1-phenylalanine - new ligands of 5-ht4-receptor

 

(57) Abstract:

The invention relates to 1-phenylalanine - new ligands of 5-HT4receptors of formula I, where R1- halogen; R2- H, C1-C4alkoxy; R3- C1-C4alkoxy, phenyl C1-C4alkoxy, where phenyl optionally substituted by 1-3 substituents, independently selected from C1-C4of alkyl, C1-C4alkyloxy, 3,4-methylendioxy; R2and R3together represent methylenedioxy, Ethylenedioxy; R4denotes a group of formula (a) or (b), where n = 3, 4, 5; p = 0; q = 1 or 2; R5and R6each C1-C4alkyl or together are - (CH2)4- , - (CH2)6-, - (CH2)2O(CH2)2-,

-CHR8CH2CR9R10CHR11CH2- where R8and R11each H or together are - (CH2)t- where t =1; R9- H, HE, C1-C8alkyl, C1-C4alkyloxy; R10- H, C1-C8alkyl, phenyl, - (CH2)xR12where x = 0, 1, 2, 3; R12HE, C1-C4alkyloxy, - C(O)NR13R14, - NR13C(O)OR14, -SO2NR13R14, -NR13SO2R14, -NR13SO2NR14R15, -NR13C(O)NR14R15; R3-C8alkenyl, phenyl C1-C4alkyl, where phenyl optionally substituted C1-C4alkyloxy, methylendioxy, Ethylenedioxy; or R7- (CH2)z- R12where z = 2, 3. The compounds I are new ligands of 5-HT4receptors, which allows their use in pharmaceutical compositions and method of treating conditions selected from the Central nervous system, disorders of the gastrointestinal tract, cardiovascular system, urinary tract. 4 C. and 34 C.p. f-crystals.

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The technical field to which the invention relates

The present invention relates to 1-phenylalkyl-1-Onam, new ligands of 5-HT4-receptor, and methods of application and receipt of such ligands.

Description of the prior art

Serotonin, a neurotransmitter with mixed and complex pharmacological characteristics, was first opened in 1948 and later became the subject of important studies. Serotonin, also called 5-hydroxy-tryptamine (5-HT) acts on the Central and peripheral discrete 5-HT receptors. Currently, the 5-HT-receptor is divided into four major subclasses: 5-HT1-, 5-HT2-, 5-HT3and 5-HT4receptors, each of which m is, for Example, 5-HT4receptors were detected in the Central nervous system (for example, autoradiographically studies show highly specific ligand binding with high affinity to 5-HT4the receptor in the olfactory tubercle, the stratum, the black substance in the upper colliculus and in the dorsal, medial and ventral hippocampus). Thus, I believe that 5-HT4the receptor must participate in the activity areas of the Central nervous system, affecting fear, depression, mental capacity, dependence, schizophrenia, appetite, and so on ; and medications that interact with 5-HT4-receptors (i.e., the ligands of 5-HT4-receptor), have different therapeutic effects on disorders of the Central nervous system (CNS).

5-HT4receptors are also found in the digestive systems of a wide variety of animal species, including humans, and found that they modulate motor function of the gastrointestinal system (see Prokinetic Agents: A Key in the Future of Gastroenterology. Reynolds R. C. Gastroenterology Clinics of North America, 1989, 18, 437-457).

In addition, 5-HT4receptors modulate smooth muscle tone of the bladder (see, for example, Corsi M, Pietra C, Toson G., D. Trist, Tuccito g, Artibani W. avago the Atria (see, for example, Kaumann, A.; Sanders L.; Brown, A.; Murray, K.; Brown, M. ; Brown, M. Naunyn-Schmiedeberg's, 1991, 344, 150-159).

A description of these and other mentioned in the application documents (for example, see "Pharmacology" in "Detailed description of the invention") is incorporated into it by reference.

A brief description of the invention

The first object of the present invention is a compound of formula I:

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where R1denotes halogen;

R2denotes hydrogen or C1-C4alkyloxy and

R3represents C1-C4alkyloxy or phenyl C1-C4alkyloxy (where the phenyl optionally substituted with one to three substituents, independently selected from halogen, hydroxyl, C1-C4of alkyl, C1-C4alkyloxy, nitro, amino, aminocarbonyl, C1-C4alkylamino, dis1-C4alkylamino, C1-C4alkanolamine and 3,4-methylendioxy) or

R2and R3together represent methylenedioxy or Ethylenedioxy; and

R4denotes a group of formula (a) or (b)

< / BR>
where n is 3, 4 or 5;

p is 0 or 1;

q is 1 or 2;

R5and R6each denote C1-C4alkyl or together form -(CH2)4-, -(CH2)8and R11each represents hydrogen or together represent -(CH2)twhere t is 1, 2 or 3, R9denotes hydrogen, hydroxyl, C1-C8alkyl, C3-C8alkenyl or C1-C4alkyloxy and R10denotes hydrogen, C1-C8alkyl or C3-C8alkenyl or phenyl, thienyl, pyrrolyl or furyl (optionally substituted by one or two substituents, independently selected from C1-C4of alkyl, C1-C4alkyloxy, trifloromethyl and Halogens), or -(CH2)xR12where x is 0, 1, 2 or 3 and R12denotes hydroxyl, C1-C4alkyloxy, -C(O)NR13R14, -NR13C(O)R14, -NR13C(O)OR14, -SO2NR13R14, -NR13SO2R14, -NR13SO2NR14R15or - NR13C(O)NR14R15where R13, R14and R15independently represent hydrogen, C1-C4alkyl, trifluoromethyl or aryl; and R7denotes hydrogen, C1-C8alkyl or C3-C8alkenyl, or panels1-C4alkyl (where the phenyl optionally substituted with one to three substituents, independently selected from C1-C4alkyloxy, methylendioxy, Ethylenedioxy or halogen), or -(Eski acceptable salt, individual isomers and mixture of isomers.

The second object of the present invention is a pharmaceutical composition comprising a therapeutically effective amount of the compounds of formula I, or individual isomers, mixtures of isomers, or pharmaceutically acceptable salt or salts in combination with one or more pharmaceutically acceptable inert fillers.

The third object of the present invention is a method of treatment of the condition can improve with medications that interact with 5-HT4-receptors, the animal, if necessary, and the method includes the introduction of such animal a therapeutically effective amount of the compounds of formula I, or individual isomers, mixtures of isomers, or pharmaceutically acceptable salt or salts.

The fifth object of the present invention is a method of obtaining compounds of formula I, and it is presented below in the "Detailed description of the invention".

Detailed description of the invention

Definition

Unless otherwise stated, the following terms used in the description and in the claims, have the following values.

"Alkyl" means a straight or rasweiler, C1-C4alkyl includes radicals: methyl, ethyl, prop-1-yl, prop-2-yl, buta-1-yl, but-2-yl, 2-methylpropyl and 2-methylprop-2-yl).

"Alkenyl" means a straight or branched unsaturated hydrocarbon radical, having from three up to the specified number of carbon atoms and in which the hydrogen atom with the free valence is saturated (for example, C3-C4alkenyl includes radicals: 2-propenyl, 2-butenyl, 3-butenyl, 1-methyl-2-propenyl and 2-methyl-2-propenyl).

"Alkyloxy" means a radical-OR where R is alkyl having from one to the specified number of carbon atoms (for example, C1-C4alkyloxy includes radicals: methoxy, ethoxy, prop-1-yloxy, prop-2-yloxy, buta-1 yloxy, but-2-yloxy, 2-methylprop-1 yloxy and 2-methylprop-2-yloxy).

"Alkanoyl" means a radical of alkylsulphonyl having from one to the specified number of carbon atoms (for example, C1-C4alkanoyl includes radicals: methanol, ethanol, propanol, butanol and 2-methylpropanoyl).

"Albanova acid or galoyanized" means a straight saturated carboxylic acid or galoyanized having from 2 to 6 carbon atoms (for example, acetic acid, propionic acid, butyric acid, Vale derived.

"Alkane or alkane-1-he" means substituted saturated straight 1-ketone having from two to a specified number of carbon atoms (for example, C2-C6alkane-1-it includes the substituted ethane-1-he, propane-1-he, butane-1-he, pentane-1-he and hexane-1-he).

"Aryl" means an organic moiety formed from an aromatic hydrocarbon, and includes monocyclic or condensed carbocyclic aromatic group having from 6 to 20 carbon atoms (for example, phenyl, naphthyl, etc.,).

"Halogen" means fluorine, chlorine, bromine or iodine. "Leaving group" has the meaning which is commonly used in relation to it in synthetic organic chemistry, i.e., denotes an atom or a group substitutable in terms of alkylation, and includes halogen and alkane - or arene-sulfonyloxy, such as mesilate, econsultancy, benzosulfimide, tosyloxy, and alkanesulfonyl, alcantarillado, aminosulfonyl, aminocarbonyl etc.

"Protective group" has the meaning which is commonly used in relation to it in synthetic organic chemistry, i.e., denotes a group which selectively blocks one reactive site in a multifunctional compound, so that the chemical is shields" or "unprotect" means the process when the protective group is removed after the selective reaction. Certain processes of the present invention is based on the fact that the protective group block reactive nitrogen atoms present in these reagents. Acceptable aminosidine groups include acetyl and tert-butoxycarbonyl, which can be easily removed by acid hydrolysis.

"Animal" includes humans, other mammals, such as dogs, cats, rabbits, cattle, horses, sheep, goats, pigs and deer, and not mammals, such as birds, etc.

"Disease" specifically includes any unhealthy condition of an animal or part thereof and includes an unhealthy condition that can be caused by, or inherent in medical or veterinary therapy, applied to this animal, i.e., "side effects" of such therapy.

"Optional" or "optionally" means that sequentially described event or circumstance may occur or it may not be present and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, the phrase "optionally substituted with one or two substituents" means that these substituents can precuts and the invention includes those compounds where one or two substituent are present, and those compounds in which the substituents are not present.

"Pharmaceutically acceptable" means that something that is suitable for obtaining a pharmaceutical composition, is completely safe, non-toxic and is not undesirable neither biological nor from another point of view and includes anything that is acceptable for use in veterinary or pharmaceutical for humans.

"Pharmaceutically acceptable salts" means salts which are pharmaceutically acceptable in the sense as defined above, and which possess the desired pharmaceutical activity. Such salts include acid additive salts formed with inorganic acids such as hydrochloric acid, Hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. or organic acids such as acetic acid, propionic acid, hexanoic acid, heptane acid, cyclopentylpropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic sour alsultanova acid, 1,2-ethicality acid, 2-hydroxyethanesulfonic acid, benzolsulfonat acid, p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid, p-toluensulfonate acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2] Oct-2-ene-1-carboxylic acid, 4,4'-Methylenebis(3-hydroxy-2-EN-1-carboxylic acid), 3-phenylpropionate acid, trimethylhexane acid, tert-Butylochka acid, louisanna acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, Mukanova acid, etc.

Pharmaceutically acceptable salts also include salts of joining the grounds, which can be formed when present acidic protons capable of reacting with inorganic or organic bases. Acceptable inorganic bases include sodium hydroxide, sodium carbonate, potassium hydroxide, aluminum hydroxide and calcium hydroxide. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, etc.

"Therapeutically effective amount" refers to an amount which, when introduced to an animal for treating a disease, is the dost is uchet:

(1) prevention of onset of disease in an animal that may be predisposed to the disease but has not yet feels and shows no symptoms of the disease,

(2) the suppression of the disease, i.e., delayed its development, or

(3) the attenuation of the disease, i.e., the call regression of the disease.

The compounds of formula I are named in accordance with the accepted rules of nomenclature commonly used in "Chemical Abstracts". For example, the compound of formula I, where R1denotes chlorine, R3denotes methoxy, and R4denotes a group of formula (a), where n is 4, p is 0 and R5and R6each denote methyl,

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named 1-(4-amino-5-chloro-2-methoxyphenyl)-5-diethylaminopentane-1-it.

Preferred embodiments of the invention

Compounds of the present invention are derived2-C6alkane-1-ones, substituted phenyl having a portion in position 1 and nitrogen-containing part of the position with the largest number. Nitrogen-containing part can be a (N, N-disubstituted)amino, (1-substituted)piperidine-4-yl, morpholine-1-yl or pyrrolidin-1-yl or optionally substituted piperidine-1-yl, azacycloheptan-1-yl, azabicyclo[2.2.1]hept-3-yl, azabicyclo[2.2.2]Oct-3-yl or azabicyclo[3.2.2] is B>alkyloxy and R4denotes a group of formula (a), denote the compounds of formula I(a):

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where n is 3, 4 or 5;

p is 0 or 1;

R1denotes halogen and

R5and R6each represents C1-C4alkyl or together form -(CH2)4-, -(CH2)6-, -(CH2)2O(CH2)2- or-CHR8CH2CR9R10CHR11CH2- where R8and R11each represents hydrogen or together represent -(CH2)twhere t is 1, 2 or 3, R9denotes hydrogen, hydroxyl, C1-C8alkyl, C3-C8alkenyl or C1-C4alkyloxy and R10denotes hydrogen, C1-C8alkyl or C3-C8alkenyl or phenyl, thienyl, pyrrolyl or furyl (optionally substituted by one or two substituents, independently selected from C1-C4of alkyl, C1-C4alkyloxy, trifloromethyl and Halogens), or -(CH2)xR12where x is 0, 1, 2 or 3 and R12denotes hydroxyl, C1-C4alkyloxy, -C(O)NR13R14, -NR13C(O)R14, -NR13C(O)OR14, -SO2NR13R14, -NR13SO2R14, -NR13SO2NR14R15or-NR13C(O)NR14

The compounds of formula I, where R2denotes hydrogen or C1-C4alkyloxy and R3represents C1-C4alkyloxy or R2and R3together represent methylenedioxy or Ethylenedioxy and R4denotes a group of formula (b), indicate the compounds of formula I(b):

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where p is 0 or 1;

q is 1 or 2;

R1denotes halogen and

R7denotes hydrogen, C1-C8alkyl, C3-C8alkenyl or panels1-C4alkyl (where the phenyl optionally substituted with one to three substituents, independently selected from C1-C4alkyloxy, methylendioxy, Ethylenedioxy or halogen), or -(CH2)zR12where z is 2 or 3 and R12denotes hydroxyl, C1-C4alkyloxy, -C(O)NR13R14, -NR13C(O)R14, NR13C(O)OR14, -SO2NR13R14, -NR13SO2R14, -NR13SO2NR14R15or-NR13C(O)NR14R15where R13, R14and R15independently represent hydrogen, C1-C4alkyl, trifluoromethyl or aryl;

and their pharmaceutically acceptable salts, individual Isom1-C4alkylphenoxy (where the phenyl optionally substituted with one to three substituents, independently selected from halogen, hydroxyl, C1-C4of alkyl, C1-C4alkyloxy, nitro, amino, aminocarbonyl, C1-C4alkylamino, dis1-C4alkylamino, C1-C4alkanolamine and 3,4-methylendioxy) denote the compounds of formula I(C):

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where

R1denotes halogen and

R4denotes a group of formula (a) or (b):

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where n is 3, 4 or 5;

p is 0 or 1;

q is 1 or 2;

R5and R6each represents C1-C4alkyl or together form -(CH2)4-, -(CH2)6-, -(CH2)2O(CH2)2- or-CHR8CH2CR9R10CHR11CH2- where R8and R11each represents hydrogen or together represent -(CH2)twhere t is 1, 2 or 3, R9denotes hydrogen, hydroxyl, C1-C8alkyl, C3-C8alkenyl or C1-C4alkyloxy and R10denotes hydrogen, C1-C8alkyl or C3-C8alkenyl or phenyl, thienyl, pyrrolyl or furyl (optionally substituted by one or two substituents, independently selected from C1-C is 0 but, 1, 2 or 3 and R12denotes hydroxyl, C1-C4alkyloxy, -C(O)NR13R14, -NR13C(O)R14, -NR13C(O)OR14, -SO2NR13R14, -NR13SO2R14, -NR13SO2NR14R15or-NR13C(O)NR14R15where R13, R14and R15independently represent hydrogen, C1-C4alkyl or trifluoromethyl; and R7denotes hydrogen, C1-C8alkyl or C3-C8alkenyl, or panels1-C4alkyl (where the phenyl optionally substituted with one to three substituents, independently selected from C1-C4alkyloxy, methylendioxy, Ethylenedioxy or halogen), or -(CH2)zR12where z is 2 or 3 and R12has the above meanings;

and their pharmaceutically acceptable salts, individual isomers and mixture of isomers.

Although the full range of compounds that are included in the scope of the invention described above in "Summary of the invention", some preferred compounds. For example, preferred compounds are compounds of formula I(a), where n is 4 and R5and R6together form-CHR8CH2CR9R10CHR11CH2-; and the compounds of formula I(b), is UP> together form-CHR8CH2CR9R10CHR11CH2- or where R4denotes a group of formula I(b), where q is 2.

Especially preferred are the compounds of formula I(a), where n is 4, R1denotes chlorine, R3denotes methoxy, and R5and R6together form-CH2CH2CHR10CH2CH2- where R10denotes hydrogen, C1-C8alkyl or -(CH2)xR12; and the compounds of formula I(b), where q is 2, R1denotes chlorine, R3denotes methoxy, and R7denotes hydrogen, C1-C8alkyl or -(CH2)zR12; and the compounds of formula I(C), where R1denotes chlorine, R3indicates 3,5-dimethoxybenzoate and R4denotes a group of formula (a), where n is 4 and R5and R6together form-CH2CH2CHR10CH2CH2- where R10denotes hydrogen, C1-C8alkyl or -(CH2)xR12or R5denotes a group of formula (b), where q is 2 and R7denotes hydrogen, C1-C8alkyl or -(CH2)zR12.

Most preferred are the following compounds of formula I(a):

1-(4-amino-5-chloro-2-methoxyphenyl) the but-5-chloro-2-methoxyphenyl)-5-(4-aminocarbonylmethyl-1-yl)pentane-1-he,

1-(4-amino-5-chloro-2-methoxyphenyl)-5-{ 4-[(methylsulphonyl)amino]piperidine-1-yl}pentane-1-he,

and the following compounds of formula I(b):

1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-methylpiperidin-4-yl)propan-1-he,

1-(4-amino-5-chloro-2-methoxyphenyl)-3-(1-ethylpiperazin-4-yl)propan-1-he,

1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(prop-1-yl)piperidine-4-yl]propane - 1-he,

1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(but-1-yl)piperidine-4-yl] propane - 1-he,

1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(Penta-1-yl)piperidine-4-yl] propane-1-he,

1-(4-amino-5-chloro-2-methoxyphenyl)-3-{ 1-[2-(methylsulphonyl)aminoethyl] piperidine-4-yl)propan-1-he,

1-(4-amino-5-chloro-2-methoxyphenyl)-3-{ 1-[2-(dimethylaminomethyl) aminoethyl]piperidine-4-yl}propane-1-he,

1-(4-amino-5-chloro-2-methoxyphenyl)-3-{ 1-[3-(methylsulphonyl)aminopropan - 1-yl]piperidine-4-yl}propane-1-he,

1-(4-amino-5-chloro-2,3-acid)-3-[1-(3-butyl-1-yl)piperidine - 4-yl]propane-1-he,

1-(4-amino-5-chloro-2,3-atlanticcity)-3-[1-(3-butyl-1-yl)piperidine - 4-yl]propane-1-he,

1-(4-amino-5-chloro-2-methoxyphenyl)-3-{ 1-[3-(4-methoxyphenyl)prop-1-yl] piperidine-4-yl}propane-1-he,

1-(4-amino-5-chloro-2-methoxyphenyl)-3-{ 1-[3-(2,3,4-trimethoxyphenyl)prop-1-yl] piperidine-4-yl}propane-1-he,

1-(4-amino-5-chloro-2-methoxyphenyl)-3-{ 1-[3-(3,4-methylenedioxyphenyl)prop - in-4-yl}propane-1-he,

1-(4-amino-5-chloro-2-methoxyphenyl)-3-{1-[3-(3,4-acid)prop-1-yl] piperidine-4-yl}propane-1-he,

1-(4-amino-5-chloro-2-methoxyphenyl)-3-{1-[3-(3,5-acid)prop-1-yl] piperidine-4-yl}propane-1-he,

1-(4-amino-5-chloro-2,3-atlanticcity)-3-{ 1-[3-(4-methoxyphenyl) prop-1-yl]piperidine-4-yl}propane-1-it;

and the following compounds of formula I(C):

1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] -5-(piperidine-1-yl) pentane-1-he,

1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl]-5-(4-methylpiperidin - 1-yl)pentane-1-he,

1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] -5-[4- (prop-1-yl)piperidine-1-yl]pentane-1-he,

1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl]-5-{4-[2- (methylsulphonyl)aminoethyl]piperidine-1-yl}pentane-1-he,

1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl]-5-[4- (methylsulphonyl)AMINOETHYLPIPERAZINE-1-yl]pentane-1-he,

1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl]-5-[4- (aminocarbonyl)AMINOETHYLPIPERAZINE-1-yl]pentane-1-he,

1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] -5-(4 - aminocarbonylmethyl-1-yl]pentane-1-he,

1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] -5- (4-hydroxypiperidine-1-yl]pentane-1-he,

1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] -5-(4-methoxypiperidine-1-yl]pentane-1-he,

1-[4-amino-5-,5-dimethoxyaniline)phenyl]-5-[4-(methylsulphonyl) aminopiperidin-1-yl]pentane-1-he,

1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] -3-[1-(but-1-yl) piperidine-4-yl]propane-1-he,

1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] -3-[1-(Penta-1-yl) piperidine-4-yl]propane-1-he,

1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl]-3-{1-[2- (methylsulfonyl)aminoethyl]piperidine-4-yl}propane-1-it;

or their pharmaceutically acceptable salts, preferably hydrochloride.

Pharmacology and use

Compounds of the present invention interact with 5-HT4-receptors (i.e., compounds have affinity for 5-HT4receptors and exhibit agonistic or antagonistic properties). Properties of the test compounds to interact with the 5-HT4the receptor is determined by quantitative analysis using dedicated breast muscles of the esophagus of rats (i.e., test compounds, which tend to cause relaxation, characterized as agonists 5-HT4-receptor, while the test compounds that inhibit caused by the agonist response of relaxation, where the mediator performs the 5-HT4-receptor, characterized as antagonists of 5-HT4-receptor). It is known that a dedicated breast muscle of the rat esophagus is obstacle (for example, see Baxter, G. S.; Craig D. A.; Clarke D. E. Naunyn-Schmiedeberg''s Arch. Pharmacol. 1991, 343, 439-446), as described in example 17.

As ligands of 5-HT4-receptor compounds of the present invention are useful for treating conditions which can be improved by interaction with 5-HT4-receptors. Such conditions include disorders of the Central nervous system, disorders of the gastrointestinal tract, disorders of the cardiovascular system, disorders of the urinary tract.

Specific Central nervous system disorders include a variety of neurological and psychiatric disorders, such as disorders of cognition, psychosis, and obsessive/compulsive and anxious/depressive behavior. Disorders cognitive abilities include lack of attention or memory, state of insanity (including senile marasmus type of Alzheimer's disease and aging), cerebral vascular insufficiency, and Parkinson's disease. Psychosis which can be treated using compounds of the present invention, include paranoia, schizophrenia and autism. Obsessive/compulsive behavior includes eating disorders (e.g. bulimia, a condition in which there is an abnormal and constant striving will is perezia, dental treatment, etc), depression, mania, seasonal affective disorder (CAP), convulsions, and fear caused by the cancellation of drugs (abstinence), such as opiates, benzodiazepine, nicotine, alcohol, cocaine and other drugs abused.

Specific digestive disorders include diseases that are directly or indirectly related to motor function of the stomach, esophagus and both thick and thin intestines. Specific diseases include, but are not limited to, dyspepsia (for example, non-ulcer dyspepsia), gastric stasis, peptic ulcers, esophageal reflux, flatulence, gastritis caused by biliary reflux syndrome pseudoprobability syndrome irritability of the colon (which can lead to chronic constipation and diarrhea, diverticular disease, impaired motility of the gallbladder (which can lead to dysfunction of the sphincter of Oddi and "draft" or microscopic crystals in the gallbladder), gastroparesis (e.g. of diabetic, postsurgical or idiopathic), irritable bowel syndrome and delayed gastric emptying. Other uses include short pokines for the implementation of diagnostic SS="ptx2">

Specific cardiovascular disorders include diseases that are associated directly or indirectly with cardiac arrhythmias. Specific disorders of the urinary tract include diseases associated directly or indirectly with dysfunction of the smooth muscle of the urinary system or innervation, leading to inadequate accumulation of urine or her control or urinary stasis, which can lead to infection, stones or kidney damage.

In General, a specific condition for treatment which may be useful compound according to the present invention, will depend on, does the connection quality agonist or antagonist. For example, certain compounds of the present invention, which are agonists of 5-HT4receptors are useful as prokinetics agents in the treatment of diseases in which a weakened motor function of the stomach, or to increase the tone of smooth muscles of the ureter in the treatment of diseases of the urinary system in which there is hypotension, bladder, or as agents that increase mental ability, in the treatment of conditions directly or indirectly associated with the impaired cognitive abilities. In contrast to this the mediator performs the 5-HT4-a receptor, and are useful in the treatment of diseases, including state hypermodernity, or may block the contraction of smooth muscle of the ureter, where the mediator performs the 5-HT4-a receptor, and are useful in the treatment of diseases associated with spasticity of the bladder, or may block positive chronotropy, where the mediator performs the 5-HT4-a receptor, and are useful as antiarrhythmic agents.

Since the condition for which can be useful in any given compound of the present invention, strongly depends on antagonistic or agonistic properties of this compound, there may be some individual differences. Thus, the ligands of 5-HT4the receptor of the present invention can further be tested in experiments in vivo or in vitro, designed to identify therapeutic activity. For example, prokinetics activity of the compounds of the present invention can be determined by measuring the speed of gastric emptying in rats after oral administration of test compounds. Prokinetics analysis in rats is a well-known model for the identification of compounds with the proxy is x2">

The properties of the compounds of the present invention to improve cognitive abilities can be determined using the test water maze Morris, in which the estimated changes in mental abilities of rats. Test water maze Morris is a well-known model to demonstrate increased cognitive abilities (for example, see Morris R. G. M., Garrud, P. , Rawlins, J. N. P., O'keefe, J. Nature, 1982, 297, 681-683), described in example 21.

Inhibiting pathological fear of the activity determined by conventional in the art will research two-chamber model Crawley and Goodwin (see , for example, Kilfoil T.; Michel, A.; Montgomery, D.; Whiting, R. L. Neuropharmacology, 1989, 28(9), 901-905). Briefly, in this method estimates the degree of influence of the compounds on the natural fear of mice in a new brightly-lit area. The study of behavior, the vast pathological fear described in example 19.

To have a calming effect activity with the abolition of drugs after their excessive consumption determine the accepted method of using the test in fear when you cancel (for example, see E. Carboni; Acquas E.; Leone, P.; Perezzani L.; Di Chiara, G. Eur. J. Pharmacol, 1988, 151, 159-160). This method uses the above research model to measure the degree of the drug substance and then abrupt cessation of this treatment. The study of fear when cancelling described in example 20.

In General, the compounds of the present invention are useful for treating conditions which can be improved by interaction with 5-HT4-receptors. Such conditions include disorders of the Central nervous system, disorders of the gastrointestinal tract, disorders of the cardiovascular system and disorders of the urinary tract. In particular, the compounds are suitable for treating conditions associated with disorders of cognitive ability, hypokinesia stomach syndrome irritability of the intestines, arrhythmia, gipotonus bladder or spasticity of the bladder.

Introduction and pharmaceutical composition

Usually the compounds according to the invention can be introduced in therapeutically effective amounts via any of the usual and acceptable methods known in the art, either individually or in combination with another compound of the formula I, or with another therapeutic agent. Therapeutically effective amount may vary depending on the severity of the disease, age and health of the subject, the efficiency of the used connections and other factors. Therapeutically effective which Preferably should be from about 0.1 to 1 mg/kg/day. Therefore, a therapeutically effective amount for a human weighing 70 kg can be from 0.7 to 700 mg/day, preferably from 7 to 70 mg/day.

Any ordinary specialist in the field of treatment of such diseases are able without conducting long-term experiments and relying on their own knowledge and description of the present invention to install for this disease a therapeutically effective amount of compounds of formula I.

Typically, compounds of the present invention can be introduced in the form of pharmaceutical compositions by one of the following routes: oral, systemic (e.g., transdermal, through the nose or by suppository), or parenteral (e.g., intramuscularly, intravenously or subcutaneously). Compositions can take the form of tablets, pills, capsules, to be semi-solid, powder, forms, continuous-release, solutions, suspensions, elixirs, aerosols, or any other suitable composition, and they usually include the compounds of formula I in combination with at least one pharmaceutically acceptable inert filler. Acceptable inert excipients are non-toxic, contribute to the introduction and have no harmful effects on therapeutic benefits coedine aerosol composition, gaseous inert filler, which is available to a person skilled in the technical field.

Solid inert pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, etc., Liquid and semi-solid inert fillers can be selected from water, ethanol, glycerin, propylene glycol and various oils, including oils derived from petroleum, animal or vegetable or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, and so on). Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

For spraying the compounds according to the invention in aerosol form can be used compressed gases. Suitable for this purpose are inert gases are nitrogen, carbon dioxide, nitrous oxide, etc. Other pharmaceutically suitable carriers and their forms described A. R. Alfonso in Remington''s Pharmaceutical Sciences, 1985, 17th edition, Easton, Pa.: Mack Publishing Company.

The number of connections of vermehren, type of inert fillers and other factors known to specialists in the field of pharmaceutical Sciences. Usually the finished composition may contain from 25 weight. % to 75 wt.% the compounds of formula I, preferably from 30 wt.% up to 50 weight. % with the addition of the missing quantity at the expense of inert filler or fillers.

Preferably the pharmaceutical composition is administered in the form of a single standard dose for continuous treatment or optionally in the form of a single standard dose, specially when you want relief of symptoms. Typical pharmaceutical compositions containing a compound of formula I, described in example 16.

Methods for producing compounds according to the invention

The method of obtaining compounds of formula I are represented by reaction scheme I.

The compounds of formula I can be obtained by a process which involves reacting the compounds of formula II or its protected derivative with a compound of formula III, oxidation, decarboxylation and, if necessary, removing any protective groups. The reaction between the compounds of formulae II and III is carried out in the presence of a strong base (for example, diisopropylamide lithium) and in a suitable rastvoratee temperature -40o0oC. the Reaction mixture is then acidified and extracted with a suitable solvent (e.g. methylene chloride). Can then be implemented decarboxylation using standard methods for the formation of compounds of formula I. Obtaining the compounds of formula I using the process depicted in reaction scheme I, described in example 3.

The compounds of formula II, where R4denotes a group of formula (a) can be obtained by the interaction of Halogens4-C6alginate with the compound of the formula with other5R6to obtain laminirovannogo C4-C6alginate and subsequent hydrolysis and conversion into an acid additive salt. The reaction with the compound of the formula with other5R6carried out in a suitable solvent (for example, 1-methyl-2-pyrrolidinone, DMF, and so on) at 25-50oC, preferably at approximately 35oC for 12-48 hours. The hydrolysis may be performed using acid (e.g. hydrochloric acid, sulfuric acid and so on) at 90-110oC, preferably at approximately the 100oC for 2-4 hours. An acid additive salt can be recovered by crystallization from solvent (for example, by dilution with acetone).

Coedge 4-hydroxypiperidine or 4-hydroxyethylpiperazine. 4-Piperidinyl alcohol is transformed into the corresponding sulfonate (i.e. 4-(p-toluensulfonate)piperidine or 4-[(p-toluensulfonate) methyl] piperidine by interacting with p-toluensulfonate). Then interact sulfonate with diethylmalonate in the presence of a base to obtain 4-[di(etoxycarbonyl)alkyl] piperidine. Then 4-[di(etoxycarbonyl)alkyl] piperidine in turn dicarboxylic acid, from which the result of decarboxylation get compound of formula II.

Protected derivatives of compounds of formula II are obtained from protected derivatives been the analogs of piperidine alcohols (for example, 1-tert-butoxycarbonyl - 4-piperidinemethanol). Getting protected derivatives of formula II, where R4denotes the formula (b) described in example 1.

The compounds of formula III can be obtained by reacting the appropriate 4-amino-5-halogenating acid hydrochloride N,O-dimethylhydroxylamine. The reaction is carried out in the presence of carbonyldiimidazole in a suitable solvent (such as N,N-dimethylformamide (DMF)). Obtaining the compounds of formula III described in example 2.

In contrast, the compounds of formula I, where R4denotes a group of formula (b) the crystals I, where R7denotes hydrogen, with a compound of the formula L-R20where L denotes a leaving group, and R20represents C1-C8alkyl, C3-C8alkenyl, panels1-C4alkyl (where the phenyl substituted as described in the "Brief description of the invention") or -(CH2)zR12(where z and R12have the values listed in the "Brief description of the invention"). The alkylation is carried out in standard amide alkylation conditions (flood T. ; Fung, S. H. Synth. Commun. 1979, 9, 757) in an inert solvent (for example, acetonitrile, DMF, THF, and so on) at the reaction temperature of 20-100oC and within 1-48 hours.

The alkylation can also be performed using the system of the catalyst phase transfer (CFP), i.e., the catalyst in the two-phase solvent system liquid-liquid (Gajda T. ; A. Zwierzak Synthesis, Communications 1981, 1005), or preferably, in the system of solid phase-liquid (Yamawaki J.; Ando T.; Hanafusa, T. Chem. Lett. 1981, 1143; Koziara A.; Zawaszki S.; A. Zwierzak Synthesis 1979, 527, 549). A two-phase system of liquid-liquid consists of an aqueous phase consisting of a concentrated solution of alkali hydroxide (e.g., 50% aqueous sodium hydroxide), organic phase comprising an inert, is not miscible with water and organic Racha/alkali carbonate, suspended in an organic solvent, and a catalyst.

The reaction is performed by slowly adding an alkylating agent to the IFC system containing a compound of formula I, until then, until it reaches 10-50% excess alkylating agent. The reaction mixture was kept at the boiling point under reflux to complete the reaction. The mixture is then cooled to room temperature and the product is produce using conventional methods. Suitable organic solvents include benzene, toluene, etc., Suitable catalysts include alumina, coated with fluoride, potassium, and Quaternary ammonium sulphate, such as bisulfate Tetra-n-butylamine and tricaprylmethyammonimum. Alkylation of compounds of formula I(b), where R7denotes hydrogen, described in example 10.

The compounds of formula I, where R4denotes a group of formula (b) and R7represents -(CH2)2NHC(O)R14, -(CH2)2NHSO2R14, -(CH2)2NHSO2R14R15or -(CH2)2NHC(O)NR14R15(where R14and R15have the values listed in the "Brief description of the invention") can be obtained by alkylation of compounds of formula I, denotes-C(O)R9, -SO2R14, -SO2NR14R15or-C(O)NR14R15. The alkylation is carried out in a suitable solvent (such as THF) at 0-20oC. Obtaining the compounds of formula I(b), where R7refers to 2-[(methylsulphonyl)amino]ethyl described in example 11.

The method of obtaining compounds of formula I, where R2denotes hydrogen and R4denotes a group of formula (a) shown in reaction scheme II.

The compounds of formula I, where R2denotes hydrogen and R4denotes a group of formula (a) (formula IV) can be obtained by a process which involves reacting the compounds of formula V with the compound of the formula VI; alkylation of a compound of the formula L-R3; interaction with the compound of the formula HNR5R6or its N-oxide and removing the protective group.

The reaction between the compound of formula V and a compound of formula VI is carried out in the presence of a Lewis acid (e.g. aluminum chloride (AlCl3), boron TRIFLUORIDE, hydrogen fluoride, phosphoric acid and so on, preferably AlCl3) and in a suitable solvent (for example, ethylene dichloride (ejh), methylene chloride, carbon disulfide, etc., preferably in ejh) for the formation of 2-hydroxyphenol potassium carbonate in a suitable solvent (for example, methylethylketone (MEK), DMF, ethanol, THF, etc., preferably in MEK) at a temperature of 40-200oC. the Reaction with the compound of the formula HNR5R6carried out in a suitable solvent (such as DMF, ethanol, THF, toluene and so on, preferably DMF) at a temperature of 40-200oC. Removal of protection can be conducted by any means of selectively removing the protective group. Obtaining the compounds of formula I(a) using the above process described in example 4.

The compounds of formula VI are either commercially available (for example, 5-haralanova acid and 5-chlorovaleryl), or can be easily obtained by gorodilova corresponding alanovoy acid. N-acetylcholin-5-methoxyaniline formula V are either commercially available or can be obtained from N-acetyl-3-methoxyaniline. For example, the compound of formula V, where R1indicates the bromide may be obtained by interaction of N-acetyl-3-methoxyaniline with bromine in a suitable solvent (e.g. dichloromethane).

The compounds of formula HNR5R6(for example, amines, such as dimethylamine, diethylamine, diprop-1-ylamine, and so on, and azacycloheptane, such as pyrrolidine, piperidine, morpholine, 4-phenylpiperidine, the, known specialists in this field of technology.

In embodiments of reaction scheme II, compounds of formula I can be obtained by reacting in the presence of Lewis acid compounds of the formula V with the compound of the formula VI; interaction with the compound of the formula HNR5R6or its N-oxide; alkylation of the compound of the formula L-R3and removal of the protective group, or by reacting the compounds of formula VI with the compound of the formula HNR5R6or its N-oxide; interaction in the presence of a Lewis acid with a compound of formula V; alkylation of the compound of the formula L-R3and removal of the protective group.

The method of obtaining compounds of formula I, where R4denotes a group of formula (b), where q is 2 and R7denotes hydrogen, depicted in reaction scheme III.

The compounds of formula I, where R4denotes a group of formula (b), where p is 0, q is 2 and R7denotes hydrogen, can be obtained through a process that includes the interaction of the compounds of formula VIII with the compound of the formula IX to obtain the derived 3-pyridin-4-yl-3-hydroxypropan-1-it, the dehydration of 3-hydroxypropan-1-it's for deriving 3-pyridin-4-improper-1-it is the changes of formulas VIII and IX is carried out in the presence of a strong base (for example, diisopropylamide lithium) in a suitable solvent (such as THF) at temperatures from -50 to 50oC. Dehydration of 3-piperidine-4-improper-1-it is carried out by standard methods (for example, acid catalyzed dehydration). If the reaction between the compound of formula VIII and IX is carried out in the presence of potassium hydroxide, dehydration occurs spontaneously, and the reaction results for one-stage 3-pyridin-4-yl-2-propen-1-it.

The hydrogenation of 3-pyridin-4-yl-2-propen-1-it is carried out with a suitable catalyst (for example, with 5% rhodium on aminoalkylation media, 10% palladium on charcoal, platinum dioxide, dihydroxide palladium and so on) in a suitable solvent (for example, acetic acid, ethanol, DMF, THF, etc. at a pressure of 5-60 pounds/square inch and within 1-48 hours. Obtaining the compounds of formula I(b) using the above-described process shown in example 7.

In contrast, the hydrogenation of 3-pyridin-4 - yl-2-propen-1-it is carried out by (I) hydrogenation of 2-propen-1-it until then, until the conversion to the corresponding 3-pyridin-4-improper-1-he (II) optional by alkylation with propane-1-it is a compound of formula L-R20or X-R21(where R20and R21have the above area. The hydrogenation propanone 3-pyridin-4-improper-1-it is carried out using a suitable catalyst (5% palladium on coal, 20% palladium hydroxide, and so on) in a suitable solvent (such as THF, acetic acid, DMF, ethanol, etc. at a pressure of 5-60 pounds/square inch and within 1-48 hours. Obtaining the compounds of formula I(b), where R7refers to 3-(4-methoxyphenyl)prop-1-yl, described in example 13.

Optional reaction with the compound of the formula L-R20or X-R21conduct similar to that described above for the alkylation of compounds of formula I, where R4denotes a group of formula (b) and R7denotes hydrogen. The hydrogenation of 3-pyridine-4-improper-1-it is carried out with a suitable catalyst (for example, with 5% rhodium on aminoalkylation media, 10% palladium on carbon, platinum dioxide, dihydroxide palladium and so on) in a suitable solvent (for example, acetic acid, ethanol, DMF, THF, etc. at a pressure of 5-60 pounds/square inch and within 1-48 hours.

The compounds of formula VIII can be obtained by methylation of the corresponding N-methoxy-N-methylbenzamide. Methylation is carried out by interaction of N-methoxy-N-methylbenzamide with meteorous agent (for example, methyllithium, methylmagnesium and so on) in owls. Obtaining the compounds of formula VIII, where R1represents chlorine and R3denotes methoxy, described in example 5.

In contrast, the compounds of formula VIII, where R2and R3together represent Ethylenedioxy, can be obtained by haloiding protected derivative of 4'-amino-2',3'-ethylenedioxythiophene and subsequent removal of the protection. Gorodilova can be conducted by reacting the acetophenone with palodiruyut agent (for example, N-chlorosuccinimide, chlorine and so on) in a suitable solvent (such as DMF, acetonitrile, and so on) at a temperature of from -20 to 80oC for 1-24 hours. Removing the protection can be carried out with a base (e.g. sodium hydroxide, etc.,) in suitable solvents (for example, methanol, etc).

4'-Amino-2', 3'-ethylenedioxythiophene can be obtained by reacting 5', 6'-dichloro-2',3'-ethylenedioxythiophene with fuming nitric acid to obtain 5',6'-dichloro-2',3'-Ethylenedioxy-4'- nitroacetophenone and subsequent recovery. Reaction with nitric acid is carried out at a temperature of 0-25oC for 0.5-2 hours. The restoration carried out in the presence of a catalyst (for example, 10% palladium on coal) in a suitable solvent (napino-2',3'- ethylenedioxythiophene can be carried out by reacting with a suitable protective agent. For example, 2', 3'- Ethylenedioxy-4'-(methylcarbonate)acetophenone obtained by interaction of unprotected acetophenone with acetic anhydride in pyridine. Reaction with acetic anhydride is carried out at a temperature of 0-30oC for 1-8 hours.

5', 6'-Dichloro-2', 3'-Ethylenedioxy-4'-nitroacetophenone can be obtained by chlorination of 1,4-benzodioxane to obtain 6,7-dichloro-1,4-benzodioxane and subsequent acetylation. The chlorination can be carried out by processing benzodioxane gaseous chlorine in acetic acid at 0 to 20oC for 1-8 hours. Acetylation can be carried out by reacting 6,7-dichloro-1,4-benzodioxane with acetyl chloride in the presence of a Lewis acid in a suitable solvent (for example 1,2-dichloroethane, carbon disulfide, nitrobenzene, and so on) at a temperature of 20-40oC and within 24-48 hours.

The method of obtaining compounds of formula I, where R4denotes a group of formula (a) shown in reaction scheme IV.

The compounds of formula I, where R4denotes a group of formula (a) can be obtained by a process which includes processing the compounds of formula XI magnesium to obtain a Grignard reagent, the interaction of the reagent G the e protection and subsequent interaction unprotected alkenone with the compound of the formula with other5R6.

Processing of magnesium is carried out by adding the compounds of formula XI in a nitrogen atmosphere to a suspension of magnesium in a suitable solvent (such as THF, diethyl ether, and so on) with such speed, to control the heat and then allow to proceed the reaction at 20-25oC for 1-2 hours.

The reaction with the Grignard reagent is carried out by cooling a solution of the compounds of formula XII in a suitable solvent (such as THF, diethyl ether, and so on) to a temperature of between -10 and -20oC, preferably to approximately -15oC, and then adding to the suspension containing the Grignard reagent was cooled to approximately the same temperature, and allow the reaction to proceed at a temperature of 0-15oC, preferably at approximately 10oC for 1-2 hours.

Removing the protection can be implemented using any ways to remove the protective group and giving the desired unprotected alkane with a good yield. Reaction of unprotected alkanones carried out in nitrogen atmosphere with 3-6 equivalents, preferably 3 to 4 equivalents other5R6in a suitable solvent (such as DMF), N-organic (NM), and so on) at a temperature of 55-85othe method described in example 14.

The compounds of formula XII can be obtained by reacting the compounds of formula III with a suitable protective agent. Detailed description of the methods applied to the protective groups and their removal can be found in T. W. Greene in Protective Groups in Organic Synthesis, John Wiley & Sons, Inc. 1981. For example, the compounds of formula XII, where the protective groups are trimethylsilyl, can be obtained by reacting the compounds of formula III with chlorotrimethylsilane. The reaction is carried out in the presence of a strong base (for example, tributyltinchloride, letibit(trimethylsilyl)amide (Litsa), and so on ) in a nitrogen atmosphere in a suitable solvent (such as THF, simple ether and so on) at a temperature of from -15 to 15oC, preferably at approximately 10oC for 15-30 minutes unprotect the compounds of formula XII, where the protective groups are trimethylsilyl, can be carried out using acids (e.g. hydrochloric acid, triperoxonane acid and so on).

The method of obtaining compounds of formula I, where R4denotes a group of formula (a) shown in reaction scheme V.

The compounds of formula I, where R4denotes a group of formula (a) can be obtained by reacting an acid additive salt is (for example, Litsa, athribis(trimethylsilyl)amide, diisopropylamide lithium, preferably Litsa) and subsequent removal of the protection. The reaction between the compounds of formulae II(a) and XIV can be carried out by cooling the mixture containing the compound of formula II(a), in a suitable solvent (such as THF, dimethyl ether of ethylene glycol, diethyl ether, and so on ) to a temperature of between 10 and 30oC, preferably approximately 15oC; adding at least 3 equivalents of a strong base and curing of 0.5-2 hours at a temperature of 10-30oC, preferably approximately at 20oC; cooling the mixture to a temperature of between 0 and 10oC, preferably approximately 5oC; and then adding the compounds of formula XIII, after which the reaction allowed to proceed at a temperature of 40-55oC for approximately 4 hours. Removing the protection can be carried out in any way that allows you to remove the protective group to obtain the desired product in good yield. Suitable protective group for the compounds of formula XIII is trimethylsilyl, which can be easily removed by acid. Obtaining the compounds of formula I using the above-described process shown in example 15.

Connection formularised and then adding protective groups. Reaction with benzoic acid is carried out at a temperature of 0-25oC, preferably at approximately 15oC for 1-4 hours. Protection can be performed using chlorotrimethylsilane in the presence of a strong base (for example, tert-butylacrylamide, Litsa and so on) in a suitable solvent.

Additional processes

The compounds of formula I, where R3represents C2-C4alkyloxy or panels1-C4alkyloxy can be obtained by demethylation of compounds of formula I, where R3denotes methoxy, and subsequent alkylation of the compound of the formula L-R22where R22represents C2-C4alkyl or panels1-C4alkyl (where the phenyl optionally substituted with one to three substituents, independently selected from halogen, hydroxyl, C1-C4of alkyl, C1-C4alkyloxy, nitro, amino, aminocarbonyl, C1-C4alkylamino, dis1-C4alkylamino, C1-C4alkanolamine and 3,4-methylendioxy). Demethylation carried out by standard methods with a suitable demetrious agent (for example, tribromide boron, trichloride boron and so on) and in an aprotic solvent (such as methylene chloride, ethylene dichloride is Fenelon-1-it. The alkylation is carried out in the presence of potassium carbonate in a suitable solvent (e.g. methyl ethyl ketone (MEK), DMF, ethanol, THF, etc. preferably IEC) at 40-200oC. Obtaining the compounds of formula 1 using the above process described in example 12.

The compounds of formula I, where p is 1, (the compounds of formula I in the form of N-oxide) can be obtained by oxidation of compounds of formula I, where p is 0. The oxidation is carried out at a reaction temperature of approximately 0oC with a suitable oxidizing agent in a suitable inert organic solvent. Suitable oxidizing agents include hydrogen peroxide or nagkalat, such as cryptocaryon acid, parmaliana acid, derbentina acid, peracetic acid and m-chloroperoxybenzoic acid. Suitable solvents include halogenated hydrocarbons such as methylene chloride, and alcohols. In contrast, the compounds of formula I, where p is 1, can be obtained with the use of derivatives, N-oxides as starting materials or intermediate products.

The compounds of formula I, where p is 0, can be obtained by recovering the compounds of formula I, where p is 1. The recovery is carried out in a hundred is EMA as the reaction temperature gradually increases in the range 0oC to 80oC. Suitable reducing agents include sulfur, sulfur dioxide, triarylphosphine (e.g., triphenylphosphine), borhydride alkali metals (e.g. lithium borohydride, sodium borohydride, and so on), phosphorus trichloride and tribromide. Suitable solvents include acetonitrile, ethanol and aqueous dioxane.

The compounds of formula I can be obtained in the form of a pharmaceutically acceptable acid additive salts by reacting the compounds of formula I in free base form with a pharmaceutically acceptable inorganic or organic acid. Alternatively, the pharmaceutically acceptable salt of attaching the base of the compounds of formula I can be obtained by reacting compounds of the formula I in the form of the free acid with a pharmaceutically suitable inorganic or organic bases. Inorganic and organic acids and bases, suitable for the production of pharmaceutically acceptable salts of the compounds of formula I above in the section "Definitions" of this description. Alternatively, the compounds of formula I in the form of salts can be obtained with the use of salts as starting materials or intermediate products.

The compounds of formula the Oia base or an acid additive salt. For example, the compounds of formula I in the form of acid additive salts can be converted into the corresponding free base by treatment with a suitable base (for example, a solution of ammonium hydroxide, sodium hydroxide, and so on). The compounds of formula I in salt form attachment base can be converted into the corresponding free acid by treatment with a suitable acid (e.g. hydrochloric acid, and so on).

In General, methods of producing compounds of the present invention are:

(A) to obtain the compounds of formula I interaction in the presence of a strong base, the compounds of formula II:

< / BR>
or a protected derivative, where R4has the values listed in the "Summary of the invention", with the compound of formula III:

< / BR>
where each of R1, R2and R3has the values listed in the "Summary of the invention"; acidification; decarboxylation and, if necessary, removing any protective groups; or

(B) to obtain the compounds of formula I, where R2denotes hydrogen and R4denotes a group of formula (a), the interaction in the presence of Lewis acid compounds of the formula V:

< / BR>
where P oboznachaet halogen or hydroxyl, R19denotes halogen and n is 3, 4 or 5; alkylation of a compound of the formula L-R3where L denotes a leaving group, and R3has the above values; interaction with the compound of the formula HNR5R6or its N-oxide, where R5and R6have the above meanings; and removing the protection; or

(C) to obtain the compounds of formula I, where R4denotes a group of formula (b), where p is 0 and q is 2, the interaction of the compounds of formula VIII:

< / BR>
where R1, R2and R3have the values listed in the "Brief description of the invention", with the compound of formula IX:

< / BR>
where R7has the values listed in the "Summary of the invention"; dehydration and subsequent hydrogenation; or

(G) to obtain the compounds of formula I, where R4denotes a group of formula (a), treatment of compounds of formula XI:

< / BR>
where n has the values listed in the "Summary of the invention", the magnesium to obtain the corresponding Grignard reagent, the interaction of the Grignard reagent with the compound of the formula XII:

< / BR>
where each P represents a protective group and R1, R2and R3have the values listed in the "Brief description of the entity(E) for obtaining the compounds of formula I, where R4denotes a group of formula (a), the interaction in the presence of a strong base, the compounds of formula II(a):

< / BR>
where R5and R6have the values listed in the "Brief description of the invention", with a compound of formula XIII:

< / BR>
where each P represents a protective group and R1, R2and R3have the values listed in the "Brief description of the invention"; or

(E) optional alkylation of the compounds of formula I, where R4denotes a group of formula (b) and R7denotes hydrogen, the compound of the formula L-R20where L denotes a leaving group, and R20represents C1-C8alkyl, C3-C8alkenyl or panels1-C4alkyl (where the phenyl optionally substituted with one to three substituents, independently selected from C1-C4alkyloxy, methylendioxy, Ethylenedioxy or halogen), or L-(CH2)zR12(where z and R12have the values listed in the "Brief description of the invention") for obtaining the compounds of formula I, where R4denotes a group of formula (b), where R7is not hydrogen; or

(G) optional alkylation of the compounds of formula I, where R4denotes a group of formula (b) means-C(O)R14, -SO2R14, - SO2NR14R15or-CONR14R15(where R14and R15have the values listed in the "Brief description of the invention") for obtaining the compounds of formula I, where R4denotes a group of formula (b), where R7denotes-CH2CH2NHC(0)R14, -CH2CH2NHSO2R14, -CH2CH2NHSO2NR14R15or-CH2CH2NHCONR14R15; or

(C) optional demethylation of compounds of formula I, where R3denotes methoxy, and subsequent alkylation of the compound of the formula L-R22where R22represents C2-C4alkyl or panels1-C4alkyl (where the phenyl optionally substituted with one to three substituents, independently selected from halogen, hydroxyl, C1-C4of alkyl, C1-C4alkyloxy, nitro, amino, aminocarbonyl, C1-C4alkylamino, dis1-C4alkylamino, C1-C4alkanolamine and 3,4-methylendioxy) to obtain the compounds of formula I, where R3represents C2-C4alkyloxy or panels1-C4alkyloxy (where the phenyl optionally substituted similarly specified in the "Summary of the invention"); or


(K) optionally recovering the compounds of formula 1, where p is 1, to obtain the compounds of formula I, where p is 0; or

(L) optional interaction corresponding mesolevel forms of the compounds of formula I with pharmaceutically acceptable inorganic or organic acid or base to obtain a pharmaceutically acceptable salt; or

(M) optional interaction of the corresponding acid additive salts or salts of attaching the base of the compounds of formula I with a suitable base or acid, respectively, to obtain the free acid or free base.

In any of the above processes, the final stage reference to formula I, II, II(a) III, IV, V, VI, VII, VIII, IX, X, XI, XII and XIII apply to such formulas, where1, R2, R3, R4, R5and R7have a wide range of values that are defined in "Summary of the invention", and these processes are primarily the best way applicable to the most preferred options of carrying out the invention.

EXAMPLE 1

3-[1-(Tert-butoxycarbonyl)piperidine-4-yl]propionic acid

Following receipt of a protected derivative of a compound peridin (27,0 g, 262 mmole) and di-tert-BUTYLCARBAMATE (51,2 g, 235 mmol) was dissolved in THF (300 ml) and the solution was stirred 12 hours at room temperature. The mixture was concentrated in vacuo and the residue was dissolved in a simple ether. The ether solution was washed with water and then with brine and dried over sodium sulfate. By evaporation of the solvents was obtained residue (51,0 g) in the form of butter.

The oily residue was dissolved in pyridine (200 ml) and the solution was cooled to 0oC. Then the solution was added p-toluensulfonate (47,5 g, 250 mmol) and the mixture was stirred at 5oC for 12 hours. The mixture was poured into water and was extracted with ethyl acetate. An ethyl acetate extract washed with 5% HCl, water and then with brine. Then the ethyl acetate was dried over sodium sulfate, and then evaporated. By crystallization from ethyl acetate-hexane was obtained 1-(tert-butoxycarbonyl)-4-[(p - toluensulfonate)methyl]piperidine (50 g, 136 mmol), tPL71-72oC.

Stage (b)

Diethylmalonate (10.4 g, 65 mmol) was added to a solution of ethoxide sodium (4.42 g, 65 mmol) in ethanol (75 ml). Was added 1-(tert-butoxycarbonyl)-4-[(p-toluensulfonate)methyl] piperidine (25 g, 68 mmol), obtained in accordance with stage (a) of example 1, and the mixture is heating tinny layer was separated, washed with water and then with brine, dried over sodium sulfate and evaporated. By purification of the residue by chromatography on silica gel (25% ethyl acetate-hexane) was obtained 1-(tert-butoxycarbonyl)-4-[2,2-di(etoxycarbonyl)ethyl] piperidine (16 g, 45 mmol) in the form of butter.

Stage (C)

1-(Tert-butoxycarbonyl)-4- [2,2-di(etoxycarbonyl)ethyl]piperidine (12.2 g, 34 mmole) obtained in accordance with stage (b) of example 1 and potassium hydroxide (4,2 g, 75 mmol) were mixed in ethanol (10 ml), THF (20 ml) and water (50 ml) and the mixture was heated under reflux for 3 hours. The mixture was cooled and washed with simple ether, acidified with sulfuric acid and was extracted with ether. The ether was dried over sodium sulfate and evaporated. By crystallization of the residue from simple ether there was obtained 1-(tert-butoxycarbonyl)-4-[2,2 - di(carboxy)ethyl] piperidine (8.5 g, 28 mmol), which was heated in an oil bath up to 165oC until stopped the production of CO2(approximately 10 minutes). The residue was cooled and by crystallization was obtained 3-[1-(tert-butoxycarbonyl)piperidine-4 - yl] propionic acid (7.2 g, 28 mmol), tPL81-83oC.

EXAMPLE 2

N-methoxy-N-methyl-4-amino-5-chloro-3-methoxybenzamide

Following receipt ethoxybenzoyl acid (10.1 g, 50 mmol) was dissolved in DMF (50 ml). To the solution was added carbonyldiimidazole (8,9 g, 55 mmol) and the mixture was stirred for 15 minutes. Was added triethylamine (7 ml, of 5.1 g, 50 mmol) and the hydrochloride of N,O-dimethylhydroxylamine (6.3 g, 65 mmol) and the mixture was stirred for 12 hours. Then the mixture was diluted with water and extracted with ethyl acetate. An ethyl acetate extract washed with 5% HCl, water and then with brine. The extract was dried over sodium sulfate and then evaporated. By crystallization from ethyl acetate was obtained N-methoxy-N-methyl-4-amino-5-chloro-2 - methoxybenzamide (10 g, 41 mmol), tPL134-135oC.

EXAMPLE 3

1-(4-Amino-5-chloro-3-methoxyphenyl)-3-(1 - piperidine-4-yl)propan-1-he

Following receipt of the compounds of formula I, where R1denotes chlorine, R3denotes methoxy, R4denotes a group of formula (b), where p is 0, q is 2 and R7denotes hydrogen.

Stage (a)

3-[1-(Tert-butoxycarbonyl)piperidine-4-yl]propionic acid (4.6 g, 18 mmol), obtained in accordance with example 1, was dissolved in HMPA (10 ml) and THF (10 ml) and this solution was added to a solution of Diisopropylamine lithium (60 mmol) -20oC. the Mixture was heated to 0oC, was stirred for 30 minutes and Westie with example 2, was dissolved in HMPA (10 ml) and THF (10 ml) and this solution was added to the mixture. The mixture was allowed to warm to 0oC for 1 hour, then was diluted with water, washed with simple ether, acidified with hydrochloric acid and was extracted with methylene chloride. Methylenchloride the extract was concentrated in vacuum and the residue was heated in an oil bath to 140oC for 30 minutes. The mixture was cooled, was divided between water and ethyl acetate. An ethyl acetate layer was separated, washed with 5% sodium hydroxide and then with brine, dried over sodium sulfate and evaporated. By cleaning using chromatographie on silica gel (40% ethyl acetate-hexane) was obtained 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(tert - butoxycarbonyl)piperidine-4-yl] propane-1-on (1.5 g, 3.8 mmole), tPL133-134oC.

Stage (b)

1-(4-Amino-5-chloro-2-methoxyphenyl)-3-[1-(tert-butoxycarbonyl) piperidine-4-yl]propane-1-on (1.5 g, 3.8 mmol) was dissolved in methylene chloride (20 ml) and to the solution was added triperoxonane acid (5 ml). After 30 minutes the solution is washed with aqueous ammonium hydroxide and dried over sodium sulfate. By evaporation of the solvents was obtained 1-(4-amino-5-chloro-3 - methoxyphenyl)-3-(1-piperidine-4-yl)propane-1-on (1.1 g, 3.8 mmol), tPL138-140oC.

Preferaly I, where R1denotes chlorine, R3denotes methoxy, R4denotes a group of formula (a), where n is 4, p is 0 and R5and R6together represent piperidine-1-yl.

Stage (a)

N-acetyl-2-chloro-5-methoxyaniline (10.0 g, 50 mmol), aluminum chloride (13.3 g, 100 mmol) and 5-chlorphentermine (11,7 g, 75 mmol) were mixed in dichloroethane (100 ml) and the mixture was stirred at room temperature and under nitrogen atmosphere for 7 days. Then the mixture was poured into ice pieces were extracted with methylene chloride. Methylenchloride the extract was washed with water and then dried. The solvent is evaporated in vacuum. By crystallization of the residue from ethyl acetate/hexane was obtained 1-(4-acetylamino-5-chloro-2 - hydroxyphenyl)-5-chloropentane-1-he (10,18 g, 35.1 mmol), tPL126-128oC.

In the same way as in stage (a) of example 4, but replacing the 1,5-dichloropentane-1-he 4-chlorobutyrate, was obtained 1-(4-acetylamino-5-chloro-2-hydroxyphenyl)-4-chlorobutane-1-hePL103-106oC.

In the same way as in stage (a) of example 4, but replacing the 1,5-dichloropentane-1-it 1.5-dibromine-1-he and N-acetyl-2-chloro-5-methoxyaniline on N-acetyl-2-bromo-5-methoxyaniline, was obtained 1-(4-acetylamino-5-bromo-2-hydroxyphenyl)-5-bromantan-1-it.

Salts) and jodean (of 0.62 ml, 10.0 mmol) were mixed in methyl ethyl ketone (20 ml) and stirred at the boiling point under reflux for 4 hours and 15 minutes. The mixture was separated between ethyl acetate and water. An ethyl acetate layer was separated, washed in brine, was dried over sodium sulfate and then evaporated to obtain a solid residue. By crystallization of the residue from ethyl acetate/hexanol was obtained 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5 - chloropentane-1-he (determined as 0.720 g, 2.37 mmol), tPL98-100oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-hydroxyphenyl)-5-chloropentane-1-it 1-(4-acetylamino-5-chloro-2-hydroxyphenyl)-4-chlorobutane-1-he got 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-4-chlorobutane-1-it is in the form of butter.

In the same way as in stage (b) of example 4, but replacing itmean 4-methoxybenzylidene, was obtained 1-[4-acetylamino-5 - chloro-2-(4-methoxybenzyloxy)phenyl]-5-chloropentane-1-it, tPL147-149oC.

In the same way as in stage (b) of example 4, but replacing itmean 3.4-dimethoxybenzidine, was obtained 1-[4-acetylamino - 5-chloro-2-(3,4-dimethoxybenzoate)phenyl]-5-chloropentane-1-he PL147oC.

In the same way as in stage (b) of example 4, but samestate-1-hePL135-137oC.

In the same way as in stage (b) of example 4, but replacing itmean 3.5-dimethoxybenzidine and 1-(4-acetylamino-5-chloro-2 - hydroxyphenyl)-5-chloropentane-1-it 1-(4-acetylamino-5-bromo-2 - hydroxyphenyl)-5-bromantan-1-he got 1-[4-acetylamino-5 - bromo-2-(3,5-dimethoxybenzoate)phenyl]-5-bromantan-1-it.

In the same way as in stage (b) of example 4, but replacing itmean 3.4-methylenedioxybenzyl, was obtained 1-[4-acetylamino-5-chloro - 2-(3,4-methylenedioxybenzyl)phenyl]-5-chloropentane-1-it, tPL132-134oC.

In the same way as in stage (b) of example 4, but replacing itmean 2-(4-methoxyphenyl)-1-Iodate, was obtained 1-{4-acetylamino-5-chloro-2-[2-(4-methoxide)ethoxy]phenyl}-5-chloropentane-1-it, tPL108-110oC.

In the same way as in stage (b) of example 4, but replacing itmean 2-(3,4-acid)-1-Iodate, was obtained 1-{ 4-acetylamino-5-chloro-2-[2-(3,4-dimethoxyphenyl)ethoxy]phenyl}- 5-chloropentane-1-it.

Stage (C)

1-(4-Acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentane-1-he (0,72 g of 2.26 mmole), sodium iodide (0.15 g, 0.1 mmole) and piperidine (1,72 g, 20 mmol) were mixed in DMF (8.0 ml) and the mixture was heated up to 80oC for 4.5 hours. Then add water with sediment. PL74-75oC.

1-(4-Acetylamino-5-chloro-2-methoxyphenyl)-5-(piperidine-1-yl) pentane-1-it was dissolved in 2 N. hydrochloric acid (25 ml) and the solution was stirred for 30 minutes. The solution was cooled in an ice bath to precipitate. The precipitate was collected by filtration and washed with water. By drying in a vacuum oven at 70oC received hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-5-(piperidine-1-yl)pentane-1-she (0.65 g, 2 mmole), tPL220-221oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)- 5-chloropentane-1-it 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-4 - chlorobutane-1-he and piperidine to diethylamin, got hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-4-diethylaminomethyl-1-it,PL145-150oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentane-1-it 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-4-chlorobutane-1-he and piperidine to pyrrolidine, got hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-4- (pyrrolidin-yl)butane-1-it, tPL221-224oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentane-1-it 1-(4-acetylamino-5-chloro-2-methoxyphenyl)38oC.

In the same way as in stage (b) of example 4, but replacing piperidine by dimethylamine, got hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-5-diethylaminopentane-1-it, tPL219-220oC.

In the same way as in stage (b) of example 4, but replacing piperidine by diethylamin, got hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-5-diethylaminopentane - 1-it, tPL178-179oC.

In the same way as in stage (b) of example 4, but replacing piperidine by di(prop-1-yl)amine, obtained the hydrochloride of 1-(4-amino-5-chloro-2-methoxyphenyl)-5-di(prop-1-yl)aminoindan-1-it, tPL162 to 165 of theoC.

In the same way as in stage (b) of example 4, but replacing piperidine by pyrrolidine, got hydrochloride 1-(4-amino-5-chloro-2 - methoxyphenyl)-5-(pyrrolidin-1-yl)pentane-1-it, tPL203-205oC.

In the same way as in stage (b) of example 4, but substituting piperidine for 4-methylpiperidin, got hydrochloride 1-(4-amino-5-chloro-2 - methoxyphenyl)-5-(4-methylpiperidin-1-yl) pentane-1-it, tPL195-197oC.

In the same way as in stage (b) of example 4, but replacing piperidine 4.4-dimethylpiperidin, got hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-5-(4,4-dimethylpiperidin-1-yl) pentane-1-it, tridin, received hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-5-(4-ethylpiperazin - 1-yl)pentane-1-it, tPL197-198oC.

In the same way as in stage (b) of example 4, but substituting piperidine for 4-(prop-1-yl)piperidine, obtained the hydrochloride of 1-(4-amino-5-chloro-2-methoxyphenyl)-5-[4- (prop-1-yl)piperidine-1-yl]pentane-1-it, tPL212-213oC.

In the same way as in stage (b) of example 4, but substituting piperidine for 4-aminocarbonylmethyl, got hydrochloride 1-(4-amino-5-chloro - 2-methoxyphenyl)-5-(4-aminocarbonylmethyl-1-yl) pentane-1-it, tPL230-235oC.

In the same way as in stage (b) of example 4, but substituting piperidine for 4-hydroxypiperidine, got hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-5-(4-hydroxypiperidine-1-yl) pentane-1-it, tPL205-207oC.

In the same way as in stage (b) of example 4, but substituting piperidine for 4-methoxypiperidine, got hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-5-(4 - methoxypiperidine-1-yl)pentane-1-it, tPL193-195oC.

In the same way as in stage (b) of example 4, but substituting piperidine for 4-(methylsulphonyl)aminopiperidin, got hydrochloride 1-(4-amino-5 - chloro-2-methoxyphenyl)-5-[4-(methylsulphonyl)aminopiperidin-1-yl] pentane-1-it, tPL
231-232oC.

In the same way as in stage (b) of example 4, but substituting piperidine for 4-phenylpiperidine, got hydrochloride 1-(4-amino-5 - chloro-2-methoxyphenyl)-5-(4-phenylpiperazin-1-yl)pentane-1-it, PL257-259oC.

In the same way as in stage (b) of example 4, but substituting piperidine for morpholine, got hydrochloride 1-(4-amino-5 - chloro-2-methoxyphenyl)-5-(morphol-1-yl)pentane-1-it, tPL229-231oC.

In the same way as in stage (b) of example 4, but replacing piperidine by azacycloheptan, got hydrochloride 1-(4-amino-5 - chloro-2-methoxyphenyl)-5-(azacycloheptane-1-yl)pentane-1-it, tPL203-205oC.

In the same way as in stage (b) of example 4, but replacing piperidine 3-azabicyclo[2.2.1] heptane, got hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-5-(3-azabicyclo[2.2.1]hept-3 - yl)pentane-1-it, tPL158-160oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)- 5-chloropentane-1-it 1-[4-acetylamino-5-chloro-2-(4 - methoxybenzyloxy)phenyl]-5-chloropentane-1-he got hydrochloride 1-[4-amino-5-chloro-2-(4-methoxybenzyl the example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)- 5-chloropentane-1-it 1-[4-acetylamino-5-chloro-2-(3,4 - dimethoxybenzoate)phenyl] -5-chloropentane-1-he got 1-[4 - amino-5-chloro-2-(3,4-dimethoxybenzoate)phenyl] -5-(piperidine-1 - yl)pentane-1-it, tPL125-127oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)- 5-chloropentane-1-it 1-[4-acetylamino-5-chloro-2-(3,4 - methylenedioxybenzyl)phenyl]-5-chloropentane - 1-he got 1-[4-amino-5-chloro-2-(3,4 - methylenedioxybenzyl)phenyl] -5-(piperidine-1-yl)pentane-1-it, tPL120-122oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentane-1-it 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] -5 - chloropentane-1-he piperidine at dimethylamine, got hydrochloride 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl]-5 - diethylaminopentane-1-it, tPL221-224oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2 - methoxyphenyl)-5-chloropentane-1-it 1-[4-acetylamino-5-chloro-2-(3,5 - dimethoxybenzoate)phenyl] -5-chloropentane-1-he and piperidine to diethylamin, was obtained 1-[4-amino-5-chloro-2-(3,5 - dimethoxybenzoate)phenyl]-5-diethylaminopentane-1-it, tPL125-127oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5 - chloropentane-1-it 1-[4-acetylamino-5-chloro-2-(3,5 - dimethoxybenzoate)phenyl]-5-chloropentane-1-he got 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl]-5-(piperidine-1 - yl)pentane-1-it, tPL128-130oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5 - chloropentane-1-it 1-[4-acetylamino-5-bromo-2-(3,5 - dimethoxy)benzyloxyphenyl] -5-bromantan-1-he got hydrochloride 1-[4-amino-5-bromo-2-(3,5-dimethoxy)benzyloxyphenyl] - 5-(piperidine-1-yl)pentane-1-it, tPL238-239oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro - 2-methoxyphenyl)-5-chloropentane-1-it 1-[4-acetylamino-5-chloro-2- (3,5-dimethoxybenzoate)phenyl] -5-chloropentane-1-he piperidine for 4-methylpiperidin, was obtained 1-[4-amino-5-chloro - 2-(3,5-dimethoxybenzoate)phenyl]-5-(4-methylpiperidin-1 - yl)pentane-1-it, tPL136-137oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)- 5-chloropentane-1-it 1-[4-acetylamino-amino-5-chloro-2-(3,5 - dimethoxybenzoate)phenyl]-5-[4-(prop-1-yl)piperidine-1-yl] pentane-1-it, tPL119-120oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5 - chloropentane-1-it 1-[4-acetylamino-5-chloro-2-(3,5 - dimethoxybenzoate)phenyl]-5-chloropentane-1-he piperidine 4.4-dimethylpiperidin, was obtained 1-[4-amino-5-chloro-2-(3,5 - dimethoxybenzoate)phenyl]-5-(4,4-dimethylpiperidin-1-yl)pentane - 1-it, tPL135-136oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentane-1 - it 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] - 5-chloropentane-1-he piperidine for 4-hydroxypiperidine, got hydrochloride 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl]- 5-(4-hydroxypiperidine-1-yl)pentane-1-it, tPL220-222oC.

In the same way as in stage (b) of example 4, but replacing 1-(4 - acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentane-1-it 1-[4 - acetylamino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] -5 - chloropentane-1-he piperidine for 4-(2-hydroxyethyl)piperidine, obtained the hydrochloride of 1-[4-amino-5-chloro-2-(3,5 - dimethoxybenzoate)phenyl] -5-[4-(2-hydroxyethyl)piperidine-1 - yl]pentane-1-it, tPL180-183oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxy is a 4-methoxypiperidine, received hydrochloride 1-[4-amino-5 - chloro-2-(3,5-dimethoxybenzoate)phenyl] -5-(4 - methoxypiperidine-1-yl)pentane-1-it, tPL195-196oC.

In the same way as in stage (b) of example 4, but replacing 1-(4 - acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentane-1-it 1-[4 - acetylamino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] -5 - chloropentane-1-he piperidine for 4-aminocarbonylmethyl, got hydrochloride 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] - 5-(4-aminocarbonylmethyl-1-yl)pentane-1-it, tPL207-209oC.

In the same way as in stage (b) of example 4, but replacing 1-(4 - acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentane-1-it 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] -5 - chloropentane-1-he piperidine for 4-(aminocarbonyl)aminopiperidin, got hydrochloride 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate) phenyl] -5-[4-(aminocarbonyl)aminopiperidin-1-yl] pentane-1-it, tPL220-224oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentane-1-it 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] -5 - chloropentane-1-he piperidine for 4-(aminocarbonyl)AMINOETHYLPIPERAZINE, got hydrochloride 1-[4 - amino-5-chloro-2-(3,5-dimethoxybenzoate)Fenice and at the stage (C) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentane-1-it 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] -5 - chloropentane-1-he piperidine for 4-(methylsulphonyl)aminopiperidin, got hydrochloride 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate) phenyl] -5-[4-(methylsulphonyl)aminopiperidin-1-yl] pentane-1-it, tPL240-245oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentane-1-it 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzoate) phenyl] -5 - chloropentane-1-he piperidine for 4-(methylsulphonyl)AMINOETHYLPIPERAZINE, got hydrochloride 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl]-5-[4- (methylsulphonyl)AMINOETHYLPIPERAZINE-1-yl]pentane-1-it, tPL211-213oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentane-1-it 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] -5-chloropentane - 1-he piperidine 4-[2-(methylsulphonyl)aminoethyl] piperidine, received hydrochloride 1-[4-amino-5-chloro-2-(3,5 - dimethoxybenzoate)phenyl]-5-{4-[2- (methylsulphonyl)aminoethyl] piperidine-1-yl}pentane-1-it, tPL205-206oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-oceanman-1-he piperidine for 4-phenylpiperidine, received hydrochloride 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl]- 5-(4-phenylpiperazin-1-yl)pentane-1-it, tPL237-239oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5-chloropentane-1-it 1-[4-acetylamino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] -5 - chloropentane-1-he and piperidine to azacycloheptan, was obtained 1-[4 - amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl]-5-(azacycloheptane-1 - yl)pentane-1-it, tPL137-139oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5 - chloropentane-1-it 1-{ 4-acetylamino-5-chloro-2-[2-(4 - methoxide)ethoxy]phenyl}-5-chloropentane-1-he got 1-{4-amino-5-chloro-2-[2-(4-methoxide)ethoxy] phenyl} -5-(piperidine-1 - yl)pentane-1-it, tPL211-212oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)-5 - chloropentane-1-it 1-{ 4-acetylamino-5-chloro-2-[2-(3,4 - dimethoxyphenyl)ethoxy]phenyl}-5-chloropentane-1-he got 1-{4 - amino-5-chloro-2-[2-(3,4-dimethoxyphenyl)ethoxy] phenyl} -5-(piperidine - 1-yl)pentane-1-it, tPL224-225oC.

In the same way as in stage (b) of example 4, but replacing 1-(4-acetylamino-5-chloro-2-methoxyphenyl)- 5-chloropentane-1-it 1-{ 4-acetyll is 1-{ 4 - amino-5-chloro-2-[2-(4-methoxide)ethoxy]phenyl}-5-(4 - methylpiperidin-1-yl)pentane-1-it, tPL226-228oC.

EXAMPLE 5

4'-Amino-5'-chloro-2'-methoxyacetophenone

Following receipt of the compounds of formula VIII, where R1denotes chlorine, R2denotes hydrogen and R3denotes methoxy.

N-methoxy-N-methyl-4-amino-5-chloro-2-methoxybenzamide (24.4 g, 100 mmol) was dissolved in THF (400 ml) and the solution was cooled to -40oC. was Added motility in ether (143 ml, 4.4 g, 200 mmol) and the mixture was allowed to warm to 0oC. was Added aqueous hydrochloric acid and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over sodium sulfate and evaporated to obtain a solid substance. By crystallization from ethyl acetate-hexane was obtained 4'-amino-5'-chloro-2'-methoxyacetophenone (15.0 g, 75 mmol), tPL114-116oC.

In the same way as in example 5, but replacing N-methoxy-N-methyl-4-amino-5-chloro-2-methoxybenzamide N-methoxy-N-methyl-4-amino-5-chloro-2,3-atlanticcanada, received 4-amino-5-chloro-2,3-ethylenediaminetriacetate, tPL133-135oC.

In the same way as in example 5, but replacing N-methoxy-N-methyl-4-amino-5-chloro-2-methoxybenzamide N-methoxy-N-methyl-4-amino-5-chloro-2,3-dimethoxybenzamide, received 4-amino-5-chloro-2,3-dimethoxyphenylacetic the Sano obtaining the compounds of formula VI, where R1denotes chlorine, and R2and R3together represent Ethylenedioxy.

Stage (a)

A solution of 1,4-benzodioxane (8.4 M, 25 ml of 0.21 mol) in 15 ml acetic acid was treated with gaseous chlorine at 10-20oC, receiving a yellow precipitate. The precipitate was isolated by filtration and washed with water. By crystallization of the precipitate from ethanol was obtained 6,7-dichloro-1,4 - benzodioxan (25,5 g, 0,124 mol), tPL147-148oC.

Stage (b)

A mixture of 6,7-dichloro-1,4-benzodioxane (of 10.25 g, 0.05 m), acetylchloride (13.5 M, 5 ml, 0,0675 mole) and aluminum chloride (10 g, of 0.075 mole) in 200 ml of 1,2-dichloroethane was stirred in nitrogen atmosphere for 24 hours. The mixture was poured into about 500 ml of ice/dilute hydrochloric acid and was extracted with methylene chloride. Methylenchloride the extract was washed with sodium bicarbonate (1x), water (1 time) and with brine (1 time) and then dried over sodium sulfate. Methylene chloride was filtered and concentrated using a rotary evaporator. By purification of the residue using column chromatography (silica 230-400 mesh mesh; 15% ethyl acetate/hexane) was obtained 5,6-dichloro-2,3-ethylenedioxythiophene (8,1 g 0,033 mol), tPL83-86oC.

Stage (C)

5',6'-Dichloro-2',3'-Ethylenedioxy, to the temperature of the reaction mixture remained below 10oC. the Mixture was stirred for 10 minutes with 5oC and then poured into 250 g of ice chips, getting a yellow precipitate. The precipitate was isolated by filtration and washed with water. By drying was obtained 5', 6'-dichloro-2',3'-Ethylenedioxy-4'-nitroacetophenone (8,9 g, 0,0341 mol), tPL181-182oC.

Stage (d)

A mixture of 5', 6'-dichloro-2', 3'-Ethylenedioxy-4'-nitroacetophenone (2 g, 7,63 mmole) and 10% palladium on coal (800 g) was hydrogenosomal in 17 ml of 15% sodium hydroxide and 160 ml of ethanol at a pressure of 57 psi for 7 hours. The mixture was filtered and concentrated using a rotary evaporator and the residue was stirred with water. By drying was obtained 4'-amino-2',3'- ethylenedioxythiophene (970 mg, 5,04 mmole), tPL135-136oC.

Stage (d)

A solution of 4'-amino-2', 3'-ethylenedioxythiophene (310 mg, 1,60 mmole) in 2.3 ml of pyridine was cooled in an atmosphere of nitrogen in a water/ice bath and was added dropwise 6.9 ml of acetic anhydride. The mixture was allowed to warm to room temperature and then was stirred for 16 hours. The mixture was concentrated using a rotary evaporator and the residue was stirred with water. The residue was isolated by filtration and washed with water. By drying /P> Stage (e)

A solution of 2',3'-Ethylenedioxy-4'- (methylcarbonate)acetophenone (250 mg, of 1.06 mmole) in 6 ml of dimethylformamide was cooled in an atmosphere of nitrogen in a water/ice bath was added N-chlorosuccinimide (156 mg, 1,17 mmole). The mixture was allowed to warm to room temperature and then kept at 55oC for 1.5 hours. Then the mixture was cooled to room temperature and was stirred for 16 hours. The mixture was concentrated using a rotary evaporator and the residue was stirred with water. The residue was isolated by filtration and washed with water. By drying was obtained 5'-chloro-2', 3'-Ethylenedioxy-4'-(methylcarbonate)acetophenone (170 mg, to 0.69 mmole), tPL181-182oC.

Stage (W)

A mixture of 5'-chloro-2',3'-Ethylenedioxy-4'-(methylcarbonate)acetophenone (152 mg, of 0.56 mmole) and sodium hydroxide (4 N., 1,4 ml, 5.6 mmole) in 5 ml of methanol was heated under reflux for 3.5 hours. The mixture was concentrated using a rotary evaporator and the residue was stirred with water. The residue was isolated by filtration and washed with water. By drying was obtained 4'-amino-5'-chloro-2', 3'- ethylenedioxythiophene (95 mg, 0,41 mmole), tPL133-136oC.

EXAMPLE 7

1-(4-Amino-5-chloro-2-methoxyphenyl)-3-(piperidine-4-yl) propan-1-he

Neither denotes a group of formula (b), where p is 0, q is 2 and R7denotes hydrogen.

Stage (a)

4-Amino-5-chloro-2-methoxyacetophenone (was 12.75 g, 64 mmole) obtained in accordance with example 5, suspended in THF (125 ml). The suspension was added to a cooled to -50oC solution diisopropylamide lithium (16,1 g, 150 mmol) in THF (200 ml) and the mixture was stirred at 0oC for 15 minutes. Added pyridine-4-carboxaldehyde (8.0 g, 75 mmol) and the mixture was allowed to warm to 5oC. was Added water ammoniacal and the mixture was extracted three times with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate and concentrated in vacuo to obtain a semi-solid residue. Added ethyl acetate-hexane and by subsequent filtration was obtained 1-(4-amino-5-chloro - 2-methoxyphenyl)-3-hydroxy-3-(pyridin-4-yl)propan-1-he (12.1 g, 40 mmol), tPL181-183oC.

Stage (b)

1-(4-Amino-5-chloro-2 - methoxyphenyl)-3-hydroxy-3-(pyridin-4-yl)propan-1-he (8.6 g, 28 mmol), obtained in accordance with stage (a) of example 6, was dissolved in concentrated sulfuric acid (40 ml) and the solution was stirred at room temperature for 15 minutes. The solution was poured on ice, increased basicity using ammonium hydroxide and then filtered-he (7.6 g, 26 mmol), tPL209-211oC.

Stage (C)

1-(4-Amino-5-chloro-2-methoxyphenyl)-3-(pyridin-4-yl)-2-propen-1-he (0.5 g, 1.7 mmole), obtained according to stage (b) of example 6, was dissolved in acetic acid (25 ml) and the solution was hydrogenosomal over a catalyst of 5% rhodium on aminoalkylation media (0.2 g) at a pressure of 50 psi for 24 hours. The solution was filtered, diluted with water, increases the basicity using ammonium hydroxide and was extracted three times with methylene chloride. The combined extracts were dried over sodium sulfate. By evaporation was obtained 1-(4-amino-5-chloro-2-methoxyphenyl)-3- (piperidine-4-yl) propan-1-he (0.35 g, 1.2 mmole).

EXAMPLE 8

1-(4-Amino-5-chloro-2-methoxyphenyl)-3-(piperidine-4 - yl)propen-1-he

Below is described a method, alternative to the method of example 7, stages (a)-(b).

Potassium hydroxide (5.0 g, 89,3 mmole) was dissolved in water (25,0 ml). To the solution was added ethanol (100 ml) and the mixture was stirred. 4-Amino-5-chloro-2-methoxyacetophenone (10.0 g, 50,5 mmole) obtained in accordance with example 5, was added to the mixed solution and after 5 minutes was added pyridine-4 - carboxaldehyde (6.4 g, 60,0 mmol) and the mixture was stirred for approximately 12 hours. Then the mixture was diluted with water and f is)-2-propen-1-he (is 12.85 g, 44,5 mmole).

In the same way as in example 8, but replacing 4-amino-5-chloro-2-methoxyacetophenone 4-amino-5-chloro - 2,3-ethylenedioxythiophene, was obtained 1-(4-amino-5-chloro-2,3 - atlanticcity)-3-(pyridin-4-yl)propen-1-it, tPL209-211oC.

In the same way as in example 8, but replacing 4-amino-5-chloro-2 - methoxyacetophenone 4-amino-5-chloro-2,3-dimethoxyacetophenone, was obtained 1-(4-amino-5-chloro-2,3-acid)-3-(pyridin-4 - yl)propen-1-it, tPL220-223oC.

EXAMPLE 9

1-(4-Amino-5-chloro-2,3-atlanticcity)-3-(piperidine-4-yl)-2-propane - 1-he

Below is described a method, alternative to the method of example 7, the stage (b).

Stage (a)

A solution of 1-(4-amino-5-chloro-2,3-atlanticcity)-3- (pyridin-4-yl)-2-propen-1-it (1.55 g, 5 mmol) in 50 ml THF was hydrogenosomal over 5% palladium on coal (0.5 g) for approximately 2 hours. The mixture was filtered and concentrated using a rotary evaporator. By purification of the residue by chromatography on silica gel (2% CH3OH-CH2Cl2+ 0.1% OF NH4OH) was obtained 1-(4-amino-5-chloro-2,3-atlanticcity)-3-(pyridin-4-yl)propan-1-he (1,23 g, 3.8 mmole).

Stage (b)

A solution of 1-(4-amino-5-chloro-2,3-atlanticcity)- 3-(pyridin-4-yl)propan-1-it (1,23 g, 3.8 mmole) ,0 g) at a pressure of 50 psi for about 20 hours. The mixture was filtered and the filter was washed several times with ethanol. The combined filtrates were concentrated in vacuo. By purification of the residue by chromatography on silica gel (20% CH3OH-CH2Cl2+ 0,2% NH4OH) was obtained 1-(4-amino-5-chloro-2,3-atlanticcity)-3-(piperidine-4 - yl)propan-1-he (0,22 g, 0.68 mmole).

EXAMPLE 10

1-(4-Amino-5-chloro-2-methoxyphenyl)-3-[1-(prop-1-yl)piperidine-4-yl] propane-1-he

Following receipt of the compounds of formula I, where R1denotes chlorine, R3denotes methoxy, R4denotes a group of formula (b), where p is 0, q is 2 and R7denotes prop-1-yl.

1-(4-Amino-5-chloro-2-methoxyphenyl)-3-(piperidine-4-yl) propan-1-he (0.2 g, 0.67 mmole) obtained in accordance with example 3 or example 7, triethylamine (0.2 ml) and 1-bromopropane (0,065 ml, 0.75 mmole) was dissolved in DMF (4 ml) and the solution was stirred at room temperature for 12 hours. The solution was divided between aqueous ammonium hydroxide and ethyl acetate. An ethyl acetate layer was separated, washed with water and then with brine, dried over sodium sulfate and evaporated. By purification of the residue by chromatography on silica gel (10% CH3OH - CH2Cl2) was obtained 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(Pro with simple ether there was obtained the hydrochloride of 1-(4-amino-5-chloro-2-methoxide-Neil)-3-[1- (prop-1-yl)piperidine-4-yl]propane-1-she (0.15 g, 0.4 mmole),PL200-201oC.

In the same way as in example 10, but replacing 1-bromopropane on logmean, got hydrochloride 1-(4-amino-5-chloro-2 - methoxyphenyl)-3-(1-methylpiperidin-4-yl)propan-1-it, tPL179-180oC.

In the same way as in example 10, but replacing 1-bromopropane on Iodate, got hydrochloride 1-(4-amino-5-chloro-2 - methoxyphenyl)-3-(1-ethylpiperazin-4-yl)propan-1-it, tPL128-130oC.

In the same way as in example 10, but replacing 1-bromopropane on idbutton, got hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)- 3-[1-(but-1-yl)piperidine-4-yl]propane-1-it, tPL195-196oC.

In the same way as in example 10, but replacing 1-bromopropane 1-bromo-2-methylpropan, got hydrochloride 1-(4-amino-5-chloro-2 - methoxyphenyl)-3-[1-(2-methylprop-1-yl)piperidine-4-yl]propane-1-it, tPL198-199oC.

In the same way as in example 10, but replacing 1-bromopropane 1-bromo-3-methylbutane, got hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(3-methylbut-1 - yl)piperidine-4-yl]propane-1-it, tPL178-179oC.

In the same way as in example 10, but replacing 1-bromopropane 1-bromopentane, got hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(Penta - 1-yl)piperidine-4-yl]bromhexin, received hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(Gex - 1-yl)piperidine-4-yl]propane-1-it, tPL212-213oC.

In the same way as in example 10, but replacing 1-bromopropane 3-bromopropene, got hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(2- propenyl)piperidine-4-yl]propane-1-it, tPL162-163oC.

In the same way as in example 10, but replacing 1-bromopropane 1-chloro-2 - methoxyethane, got hydrochloride 1-(4-amino-5-chloro-2 - methoxyphenyl)-3-[1-(2-methoxyethyl)piperidine-4-yl]propane-1-it.

In the same way as in example 10, but replacing 1-bromopropane 2-bromo-1-[(dimethylaminoacetyl)amino] ethyl, got hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-3-{ 1-[2- (dimethylaminomethyl)aminoethyl]piperidine-4-yl}propane-1-it, tPL195-196oC.

In the same way as in example 10, but replacing 1-bromopropane 2-bromo-1-[(dimethylaminoethyl)amino] ethyl, got hydrochloride 1-(4 - amino-5-chloro-2-methoxyphenyl)-3-{1-[2-(dimethylaminoethyl)aminoethyl] piperidine-4-yl}propane-1-it, tPL167-171oC.

In the same way as in example 10, but replacing 1-bromopropane 2-bromo-1-[(methoxycarbonyl)amino] ethyl, got hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-3-{ 1-[2- (methoxycarbonyl replacing 1-bromopropane 2-bromo-1-[(trifloromethyl)amino] ethyl, received hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-3-{ 1-[2- (trifloromethyl)aminoethyl]piperidine-4-yl}propane-1-it, tPL235-238oC.

In the same way as in example 10, but replacing 1-bromopropane 3-bromo-1-[(methylsulphonyl)amino] propyl, got hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-3-{1-[3- (methylsulphonyl)aminopropan-1-yl]piperidine-4-yl} propane-1-it, tPL194-195oC.

In the same way as in example 10, but replacing 1-bromopropane on idbutton and 1-(4-amino-5-chloro-2-methoxyphenyl)-3- (piperidine-4-yl)propan-1-it 1-(4-amino-5-chloro-2,3 - atlanticcity)-3-(piperidine-4-yl)propan-1-he got hydrochloride 1-(4-amino-5-chloro-2,3-atlanticcity)-3-[1-(but-1 - yl)piperidine-4-yl]propane-1-it, tPL265-267oC.

In the same way as in example 10, but replacing 1-bromopropane on idbutton and 1-(4-amino - 5-chloro-2-methoxyphenyl)-3-(piperidine-4-yl) propan-1-it 1-(4-amino-5-chloro-2,3-acid)-3-(piperidine-4-yl) propan-1-he got hydrochloride 1-(4-amino-5-chloro-2,3-acid)-3-[1- (but-1-yl)piperidine-4-yl]propane-1-it, tPL175-176oC.

EXAMPLE 11

1-(4-Amino-5-chloro-2-methoxyphenyl)-3-{1-[2-(methylsulphonyl)aminoethyl] piperidine-4-yl}propane-1-he

The following describes the connection formul 0, q is 2 and R7refers to 2-[(methylsulphonyl)amino]ethyl.

Ethylenimine (40 mg, 0.9 mmole) was dissolved in toluene (5 ml) and the solution was cooled in an ice bath. Was slowly added a solution of methanesulfonamide in toluole (1 ml, 0.1 mg, 1 mmol) and the mixture was stirred for 20 minutes with formation of a solution of 1-[2-(methylsulphonyl)ethyl]etilenimina.

1-(4-Amino-5-chloro-2 - methoxyphenyl)-3-(piperidine-4-yl)propan-1-he (240 mg, 0.8 mmole) obtained in accordance with example 3 or example 7, was dissolved in THF (20 ml) and through the filter solution was added 1-[2- (methylsulphonyl)ethyl]etilenimina. The mixture was heated under reflux for 1 hour and then concentrated in vacuum. The residue was dissolved in ethyl acetate and this solution is washed three times with water, dried over sodium sulfate and evaporated. By purification using chromatography on silica gel (15% CH3OH - CH2Cl2) was obtained 1-(4-amino-5-chloro-2-methoxyphenyl)-3-{ 1-[2- (methylsulphonyl)aminoethyl] piperidine-4-yl} propane-1-on. By crystallization from ethanolic hydrochloric acid was obtained the hydrochloride of 1-(4-amino-5-chloro-2-methoxyphenyl)-3-{ 1-[2- (methylsulphonyl)aminoethyl]piperidine-4-yl}propane-1-it, tPL123-126oC.

EXAMPLE 12

1-[4-Amino-5-chloro-2-(3,5-DNA the compounds of formula I, where R1denotes chlorine, R3indicates 3,5-dimethoxybenzoate, R4denotes a group of formula (b), where p is 0, q is 2 and R7denotes 2-(methylsulphonyl)aminoethyl.

Stage (a)

1-[4-Amino-5-chloro-2-methoxyphenyl] -3-{ 1-[2- (methylsulphonyl)aminoethyl] piperidine-4-yl} propane-1-he (1.19 g, 2.8 mmole) obtained in accordance with example 11, was dissolved in dichloroethane (50 ml). Added trichromacy boron in methylene chloride (4 ml, 1.0 g, 4.0 mmole) and the mixture was stirred for approximately 12 hours. The mixture is then poured on ice and added to methylene chloride (150 ml) and ammonium hydroxide. This two-layer mixture was stirred to form a solution in methylene chloride layer. The aqueous layer was removed and mixed with fresh methylene chloride (100 ml) and this two-layer mixture was stirred. Methylenchloride layers were combined and dried over potassium carbonate. By filtration and concentration was obtained 1- (4-amino-5-chloro-2-hydroxyphenyl)-3-{ 1-[2- (methylsulphonyl)aminoethyl]piperidine-4-yl}propane-1-he (0.8 g, 2.0 mmole).

Stage (b)

1-(4-Amino-5-chloro-2-hydroxyphenyl)-3-{ 1-[2- (methylsulphonyl)aminoethyl] piperidine-4-yl} propane-1-he (0,78 g of 1.93 mmole), 3,5-dimethoxybenzoate (0,396 g, 2.12 mmole) and potassium carbonate (2.6 g, 18,8 mmole) were mixed in On methoxybenzylamine (0.05 g, of 0.13 mmole) and the mixture was stirred for 24 hours. The solvent was removed under reduced pressure and the remaining solids were added methylene chloride and aqueous sodium bicarbonate, and this two-layer mixture was stirred. Methylenchloride layer was separated, washed twice with water and dried over potassium carbonate. By filtration and concentration was obtained the crude product (1.2 g).

By purification using chromatography on silica gel (3% CH3OH-CH2Cl2) was obtained 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] -3-{ 1-[2- (methylsulphonyl)aminoethyl] piperidine-4-yl} propane-1-he (0,53 g to 0.98 mmole). By crystallization from ethanolic hydrochloric acid was obtained the hydrochloride of 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl]-3- {1-[2-(methylsulphonyl)aminoethyl] piperidine-4-yl}propane-1-it (0.54 g, of 0.93 mmole), tPL123-126oC.

In the same way as in example 12, step (a), but replacing 1-[4-amino-5-chloro-2-methoxyphenyl]-3-{1- [2-(methylsulphonyl)aminoethyl]piperidine-4-yl} propane-1-it 1-(4 - amino-5-chloro-2-methoxyphenyl)-3-[1-(but-1-yl)piperidine-4-yl]propane - 1-it, and then in accordance with example 12, step (b), was obtained the hydrochloride of 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl]- 3-[1-(but-1-yl)piperidine-4-yl]propane-1-it, tpanel]-3-{1-[2-(methylsulphonyl)aminoethyl] piperidine-4-yl} propane-1-it 1-(4-amino-5-chloro-2-methoxyphenyl)-3- [1-(Penta-1-yl)piperidine-4-yl] propane-1-it, and then in accordance with example 12, step (b), was obtained the hydrochloride of 1-[4-amino-5-chloro-2-(3,5 - dimethoxybenzoate)phenyl]-3-[1-(Penta-1-yl)piperidine-4-yl] propane-1-it, tPL174-176oC.

In the same way as in example 12, but substituting 1-[4-amino-5-chloro-2-methoxyphenyl] -3-{1-[2- (methylsulphonyl)aminoethyl]piperidine-4-yl}propane-1-it 1-(4 - amino-5-chloro-2-methoxyphenyl)-3-[1-(2-methoxyethyl) piperidine-4-yl] propane-1-it, and then in accordance with example 12, stage (b), was obtained the hydrochloride of 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] - 3-[1-(2-methoxyethyl)piperidine-4-yl]propane-1-it, tPL183-184oC.

In the same way as in example 12, step (a), but replacing 1-[4-amino-5-chloro-2-methoxyphenyl]-3-{1-[2- (methylsulphonyl)aminoethyl]piperidine-4-yl} propane-1-it 1-[4-amino-5-chloro-2-methoxyphenyl]-3-{1-[2- (dimethylaminomethyl)aminoethyl] piperidine-4-yl}propane-1-it, and then in accordance with example 12, step (b), was obtained the hydrochloride of 1-[4-amino-5-chloro-2-(3,5-dimethoxybenzoate)phenyl] - 3-{1-[2-(dimethylaminomethyl)aminoethyl] piperidine-4-yl} propane-1-it, tPL173-176oC.

In the same way as in example 12, step (b), but substituting 3,5-dimethoxybenzoic on benzylchloride, got hydrochloride 1-(4-amino-5-chloro-2-benzyloxy obom, as in example 12, step (b), but substituting 3,5-dimethoxybenzoic 3-methoxybenzylidene, got hydrochloride 1-[4-amino-5-chloro-2-(3 - methoxybenzyloxy)phenyl]-3-{1-[2-(methylsulphonyl)aminoethyl] piperidine-4-yl}propane-1-it, tPL174-176oC.

In the same way as in example 12, step (a), but replacing 1-[4-amino-5-chloro-2 - methoxyphenyl] -3-{ 1-[2-(methylsulphonyl)aminoethyl]piperidine-4 - yl} propane-1-it 1-[4-amino-5-chloro-2-methoxyphenyl] -5- (piperidine-1-yl)pentane-1-it, and then in accordance with example 12, stage (b), but substituting 3,5-dimethoxybenzoic on Iodate, got hydrochloride 1-[4-amino-5-chloro-2-ethoxyphenyl] -5- (piperidine-1-yl)pentane-1-it, tPL230-231oC.

In the same way as in example 12, step (a), but replacing 1-(4-amino-5-chloro-2 - methoxyphenyl)-3-{ 1-[2-(methylsulphonyl)aminoethyl] piperidine-4 - yl} propane-1-it 1-[4-amino-5-chloro-2-methoxyphenyl] -5- (piperidine-1-yl)pentane-1-it, and then in accordance with example 12, stage (b), but substituting 3,5-dimethoxybenzoic 1-bromopropane, got hydrochloride 1-[4-amino-5-chloro-2-(prop-1-yloxy)phenyl] -5- (piperidine-1-yl)pentane-1-it, tPL232-233oC.

In the same way as in example 12, step (a), but replacing 1-(4-amino-5-chloro-2 - methoxyphenyl)-3-{1-[2-(methylsulphonyl)amestoy with example 12, stage (b), but substituting 3,5-dimethoxybenzoic 3.5-dimethylbenzylamine, got hydrochloride 1-[4-amino-5-chloro-2-(3,5 - dimethylsiloxy)phenyl] -5-(piperidine-1-yl)pentane-1-it, tPL218-233oC.

In the same way as in example 12, step (a), but replacing 1-[4-amino-5-chloro-2-methoxyphenyl]-3-{1-[2- (methylsulphonyl)aminoethyl]piperidine-4-yl} propane-1-it 1-(4-amino-5-chloro-2-methoxyphenyl)-5-(4 - aminocarbonylmethyl-1 - yl)pentane-1-it, and then in accordance with example 12, stage (b), but substituting 3,5-dimethoxybenzoic 3-methoxybenzylidene, got hydrochloride 1-[4-amino-5-chloro-2-(5 - methoxybenzyloxy)phenyl] -5-(4-aminocarbonylmethyl-1-yl)pentane - 1-it, tPL204-205oC.

EXAMPLE 13

1-(4-Amino-5-chloro-2-methoxyphenyl)-3-{ 1-[3-(4-methoxyphenyl)prop-1-yl] piperidine-4-yl}propane-1-he

Following receipt of the compounds of formula I, where R1denotes chlorine, R2denotes hydrogen, R3denotes methoxy, and R4denotes a group of formula (b), where p is 0, q is 2 and R7refers to 3-(4-methoxyphenyl)prop-1-yl.

Stage (a)

A mixture of 1-(4-amino-5-chloro-2 - methoxyphenyl)-3-pyridin-4-improper-1-she (1.5 g, 5,16 mmole), obtained according to example 3 or 7, 3-(4-methoxyphenyl)-1 - jumprope (1.64 g, 5,93 the owls. The mixture was concentrated in vacuum and by purification of the residue by chromatography on silica gel (5% CH3OH-CH2Cl2+ 0,1%

NH4OH) received hydroiodic 1-(4-amino-5-chloro-2-methoxyphenyl- 3-{1-[3-(4-methoxyphenyl)prop-1-yl]pyridinyl-4-yl}propane-1-it (1,82 g of 3.28 mmole).

Stage (b)

The solution hydroiodide 1-(4-amino-5 - chloro-2-methoxyphenyl)-3-{1-[3-(4-methoxyphenyl)prop-1 - yl]pyridinyl-4-yl}propane-1-it (1,82 g of 3.28 mmole) in 30 ml DMF was hydrogenosomal over a catalyst of platinum oxide (IV) (350 mg) at a pressure of 50 psi. The reaction mixture was filtered and concentrated under high vacuum. The residue was dissolved in 150 ml of methylene chloride and the solution was diluted with ammonium hydroxide solution. Methylenchloride layer was separated and washed with ice water (3 times). Methylenchloride layer was dried over sodium sulfate and concentrated in vacuum. By crystallization of the residue from ethanolic hydrochloric acid was obtained the hydrochloride of 1-(4-amino-5-chloro-2-methoxyphenyl)-3- {1-[3-(4-methoxyphenyl)prop-1-yl]piperidine-4-yl}propane-1-it (1,33 g, to 3.09 mmole), tPL188-190oC.

In the same way as in example 13, step (a), but replacing 3-(4-methoxyphenyl)-1-improper 3-(3,5-acid)-1-jumprope, and then in accordance with example 13, propane-1-it, tPL160-163oC.

In the same way as in example 13, step (a), but replacing 3-(4-methoxyphenyl)-1-improper 3-(3,4-acid)-1-jumprope, and then in accordance with example 13, step (b), was obtained the hydrochloride of 1-(4-amino-5-chloro-2 - methoxyphenyl)-3-{1-[3-(3,4-acid)prop-1-yl]piperidine-4 - yl} propane-1-it, tPL177-179oC.

In the same way as in example 13, step (a), but replacing 3-(4-methoxyphenyl)-1-improper 3-(3,4-atlanticcity)-1-jumprope, and then in accordance with example 13, step (b), was obtained the hydrochloride of 1-(4-amino-5-chloro-2 - methoxyphenyl)-3-{1-[3-(3,4-atlanticcity)prop-1 - yl]piperidine-4-yl}propane-1-it, tPL168-170oC.

In the same way as in example 13, step (a), but replacing 3-(4-methoxyphenyl)-1-improper 3-(3,4-methylenedioxyphenyl)-1 - jumprope, and then in accordance with example 13, step (b), was obtained the hydrochloride of 1-(4-amino-5-chloro-2-methoxyphenyl)-3-{ 1-[3- (3,4-methylenedioxyphenyl)prop-1-yl]piperidine-4-yl}propane-1-it, tPL200-202oC.

In the same way as in example 13, step (a), but replacing 3-(4-methoxyphenyl)-1-improper 3-(3,4,5 - trimethoxyphenyl)-1-jumprope, and then in accordance with example 13, step (b), was obtained the hydrochloride of 1-(4-amino-5-chloro-2 - methoxyp what procedure as in example 13, stage (a), but replacing 1-(4-amino-5-chloro-2 - methoxyphenyl)-3-pyridin-4-improper-1-it 1-(4-amino-5-chloro-2,3 - atlanticcity)-3-pyridin-4-improper-1-it, and then in accordance with example 13, step (b), was obtained the hydrochloride of 1-(4 - amino-5-chloro-2,3-atlanticcity)-3-{ 1-[3-(4- methoxyphenyl)prop-1-yl]piperidine-4-yl}propane-1-it, tPL188-189oC.

EXAMPLE 14

1-(4-Amino-5-chloro-2-methoxyphenyl)-5-piperidine-1-alpental-1-

Following receipt of the compounds of formula I, where R1denotes chlorine, R2denotes hydrogen, R3denotes methoxy, and R4denotes a group of formula (a), where p is 0, n is 4 and R5and R6together represent piperidine-1-yl.

Stage (a)

Magnesium (236 g, 9,71 mole) suspended in 3.5 l of THF under nitrogen atmosphere was added 1-bromo-4-chlorobutane (1,11 l, 8,68 M, 9,63 mol) at such a speed that the temperature of the mixture remained below the 25oC. Solution of N-methoxy-N - methyl-4-amino-5-chloro-2-methoxybenzamide (400 g, of 1.64 mol), obtained in accordance with example 2, was cooled to -20oC in nitrogen atmosphere in a 4 l of THF and was added 410 ml of chlorotrimethylsilane. The mixture was allowed to warm to temperatures between -12 and 30oC and then for about 20 minutes was added 2.5 l of solution, soderjaschegosya in 5 l of water. The mixture was heated to 32oC, was stirred for 15 minutes and then diluted to approximately 2 l of ethyl acetate. The organic layer was separated and washed sequentially with 2 l of water and 2 l of a mixture of 1:1 water/saturated sodium chloride solution and saturated sodium chloride solution. All aqueous layers were combined and extracted with ethyl acetate. All organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was mixed with hot hexane and left to stand at room temperature for about 12 hours, receiving sediment. The precipitate was isolated by filtration and washed with hexane. By drying in a vacuum oven at a temperature between 50 and 55oC by injecting gaseous nitrogen was obtained 1-(4-amino-5-chloro-2 - methoxyphenyl)-5-chloropentane-1-he (365 g of 1.33 mol).

Stage (b)

A mixture of 1-(4-amino-5-chloro-2-methoxyphenyl)-5-chloropentane-1-she (365 g of 1.33 mol), piperidine (620 g, 7 mol) and sodium iodide (30 g, 0,2 mol) in 1 l DMF was kept between 78 and 82oC for 4 hours. The reaction mixture was allowed to cool to 50oC, then stirred for about 12 hours and was added to 5 l of water. The mixture was stirred at 25-30oC for 1 hour, receiving sediment, and sediment viduslatgale approximately 2 l of ethyl acetate by heating to approximately the 50oC and then added 130 ml of concentrated hydrochloric acid in a total volume of 4 liters of water. The mixture was stirred for 30 minutes and then stirred for 3 hours in an ice-water bath, receiving sediment. The precipitate was isolated by filtration and washed with 1 l of cold 1:1-mixture of water/ethyl acetate and then 1 l of ethyl acetate. The precipitate was dried in a vacuum oven at a temperature between 45 and 50oC by injecting gaseous nitrogen for 24 hours at 50-55oC for 24 hours and then at room temperature for 48 hours.

The dry residue was dissolved in approximately 9 l of boiling methanol. The solution was filtered and then distilled under vacuum to a volume of about 4 liters) was Added reactive alcohol and the mixture was distilled at atmospheric pressure until the boiling point of between 72 and 74oC and to a total volume of approximately 5 liters

The remaining mixture was stirred at room temperature for about 12 hours and then in an ice bath for 4 hours, obtaining a residue. The precipitate was isolated by filtration and washed with about 1.5 liters of alcohol. Selected sediment was dried with suction for 2 hours and then in a vacuum oven at a temperature of between 55 and 60oC by injecting gazoo the ay further drying in a vacuum oven at a temperature of between 55 and 60oC by injecting nitrogen gas for approximately 48 hours received hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-5-piperidine-1-alpental-1-she (357 g of 0.99 mol), tPL220-222oC.

In the same way as in example 14, but substituting piperidine for 4-methylpiperidin, got hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-5-(4-methylpiperidin-1-yl)pentane - 1-it, tPL197-198oC.

EXAMPLE 15

1-(4-Amino-5-chloro-2-methoxyphenyl)-5-piperidine-1-alpental-1-

Following receipt of the compounds of formula I, where R1denotes chlorine, R2denotes hydrogen, R3denotes methoxy, and R4denotes a group of formula (a), where p is 0, n is 4 and R5and R6together represent piperidine-1-yl.

The suspension of the hydrochloride of 5-(piperidine-1-yl)valerianic acid (6.6 g, 30 mol) in 100 ml THF was cooled in an ice bath was added 100 ml of 1 N. letibit(trimethylsilyl)amide in THF. The ice bath was removed and the resulting solution was stirred at room temperature for 1 hour. A mixture of methyl 2-methoxy-4-amino-5-chlorobenzoate (2.15 g, 10 mmol) and chlorotrimethylsilane (2.5 ml, 20 mmol) in 25 ml THF was cooled in an ice bath was added 20 ml of 1 N. letibit(trimethylsilyl)amide in THF. The solution, sod shall Uchenie 5 minutes was added to the mixture, containing methyl-2-methoxy-4-amino-5 - chlorobenzoate. The reaction mixture was removed from ice bath and stirred at 50-55oC for 2 hours and then the solution was added 25 ml of concentrated hydrochloric acid in 175 ml of water. The mixture was stirred at 50-55oC in a weak stream of nitrogen and then added 120 ml of ethyl acetate. The mixture was stirred in an ice bath for 1 hour, obtaining a residue. The precipitate was isolated by filtration and washed with ethyl acetate. The residue was stirred in 40 ml of boiling isopropanol for 30 minutes and then for 1 hour in an ice bath. The precipitate was isolated by filtration and washed with isopropanol. By drying in a vacuum oven at a temperature of between 55 and 60oC by injecting gaseous nitrogen for 18 hours received hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-5 - piperidine-1-alpental-1-she (2.9 g, 8 mmol).

EXAMPLE 16

Below are typical pharmaceutical compositions containing the compound of formula I.

COMPOSITION FOR ORAL ADMINISTRATION

The typical solution for oral administration includes:

The compound of formula I - 100-1000 mg

Citric acid monohydrate - 105 mg

Sodium hydroxide - 18 mg

Corrigent -

Water - d to 100 K. the em:

The compound of formula I - 10-100 mg

Dextrose monohydrate - D. K. to isotonicity

Citric acid monohydrate - 1,05 mg

Sodium hydroxide - 0.18 mg

Water for injection - D. K. to 1.0 ml

COMPOSITION FOR TABLETS

Typical tableted form the compounds of formula I may contain:

The compound of formula I - 1%

Microcrystalline cellulose - 73%

Stearic acid - 25%

Colloidal silicon 1%

EXAMPLE 17

Study 5-HT4-receptor thoracic part of the esophagus

Below described method to study the in vitro using selected muscle of esophageal mucosa in rats to identify test compounds that are ligands of 5-HT4-receptor.

Thoracic part of the esophagus was isolated from male rats Sprague-Dawley and placed in a solution of Tyrode. External striated muscle is removed for exposure of the muscular mucosa. Every mucosa were hung vertically in a 10 ml tissue bath containing methysergide (1 μm), cocaine (30 μm) and corticosterone (30 μm) in a solution of Tyrode, maintaining the temperature of the 37oC and constantly blowing a gas mixture of 95% O2and 5% CO2.

To cardomom put 0.5, Under carbachol (3 μm) reaches a stationary reduced state and then the fabric is treated with 5-HT in terms of kumulirana concentration, which increases until the maximum or close to maximum relaxation. 5-HT network-dependent concentration relaxation of the muscle tissue of the mucous membrane, where the mediator performs the 5-HT4.

The fabric is subjected to the action of the solution Tirade without medication within 30 minutes, and then reduce by using carbachol. Then the fabric is subjected to the action of the test compounds. If self test connection does not cause relaxation of the muscle tissue of the mucous membrane of the esophagus, the fabric is subjected to the action of 5-HT in the presence of test compounds. Compounds which actually cause relaxation, characterized as agonists 5-HT4-receptor. Compounds that inhibit the relaxation response induced 5-HT, are characterized as antagonists of 5-HT4-receptor.

Using the method described in example 17, got the following results for compounds of the present invention.

Connection - affinity Constant (-log)

A - 7,4

B - 7,5

IN AN 8.4

MR. 8,2

DR. 8,8

Amino-5-chloro-2-methoxyphenyl)-5-(4-methylpiperidin-1 - yl)pentane-1-it

In: hydrochloride 1-(4-amino-5-chloro-2 - methoxyphenyl)-3-{2-[(methylsulphonyl)amino]ethyl}piperidine-4 - yl)propan-1-it

G: hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)- 3-[1-(n-butyl)piperidine-4-yl]propane-1-it

D: hydrochloride 1-(4 - amino-5-chloro-2-methoxyphenyl)-3-{ 1-[3-(3,4-acid)prop-1-yl]piperidine-4-yl}propane-1-it

E: 3-(4-methoxyphenyl)prop-1-yl, namely hydrochloride 1-(4-amino-5 - chloro-2,3-atlanticcity)-3- {1-[3-(4-methoxyphenyl)-prop-1-yl]piperidine-4-yl}propane-1-it

EXAMPLE 18

The study prokinetics activity

Below is described a method of in vivo studies, allowing to determine prokinetics activity by measuring the impact of drugs on the rate of gastric emptying in rats from the test Breakfast. This method is described Droppleman, etc. mentioned above.

Trial Breakfast prepared by slowly adding 20 g of cellulose resin (Hercules Inc. Wilmington, Delaware) to 200 ml of cold distilled water, mixing in the homogenizer of Moringa at approximately 20,000 rpm Mixing continued until, until complete dispersion and hydration of cellulose resin (approximately 5 minutes). Three beef bouillon cube dissolved in 100 ml of warm water and then mixed with saharnoi powder, 8 g of corn starch and 1 g of carbon powder. Each ingredient added slowly and thoroughly mixed, resulting in the approximately 325 ml homogeneous paste dark grey or black. This food is then kept in the refrigerator over night, and during this time trapped air escapes. Before the experiment, food take out from the refrigerator and allowed to warm to room temperature.

Male rats Sprague-Dawley (weight 170-204 g), which reached full development, are deprived of food for 24 hours, allowing the desire to drink water. On the morning of the experiment, each animal is weighed and distributed randomly designated for processing groups of ten animals each. Each rat receives by intraperitoneal injections of either filler, or a trial Breakfast or as a standard metoclopramide. After 0.5 hours after injection using a 5.0-ml disposable syringe each rat oral route is injected 3.0 ml of the test Breakfast. Five samples of the test Breakfast is weighed on an analytical balance, and these weights average to determine the average weight of the test Breakfast. 1.5 hours after injection, each rat killed by asphyxia carbon dioxide and the second sphincter. Taking precautions to avoid any loss of its contents, each stomach was placed on a small, pre-weighed and marked accordingly 7 ml bath for weighing and immediately weighed on an analytical balance. Each stomach is dissected along the lines of lesser curvature, washed with tap water, gently soak dry to remove excess moisture and weighed. Remaining in the stomach of test Breakfast is defined as the difference between the weight of a full stomach and a weight drained stomach. The difference between the remaining amount of trial and Breakfast average weight of the test Breakfast is the number of trial Breakfast, which came out within 1.5 hours after injection.

The results are in the form of released grams of food or percent change relative to control. Average values and standard deviations in the test groups compared with those in the control groups. Significance was determined by t-test Dunnet (Statistical Association Journal, December 1955, 1096-112).

Using the method described in example 18, found that the compounds of the present invention have prokinetics activity.

EXAMPLE 19

Uninfected male mice C5BI/6J, weighing 18-20 g, were kept in groups of 10 mice in cages with controlled noise, temperature and humidity. Feed and water were available on request. Mice were kept at the next light cycle: 12 hours light and 12 hours darkness, with light include at 6.00 o'clock in the morning and off at 6.00 PM. All experiments begin at least 7 days after delivery to the site.

Automatic apparatus for determining changes in the research activity was purchased from the company's Omni-Tech Electronics Columbus Ohio, it is similar to the one used Crawley and Goodwin (1980), as described in the above-mentioned Kilfoil, etc. in short, the camera consists of a Plexiglas box (44 x 21 x 21 cm), divided into two chambers by using a dark Plexiglas partitions. In the partition separating the two chambers, there is a hole the size of 13 x 5 cm, through which a mouse can easily pass. Dark chamber has a transparent wall and white floor. The only lighting gives fluorescent lamp (40 W), is placed over the camera. Monitoring system activity of animals Digiscan Animal Activity Monitor System RXYZCM16 (firm Omni-Tech Electronics) registers issledovatelnitsa to laboratory conditions. After the mouse was obtained by intraperitoneal injection of either the test compound or filler, it returned to its original Sadok 15 min after treatment. Then the mouse was placed in the center of the illuminated chamber and controlled within 10 minutes.

Antirobe manifests itself as a General increase in research activity in the illuminated region. The increase in research activity is manifested in the increase in the latent state (period of time required for the mouse starts to move in a dark cell, when it is first placed in the centre of the illuminated area), an increase of Shuttle activity, increase or no change in locomotor activity (number of crossed lines markup) and reducing the time spent in the dark compartment.

EXAMPLE 20

The study of fear when the syndrome

The following describes the method of determining the in vivo reduction of the intensity of symptoms caused by the cancellation of drugs, by measuring the impact of drugs on fear, which occurs in mice after chronic injection drug substances and then abrupt cessation of these treatments.

Uninfected male mice BKW (25-30 g) spny as desired. Mice were kept at the next light cycle: 12 hours light and 12 hours darkness and light included at 6.00 o'clock in the morning and off at 6.00 PM. All experiments were started at least 7 days after delivery to the site.

Levels of fear were determined using a two-chamber research model Crawley and Goodwin (see example 19). Antirobe manifests itself as a General increase in research activity in the illuminated region. The increase in research activity is manifested in the increase in the latent state (period of time required for the mouse starts to move in a dark cell, when it is first placed in the centre of the illuminated area), increase or no change in locomotor activity (number of crossed lines markup), the increase in the number rise on his hind legs and reducing the time spent in the dark compartment. The increase in research activity in the illuminated region is caused by injecting mice within 14 days of ethanol (8.0% in terms of weight to volume in drinking water), nicotine (0.1 mg/kg, intraperitoneally, twice a day) or cocaine (1.0 mg/kg, intraperitoneally, twice a day). Antifoul was evaluated at 1, 3, 7 and 14 days after the start of application of the drug. Skin area. The filler or the test compound was administered during phase cancellation by intraperitoneal injection. Response was assessed by the inhibition of the reduction antiphonale behavior after stopping the introduction of ethanol, cocaine, or nicotine.

EXAMPLE 21

Research increase cognitive ability

The following describes a model for determining the activity of increasing cognitive abilities by measuring the extent to which the test compound is able to compensate for the deficit of cognitive abilities caused by atropine (30 mg/kg, intraperitoneally) using a water maze Morris.

Rats Sprague Dawley (240-260 g) were kept in the laboratory during the night before the test and left there during the whole experiment. Water maze Morris consisted of a circular basin, made of black Plexiglas (with a diameter of 122 cm, height 46 cm, with 15-inch rim) filled with opaque water to a height of 35 see the Hidden platform made of black plexiglass was placed 1-2 cm below the water surface. The pool was divided into four quadrants, conventionally corresponding to North, South, East and West. The platform was placed in the southern quadrant, will bring transivernyh landmarks. Television camera tracked the ways in which floated rats, and thus obtained data were analyzed to determine the time in seconds required for the rats to find the platform (latency avoidance of danger). The test began by placing the rat in one of the four quadrants of the muzzle to the wall. Trials consisted of a block of six experiments (first started in the Northern quadrant, then East, South, West, North, and finally again in the East) in each of two consecutive days. For every experiment, the rat was given 90 seconds to find the platform. If the rat successfully found the platform, she was given 30 seconds to "study" spatial reference. If the rat failed to find the platform within 90 seconds, she was accrued expense in 90 seconds and placed on the platform for 30 seconds.

Used the following groups of 8 rats each: 1) control-treated filler; 2) control treated with atropine; 3) treated with atropine plus test drug. Thus, these studies were intended to determine, could feel the medication to compensate the deficit of cognitive abilities caused by atropine (30 mg/kg, vnutri the Oia learning curves.

Following the procedure outlined in example 21, was identified compounds according to the present invention has properties of increasing cognitive abilities. For example, the hydrochloride of 1-(4 - amino-5-chloro-2-methoxyphenyl)-5-(piperidinyl-1-yl)pentane-1-she hydrochloride and 1-(4-amino-5-chloro-2-methoxyphenyl)-5-(4 - methylpiperidin-1-yl)pentane-1-it was effective after intraperitoneal injection (10 ng/kg to 1 mg/kg) in this study.

EXAMPLE 22

Toxicity

Rats were administered oral doses of 5, 15 and 50 mg/kg/day of the hydrochloride of 1-(4-amino-5-chloro-2 - methoxyphenyl)-5-(piperidinyl-1-yl) pentane-1-it within one month. Did not reveal any pathological changes associated with the processing of any of these doses.

Although the present invention is described with respect to specific examples of carrying out the invention, specialists in the art will understand that can be made various changes and may be replaced by equivalents without departure from the true nature and scope of the invention. It is implied that all such modifications fall under the scope of the applied claims.

Example 23

1-(4-Amino-5-chloro-2-methoxyphenyl)-5-piperidine-1-alpental-1-

A solution of N-oxide 1-(4-AMI mmol) in 25 ml of dioxane was heated at the boil under reflux for 2.5 hours. The mixture was cooled to room temperature, diluted with water and podslushivaet potassium carbonate. The mixture was extracted with ethyl acetate and the extract was washed with water, dried over sodium sulfate and evaporated to obtain the crude free base. Conversion into the hydrochloride using HCl in isopropanol resulted in obtaining hydrochloride 1-(4-amino-5-chloro-2-methoxyphenyl)-5-piperidine-1 - alpental-1-it (2,40 g, 6.7 mmole), tPL220-222oC.

1. Phenylalanine formula I

< / BR>
where R1denotes halogen;

R2denotes hydrogen or C1-C4alkoxy;

R3stands WITH1-C4alkoxy or panels1-C4alkoxy (where the phenyl optionally substituted with one to three substituents, independently selected from C1-C4of alkyl, C1-C4alkyloxy, 3,4-methylendioxy), or R2and R3together represent methylenedioxy or Ethylenedioxy;

R4denotes a group of formula (a) or (b)

< / BR>
or

< / BR>
where n is 3, 4 or 5;

p is 0;

q is 1 or 2;

R5and R6each stands WITH1-C4alkyl or together form -(CH2)4-, -(CH2)6-, -(CH2)2O(CH2)2or Vmeste represent -(CH2)t- where t is 1, R9denotes hydrogen, hydroxyl, C1-C8alkyl or C1-C4alkyloxy; R10denotes hydrogen, C1-C8alkyl or phenyl, or -(CH2)xR12where x is 0, 1, 2 or 3 and R12denotes hydroxyl,1-C4alkyloxy, -C(O)NR13R14, -NR13C(O)OR14, -SO2NR13R14, -NR13SO2R14, -NR13SO2NR14R15or-NR13C(O)NR14R15where R13, R14and R15independently represent hydrogen, C1-C4alkyl, trifluoromethyl;

R7denotes hydrogen, C1-C8alkyl, C3-C8alkenyl, or panels1-C4alkyl (where the phenyl optionally substituted with one to three substituents, independently selected from C1-C4alkyloxy, methylendioxy, Ethylenedioxy), or -(CH2)zR12where z is 2 or 3 and R12matter mentioned above,

and its pharmaceutically acceptable salts, individual isomers and mixture of isomers.

2. Connection on p. 1 having the following formula I(a):

< / BR>
where n is 3, 4 or 5;

p is 0;

R1denotes halogen;

R3stands WITH1-C4)4-, -(CH2)6-, -(CH2)2O(CH2)2- or-CHR8CH2CR9R10CHR11CH2- where R8and R11each represents hydrogen or together represent -(CH2)t- where t is 1, R9denotes hydrogen, hydroxyl, C1-C8alkyl or C1-C4-alkyloxy and R10denotes hydrogen, C1-C8alkyl or phenyl, or -(CH2)xR12where x is 0, 1, 2 or 3 and R12denotes hydroxyl,1-C4alkyloxy, -C(O)NR13R14, -NR13C(O)OR14, -SO2NR13R14, -NR13SO2R14, -NR13SO2NR14R15or-NR13C(O)NR14R15where R13, R14and R15independently represent hydrogen, C1-C4alkyl or trifluoromethyl,

and its pharmaceutically acceptable salts, individual isomers and mixture of isomers.

3. Connection on p. 2, where p is 0, a R5and R6together form-CHR8CH2CR9R10CHR11CH2-.

4. Connection on p. 3, where n is equal to 4.

5. Connection on p. 4, where R1denotes chlorine, R3denotes methoxy, and each of R8, R9and R11denotes vooropleiding-1-yl)pentane-1-it and its pharmaceutically acceptable salts.

7. Connection on p. 6, which is the hydrochloride of 1-(4-amino-5-chloro-2-methoxyphenyl)-5-(piperidinyl-1-yl)pentane-1-it.

8. Connection on p. 5, where R10denotes methyl, namely, 1-(4-amino-5-chloro-2-methoxyphenyl)-5-(4-methylpiperidin-1-yl)pentane-1-it and its pharmaceutically acceptable salts.

9. Connection on p. 8, which is the hydrochloride of 1-(4-amino-5-chloro-2-methoxyphenyl)-5-(4-methylpiperidin-1-yl)pentane-1-it.

10. Connection on p. 1 having the following formula I(b):

< / BR>
where p is 0;

q is 1 or 2;

R1denotes halogen;

R2denotes hydrogen or C1-C4alkyloxy, and R3stands WITH1-C4alkyloxy or R2and R3together represent methylenedioxy or Ethylenedioxy;

R7denotes hydrogen, C1-C8alkyl, C3-C8alkenyl, or panels1-C4alkyl, where phenyl optionally substituted with one to three substituents, independently selected from C1-C4alkyloxy, methylendioxy, Ethylenedioxy, or -(CH2)zR12where z is 2 or 3 and R12denotes hydroxyl,1-C4alkyloxy, -C(O)NR13R14, -NR13C(O)OR14, -SO2NR13R1413
, R14and R15independently represent hydrogen, C1-C4alkyl, trifluoromethyl,

and its pharmaceutically acceptable salts, individual isomers and mixture of isomers.

11. Connection on p. 10, where q is 2.

12. Connection on p. 11, where R1denotes chlorine, R2denotes hydrogen and R3denotes methoxy.

13. Connection on p. 12, where p is 0 and R7denotes n-butyl, 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(n-butyl)piperidine-4-yl]propane-1-it and its pharmaceutically acceptable salts.

14. Connection on p. 13, which is the hydrochloride of 1-(4-amino-5-chloro-2-methoxyphenyl)-3-[1-(n-butyl)piperidine-4-yl]propane-1-it.

15. Connection on p. 12, where p is 0 and R7refers to 2-[(methylsulphonyl)amino] ethyl, 1-(4-amino-5-chloro-2-methoxyphenyl)-3-{ 2-[(methylsulphonyl)amino] ethyl} piperidine-4-yl]propane-1-it and its pharmaceutically acceptable salts.

16. Connection on p. 15, which is the hydrochloride of 1-(4-amino-5-chloro-2-methoxyphenyl)-3-{2-[(methylsulphonyl)amino]ethyl}piperidine-4-yl]propane-1-it.

17. Connection on p. 12, where p is 0 and R7refers to 3-(3,4-acid)prop-1-yl, 1-(4-amino-5-chloro-2-methoxyphenyl)-3-{ 1-[3-(3,4-dimethoxyphenethyl is the hydrochloride of 1-(4-amino-5-chloro-2-methoxyphenyl)-3-{ 1-[3-(3,4-acid)prop-1-yl] piperidine-4-yl} propane-1-it.

19. Connection on p. 11, where R1represents chlorine and R2and R3together represent Ethylenedioxy.

20. Connection on p. 19, where p is 0 and R7refers to 3-(4-methoxyphenyl)prop-1-yl, 1-(4-amino-5-chloro-2,3-atlanticcity)-3-{1-[3-(4-methoxyphenyl)prop-1-yl] piperidine-4-yl} propane-1-it and its pharmaceutically acceptable salts.

21. Connection on p. 20, in which R7is 3-(4-methoxyphenyl)prop-1-yl, namely, the hydrochloride of 1-(4-amino-5-chloro-2,3-atlanticcity)-3-{ 1-[3-(4-methoxyphenyl)prop-1-yl]piperidine-4-yl}propane-1-it.

22. Connection on p. 1 having the following formula I(C)

< / BR>
where R1denotes halogen;

R3indicates finals1-C4alkoxy, where phenyl optionally substituted with one to three substituents, independently selected from C1-C4of alkyl, C1-C4alkyloxy, 3,4-methylendioxy;

R4denotes a group of formula (a) or (b)

< / BR>
or

< / BR>
where n is 3, 4 or 5;

p is 0;

q is 1 or 2;

R5and R6each represents C1-C4alkyl or together form -(CH2)4-, -(CH2)6-, -(CH2)2O(CH2)2- or-CHR8CH2CR9R10CHR11 the e t is 1, R9denotes hydrogen, hydroxyl, C1-C8alkyl or C1-C4alkyloxy and R10denotes hydrogen, C1-C8alkyl or phenyl, or -(CH2)xR12where x is 0, 1, 2 or 3 and R12denotes hydroxyl, C1-C4alkyloxy, -C(O)NR13R14, -NR13C(O)OR14, -SO2NR13R14, -NR13SO2R14, -NR13SO2NR14R15or-NR13C(O)NR14R15where R13, R14and R15independently represent hydrogen, C1-C4alkyl or trifluoromethyl;

R7denotes hydrogen, C1-C8alkyl or C3-C8alkenyl, or panels1-C4alkyl, where phenyl optionally substituted with one to three substituents, independently selected from C1-C4alkyloxy, methylendioxy, Ethylenedioxy, or -(CH2)zR12where z is 2 or 3 and R12matter mentioned above,

and its pharmaceutically acceptable salts, individual isomers and mixture of isomers.

23. Connection on p. 22, where R3denotes optionally substituted phenyls1-C4alkyloxy and R4denotes a group of formula (a).

24. Connection on p. 23, where R5and R6the n is 4.

26. Connection on p. 22, where R3denotes optionally substituted phenyls1-C4alkyloxy and R4denotes a group of formula (b).

27. Connection on p. 26, where q is 2.

28. Derivatives phenylalaninol formula I on PP. 1 - 27 with affinity for 5-HT4-receptors.

29. Pharmaceutical composition for treatment of conditions that can be alleviated by exposure to 5-HT4receptors, including the active ingredient, characterized in that as the latter is used as a compound of the formula I on PP.l - 27 in therapeutically effective amounts.

30. A method of treating conditions that may be alleviated by the introduction of tools that interact with 5-HT4receptors of the animal, wherein the animal is administered the compounds of formula I on PP.1 - 27 in therapeutically effective amounts.

31. The method according to p. 29, in which the condition is selected from disorders of the Central nervous system, disorders of the gastrointestinal tract, disorders of the cardiovascular system and disorders of the urinary tract.

32. The method of obtaining the compounds of formula I

< / BR>
where R1denotes halogen;

R2denotes hydrogen or C1-C4and battelino substituted with one to three substituents, independently selected from C1-C4of alkyl, C1-C4alkyloxy, 3,4-methylendioxy, or R2and R3together represent methylenedioxy or Ethylenedioxy;

R4denotes a group of formula (a) or (b)

< / BR>
or

< / BR>
where n is 3, 4 or 5;

p is 0;

q is 1 or 2;

R5and R6each represents C1-C4alkyl or together form -(CH2)4-, -(CH2)6-, -(CH2)2O(CH2)2- or-CHR8CH2CR9R10CHR11CH2- where R8and R11each represents hydrogen or together represent -(CH2)t- where t is 1, R9denotes hydrogen, hydroxyl, C1-C8alkyl or C1-C4alkyloxy and R10denotes hydrogen, C1-C8alkyl or phenyl, or -(CH2)xR12where x is 0, 1, 2 or 3, and R12denotes hydroxyl, C1-C4alkyloxy, -C(O)NR13R14, -NR13C(O)OR14, -SO2NR13R14, -NR13SO2R14, -NR13SO2NR14R15or-NR13C(O)NR14R15where R13, R14and R15independently represent hydrogen, C1-C4alkyl, trifluoromethyl and R7about phenyl optionally substituted with one to three substituents, independently selected from C1-C4alkyloxy, methylendioxy, Ethylenedioxy) or -(CH2)zR12where z is 2 or 3 and R12matter mentioned above,

and its pharmaceutically acceptable salts, individual isomers and mixtures of isomers, characterized in that the compound of formula II

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or a protected derivative,

where R4matter mentioned above,

subjected to interaction with the compound of the formula III

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where each of R1, R2and R3has the values listed in the above, with subsequent acidification, decarboxylation, if necessary, removing the protective groups.

33. The method of obtaining compounds of formula I under item 1, in which R4denotes a group of formula (b), where p is 0 and q is 2, characterized in that the compound of formula VIII

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where R1, R2and R3have the values listed in paragraph 1, is subjected to the interaction with the compound of the formula IX

< / BR>
where R7matter specified in paragraph 1, followed by dehydration and hydrogenation.

34. The method of obtaining compounds of formula I on p. 1, where R4denotes a group of formula (b), where p is 0 , q is 1 or p, q above, a R7means hydrogen, is subjected to alkylation of compound L-R20or L-(CH2)zR12where L is a leaving group, R20means C1-C8alkyl, C3-C8alkenyl or panels1-C4alkyl, where phenyl optionally substituted with one or three substituents, independently selected from C1-C4alkyloxy, methylendioxy, Teledixi; R12matter listed in paragraph (1; z is 2 or 3.

35. The method of obtaining compounds of formula I on p. 1, where R4denotes a group of formula (b), p is 0 and q is 1 or 2, a R7means - CH2CH2NHC(O)R14, -CH2CH2NHSO2R14, -CH2CH2NHSO2NR14R15or CH2CH2NHC(O)NR14R15where the values of R14and R15listed in paragraph 1, characterized in that the compound of formula I, where the values of R4, p, q given above, and R7means hydrogen, is subjected to alkylation of the compound of the formula X-R21where X means acutiloba-1-yl, R21means-C(O)R14, -SO2R14, -SO2NR14R15, -C(O)NR14R15where the values of R14and R15above.

36. The method of obtaining audiostream the compounds of formula I, where R1, R2, R3and R4above, a p is 1.

37. The method of obtaining compounds of formula I under item 1 in the form of their salts by reacting the corresponding mesolevel forms with pharmaceutically acceptable inorganic or organic acid or base.

38. The method of obtaining compounds of formula I on p. 1 in free form by reacting the corresponding acid additive salts or salts of attaching the base of the compounds of formula I with suitable bases or acid, respectively.

Priority signs:

26.05.1993 in addition to R2- C1-C4alkoxy, R2and R3together, methylenedioxy or Ethylenedioxy; R12- NR13C(O)OR14; R7- phenyl C1-C4alkyl, where phenyl optionally substituted with one or three substituents, independently selected from C1-C4alkyloxy, methylendioxy, Ethylenedioxy;

26.04.1994, where R2- C1-C4alkoxy; R2and R3together, methylenedioxy or Ethylenedioxy; R12-NR13C(O)OR14; R7- phenyl C1-C4alkyl, where phenyl optionally substituted with one or three substituents, independently selected from C1-C4alkyloxy

 

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which are biologically active substances and can find application in pharmacology and adamant-1-ylamine is the basis of the drug midantana"

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(I) where R is a hydrogen atom, a lower alkyl or a group of the formula

orwhere R1means-Cho or - CN, namely, that on-halogenoalkane derivative of the formula:

where R has the above meanings, is subjected to the interaction with R3SH, where R3- benzyl, environment aprotic organic solvent, with the formation of the compounds of formula

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(I)

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The invention relates to compounds of formula I:

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where X denotes O, S, NH or NA;

Y represents substituted with R2aziridinyl, azetidinone, pyrolidine, piperidinyl, hexahydroazepin or pieperazinove the rest;

R1indicatesor< / BR>
R2represents CrH2r-COOR3;

R3denotes H, A or Ar;

A denotes alkyl with 1-6 C-atoms;

B denotes H, a, cycloalkyl with 3-7 C atoms, Ar-CkH2kor aydinbey the rest;

Ar denotes unsubstituted or mono - or twice substituted with A, Cl, Br, I, NO2, CN, OA, OH, NH2, NHA and/or NA2phenyl or benzyl residue;

"k" denotes 1, 2, 3 or 4;

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"n" represents 2, 3 or 4,

and their physiologically acceptable salts

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