Amides of acids, method for their production and pharmaceutical composition based on them

 

The invention relates to new Amida acids of the formula Iwhere R1- C1-C6alkanoyl,1-C6alkoxycarbonyl, benzoyl, benzoyl substituted halogen (C1-C6)-alkoxy, C1-C6alkylsulfonyl, phenylsulfonyl, phenylsulfonyl, substituted with halogen, or cyclo (C3-C6) alkylsulphonyl, R2- phenyl, phenyloxy or phenylamino, where each phenyl may be substituted with halogen; pyridyl or pyridylamino, a represents a single bond, E is ethylene, X represents CH, Y is-NR5where R5is hydrogen, Q is-C(O)- or-SO2-, R3and R4together form ethylene, or their pharmaceutically acceptable salts. The compounds of formula I can be used for the treatment and/or prevention of diseases of the Central nervous system, such as amnesia, schizophrenia or dementia. 3 s and 5 C.p. f-crystals, 1 table.

Technical FIELD the Present invention relates to new amide compounds and their pharmaceutically acceptable salts that can be used as a medicine.

The PRIOR art Some of aminopiperidine derivatives were opisie PCT W091/01979 and WO 98/35951.

Description of the INVENTION the Present invention relates to new amide compounds and their pharmaceutically acceptable salts.

More specifically, it relates to new amide compounds and their pharmaceutically acceptable salts, which have cholinergic activity, to processes for their preparation, to contain their pharmaceutical compositions and to a method of treatment and/or prevention of disorders of the Central nervous system in mammals and, more particularly, to a method of treating and/or preventing amnesia, dementia (e.g., senile dementia, dementia of Alzheimer's, dementia associated with various diseases, such as cerebral vascular dementia, cerebral post-traumatic dementia, dementia due to brain tumors, dementia due to chronic subdural hematoma, dementia due to hydrocephalus at normal pressure, postmeningitic dementia, dementia type, Parkinson's disease, and so on), etc. in Addition, it is expected that the target connection will be useful as a therapeutic and/or prophylactic agents in the case of schizophrenia, depression, stroke, head injury, nicotine withdrawal symptoms, spinal cord injury, anxiety, pKa attention excessive sleepiness in the daytime (narcolepsy), Parkinson's disease or autism.

One of the objects of the present invention are new and useful amide compounds and their pharmaceutically acceptable salts with cholinergic activity.

The next object of the present invention are methods of obtaining these amide compounds and their salts.

Another object of the present invention is a pharmaceutical composition containing as active ingredient the above amide compounds and their pharmaceutically acceptable salts.

Another object of the present invention is a therapeutic method of treating and/or preventing the above diseases in mammals using these amide compounds and their pharmaceutically acceptable salts.

Amide compounds of the present invention are new and can be represented by the following General formula [I]:in which R1represents acyl, R2represents lower alkyl, lower alkoxy, lower alkylamino, lower alkenyl, lower alkenylacyl, lower alkynylamino, lower quinil, lower alkyloxy, lower alkynylamino, cyclo(NISS is, or amino, substituted heterocyclic group, each of which may be substituted by a suitable(and) substituent(s); or acyl; a represents a single bond,or-SO2-,
E represents the lowest alkylene, optionally substituted with a suitable(and) Deputy(mi),
X is CH or N,
Y represents a single bond, lower alkylene, or(where R5represents hydrogen, lower alkyl, substituted lower alkyl, N-protective group, aryl, acyl or heterocyclic group);
Q represents-CH2-,, -SO2- or-N=CH-, and
R3and R4each represent hydrogen or lower alkyl, or, taken together, form lower alkylene, optionally condensed with a cyclic hydrocarbon or heterocyclic ring,
provided that when X is N,
then: (1) Y represents a single bond,
and
Q represents-CH2-,or-SO2- or
2) Y is the lowest alkylene,
and their pharmaceutically acceptable salts.

The target compound [I] or its salt can be obtained by the methods shown in the reaction schemes set forth at the end of the description of uceni in the scope of the present invention, explained in detail below.

The term "lower" means a group containing from 1 to 6 carbon atoms, unless otherwise indicated.

The lowest group in the term "lower alkenyl", "lower alkenylacyl", "lower alkynylamino", "lower quinil", "lower alkyloxy" and "lower alkylamino" means a group containing from 2 to 6 carbon atoms.

The lowest group in terms of "cyclo(lower)alkyl, cyclo(lower)alkyloxy" and "cyclo(lower)alkylamino" means a group containing from 3 to 6 carbon atoms.

Suitable "lower alkyl" and lower alkyl group, the term "substituted lower alkyl", "ar(lower)alkyl, halo(lower)alkyl", "lower alkylamino", "lower alkylsilane", "lower alkylthio" and "lower alkylsulfonyl" may represent a linear or branched C1-C6alkyl, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, ethylpropyl, hexyl, or similar, of which the preferred methyl.

Suitable "lower alkenyl and lower Alchemilla part in terms of "lower alkenylacyl" and "lower alkynylamino' may be a linear or branched C2-C6alkenyl, such as ethynyl, propenyl, butenyl, pentenyl, hexenyl, Isopropenyl, butadienyl, pentadienyl,"lower quinil and lower Alchemilla group in the term "lower alkyloxy" and "lower alkynylamino' may be a linear or branched C2-C6quinil, such as ethinyl, propargyl, butynyl or etc., of which is preferable ethinyl.

Suitable "cyclo(lower)alkyl and cyclo(lower)alkyl group in terms of "cyclo(lower)alkyloxy" and "cyclo(lower)alkylamino" can be a cyclo(C3-C6)alkyl, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, of which the preferred cyclopropyl.

Suitable "aryl" or agrupa in the terms "ar(lower)alkoxy", "aryloxy", "arylamino", "arylsulfonyl", "aroyl" and "ar(lower)alkyl" may be phenyl, naphthyl, phenyl, substituted lower alkyl [e.g. tolyl, xylyl, mesityl, cumenyl, di(tert-butyl)phenyl, etc.] and so forth, of which preferred is phenyl or tolyl.

Suitable "ar(lower)alkyl" may be a benzyl, phenethyl, phenylpropyl, benzhydryl, trityl and so on, of which preferred is benzyl.

Suitable "lower alkylene and lower Allenova group in the term "lower alkylenedioxy" can be a linear or branched C1-C6alkylene, such as methylene, ethylene, trimethylene, propylene, tetramethylene, pentamethylene, hexamethylene, ethylethylene or so forth, of which prefers the terms "ar(lower)alkoxy and halo(lower)alkoxy" may be a linear or branched C1-C6alkoxy, such as methoxy, ethoxy, propoxy, isopropoxy, methylpropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy, hexyloxy or so forth, of which preferred is methoxy or tert-butoxy.

Suitable "ar(lower)alkoxy" may be a benzyloxy, penetrate, phenylpropoxy, benzhydrylamine, trityloxy etc.

Suitable "halogen" and a halogen group in the term "halo(lower)alkyl" may be fluorine, chlorine, bromine and iodine, of which preferred is fluorine, chlorine or iodine.

Suitable "halo(lower)alkyl" may be lower alkyl, substituted by one or more halogen atoms, such as chloromethyl, dichloromethyl, vermeil, deformity, trifluoromethyl, pentachloride or so forth, of which preferred is trifluoromethyl.

Suitable "halo(lower)alkoxy" may be a lower alkoxy, substituted by one or more halogen atoms, such as chloromethoxy, dichloromethoxy, formatosi, deformedarse, triptoreline, pentachloroethane or so forth, of which preferred is triptoreline.

Suitable "lower alkylamino" can be a mono - or di(lower alkylenediamine, hexylamino, dimethylamino, diethylamino, dipropylamino, dibutylamino, diisopropylamino, diphenhydamine, digoxigenin, N-methylethylamine or so forth, of which preferred is dimethylamino.

Suitable "lower alkylsilane" can be a mono-, di -, or three(lower)alkylsilane, such as trimethylsilyl, dimethylsilane, triethylsilyl or so forth, of which preferred is trimethylsilyl.

Suitable "lower alkylenedioxy" can represent methylenedioxy, Ethylenedioxy and so on, of which preferred is methylendioxy.

Suitable "heterocyclic group" may be a group containing at least one heteroatom selected from nitrogen atoms, sulfur and oxygen, and may include saturated or unsaturated, monocyclic or polycyclic heterocyclic group, and preferable heterocyclic group may represent a N-containing heterocyclic group such as unsaturated 3-6 membered heterophilically group containing 1 to 4 nitrogen atoms, for example pyrrolyl, pyrrolidyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl [e.g., 4H-1,2,4-triazolyl, 1H-1,2,3-triaina heterophilically group, containing 1 to 4 nitrogen atoms [e.g., pyrrolidinyl, imidazolidinyl, piperidyl, piperazinil, homopiperazine and so on];
unsaturated condensed heterophilically group containing 1 to 5 nitrogen atoms, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, hinely, ethanolic, imidazopyridine, indazoles, benzotriazolyl, tetrasulphide-sinil [for example, tetrazolo[1,5-b]pyridazinyl etc.], honokalani etc;
unsaturated 3-6 membered heterophilically group containing an oxygen atom, such as pyranyl, furyl, etc.;
saturated 3-6 membered heterophilically group containing an oxygen atom, for example, 1H-tetrahydropyranyl, tetrahydrofuranyl etc;
unsaturated 3-6 membered heterophilically group containing 1 to 2 sulfur atoms, for example thienyl etc;
unsaturated 3-6 membered heterophilically group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example oxazolyl, isoxazolyl, oxadiazolyl [e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl etc.], oxazolines [e.g., 2-oxazolyl etc] etc.;
saturated 3-6 membered heterophilically group containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [on the 2 oxygen atoms and 1 to 3 nitrogen atoms [e.g., benzofurazanyl, benzoxazolyl, benzodiazepin and so on];
unsaturated 3-6 membered heterophilically group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example thiazolyl, thiadiazolyl [e.g., 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl etc] etc.;
saturated 3-6 membered heterophilically group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., diazolidinyl and so on];
unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [e.g., benzothiazolyl, benzothiadiazole and so on];
unsaturated condensed heterocyclic group containing 1 to 2 oxygen atoms [e.g., benzofuranyl, benzodioxolyl, bromanil and so on] and etc.

Mentioned "heterocyclic group" may be substituted by lower alkyl, examples of which are listed above, among which preferred is thienyl, pyridyl, methylpyridyl, hinely, indolyl, honokalani, benzofuranyl, or tetramethylchroman, and more preferred is pyridyl.

Suitable "acyl" may be carboxypropyl; the esterified carboxypropyl; carbarnoyl, substituted lower alkyl, aryl, ar(lower)alkyl, ar who were radioactive; lower alkylsulfonyl; cyclo(lower)alkylaryl; lower alkanoyl; substituted or unsubstituted, aroyl; heterocyclicamines etc.

Esterified carboxypropyl can be a substituted or unsubstituted lower alkoxycarbonyl [e.g., methoxycarbonyl, etoxycarbonyl, propoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, hexyloxyphenyl, 2-iodoxybenzoic, 2,2,2-trichlorocyanuric and etc.], substituted or unsubstituted aryloxyalkyl [e.g., phenoxycarbonyl, 4-nitrophenoxide, 2-naphthaleneboronic and etc.], substituted or unsubstituted ar(lower)alkoxycarbonyl [e.g., benzyloxycarbonyl, ventilatsioonil, benzylaminocarbonyl, 4-nitrobenzenesulfonyl and so on] and so forth, of which preferred is unsubstituted lower alkoxycarbonyl, and more preferred is methoxycarbonyl or tert-butoxycarbonyl.

Carbarnoyl, substituted lower alkyl, could constitute methylcarbamoyl, ethylcarbitol, propellerblades, dimethylcarbamoyl, diethylcarbamoyl, N-methyl-N-ethylcarbamate etc.

Carbarnoyl, substituted aryl, could constitute phenylcarbamoyl, afterburner, phenylcarbamoyl, substituted lower alkyl [establet benzylcarbamoyl, phenetically, phenylpropionyl and so on, of which preferred is benzylcarbamoyl.

Carbarnoyl, replaced by arylsulfonyl, could constitute phenylsulfonylacetate, tolylsulfochloride etc.

Carbarnoyl, substituted lower alkylsulfonyl, could constitute methylsulfonylbenzoyl, ethylsulfonyl etc.

Carbarnoyl, substituted heterocyclic group, can be a carbarnoyl, replaced the above heterocyclic group.

Lowest alkanoyl may be a formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl and so on, of which preferred is acetyl or pivaloyl.

Substituted or unsubstituted, aroyl may be a benzoyl, Naftoli, toluoyl, di(tert-butyl)benzoyl, halogen(lower)alkoxybenzyl [e.g., trifloromethyl and so on] and so forth, of which preferred is benzoyl or trifloromethyl.

Substituted or unsubstituted arylsulfonyl can be phenylsulfonyl, tamilselvan, halogenerator [for example, perpenicular etc.] and so forth, of which preferred is perpersonperbooking is methylsulphonyl.

Cyclo(lower)alkylaryl can be a cyclo (C3-C6) alkylsulphonyl, such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl or cyclohexylcarbonyl, of which is preferable cyclopropanecarbonyl.

Heterocyclic group, the term "heterocyclicamines" may be one of the above heterocyclic groups.

Suitable "acid residue" may be halogen (e.g. fluorine, chlorine, bromine, iodine], arenesulfonic [for example, benzosulfimide, tosyloxy etc.], alkanesulphonic [for example, mesilate, econsultancy and so on] and so forth, of which preferred is halogen.

Suitable "N-protective group" may be a conventional N-protecting group, such as substituted or unsubstituted lower alkanoyl [e.g. formyl, acetyl, propionyl, TRIFLUOROACETYL, etc. ], lowest alkoxycarbonyl [e.g., tert-butoxycarbonyl, tert-aryloxyalkyl and etc.], substituted or unsubstituted Uralelectromed [e.g., benzyloxycarbonyl, p-nitrobenzenesulfonyl etc.], 9-fluorenylmethoxycarbonyl, substituted or unsubstituted arenesulfonyl [for example, benzazolyl, tosyl etc.], nitrophenyloctyl, the Aral sea is more preferred is tert-butoxycarbonyl.

Suitable "cyclic hydrocarbon" may represent a saturated or unsaturated cyclic hydrocarbon, such as cyclopentane, cyclohexane, benzene, naphthalene, indan, inden, or etc.

Suitable "substituted lower alkyl" may be lower alkyl substituted by halogen, aryl, acyl, lower alkoxy, aryloxy and so on , of which preferred is benzyl.

Suitable "heterocyclic ring" may be a ring, which is the above heterocyclic group, with the accession of hydrogen.

Preferred "acyl" for R1may be lower alkanoyl; lower alkoxycarbonyl; aroyl, optionally substituted by halogen(lower)alkoxy; arylsulfonyl, optionally substituted with halogen; lower alkylsulfonyl; or cyclo(lower)alkylaryl, of which more preferred is acetyl, pivaloyl, methoxycarbonyl, tert-butoxycarbonyl, benzoyl, trifloromethyl, perpenicular, methylsulphonyl or cyclopropanecarbonyl.

Preferred suitable Deputy" as a substituent of lower alkyl, lower alkoxy, lower alkylamino lowest alkenyl, lower alkenylacyl, lower alkynylamino, messagessexo)alkylamine, aryl, aryloxy, arylamino, heterocyclic group or amino substituted heterocyclic group, R2can be a halogen(lower)alkyl, halo(lower)alkoxy, lower alkenyl, lower quinil, lower alkylamino, acylamino, acyl, lower alkylsilane, lower alkoxy, aryl, lower alkylenedioxy, acyloxy, hydroxy, nitro, amino, cyano, halogen, aryloxy, lower alkylthio etc.

Preferred "aryl which may be substituted by a suitable(and) substituent(s)" for R2may represent aryl, optionally substituted with halogen, which is preferred forfinal.

Preferred "arylamino, which may be substituted by a suitable(and) substituent(s)" for R2may be arylamino, optionally substituted with halogen, of which preferred is phenylamino or forgenerating.

Preferred "aryloxy, which may be substituted by a suitable(and) substituent(s)" for R2may be aryloxy, optionally substituted with halogen, of which preferred is fervency.

Preferred "lower alkylene" for Y can be methylene.

Preferred "lower alkit-butoxycarbonyl.

Preferred "appropriate Deputy as the Deputy of the lower alkylene for E can be oxo, lower alkyl, hydroxy(lower)alkyl or acyl, of which more preferred is oxo, dioxo, methyl, dimethyl, hydroxymethyl or benzylcarbamoyl.

Preferred "lower alkylene" for E can be methylene, ethylene or trimethylene and more preferred is ethylene.

Preferred "lower alkyl" for R3and R4can be methyl.

Preferred "lower alkylene, which form an R3and R4taken together may be ethylene or trimethylene.

Preferred cyclic hydrocarbon, which condensed the lowest alkylene" may represent a benzene.

The preferred compound [I] is a compound containing a lower alkanoyl, lower alkoxycarbonyl, aroyl, aroyl, substituted halogen(lower)alkoxy, lower alkylsulfonyl, arylsulfonyl, arylsulfonyl, substituted with halogen, or cyclo(lower)alkylaryl as R1, aryl, aryloxy or arylamino, where each aryl may be substituted with halogen; pyridyl; or pyridylamino as R2single link as Well, ethylene as E, SN as X3 and R4that you need to take along for his education, or lower alkanoyl, lower alkoxycarbonyl, aroyl, aroyl, substituted halogen(lower)alkoxy, lower alkylsulfonyl, arylsulfonyl, arylsulfonyl, substituted with halogen, or cyclo(lower)alkylaryl as R1, aryl, aryloxy or arylamino, each aryl which may be substituted with halogen; pyridyl or pyridylamino as R2single link as Well, ethylene as E, N as X, single link as Y,as Q and ethylene as R3and R4that you need to take along for his education.

Suitable pharmaceutically acceptable salt of the target compound [I] are conventional non-toxic salts and include salt accession acid, such as salt accession inorganic acid [e.g. hydrochloride, hydrobromide, sulfate, phosphate, etc.], salt accession of organic acid [e.g. formate, acetate, triptorelin, maleate, tartrate, methanesulfonate, bansilalpet, toluensulfonate and so on], the salt of the amino acids [for example, salt, aspartic acid salt, glutamic acid and so on], salt of the metal, such as a salt of alkali metal, magnesium salt etc], etc.,

The methods of obtaining the target compound [I] are explained in detail next.

Method 1
The compound [Ia] or its salt can be obtained by reacting compound [II] or its salt with the compound [III] or its reactive compound by carboxy or sulfogrupp, or its salt.

Suitable salts of the compounds [Ia] and [II] may be the same as salt, is given as an example for the compound [I].

Suitable salts of the compound [III] or its reactive derivative of the carboxy - or sulfogrupp can be a metal salt or alkaline earth salt of the metal, is shown as an example for the compound [I].

A suitable reactive derivative of the carboxy - or sulfogrupp or compound [III] may include ester, halogenmethyl acid, acid anhydride, etc., Suitable examples of these reactive derivatives can be gelegenheid acid [e.g. acid chloride acid, bromohydrin acid, etc.]; symmetric acid anhydride; a mixed acid anhydride of the acid such as aliphatic carboxylic acid [e.g. acetic acid, pavlikova acid, etc.], substituted phosphoric acid [e.g. dialkylamino lower alkyl [e.g., methyl ether, ethyl ether, propyl ether, hexyl ether, trichlorethylene ether and so on], ester substituted or unsubstituted ar(lower)alkyl [e.g. benzyl ester, benzhydryl ether, p-chlorbenzoyl ether and so on], ester substituted or unsubstituted aryl [e.g. phenyl ester, colliny ether, 4-nitroaniline ether, 2,4-dinitrophenyl ether, pentachlorophenyl ether, nattily ether and so on] or an ester of N,N-dimethylhydroxylamine, N-hydroxysuccinimide, N-hydroxyphthalimide or 1-hydroxybenzotriazole, 1-hydroxy-6-chloro-1H-benzotriazole or so on These reactive derivatives can optionally be selected in accordance with the type of compound [III] to be used.

The reaction is usually carried out in a standard solvent such as water, acetone, dioxane, chloroform, dichloromethane, dichloroethane, tetrahydrofuran, acetonitrile, ethyl acetate, N,N-dimethylformamide, pyridine or any other organic solvent which does not affect the reaction adverse effects. Of these solvents, hydrophilic solvents can be used in a mixture with water.

The reaction is also preferably conducted in the presence of a conventional base such as t is connected [III] used in the reaction in the form of the free acid or in the form of its salts, the reaction is preferably carried out in the presence of a conventional condensing agent such as N,N'-dicyclohexylcarbodiimide, N-cyclohexyl-N'-morpholinobutyrophenone, N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide, thionyl chloride, oxalicacid, lower alkoxycarbonylmethyl [e.g., ethylchloride, isobutylparaben and so on], 1-(p-chlorobenzenesulfonate)-6-chloro-1H-benzotriazol or etc.

The reaction temperature is not critical and the reaction can be carried out under conditions of from cooling to heating.

Method 2
The compound [Ib] or its salt can be obtained by reacting compound [II] or its salt with a compound [IV].

Suitable salts of the compound [Ib] and [II] may be the same as salt, is given as an example for the compound [I].

This reaction is usually conducted in a solvent such as dioxane, tetrahydrofuran, benzene, toluene, chloroform, methylene chloride, or any other organic solvent which does not affect the reaction adverse effects.

The reaction temperature is not critical and the reaction is usually carried out under conditions of from cooling to heating up.

Method 3
The compound [IC] or its salt can be obtained by joint interaction with its salt.

Suitable salts of the compounds [IC] and [V] may be the same as salt, is given as an example for the compound [I].

Suitable salts of the compound [III] or its reactive derivative of the carboxy - or sulfogrupp can be a metal salt or alkaline earth salt of the metal, is shown as an example for the compound [I] .

This reaction can be carried out in substantially the same way as the 1 and, consequently, with respect to the carrying out of the reaction and reaction conditions [e.g. solvent, reaction temperature, etc.] for this reaction, it is necessary to refer to the method and conditions explained in method 1.

Method 4
The compound [Id] or its salt can be obtained by reacting compound [V] or its salt with a compound [IV].

Suitable salts of the compounds [Id] and [V] may be the same as salt, is given as an example for the compound [I].

This reaction can be carried out in substantially the same way as the 2 and, consequently, with respect to the carrying out of the reaction and reaction conditions [e.g. solvent, reaction temperature, etc.] for this reaction, it is necessary to refer to the method and conditions explained in method 2.

Method 5
Soeda reactive derivative at carboxy - or sulfogrupp, or its salt.

Suitable salt of the compound [VI] may be the salt of the accession acid is given as an example for the compound [I].

Suitable salts of the compound [VII] or its reactive derivative of the carboxy - or sulfogrupp can be a metal salt or alkaline earth salt of the metal, is shown as an example for the compound [I] .

This reaction can be carried out in substantially the same way as the 1 and, consequently, with respect to the carrying out of the reaction and reaction conditions [e.g. solvent, reaction temperature, etc.] for this reaction, it is necessary to refer to the method and conditions explained in method 1.

Method 6
The compound [Ie] or its salt can be obtained by reacting compound [VIII] or its reactive derivative of the carboxy - or sulfogrupp or its salt with a compound [IX] or its salt.

Suitable salts of the compounds [I], [VIII] and its reactive derivative at carboxy - or sulfogrupp can be the same as those given as examples for the compound [I].

Suitable salt of the compound [IX] can be the salt of the accession acid is given as an example for the compound [I].

Daoba the reaction and the reaction conditions [for example, solvent, reaction temperature, etc.] for this reaction, it is necessary to refer to the method and conditions explained in method 1.

Method 7
The compound [If] or its salt can be obtained as a result of interaction of the compound [X] or its salt with a compound [XI].

Suitable salts of the compounds [If] and [X] can be the same as those given as examples for the compound [I].

This reaction is preferably carried out in the presence of a base such as an alkali metal [e.g., lithium, sodium, potassium, etc.], alkaline earth metal [e.g. calcium, etc.], alkali metal hydride [e.g. sodium hydride, etc.], hydride alkaline earth metal [e.g. calcium hydride, etc.], the hydroxide or carbonate or bicarbonate of an alkali metal or alkaline earth metal [e.g. potassium bicarbonate, etc.], etc.,

This reaction is usually conducted in a solvent such as N,N-dimethylformamide, diethyl ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, or any other organic solvent which does not affect the reaction adverse effects.

The reaction temperature is not critical and the reaction can be carried out under conditions of from cooling to heating.

removal of the N-protective group.

Suitable salts of the compounds [If] and [Ig] can be salts of joining acids, such as shown as an example for the compound [I].

This reaction is carried out in the usual way, such as hydrolysis, recovery, etc.,

The hydrolysis is preferably carried out in the presence of a base or an acid including Lewis acid.

Suitable base may include an inorganic base and organic base such as an alkali metal [e.g. sodium, potassium, etc. ], alkaline earth metal [e.g. magnesium, calcium, etc.], hydroxides, or carbonates, or bicarbonates, hydrazine, alkylamine [for example, methylamine, trimethylamine, triethylamine, etc.], picoline, 1,5-diazabicyclo[4.3.0] non-5-ene, 1,4-diaza-bicyclo[2.2.2] octane, 1,8-diazabicyclo[5.4.0]undec-7-ene, or etc.

Suitable acid may include an organic acid [e.g. formic acid, acetic acid, propionic acid, trichloroacetic acid, triperoxonane acid and so on], an inorganic acid [e.g. hydrochloric acid, Hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, hydrogen fluoride, and so on] and compound salts join acid [e.g. hydrochloride feast is referencesee acid, etc.] or etc. preferably carried out in the presence of agents that monitor cations [e.g., anisole, phenol, etc.].

The reaction is usually conducted in a solvent such as water, alcohol [e.g. methanol, ethanol, etc.], methylene chloride, chloroform, carbon tetrachloride, dioxane, tetrahydrofuran, mixtures thereof, or any other solvent which does not affect the reaction adverse effects. The solvent can also use a liquid base or acid. The reaction temperature is not critical and the reaction can be carried out under conditions of from cooling to heating.

The recovery method that is suitable for the reaction of removal, may include chemical reduction and catalytic reduction.

Suitable reducing agents for use in chemical recovery, are a combination of metal [e.g. tin, zinc, iron, etc.], or compounds of metal [e.g. chromium chloride, chromium acetate, and so on] and an organic or inorganic acid [e.g. formic acid, acetic acid, propionic acid, triperoxonane acid, p-toluenesulfonic acid, hydrochloric acid, Hydrobromic acid, etc.].

When the N-protective group is a benzyl, restore preferably carried out in the presence of a combination of palladium catalysts [e.g., palladium mobiles, palladium on coal and so on] and formic acid or a salt thereof [for example, ammonium formate and so on].

Recovery is usually carried out in a conventional solvent which does not adversely affect the reaction, such as water, methanol, ethanol, propanol, N, N-dimethylformamide or a mixture thereof. In addition, by the by liquids, they can also be used as solvent. Moreover, a suitable solvent designed for use in the catalytic reduction, can represent the above-mentioned solvent and other conventional solvent such as diethyl ether, dioxane, tetrahydrofuran, etc. or a mixture thereof.

The reaction temperature is not critical and the reaction can be carried out under conditions of from cooling to heating.

Method 9
The compound [Ii] or its salt can be obtained as a result of interaction of the compound [Ih] or its salt with a compound [XII].

Suitable salts of the compound [Ih] and [Ii] may be the same as salt, is given as an example for the compound [I].

This reaction can be carried out in substantially the same way as the 7 and, consequently, with respect to the carrying out of the reaction and reaction conditions [e.g. solvent, reaction temperature, etc.] for this reaction, it is necessary to refer to the method and conditions explained in method 7.

Method 10
The compound [Ij] or its salt can be obtained by reacting compound [II] or its salt with a compound [XIII].

Suitable salts of the compounds [Ij] and [II] may be the same as salt provided as is, sledovatelno, regarding the carrying out of the reaction and reaction conditions [e.g. solvent, reaction temperature, etc.] for this reaction, it is necessary to refer to the method and conditions explained in method 7.

Compounds obtained by the above methods, you can select and clean a conventional method such as pulverization, recrystallization, column chromatography, pereosazhdeniya or etc.

It should be noted that the compound [I] and other compounds may include one or more stereoisomer(s), such as optical isomer(s) or geometrical isomer(s) due to the presence of asymmetric atom(EAM) carbon double bond(sa), and all of these isomers and their mixtures are included in the scope of the present invention.

In addition, it should be noted that any MES [for example, a connection of inclusion (e.g., hydrate etc.,)] compounds [I] or its pharmaceutically acceptable salts are also included in the scope of the present invention.

The target compound [I] and its pharmaceutically acceptable salts have a strong cholinergic activity and are useful for the treatment and/or prevention of disorders of the Central nervous system in mammals and, more specifically, amnesia, ultralights is s, such as cerebral vascular dementia, cerebral post-traumatic dementia, dementia due to brain tumors, dementia due to chronic subdural hematoma, dementia due to hydrocephalus at normal pressure, postmeningitic dementia, dementia type, Parkinson's disease, and so on), etc. in Addition, it is expected that the target compound can be used as a therapeutic and/or preventive agents in schizophrenia, depression, stroke, head injury, nicotine withdrawal symptoms, spinal cord injury, anxiety, pollakiuria, urinary incontinence, muscular dystrophy, a disorder associated with increased activity and lack of attention, excessive sleepiness in the daytime (narcolepsy), Parkinson's disease or autism.

To illustrate the usefulness of the target compound [I] the following pharmacological data for compound [I].

Test
The erection of penis in rats
(This test was performed in a manner analogous to that described in Jpn. J. Pharmacol., Vol. 64, 147-153 (1994)).

(i) Method
Used 344 male rats Fischer age 8 weeks (n=7). All rats kept for 3 minutes a day for three consecutive days before testing. Cu is E. Test compounds suspended in 0.5% methylcellulose immediately before use and injected intraperitoneally in a volume of 1 ml/kg immediately prior to the test. Immediately after injection, each rat was placed in a box from Lucite (HH cm) and observed its behavior within 60 minutes, during which produced a count of the number of erections of the penis. Behind each box was placed mirror to facilitate the rat. Data were expressed as the average number.

(ii) research Results (see tab. 1).

From the description in the Journal of Pharmacology and Experimental Therapeutics, Vol. 279, 3, 1157-1173 (1996) it is clear that the compounds having the above activity, improve memory (amnesia, dementia and so on) in Addition, on the basis of a number of patent applications (e.g., international PCT publication WO 98/27930 etc) expect that the compounds having the above activity can be used as a therapeutic and/or preventive method with the above-mentioned diseases.

For therapeutic purpose, the compound [I] or its pharmaceutically acceptable salt according to the present invention can be used in the form of pharmaceutical preparation containing one of these compounds as activivity, semi-solid or liquid excipient, suitable for oral or parenteral administration. Pharmaceuticals can represent gelatin capsules, tablets, pills, granules, suppositories, solution, suspension, emulsion, or etc., If desired, these drugs can include excipients, stabilizers, wetting or emulsifying agents, buffers, and other commonly used additives.

Although the dosage of the compound [I] will vary depending on the age and condition of the patient, for the treatment of the above diseases may prove to be effective average single dose, which constitutes about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound [I]. As a rule, the day you can enter the number, in the range from 0.1 mg/body weight to about 1000 mg/body weight.

Following receipt and examples are given to illustrate the present invention.

Getting 1
To a solution of 1-benzyl-4-aminopiperidine (50 g) in water (360 ml) was added dropwise a solution of di-tert-BUTYLCARBAMATE (61 g) in acetone (360 ml) under cooling in a water bath with ice. After stirring for 2.5 hours the precipitate was collected on a filter, washed with water and dried. The crude product Oia received O-tert-butyl N-(1-benzylpiperidine-4-yl)carbamate (66,9 g).

NMR (DMSO-d6,): 1,2-1,5 (2H, m), 1,37 (N, C) of 1.66 (2H, Shir. d, J=9.9 Hz), at 1.91 (2H, Shir. t, J=10,7 Hz), 2,73 (2H, distorted d, J=11.8 Hz), and 3.2 (1H, m) to 3.41 (2H, s), of 6.75 (1H, d, J=7.8 Hz), and 7.1 to 7.4 (5H, m).

Mass spectrum (APCI) (m/z): 291.

Getting 2
In a mixture of O-tert-butyl N-(1-benzylpiperidine-4-yl)carbamate (45 g) and 10% palladium on coal (50% wet, 9 g) in methanol (1 l) was barbotirovany hydrogen gas with stirring at room temperature. The catalyst was removed with a glass filter and the solvent was removed under reduced pressure. After washing diisopropyl ether was obtained O-tert-butyl N-(piperidine-4-yl)carbamate (28,35 g). The washing solvent was removed under reduced pressure and washed the rest of diisopropyl ether. Received a second fraction of O-tert-butyl N-(piperidine-4-yl)carbamate (344 mg).

NMR (DMSO-d6,): of 1.18 (2H, DDD, J=3,8, 11,8, and 11.8 Hz), 1,37 (N, C) of 1.62 (2H, distorted d, J=10,8 Hz), of 1.85 (1H, m), of 2.38 (2H, dt, J=2,2, 12.0 Hz), of 2.86 (2H, distorted d, J=12.3 Hz), and 3.2 (1H, m), 6,72 (1H, Shir. d).

Mass spectrum (APCI) (m/z): 201.

Getting 3
To a suspension of O-tert-butyl N-(piperidine-4-yl)carbamate (4.0 g) in dichloromethane (40 ml) was added pyridine (1,94 ml), dichloromethane (40 ml), acetic anhydride (20,8 ml) and then N,N-dimethylaminopyridine (0.1 g) when teletai, water and saturated salt solution. After drying over magnesium sulfate the solvent was removed under reduced pressure. After washing diisopropyl ether was obtained O-tert-butyl N-(1-acetylpiperidine-4-yl)carbamate (4,01 g).

NMR (DMSO-d6,): of 1.23 (2H, m), 1,38 (N, C) to 1.70 (2H, distorted t, J= 11.4 in Hz) of 1.97 (3H, s) of 2.64 (1H, Shir. t, J=11,1 Hz), 3.04 from (1H, dt, J=2,8, and 11.5 Hz), 3,42 (1H, m), and 3.72 (1H, Shir. d, J=15,0 Hz), 4,19 (1H, Shir. d, J= 13.1 Hz), 6,86 (1H, d, J=7.5 Hz).

Mass spectrum (APCI) (m/z): 243.

Getting 4
To a solution of O-tert-butyl N-(1-acetylpiperidine-4-yl)-carbamate (2,42 g) in dichloromethane (24 ml) was added 4 N. hydrogen chloride in dioxane (24 ml). The solvents were removed under reduced pressure. After washing diisopropyl ether was obtained the hydrochloride of 1-acetyl-4-aminopiperidine (2,02 g).

NMR (DMSO-d6,): of 1.41 (2H, m) of 1.93 (2H, distorted t) a 2.00 (3H, s), 2,60 (1H, Shir. t, J=10.4 Hz), 3,06 (1H, Shir. t, J=11.3 Hz), of 3.12 (1H, m), a-3.84 (1H, Shir. d, J=14,0 Hz), 4,34 (1H, Shir. d, J=13,0 Hz), 8,32 (3H, Shir. C).

Mass spectrum (APCI) (m/z): 143.

Getting 5
To a solution of phenylcarbamate (5,64 g) in dichloromethane (70 ml) was added a solution of 4-aminopyridine (2,84 g) and triethylamine (5,02 ml) in dichloromethane (100 ml) dropwise under cooling in a water bath with ice. After stirring within the organic phase was separated and washed with water and saturated salt solution. After drying over magnesium sulfate the solvent was removed under reduced pressure. The reaction mixture was diluted with diisopropyl ether and was filtered precipitation. After washing diisopropyl ether was obtained O-phenyl N-(4-pyridyl)carbamate (5,07 g).

NMR (CDCl3,): 7,17 (2H, m), 7,27 (1H, m), 7,3-7,5 (4H, m), and 8.50 (2H, DD, J=1,4, 5.0 Hz), of 8.06 (1H, s).

Mass spectrum (APCI) (m/z): 215.

Getting 6
To a solution of chloride of Sulfuryl (3.55 ml) in chloroform (45 ml) was added a solution of 1-acetylpiperidine (5,66 mg) and triethylamine (6,16 ml) in chloroform (15 ml) dropwise under cooling in a water bath with ice. After stirring for 6 hours the precipitate was collected by filtration. After drying over sodium hydroxide was obtained 1-acetylpiperidine-4-sulphonylchloride (2,43 g).

NMR (CDCl3,): of 2.15 (3H, s) to 3.35 (4H, m), of 3.69 (2H, t, J=5,1 Hz), 3,83 (2H, Shir. C).

Mass spectrum (APCI) (m/z): 227.

Getting 7
To a solution of 1-benzyl-4-aminopiperidine (1.13 g) in dichloromethane (10 ml) was added a solution of 4-tormentilla (0,99 g) in dichloromethane (1 ml) and diisopropylethylamine (1,09 ml) under cooling in a water bath with ice. The mixture gave to slowly warm to ambient temperature with stirring. The mixture was diluted with dichloromethane and the drying over magnesium sulfate the solvent was removed under reduced pressure. The residue was purified column chromatography (silica gel 100 ml, dichloromethane:methanol= 15: 1). After washing with a mixture of diisopropyl ether n-hexane (1:1) was obtained N-(1-benzyl-piperidine-4-yl)-4-perbenzoic (1.31 g).

NMR (DMSO-d6,): 1,4-1,7 (2H, m), 1.7 to 1.9 (2H, m), a 2.01 (2H, Shir. t, J= 10,7 Hz), of 2.81 (2H, Shir. d, J=11,6 Hz), of 3.46 (2H, s), of 3.73 (1H, m), 7,2-7,4 (7H, m), of 7.90 (2H, DD, J=5,6, 8,9 Hz), compared to 8.26 (1H, Shir. d, J=7,7 Hz).

Mass spectrum (APCI) (m/z): 313.

Getting 8
The following compound was obtained using 4-amino-1-benzylpiperidine as a starting compound in a manner analogous to the method of example 2.

N-(1-benzylpiperidine-4-yl)-N'-(4-forfinal)urea
NMR (DMSO-d6,): 1,25-1,5 (2H, m), 1.7 to 1.9 (2H, m), of 2.0-2.2 (2H, m), 2,65-2,8 (2H, m), 3,4-3,6 (3H, m), 6,07 (1H, d, J=7,6 Hz), 7,05 (2H, t, J=9 Hz), 7,2 was 7.45 (2H, m), 8,35 (1H, s).

Mass spectrum (APCI) (m/z): 328.

9
To a solution of N-(1-benzylpiperidine-4-yl)-N'-(4-forfinal)-urea (3.0 g) in a mixture of methanol (15 ml) and tetrahydrofuran (15 ml) was added palladium on coal (10% weight/weight, 50% wet, 0.6 g) and was first made this mixture under atmospheric pressure of hydrogen for 8 hours. The catalyst was filtered and evaporated the solvent under reduced pressure, obtaining a residue, which is triturated with diisopropyl e is 1-1,4 (2H, m), 1,65-of 1.85 (2H, m), 2,3-to 2.65 (2H, m), 2.8 to 3.0 (2H, m), 3,3-3,7 (1H, m), between 6.08 (1H, d, J=8 Hz),? 7.04 baby mortality (2H, t, J=9 Hz), of 7.25 and 7.5 (2H, m), with 8.33 (1H, s).

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

Receive 10
A mixture of N-(1-benzylpiperidine-4-yl)-4-fermentated (937 mg) and 10% palladium on coal (50% wet, 0.2 g) in methanol (20 ml) was stirred in hydrogen atmosphere for a period of 7.5 hours at ambient temperature. The catalyst was removed by a glass filter and the solvent was removed under reduced pressure. After washing diisopropyl ether was obtained N-(piperidine-4-yl)-4-perbenzoic (653 mg).

NMR (DMSO-d6,): 1,40 (2H, DDD, J=4,0, 11,9, to 23.8 Hz), 1,72 (2H, Shir. d, J= 9.5 Hz), 2,3-2,7 (2H, m), is 2.8-3.2 (2H, m), 3,80 (1H, m), 7,27 (2H, t, J=8,9 Hz), 7,92 (2H, DD, J=5,6, 8,9 Hz), compared to 8.26 (1H, d, J=7,7 Hz).

Mass spectrum (APCI) (m/z): 223.

Example 1
To a solution of O-phenyl N-(4-pyridyl)carbamate (446 mg) in 1,2-dichloroethane (5 ml) was added a suspension of 1-acetylpiperidine (1.12 g) in 1,2-dichloroethane (20 ml) at ambient temperature. The mixture was heated at 60oWith stirring for 9 hours. The mixture was cooled to ambient temperature and was diluted with dichloromethane and water. The aqueous phase was separated and brought to a pH of 11.5 with sodium hydroxide solution. To the water solution was added an excess of sodium chloride. The mixture extra is. the donkey drying over magnesium sulfate the solvent was removed under reduced pressure. The residue was purified column chromatography (silica gel 100 ml, dichloromethane: methanol: aqueous ammonia = 10:1:0,1). After washing diisopropyl ether was obtained 1-acetyl-4-(4-pyridylmethyl)piperazine (398 mg).

NMR (DMSO-d6,): 2,03 (3H, s), i.e., 3.3 to 3.6 (8H, m), 7,47 (2H, DD, J=1.5 and 4.8 Hz), 8,31 (2H, DD, J=1.5 and 4.8 Hz), 9,01 (1H, s).

Mass spectrum (APCI) (m/z): 271.

Example 2
To a solution of 1-acetylpiperidine (0,648 g) in tetrahydrofuran (10 ml) was added with stirring 4-forgenerations (0,574 g) at ambient temperature. After stirring at ambient temperature for 1 hour the solvent was removed by evaporation under reduced pressure, and the residue is triturated with diisopropyl ether, receiving 1-acetyl-4-(4-tortenelmebol)piperazine (1,25 d).

NMR (DMSO-d6,): 2,03 (3H, s), i.e., 3.3 to 3.6 (8H, m), 7,07 (2H, t, J=9 Hz), 7,46 (2H, DD, J=5,9 Hz), 8,61 (1H, s).

Mass spectrum (APCI) (m/z): 266.

Example 3
The following compound was obtained using 1-tert-butoxycarbonylmethyl as parent compound, in a manner analogous to the method of example 2.

1-tert-butoxycarbonyl-4-(4-tortenelmebol)-piperazine
NMR (Dctr (LD) (m/z): 346,2.

Example 4
To a solution of pyridine-4-carboxylic acid (1.0 g) and triethylamine (1.2 ml) in toluene (20 ml) was added diphenylphosphoryl (1.75 ml) at ambient temperature. The resulting mixture was heated at the boil under reflux for 30 minutes and was cooled to 0oC. To the mixture was added 1-tert-butoxycarbonylmethyl (1.51 g) and gave the mixture heated to 90oC for 1 hour. After cooling to ambient temperature the reaction mixture was dissolved in ethyl acetate, washed in turn with water and saturated salt solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographically on silica gel (150 ml) and elution 0-7% methanol in dichloromethane. In the trituration with a mixture of diisopropyl ether and ethanol was obtained 1-tert-butoxycarbonyl-4-(pyridine-4-ylcarbonyl)piperazine (0.66 g).

NMR (DMSO-d6,): 1,42 (N, C) at 3.25 to 3.5 (8H, m), 7,46 (2H, d, J=1,5,5 Hz), 8,30 (2H, d, J=1.5 and 5 Hz), of 9.00 (1H, s).

Mass spectrum (LD) (m/z): 307,2.

Example 5
To a suspension of the hydrochloride of 1-acetyl-4-aminopiperidine (0.4 g) in dichloromethane (5 ml) were added to queue pyridine (0.54 ml) and 4-ftorhinolonami (0,29 ml) at 0oC. the Mixture was allowed to warm up to the ambient temperature is amywali turns hydrochloric acid (1 to N. ), aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over magnesium sulfate. In the process of evaporation under reduced pressure, the obtained residue, which was triturated with diisopropyl ether, receiving 1-acetyl-4-(4-perfunctionary)piperidine (347 mg).

NMR (DMSO-d6,): 1,15-of 1.55 (2H, m), 1,7-of 1.95 (2H, m), from 2.00 (3H, s), 2,65-to 2.85 (1H, m), from 3.0 to 3.25 (1H, m), of 3.5-3.7 (1H, m), of 3.7-3.9 (1H, m), 4,15-up was 4.3 (1H, m), 7,05 of 7.3 (4H, m), 7,86 (1H, d, J=8 Hz).

Mass spectrum (APCI) (m/z): 281.

Example 6
To a suspension of the hydrochloride of 1-acetyl-4-aminopiperidine (715 mg) in dichloromethane (7 ml) were added diisopropylethylamine (1,83 ml) and a solution of 4-perbenzoic chloride (0,83 mg) in dichloromethane (2 ml) at ambient temperature. After stirring for 6.5 hours, the reaction mixture was diluted with dichloromethane and washed with water, saturated aqueous sodium hydrogen carbonate and a saturated solution of salt. After drying over magnesium sulfate the solvent was removed under reduced pressure. The residue was purified column chromatography (silica gel 50 ml, dichloromethane:methanol = 50:1 to 10:1). After washing diisopropyl ether was obtained N-(1-acetylpiperidine-4-yl)-4-perbenzoic (738 mg).

NMR (DMSO-d6,): of 1.40 (2H, m), is 1.81 (2H, ISCA,7 Hz), 7,29 (2H, t, J=8,9 Hz), 7,92 (2H, DD, J=5,5, 8,8 Hz), 8,31 (1H, d, J=7,7 Hz).

Mass spectrum (APCI) (m/z): 265.

Example 7
To a suspension of the hydrochloride of 1-acetyl-4-aminopiperidine (536 mg) in dichloromethane (5 ml) were added hydrochloride isonicotinohydrazide (534 mg) and diisopropylethylamine (1,05 ml) at ambient temperature. After stirring for 8 hours, the reaction mixture was poured into water and diluted with dichloromethane. Brought the pH of the mixture to 8.5 with 1 n sodium hydroxide solution. Was added to a mixture of sodium chloride and separated the organic phase. The aqueous phase was extracted with dichloromethane and the combined organic phase was dried over magnesium sulfate. The solvents were removed under reduced pressure. The residue was purified column chromatography (silica gel 50 ml, dichloromethane:methanol = 10:1). After crystallization from a mixture of diisopropyl ether:n-hexane was obtained N-(1-acetylpiperidine-4-yl)-N-isonicotinamide (477 mg).

NMR (DMSO-d6,): 1,4 (2H, m) and 1.83 (2H, distorted t, J=11 Hz), a 2.01 (3H, s), 2,69 (1H, Shir. t, J=11 Hz), 3,14 (1H, Shir. d, J=12 Hz), 3,83 (1H, Shir. d, J= 14.1 Hz), a 4.03 (1H, m) to 4.33 (1H, Shir. d, J=13.1 Hz), of 7.75 (2H, DD, J=1,7, 4,4 Hz), to 8.62 (1H, d, J=7.5 Hz), 8,72 (2H, DD, J=1,6, 4,4 Hz).

Mass spectrum (APCI) (m/z): 248.

Example 8
To a suspension of the hydrochloride of 1-acetyl-4-amino orida (0,83 mg) in dichloromethane (2 ml) at ambient temperature. After stirring for 6.5 hours, the reaction mixture was diluted with dichloromethane and washed with water, saturated aqueous sodium hydrogen carbonate and a saturated solution of salt. After drying over magnesium sulfate the solvent was removed under reduced pressure. The residue was purified column chromatography (silica gel 50 ml, dichloromethane:methanol 50:1 to 20:1). After washing diisopropyl ether was obtained N-(1-acetylpiperidine-4-yl)-4-forbindelsesfaneblad (859 mg).

NMR (DMSO-d6,): to 1.21 (2H, m), and 1.54 (2H, m), of 1.94 (3H, s) to 2.66 (1H, Shir. t, J=10,8 Hz), to 3.02 (1H, dt, J=2,9, 12.0 Hz), up 3.22 (1H, m) to 3.64 (1H, Shir. d, J= 14,0 Hz), of 4.05 (1H, Shir. d, J=13,2 Hz), 7,44 (2H, t, J=8,9 Hz), 7,8-8,0 (3H, m).

Mass spectrum (APCI) (m/z): 301.

Example 9
To a solution of O-phenyl N-(4-pyridyl)carbamate (0,81 g) in chloroform (10 ml) was added the hydrochloride of 1-acetyl-4-amino-piperidine (0.68 g) and triethylamine (1,06 ml) at ambient temperature. After stirring for 1 day, the mixture was turned into a solution. The solvents were removed under reduced pressure. The residue was purified column chromatography (silica gel 100 ml, dichloromethane: methanol = 10:1 to 5:1 and a silica gel 50 ml, dichloromethane:methanol:aqueous ammonia = 10:1:0,1). The solvents of the required fractions were removed under reduced pressure is the Xan (1.5 ml). The solvents were removed under reduced pressure, and the residue azeotrope was evaporated with methanol. After crystallization from diisopropyl ether and n-hexane was obtained N-(1-acetylpiperidine-4-yl)-N'-(4-pyridyl)urea (343 mg).

NMR (DMSO-d6,): 1,1-1,6 (2H, m), 1.77 in (2H, m), a 2.01 (3H, s) to 2.94 (1H, Shir. t, J=10.4 Hz), up 3.22 (1H, Shir. t, J=10.1 Hz), 3,76 (2H, m), of 4.05 (1H, d, J= 13,6 Hz), 7,60 (1H, d, J=7.8 Hz), 7,83 (2H, d, J=6.8 Hz), charged 8.52 (2H, d, J= 7,1 Hz), 11,21 (1H, s), 14,66 (1H, Shir. C).

Mass spectrum (APCI) (m/z): 263.

Example 10
To a suspension of the hydrochloride of 1-acetyl-4-aminopiperidine (536 mg) in dichloromethane (5 ml) was added 4-forgenerations (575 μl) and diisopropylethylamine (5,75 μl) at ambient temperature. After stirring for 3 hours the reaction mixture was diluted with dichloromethane. The organic phase was separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was dried over magnesium sulfate and removed the solvent under reduced pressure. After crystallization from diisopropyl ether and n-hexane was obtained N-(1-acetylpiperidine-4-yl)-N'-(4-forfinal)urea (448 mg).

NMR (DMSO-d6,): 1,1-1,5 (2H, m), of 1.80 (2H, distorted t, J=10 Hz), a 2.00 (3H, s), 2,77 (1H, Shir. d, J=10,8 Hz), 3,14 (1H, Shir. d, J=11,1 Hz), of 3.5-3.9 (2H, m), 4,16 (1H, Shir. d, J=13,2 Hz), 6,15 4-(4-perbenzoate)piperidine (0.25 g) in dichloromethane (5 ml) were added to queue pyridine (0,14 ml) and methylchloroform (87 μl) at 0oC. the Mixture was allowed to warm to ambient temperature and was stirred for 1 hour. To the mixture was added N,N-dimethylaminopyridine (0,13 g) and left under stirring for another 1 hour. The reaction mixture was dissolved in a mixture of water and ethyl acetate. The separated organic layer was washed in turn hydrochloric acid (1 ad), aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over magnesium sulfate. In the process of evaporation under reduced pressure, the obtained residue, which was triturated with diisopropyl ether, receiving 4-(4-perbenzoate)-1-ethoxycarbonylpyrimidine (0,265 g).

NMR (DMSO-d6,): 1,3-1,6 (2H, m), 1,75-1,9 (2H, m), 2,8-3,05 (2H, m), of 3.60 (3H, s), 3,85 of 4.1 (2H, m), 7,29 (2H, t, J=9 Hz), of 7.90 (2H, DD, J=6.9 Hz), 8,30 (1H, d, J=8 Hz).

Mass spectrum (APCI) (m/z): 281.

Example 12
To a solution of 4-(4-perbenzoate)piperidine (0.25 g) in pyridine (5 ml) were added to queue 4-triftorbyenzola-sulphonylchloride (0,219 g) and a catalytic amount of N,N-dimethylaminopyridine at 0oC. the Mixture was allowed to warm to ambient temperature and was stirred for 1 hour, then was dissolved in a mixture of water and dichloromethane. The separated organic layer was washed in turn hydrochloric acid (1 ad), aq is under reduced pressure, the obtained residue, which is triturated with diisopropyl ether, receiving 4-(4-perbenzoate)-1-(4-triftorperasin)-piperidine (0,38 g).

NMR (DMSO-d6,): 1,45-1,7 (2H, m), 1,8-of 1.95 (2H, m), 2,35 is 2.55 (2H, m), 3,5-of 3.85 (3H, m), 7,28 (2H, t, J=9 Hz), 7,50 (2H, t, J=9 Hz), 7,75-of 7.95 (4H, m), 8,31 (1H, d, J=8 Hz).

Mass spectrum (APCI) (m/z): 381.

Example 13
To a solution of 4-(4-perbenzoate)piperidine (0.15 g) in dichloromethane (5 ml) were added to queue pyridine (82 μl) and 4-cryptomaterial (106 μl) at 0oC. the Mixture was allowed to warm to ambient temperature and was stirred for 4 hours, then was dissolved in a mixture of water and dichloromethane. The separated organic layer was washed in turn hydrochloric acid (1 ad), aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over magnesium sulfate. Upon evaporation of the solvent under reduced pressure was obtained 4-(4-perbenzoate)-1-(4-trifloromethyl)piperidine (205 mg).

NMR (DMSO-d6,): 1,3-1,7 (2H, m), 1,7-2,0 (2H, m), 2,7-3,4 (2H, m), 3,4-3,8 (1H, m), 3,9-4,2 (1H, m), 4,2-4,6 (1H, m), 7,30 (2H, t, J=9 Hz), 7,35 and 7.6 (4H, m), to $ 7.91 (2H, DD, J=6.9 Hz), 8,35 (1H, d, J=8 Hz).

Mass spectrum (LD) (m/z): 433,2.

Example 14
To a solution of 4-(4-perbenzoate)piperidine (0.15 g) in dichloromethane (5 ml) paratory environment and was stirred for 1 hour. To the mixture was added N,N-dimethylaminopyridine (0,13 g) and left under stirring for another 1 hour. The reaction mixture was dissolved in a mixture of water and dichloromethane. The separated organic layer was washed in turn hydrochloric acid (1 ad), aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over magnesium sulfate. In the process of evaporation under reduced pressure, the obtained residue, which was triturated with diisopropyl ether, receiving 4-(4-perbenzoate)-1-methylsulfonylmethane (0,30 g).

NMR (DMSO-d6,): 1,45-1,7 (2H, m), 1,8-of 2.05 (2H, m), 2,7-2,95 (2H, m), is 2.88 (3H, s), 3,5-of 3.65 (2H, m), 3,8-of 4.05 (1H, m), 7,30 (2H, t, J=9 Hz), to $ 7.91 (2H, DD, J=6.9 Hz), at 8.36 (1H, d, J=8 Hz).

Mass spectrum (APCI) (m/z): 301.

Example 15
To a solution of N-(piperidine-4-yl)-N'-(4-forfinal)urea (0.3 g) in tetrahydrofurane (4 ml) were added to queue pyridine (0,28 ml), methylchloroform (98 μl) and a catalytic amount of N,N-dimethylaminopyridine at 0oC. the Mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The reaction mixture was dissolved in a mixture of water and ethyl acetate. The separated organic layer was washed in turn hydrochloric acid (1 ad), aqueous sodium hydrogen carbonate solution and saturated dissolve Irali with diisopropyl ether, receiving N-(1-ethoxycarbonylpyrimidine-4-yl)-N'-(4-forfinal)-urea (0.312 g).

NMR (DMSO-d6,): 1,1-1,4 (2H, m), 1.7 to 1.9 (2H, m), 2,8-3,1 (2H, m), 3,5-of 3.75 (1H, m) and 3.59 (3H, s), 3.75 to of 3.95 (2H, m), x 6.15 (1H, d, J=7,6 Hz), 7,05 (2H, t, J=9 Hz), 7,37 (2H, DD, J=5,9 Hz), of 8.37 (1H, s).

Mass spectrum (APCI) (m/z): 296.

Example 16
To a solution of N-(piperidine-4-yl)-N'-(4-forfinal)urea (0.3 g) in tetrahydrofuran (4 ml) were added to queue N,N-dimethylaminopyridine (0,23 g) and 4-forbindelsesfaneblad (0.25 g) at 0oC. the Mixture was allowed to warm to ambient temperature and was stirred for 1 hour. The reaction mixture was dissolved in a mixture of water and dichloromethane. The separated organic layer was washed in turn hydrochloric acid (1 ad), aqueous sodium hydrogen carbonate solution and saturated salt solution and dried over magnesium sulfate. In the process of evaporation under reduced pressure, the obtained residue, which was triturated with diisopropyl ether, receiving N-(1-(4-perpenicular)-piperidine-4-yl)-N'-(4-forfinal)urea (0,468 g).

NMR (DMSO-d6,): 1,3-1,6 (2H, m), 1,75-of 1.95 (2H, m), 2,45-2,7 (2H, m), 3,35-3,6 (3H, m), 6,14 (1H, d, J=7.5 Hz), 7,03 (2H, t, J=9 Hz), 7,34 (2H, DD, J=5, 9 Hz), 7,50 (2H, t, J=9 Hz), 7,75-of 7.95 (2H, m), 8,31 (1H, s).

Mass spectrum (APCI) (m/z): 396.

Example 17
To suspense olklore (290 μl) at ambient temperature. After stirring for 3.5 hours the mixture was poured in water (5 ml). The organic layer was separated and washed with water and saturated salt solution. After drying over magnesium sulfate the solvent was removed under reduced pressure. The residue was purified column chromatography (silica gel from a mixture of toluene:ethyl acetate = 1:1 to ethyl acetate). After washing diisopropyl ether was obtained N-(1-benzoylpiperidine-4-yl)-4-perbenzoic (515 mg).

NMR (DMSO-d6,): 1,50 (2H, Shir. C) of 1.85 (2H, Shir. C), 2,8-3,3 (2H, m), 3,61 (1H, m), 4,1 (1H, m), 4,35 (1H, m), 7,29 (2H, t, J=8,9 Hz), 7,3-7,5 (5H, m), 7,92 (2H, DD, J=5,6, 8,9 Hz), a 8.34 (1H, d, J=7.9 Hz).

Mass spectrum (APCI) (m/z): 327.

Example 18
To a suspension of N-(piperidine-4-yl)-4-fermentated (556 mg) in dichloromethane (5 ml) were added pivaloate (0,37 ml), pyridine (0,24 ml) and N,N-dimethylaminopyridine (25 mg) at ambient temperature. After stirring for 1 day, the mixture was diluted with dichloromethane and washed with water and saturated salt solution. After drying over magnesium sulfate the solvent was removed under reduced pressure. After trituration with diisopropyl ether was obtained N-(1-Jaloliddin-4-yl)-4-perbenzoic (305 mg).

NMR (DMSO-d6,): 1,20 (N, C) of 1.41 (2H, m), 1.7 to 1.9 (2H, m), 2.91 in (2N, SiS) (m/z): 329.

Example 19
To a suspension of N-(piperidine-4-yl)-4-fermentated (556 mg) in dichloromethane (6 ml) was added cyclopropanecarbonyl acid (0,20 ml), 1-hydroxybenzotriazole (338 mg) and the hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (480 mg) at ambient temperature. After stirring for 21 hours, the mixture was diluted with dichloromethane and washed with water, saturated sodium hydrogen carbonate solution and saturated salt solution. After drying over magnesium sulfate the solvent was removed under reduced pressure. After crystallization from diisopropyl ether was obtained N-(1-cyclopropanecarbonitrile-4-yl)-4-perbenzoic (627 mg).

NMR (DMSO-d6,): 0,6-0,8 (4H, m), 1,2-1,6 (2H, m), 1,7-2,0 (2H, m), of 1.85 (1H, m), of 2.72 (1H, m), 3,21 (1H, m), Android 4.04 (1H, m), 4,30 (2H, m), 7,29 (2H, t, J=8,9 Hz), 7,92 (2H, DD, J=5,6, 8,9 Hz), 8,31 (1H, d, J=7,7 Hz).

Mass spectrum (APCI) (m/z): 313.

Example 20
1-Tert-butoxycarbonyl-4-(4-tortenelmebol)-piperazine (0,30 g) was dissolved in a solution of hydrogen chloride in ethyl acetate (4 ad, 2 ml) and stirred the solution at ambient temperature for 1 hour. The solvent was removed by evaporation under reduced pressure, obtaining 1-(4-tortenelmebol)piperazine (3 ml) as a white powder, which was dissolved in eliticism number N, N-dimethylaminopyridine. After stirring at ambient temperature for 12 hours the mixture was washed in turn hydrochloric acid (0,5 N. ), aqueous sodium hydrogen carbonate solution and saturated salt solution, dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographically on silica gel (50 ml) and elution 0-3% methanol in dichloromethane, getting 1-(4-tortenelmebol)-4-(4-trifloromethyl)-piperazine (0,19 g).

NMR (DMSO-d6,): of 3.2 to 3.8 (8H, m), was 7.08 (2H, t, J=9 Hz), 7,35 and 7.5 (4H, m), 7.5 to the 7.65 (2H, m).

Mass spectrum (LD) (m/z): of 434.1.

Example 21
The following compound was obtained using methylchloroform as the reactive derivative of carboxylate, in a manner analogous to the method of example 20.

1-Methoxycarbonyl-4-(4-tortenelmebol)piperazine
NMR (DMSO-d6,): 3,3-3,5 (8H, m), 3,62 (3H, s), 7,07 (2H, t, J=9 Hz), 7,44 (2H, DD, J=5,9 Hz), to 8.62 (1H, s).

Mass spectrum (APCI) (m/z): 282.

Example 22
A mixture of N-acetylpiperidine-4-carboxylic acid (514 mg), 1-hydroxybenzotriazole (405 mg), hydrochloride of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (575 mg) and 4-foronline (284,2 ml) in dichloromethane (5 ml) was stirred for 18 hours at embroilment sodium, water and saturated salt solution. After drying over magnesium sulfate the solvent was removed under reduced pressure. The residue was purified column chromatography (silica gel (40 ml, dichloromethane:methanol = 15:1). After trituration with diisopropyl ether was obtained 1-acetyl-4-(4-forfinal)carbamoylbiphenyl (532 mg).

NMR (DMSO-d6,): 1,3-1,7 (2H, m), 1,8 (2H, m), a 2.01 (3H, s), and 2.5 (2H, m), 3,05 (1H, Shir. t, J=10,6 Hz), a 3.87 (1H, Shir. d, J=14.1 Hz), and 4.40 (1H, Shir. d, J= 13.1 Hz), 7,12 (2H, t, J=8,9 Hz), to 7.61 (2H, DD, J=5,1, and 9.1 Hz), 9,96 (1H, s).

Mass spectrum (APCI) (m/z): 265.

Example 23
To a solution of 1-acetylpiperidine-4-sulphonylchloride (0,91 g) in chloroform (10 ml) was added 4-ftoranila (0,38 ml) and triethylamine (of 0.56 ml) at ambient temperature. After stirring for 6 days, the solvent was removed under reduced pressure. The residue was purified column chromatography (silica gel 100 ml, dichloromethane:methanol = 19:1). After washing diisopropyl ether was obtained 1-acetyl-4-(4-forfinal)sulfamoylbenzoyl (716 mg).

NMR (CDCl3,): of 1.97 (3H, s) to 3.09 (4H, m), 3,37 (4H, m), 7,20 (4H, m), 10,00 (1H, s).

Mass spectrum (APCI) (m/z): 302.

Example 24
To a solution of O-tert-butyl(1-acetylpiperidine-4-yl)carbamate (0.97 g) in N, N-dimethylformamide (10 ml) was added 60% g and was added 4-florantyrone (0.6 ml). After additional stirring for 4 hours the reaction mixture was poured into a mixture of ethyl acetate (50 ml) and water (10 ml). The organic phase was separated and washed with water and saturated salt solution. After drying over magnesium sulfate the solvent was removed under reduced pressure. The residue was purified column chromatography (silica gel 100 ml of toluene:ethyl acetate = 1:1 to 1:2). After crystallization from diisopropyl ether and n-hexane were obtained O-tertbutyl N-(4-terbisil)-N-(1-acetylpiperidine-4-yl)carbamate (922 mg).

NMR (DMSO-d6,): 1,35 (N, Shir. (C) 1,3-1,8 (4H, m), of 1.95 (3H, s), 2,3-2,6 (1H, m), of 2.97 (1H, m), 3,80 (1H, Shir. d, J=15.2 Hz), 4,0 (1H, m), 4,32 (2H, s), 4,2-4,6 (1H, m), 7,0-7,4 (4H, m).

Mass spectrum (APCI) (m/z): 295.

Example 25
To a solution of O-tert-butyl N-(4-terbisil)-N-(1-acetyl-piperidine-4-yl)carbamate (0.5 g) in dichloromethane (5 ml) was added 4 N. hydrogen chloride in dioxane (5 ml). The reaction mixture was diluted with diisopropyl ether and collected precipitation by filtration. After drying under reduced pressure was obtained the hydrochloride of 1-acetyl-4-(4-terbisil)-aminopiperidine (409 mg).

NMR (DMSO-d6+D2O,): and 1.54 (2H, m), 2,02 (3H, s), 2,0-2,3 (2H, m), 2,4-2,7 (1H, m), 3.04 from (1H, Shir. t, J=12.1 Hz), 3,29 (1H, m) of 3.9 (1H, m), 4,17 (2H, s), of 4.44 (1H, Shir. d, J=13,ridin-4-yl)-4-fermentated (529 mg) in N,N-dimethylformamide (5 ml) was added sodium hydride (0.1 g). After stirring for 45 minutes the solution was added methyl iodide (623 ml). After stirring for 45 minutes the mixture was diluted with ethyl acetate (100 ml) and water (50 ml). The organic phase was separated and washed with water and saturated salt solution. After drying over magnesium sulfate the solvent was removed under reduced pressure. After trituration with diisopropyl ether was obtained N-(1-acetylpiperidine-4-yl)-N-methyl-4-perbenzoic (248 mg).

NMR (DMSO-d6,): of 1.65 (4H, m), from 2.00 (3H, s), 2,78 (3H, s), and 3.8 (1H, m), 4,4 (1H, m), 2,0-4,6 (3H, Shir. m), 7,26 (2H, t, J=8,9 Hz), 7,46 (2H, DD, J= 5,6, 8,7 Hz).

Mass spectrum (APCI) (m/z): 301.

Example 27
A suspension of 1-acetylpiperidine (0,627 g), 2-chloro-4'-fortetienne (services, 0.844 g) and potassium bicarbonate (0,735 g) in acetonitrile (12 ml) was stirred at ambient temperature for 3 days. After removing solids by filtration, the filtrate was evaporated under reduced pressure, obtaining the remainder, which was chromatographically on silica gel (100 m) elution 0-5% methanol in dichloromethane. The desired compound in the free form was dissolved in ethyl acetate (2 ml) and was added to this solution a solution of hydrogen chloride in ethyl acetate (4 ad, 2 ml). The precipitate was collected by filtration, p is piperazine (1.47 g).

NMR (DMSO-d6,): to 2.06 (3H, s), 2.95 and-3,8 (6N, m), 3.9 to to 4.15 (1H, m), 4,2 is 4.45 (1H, m) to 5.13 (2H, s), of 7.48 (2H, t, J=9 Hz), of 8.09 (2H, DD, J=5,9 Hz).

Mass spectrum (APCI) (m/z): 265.


Claims

1. The compound of the formula I

in which R1represents a C1-C6alkanoyl, C1-C6alkoxycarbonyl, benzoyl, benzoyl substituted halogen (C1-C6) alkoxy, C1-C6alkylsulfonyl, phenylsulfonyl, phenylsulfonyl, substituted with halogen; or cyclo (C3-C6) alkylsulphonyl,
R2represents phenyl, phenyloxy or phenylamino, where each phenyl may be substituted with halogen, pyridyl, or pyridylamino;
A represents a single bond;
E represents ethylene;
X represents CH;
Y represents-N(R5)- (where R5represents hydrogen);
Q represents-C(O)- or-SO2-;
R3and R4taken together form ethylene,
and its pharmaceutically acceptable salt.

2. Connection on p. 1, where Q represents-C(O)-.

3. Connection on p. 2, representing N-(1-acetylpiperidine-4-yl)-4-perbenzoic.

4. The connection of lubmarine of disorders of the Central nervous system in mammals.

5. Connection on p. 4 or its pharmaceutically acceptable salt, where the disorder of the Central nervous system selected from amnesia, schizophrenia, or dementia.

6. The method of obtaining the compounds of formula I

where R1, R2, R3, R4, A, E, Q, X and Y are such as defined in paragraph 1, or its salt by reacting the compounds of formula V

or its salt with the compound of the formula III
HO-Qa-R2, [III]
or its reactive derivative at carboxy - or sulfogrupp, or its salt,
where in the above formulas, Qarepresents-C(O)- or-SO2-;
R1, R2, R3, R4, A & E such as shown in paragraph 1.

7. Pharmaceutical composition for treatment and/or prevention of disorders of the Central nervous system containing compound under item 1 as an active ingredient in combination with pharmaceutically acceptable, substantially nontoxic carrier or excipient.

8. The pharmaceutical composition according to p. 7, where the disorder of the Central nervous system selected from amnesia, schizophrenia, or dementia.

 

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