from 0oC to approximately the temperature of the distillation of the solvent. Preferably recovered by the use of the GDS Q represents a group of formula II, the starting materials of formula X can be obtained by way described in Application for U.S. patent ser. N 566338, filed July 20, 1990, the firm "Pfizer Inc. This application is fully incorporated into the present text.

In those cases, when Q represents a group of formula III, the starting materials of formula X can be obtained by a method described in the patent Application U.S. ser. N 532525, filed June 1, 1990, and in the application for PCT patent with a priority of April 25, 1991, entitled "3-amino-2-aryl-hioliday". Both of these applications filed by the company "Pfizer Inc" and fully incorporated into the present text.

In those cases, when Q represents a group of formula IV, V or VI, the starting materials of formula X can be obtained by a method described in the patent Application U.S. ser. N 557442, filed July 23, 1990, and in the patent application PCT priority from may 15, 1991, entitled "Derivatives of hinoklidina". Both of these applications filed by the company "Pfizer Inc" and fully incorporated into the present text.

In those cases, when Q represents a group of formula VII, starting materials of formula X can be obtained by the method described in the following patent applications of the company "Pfizer Inc., application for U.S. patent ser. N 619361, filed November 28, 1990, application for U.S. patent ser. N 675244 filed March 26, 1991 , application for U.S. patent ser. N 800667 the awn is incorporated into the present text.

In those cases, when Q represents a group of formula VIII, starting materials of formula X can be obtained by a method described in the patent Application U.S. ser. N 590423, filed September 28, 1990, the company "Pfizer Inc". This application is fully incorporated into the present text.

Scheme 2 illustrates an alternative method of obtaining the compound of formula I, where Q represents a group of formula VII.

As shown in scheme 2, reductive amination of the compounds of formula XII using cyanoborohydride sodium or triacetoxyborohydride sodium and compounds of formula XIII to give a compound of formula XIV. This reaction is usually carried out in a polar organic solvent such as acetic acid or lower alkanol, at a temperature of 0 - 50oC. the Preferred solvent is methanol, and the reaction is best carried out at a temperature of approximately 25oC. it is Desirable that the pH of the reaction mixture was 4 - 5.

The recovery of the compounds of formula XIV to give a compound of formula I, where Q represents a group of formula VII, and m is 0.

Suitable reducing agents include borane-dimethyl sulfide in THF, alumoweld lithium borane in THF and sodium borohydride - chloride titanium (IV). Best resonates to about 150oC, preferably at a temperature of distillation of the solvent.

The compounds of formula I can be converted to a compound of formula I, where Q represents a group of formula VII, and m is not equal to 0, has the same stereochemical structure by interaction with a corresponding compound of formula R10-(CH2)-L', where L' represents a halogen, mesilate or toilet, and where one of the simple relations of the carbon-carbon bonds in the specified radical (CH2)mcan be replaced by a double bond carbon-carbon triple bond, and where one of the carbon atoms in (CH2)mcan be substituted for R11. This reaction is usually carried out in the presence of a base such as triethylamine or tert-piperonyl potassium, in a polar solvent such as methylene chloride or dichloroethane, at temperatures from room temperature up to about 150oC. it is Preferable to conduct the reaction at a temperature of distillation of the methylene chloride in the presence of triethylamine.

Starting materials of formula XIII can be obtained by a method described in the patent Application U.S. ser. N 619361, filed November 28, 1990, the firm "Pfizer Inc. This application is fully incorporated in the present text.

Figure 3, presents at the end of the op is rmula VIII.

As shown in scheme 3, reductive amination of the compounds of formula XII in the presence of the compounds of formula XV to give a compound of formula XVI. Among the reducing agents that may be used in this reaction, hydrogen in the presence of a metal catalyst, sodium borohydride, cyanoborohydride sodium and triacetoxyborohydride sodium. This reaction is usually carried out in a polar solvent such as acetic acid, or lower alkanol, in the presence of a desiccant such as molecular sieves, at a temperature of 0 - 50oC. the Preferred solvent is methanol, the reaction is preferably carried out at 25oC. it is also Desirable that the pH of the reaction mixture was 4 - 5.

In another embodiment, the compounds of formula XVI is obtained by acylation of compounds of formula XV compound of the formula

< / BR>
then the obtained amide restore. The acylation is usually carried out in a polar solvent, such as dichloromethane, THF or ethyl ether, at a temperature of 0 - 60oC. the Preferred solvent is dichloromethane, the reaction is preferably carried out at a temperature of approximately 25oC. among the reducing agents used to restore the amide - alumoweld lithium and borane-dim is the temperature from about 0oC to the temperature of distillation of the solvent, preferably at room temperature.

The compounds of formula XVI can be converted into the corresponding compounds of formula I, where Q represents a group of formula VIII, and m is 0, by reaction with ammonium formate in the presence of palladium on charcoal, for example 10% palladium on coal. Usually use such a polar solvent like ethyl acetate or low alcohol, and the reaction proceeds at temperatures from room temperature up to about 150oC for 0.5 - 24 hours is Preferable to conduct the reaction in ethanol at room temperature for 3 to 24 hours

The compounds of formula I, obtained as described above, can be converted into compounds that are identical in everything except that m is not equal to 0, using the above method of obtaining compounds of formula I, where Q represents a group of formula VII, and m is not equal to 0.

Starting materials of formula XV can be obtained by a method described in the patent Application U.S. ser. N 590423, filed September 28, 1990, the company "Pfizer Inc". This application is fully incorporated into the present text.

The compounds of formula I, where Q represents a group of formula II and which has a double bond between Q what their benzylamino. The condensation is usually carried out in digitoxigenin a solvent such as benzene, toluene or THF, using this acid as methanesulfonate or p-toluensulfonate, at a temperature of 20oC to the temperature of distillation of the solvent. It is preferable to conduct the reaction using camphorsulfonic acid in toluene at a temperature of distillation.

< / BR>
Obtain other compounds of formula I, is described in the following experimental part, carried out by various combinations of the above reactions, such combinations are obvious to experts.

In each reaction described herein or shown in the diagrams, the pressure is not an important parameter, except where otherwise stated. Usually permissible pressure of 0.5 to 5 ATM., and atmospheric pressure, i.e., about 1 ATM., the reaction can be performed at any pressure, what is considered comfortable.

The new compounds of formula I and pharmaceutically acceptable salts of these compounds are used as antagonists of substance P, i.e., they have the ability to counteract the effects of substance P on the stretch receptor of this substance in mammals, and therefore those with the s and diseases of mammals.

The compounds of formula I, which, by their nature, main, can form a variety of salts with inorganic and organic acids. Although such salts must be pharmaceutically acceptable for the purpose of their animals, in practice often have to first identify the compound of formula I from the reaction mixture in the form of a pharmaceutically unacceptable salt and then simply convert the connection back to the free base by treatment with an alkaline reagent, after which the free base is converted into pharmaceutically acceptable salt by adding acid. Salts of the compounds according to the invention, the resulting additive acids, can be obtained by processing the primary connection equivalent amount of the chosen mineral or organic acid in an aqueous solvent or in a suitable organic solvent, such as methanol or ethanol. After careful evaporation of the solvent to obtain the desired salt.

Those compounds of formula I that are acidic in nature, e.g., where R1is carboxyphenyl able to form basic salts with various pharmacologically praml is Riya and potassium. All these salts get in the usual ways. To obtain pharmaceutically acceptable basic salts according to the invention as reagents use those bases which form non-toxic basic salts with the acidic compounds of formula I. Such non-toxic basic salts include salts derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc., Such salts are readily obtained by treatment of the corresponding acid compounds with an aqueous solution containing the desired pharmacologically acceptable cations, after which the resulting solution is evaporated to dryness, preferably under reduced pressure. In another embodiment, these salts can be obtained by mixing solutions of the acid compound according to the invention in the lower alkanols with the desired alkali metal alkoxide, after which the resulting solution is evaporated to dryness as described above. In any case, it is preferable to apply the reagents in stoichiometric quantities to ensure completion of the reaction and the maximum yield of the desired product.

The activity of compounds of the formula I and their pharmaceutically acceptable salts is that they bind receptors substance P, this AK is or prevention of which is carried out by reducing neurotransmission, through substance P. Such painful conditions include inflammatory diseases (such as arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or estimatesa disorders, colitis, psychosis, pain, gastroesophageal reflux, allergies such as eczema and rhinitis, chronic obstruction of the Airways, increased sensitivity, vasospastic diseases such as angina, migraine and Raynaud's disease, fibrosis and collagen diseases such as sclerodermataceae and eosinophilic fascioliasis, degeneration of sympathetic reflexes, such as the brachial syndrome, alcoholism, somatic disorders caused by stress, peripheral neuropathy, neuralgia, neurotic diseases disorders such as Alzheimer's disease, dementia caused by AIDS, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or weakening, such as systemic lupus erythematosus, and rheumatic diseases such as fibrosis. Thus, the compounds according to the invention can be used for therapeutic purposes as antagonists of substance P to control and/or treatment of any of the above bol is ielemia salt can be assigned for parenteral, oral or topical application. Usually the dosage that is prescribed these compounds range from 5.0 mg to 1500 mg per day, although there may be other dosages depending on the weight and condition of the patient and the route of administration. However, the optimal dose is the dose of 0.07 - 21 mg per 1 kg of body weight per day. There may be other dosages depending on the type of animal to be treated and its individual response to the specified medication, as well as depending on the form of a pharmaceutical preparation and a period of introduction, as well as intervals between meals. In some cases, the required dosage is below the minimum specified limits, and in other cases it is possible to apply higher doses without harmful side effects, provided that large doses are divided into several smaller doses that will be entered several times a day.

Compounds according to the invention may be prescribed alone or in combination with pharmaceutically acceptable carriers or diluents, the introduction of the daily dose can be carried out in one or several stages. In particular, new therapeutic substances according to the invention can be part of different dosage forms, i.e., in combination with various farmacevtuli, pastes, ointments, suppositories, jellies, gels, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, etc., Such carriers include solid fillers, sterile water and various non-toxic organic solvents, etc., pharmaceutical compositions for oral administration can be sweetened and/or flavored. Usually therapeutically-active compounds according to the invention are present in these dosage forms in concentrations of 5.0 - 70 wt.%.

For oral administration may be tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine, as well as various substances that contribute to decomposition, such as starch (preferably corn, potato or starch from cassava tubers), alginic acid and certain complex silicates, together with a binder for granulation, such as polyvinylpyrrolidone, sucrose, gelatin and acacia.

Often for the manufacture of tablets also use lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc. Solid compositions of a similar type may also be used in Cutesy sugar, as well as the glycols of high molecular weight. In those cases, when administered orally using suspensions and/or elixirs, the active ingredient combined with various sweetening or flavoring agents, coloring agents and, optionally, emulsifiers and/or suspendresume agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations of these substances.

For parenteral use, solutions of therapeutic compounds according to the invention in sesame or peanut oil or in aqueous propylene glycol. Aqueous solutions must contain a suitable buffer in cases when it is necessary and when the liquid diluent first make isotonic. Such aqueous solutions are suitable for intravenous injection. The oily solutions are suitable for intra-articular, intramuscular and subcutaneous injection. Obtaining all these solutions under sterile conditions is carried out by standard methods, well known to experts.

Additional compounds according to the invention can be administered for local application in the treatment of inflamed skin, and in this case, these compounds are administered in the form of creams, jellies, gels, PA is briteney as antagonists of substance P is determined by their ability to inhibit the binding of substance P at the site of a receptor in the caudal bovine tissues, in order by using autoradiography to conduct a study tachykinin receptors using radioactive ligands. The active compounds according to the invention can be assessed using standard research procedures that are described in the work of M. A. Cacciari and others, Journal of Biological Chemistry, 258 so, 5158 S. 1983. In this way determine what the concentration of the individual compound required for 50% to reduce the number radiomaterialah ligand substance P on the plot of their receptor in specified tissues of the animal, whereby gain characteristic exponents IC50for each test compound.

During this test, the caudal bullish fabric is removed from the freezer at -70oC and homogenized in 50 volumes (M/o) of ice-cold 50 mm Tris (i.e., trimethylamine, which is 2-amino-2-hydroxymethyl-1,3-propandiol) cleaners containing hydrochloride buffer with a pH of 7.7. The homogenate was centrifuged at 30,000 G for 20 minutes the Ball re-suspended in 50 volumes of Tris buffer, re-homogenized and then centrifuged at 30,000 G for 20 minutes Then the ball is re-suspended in 40 volumes of ice-cold 50 mm Tris buffer (pH of 7.7) containing 2 mm of chloride keyword. In this step completes the preparation of the tissue.

This is followed by binding of radioligand that is as follows: the reaction initiated by addition of 100 μm of the test compound in a concentration of 1 μm, then add 100 μl of the radioactive ligand in a final concentration of 0.5 µm, and finally, add 800 ál of the drug to the tissue obtained in the above way. The final volume is 1.0 ml, the reaction mixture was shaken and incubated at room temperature (about 20oC) for 20 minutes and Then the tube was filtered using a cell harvester and the filters glass fiber (Whatman CF/B"), washed four times with 50 mm Tris buffer (pH of 7.7), with filters pre-soaked for 2 h before filtering. Then determine the radioactivity in the counter beta particles in 53% counting efficiency, then calculate the indicator IC50using standard statistical methods.

Antipsychotic activity of the compounds according to the invention is used as antipsychotic agents for control of various psychotic disorders, can be determined by studying the ability of these compounds to inhibit the hyperkinesia of Guinea pigs induced by substance P or beset dose control connection or the corresponding compounds according to the invention, then the pigs do injections of substance P or a substance having affinity to the receptor for substance P (intracerebral, through the cannula, and then measure individual response to such a stimulus.

Example 1. 2-(diphenylmethyl)-N-((2-deformedarse)phenyl)methyl-1 - azabicyclo[2.2.2]Octan-3-amine.

A. 2-(deformedarse)benzaldehyde.

In a 500 ml three-neck round bottom flask equipped with a condenser and a tube for the gas inlet, was placed 5.0 g (40,98 mmol) salicylaldehyde, 150 ml of dioxane, 150 ml (164 mmol) of 1,1 H of an aqueous solution of sodium hydroxide. The mixture was heated to 60oC, passing through it Chlorodifluoromethane in the form of a gas, the reaction mixture was stirred at this temperature for 2 hours Then the reaction mixture was cooled and was extracted with ether. The organic layer was dried with sodium sulfate, filtered and evaporated. The residue was subjected to chromatography on silica gel with hexane/ethyl acetate as eluent to obtain pale yellow oil, 1.63 g (23%).

1H NMR ( , CDCl3): only 6.64 (t, J = 72,7 (H-F), 1H), 7,16 (d, J = 7, 1H), 7,24 (t, J = 7,1 H), 7,53 (m, 1H), 7,81 (m, 1H), 10,29 (s, 1H),

13With NMR (CDCl3): 112,2 115,6 115,645 115,7 119,1 119,2 119,5 125,6 125,7 125,8 125,9 127,5 128,8 128,9 135,7 152,71 152,73 188,4.

IR (cm-1net.): 1700 (C = Calculated data for C8H6F2O21/4H2O: C 54,50 H 3,71.

Found: C 54,68 H Of 3.33.

Century 2-(diphenylmethyl)-N-((2-deformedarse)phenyl)methyl - 1-azabicyclo[2.2.2] Octan-3-amine.

A 25 ml round bottom flask equipped with an inlet tube for nitrogen, was placed 500 mg (1,71 mmol) 2-diphenylmethyl-1-azabicyclo [2.2.2]Octan-3-amine (obtained by the method described Warawa and other J. Med. Chem. 17, 497, 1974), and 8.5 ml of methanol, 383 mg (2,23 mmol) 2- (deformedarse)benzaldehyde and 216 mg (3,42 mmol) cyanoborohydride sodium. The reaction mixture was stirred at room temperature for 30 h, then was divided between ethyl acetate and water. The organic layer was separated, washed with brine, dried with sodium sulfate and evaporated. In order to remove the last traces of unreacted amine and the mixture was treated with traceabilities sodium in acetic acid at room temperature for 16 h, then was treated with an aqueous solution of sodium hydroxide and methylene chloride. The remainder crystallizable from isopropanol to yield a white solid, melting point which 144-147oC, weight of 206 mg (27%).

1H NMR ( , CDCl3): of 1.27 (m, 1H), 1,4 - 1,8 (m, 2H), 1,90 (m, 1H), 2.05 is (m, 1H), 2.63 in (m, 1H), 2,78 (m, 2H), 2,88 (m, 1H), 3,19 (m, 1H), 3.45 points (ABq, JAB= 9 25,4 42,0 45,8 49,4 49,5 55,0 61,8 116,3 119,0 125,4 126,0 126,5 127,5 127,8 127,9 128,0 128,4 128,5 128,6 129,1 129,2 130,0 131,6 143,2 145,2 149,3.

IR (cm-1net.): 2940 (C-H), 1599 (C=C).

Mass spectrum, %: 449, (<1, bear.+1), 291 (51), 281 (100), 84 (66), 49 (69).

Estimated this to C28H30F2N2O: C 74,98 H 6,74 N 6,25.

Found: C 74,72 H 6,70 N 6,23.

Example 2. (2S,3S)-N-(2-methoxy-5-trifloromethyl)methyl-2-diphenylmethyl-1-azabicyclo[2.2.]Octan-3-amine, salt methanesulfonic acid.

The desired compound was obtained in a manner analogous to the method described in example 1, substituting 2-(deformedarse)benzaldehyde 2 - methoxy-5-triftormetilfullerenov on stage Century.

Melting point 135oC.

1H NMR (CDCl3): 1.8 to 2.3 (m, 2H), about 2.2 - 2.8 (m, 6H) to 2.66 (s, 6H), of 3.56 (s, 3H), 3,3 - 3,7 (m, 3H), 3,90 (m, 3H), 4,16 (m, 2H), is 5.06 (m, 1H), 5,20 (br, 1H), 5,50 (m, 1H), ceiling of 5.60 (br, 1H), 6,77 (d, 1H, J = 9,2), 7,02 (m, 1H), 7,2 - 7,8 (m, 11H), of 8.00 (br, 1H) 10,8 (br, 1H).

IR (cm-1, KBr): 3180 3140 3000 1500 1200 1062 782.

Example 3. (2S,3S)-2-phenyl-3-[2-(2,2,2-triptoreline) benzyl]aminopiperidine.

A. 2-(2,2,2-triptoreline)benzaldehyde.

In a nitrogen atmosphere in a round bottom flask equipped with a condenser, was placed 0.2 g (1 mmol) of 2-(2,2,2-triptease)-benzonitrile (J. Org. Chem., 377, 1983) and 5 ml of formic acid. To this solution is added about 0.2 g of Nickel Raney and the mixture was heated with oratoriarum (CHCl3). The layers were separated and the aqueous phase was extracted with three portions of chloroform. The combined organic fractions of saturated aqueous sodium bicarbonate and water, dried with sodium sulfate (Na2SO4) and concentrated (rotary evaporator) to obtain 176 mg of the desired compound as a yellow solid, melting point 33-34oC.

C. (2S, 3S)-2-phenyl-C[2-(2,2,2-triptoreline)benzyl] amino-piperidine hydrochloride.

In a nitrogen atmosphere in a round bottom flask was placed 112 mg (0,63 mmol) (2S,3S)-3-amino-2-phenylpiperidine, 155 mg (0,76 mmol of the aldehyde obtained in step a above, and about 2 ml of acetic acid, the resulting solution was stirred at room temperature for 1 h In the system added 294 mg (1,39 mmol) triacetoxyborohydride sodium (portions) and the mixture was stirred at room temperature overnight. The mixture is then concentrated in a rotary evaporator and divided between 1M aqueous solution of sodium hydroxide (NaOH) and methylene-chloride (CH2Cl2). The layers were separated and the aqueous phase was extracted with three portions of CH2Cl2. The combined organic fractions were extracted with three portions 2N aqueous solution of HCl extracts were made alkaline extracts were dried (Na2SO4) and concentrated. The resulting oil was dissolved in 2 ml ethyl acetate and treated with ether saturated hydrogen chloride (HCl).

Received whiter solid (73 mg, melting point >275oC) was collected. This material was converted to the free base by partitioning between 1N aqueous solution of NaOH and CH2Cl2. The free base (58 mg) was purified flash chromatography on columns, elwira chloroform (CHCl3), and then a mixture of 1: 19 methanol/CHCl3to obtain 32 mg of oil. Conversion of the free base to the corresponding hydrochloric salt, as described above, allowed us to obtain 17 mg of the desired compound, melting point >275oC.

1H NMR (free base, CDCl3) of 1.44 (m, 1H), 6,63 (m, 1H), of 1.88 (m, 1H), 2,1 (m, 1H), 2,80 (m, 1H), 3,26 (m, 1H), 3,38 (d, 1H, J = 15), 3,66 (d, 1H, J = 15), 3,88 (s, 1H), 4,08 (m, 2H), of 6.68 (d, 1H, J = 6) of 6.90 (m, 1H) 6,98 (m, 1H, J = 6), 7,16 (m, 1H) 7,26 (m, 5H).

The mass spectrum. estimates for C20H24F3N2O3(bear.+1): 365,1835. Found: 365,1980.

Estimates for C20H23F3N2O2HCl1/3H2O: C TO 54.19 OF 5.84 H N 6,32.

Found: C 54,22 H 5,57 N 6,28.

Example 4. (2S,3S)-3-(2-methoxy-5 - cryptomaterial)amino-2-Finistere nitrogen in a round bottom flask was placed 3,63 ml (28 mmol) of 4-cryptomaterial and 25 ml of acetone. With stirring, this solution was added to 7.75 g (56 mmol) of potassium carbonate and of 3.48 ml (56 mmol) under the conditions, the reaction mixture was stirred at room temperature overnight. Solids were removed by filtration and the filtrate was washed with acetone. The filtrate was concentrated to obtain 6.5 g of a mixture of solids with oil. The resulting mixture was diluted with CHCl3and filtered, the filtrate was concentrated to obtain 5.5 g of 1-methoxy-4-cryptomaterial in the form of a yellow oil.

1H NMR (CDCl3) of 3.78 (s, 3H), 6,83 (d, 1H, J = 12), 7,10 (d, 1H, J = 12). The mass spectrum. m/z: 192 (bear.).

In a nitrogen atmosphere in a round bottom flask was placed 1-methoxy-4 - cryptomaterial (5.5 g 29 mmol) and 110 ml of CH2Cl2. In this mixture, cooled in a bath (ice/acetone) was added 3.77 ml (34 mmol of titanium tetrachloride (TiCl4), additive produced for about 1 min. Then the reaction mixture was stirred for 30 min and added 5,69 ml (63 mmol) , -dichlorodimethyl ether. The ice bath was removed and the mixture was stirred at room temperature overnight. The mixture is then carefully poured into water and was extracted with three portions of CH2Cl2. The United extracts were washed with water and brine, dried (Na2SO4) ericales), using a mixture of 1:9 ethyl acetate/hexane as eluent to obtain 920 mg of the desired compound containing a small amount of impurities, 3.27 g of pure desired compound.

1H NMR (CDCl3) of 3.94 (s, 3H), of 7.00 (d, 1H, J = 9), 7,38 (dd, 1H, J = 3,9), 7,66 (d, 1H, J = 3), of 10.4 (s, 1H). The mass spectrum. m/z: 220 (bear.).

C. (2S, 3S)-3(2-methoxy-5-cryptomaterial)-amino-2-phenylpiperidine, hydrochloric salt.

In a nitrogen atmosphere in a round bottom flask was placed 525 mg (2.4 mmol) of 2-methoxy-5-triphtalocyaninine, 350 mg (2.0 mmol) (2S,3S)-3-amino-2-phenylpiperidine and 5 ml of acetic acid. The reaction mixture was stirred at room temperature for 3 days and then concentrated in a rotary evaporator. The residue was divided between 1N aqueous solution of sodium hydroxide and chloroform (CHCl3), then the mixture was extracted with three portions of chloroform. The United extracts were extracted with three portions 1N aqueous solution of hydrochloric acid. United HCl extracts were made alkaline by means of concentrated aqueous sodium hydroxide solution and was extracted with four portions of chloroform. The extracts were dried (Na2SO4) and concentrated in a rotary evaporator to obtain 760 mg of oil. MA the solution was collected by vacuum filtration and washed with ether to obtain 600 mg of the desired compound, melting point >250oC.

1H NMR (free base, CDCl3) 1,36 (s, 1H), and 1.54 (m, 1H), to 1.86 (m, 1H) to 2.06 (m, 1H), was 2.76 (m, 2H), up 3.22 (m, 1H), 3,32 (d, 1H, J = 15), of 3.48 (s, 3H), to 3.58 (d, 1H, J = 15) of 3.85 (d, 1H, J = 3), to 6.57 (d, 1H, J = 9) to 6.80 (d, 1H, J =3) 6,92 (dd, 1H, J = 3,9) 7,22 (m, 5H).

Mass spectrum, calculated data for C20H23F3N2O2: 380,1711. Found: 380,1704.

Estimates for C20H23F3N2O20,2 H2O: C 52,57 H CEILING OF 5.60 N 6,13.

Found: C 52,53 H Of 5.40 N 5,97.

Example 5. (2S,3S)-1-(5,6-dimethoxyphenyl)-3-(methoxy-5-cryptomaterial) amino-2-phenylpiperidine hydrochloride.

In a nitrogen atmosphere in a round bottom flask were placed 250 mg (0.66 mmol) (2S, 3S)-3-(2-methoxy-5-cryptomaterial)amino - 2-phenylpiperidine, 2 ml of tetrahydrofuran (THF) and 0.28 ml (2.0 mmol) of triethylamine. In this system added 475 mg (2.0 mmol) of 5,6-dimethoxy-1 - methylsulfonylmethane (obtained from 1,5,6-hexanetriol by sequential formation of the acetonide (acetone, p - toluensulfonate acid), acetylation (acetylchloride, triethylamine, THF), removal of the acetonide (60% acetic acid/ water), demetilirovania (sodium hydride, methyliodide, THF), deacetylation (sodium methoxide, methanol) and education meanswhen is. the ATEM reaction mixture was divided between CHCl3and saturated aqueous sodium bicarbonate and was extracted with three portions CHCl3. The combined organic fractions were dried (Na2SO4), filtered and concentrated to obtain 853 mg of an orange oil. The crude material was purified column flash chromatography (35 g silica gel) using a mixture of 1: 19 methanol/chloroform as eluent, to obtain 185 mg of a yellow oil. The oil was dissolved in ethyl acetate and was added ether saturated with HCl. The mixture was concentrated and the residue triturated with ether to obtain 190 mg of the desired compound.

1M NMR (free base, CDCl3) to 1.15 (m, 2H), 1,38 (m, 6H), to 1.76 (m, 2H), 1,96 (m, 3H), of 2.50 (m, 2H), and 3.16 (m, 2H), 3,26 (m, 9H), of 3.46 (s, 3H) to 3.58 (d, 1H, J = 15) of 6.52 (d, 1H, J = 9), and 6.9 (m, 1H), 6,86 (m, 1H), 7,22 (m, 5H).

Mass spectrum calculation. C28H39F3N2O4: 524,28616. Found: 524,28634.

Estimates for C28H39F3N2O40,75 H2O: C 55,03 H 7,00 N 4,58.

Found: C 55,04 H 7,12 N 4,51.

Example 6. (2S,3S)-2-phenyl-3-(2-cryptomaterial)-amino - piperidine monohydrochloride salt.

In a nitrogen atmosphere in a round bottom flask was placed 3.0 ml (23 mmol) of cryptomaterial and methyl ester. Then to the solution was added 6,13 g (46 mmol) of aluminium chloride (AlCl3), additive produced portions.

After the reaction mixture was allowed to gradually warm to room temperature and was stirred at room temperature overnight. After that, the reaction mixture is slowly poured into water and was extracted with three portions of dichloromethane. The combined organic fractions were washed with water, dried (Na2SO4) and concentrated in a rotary evaporator to obtain 3.7 g of oil. This material, containing a mixture of 4 - and 2-triphtalocyaninine, was purified column flash chromatography (160 g silica gel) using a mixture of 1: 49 ethyl acetate/hexane as eluent, to obtain 500 mg of material saturated with 2-triftormetilfullerenov.

In a nitrogen atmosphere in a round bottom flask was placed 105 mg (0.88 mmol) (2S, 3S)-3-amino-2-phenylpiperidine, aldehyde, obtained as described above, and 2 ml of acetic acid. In this system was added 370 mg (1.8 mmol) of triacetoxyborohydride sodium and the mixture was stirred at room temperature overnight. The mixture was concentrated and the residue was divided between 1N aqueous sodium hydroxide solution and dichloromethane and extracted three partyanimal in alkaline with 1N aqueous NaOH solution and was extracted with three portions of dichloromethane. The extract was dried and concentrated to obtain 190 mg of oil, which was purified column flash chromatography (5 g silica gel) using a mixture of 1:9 methane/chloroform as eluent, to obtain 95 mg of the free base of the desired compound. The free base was dissolved in ethyl acetate and the solution was added ether saturated with HCl. The obtained white solid was collected by vacuum filtration and washed with ether to obtain 72 mg of the desired compound, melting point 231 - 233oC.

1H NMR (free base, CDCl3) of 1.40 (m, 1H), 1,60 (m, 1H), of 1.84 (m, 1H), 2.05 is (m, 1H) 2,78 (m, 2H) 3,22 (m, 1H), 3,42 (d, 1H, J = 15), of 3.56 (d, 1H, J = 15), 3,86 (d, 1H, J = 3), was 7.08 (m, 4H), from 7.24 (m, 5H).Mass spectrum: m/z 350 (bear.). Estimates for C19H21F3N2O2HCl0,25H2O: C 53,34 H 5,54 N 6,54.

Found: C 53,19 Of 5.40 H N 6,54.

Example 7. (2S,3S)-3-(2-hydroxy-5-cryptomaterial) amino-2-phenylpiperidine hydrochloride.

A. 2-hydroxy-5-triphtalocyaninine.

In a nitrogen atmosphere in a round bottom flask were placed 300 mg (1.4 mmol) of 2-methoxy-5-triphtalocyaninine and 30 ml of dichloromethane. In this system, cooled in a bath (dry ice/ acetone) was added of 0.26 ml (2.7 mmol) of tribromide boron (BBr3), additive it was replaced with an ice bath and stirred the mixture for 1 h In this system was slowly added 10 ml of saturated aqueous sodium bicarbonate solution, and then 10 ml of water, after which the mixture is warmed up to room temperature. The mixture was extracted with two portions of dichloromethane, the extracts were dried (Na2SO4) and concentrated. The obtained oil (280 mg) was dissolved in CH2Cl2the solution was extracted with two portions of 1 M aqueous NaOH solution. Combined aqueous extracts were acidified with 2M aqueous HCl and was extracted with three portions of dichloromethane. The obtained extracts were dried (Na2SO4) and concentrated to obtain 200 mg of the desired compound.

1M NMR (CDCl3) of 6.96 (d, 1H, J = 9) of 7.36 (m, 2H), 9,84 (s, 1H), up 10.9 (s, 1H).

C. (2S, 3S)-3-(2-hydroxy-5-cryptomaterial)- amino-2-phenylpiperidine hydrochloride.

The desired compound was obtained in a manner analogous to the method described in example 4, substituting 2-methoxy-5-triphtalocyaninine-2 - hydroxy-5-triftormetilfullerenov.

1H NMR (free base, CDCl3) to 1.60 (m, 3H), 2,04 (m, 1H), was 2.76 (m, 1H), 2,88 (m, 1H), 3,18 (m, 1H) 3,42 (s, 2H), 3,90 (m, 1H), of 6.52 (m, 1H) 6,64 (d, 1H, J = 9), 6.89 in (m, 1H), 7,30 (m, 5H).

The mass spectrum. the calculations for C19H21F3N2O2: 366,1545.

O: C 51,25 H 4,90 N 6,29.

Found: C 51,30 H 4,75 N 6,22.

Example 8. (2S, 3S)-3-(5-chloro-2-[2,2,2]-triptoreline]benzyl) amino-2-phenylpiperidine hydrochloride.

A. 5-chloro-2-(2,2,2-triptoreline)benzaldehyde.

In a nitrogen atmosphere in a round bottom flask was placed 880 mg (22 mmol) of 60% sodium hydride (NaH) and 12 ml of N,N-dimethylformamide. In this system was added to 2.9 ml (4 g, 40 mmol) 2,2,2 - triptoreline, additive produced via syringe over 15 min, then the mixture was stirred at room temperature for 20 minutes then added 1,72 g (10 mmol) of 2,5-dichlorobenzonitrile and the mixture was heated to 90oC for three days. Then the mixture was cooled to room temperature, poured into 50 ml of 1M aqueous HCl and was extracted with three portions of ether. The combined organic fractions were dried (Na2SO4) and concentrated to obtain 2.5 g of a solid substance. The crude material was purified column flash chromatography using a mixture of 1: 49 ethyl acetate/hexane as eluent, to obtain 1.4 g of 5-chloro-2- (2,2,2-triptoreline) benzonitrile in the form of a white solid. Melting point 61-62oC.

In a nitrogen atmosphere in a round bottom flask, equipped with reflux condenser, were placed the I and within 6 h was heated mixture under reflux, then was stirred at room temperature overnight. The mixture was filtered through a filter made of diatomaceous earth, and then washed the filter with water and CHCl3. The layers were separated and the aqueous phase was extracted with three portions CHCl3. The combined organic fractions were dried and concentrated to obtain 270 mg of the desired compound.

1H NMR (CDCl3) was 4.42 (m, 2H), 6,86 (d, 1H, J = 10), 7,46 (m, 1H), 7,80 (d, 1H, J = 3) (s, 1H).

Mass spectrum: m/z 238 (bear.).

C. (2S, 3S)-3-(5-chloro-2-[2,2,2-triptoreline] - benzyl)amino-2-phenylpiperidine hydrochloride.

The desired compound was obtained in a manner analogous to the method described in example 4, substituting 2-methoxy-5-triptoreline - benzaldehyde 5-chloro-2-(2,2,2-triptoreline) benzaldehyde. Melting point 267 - 269oC.

1H NMR (free base, CDCl3) 1,4 (m, 1H), 1,6 (m, 1H), equal to 1.82 (m, 1H), 2,02 (m, 1H), 2,78 (m, 2H), 3,2 (m, 1H), 3,3 (d, 1H, J = 15), of 3.54 (d, 1H, J = 15), of 3.84 (d, 1H, J = 3), 4,0 (m, 2H), is 6.54 (d, 1H, J = 10), 6,92 (d, 1H, J = 3), 6,04 (m, 1H), from 7.24 (m, 5H).

Estimates for C20H22ClF3N2O 1,4 (m, 1H), and 1.56 (m, 1H), 1,78 (m, 1H), 1,96 (m, 1H), was 2.76 (m, 1H), 3,18 (m, 1H), 3,30 (d, 1H, J = 15), of 3.46 (d, 1H, J = 15), of 3.84 (d, 1H, J = 3), 6,79 (s, 1H), 6,85 (d, 1H, J = 6), 6,94 (m, 1H), for 7.12 (m, 1H), from 7.24 (m, 5H).

Estimates for C19H21F3N2

Example 10. (2S,3S)-3-[5-chloro-2-(2,2,2-triptoreline)benzyl]amino-2-phenylpiperidine hydrochloride.

Melting point 267 - 269oC.

1H NMR (free base, CDCl3) ] of 1.40 (m, 1H), 1,60 (m, 1H), equal to 1.82 (m, 1H), 2,02 (m, 1H), was 2.76 (m, 2H), 3,20 (m, 1H), 3,28 (d, 1H, J = 15), 3,52 (d, 1H, J = 15), of 3.84 (d, 1H, J = 3), of 4.00 (m, 2H), is 6.54 (d, 1H, J = 10), 6,92 (d, 1H, J = 3),? 7.04 baby mortality (m, 1H), from 7.24 (m, 5H).

The mass spectrum. estimates for C20H22ClF3N2O: 398,1368.

Found: 398,1352.

Estimates for C20H22ClF3N2O of 1.20 (s, 9H), of 1.40 (m, 1H), of 1.52 (m, 1H), of 1.84 (m, 1H), 2.06 to (m, 1H), 2,80 (m, 2H), up 3.22 (m, 1H), 3,38 (d, 1H, J = 15), to 3.58 (d, 1H, J = 15), 3,86 (d, 1H, J = 3), 6,98 (m, 1H), 7,12 (m, 2H), 7,26 (m, 5H).

The mass spectrum. estimates for C23H29F3N2O: 406,2225.

Found: 406,2271.

Estimates for C23H29F3N2O2HCl1/3H2O: C 56,92 H 6,56 N 5,77.

Found: C 56,99 H 6,41 N 6,03.

Example 12. (2S,3S)-3-[5-isopropyl-2-(2,2,2-triptoreline)benzyl]amino-2-phenylpiperidine hydrochloride.

The mass spectrum. estimates for C23H30F3N2O (M+1): 407,2303.

Found: 407,2287

Estimates for C23H29F3N2O2HCl1/2H2O: C 56,55 H 6,60 N 5,70.

Found: C 56,17 H 6,39 N 5,77.

Example 13. (2S,3S)-3-[5-dimethylamino-2-(2,2,2-triptoreline)benzyl]amino-2 - phenylpiperidine hydrochloride.

The melting point of 250 - 252oC.

1H NMR (free base, CDCl3) of 1.40 (m, 1H), 1,60 (m, 1H), to 1.86 (m, 1H), 2,10 (m, 1H), 2,82 (m, 8H), up 3.22 (m, 1H), 3,34 (d, 1H, J = 15), to 3.58 (d, 1H, J = 15), 3,88 (d, 1H, J = 3), of 4.00 (m, 2H), 6.42 per (d, 1H, J = 3), 6,50 (m, 1H), only 6.64 (d, 1H, J = 10), 7,30 (m, 5H).

The mass spectrum. estimates for C22H28F3N3O: 407,2178.

Found: 407,2179.

Example 14. (2S,3S)-3-(2-deformedarse-5-N,N-dimethylaminoethyl)amino-2 - phenylpiperidine hydrochloride.

Melting point 243 - 245oC (decomp.).

1H NMR (free base, CDCl3) of 1.44 (m, 1H), 1,72 (m, 2H), 2,10 (m, 1H) 2,84 (m, 8H), 3,21 (m, 1H), 3,28 (d, 1H, J = 15), 3,55 (d, 1H, J = 15), 3,88 (d, 1H, J = 3) between 6.08 (t, 1H, J = 72), 6,36 (d, 1H, J = 3) 6,46 (dd, 1H, J = 3,9) 6,86 (d, 1H, J = 9), 7,28 (m, 5H).

The mass spectrum. the calculated d is C21H27F2N3O1HCl1/2H2O: C 51,07 H 6,44 N 8,51.

Found: C 50,71 H Between 6.08 N 8,28.

Example 15. (2S,3S)-3-[2,5-bis-(deformedarse)benzyl]amino-2-phenylpiperidine hydrochloride.

Melting point 238-239oC.

1H NMR (free base, CDCl3) of 1.64 (m, 3H), 2,04 (m, 1H), was 2.76 (m, 2H), 3,18 (m, 1H), 3,28 (d, 1H, J = 12), 3,52 (d, 1H, J = 12), of 3.84 (d, 1H, J = 3), 6,12 (t, 1H, J = 75), 6,40 (t, 1H, J = 75), to 6.75 (m, 2H), 6,94 (d, 1H, J = 9), from 7.24 (m, 5H).

The mass spectrum. estimates for C20H22F4N2O2: 398,1612.

Found: 398,1591.

Example 16. (2S,3S)-3-(5-tert-butyl-2-deformational)-amino-2-phenylpiperidine hydrochloride.

Melting point 263 - 264oC (decomp.).

1H NMR (free base, CDCl3)% 1,24 (s, 9H), of 1.42 (m, 1H), 1,62 (m, 1H), 1,80 (m, 1H), 2,10 (m, 1H), 2,80 (m, 2H), 3,24 (m, 2H), to 3.58 (d, 1H, J = 12), a 3.87 (brs, 1H) 6,18 (t, 1H, J = 72), 6,86 (d, 1H, J = 6), 7,00 (brs, 1H), for 7.12 (m, 1H), from 7.24 (m, 5H).

The mass spectrum. estimates for C23H30F2N2O: 388,23121.

Found: 388,2336.

Example 17. (2S,3S)-3-(2-isopropoxy-5-cryptomaterial)amino-2-phenylpiperidine hydrochloride.

Melting point 245 - 246oC (decomp.).

1H NMR (free base: CDCl3) a 1.08 (d, 31H, J = 9) PC 6.82 (m, 1H) 6,91 (m, 1H), from 7.24 (m, 5H).

The mass spectrum. estimates for C22H27F3N2O2: 408,2024.

Found: 408,2019.

Estimates for C22H27F3N3O2the 1.44 (m, 1H), 1,58 (m, 1H): 1,78 (m, 1H), 2,03 (m, 1H), 2,78 (m, 2H), 3,20 (m, 1H), 3,32 (d, 1H, J = 15), of 3.54 (d, 1H, J = 15), a 3.87 (d, 1H, J = 2), x 6.15 (t, 1H, J = 72), 6,94 (m, 3H) 7,26 (m, 5H).

The mass spectrum. estimates for C20H21F3N2O2: 416,1523.

Found: 416,1501.

Estimates for C20H21F5N2O21/3H2O: C 48,50 H 4,81 N 5,65.

Found: C 48,45 H 4,57 N 5,66.

Example 19. (2S,3S)-3-(2-ethoxy-5-cryptomaterial)amino-2-phenyl-piperidine hydrochloride.

Melting point > 275oC (decomp.).

1H NMR (free base, CDCl3) of 1.13 (t, 3H, J = 6), to 1.38 (m, 1H), 1,70 (m, 2H), 2.06 to (m, 1H), 2,74 (m, 2H), up 3.22 (m, 1H), 3,30 (d, 1H, J = 15), 3,68 (m, 3H), of 3.84 (brs, 1H), 6,55 (d, 1H, J = 9), 6,79 (brs, 1H), 6.90 to (m, 1H), to 7.2 (m, 5H).

The mass spectrum. estimates for C21H25F3N2O2: 394,1868.

Found: 394,1875.

Estimates for C21H25F3N2O21,50 (m, 1H), of 1.66 (m, 1H) to 1.98 (m, 2H), 2,82 (m, 2H), or 3.28 (m, 1H), 3,42 (d, 1H, J = 15), to 3.64 (d, 1H, J = 15), of 3.95 (d, 1H, J = 2), 6,30 (t, 1H, J = 72), 7,3(M+1): 378,1629.

Found: 378,1597.

Example 21 (2S,3S)-3-(2-deformedarse-5-isopropylbenzyl)amino-2-phenyl-piperidine hydrochloride.

Melting point 245 - 247oC (decomp.).

1H NMR (free base, CDCl3) to 1.19 (2d, 6H, J = 7), 1,50 (m, 1H), about 1.75 (m, 2H), 2,12 (m, 1H), and 2.83 (m, 3H), of 3.25 (m, 1H), 3,35 (d, 1H, J = 14), 3,60 (d, 1H, J = 14), 3,90 (d, 1H, J = 3), of 6.20 (t, 1H, J = 75), of 6.90 (m, 2H), 7,00 (m, 1H), 7,39 (m, 5H).

The mass spectrum. raschet. data for C22H28F2N2O: 374,2170.

Found: 374,2207.

Estimates for C22H28F2N2O2HCl1/3H2O: C 58,28 H 6,67 N 6,18.

Found: C 58,17 H 6,52 N 6,17.

Example 22. (2S,3S)-3-[5-acetamido-2-(2,2,2-triptoreline)benzyl]amino-2 - phenylpiperidine hydrochloride.

Melting point > 270oC.

1H NMR (free base, CDCl3) of 1.46 (m, 1H), equal to 1.82 (m, 1H), 2,08 (m, 1H), 2,12 (m, 3H), was 2.76 (m, 2H), 3,20 (m, 1H), 3,48 (d, 1H, J = 15), to 3.58 (d, 1H, J = 15), 3,82 (m, 1H), 4,08 (m, 2H), 6,44 (m, 1H), return of 6.58 (d, 1H, J = 10), is 6.78 (m, 1H), 7,26 (m, 5H), 7,58 (m, 1H).

Example 23. (2S, 3S)-3-(2-deformedarse-5-active compounds)amino-2-phenylpiperidine hydrochloride.

Melting point 254 - 255oC.

1H NMR (free base, CDCl3) of 1.12 (t, 3H, J = 10), of 1.36 (m, 1H), 1,44 (m, 1H), equal to 1.82 (m, 1H), 2,10 (m, 1H), 2,48 (g, nie data for C21H26F2N2O2HCl: C 58,19 H 6,51 N 6,47.

Found: C 57,90 H 6,52 N 6,64.

Example 24. CIS-3-(5-tert-butyl-2-methoxybenzyl) amino-2-(3-trifloromethyl)piperidine hydrochloride.

A. CIS-5-nitro-6-(trifloromethyl)piperidine-2-it.

In a nitrogen atmosphere in a round bottom flask were placed 15 g (79 mmol) of 3-triphtalocyaninine, 80 ml of ethanol, 11 g (0.26 mol) of ammonium acetate and 12.6 ml (79 mmol) of methyl-4 - nitrobutane, the mixture was heated under reflux for 6 hours After cooling to room temperature the mixture are condensed. The remaining material was stirred with 200 ml (approximately) CHCl3for 30 min, filtered and concentrated. The residue was purified column flash chromatography, elwira mixture 1:49 methanol-chloroform and then a mixture of 1:19 methanol/chloroform to obtain 24 g of 5-nitro-6-(3 - trifloromethyl)piperidine-2-it.

In a round bottom flask was placed 20 g (66 mmol) of the product of the above reaction, 13 g of KOH and 100 ml of ethanol, and the mixture was stirred at room temperature for 90 minutes In this system added about 35 ml of a mixture of 33% sulfuric acid/ethanol. The mixture was poured into 150 ml of water and was extracted with three portions of 100 ml CHCl3. United extracy chromatography (300 g silica gel), using ethyl acetate and then a mixture of 1:99 methanol/ethyl acetate as eluent, to obtain 5.8 g of CIS-5-nitro-6-(3-trifloromethyl)piperidine-2-it, which contained about 12% of the corresponding transisomer. This material was purified by chromatography (re) to obtain 4.6 g of the CIS product.

C. CIS-5-amino-6-(3-trifloromethyl)piperidine-2-it.

In a nitrogen atmosphere in a three-neck round bottom flask equipped with a thermometer and mechanical stirrer was placed the obtained CIS - material and a mixture of THF (200 ml), methanol (50 ml) and water (5 ml). With stirring, this solution was added aluminum amalgam (obtained by washing 4.1 g of strips of aluminum foil ether and immersion in a 2% aqueous solution of HgCl29 30 - 45 s and repeated washing with ether, the resulting mixture was stirred at room temperature overnight. The mixture was filtered through a filter made of diatomaceous earth and the filter washed with THF. The filtrate was concentrated, dissolved in ethyl acetate and treated with 30 ml of ether saturated with HCl. After concentration was obtained 3.7 g of crude CIS-5-amino-6-(3-trifloromethyl) piperidine-2-it is in the form of a waxy solid, melting point 126 - 130oC.

C. CIS-3-(5-tert-is padonou flask was placed 0,38 g (1.4 mmol) obtained as described above amine, 6 ml of acetic acid and 0.32 g (of 1.66 mmol) of 5-tert-butyl-2-methoxy - benzaldehyde. The mixture was stirred for 45 minutes In the system added to 0.60 g (3.0 mmol) of triacetoxyborohydride sodium (portions) and the mixture was stirred at room temperature overnight. The mixture was concentrated and divided between chloroform and H2O and podslushivaet aqueous solution of 1H NaOH. The layers were separated and the aqueous phase was extracted with two portions of CHCl3. The combined organic fractions were washed H2O, dried and concentrated. The crude product was purified flash column - chromatography to obtain 0.4 g of CIS-5-(5-tert-butyl-2 - methoxybenzyl)amino-6-3-trifloromethyl)piperidine-2-it.

In a nitrogen atmosphere in a round bottom flask was placed 0.4 g (0.9 mmol) of the product obtained above and 10 ml THF. To the system was added 2.2 ml (4.4 mmol) of 2M complex, borane-methyl sulfide in THF and gradually heat the mixture under reflux for 4 hours the Mixture was cooled to room temperature, was added 2 ml of methanol and the mixture was concentrated. Then the system was added 5 ml of ethanol and 2.45 K2CO3then the mixture was heated under reflux for 8 h and stirred at room temperature overnight. The mixture UB>2Cl3. The combined organic fractions were dried and concentrated to obtain oil. The oil was dissolved in ethyl acetate and the solution was treated with ether saturated with HCl. After concentration were obtained 70 mg of the desired compound in the form of a solid similar to a wax substance.

Melting point 247 - 249oC.

1H NMR (free base, CDCl3) of 1.26 (s, 9H), 1,6 (m, 1H), 1,90 (m, 2H), 2,12 (m, 1H), 2,80 (m, 2H) 3,24 (m, 1H), 3,36 (d, 1H, J = 15), of 3.48 (s, 3H), of 3.64 (d, 1H, J = 15), 3,86 (m, 1H), 6,60 (d, 1H, J = 10), 7,18 (m, 6H).

The mass spectrum. estimates for C24H31N2O2F3: 436,2330.

Found: 436,2326.

Example 25. CIS-2-(3,5-dibromophenyl)-3-(2-methoxy-5-cryptomaterial)-aminopiperidin.

The desired compound was obtained in a manner analogous to the method described in example 25, except that the nitrogen substituent in the product of the initial reaction /6-(3,5-dibromophenyl)-5-nitro-piperidine-2-it/ were converted into the amino group by sequential oxidative cleavage (O3, KO+Bu), formation of oxime (H2NOH) and recovery of Nickel Raney. The final product can be Patision through processing (R) - (-)- almond acid isopropyl is electroplated in an aqueous solution of sodium bicarbonate was obtained (2S,3S)-enantiomer, []D(salt almond acid): + 4,11o.

(MeOH, c = 0,51)

1H NMR (CDCl3) of 1.36 (m, 1H), 1,50 (m, 1H), 1,80 (m, 1H), 2,04 (m, 1H), 2,70 (m, 2H), 3,18 (m, 1H), 3,30 (d, 1H, J = 18), only 3.57 (s, 2H), 3,66 (d, 1H, J = 18 in), 3.75 (m, 1H), 6,63 (d, 1H, J = 9), 6,86 (d, 1H, J = 3), 6,97 (dd, 1H, J = 6), 9), 7,32 (m, 2H), of 7.48 (s, 1H).

Example 26.

(2S, 3S)-3-(2-deformedarse-5-methylbenzyl)amino-2-phenylpiperidine.

The desired compound was obtained by the method described in example 4.

Melting point > 275oC.

1H-NMR (free base, CDCl3) of 1.44 (m, 1H), 1,6 (m, 1H), of 1.84 (m, 1H), 2,10 (m, 1H), measuring 2.20 (s, 3H), 2,80 (m, 2H), up 3.22 (m, 1H), 3,34 (d, 1H, J = 15) to 3.58 (d, 1H, J = 15), 3,90 (d, 1H, J = 3) 6,10 (t, 1H, J = 72), at 6.84 (m, 2H), 7,26 (m, 5H).

The mass spectrum. estimates for C20H24F2N2O: 347,1929 (M+1).

Found: 347,1911.

Estimates for C20H24F2N2O2HCl0,25H2O: C 56,67 H 6,30 N 6,61.

Found: C 56,81 H 6,16 N 6,50.

1. Peralkaline derivatives of nitrogen-containing heterocycles of General formula

< / BR>
where X1is hydrogen, C1-C10-alkoxy, optionally substituted with one to three fluorine atoms, or C1-C10-alkyl, possibly substituted by one to three fluorine atoms;

X2and X31-C10-alkoxy, possibly substituted by one to three fluorine atoms, hydroxy, CI-C1-C6-alkylamino, and

< / BR>
provided that if any two of X1X2and X3both are not hydrogen, then the remaining third must be hydrogen; Q is a group of formula II or VII

< / BR>
< / BR>
where R1is phenyl;

R13is phenyl;

o = 2;

X - (CH2)qwhere q is the integer 3;

m is an integer from 0 to 8,

and any of the carbon atoms in (CH2)mcan be substituted for R11;

R6radical selected from C3-C7-cycloalkyl or phenyl, optionally substituted with one or more substituents selected independently from halogen and C1-C10-alkoxy, possibly substituted by one to three fluorine atoms;

R7is hydrogen;

R8and R9each is hydrogen;

R10is hydrogen or C1-C6-alkoxy;

R11is hydrogen or C1-C6-alkoxy, provided that a) when m = 0, one of R10and R11no, and the other represents hydrogen; (b) when none of X1X2and X3- the fluorinated alkoxygroup, R6is a phenyl group substituted fluorinated alkoxygroup, and (C) to the S="ptx2">

2. Connection on p. 1, wherein Q is a group of formula II, where o = 2.

3. Connection on p. 1, wherein Q is a group of formula VII, where q = 3.

4. Connection on p. 1, characterized in that the said compound is 2-(diphenylmethyl)-N-((2-deformedarse)-phenyl)methyl-1-azabicyclo[2,2,2]-Octan-3-amine.

5. Connection on p. 1, characterized in that the compound is a (2S,3S)-N-(2-methoxy-5-triptoreline-phenyl)methyl-2-diphenylmethyl-1-azabicyclo[2,2,2]Octan-3-amine.

6. Connection on p. 1, characterized in that the compound is a (2S,3S)-2-phenyl-3-[2-(2,2,2-triptoreline)benzyl]aminopiperidin.

7. Connection on p. 1, characterized in that the compound is a (2S, 3S)-3-(2-methoxy-5-triptoreline-benzyl)amino-2-phenylpiperidine.

8. Connection on p. 1, characterized in that the compound is a (2S,3S)-3-(2-hydroxy-5-triptoreline-benzyl)amino-2-phenylpiperidine.

9. Connection on p. 1, characterized in that the compound is a (2S,3S)-2-phenyl-3-(3-triptoreline-benzyl)aminopiperidin.

10. Connection on p. 1, characterized in that it is a (2S, 3S)-1-( notable what is (2S, 3S)-2-phenyl-3-(2-cryptomaterial)aminopiperidin.

12. Connection on p. 1, characterized in that it is a (2S, 3S)-2-[5-chloro-2-(2,2,2-triptoreline)benzyl]amino-2-phenylpiperidine.

13. Connection on p. 1, characterized in that it is a (2S, 3S)-3-(5-tert-butyl-2-cryptomaterial)amino-2-phenylpiperidine.

14. Connection on p. 1, characterized in that a represents a 3-(5-tert-butyl-2-methoxybenzyl)amino-2-(3-trifloromethyl)piperidine.

15. Connection on p. 1, characterized in that a represents a 3-(2-isopropoxy-5-cryptomaterial)amino-2-phenyl)-piperidine.

16. Connection on p. 1, characterized in that a represents a 3-(2-deformedarse-5-cryptomaterial)amino-2-phenylpiperidine.

17. Connection on p. 1, wherein X1- 5-triptoreline; X2is hydrogen; X3- 2-methoxy.

18. Connection on p. 1, wherein X1- 2-triptoreline and each of X2and X3- hydrogen.

19. Connection on p. 1, wherein X1- 2-(2,2,2-triptoreline) and each of X2and X3- hydrogen.

20. Connection on p. 1, wherein Q is a group of four -C6-alkyl or 5-C1-C6-alkoxy, possibly substituted by one to three fluorine atoms, and R6substituted or unsubstituted phenyl.

21. Connection on p. 1, wherein Q represents a group of the formula

< / BR>
where R1and R13independently selected from unsubstituted or substituted phenyl;

X1- 2-triptoreline, 2-methoxy or 2-(2,2,2-triptoreline);

X2- 5-halo, 5-C1-C6-alkoxy, possibly substituted by one to three fluorine atoms.

22. Connection on p. 1, characterized in that it is expressed by the formula

< / BR>
where n = 2;

X1is hydrogen or C1-C4-alkyl;

X2- OCF3or OCHF2;

R6- phenyl, possibly substituted by a Deputy selected from C1-C4-alkyl, C1-C4-alkoxy, fluorine and chlorine.

23. Connection on p. 1, characterized in that it is expressed by the formula

< / BR>
where n = 2;

X1- OCF3or OCHF2;

X2- C1-C4-alkoxy;

R6- phenyl, possibly substituted by a Deputy selected from C1-C4-alkyl, C1-C4-alkoxy, fluorine or chlorine.

24. Connection on p. 1, wherein X1- 2-C1- ausina fact, X1- 2-OCF3or 2-OCHF2;

X2is hydrogen and X3- C1-C4-alkyl.

26. Connection on p. 1, wherein R6selected from phenyl, possibly substituted C1-C4-alkyl, C1-C4-alkoxy, fluorine, chlorine or triptoreline, each of R7, R8, R9and R10if these radicals are present, is hydrogen, m = 0, if Q is a group of the formula VII.

27. Pharmaceutical composition having antagonistic activity against substance P, including an active ingredient and pharmaceutically acceptable additives target, characterized in that as the active ingredient it contains an effective amount of the compounds under item 1.

28. Method of inhibiting the action of substance P in a mammal, comprising introducing into their body antagonist of substance P, characterized in that as an antagonist of substance P using a connection on p. 1 in an effective dose.

 

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3 ex

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26 cl, 2 tbl, 253 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes diazepane derivative of the general formula (I)

or its pharmaceutically acceptable salt wherein ring B means phenyl; ring A means pyridyl substituted with halogen atom optionally, or phenyl substituted optionally with lower alkyl, lower alkoxy-group or halogen atom; X1 represents -C(=O)-NR2- or -NR2-C(=O)- wherein R2 means hydrogen atom; X2 represents -C(=O)-NR3- or NR3-C(=O)- wherein R3 means hydrogen atom; R represents hydrogen atom or halogen atom; R1 means lower alkyl. Also, invention relates to a pharmaceutical composition and inhibitor of blood coagulation activated factor X that can be used for prophylaxis and treatment of patients suffering with thrombosis or embolism.

EFFECT: valuable medicinal properties of compound.

5 cl, 5 tbl, 6 ex

FIELD: organic chemistry, medicine, oncology, pharmacy.

SUBSTANCE: invention relates to a new pentacyclic compound derivative of taxane represented by the formula:

wherein R1 represents dimethylaminomethyl group or morpholinomethyl group; R2 represents halogen atom or alkoxy-group comprising from 1 to 6 carbon atoms, or its salt eliciting an antitumor effect, and to a medicine agent based on its. Invention provides preparing new derivatives of taxane eliciting the valuable biological effect.

EFFECT: valuable medicinal properties of compound.

13 cl, 1 dwg, 4 tbl, 16 ex

FIELD: organic chemistry, cardiology, pharmacy.

SUBSTANCE: invention describes compounds of the formula (I)

wherein R1, R2, R3 and Ra-Rh have values given in the description. Proposed compounds are useful in prophylaxis and treatment of arrhythmia, in particular, atrial and ventricular arrhythmia, Also, the invention relates to methods for preparing compounds of the formula (I) and intermediate compounds.

EFFECT: valuable medicinal properties of compounds.

41 cl, 1 tbl, 8 ex

FIELD: medicine.

SUBSTANCE: the present innovation deals with preventing hemodynamic complications at restoring circulation in a prolongly ischemized limb, or due to premeditated tourniquet application during operative interference. For this purpose, 5-12 min before the onset of circulatory restoration it is necessary to start intravenous injection of antihistamine and glucocorticosteroid preparations, followed by drop-by-drop infusion of inhibitors of proteolytic enzymes which should be continued after tourniquet removal, as well. The method provides tourniquet shock and tourniquet shock-associated complications along with developing the chance for increasing the duration period of operation.

EFFECT: higher efficiency of prophylaxis.

3 ex

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