Derivatives of n-(4-piperidinyl)(dihydrobenzofuran or dihydro - 2h-benzopyran)-carboxamide or their salts, or stereoisomers, methods for their preparation, intermediate compounds for them, the pharmaceutical composition based on the derivatives of n-(4-piperidinyl)(dihydrobenzofuran or dihydro - 2h-benzopyran)carboxyamide

 

(57) Abstract:

Usage: in medicine as substances that stimulate the activity of the gastrointestinal system. The essence of the invention: derivatives of N-(4-piperidinyl)(dihydrobenzofuran or dihydro-2H-benzopyran) f-ly I:

< / BR>
where a is a radical of the formula:

-CH2-CH2- - (a-1)

-CH2-CH2-CH2- - (a-2)

or

-CH2-CH2-CH2-CH2- - (a-3)

where one or two hydrogen atom in the radicals (a-1) to (a-3) can be replaced WITH1-6alkylation; R1- the atom of hydrogen or halogen, R2is a hydrogen atom, amino, mono - or di(C1-6alkyl) amino group or1-6alkylcarboxylic, R3is a hydrogen atom, or1-6alkyl, L-C3-6cycloalkyl,5-6cycloalkane,3-6alkenyl, selectively substituted aryl, or L is a radical of the formula:

Alk - R4- (b-1)

Alk - X - R5- (b-2)

Alk - Y-C(=O)-R7- (b-3)

R4is a hydrogen atom, cyano, C3-6cycloalkyl, aryl, di(arylmethyl) or Het, R5is a hydrogen atom, a C1-6alkyl, hydroxy-C1-6alkyl, C3-6cycloalkyl, aryl or Het; X is O or NH; R7is a hydrogen atom, a C1-6alkyl, aryl, C1-and aryl; each aryl is unsubstituted phenyl or phenyl substituted by 1-3 substituents each independently selected from a halogen atom or WITH1-6alkyloxy, and each Het - tetrahydrofuranyl, 1,3-DIOXOLANYL, substituted C1-4by alkyl; 3,4-dihydro-1(2H)-benzopyranyl; piperidinyl; pyridinyl, in case of JV; pyrazinyl, substituted C1-4by alkyl; indolyl; 2,3-dihydro-2-oxo-1H-benzimidazolyl, optionally substituted C1-4alkyl; 2-oxo-1-imidazolidinyl, substituted C1-4by alkyl; 3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl, substituted WITH three1-4alkyloxyaryl; 1-oxo-2(1H)-phthalazine; 2,3-dihydro-5-oxo-5H-thiazol-[3,2-a]pyrimidine-6-yl, substituted C1-4by alkyl; (5-oxo-5H-thiazol-[3,2-a]pyrimidine-6 substituted C1-4by alkyl); 1,6-dihydro-6-oxo-1-pyridazinyl, substituted C1-4the alkyl or a halogen atom; or 1,2,3,4-tetrahydro-2,4-dioxo-3-hintline, or their salts, or stereoisomers having properties stimulating the activity of the gastrointestinal system, the retrieval method, the intermediate compound and pharmaceutical composition thereof. 4 C. and 8 C.p., 3 table.

The invention concerns new derivatives of N-(4-piperidinyl) (dihydrobenzofuran or dihydro-2H-benzopyran) carboxyamide have the data connection, pharmaceutical compositions based on them and intermediates for obtaining the derivatives.

A known number of derivatives of substituted /3-hydroxy-4-piperidinyl/benzamide, used as stimulant activity gastrointestinal systems EP-A-0,076, 530, EP-A-0,299, 566 and EP-A-0,309, 043, IN EP-A-0,307, 172, EP-A-0,124, 783, DE-3,702,005, EP-A-0,147,044 EP-A-0,234,872 and US-4,772,459.

Known derivatives benzofuran, benzopyran and benzocaine, in which the nitrogen atom may be substituted by alkylamino group or a mono - or bicyclic heterokonta in the alkyl chain (EP-A-0,234,872, US-4772459). These compounds can be used as antibotic, antipsychiatry or neuroleptic agents.

The objective of the invention is to provide new derivatives of N-(4-piperidinyl)(dihydrobenzofuran or dihydro-2H-benzopyran)-carboxyamide able to actively stimulate the gastrointestinal system, as well as new intermediates for obtaining the derivatives, and in addition, the creation of a new pharmaceutical compositions used for treating disorders of the gastrointestinal system.

The task is achieved with new derivatives of N-(4-piperidinyl)(dihydrobenzofuran or dihydro-2H-be the BR>
-CH2-CH2-CH2(a-2) or

-CH2-CH2-CH2-CH2(a-3)

in which one or two hydrogen atoms may be substituted WITH1-6by alkyl;

R1the atom of hydrogen or halogen;

R2a hydrogen atom, amino or mono (C1-6alkyl) amino;

R^the atom of hydrogen or C1-6alkyl;

L C3-6cycloalkyl, C3-6alkenyl, if necessary, substituted aryl, or L is a radical of the formula:

Alk R4(b-1)

Alk-X-R5(b-2) or

Alk-Y-C(=O)-R7(b-3),

where each Alk is C1-6alcander; and

R4a hydrogen atom, a cyanide, WITH3-6cycloalkyl, aryl, di(aryl)-methyl or Het;

R5a hydrogen atom, a C1-6alkyl, hydroxy1-6alkyl, C3-6cycloalkyl, aryl or Het;

X is O or NH;

R7a hydrogen atom, a C1-6alkyl, aryl, C1-6alkyloxy - or hydroxy-group;

Y is NR8or a direct link, the specified R8a hydrogen atom or aryl; each aryl unsubstituted phenyl or phenyl substituted by 1-3 substituents each independently selected from a halogen atom or WITH1-6alkyloxy and each Het tetrahydrofuranyl, 1,3-DIOXOLANYL, substituted C1-4by alkyl; 3,4-dig the config WITH1-4by alkyl; indolyl; 2,3-dihydro-2-oxo-1H-benzimidazolyl, optionally substituted C1-4by alkyl; 2-oxo-1-imidazolidinyl, substituted C1-4by alkyl; 3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl, substituted WITH three1-4alkyloxyaryl; 1-oxo-2(1H)-phthalazine; 2,3-dihydro-5-oxo-5H-thiazol-[3,2-a]pyrimidine-6-yl, substituted C1-4by alkyl; 5-oxo-5H-thiazol-[3,2-a]pyrimidine-6-yl, substituted C1-7by alkyl; 1,6-dihydro-6-oxo-1-pyridazinyl, substituted C1-4the alkyl or a halogen atom; or 1,2,3,4-tetrahydro-2,4-dioxo-3-hintline or their salts or stereoisomers.

These compounds are obtained by N-alkylation of compounds of formula II

< / BR>
where R1, R2, R3and a have the above meanings, a compound of formula L W (III),

where L has the above meanings, and W is a halogen atom or sulfonyloxy in an inert solvent, if necessary, in the presence of bases and/or salts of iodine, and produce the target product in free form or in the form of a therapeutically active non-toxic salt processing the base of the corresponding acid or back turn salt into the free base by treatment with alkali, and/or the compound of the formula I containing functionaliy base and a solvent, or a compound of the formula I carrying protective dioxalane ring may be deacetylase to the corresponding oxo compounds by the action of the acidic aqueous medium, or a compound of the formula I containing as Vice-CN group, can be converted into the corresponding amine by the action of hydrogen in the presence of an appropriate catalyst, optionally in the presence of a base, or a compound of the formula I containing an amino group may be alkylated by the action of the corresponding alkylating agent, or a compound of the formula I containing an amino group can be obtained by treating the carbamate base, or a compound of the formula I containing ether groups, can be converted into the corresponding carboxylic acid by treatment of aqueous alkali or aqueous acid solution.

N-alkylation is carried out in inert solvents, such as water, aromatic hydrocarbons, benzene, methylbenzol, xylene, chlorobenzene, methoxybenzoyl, etc., and also alcohols, such as methanol, ethanol, 1-butanol and other halogen derivatives of hydrocarbons, for example dichloromethane, trichloromethane and other esters, ethyl acetate, butyrolactone and other ketones: 2-propanone, 4-methyl-2-pentanone and other simple efimed, dimethyl-sulfoxide, hexamethylphosphoric triamide, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, 1,3-dimethyl-2-imidazolidinone, 1,1,3,3-tetramethylrhodamine, nitrobenzene, 1-methyl-2-pyrrolidinone, etc. as well as mixtures of these solvents.

The introduction of appropriate bases, such as alkali carbonates, alkaline earth metals, carbonates, carboxylates, amides, oxides, hydroxides or alkoxides, for example sodium carbonate, sodium bicarbonate, potassium carbonate, calcium oxide, sodium acetate, sodium amide, sodium hydroxide, sodium methoxide, etc. or organic bases, for example amines, N,N-dimethyl-4-pyridylamine, N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine, 1,4-diazobicyclo (2,2,2) octane, 4-ethylmorpholine etc. neutralize the acid in the reaction. In some cases the use of the iodide salt, preferably iodides of alkali metals or esters. Stirring and a slight increase in temperature can increase the reaction rate. Additionally you can spend an N-alkylation in an inert atmosphere (oxygen, argon or nitrogen). Alternative N-alkylation is carried out by stirring the reactants in the presence of bases, in an appropriate inert atmosphere and in the presence of a catalyst, for example Tria is the Ulfat, etc.

The reaction products are separated from the reaction mixture and, if necessary, further purified by extraction, distillation, trituration and chromatography.

The compounds of formula (I) can be converted into compounds with other functional groups by known methods.

For example, the compounds of formula (I) containing a hydroxy-group, can be O-alkylated, for example, by stirring in the presence of the appropriate alkylating agents and, if necessary, in the presence of bases and solvents.

The compounds of formula (I) containing blocking dioxalane ring, can be deacetylase to get exocoetidae. The above-mentioned deacetylation can be conducted by known methods, for example by the interaction of source materials in aqueous-acidic medium.

The compounds of formula (I) containing cyanosubstituted, can be converted into the corresponding substituents of the amines by mixing or, if necessary, heat source cyanocobalamine in a hydrogen environment in the presence of a catalyst such as platinum on charcoal, Raney Nickel, and in the presence or bases, for example amines, i.e. N,N-diethylethanamine and the like, or hydroxides (guide furan and others) or a mixture of such solvents.

The compounds of formula (I) containing an amino group, can be prepared by treatment of carbamates bases, such as hydroxides (potassium hydroxide, sodium hydroxide and others ). Suitable solvents are alcohols (methanol, 2-propanol, and others), ethers (tetrahydrofuran, and others).

The amino group can be alkylated in accordance with known methods, for example, N-alkylation, reductive N-alkylation, and other methods described above.

The compounds of formula (I) containing ether groups, can be converted to carboxylic acid in accordance with known methods of saponification, for example, by treatment of the parent compounds with aqueous solutions of acids or alkalis.

The compounds of formula (I), where R1-halo, can be converted into compounds with R1-hydrogen in accordance with known methods of hydrolysis, for example by stirring or, if necessary, by heating the starting compounds in inert solvents in the presence of hydrogen and of a catalyst (palladium on coal and other ).

The compounds of formula (I) can be converted into compounds with N-oxide groups by switching the 3-valent nitrogen N-oxide. The reaction of N-oxidation may be carried out by saimniecei sodium, potassium, barium peroxide benzocoronene acid, peroxide 3-chlorobenzoxazole acid, peroxide acetic acid, Gidropress butyl and others).

N-oxidation may be conducted in appropriate solvents: water, lower alcohols (methanol, ethanol, butanol, propanol, and others), hydrocarbons (benzene, methylbenzol, xylene, and others), ketones -(2-propane, 2-butanol, and others ), halogenated hydrocarbons (dichloromethane, trichloromethane, etc. or mixtures of such solvents. To increase the rate of reaction can be used to heat the reaction mixture.

Some of the above intermediate products or starting materials are already known and some new ones. They can be prepared according to known methods (EP-A-0,389,037). Ways to get some intermediates will be described below.

Intermediates of formula (II) can be obtained from substituted piperidine of formula (XVII) in collaboration with the reagent of formula (V) or a functional derivative with subsequent miditacia and the subsequent removal of the group P' of the product (XVIII), for example, by carrying out the hydrolysis in an acidic or alkaline medium or by catalytic hydrogenation, in a dependent is rirovanie or hydrolysis. Preferably hydrolyzed groups, for example, were, WITH1-4allyloxycarbonyl, etoxycarbonyl, benzyloxycarbonyl etc.

Intermediates of formula (II), where R3hydrogen, represented by formula (II-a), can be an alternative obtained by the interaction of the isocyanate of the formula (XIX) with an intermediate product of the formula (XVIII). The product represented by formula (XVIII-a). In the formula (XX) W5alkaline methyl (lithium, sodium, and others) or halogen magnesium (chloride or bromide of magnesium). The reaction can be carried out in inert solvents (tetrahydrofuran, 1,1'-oxybisethane, 1,2-dimethoxyethan, pentane, hexane, and others). The interaction may be carried out by a known method (Tetrahedron Zetters. 270 1971 (1986) or Org.Chem. 32, 1273 (1967)).

< / BR>
Thus obtained intermediate product (XVIII-a) can be obtained analogously to the product of the formula (II-a) as described above.

Interesting are compounds of General formula (I) in which R1is hydrogen or halogen, and/or R2is hydrogen, amino or1-2alkylamino, and/or R3is hydrogen.

Of interest are also compounds of formula (I), where R1is hydrogen or halogen, and/or R2yavlyaetsya compounds are those where L is a C3-6cycloalkyl or3-6alkenyl, selectively substituted aryl, or L is a radical of formula (b-1), where R4is hydrogen, cyano, C3-6cycloalkyl, aryl, di(aryl)stands or Het or

L is a radical of formula (b-2), where X is O or NH and R5is hydrogen, C1-4the alkyl, C3-6cycloalkyl, aryl or Het, or

L is a radical of formula (b-3) where Y is NR8or a direct link, R8is hydrogen or aryl and R7is hydrogen, C1-4the alkyl, aryl, C1-4alkyloxy or hydroxy.

The most interesting compounds are those where a is a radical of formula (a-1) or (a-2), where the carbon atom adjacent to the oxygen atom and is selectively substituted by one or two1-4alkyl substituents.

Most preferred of these compounds are those where L represents a C5-6cycloalkyl or3-6alkenyl, selectively substituted aryl, or

L is a radical of formula (b-1), where Alk is C1-4Alcantara and R4is cyano, C3-6cycloalkyl, diarylamino or Het,

or L is was radical is B>1-4
the alkyl, C3-6cycloalkyl, aryl or Het,

or L is a radical of formula (b-2), where Alk is C1-4Alcantara, Y is NH or a direct bond and R7is1-4the alkyl, aryl, C1-4alkyloxy or hydroxy.

Preferred are those compounds where Het is piperidinyl, pyridinyl, selectively substituted or cyano, pyrazinium, selectively substituted C1-6the alkyl, benzimidazolyl, selectively substituted C1-6the alkyl, or indolium.

Especially preferred are those compounds where Het is tetrahydrofuranyl, 1,3-DIOXOLANYL, selectively substituted C1-4the alkyl, 3,4-dihydro-1(2H)-benzopyranyl, piperidinyl, pyridinyl, selectively substituted by cyano, pyrazinium, selectively substituted C1-4the alkyl, benzimidazolyl, indolium, 2,3-dihydro-2-oxo-1H-benzimidazolium, selectively substituted C1-4the alkyl, 2-oxo-1-imidazolidinyl, selectively substituted C1-4the alkyl, 3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl, selectively substituted WITH three1-4alkyloxyaryl, 1-oxo-2-(1H)-phthalazinium, 2,3-dihydro-5-oxo-5H-thiazolo-(3,2-a)pyrimidine-6-yl, SBIR/SUB> the alkyl, 1,6-dihydro-6-oxo-1-pyridazinyl, selectively substituted C1-4by alkyl or halogen, and 1,2,3,4-tetrahydro-2,4-dioxo-3-hinazolinam.

Most preferred are compounds where R1is hydrogen or chlorine, and/or R2is hydrogen, amino or (1-methylethyl)amino, and/or R3is hydrogen, and/or L is a radical of formula (b-1), where R4is cyano, cyclopentyloxy, tetrahydrofuranyl, piperidinyl, 7-methyl-5-oxo-5H-thiazole (3,2-a)pyrimidine-6-yl, 3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazolium, 1,6-dihydro-3-methyl-6-oxo-1-pyridazinyl, or

L is a radical of formula (b-2), where X is O or NH and R5is hydrogen or 4-florfenicol, or

L is a radical of formula (b-3) where Y is NH or a direct bond and R7is stands, ethoxy or 3,4,5-trimethoxyphenyl.

Most preferred are the compounds:

5-amino-6-chloro-3,4-dihydro-N-/1-/(tetrahydro-2-furanyl)methyl/4 - piperidinyl/-2N-1-benzopyran-8-carboxamide,

/-/-/E/-5-amino-6-chloro-3,4-dihydro--/1-/(tetrahydro-2-furanyl)methyl/-4-piperidinyl/-2N-1-benzopyran-8-carboxamide,

4-amino-5-chloro-2,3-dihydro--/1-/tetrahydro-2-furanyl)methyl/- piperidinyl/-7-benzoguanamine,

/4-amino-5-chloro-2,3-dihydro--/1-/(tetrahydro-2-furanyl)methyl/-4-piperidinyl/-7-benzoguanamine,

/+/-/S/methyl/-4-piperidinyl/-7-benzoguanamine, ethyl/2-/4-//(5-amino-6-chloro-3,4-dihydro--1-benzopyran/8-yl/carbonyl/ amino/-1-piperidinyl/ethyl/carbamate,

5-amino-6-chloro--/1-/4-(3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-yl) butyl/-4-piperidinyl/-3,4-dihydro--1-benzopyran-8-carboxamide,

ethyl 4-//(5-amino-6-chloro-3,4-dihydro--1-benzopyran-8-yl/ carbonyl/amino/-1-piperidinemethanol,

5-amino-6-chloro-3,4-dihydro--/1-(4-oxopent/-4-piperidinyl/ -1-benzopyran-8-carboxamide, and

4-amino-5-chloro-2,3-dihydro-2,2-dimethyl--/1-(4-oxobutyl)-4 - piperidinyl/-7-benzoguanamine,

stereoisomers and pharmaceutically suitable acid salt.

The compounds of formula (I) may have asymmetric carbon atoms, their exact position can be indicated stereochemical arrangement of R and s

Stereoisomeric structure of the intermediates described in the schemes of reactions and compounds of formula (I) can be obtained by known methods. For example, diastereoisomers can be separated by physical methods: distillation, crystallization, chromatography (distribution by the countercurrent method, liquid chromatography) and other Pure enantiomers can be obtained by crystallization of their diastereomeric Sol who's chiral phases, etc. Alternative enantiomerically pure patterns can be obtained from enantiomerically pure isomeric structures of starting materials, provided that the reaction proceeds in a stereospecific.

The compounds of formula (I) and the intermediates of formula (II), N-oxide structure and pharmaceutically passing salts stimulate the activity of the gastrointestinal system, particularly thick guts. These properties are confirmed by the results of the tests (Colon ascendens induced contractions), described below.

The stimulating effect of the compounds of formula (I) and (II) evidenced by a variety of test methods (The Iournal of Pharmacology and Experimental Therapeutics, 234, 775-783 (1985) and "Drug Development Research", 8,243-250 (1986)).

In addition, the compounds of formula (I) and (II), N-oxide structure, pharmaceutically suitable acid salts and impurities some stereoisomeric structures have reinforcing properties. Some groups of compounds of the invention, especially where the radical not substituted WITH1-6the alkyl are weak NT3antagonistic activity.

For most of the compounds of the present invention is not marked receptore-binding affinity with serotonergic NT1and serotonergic NT2and the typical small or about asiausa active effects on the gastrointestinal system, can have several options for therapeutic purposes.

To obtain the pharmaceutical compounds of the invention the active ingredients (base, acidic impurity salts are mixed with an appropriate carrier. The obtained pharmaceutical composition is a single dose for oral, rectal or other related method.

For example, for oral method can be used in liquid media (water, glycols, oils, alcohols) in the manufacture of liquid medication type suspensions, syrups, elixirs or solutions.

As solid carriers can be used for sugar, starch, kaolin, lubricants, binders, dezintegriruetsja agents for the preparation of powders, pills, capsules and tablets. For a better solution may be added other ingredients. The solutions can be introduced, for example, saline solution or glucose solutions or their mixture. In compositions intended for subcutaneous injection, the carrier may include additives, activating penetration, and/or wetting agents. These additives must not have a harmful effect on the skin. The composition can be applied in the form of superimposed bands, lubricants and other Acidic dubawi. Reviewed here dose, calculated as the unit, are designed to provide a therapeutic effect in combination with the required pharmaceutical carrier. Doses are given in table. 1 3.

Compounds of the invention have the ability to stimulate the activity of the colon, to normalize and improve the gastrointestinal system and peristalsis of the stomach and/or small and/or large intestines.

Compounds intended for the treatment of warm-blooded animals suffering from disorders of the gastrointestinal system, for example, gastroparesis, spacenode, ulcers, pseudoprobability and especially in violation of intestinal permeability. For treatment of the above disorders, the most suitable are the compounds of formula (I), N-oxides, pharmaceutically suitable acid salts or impurities stereoisomeric structure. Feature of the compounds of the invention is also a therapeutic effect on the activity of the upper intestines and esophagus in violation of their work.

The effectiveness of the compounds depends on the input doses that are defined in the test result and amount of 0.001 to 10 mg/kg, most preferably 0.01 to 1 mg/kg body weight.

Experimental frequent is ylamino)-2-hydroxybenzoate in 2820 PM N,N-dimethylformamide added in small portions 71 including dispersion of hydrate of sodium in mineral oil (50) and after stirring for 1 h at room temperature, add one crystal of potassium iodide to 172 hours 3-chloro-3-methyl-1-butyne in nitrogen atmosphere. The resulting mixture was stirred for 24 h at 90oC, and then poured into 10 aqueous solution of NaOH. The resulting product is extracted in dichloromethane. The extract was dried, filtered and evaporated. The precipitate is stirred in petroleum ether and dissolved in dichloroethane. This solution is washed with water, 10% NaOH solution and again with water, and then dried, filtered and evaporated. Sediment transported into chromatographic columns (silica gel, CH2Cl2). The purified fraction is evaporated. Of the two fractions obtained 41 PM (10,1) methyl 4-(acetylamino)-2-(1,1-dimethyl-2-propenyloxy) benzoate (ex. cont. 1).

b) a Mixture of 36 hours (intermediate 1) and 188 including N,N-dimethylacetamide is stirred for 24 h at boiling temperature. The reaction mixture is evaporated, and the residue dissolved in dichloromethane. The solution is washed with water, 5% NaOH solution and again with water, and then dried, filtered and evaporated. The precipitate purified in khromatograficheskii 5-(acetylamino)-2,2-dimethyl-2H-1-benzopyran-8-carboxylate (ex. cont. 2).

(C) a Mixture of 23.7 hours intermediate 2 and 148 hours of methanol immediately hydrogenizing at normal pressure and room temperature in the presence of palladium-carbon catalyst (10). Next, the calculated amount of hydrogen was removed and the catalyst is filtered off and evaporated. Get to 21.2 hours (88,9) methyl 5-(acetylamino)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-8-carboxylate (ex.cont.3).

d) a Mixture of 21.2 hours intermediate product 3, 10,3 hours of chlorosuccinimide and 158 hours of acetonitrile is stirred for 2 hours at boiling point. The reaction mixture is then evaporated and the residue dissolved in dichloromethane. This solution is washed with water, dried, filtered and evaporated. Sediment transported into chromatographic columns (silica gel: CH2Cl2/CH3OH 99:1). The purified fraction is evaporated. Get 23 PM (95,8) methyl 5-(acetylamino)-6-chloro-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-8 - carboxylate (ex. cont.4).

e) a Mixture of 20 hours intermediate product 4, 36 hours of potassium hydroxide and 250 hours of water is stirred for 16 h at boiling point.

After cooling, the solution is decanted and the precipitate washed with dichloromethane twice. The aqueous residue is acidified to 69.9 h Hcl (contentheader-2,2-dimethyl-2H-1-benzopyran-8-carboxylic acid. So pl. 165oC (prom.cont.5).

Example 2.

a) a Mixture of 58 hours of methyl 4-(acetylamino)-2,3-dihydro-2,2-dimethyl-7-benzophenoneoxymate, 123 including potassium hydroxide and 1100 hours the water is stirred for 3 hours at boiling point. After cooling, the reaction mixture is acidified to pH 1 with hydrochloric acid. The precipitate is filtered and dried in vacuum at 80oC. Receive 36 hours (79,0) 4-amino-2,3-dihydro-2,2-dimethyl-7-benzopyrrocolines acid (prom.cont.6).

b) a Mixture of 36 hours of the intermediate product 6, 66,2 including sulfonic acids and 142 hours of methanol is stirred for 30 minutes at boiling temperature. After cooling, the reaction mixture is alkalinized with methanol saturated with ammonia, and then the mixture is evaporated. The residue is dissolved in dichloromethane and water. The organic portion was separated, washed with water, dried, filtered and evaporated. Another part of the sediment vykristallizovyvalas of acetonitrile at 0oC. the Product is filtered and dried in vacuum at 40oC. Received 20 hours (53,2) methyl-4-amino-2,3-dihydro-2,2-dimethyl-7-benzophenoneoxymate (prom.cont.7).

C) a Mixture of 15.3 hours of the intermediate product 7, 23,3 including 2-iodopropane, 9,13 including N,N-diethylethanamine and 72,1 including hexamethylphosphoric triamide stirred during the extract washed with water, dried and evaporated. Sediment transported into chromatographic columns (silica gel: CH2Cl2/CH3OH 99:1).

The purified fraction is evaporated, and the residue vykristallizovyvalas of 2,2-oxybisethane at 0oC. the Product is filtered and dried in vacuum at 40oC. Receive 10 hours (54,2) methyl-2,3-dihydro-2,2-dimethyl-4-/(1-methylethyl)amino/-7-benzophenoneoxymate (prom.cont.8).

d) a Mixture of 9 PM intermediate 8, 3,2 including sodium hydroxide and 60 h of water is stirred for 1 h at boiling temperature. After cooling, the reaction mixture is acidified to pH 6 Hcl (conc.). The precipitate is washed with water and dried in vacuum at 60oC. Gain of 7.2 hours (76,9) 2,3-dihydro-2,2-dimethyl-4-/(1-methylethyl)amino/-7-benzopyrrocolines acid (prom. cont.9).

Example 3.

a) a suspension of 17 hours 4-amino-5-chloro-2,3-dihydro-7-benzopyrrocolines acid (prepared according to EP-A-0,389,037) 435 hours of trichlormethane add sequentially 9,13 including N,N-dimethylethanamine and 8,68 including ethylchloride. Store the suspension at a temperature below 5oC. After stirring for 2 hours while cooling on ice the whole suspension is added to a solution of 14.5 G. of ethyl-4-amino-1-piperidinecarboxylate the mixture was washed with 5% NaOH solution (twice) and water (twice), and then dried, filtered and evaporated. Sludge 3 admission fray with 2,2'-oxybisethanol, and then vykristallizovyvalas from acetonitrile. The product is filtered, washed with acetonitrile and dried. Get to 19.7 hours (66,9) product. More product 1,2 h (4,1) is obtained from layers 2,2'-oxybisethane. Just received: 20,9 h (71) ethyl 4-//(4-amino-5-chloro-2,3-dihydro-7-benzofuranyl)carbonyl/amino/-1 - piperidine-carboxylate; so pl. 158,6oC (prom.cont. 10).

C) a Solution of 18.4 hours intermediate product 10 and 28 g of sodium hydroxide in 125 hours of 2-propanol is stirred for 4 hours at boiling point. Then the solvent is evaporated and add 100 including water. The mixture is evaporated again and the residue is stirred in 100 hours of water for 15 minutes while heating on a water bath. After cooling, the solid composition is filtered off, washed with water and dissolved in boiling 2-propanol. To the solution add 40 hours of water. Product bicrystalline when cooled, filtered, washed with water and dried. Get to 12.35 PM (83,5) 4-amino-5-chloro-2,3-dihydro-N-(4-piperidinyl)-7-benzophenoneoxymate; so pl. 190,3oC (prom.cont.11).

All intermediate products, are given in table. 1, is not) a mixture of 20 hours (-)-(R)-tetrahydro-2-furanmethanol and 39.2 hours of pyridine was added a drop of 24.7 hours of chloride methanesulfonamide. Stirring was performed at room temperature for 16 hours To the reaction mixture was added dichloromethane and the mixture is washed with 1N HCl, dried, filtered and evaporated. Sediment transported into chromatographic columns (silica gel: CH2Cl2OH of 99.5: 0.5 to). The purified fraction is evaporated. Get to 26.7 hours (75,6) (-)-(R)-tetrahydro-2-furanmethanol methansulfonate (ether); []2D0-15078 (conc. 1) in CH2Cl2) (prom.cont. 19).

Similarly prepared (+)-(S)-tetrahydro-2-furanmethanol methanesulfonate (ester); []2D0+16,17o(conc. 1 in CH2Cl2) (prom.cont.20).

Example 5.

To a solution of 10 hours 3-(cyclohexyloxy)-1-propanol 160 hours dichloromethane add 11,2 including N,N-diethylethanamine and dropwise 8,14 including chloride methanesulfonyl. The whole mixture is stirred for 9 h at room temperature. The reaction mixture was washed with Na2CO3(water) and water, then dried, filtered and evaporated. Sediment transported into chromatographic columns (silica gel: CH2Cl2/CH3OH 99:1). The purified fraction is evaporated, and the residue was what ol-methansulfonate (ether) (prom. cont.21).

Example 6.

A solution of 5,5 hours 3,3-bis(4-forfinal)-1-propanol and 2,92 including thionyl chloride 39.9 hours of dichloromethane was stirred at 60oC for 4 h, the Reaction mixture is evaporated, and then mixed with methylbenzol and again evaporated. The residue is dissolved in ethyl acetate and the solution washed with Na2CO3(aq.) water and NaCl (feast upon.), and then dried, filtered and evaporated. Sediment transported into chromatographic columns (silica gel, (C2H5)2O/n-hexane 2: 98). The purified fraction is evaporated, get to 4.5 hours (76,7) 1-/3-chloro-1-(4-forfinal)propyl/-4-fervently (prom.cont.22).

B. Obtain the target compounds.

Example 7.

The solution of 2,96 including intermediate cont. 11, 3,2 h of a solution of sodium carbonate and 160 hours 4-methyl-2-pentanone stirred for 30 minutes at boiling temperature in the presence of wadepolicies. To this solution was added to 3.6 hours tetrahydro-2-furanmethanol of ester methanesulfonic acid and everything is stirred at the boiling temperature for 48 hours the Reaction mixture was mixed with dichloromethane and the resulting solution was washed with water, dried, filtered and evaporated. Sediment transported into chromatographic columns (si is onitrile. The product is filtered and dried. Get 1,63 hours (42,9 ) 4-amino-5-chloro-2,3-dihydro-N-/1-/(tetrahydro-2-furanyl)methyl-4-piperidinyl/-7/benzophenoneoxymate; so pl. 175,4oC (Conn.3).

Example 8.

A mixture of 3,09 including intermediate product 12, 13,28 including sodium carbonate and 160 hours 4-methyl-2-pentanone stirred at the boiling temperature in the presence of wadepolicies. Then add 2,74 including 6-(2-chloroethyl)-7-methyl-5H-thiazole(3,2-a)-pyrimidine-5-pyrimidine and 0.1 g potassium iodide and everything is stirred at the boiling temperature for 36 h, the Reaction mixture is evaporated, and the residue is dissolved in trichloromethane and water. The organic part of the sludge is separated, washed with water, dried, filtered and evaporated. Another part of the sediment transported into chromatographic columns (silica gel: CH2Cl2/CH3OH 90: 10). The purified fraction is evaporated, and the residue is boiled in acetonitrile. After cooling the product is filtered and dried. Get to 2.7 hours (53,8 ) 5-amino-6-chloro-3,4-dihydro-N-/1-/2-(7-methyl-5-hydroxy-5H-thiazol-/3,2-a/pyrimidine-6-yl)ethyl/-4-piperidine/-2N-1-benzopyran-8-carboxamide; so pl. 211,8oC (Conn.2).

Example 9.

A mixture of 21.7 parts of the intermediate product 12, 5, 7 CH chloroacetonitrile, 9,2 including N,N-diethylpropion and to the precipitate add Na2CO3(aq.). The product is extracted with dichloromethane (three times). The extract is dried, filtered and evaporated. From the precipitate of preparing a suspension in acetonitrile. The first product fraction is filtered off and the filtrate is evaporated. Sediment transported into chromatographic columns (silica gel: CH2Cl2/CH3OH (NH397:3). The purified fraction is evaporated, and the residue is mixed with acetonitrile and receive the second fraction, and then both fractions are dried in vacuum. Get to 22.1 hours (90,5% ) of 5-amino-6-chloro-N-(1-(cyanomethyl)-4-piperidinyl)-3,4-dihydro-2H-1 - benzopyran-8-carboxamide, so pl. 194oC (Conn.10).

Example 10.

The mixture of the 4.3 hours 2-(3-chlorpropyl)-2-methyl-1,3-dioxolane: 7,4 including intermediate product 13, 4, 7 o'clock N,N-diethylethanamine, the required quantity of catalyst of potassium iodide and 106 including N,N-dimethylformamide was stirred at 70oC for 17 h, the Reaction mixture is evaporated and to the precipitate add Na2CO3(aq. ). The product is extracted with dichloromethane, and the extract was dried, filtered and evaporated, and then purified in chromatographic columns (silica gel: CH2Cl2/CH3OH(NH3) 97:3). The purified fraction is evaporated and the residue triturated with 2,2'-oxybisethanol. the EN-2-yl)propyl/-4-piperidinyl/-7-benzophenoneoxymate. So pl. 136,5oC (Conn.8).

Example 11. A mixture of 6 hours intermediate product 14, 1,13 hours of propionitrile and 78 h 2-propanol is stirred for 4 hours at boiling point. The reaction mixture is evaporated, and the residue is suspended in 2,2'-oxopiperidine. The precipitate is filtered off and dried in vacuum at 60oC. Receive 608 hours (96,6) 5-amino-6-chloro-N-/1-(2-cyanoethyl)-4-piperidinyl) 3,4-dichloro-2,2 - dimethyl-2H-1-benzopyran-8-carboxamide (Conn.25).

Example 12.

A mixture of 22 hours in the connection 10 of 356 hours of tetrahydrofuran and 79 hours of methanol is treated at normal pressure and room temperature for 6 hours the catalyst is Raney Nickel. After completion of the reaction, the catalyst was filtered, and the filtrate is evaporated. The precipitate purified in chromatographic columns (silica gel: CH2Cl2/CH3OH(NH3) 93:7). The purified fraction is evaporated, and the residue is triturated in 2,2'-oxybisethane, and then mix in a small amount of acetonitrile. The product is filtered and dried. Get 14 hours (63,0) 5-amino-N-/1-(2-amino-ethyl)-4-piperidinyl)-6-chloro-3,4-dihydro-2H-1 - benzopyran-8-carboxamide; so pl. 130oC (Conn.11).

Example 13.

A mixture of 16.7 hours connection 55, 19 including potassium hydroxide and 92 hours 2-propanol is t with water (twice) and then dissolved in dichloromethane, methanol and water, the aqueous portion of the sludge is separated and extracted in dichloromethane. The remaining 2 organic part of the sludge is dried and filtered. Get to 8.3 hours (65,1) N-/1-(3-aminopropyl)-4-piperidinyl/-5-chloro-2,3/dihydro-2,2 - dimethyl-7-benzophenoneoxymate hemihydrate; so pl. 123,1oC (Conn.71).

Example 14.

To a cooled (bath with ice) a mixture of 2,3-hours connection 11 and 74 hours of trichlormethane add 0,86 including N,N-diethylethanamine and one drop of a solution of 0.77 g ethylchloride 40 hours of trichloromethane at temperatures below 10oC. After stirring for 30 min at room temperature, the reaction mixture is washed with water, dried, filtered and evaporated. Sediment transported into chromatographic columns (silica gel: CH2Cl2/CH3OH (NH395:5). The purified fraction is evaporated, and the residue is crystallized from acetonitrile. The product is filtered and dried. Get 1.4 hours (50,7) ethyl/2-/4-//(5-amino-6-chloro-3,4-dihydro-2H-1-benzopyran-8-yl)carbonyl /amino/-1-piperidinyl/-ethyl/carbamate; so pl. 160,3oC (Conn.16).

Example 15.

A mixture of 3,67 including connections 14, 1,85 h 2-chloro-1H-benzimidazole; 4,7 including N, N-dimethylacetamide, the required quantity of catalyst of potassium iodide and 2.10 p.m carbonate NAT is, filtered and evaporated. Sediment transported into chromatographic columns (silica gel: CH2Cl2/CH3OH(NH3) 95:5. The purified fraction is evaporated, and the residue is converted into a salt solution of candiota (1:2) in ethanol. The product is filtered and dried. Get 0,56 hours (8,3 ) 4-amino-N-/1-/2-(1H-benzimidazole-2-ylamino)/ethyl/- 4-piperidinyl/-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuran-carboxamid of candiota (1:2) hemihydrate. So pl. 211,7oC (Conn. 70).

Example 16.

The mixture of 3.1 h 2-chloro-3-methylpyrazine, 4,4 including connections 14 and 0.79 including calcium oxide is stirred for 24 h at 120oC. After cooling, the reaction mixture is dissolved in dichloromethane and NH4OH (razb.). The water portion of the precipitate is separated and re-extracted in dichloromethane. Both organic part of the sludge is dried, filtered and evaporated, filtered and evaporated. Sediment transported into chromatographic columns (silica gel: CH2Cl2/CH3OH(NH3) 98: 2). The purified fraction is evaporated, and the residue is dissolved in 2,2'-oxybisethane. The product is filtered and dried. Get to 3.3 hours (59,9) 4-amino-4-chloro-2,3-dihydro-2,2-dimethyl-N-/1-/2//(3-methyl-2-pyrazinyl) amino/ethyl/-4-piperidinyl/-7-benzophenoneoxymate: melting point 163,22Cl2/CH3OH (NH3) 95:5). The purified fraction is evaporated, and the residue vykristallizovyvalas from acetonitrile. The product is filtered and dried in vacuum at 70oC. Get 1,64 hours (40,2) 4-amino-5-chloro-2,3-dihydro-N-/1-(2 - hydroxy-ethyl)-4-piperidinyl)-7-benzophenoneoxymate; so pl. 185,7oC (Conn.49).

Example 18.

To a mixture of 12,2 including connections 8 and 83 hours water is added 1,53 including sulfonic acids. After stirring for 4.5 h at room temperature, the reaction mixture was poured into a mixture of NH4OH (razb.) and ice. Then the product is extracted with dichloromethane, and the extract was dried, filtered and evaporated. Sediment transported into chromatographic columns (silica gel, CH2Cl2/CH3OH (NH397: 3). The purified fraction is evaporated, and the residue is triturated in 2,2-oxybisethane. Then the product is filtered and dried. Get to 2.3 hours (40,3) 4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-N-/1-(4-oxobutyl)-4-piperidinyl)-7-benzophenoneoxymate; so pl. 119,2oC (neighbor.9).

Example 19.

a) a Mixture of 7,6 including connections to 3.5 hours oxynooidea catalyst 10 After determining the number of hydrogen atoms, the catalyst is filtered off and the filtrate is evaporated. Get 6,91 h (100 ) 4-amino-2,3-dihydro-N-/1-/tetrahydro-2-furanyl)methyl/-4-piperidinyl/-7-benzophenoneoxymate (Conn. 75).

b) a Mixture of 8 hours connection 75,5 including 2-iodopropane, 3,1 including N,N-diethylethanamine and 25.8 hours hexamethylphosphoric triamide stirred for 20 h at 130oC. After cooling, the reaction mixture was poured into water. After extraction into dichloromethane extract is washed with water, dried, filtered and evaporated. The residue is treated with 2,2'-oxybisethane. After filtration the solution is evaporated, and the obtained residue is treated with 2-propanol. 2,2'-oxybisethane add to increase the degree of crystallization. The precipitate is filtered and dissolved in dichloromethane. This solution is washed with water, dried, filtered and evaporated. The precipitate purified in chromatographic columns (silica gel: CH2Cl2(CH3OH (NH397:3). The purified fraction is evaporated, and the residue is converted into the salt of candiota (1:1). The product is filtered and dried in vacuum at 60oC. Gain of 0.3 h (2,7) 2,3-dihydro-4-/(1-methylethyl)-amino/-N-/1-/(tetrahydro-2-furanyl) -methyl/-4-piperidinyl/-benzoguanamine of candiota (1: 1), so pl. 211,7 e 1 h at boiling temperature. After cooling, the reaction mixture is evaporated. The residue is stirred 5 hours of water. Then the product is filtered, washed with a small amount of water and dried in vacuum at 70oC. Receiving PM 107(31,5. ) 4-//(5-amino-6-chloro-3,4-dihydro-2H-1-benzopyran-8-yl)carbonyl/- amino/-1-piperidinemethanol acid monohydrochloride monohydrate; so pl. 204,5oC (Conn. 68). All compounds listed in table. 2 and 3 receive the same methods described in examples 7 to 20.

Example 21.

The effect on the contractility of the colon.

The experiment was conducted in accordance with the method described in "The Journal of Pharmacology and Experimental Therapeutics", 234, 776-783, 1985. The segment of the colon length 4.5 cm vertically hung with a load of 2 g in 100 ml vessel De Zalon solution (KCl 5.6 mm, l22H2O 0,54 mm NaHCO35,9 mm NaCl 154,1 mm, 2.8 mm glucose) at a 37.5oC filled with a gas mixture of 95 O2and 5 CO2. Reduction substituted in accordance with the methodology HP 7 DST-1000, IS IA Displacement Trausducer Control Unit.

After stabilization for 20 min 3.4 x 106M methacholine injected within 15 minutes When the reduce segment of bowel reproduced, trials continue in the solution for 10 min with a maximum concentration methods non the compounds of formula (I).

D. Examples of the connection.

Pharmaceutical compounds in accordance with the present invention for dosed systematic or temporary use for warm-blooded animals.

Active ingredients (AI) used in the examples (pharmaceutically suitable acid, the addition salts and stereoisomers), are compounds of formula (I).

Example 22.

Solutions for oral administration.

9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate dissolved in 4 l of boiling purified water. In 3 l of this solution are dissolved first 10 g of 2,3-dihydroxybutanedioate acid, and then 20 g AI. Then to this solution add the remaining 1 l of a solution and in this General solution add 12 l 1,2,3-propanetriol and 3 l 70-aqueous sorbitol, 40 g of saccharin sodium are dissolved in 0.5 l of water, and then add 2 ml of raspberry and gooseberry family essences. The resulting solution is mixed with the previous solution and diluted with water to a volume of 20 L. This oral solution contains 5 mg of AI. Solution stored in appropriate containers.

Example 23.

The capsule.

20 g AI, 6 g of sulfate of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal dioxide kr is gelatin. Each capsule contains 20 mg of AI.

Example 24.

Tablets with a film.

Preparation of tablets: a mixture of 100 g AI, 570 g lactose and 200 g starch are thoroughly mixed and moistened with a solution of 5 g of dodecyl sodium sulfate and 10 g polyvinylpyrrolidone (Kollidon - K90) in 200 ml of water. The powder mixture is passed through a sieve, dried and again passed through a sieve. Then add 100 g microcrystalline cellulose (Avicel) and 15 g hydrogenated vegetable oil (Sterofex). The resulting mixture is stirred and tabletirujut. The number of received 1000 tablets. Each tablet contains 10 mg of AI.

Floor.

To a solution of 10 g methyl cellulose (Methocel 60HG) in 75 ml of denatured ethanol is added 5 g of ethyl cellulose (Ethocel 22 cps) in 150 ml of dichloromethane. In the resulting solution was added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 g of polyethylene glycol soften and dissolve in 75 ml of dichloromethane. This mixture was added to the previous solution and injected 2.5 g of octadecene magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated colour suspension (Opaspray K-1-2109) and the entire mixture is homogenized. The mixture is covered tablets in a special apparatus.

1. The method of obtaining derivatives of N-(4-piperid2-CH2- (a-1), -CH2-CH2-CH2- (a-2) or-CH2-CH2-CH2-CH2- (a-3), in which one or two hydrogen atoms may be substituted WITH1WITH6-alkyl;

R1hydrogen or halogen;

R2hydrogen, amino or mono (C1C6-alkyl) amino;

R3hydrogen or C1C6-alkyl;

L3C6-cycloalkyl,3C6alkenyl, if necessary, substituted aryl, or L is a radical of formula-Alk R4(b-1), -Alk-X-R5(b-2) or-Alk-Y-C(= O)-R7(b-3), in which each Alk1WITH6-alcander;

R4hydrogen, cyano, C3WITH6-cycloalkyl, aryl, dailmer or Het;

R5hydrogen, C1WITH6-alkyl, hydroxy-C1- C6- alkyl, C3WITH6-cycloalkyl, aryl or Het;

X is oxygen or NH;

R7hydrogen, C1WITH6is alkyl, aryl, C1- C6-alkyloxy - or hydroxy-group;

Y NR8or a direct link, where R8hydrogen or aryl; each aryl unsubstituted phenyl or phenyl substituted 1 to 3 substituents each independently selected from a halogen atom or WITH1WITH6-alkyloxy and each Het tetrahydrofuranyl, 1,3-DIOXOLANYL, the fed substituted by cyano; pyrazinyl, substituted C1- C4-alkyl; indolyl; 2,3-dihydro-2-oxo-1H-benzimidazolyl, optionally substituted C1WITH4-alkyl; 2-oxo-1-imidazolidinyl, substituted C1WITH4-alkyl; 3,4-dihydro-4-oxo-1,2,3-benzotri-Zin-3-yl, substituted WITH three1- C4-alkylacrylate; 1-oxo-2(1H)-phthalazine; 2,3-dihydro-5-oxo-5H-thiazol-[3,2-a]-pyrimidine-6-yl, substituted C1- C4-alkyl; 5-oxo-5H-thiazole [3,2-a]-pyrimidine-6-yl, substituted C1WITH4-alkyl; 1,6-dihydro-6-oxo-1-pyridazinyl, substituted C1- C4-alkyl or halogen; or 1,2,3,4-tetrahydro-2,4-dioxo-3-hintline,

or their salts, or stereoisomers, characterized in that the compound of General formula II

< / BR>
where R1, R2, R3and have the specified values,

subjected to N-alkylation of the action of compounds of General formula III L-W, where L is the specified values, W is halogen or sulfonyloxy, in an inert solvent, if necessary in the presence of bases and/or salts of iodine, and produce the target product in free form or in the form of a therapeutically active non-toxic salt processing the base of the corresponding acid or turn back the salt free is to be O-alkylated by the action of the corresponding alkylating agent in the presence of base and solvent, or a compound of the formula I carrying protective dioxalane ring may be deacetylase to appropriate exocoetidae the action of the acidic aqueous medium, or a compound of the formula I containing as Vice-CN-group, can be converted into the corresponding amine by the action of hydrogen in the presence of an appropriate catalyst, optionally in the presence of a base, or a compound of the formula I containing an amino group may be alkylated by the action of the corresponding alkylating agent, or a compound of the formula I containing an amino group can be obtained by treating the carbamate base, or a compound of the formula I containing ether groups, can be converted into the corresponding carboxylic acid by treatment of aqueous alkali or aqueous acid solution.

2. Derivatives of N-(4-piperidinyl)(dihydrobenzofuran or dihydro-2H-benzopyran)carboxyamide General formula I, where L, R1, R2, R3and As are specified in paragraph 1.

3. Connection on p. 2, where R1hydrogen or halogen, R2is hydrogen, amino or mono(C1-C6-alkyl)amino group, and R3- hydrogen.

4. Connection on p. 2, where L3WITH6-cycloalkyl the ASC WITH1WITH6-alcander, R4hydrogen, cyano, C3WITH6-cycloalkyl or Het, or L is a radical of the formula ASC-X-R5where X is oxygen or NH and R5is hydrogen, C1WITH4-alkyl, C3WITH6-cycloalkyl, aryl or Het, ASC1WITH6-alcander, or L is a radical of the formula-ASA-Y-C(= O)-R7where Y NR8or a direct link, ASC1- C6-alcander, R8hydrogen or aryl and R7hydrogen, C1WITH4is alkyl, aryl, C1WITH4-alkyloxy - or hydroxy-group.

5. Connection on p. 2, where a radical of the formula CH2-CH2- or-CH2-CH2-CH2is optionally substituted by one or two1WITH4-alkylsalicylate.

6. Connection on p. 4, where L3WITH6- cycloalkyl or3WITH6alkenyl, optionally substituted aryl, or L is a radical of the formula-ASC-R4-, where Alk1WITH4-alcander and R4cyano, C3WITH6-cycloalkyl, dailmer or Het, or L is a radical of the formula-ASA-X-R5where Alk1- C4-alcander, X is oxygen or NH and R5hydrogen, C1- C4- alkyl, C3WITH6-cycloalkyl, aryl or Het, or L is a radical of the formula-ASA-Y-C(= O)-R7where Alk is lexi - or hydroxy-group.

7. Connection on p. 6, where the Het piperidinyl, pyridinyl, optionally substituted by cyano, pyrazinyl, optionally substituted C1WITH4-alkyl, or Het tetrahydrofuranyl, 1,3-DIOXOLANYL, substituted C1WITH4-alkyl, Het - 2,3-dihydro-2-oxo-1H-benzimidazolyl, optionally substituted C1- C4-alkyl, 3,4-dihydro-1(2H)-benzopyranyl, 2-oxo-1-imidazolidinyl, substituted C1WITH4-alkyl, 3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl, substituted WITH three1- C4-alkyloxyaryl, 1-oxo-2(1H)-phthalazine, 1,6-dihydro-6-oxo-1-pyridazinyl, substituted C1WITH4-alkyl or halogen, or 1,2,3,4-tetrahydro-2,4-dioxo-3-hintline, 2,3-dihydro-5-oxo-5H-thiazol-[3,2-a] -pyrimidin-6-yl, substituted C1- C4-alkyl, 5-oxo-5H-thiazol- [3,2-a]-pyrimidine-6-yl, substituted C1WITH4-alkyl.

8. Connection on p. 7, where the Het tetrahydrofuranyl, 1,3-DIOXOLANYL, optionally substituted C1WITH4-alkyl, 3,4-dihydro-1(2H)-benzopyranyl, piperidinyl, pyridinyl, optionally substituted by cyano, pyrazinyl, optionally substituted C1- C4-alkyl, indolyl, 2,3-dihydro-2-oxo-1H-benzimidazolyl, optionally substituted,2,3-benzotriazin-3-yl, substituted WITH three1- C4-alkyloxyaryl, 1-oxo-2(1H)-phthalazine, 2,3-dihydro-2-oxo-1H-thiazolo (3,2-a) pyrimidine-6-yl, substituted C1C4-alkyl, 5-oxo-5H-thiazole, (3,2-a) pyrimidine-6-yl, substituted C1C4-alkyl, 1,6-dihydro-6-oxo-1-pyridazinyl, substituted C1C4-alkyl or halogen and 1,2,3,4-tetrahydro-2,4-dioxo-3-hintline.

9. Connection on p. 7, where R1hydrogen or chlorine, R2is hydrogen, amino or /1-methylethyl/amino group, R3hydrogen, and L is a radical of formula ( b-1), where R4cyano, cyclopentyl, tetrahydrofuranyl, piperidinyl, 7-methyl-5-oxo-5H-thiazolo-/3,2-a/-pyrimidine-6-yl, 3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazolyl, 1,6-dihydro-3-methyl-6-oxo-1-pyridazinyl, or L is a radical of formula (b-2), where X is oxygen or NH and R5hydrogen or 4-forfinal, or L is a radical of formula (b-3) where Y is NH or a direct bond and R7methyl, ethoxypropan or 3,4,5-trimethoxyphenyl.

10. Connection on p. 2 selected from the group selected from 5-amino-6-chloro-3,4-dihydro-N-/1-//tetrahydro-2-furanyl/methyl/-4 - piperidinyl/-2N-1-benzopyran-8-carboxamide, (-)-(R)-5-amino-6-chloro-3,4-dihydro-N- /1-//tetrahydro-2-furanyl/-methyl/-4-piperidinyl/-2N-1-benzopyran-8 - carboxamide, 4-amino-5-chloro-2,3-dihydro-N-/1-/tetrahedr the methyl/-4 - piperidinyl/-7-benzophenoneoxymate, (+)-(S)-4-amino-5-chloro-2,3-dihydro-N-/1-//tetrahydro-2-furanyl/methyl/-4 - piperidinyl-7-benzophenoneoxymate, ethyl/2-/4-///5-amino-6-chloro-3,4-dihydro-2H-1-benzopyran-8-yl/ carbonyl/amino/-1-piperidinyl/ethyl/carbamate, 5-amino-6-chloro-N-/1-/4-/3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazole-1-yl/ butyl/-4-piperidinyl-3,4-dihydro-2H-1-benzopyran-8-carboxamide, ethyl-4-///5-amino-6-chloro-3,4-dihydro-2H-1-benzopyran-8-yl - carbonyl/amino/-1 piperidinemethanol, 5-amino-6-chloro-3,4-dihydro-N-/1-/4-oxopent/-4-piperidinyl/-2N-1 - benzopyran-8-carboxamide, or 4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-N-/1-/4-oxopent/-4 - piperidinyl/-7-benzophenoneoxymate,

or their salts or stereoisomers.

11. The pharmaceutical composition of stimulating gastrointestinal system containing the active ingredient and an inert carrier, characterized in that it contains as active ingredient compounds on p. 1 of 5 to 20 mg per dosage unit.

12. Derivatives of piperidine of General formula II

< / BR>
where R1, R2, R3and a have the meanings specified in paragraph 1,

as an intermediate product for the synthesis of derivatives of N-/4-piperidinyl/-dihydrobenzofuran or dihydro-2H-benzopyran-carboxyamide with action, with

 

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