Dimethylbenzofuran and dimethylbenzophenone, their use as 5-ht3-antagonists, processes for their preparation and pharmaceutical composition

 

(57) Abstract:

1 the invention relates to the field of organic chemistry and medicine. Proposed new compounds of General formula (I), where R1and R2represent hydrogen or R1and R2together form a bivalent radical (a) -CH = CH-CH= C-; (b) -CH = C(Cl)-CH = CH -, or (c) -CH = CH-C(Cl) = CH-; n is the number 2, 3 or 4; R3is hydrogen or a methoxy group; m is 1 or 2; R4is hydrogen, amino or C1-C3-alkylcarboxylic; R5is hydrogen or halogen, and their stereochemical isomers, and intermediate products for the synthesis of formula XIXa, such as isomer of formula Ia (R3= OCH3). The methods of obtaining new compounds. The proposed pharmaceutical composition and a means on the basis of the compounds of General formula I for the treatment of 5-HT3-mediasound violations, 6 C. and 4 h.p. f-crystals, 4 PL.

The invention relates to the field of organic chemistry and medicine. In EP N 0389037, 1990, describes derivatives of N-(3-hydroxy-4-piperidinyl) (dihydrobenzofuran, dihydro-2H-benzopyran or dihydrobenzoic)carboxamide and EP N 0445862, 1991, describes derivatives of N-(4-piperidinyl) (dihydrobenzofuran or dihydrobenzo-2H-benzopyran)carboxamide. Both for the of childelementname, dimethyldithio-2H-benzopyran of the invention are 5-HT3-antagonism (antagonism to 5-gidroksitriptaminu 5-HT3receptors).

The invention relates to a method of treating warm-blooded animals suffering from 5-HT3-Mediolanum disorders, such as anxiety, psychosis, depression, schizophrenia, impaired cognitive abilities, drug abuse, migraine, vomiting, irritable bowel syndrome and similar disorders, systemic introduction this warm-blooded animal an effective 5-HT3-antagonistic amount of a compound of the formula

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or a pharmaceutically suitable salt with an acid or a stereochemical isomer of this compound

where

R1and R2is hydrogen or R1and R2together form a bivalent radical of formula (a), (b) or (c):

-CH=CH-CH=CH- (a)

-CH=C(Cl)-CH=CH- (b),

-CH=CH-C(Cl)=CH- (c);

n = 2,3 or 4;

R3is hydrogen or a methoxy group;

m = 1 or 2;

R4is hydrogen, amino or C1-C3- alkylcarboxylic;

R5is hydrogen or halogen.

The invention relates also to the use of compounds of the formula I and their pharmaceutically suitable salts with acids and CTE is new violations, for example, anxiety, psychosis, depression, schizophrenia, disorders of cognitive abilities, abuse drugs, migraine, vomiting, irritable bowel syndrome and similar disorders.

In the above and subsequent definitions of the term "halogen" denotes fluorine, chlorine, bromine and iodine, preferably chlorine; C1-C4-denotes alkyl containing from 1 to 4 carbon atoms, saturated hydrocarbon radicals with normal or branched chain, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl or 1,1-dimethylethyl, preferably methyl. C1-C6-Alkyl represents C1-C4-alkyl and the higher homologues, for example of pentyl and hexyl. C1-C3-Alkylsulphonyl denotes the atilov normal or branched structure, such as methylcarbamoyl, ethylcarboxyl, propylmalonic, preferably methylcarbamyl.

The term "pharmaceutically suitable salt with an acid refers to non-toxic, therapeutically active salts with acids, which can form compounds of formula (I). The compounds of formula (I) have basic properties can be converted into the corresponding therapiestudie acid standard practices. Examples of suitable acids are inorganic acids, such as halogenation acid, for example hydrochloric, Hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoric acid and the like acids, or organic acids, for example acetic, propionic, hydroxyestra, 2-hydroxypropionate, 2-oxopropionate, proportionaly, batandjieva, (Z)-2-potentionaly, (E)-2-potentionaly, 2-hydroxybutanone, 2,3-dihydroxybutanedioate, 2-hydroxy-1,2,3-propanetricarboxylate, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. The term "suitable pharmaceutical salts" also includes a solvate, which the compounds of formula (I) can form, for example an alcoholate, in particular the hydrates.

The compounds of formula (I) may also be present in their tautomeric forms. It is assumed that these forms, although they are not listed above, included in the scope of the invention.

The term "stereochemical isomers" refers to the various isomeric forms, which may be of the compounds of formula (I). Unless otherwise stated or not stated otherwise, the chemical definition of the compounds are a mixture of all possible sparnaay patterns. It is assumed that all stereochemical isomeric forms of the compounds of formula (I) in pure form and in mixtures with each other included in the scope of the invention.

The term "enantiomerically pure" refers to compounds having the content enantiomer from at least 94% (i.e., the minimum content of one enantiomer 97% and the maximum content of the other enantiomer of 3%) to 100% (i.e., the contents of one enantiomer 100% and no other), in particular compounds having the content enantiomer from 96% to 100%, more specifically compounds having the content enantiomer from 98% to 100%. The term "enantiomerically enriched" refers to compounds having the content of the enantiomers of from more than 0% to about 94%. The terms "diastereomeric enriched" and "diastereomers clean", which will be given below, should be understood in the same way, but for the content of diastereoisomer in this mixture.

For use as a 5-HT3-antagonists interesting compounds of formula (I) in which R5represents a halogen, preferably chlorine.

For use as a 5-HT3-antagonists also of interest are compounds of formula (I) in which R4represents hydrogen or aminoglutaric R1and R2is hydrogen; n = 1 or 2; R3- methoxy group and has the CIS-configuration; m = I; R4- amino group and R5halogen.

In particular, interesting for use as 5-HT3-antagonists are compounds of formula (I) in which R3represents a methoxy group and has the CIS-configuration, which are levogyrate.

The preferred compounds are (-)-CIS-4-amino-5-chloro-2,3-dihydro-N-[1-[3-[(3,4-dihydro-4-oxo-2-pyrimidinyl)amino]propyl]-3-methoxy-4-piperidinyl] -2,2 - demethyl-7-benzofuroxan and (-)-CIS-4-amino-5-chloro-N-[1-[2-[(3,4-dihydro-4-oxo-2-pyrimidinyl)amino] ethyl]-2,3-dihydro-3-methoxy-4-piperidinyl]-2,2-dimethyl-7 - benzofuran carboxamide and their pharmaceutically suitable salts with acids.

The compounds of formula (I) in which R3represents a methoxy group and has the CIS-configuration represented by the formula (I-a). The following intermediate products, in which R3represents a methoxy group and may have the CIS-configuration will be designated by adding the letter a to their rooms.

An additional characteristic of the invention is the fact that levogyrate enantiomers of compounds of formula (I) in which R

The compounds of formula (I) can generally be obtained by known methods, for example described in EP N 389037, and other known methods. Some of the intermediates of formula (II), (III), (IV), (V), (VI), (VII), (IX), (X) and (XIII) described in EP N 0389037, EP N 0445862 and EP N 0076350. Some methods for obtaining compounds of formula (I), especially compounds of the formula (I-a) and new intermediates will be described below.

In the above methods of obtaining the reaction products can be isolated from the reaction mixture and, if necessary, further cleaned by methods generally known in this field, such as extraction, distillation, crystallization, grinding and chromatography.

To simplify the structural image of the compounds of formula (I) and some of the starting compounds and intermediate products for their radical of the formula

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next will be denoted by D, a radical of the formula

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next will be denoted by the symbol L.

The compounds of formula (I) can be obtained N-alkylation of the piperidine of formula (II) an intermediate product of the formula (III)

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W1shown in the reaction scheme, the compound (III) with (II) and subsequent reaction schemes, refers to appropriate philokyprou, 4-methylbenzenesulfonamide and remove such groups. The reaction of N-alkylation of compound (II) compound (III) is usually carried out by known methods of alkylation.

The compounds of formula (I) can also be obtained N-acylation of amine of formula (IV) carboxylic acid of formula (V) or its functional derivatives, such as allelochemical, symmetrical or mixed anhydride or ester, preferably an activated ester, known methods.

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It may be appropriate to protect the amino - or hydroxy-group in the process of carrying out the reaction in order to avoid undesirable side reactions. Suitable protective groups are easily removable group, for example, C1-C4-alkylsulphonyl, C1- C4-allyloxycarbonyl, phenylmethyl, tert-butyl and the like of the protective group.

The compounds of formula (I) can also be obtained N-alkylation of an intermediate product of the formula (VII) alkylating reagent of formula (VI) in which R6represents hydrogen or C1-C6-alkyl and W2is a corresponding delete the group, such as halogen, for example chlorine, bromine or iodine; sulfonyloxy, for example methanesulfonyl xygraph; C1-C6-allylthiourea, such as methylthiourea, ethylthiourea. When R6represents a C1-C6-alkyl, formed intermediate product of the formula (VIII), which can then be converted into the target compound by removal of the protective simple ester group. Such removal can be accomplished by treatment of the intermediate product of formula (VIII) acid, such as halogenation acid, for example hydrochloric acid.

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The compounds of formula (I) can alternatively be obtained N-alkylation of 2-aminopyridine of formula (IX) an intermediate product of the formula (X).

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The reaction of alkylation of compounds of formula (VI) compounds (VII) and the compounds of formula (IX) with compound (X) can be performed by known methods, for example by stirring, and sometimes by heating the reactants without solvent or in a mixture with an inert organic solvent such as an alcohol, for example 2-propanol, butanol, dipolar aprotic solvent, for example acetonitrile, possibly in the presence of a suitable base, for example potassium carbonate.

The compounds of formula (I) can also be transformed into each other by known reactions transformations.

The amino group can turn the UB>3-alkylcarboxylic can be converted into amino group by known hydrolysis reactions.

The compounds of formula (I) in which R5represents hydrogen, can be converted into the corresponding compounds in which R5is a halogen, by means of known methods of halogenation.

Intermediates of formula (VII) can be obtained N-alkylation of an intermediate product of the formula (II) with a reagent of formula (XI) with subsequent removal of the protective group P in the thus obtained intermediate product (XIII) by known methods reactions.

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In the compounds of formulas (XI) and (XIII) and other intermediate products containing the group P, the above patterns P represents a suitable protective group can be easily removed, for example, by hydrogenolysis or hydrolysis. Preferred protective groups are, for example, C1- C4-alkylcarboxylic, such as methylcarbamoyl, ethylcarboxyl; C1- C4-alkoxycarbonyl, for example etoxycarbonyl, 1,1'-dimethylthiocarbamyl; trihalomethanes, such as triptorelin; diphenylmethyl; triphenylmethyl or arylmethyl, where aryl represents phenyl, which may have to TLDs of formula (II) can be obtained by known methods for the formation of amides reactions respectively substituted piperidine of formula (XIV) with an intermediate acid of formula (V) or its functional derivative with subsequent removal of the protective group P1known methods. P1represents an easily removable protective group, and has the same meaning as the above group P.

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Intermediates of formula (XIV) in which R3represents a methoxy group and has the CIS-configuration, i.e., 3-methoxy-4-aminopiperidine formula (XIV-a), can be obtained, for example, by catalytic hydrogenation of the imine of formula (XVI-a) with subsequent conversion of the secondary amine of formula (XV-a) 3-methoxy-4-aminopiperidine formula (XIV-a) by hydrogenolysis. Imine formula (XVI-a) can be obtained by the known methods of education Iminov of 3-methoxy-4-oxopiperidine formula (XVII-a) and imine of the formula (XVIII).

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In the intermediate products of the formula (XVIII), (XVI-a) and (XV-a) R7represents hydrogen, C1-C6-alkyl or hydroxy-C1-C6is alkyl and Ar is a phenyl, possibly substituted with halogen, C1-C6-alkyl, C1-C6-alkyloxy, or naphthyl, possibly substituted with halogen, C1-C6-alkyl, C1-C6-alkyloxyaryl.

The sequence of reactions from the intermediate product of formula (XVII-a) before the formation of the intermediate product of formula (XIV-a) can also be carried out on m is s formula (XV-a) and (XIV-a) can be obtained in one of the following methods.

The original racemic 3-methoxy-4-oxopiperidin formula (XVII-a) or equivalent ketal, such as di-C1-C6- alkylthiol, for example 4,4-diethoxy-3-methoxypiperidine can be divided into its enantiomers and then converted into enantiomerically pure CIS-3-methoxy-4-aminopiperidin formula (XIV-a), as described above. This separation of enantiomers can be carried out, for example, column chromatography using chiral stationary phase, for example Chiracell OD.

Alternative intermediate Imin formula (XVI-a) can be obtained by using one of the enantiomers of chiral amine of formula (XVIII) in which R7has the above values, except hydrogen, and these amines represented by formula (XVIII-b), for example (-)-(R)- aminobenzonitrile or (+)-S - -aminobenzoate, which after hydrogenation into diastereomeric amines of formula (XV-a), which can, as usual, divided by physical separation techniques such as selective crystallization or chromatographic methods. Remove arylmethyl formula Ar-CH(R7) the corresponding diastereomeric amines of formula (XV-a) by hydrogenolysis receive the corresponding enantiomeric 3-methoxy-4-aminopiperidine formula (XIV-the second way of obtaining enantiomerically pure 3-methoxy-4-aminopiperidine formula (XIV-a). If the reaction of racemic ketone, such as 3-methoxy-4-oxopiperidine formula (XVII-a) with enantiomerically pure chiral amine of formula (XVIII-b), for example (-)-(S)- -methylbenzylamine, and subsequent hydrogenation formed so imine of formula (XVI-a) is the expected ratio of the diastereomeric amines of formula (XV-a) is about 1: 1. However, it was found that after carrying out the above reaction sequence obtained diastereomer ratio is significantly different from a ratio of 1:1. In other words, amines of formula (XV-a) were diastereomeric enriched or even diastereomers clean. Therefore, in the reaction process sequence of one diastereoisomer turns into another configuration address stereocenter having a methoxy group.

Therefore, the found new and inventive way to generate new enantiomerically enriched or enantiomerically pure 3-methoxy-4-aminopiperidine formula (XIV-a) and in more General form intermediates of formula (XIX-a) according to the method described hereinafter in more detail.

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In the formula (XIX), (XX), (XXI) and (XXII-a), the radical A represents hydrogen, -(CH2)n- NH2, -(CH2)nis apipeline formula (XXII-a) with a single enantiomer chiral amine of formula (XXIII), in which R8represents a C1-C6-alkyl or hydroxy-C1-C6-alkyl, Ar is a phenyl, possibly substituted with halogen, C1-C6-alkyl, C1-C6-alkyloxy; or naphthyl, possibly substituted with halogen, C1-C6-alkyl, C1-C6-alkyloxyaryl get diastereomer a mixture of the intermediate imine of formula (XXI-a). This reaction can be performed using known methods of education Iminov, for example by stirring the reactants at the boiling temperature in an inert under reaction conditions a solvent such as an aromatic hydrocarbon, such as methylbenzol, with the device's use of Dean-stark.

Imin formula (XXI-a) can be identified and, if necessary, be cleaned, for example, column chromatography, distillation or crystallization. Then Imin you can gidrirovanii mixing it in a hydrogen atmosphere in a suitable solvent, such as alcohol, for example methanol or ethanol; a simple ether, for example tetrahydrofuran or 2,2'-oxybisethane; ester such as ethyl acetate; aromatic hydrocarbons, such as methylbenzol, in the presence of suitable catalysts, for example palladium on charcoal, platinum on charcoal, roggli (XX-a).

Alternatively, the intermediate Imin formula (XXI-a) is not isolated. In this case, the racemic mixture of 3-methoxy-4-oxopiperidine formula (XXII-a) is treated with one of the enantiomers of chiral amine of formula (XXIII) in the conditions of hydrogenation, getting diastereomeric enriched or diastereomers pure intermediate amines of formula (XX-a). This reaction is carried out under conditions similar to those described above. However, in this case the reaction is preferably carried out in a mixture of acid, for example acetic acid, oxalic acid, Chloroacetic acid, 2-hydroxy-1,2,3-propanetricarboxylic acid and, in particular, (-)-[S-(R*, R*)]-2,3-dihydroxybutanedioate acid, especially when the solvent is alcohol.

In amines have had of the formula (XXIII) R8represents hydroxymethyl, methyl or ethyl, especially methyl, and Ar preferably represents unsubstituted phenyl or naphthyl, especially phenyl. Preferred amines of the formula (XXIII) are enantiomers-methylbenzylamine, i.e., (- )- (S)- -methylbenzylamine or (+)-(R)- -methylbenzylamine.

Sometimes in the process of hydrogenation reactions can form a small amount of TRANS-3-methoxy-4-amino compounds which can be removed Cristallago amine of the formula (XX-a) includes obtaining first imine of formula (XXI-a) with the use of enantiomer-methylbenzylamine and subsequent hydrogenation of the imine of formula (XXI-a) by mixing it in methylbenzol in hydrogen atmosphere using rhodium catalyst.

To avoid unwanted further hydrogenation of some functional groups in the reactants and reaction products, it is useful to add to the reaction medium a poison for the catalyst, for example thiophene, quinoline-sulfur, etc. Elevated pressure and/or temperature can increase the speed of reaction.

The obtained intermediate product of the formula (XX-a) is the ratio of diastereomers, which is very different from a ratio of 1:1. In other words, the intermediate compound of formula (XX-a) diastereomeric enriched or diastereomers clean. Appropriate diastereomer forms can then, if necessary, to share with conventional physical methods, for example by chromatography or by fractional crystallization, possibly after the formation of the salt. Thus obtained diastereomeric pure amines of the formula (XX-a) can then hydrogenolysis to remove additional chiral group Ar-CH(R8) to turn in enantiomerically pure 3-methoxy-4-aminopiperidine formula (XIX-a).

Noteworthy is the observation that the configuration of the stereocenter having a methoxy group, is determined by the configuration of the applied source enantiomerically pure amine of formula (XVIII). Therefore, any to the but further note, the choice of acid used in the process of hydrogenation of imine can also be affected to some extent on the ratio of the diastereomers of amines of the formula (XIX-a). The choice of catalyst can also be influenced to some extent by the number formed by TRANS-4-amino-3-methoxycoumarin.

Diastereomeric enriched or diastereomers pure intermediates of formula (XX-a) and enantiomerically enriched or enantiomerically pure intermediates of formula (XX-a) and their pharmaceutically suitable salts with acids are considered to be new compounds. The new compounds are enantiomerically enriched or enantiomerically pure intermediates of formula (II-a), (IV-a), (VII-a) (X-a), (XIII-a), (XIV-a) and their pharmaceutically suitable salts with acids. These intermediate products can be obtained, as described above, enantiomerically enriched or enantiomerically pure intermediates of formula (XIV-a).

Using this technique described above enantiomerically enriched or enantiomerically pure intermediates proposed a new and inventive way to obtain enantiomerically enriched or enantiomerically pure compounds of the formula (I-a), especially levogyrate EN the unity of the formulas (I), (I-a) or any other intermediate products can also be split into their optical isomers, CIS-(+)-, CIS-(-)-, TRANS-(+)- and TRANS-(-)-isomers by known methods. The diastereomers can be divided by physical separation methods such as selective crystallization and chromatography, such as countercurrent distribution. The enantiomers can be divided from each other by the selective crystallization of their diastereomeric salts with enantiomerically pure acids or their enantiomerically pure derivatives.

The compounds of formula (I) and their pharmaceutically usable salts and stereoisomers are antagonists of 5-HT3receptors, which is proved by the fact that they are active in showing, for example, antagonism chemoreflex von Bejold-Jarish, induced by serotonin (5-HT) in the rat (Pharmacology and Toxicology, 70, 11, 17-22 (1992)). This test is described below as example 10.

The compounds of formula (I), especially compounds of the formula (I-a), active for a long period of time. In addition, the compounds of formula (I), especially compounds of the formula (I-a), exhibit a high degree of safety for the cardiovascular system.

Due to the manifestations of 5-HT3-antagonism of the compounds of the invention can be produced in various Festo this connection in the form of free bases or salts of acid, used as an active ingredient, is intimately mixed with a pharmaceutically suitable carrier. Depending on the form of preparation desired for administration, use various forms of media. These pharmaceutical preparations are preferably produced in the form of standardized doses, preferably suitable for administration orally, rectally or parenterally injection. For example, to obtain drugs in oral dosage form as usual pharmaceutical environment can be applied, for example, water, glycols, oils, alcohols, and similar substances in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions, or solid carriers such as starches, sugars, kaolin, lubricants, binders, dezintegriruetsja funds and similar substances in the case of powders, pills, capsules and tablets. Due to the ease of the introduction of tablets and capsules are the most favorable oral dosage form. It is clear that in this case, use solid pharmaceutical carriers. For parenteral drug carrier is usually a sterile water, at least in large part, although you can include other components, for example components for the fight salt solution, the glucose solution or a mixture of saline and glucose solution. You can also get injectable suspension, in this case, you can use the appropriate liquid carriers, suspendresume funds and similar funds. In preparations suitable for percutaneous administration, the carrier may contain a means of enhancing the penetration of the active component, and/or a suitable wetting agent, possibly in combination with suitable additives of any nature in small amounts. But these additives should not cause a significant adverse effect on the skin. These supplements can facilitate the introduction of the active ingredient into the skin and/or may be useful for the preparation of the required drugs. These drugs can be administered in a number of methods, such as percutaneous bandages, applying spots on the skin or in the form of ointments. Salts of compounds of formula (I) with acids due to the increased solubility compared with the corresponding basis is clearly more suitable for preparing aqueous preparations.

Especially, it is preferable to prepare the above drugs in the form of doses at one time to facilitate their introduction and consistent dosage. The shape of the dose at one time in the description of the invention called the given number of the active component, designed to induce the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such dosage forms at one time are tablets (including tablets with labels and wrappers), capsules, pills, packets of powder, pills injectable solutions or suspensions of drugs in the number of teaspoons or tablespoons, and so on, and such forms as multiples of this dose parts.

Thanks to the 5-HT3-antagonistic activity of the compounds of formula (I) and especially the new compounds of formula (I-a) is suitable for the treatment of 5-HT3-mediasound disorders, such as anxiety, psychosis, depression (Arzneim, Forsch. , 42(1), 239-246 (1992)), schizophrenia, disorders of cognitive abilities, such as insufficient memory (Arzneim, Forsch. , 42(1) 246-249 (1992)), abuse of drugs, migraine, vomiting, such as induced receiving cytotoxic drugs and radiation (Drugs 42(4), 551-568 (1991)), of irritable bowel syndrome, especially dearreadermusic of irritable bowel syndrome and similar disorders. Consequently, the invention features a method of treating warm-blooded animals suffering from 5-HT3mediasound the s cognitive memory, abuse of drugs, migraine, vomiting, for example, induced cytotoxic drugs or radiation, irritable bowel syndrome, especially dearreadermusic of irritable bowel syndrome and similar disorders. This method provides a systematic introduction warm-blooded animal an effective 5-HT3-antagonistic amount of a compound of formula (I), its pharmaceutically suitable salt with an acid or a stereoisomer.

The compounds of formula (I) are suitable for the preparation of a drug intended for the treatment of 5-HT3-mediasound violations. The new compounds of formula (I-a) is suitable as a drug.

In General it is assumed that the effective number should be from about 0.001 mg/kg to about 50 mg/kg body weight, preferably from about 0.02 mg/kg to about 5 mg/kg of body weight. The treatment method may also include the introduction of the active component according to the scheme providing for the reception of his 2 - 4 times a day.

Experimental part

A. Obtaining an intermediate product

Example 1

a) 3,4,4-Trimetoksi-1-(phenylmethyl)piperidine (0,676 mol) was purified speakers chromatog is Ali. This residue (mixture of enantiomers) was separated into enantiomers column chromatography on a column with Chiracell OD (eluent: hexane/2-propanol, to 98.5:1.5 to). Selected fraction corresponding to the first chromatographic peak and the solvent evaporated. The sample was purified by distillation (so Kip. 120oC at 0.5 mm RT.cent.), receiving 56 g of (-)-3,4,4-trimetoksi-1-(phenylmethyl)piperidine []D20= -54,00o(C = 0.5% in methanol) (intermediate 1).

Selected fraction corresponding to the second chromatographic peak and the solvent evaporated. The sample was purified by distillation (so Kip. 120oC at 0.5 mm RT.cent.), getting 64 g of (+)-3,4,4-trimethoxy-1-(phenylmethyl)piperidine []D20= 49,60o(C = 0.5% in methanol) (intermediate 2).

b) a Mixture of intermediate 1 (0.21 mol) in methanol (600 ml) was first made at the 50ousing as catalyst 10% (3 g), palladium on coal. After absorption of H2(1 equiv), the catalyst was separated by filtration. To the filtrate was added calcium oxide (0,63 mol). The reaction mixture was stirred at room temperature. Was added dropwise ethylchloride (0,63 mol) and the reaction mixture was stirred 2 h at 50oC, then at room t is trevali and the filtrate evaporated. The residue was purified by distillation, obtaining a 32.6 g (63%) of (-)-ethyl-3,4,4-trimetoksi-1 piperidinecarboxylate with []D20= -39,40o(C = 0.5% in methanol) (intermediate 3).

c) a Mixture of intermediate 3 (0,132 mol), 4-methylbenzenesulfonate (0.6 g) in 2-propanol (180 ml) and water (30 ml) was stirred and boiled under reflux for 18 hours the Reaction mixture was cooled and was added N, N-diethylethanamine (0.6 ml). The solvent was removed by evaporation (temperature maintained below 40oC). The residue was dissolved in CH2Cl2. The residue was washed twice with a saturated solution of NaCl. The organic layer was separated, dried (MgSO4), filtered and evaporated to remove solvent. The residue was purified by distillation, obtaining of 19.2 g of (-)-ethyl-3-methoxy-4-oxo-1-piperidinecarboxylate (72,3%) [] D20= -44,40o(c = 0.5% in methanol) (intermediate 4).

d) a Mixture of intermediate 4 (0,095 mol) and benzoylmethylene (0.11 mol) in methanol (200 ml) was first made in atmospheric conditions using as catalyst 10% (2 g) of palladium on charcoal in the presence of 4% aqueous solution of thiophene in 2',2-oxybisethane (2 ml). After hydrogen absorption, the catalyst was separated by filtration and neniam as catalyst 10% (2 g) of palladium on charcoal. After uptake of hydrogen (1 equiv), the catalyst was separated by filtration and the filtrate evaporated. The residue was purified by distillation (so Kip. 85oC at 0.1 mm RT. Art.), receiving a 13.4 g (70%) of ethyl-(-)-CIS-4-amino-3-methoxy-1-piperidinecarboxylate with []D20= -78,9o(c = 1% in methanol) (intermediate 5).

Similarly, but from the intermediate product 2 was obtained (+)-ethyl-CIS-4-amino-3-methoxy-1-piperidinecarboxylate with []D20= -80,64o(c = 0.6% in methanol) (intermediate 6).

Example 2

a) a Mixture of ethyl-3-methoxy-4-oxo-1-piperidinecarboxylate (0.5 mol), (-)-(S)- -methylbenzeneethanamine (of 0.53 mol), monohydrate 4-methylbenzenesulfonate (1,25 d) and methylbenzene (625 ml) was stirred and boiled under reflux with the use of the device, Dean-stark for 3 hours, the Reaction mixture was evaporated and distilled to getting 121 g (79.5%) of (-)-ethyl-[CIS - (S)]-3-methoxy-4-[(1-phenylethyl)imino]-1 - piperidinecarboxylate (intermediate 7).

b) a Mixture of intermediate 7 (0.4 mol) and methylbenzene (750 ml) was first made at room temperature and atmospheric pressure using a catalyst of rhodium on coal (5 g). After uptake of hydrogen (1 equiv), the catalyst of addeventcallback (1 : 1), applying the monohydrate of 4-methylbenzenesulfonate (1 EQ). Salt was filtered and dried. This fraction was recrystallized twice from a mixture of 2,2'-oxybisethane/methanol (250 ml/180 ml). The precipitated product was filtered and dried, obtaining of 61.7 g (32,5%) 4-methylbenzenesulfonate (-)-ethyl-[CIS - (S)]-3-methoxy-4-[(1-phenylethyl)amino] -1-piperidinecarboxylate (1 : 1) with []D20= -62,16o(c = 1% in methanol) (intermediate 8).

Similarly, but using (+)-(R)- -methylbenzeneethanamine, received 4-methylbenzenesulfonate (+)-ethyl-[CIS - (R)] -3-methoxy-4-[(1-phenylethyl)amino] -1 - piperidinecarboxylate (1 : 1) with []D20= 62,79o(c = 1% in methanol) (intermediate 9).

Example 3

a) a Mixture of ethyl-3-methoxy-4-oxo-1-piperidinecarboxylate (0.2 mol), (-)-(S)- -methylbenzeneethanamine (0.4 mol) and (-)-[S-(R*,R*)]-2,3-dihydroxybutanedioate acid (0.2 mol) in methanol (500 ml) was first made at room temperature and atmospheric pressure using as catalyst 10% (2 g) of palladium on charcoal in the presence of 4% aqueous solution of thiophene 2,2'-oxybisethane (2 ml). After absorption of H2(1 equiv), the catalyst was separated by filtration and the filtrate evaporated. The residue was distributed between the removal of the solvent. The residue was dissolved in 4-methyl-2-pentanone and was turned into a salt with 4-methylbenzenesulfonate (1 : 1), using the monohydrate of 4-methylbenzenesulfonate (1 EQ). Salt was filtered and dried. This fraction was recrystallized from a mixture of 2,2'-oxybisethane/-CH3OH (500 ml/100 ml). The mixture was stirred 24 hours the Precipitate was separated by filtration and dried (vacuum, 50oC) to give 32 g of 4-methylbenzenesulfonate (-)-ethyl-[CIS - (S)]-3-methoxy-4-[(1-phenylethyl)amino]-1 - piperidinecarboxylate (1 : 1) with []D20= -61,6o(c = 0.5% in methanol) (intermediate 8).

Similarly, but using (+)-(R)- methylbenzeneethanamine also received 4-methylbenzenesulfonate (+)-ethyl-[CIS - (R)]-3-methoxy-4-[(1-phenylethyl)amino] -1 - piperidinecarboxylate (1 : 1) (intermediate 10).

b) the Intermediate product 8 (0,067 mol) was converted into the free base with aqueous ammonia. This mixture was extracted with methylbenzol. The organic layer was separated, dried (MgSO4), filtered and evaporated to remove solvent. The remaining free base was dissolved in methanol (250 ml) and was first made at room temperature and atmospheric pressure using as catalyst 10% (2 g) of palladium on activated coal is by distillation (so the TRC. 85oC at 0.1 mm RT. Art. ), receiving of 9.9 g (79,2%) of ethyl-(-)-CIS-4-amino-3-methoxy-1-piperidinecarboxylate (intermediate 5).

Similarly, but from the intermediate product 9 was also obtained (+)-ethyl-CIS-4-amino-3-methoxy-1-piperidinecarboxylate (intermediate 6).

Example 4

A mixture of 53.3 per g of ethyl-3-methoxy-4-oxo-1-piperidinecarboxylate (described in EP-patent N 76350), 33 g of (-)-(R)- -aminobenzonitrile and 700 ml of ethanol was boiled under reflux overnight. After cooling, the reaction mixture is evaporated and the residue was distilled, getting to 59.1 g (92%) of ethyl-(R)-4-[(2-hydroxy-1-phenylethyl)imino] - 3-methoxy-1-piperidinecarboxylate with so Kip. 180oC (pressure of 3.75 10-4Pa) (intermediate 6).

b) the Solution to 59.1 g of the intermediate product 10 in 500 ml of ethanol was first made at normal pressure and at room temperature using, as a catalyst, 2 g of platinum on coal. After absorption of the calculated amount of hydrogen the catalyst was separated by filtration and the filtrate evaporated. The residue was purified by NH2-silica gel (eluent: a mixture of methylene chloride/cyclohexane/methanol, 60 : 40 : 0.5 in). Pure fractions were collected, of which evaporated eluent, obtaining 18 g (30%) of ethyl-(-)-[4(R) - CIS]-4-[(2-HYDR is (c = 0.5% in methanol) (intermediate 11).

c) a Solution of 18 g of the intermediate product 11 in 250 ml of methanol was first made at normal pressure and room temperature using, as a catalyst, 2 g of palladium on coal (10%). After absorption of the calculated amount of hydrogen the catalyst was separated by filtration and the filtrate evaporated. The residue was distilled, obtaining 6.2 g (55%) of ethyl-(-)-CIS-4-amino-3-methoxy-1-piperidinecarboxylate (intermediate 5).

Example 5

a) 4-Amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranol acid (described in EP N 0389037) (0.05 mol) was dissolved in a mixture of N,N-diethylethanamine (7 ml) and trichloromethane (250 ml). Ethylcarbodiimide (0.05 mol) was added dropwise at a temperature below 10oC. the Reaction mixture was stirred 30 min at a temperature below 10oC. the Mixture was added to a solution of intermediate 5 (0,047 mol) in trichloromethane (250 ml), was stirred in 10oC. the Reaction mixture was stirred 30 min at room temperature, then washed with water, 5% NaOH and again with water. The organic layer was separated, dried (MgSO4), filtered and the solvent evaporated. The residue was purified column chromatography on silica gel (eluent: CH2Cl2/CH3OH, 98:2). Pure fractions were collected and the solvent of myprivateregistration.com (intermediate 12).

b) a Mixture of intermediate 12 (0.045 mol) and sodium hydroxide (0.45 mol) in 2-propanol (300 ml) was stirred and boiled under reflux for 12 hours the Reaction mixture was cooled and the solvent evaporated. To the residue was added water (100 ml). The solvent is evaporated. The residue was distributed between dichloromethane and water. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent evaporated. The residue was purified columnar chromatography on silica gel (eluent: CH2Cl2/(CH3OH/NH3), 97:3). Pure fractions were collected and the solvent evaporated. The residue was dried (vacuum, 50oC) to give 12.5 g of (+)-CIS-4-amino-5-chloro-2,3-dihydro-N-(3-methoxy-4-piperidinyl)-2,2 - dimethyl-7-benzoperoxide (77,2%) [] D20= 33,40o(C = 0.5% in methanol) (intermediate 13).

Example 6

a) a Mixture of intermediate 13 (of 0.017 mol), ethyl-(2-chloroethyl)carbamate (0.02 mol) and N,N-diethylethanamine (0,022 mol) in N,N-dimethylformamide (150 ml) was stirred 72 h at 70oC. the Reaction mixture was cooled and the solvent evaporated. The residue was distributed between dichloromethane and water. The organic layer was separated, dried (MgSO4), filtered and evaporated to remove dissolve the SUB>OH, 97:3). Pure fractions were collected and the solvent evaporated, obtaining 5 g of (+)-ethyl-CIS-[2-[4-[[(4-amino-5-chloro-2,3-dihydro-2,2-dimethyl-7-benzofuranyl)carbonyl]amino]-3-methoxy-1-piperidinyl] ethyl] carbamate (63%) [] D20= 1,20o(c = 0.5% in methanol) (intermediate 14). b) a Mixture of intermediate 14 (0,0106 mol) and sodium hydroxide (0,106 mol) in 2-propanol (45 ml) was stirred and boiled under reflux 4 h the Mixture was cooled, the solvent evaporated and the residue was stirred in water, then evaporated again. The residue was dissolved in dichloromethane and the solution washed with a small volume of water, dried (MgSO4), filtered and the solvent evaporated. The residue was purified by passing through silica gel on a glass filter (eluent: CH2Cl2/CH3OH/(CH3OH/NH3), 90:9:1). Pure fractions were collected and the solvent evaporated, obtaining 3.2 g (76%) of (-)-CIS-4-amino - N -[1-(2-amino-ethyl) -3-methoxy-4 - piperidinyl] -5-chloro-2,3-dihydro-2,2-dimethyl-7-benzoperoxide with []D20= -1,50o(c = 0.2% in methanol) (intermediate 15).

Example 7

a) a Mixture of intermediate 13 (0,023 mol) and 2-propenenitrile (0,028 mol in 2-propanol (150 ml) was stirred and boiled with reverse holodilniki)-3-methoxy-4-piperidinyl] -2,3-dihydro-2, 2-dimethyl-7-benzoperoxide with []D20= -1,60o(c = 0.5% in methanol) (intermediate 16).

b) a Mixture of intermediate 16 (0.02 mol) in methanol (250 ml) and tetrahydrofuran (100 ml) was first made at atmospheric conditions, using as a catalyst of Raney Nickel (3 g). After uptake of hydrogen (2 equivalents), the catalyst was separated by filtration and the filtrate is evaporated, receiving 7 g (to 85.2%) of (-)-CIS-4-amino - N -[1-(3-aminopropyl)-3-methoxy-4-piperidinyl]-5-chloro-2,3-dihydro-2,2 - dimethyl-7-benzoperoxide (intermediate 17).

Example 8

a) an Intermediate product 17 (0,769 mol) was dissolved in 1-butanol (2310 ml) (requires heated to 50oC). When 30oC was added (heterogeneous), potassium carbonate (1,538 mol). Was then added 2-chloro-4-methoxypyridine (0,960 mol) and the reaction mixture was heated to boiling point (104oC). The reaction mixture was stirred and boiled under reflux for 11 hours and the Mixture was left to cool to 20oC and then to it was added water (769 ml) and the mixture was stirred 15 minutes, the Layers were separated. The organic layer is evaporated (60oC when 1,66 mm Hg),receiving 458,9 g (92.1 per cent) (a)-CIS-4-amino-5-chloro-2,3-dihydro - N -[3-methoxy-1-[3-[(4-methoxy-2-pyrimidinyl)amino]drink 2-propanol (434 ml) was added dropwise over 15 min to a solution of intermediate 18 (0,769 mol) in 4-methyl-2-pentanone (3845 ml), the mixture was stirred at 15 - 20oC (if necessary, cooled in an ice bath). The reaction mixture was stirred 1 h at 15oC. the Precipitate was separated by filtration, washed with 4-methyl-2-pentanone (769 ml) and dried (50oC, vacuum), receiving 425,9 g (93,6%) dihydrochloride ()-CIS-4-amino-5 - chloro-2,3-dihydro-N-[3-methoxy-1-[3-[(4-methoxy-2 - pyrimidinyl)amino]propyl]-4-piperidinyl]-2,2-dimethyl-7-benzoperoxide (intermediate 19).

B. obtain the final compounds

Example 9. A mixture of intermediate 17 (of 0.017 mol) and 2-methylthio-4-pyrimidinone (0,022 mol) in acetonitrile (300 ml) was stirred and boiled under reflux for 16 hours was Added an additional amount of 2-methylthio-4-pyrimidinone (2 g) and the reaction mixture was stirred and boiled under reflux for 16 hours, the Reaction mixture was cooled, the solvent is evaporated. The residue was purified by passing through silica gel on a glass filter (eluent: CH2Cl2/CH3OH/(CH3OH/NH3), 90:9:1). Pure fractions were collected and the solvent evaporated. The residue is triturated in 2,2'-oxybisethane. The solid portion was separated by filtration and dried (room temperature, vacuum) to give 2.6 g (29,7%) (-)-CIS-4 - amino-5-chloro-2,3-dihydro - N-[1-[3-[(3,4-dihydro-4-P>C and []D20= -17,54o(c =1% in methanol) (connection 1).

In a similar manner there were obtained the compounds shown in table.1.

Example 10. A mixture of 4.15 g of 2-chloro-4-hydroxyquinazoline, of 4.57 g of 4-amino-N-[1-(3-aminopropyl)-4-piperidinyl] -5-chloro-2,3-dihydro - 2,2-dimethyl-7-benzoperoxide (described in EP N 0445862) and 0.80 g of calcium oxide was stirred for 1 h at 140oC. the Reaction mixture was dissolved in a mixture of dichloromethane and methanol. The entire solution was washed with water, dried, filtered and evaporated. The residue was purified twice column chromatography (silica gel; CH2Cl2/CH3OH(NH3), 90:10; CH2Cl2/CH3OH(NH3), 88:12). Eluent target fraction evaporated and the residue was boiled in 2,2'-oxybisethane. The product was filtered and dried, obtaining 3.2 g (50,8%) 4-amino-5-chloro-2,3-dihydro-N-[1-[3-[4-hydroxy-2-hintline)amino] propyl] - 4-piperidinyl] -2,2-dimethyl-7-benzoperoxide with so pl. 159,6oC (compound 12).

Similarly obtained compounds are shown in table. 2.

Example 11

A mixture of 2.6 g of 2,6-dichloro-4-chinoline (described in J. Med. Chem., 1968, p. 130), 3.7 g of 4-amino-N-[1-(2-amino-ethyl)-4-piperidinyl]-5-chloro - 2,3-dihydro-2,2-dimethyl-7-benzoperoxide (operational the mixture is evaporated and the residue was dissolved in a mixture of dichloromethane and methanol. A product was rinsed with water. Partially precipitated product was separated by filtration (the first fraction). The organic layer decantation, dried, filtered and evaporated (the second fraction). The combined fraction was purified two times by column chromatography (silica gel; CH2Cl2/CH3OH(NH3), 95 : 5; CH2Cl2/CH3OH, 92 : 8). Eluent target fraction evaporated and the residue was led from acetonitrile. The product was filtered at 0oC and dried in vacuum at 60oC, receiving 1 g (18,3%) 4-amino-5-chloro-N-[1-[2-[(6-chloro-4-hydroxy-2 - hintline)amino] ethyl] -4-piperidinyl]-2,3-dihydro-2,2-dimethyl-7 - benzoperoxide with so pl. to 206.6oC (compound 21).

In a similar manner there were obtained the compounds shown in table.3.

Example 12. Water (2880 ml) was added to the intermediate product 19 (to 0.72 mol) for its complete dissolution, and then was added dropwise hydrochloric acid (193 ml). The reaction mixture was heated to boiling point (95oC) and then stirred and boiled under reflux for 24 hours While boiling added additional hydrochloric acid (128.6 ml). The reaction mixture was stirred and boiled under reflux for 2.5 hours, the Heating was stopped and added dichloro 25oWith the addition of ammonium hydroxide (433 ml) to pH above 10 for 30 min, and required external cooling. The first mixture was a homogeneous system, then at pH 6 - 7 formed precipitate, which was dissolved at higher pH values. The layers were separated. The aqueous layer was extracted with dichloromethane (360 ml). The organic extracts were combined, dried and evaporated (40oC, vacuum). The residue was dried (40oC, vacuum), receiving 321,2 g (88,3%) (-)-CIS-4-amino-5-chloro-N-[1-[3-[(3,4-dihydro-4-oxo-2 - pyrimidinyl] amino] propyl] -3-methoxy-4-piperidinyl] -2,3-dihydro-2,2 - dimethyl-7-benzoperoxide (connection 1).

C. Pharmacological example

Example 13. Determining by the method of von Bezold-Jorish

Spontaneously hypertensive male rats ( 6 months) was anestesiologi the inhalation of ether, and the femoral vein and artery were cut off and were Coulibaly polyethylene catheter. For induction of local anesthesia in the wound around the cannula was administered lidocaine (20%).

Animals were placed in cages Bollman and arterial catheter was connected with a sensor tenzimetricheskikh blood pressure and analyzed systolic pressure. When the animals were fully awake, they were introduced by the injection control serotonininto serotonin usually develops in three phases: 1) a short and sharp decrease (reflex von Bezold-Jorish ), 2) increase, and 3) long-lasting increase in systolic blood pressure. Inhibition of the first acute lowering of blood pressure (reflex von Bezold-Jorish ) is considered as a criterion of 5-HT3-antagonism. Some time after control injections of serotonin intraperitoneal injection was administered the test compound. After 30 min serotonin were injected with intravenous again and recorded the presence or absence of the first short and sharp pressure reduction. The same procedure was repeated after 60 minutes of the Compounds were tested at different doses.

The lowest active dose (LAD), which are listed in the table. 4, can be defined as the dose (in mg/kg body weight) at which at least half of the test animals shows inhibition of reflex von Bezold-Jorish.

D. Examples of drugs

Examples of typical pharmaceutical preparations in doses at one time, suitable for systemic or local injection of warm-blooded animals in accordance with the invention are the following compounds.

The term "active component" (A. I.), used in all of these examples relates to a compound of formula (I), its pharmaceutically suitable salt with an acid or stereochemical ITA dissolved in 4 l of boiling purified oxen. In 3 l of this solution are dissolved first 10 g of 2,3-dihydroxybutanedioate acid and then 20 g of A. I. Recent solution combine with the rest of the first solution and the joint part type 12 l 1,2,3-propanetriol and 3 l of 70% aqueous solution of sorbitol. 0.5 l of water dissolve 40 g of sodium salt of saccharin and add 2 ml of raspberry and 2 ml of gooseberry family essences. The latter solution is combined with the first, add the required amount of water to achieve total volume of 20 l, receiving oral solution containing 5 mg A. I. in one teaspoon (5 ml). The resulting solution was placed in appropriate containers.

Example 15. Capsules

A mixture of 20 g A. I., 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of stearine magnesium vigorously stirred. The mixture then fill 1000 suitable hardened gelatin capsules, each capsule contains 20 mg A. I.

Example 16. Tablets with sheath

Preparation of core tablets. A mixture of 100 g A. I., 570 g lactose and 200 g starch is mixed well and then moisturize with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone in about 200 ml of water. Wet powder mixture is sieved, dried and sieved the Xu the mass is well mixed and pressed into tablets, getting 10,000 tablets each containing 10 mg of the active component.

The coatings. In a solution of 10 g of methyl cellulose in 75 mg of denatured ethyl alcohol add a solution of 5 g of ethyl cellulose in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. Melt 10 g of polyethylene glycol and added to 75 ml of dichloromethane. The last solution is added first and then add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated suspensions coloring tools and the whole mass is homogenized. Core tablets cover the thus obtained mixture in a device for the formation of shells.

1. The compound as an active ingredient of the drug for treatment of 5-HT3meierovich violations of the General formula I

< / BR>
or its pharmaceutically suitable additive salt of the acid or stereochemical isomer of this compound,

where R1and R2is a hydrogen atom, or R1and R2together form a bivalent radical of the formula

-CH=CH-CH=CH-, (a),

-CH=C(Cl)-CH=CH-, (b),

-CH=CH-C(Cl)=CH-, (c);

n = 2, 3, or 4;

R3is a hydrogen atom or a methoxy group;

m = 1 or 2;

R4is a hydrogen atom, amino group or the C3represents a methoxy group and has the CIS-configuration.

3. Connection on p. 2, representing levogyrate connection.

4. Connection on p. 1, representing a compound selected from the group comprising (-)-CIS-4-amino-5-chloro-2,3-dihydro-N-[1-[3-[(3,4-dihydro-4-oxo-2-pyrimidinyl)amino] propyl]-3-methoxy-4-piperidinyl]-2,2-dimethyl-7-benzofuroxan or (-)-CIS-4-amino-5-chloro-N-[1-[2-[(3,4-dihydro-4-oxo-2-pyrimidinyl) amino] ethyl] -2,3-dihydro-3-methoxy-4-piperidinyl] -2,2-dimethyl-7-benzofuroxan or their pharmaceutically suitable acid salt additive.

5. The Union, representing levogyrate enantiomer of General formula I-and

< / BR>
or its pharmaceutically suitable additive salt of the acid,

where R1and R2is a hydrogen atom, or R1and R2together form a bivalent radical of the formula

-CH=CH-CH=CH-, (a),

-CH=C(Cl)-CH=CH-, (b), or

-CH=CH-C(Cl)=CH-, (c);

n is an integer equal to 2, 3 or 4;

R3represents a methoxy group and has the CIS-configuration;

m is an integer equal to 1 or 2;

R4is a hydrogen atom, amino group or C1- C3-alkylcarboxylic;

R5- the atom of hydrogen or halogen is rimidine) amino] propyl]-3-methoxy-4-piperidinyl] -2,2-dimethyl-7-benzofuroxan or (-)-CIS-4-amino-5-chloro-N-[1-[2-[(3,4-dihydro-4-oxo-2-pyrimidinyl)amino] ethyl] -2,3-dihydro-3-methoxy-4-piperidinyl] -2,2-dimethyl-7-benzofuroxan or its pharmaceutically suitable additive salt of the acid.

7. Pharmaceutical composition for treating disorders caused by 5-HT3, characterized in that it contains an inert carrier and as active ingredient an effective 5-HT3- antagonistic amount of a compound under item 5.

8. Enantiomerically enriched or enantiomerically pure CIS-3-methoxy-4-aminopiperidin formula XIX-a

< / BR>
or its pharmaceutically suitable additive salt of the acid,

where A - P1where P1- C1- C4-alkylsulphonyl, C1- C4-allyloxycarbonyl, trihalomethanes or phenylmethyl.

9. The method of obtaining enantiomers enriched or enantiomerically pure CIS-3-methoxy-4-aminopiperidine formula XIX-a

< / BR>
where A - P1where P1- C1- C4-alkylsulphonyl, C1- C4-allyloxycarbonyl, trihalomethanes or phenylmethyl,

characterized in that carry out the reaction Reznichenko 3-methoxy-4-oxo-piperidine of formula XXII-a, where A has the above meanings, with a single enantiomer chiral amine of formula XXIII, where R8- C1- C6-alkyl or hydroxy-C1- C6is alkyl and Ar is phenyl, possibly substituted with halogen, C1- C6-alkyl or C1- C6-al is lilacsigil, with the formation of the intermediate product of formula XXI-a, where A, Ar and R8have the specified values, which hydronaut in the presence of a catalyst, for example palladium on charcoal, platinum on coal or mixed coal-fired

< / BR>
< / BR>
with the formation of diastereomeric enriched or diastereomers pure intermediate product of formula XX-a, where A, Ar and R8have the specified values, and the subsequent removal of the chiral auxiliary group Ar-CH(R8)- and, if necessary, convert the intermediate product of formula XIX-and acid additive salt by treatment with an acid, or conversely, make additive salt of the acid to the free base by treatment with alkali.

10. The method of obtaining such enantiomers of formula I-and

< / BR>
where R3, R4and R5have the specified values,

characterized in that carry out the following stages: a) carry out the reaction of enantiomerically enriched or enantiomerically pure intermediate product of the formula XIV-a, where P1- C1- C4-alkylsulphonyl, C1- C4-allyloxycarbonyl, trihalomethanes or phenylmethyl, with the acid of formula V or its functional derivative with subsequent removal of the protective group P1and Paul the/SUP> and R5and m have the specified values

< / BR>
< / BR>
where R3, R4and R5have the listed meanings: (b) N-alkylate enantiomerically enriched or enantiomerically pure intermediate product of formula II-a reagent of formula XI, where P is a suitable protective group, legkodelimae, for example, by hydrogenolysis or hydrolysis, W1- removable group, such as halogen or methysulfonylmethane, with the subsequent removal of the protective group P, obtaining enantiomerically enriched or enantiomerically pure intermediate product of formula VII-a

< / BR>
C) the reaction of enantiomerically enriched or enantiomerically pure intermediate product of formula VII-a, where R4, R5, m and n have the above meanings, with a reagent of formula VI, where R6is hydrogen or C1- C6-alkyl, and W2is a corresponding delete the group, such as, for example, halogen, for example chlorine, bromine or iodine, sulfonyloxy, such as methanesulfonamido, methylbenzenesulfonamide, C1- C6-alkyloxy, for example methoxy-, ethoxy-, C1- C6-allylthiourea, for example methylthio, ethylthio-, and R2has the specified values, and if necessary, otscheplaut protective ether is/BR> and if necessary carry out further purification of enantiomerically enriched compounds of formula I and to obtain enantiomerically pure compounds of formula I-a, and, if further necessary, turn the compound of formula I and pharmaceutically acceptable additive acid salt by treatment with an acid, or conversely, make an acidic additive salt into the free base by treatment with alkali.

 

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The invention relates to new chemical compounds with valuable properties, in particular to piperidinylmethyl derived chromane General formula (I)

< / BR>
where A is hydrogen or lower alkoxy,

E is hydrogen, hydroxyl, phenyl or piperidyl,

G phenyl not substituted or substituted with halogen and/or trifluoromethyl, fenoxaprop substituted by trifluoromethyl, benzyl, substituted phenylcarbinol, aminocarbonyl,

provided that E does not mean hydrogen or hydroxide, when G is phenyl, and their salts with inorganic acids

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The invention relates to compounds of the formula I

(I) or pharmaceutically acceptable salt accession acids him or stereoisomeric form of the compound, where

-A1= AND2- A3= AND4- bivalent radical having the formula

-CH=CH-CH=CH- (a-1)

-N=CH-CH=CH- (a-2)

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-N=CH-N=CH- (and-6),

n=1 or 2

IN - NR4or CH2< / BR>
R4is hydrogen or C1-C6alkyl

L is hydrogen, C1-C6alkyl, C1-C6allyloxycarbonyl, or a radical of the formula

-Alk - R5(b-1),

-Alk - Y - R6(b - 2),

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-CH2- SNON - CH2- O - R8(b-4), where R5is cyano, phenyl optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5-oxo-1-N-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-N-benzimidazolyl; or bicycling radical of formula (C-4-a)

Gwhere G2- CH=CH-CH=CH-, -S-(CH2)3,- -S-(CH2)/2-, -S-CH=CH - or-CH=C(CH3)-O-;

R6- C1-C6-alkyl, pyridinyl optionally substituted by nitro; pyrimidinyl; feast
R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

Y is O or NH;

Z1or Z2each independently NH or a direct link X-O

each Аlk independently - C1-C6alcander

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The invention relates to new biologically active chemical compounds, in particular to cyclic amino compounds of the formula I

BANwhere In - perederina, piperidinyl or pyrrolidinyl group, each of which may be substituted by a lower alkyl group, lower alkylcarboxylic group, carbobenzoxy, afterburner (lower) accelgroup, phenylketone (lower) alkyl group, phenylcarbamoyl (lower) alkyl group or phenyl (lower) alkyl group, each of which may be substituted by a halogen atom or a lower alkoxygroup; p is 1 or 2; And -- is a bond, or two-, or trivalent aliphatic C1-6hydrocarbon residue which may be substituted by a lower alkyl group, oxo, hydroximino or hydroxy-group;means either simple or double bond, provided that when a represents a bond, thenmeans of a simple bond; R2and R3independent means ATO condition, both R2and R3are not hydrogen atoms, or R2and R3together with the adjacent nitrogen atom form piperidino, hexamethyleneimino, morpholino, pyrolidine, pieperazinove or 1-imidazolidinyl group, each of which may be substituted by a lower alkyl group, a phenyl (lower) alkyl group, a lower alkylcarboxylic group or diphenyl (lower) alkyl group or a physiologically acceptable salt additive acid

The invention relates to novel 1,2,4-substituted piperidines formula 1, where R1is unsubstituted or substituted with halogen and/or trifluoromethyl phenyl or diphenyl-C1-C4-alkyl, ; 9-fluorenyl, pyridil-C1-C4-alkyl; chinolin-C1-C4-alkyl; 5-chloro-2-[1H-1,2,4-triazolyl-1-yl]-phenoxy-C1-C4-alkyl, unsubstituted or substituted C1-C4-alkyl, C1-C4-alkoxyl, hydroxyl, halogen, trifluoromethyl, di-C1-C4-alkylamino-group and/or cyano benzoyl; naphtol; 2-fluorenyl; phenyl - or diphenyl-C2-C4-alkanoyl; naphthyl-C2-C4-alkanoyl; dimethylcyclohexanols; hinolincarbonova; pyridyl-C2-C4-alkanoyl; benzyloxycarbonyl, unsubstituted or substituted by acetyl or 4-carboxymethylation phenylalanine or phenylcarbamoyl; 2,3,4,9-tetrahydro-1H-pyrido[3,4-b] indol-3-yl-carbonyl; R2is unsubstituted or substituted with halogen phenyl or naphthyl; R3is hydrogen, C1-C4-alkyl, cyclohexyl or phenylcarbamoyl, or 3-aminocarbonylmethyl; R4- if necessary substituted C1-C4-alkyl or C1-C4-alkoxyl phenyl, naphthyl, benzyl, pyridyl, if necessary, C-Zam the sludge; if necessary substituted C1-C4the alkyl benzothiophenes, dihydrobenzofuranyl or aniline group, X1- simple bond, methylene, hydroxymethylene or carbonyl, X2- a simple link, X3- simple bond, methylene, ethylene, benzylidene or carbonyl or their salts

The invention relates to medicine and immunology, and can be used in the search and selection of optimal immunomodulators immunodeficieny States caused by disturbances in the system of neutrophilic granulocytes

The invention relates to new derivatives of N-(3-hydroxy-4-piperidinyl) (dihydro-2H-benzopyran or dihydrobenzoic) carboxamide, having valuable pharmaceutical properties, namely activity to stimulate gastrointestinal peristalsis

The invention relates to pharmaceutical compositions on the basis of benzothiophenes and to use the latter for treating or preventing osteoporosis by inhibiting bone rarefaction

The invention relates to a new resolutional crystalline form of 6-hydroxy-2-(4-hydroxyphenyl)-3-/4-(2-piperidinoethyl)benzoyl/benzo[b] difengidramin, which can be used as a pharmaceutically active agent, a pharmaceutical composition
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