Derivatives of amides of carboxylic acids with heterocyclic substituents and the composition possessing the ability to inhibit 5-ht1aand/or1and/or2aand/or2dand/or d2receptors

 

(57) Abstract:

Describes new derivatives of amides of carboxylic acids with heterocyclic substituents of General formula I, including pharmaceutically acceptable salts, where q means the number 0, 1, 2, 3 or 4, R1means (a) a halogen atom, b) unsubstituted or substituted by one or more atoms of halogen alkyl group with the number of carbon atoms and from one to three, in) CNS group with the number of carbon atoms and from one to three, d) unsubstituted or substituted by one or more halogen atoms alkylsulfonates with the number of carbon atoms and from one to three, and denoted by R1the substituents can be identical or different, provided that q means the number 2, 3 or 4; U means alkylenes chain with the number of carbon atoms and from one to three; Q means biradical formula IIA, or IIB, V represents a relationship or alkilinity chain with the number of carbon atoms and from one to three; X means alkylenes chain with the number of carbon atoms is 0, 1 or 2; X1means alkylenes chain with the number of carbon atoms one to four, provided that the total number of carbon atoms in X and X1is three or four; T mean acyl residue of heterocyclic is DIL, 2 - or 3-thienyl, 2-, 3-, 4 - or 8-chinoline, each of which can be unsubstituted or substituted by one or more substituents from the group comprising (a) a halogen atom, b) an alkyl group with the number of carbon atoms and from one to three, in) CNS group with the number of carbon atoms and from one to three, g) alkylthiol group with the number of carbon atoms and from one to three, d) amino group, (e) 1-pyrrolidinyl group. Connections can be an active substance composition having the ability of inhibitors of 5-HT1Aand/or1and/or2Aand/or2Dand/or D2receptors containing a therapeutically effective amount of the compounds of formula I, or salts thereof together with a pharmaceutically acceptable diluent or carrier. 2 S. and 4 C.p. f-crystals.

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The invention relates to new derivatives of amides of carboxylic acids, more particularly to derivatives of amides of carboxylic acids with heterocyclic substituents, as well as to a composition having the ability to inhibit 5-HT1Aand/or1and/or2Aand/or2Dand/or D2the receptors.

Known derivatives of amides of carboxylic acids with heterocyclic substituents, which can be applied to any smooth surface is, the/or2Aand/or2Dand/or D2receptors (see application WO N 95/07274, class C 07 D 405/12, A 61 K 31/335, 16.03.1995 year).

Object of the invention is the expansion of the range of the derivatives of amines carboxylic acids with heterocyclic substituents, which may serve as an active substance composition having the ability to inhibit 5-HT1Aand/or1and/or2Aand/or2Dand/or D2the receptors.

The problem is solved proposed derivatives of amides of carboxylic acids with heterocyclic substituents of General formula (I)

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including their pharmaceutically acceptable salts,

where g denotes the number 0, 1, 2, 3, or 4

R1means (a) a halogen atom, b) unsubstituted or substituted by one or more atoms of halogen alkyl group with the number of carbon atoms and from one to three, in) CNS group with the number of carbon atoms and from one to three, d) unsubstituted or substituted by one or more halogen atoms alkylsulfonates with the number of carbon atoms and from one to three, and denoted by R1the substituents can be identical or different, provided that g means the number 2, 3 or 4;

U mean alkylenes chain V means communication or alkilinity chain with the number of carbon atoms and from one to three;

X means alkylenes chain with the number of carbon atoms is 0, 1 or 2;

X' means alkylenes chain with the number of carbon atoms one to four, provided that the total number of carbon atoms in X and X' is equal to three or four;

T means the acyl residue of heterocyclic carboxylic acids, heterocyclic fragment (Het) which is represented by the following residues: 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2-, 3-, 4 - or 8-chinoline, each of which can be unsubstituted or substituted by one or more substituents from the group comprising (a) a halogen atom, b) an alkyl group with the number of carbon atoms and from one to three, in) CNS group with the number of carbon atoms and from one to three, g) alkylthiol group with the number of carbon atoms and from one to three, d) amino group, (e) 1-pyrrolidinyl group.

In the first group of preferred derivatives of amides of carboxylic acids with heterocyclic substituents include compounds of formula (I) in which g denotes the number 0, 1 or 2; R1means a halogen atom (e.g. fluorine atom, chlorine or bromine), an unsubstituted or substituted by one or more atoms of halogen alkyl group with the number of carbon atoms and from one to three, CNS group number at which iphoneography with the number of carbon atoms and from one to three; U represents a methylene group; Q means a group of formula IIA or IIB; V means a methylene group; X and X' both mean the ethylene group, and a heterocyclic fragment presents 2-, 3 - or 4-pyridium, 8-hyalinella or 2-tanila, and each of these residues can be unsubstituted or substituted by one or more substituents from the group comprising methyl, methoxy group, halogen atom, methylthiophenyl group, 1-pyrrolidinyl group and amino group.

The second group preferred derivatives of amides of carboxylic acids with heterocyclic substituents include compounds of formula (I), in which the heterocyclic fragment presents 2-pyridium, 3-pyridium, 8-hyalinella or 2-tanila, and each of these residues can be unsubstituted or substituted by amino, methyl, metaxylene, 1-pyrrolidino, methylthiophenol group or a bromine atom.

In a third preferred group of derivatives of amides of carboxylic acids with heterocyclic substituents include compounds of formula (I), in which the heterocyclic fragment presents 2-pyridium or 3-pyridium and each of these residues can be unsubstituted or substituted amino group.

In particular, preferred compounds obter}pyridine-3-carboxamide;

2-amino-N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{[1-(8-fluoro-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{ [1-(1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{ [1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl} pyridine-3-carboxamide;

N-{ [1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl} pyridine-2 - carboxamide;

2-amino-N-{[1-(7-methoxy-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl} pyridine-3-carboxamide;

N-{ [1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl} quinoline-8 - carboxamide;

N-{ [1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl}-2 - methylpyridin-3-carboxamide;

2-amino-N-{[1-(7-fluoro-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{[1-(8-methoxy-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl} pyridine-3-carboxamide;

N-{ [1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl}pyridine-2-carboxamide;

2-amino-N-{ [1-(8-methyl-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl} pyridine-3-carboxamide,

2-amino-N-{ [1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl}-6-methylpyridin-3-carboxamide;

3-amino-N-{ [1-(1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]matild;

N-{ [1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl}-2 - methylpyridin-3-carboxamide;

1-(2-aminonicotinic)-4-[N-(7-chloro-1,4-benzodioxan-2 - ylmethyl)aminomethyl]piperidine;

2-amino-N-{ [1-(8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl] methyl}pyridine-3-carboxamide;

2-amino-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl}pyridine-3-carboxamide;

N-{ [1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl}pyridine-3-carboxamide;

N-{ [1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl}quinoline-8-carboxamide;

N-{ [1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl}pyridine-3-carboxamide;

N-{ [1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl}-6 - methylpyridin-2-carboxamide;

N-{ [1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl}-2 - methoxypyridine-3-carboxamide;

2-amino-N-{ [1-(7,8-debtor-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{ [1-(8-tripterocalyx-1,4-benzodioxan-2 - ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

4-[N-(7-chloro-1,4-benzodioxan-2-ylmethyl)aminomethyl] -1-(2 - pyridylcarbonyl)piperidine;

as well as pharmaceutically acceptable salts of these compounds in the form of individual enantiomers, racemates, or other this with pharmaceutically acceptable acids. Examples of such salts are hydrochloride, hydrobromide, sulphates, methansulfonate, nitrates, maleate, acetates, citrates, fumarate, tartratami (for example, (+)-tartratami, (-)-tartratami or mixtures thereof, including racemic mixtures), succinate, benzoate and salts with amino acids such as glutamic acid. The compounds of formula (I) may exist in the form of a solvate such as a hydrate.

The compounds of formula (I) contain one or more chiral centers, and exist in different optically active isomers. If the compounds of formula I contain one chiral center, they exist in two enantiomeric forms and the scope of the present invention includes both enantiomers and the mixture of enantiomers. Enantiomers can be separated by well-known specialists in this field by, for example, due to the formation of diastereoisomeric salts which may be separated, for example, by crystallization, and the formation of diastereoisomeric derivatives or complexes which may be separated, for example by crystallization or by using gas-liquid or liquid chromatography, separation is also possibly due to the selective interaction of one of the enantiomers with stereosize or liquid chromatography in a chiral environment, for example, on a chiral stationary phase, for example, on silica gel, which is associated with the chiral ligand or in the presence of a chiral solvent. It is important that after transformation of the target enantiomer to another chemical compound according to one of the above methods of separation, already at the next stage, it was possible to obtain the desired enantiomeric form. In an alternative scheme, the individual enantiomers may be synthesized in asymmetric transformation involving optically active reagents, substrates, catalysts or solvents, or by translation of one enantiomer into the other when asymmetric transformation.

The compounds of formula (I) containing more than one chiral center may exist then reduced to diastereoisomeric forms. A pair of diastereoisomers can be separated by well-known experts in this field ways, for example by chromatographytandem or crystallization, and individual enantiomers in each of the pairs can be separated using methods described above. In the scope of the invention includes all diastereoisomeric compounds of formula (I) and mixtures thereof.

Some compounds of formula (I) and their salts may exist in more than one crystalline fo is inane formula (I) and their salts may exist in the form of a solvate, for example hydrates, and the scope of the present invention includes each solvate and mixtures thereof.

Compounds of General formula (I) can be obtained in the following ways, which are preferably carried out at atmospheric pressure.

The compounds of formula (I), where Q stands for a group of the formula IIA, in which V denotes (CH2)n+1where n means the number 0, 1 or 2, can be obtained by the coupling of compounds of formula (III)

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with the compound of the formula (IV)

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with the subsequent reaction of the intermediate of the resulting imine with a reducing agent, for example with sodium borohydride.

In addition, the compounds of formula (I) in which Q means a group of formula (IIA), where V means (CH2)n+1where n means the number 0, 1 or 2, can be obtained by the coupling of compounds of formula (III) with the compound of the formula (V)

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in which Y represents a leaving group, for example p-toluensulfonate, in the presence of, if necessary, a suitable solvent and in the presence of, if necessary, a base such as potassium carbonate.

In addition, the compounds of formula (I), where Q stands for a group of the formula IIA, in which V denotes (CH2)n+1where n means the number 0, 1 or 2, m where Z denotes a leaving group, for example, p-toluensulfonate, in the presence of, if necessary, a suitable solvent and in the presence of, if necessary, a base such as potassium carbonate.

The compounds of formula (I), where U represents a methylene group, and Q means a group of the formula IIA, in which V denotes (CH2)n+1where n means the number 0, 1 or 2, can be obtained by the coupling of compounds of formula (VIII)

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with the compound of the formula (VI), followed by reaction of the intermediate of the resulting imine with an appropriate reducing agent, for example with sodium borohydride.

The compounds of formula (III), in which U represents (CH2)m+1where m denotes the number 0, 1 or 2, can be obtained by reduction of compounds of formula (IX)

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the action of a reducing agent such as lithium aluminum hydride.

The compounds of formula (IX) can be obtained by the reaction of compounds of formula (X)

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with vicinal disubstituted nitrile of the formula (XI)

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in which Y represents such a leaving group like halogen atom such as bromine atom, in the presence of a base, for example potassium carbonate.

The compounds of formula III can be obtained from compounds of formula (XII)

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which is the result catalyzed by acids or bases hydrolysis or splitting in this reagent, as hydrazinehydrate.

The compounds of formula (XII), in which the fragment of E together with the United with him by a nitrogen atom represents the residue of phthalimide, can be synthesized by the reaction of compounds of formula (VII) in which Z denotes a leaving group, for example p-toluensulfonate, phthalimide potassium.

The compounds of formula (III), where U represents a methylene group, can be obtained by reduction of compound of formula (XIII)

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appropriate reducing agent such as lithium aluminum hydride.

The compounds of formula (XIII) can be synthesized by the reaction with ammonia compounds of the formula (XIV)

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in which m represents the number 0, and L denotes an alkyl group with the number of carbon atoms of from one to six.

The compounds of formula (IV) can be obtained from compounds of formula (XV)

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in which R2means CNS group with the number of carbon atoms one to four, as a result of interaction with a reducing agent, for example, bis-(2-methoxyethoxy)aluminum hydride, sodium in a solvent, such as toluene.

The compounds of formula (XV) can be obtained by the reaction of compounds of formula (XVI)

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with allermuir agent of the formula X-CO-Het, in kotona group, and Het denotes one of the above heterocyclic fragments, in the presence of a base, such as triethylamine, or such used for the formation of amide bond of the reagent, as carbonyldiimidazole, in an appropriate solvent, such as methylene chloride.

The compounds of formula (IV) can be obtained by the oxidation of compounds of formula (XVII)

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the action of an appropriate oxidant, such as action resulting from oxalicacid and dimethyl sulfoxide reagent.

The compounds of formula (V), where (Y) denotes the p-toluensulfonate can be obtained by the reaction of compounds of formula XVII with tailroom agent, for example with p-toluenesulfonyl chloride.

The compounds of formula (XVII) can be synthesized by the reaction of compounds of formula (XVIII)

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with allermuir reagent of the formula X-CO-Het, in which X represents a leaving group such as halogen atom, CNS, hydroxyl or alkoxycarbonyl group, in the presence of a base, such as triethylamine, or such used for the formation of amide bond of the reagent, as carbonyldiimidazole, in an appropriate solvent, such as methylene chloride.

Connection ilen group with the number of carbon atoms one to four, used for recovery agent, for example lithium aluminum hydride.

The compounds of formula (VI) can be synthesized by the reaction of compounds of formula (XIX)

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in which D denotes a protective group, such as 5-bromo-2-hydroxybenzylidene group, with allermuir agent of the formula X-CO-Het, in which X represents a leaving group such as halogen atom, CNS, hydroxyl or alkoxycarbonyl group, in the presence of a base, such as triethylamine, or such used for the formation of amide bond of the reagent, as carbonyldiimidazole, in an appropriate solvent, such as methylene chloride, followed by removing the protective group, for example, using acid-catalyzed hydrolysis.

The compounds of formula (XIX) can be obtained by the reaction of compounds of formula (XX)

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reagent used for the protection of primary amino groups, for example 5-bromo-2-hydroxybenzaldehyde.

The compounds of formula (XX) can be synthesized by the reduction of compound of formula (XVI), where R6mean NH2the group, under the action of such a reducing agent as alumalite lithium.

The compounds of formula (VII), where Z denotes p-toluensulfonate, in the presence of a base, for example pyridine.

The compounds of formula (XXI), where U represents (CH2)m+1can be obtained by reduction of compound of formula (XIV), where L denotes an alkyl group with the number of carbon atoms one to four and m denotes the number 0, 1 or 2, by the action of a reducing agent such as lithium aluminum hydride.

The compounds of formula (XXI), where U represents a methylene group, can be obtained by the interaction of the compounds of formula (XXII)

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in which Z denotes a leaving group such as chlorine atom or C-toluensulfonate, with a compound of formula X in an appropriate solvent, for example in water or dimethylformamide, in the presence of a base, for example sodium hydroxide. If the reaction is injected enantiomerically pure form the compounds of formula (XXII), for example (R)-glycidyl-p-toluensulfonate, the product of interaction becomes the only (S)-enantiomer of compounds of formula (XXI).

The compounds of formula (XXI), where U represents a methylene group, and R1means CNS group with the number of carbon atoms and from one to three, can be obtained by alkylation of the corresponding compounds of formula (XXI), where R1means hydroxylysine sodium.

The compounds of formula (XXI), where U represents a methylene group, can be obtained by cyclization of compounds of formula (XXIII)

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in which R means a hydrogen atom or alkyl group with the number of carbon atoms one to four, in the presence of a base, such as sodium methylate.

The compounds of formula (XXIII) can be obtained by oxidation of compounds of formula (XXIV)

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nagkalat, for example 3-chlormadinone acid.

The compounds of formula (XXIV) can be obtained by alkylation of compounds of formula (XXV)

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compounds of the formula (XXII), in which Z denotes a leaving group, for example, a chlorine atom or C-toluensulfonate, in an appropriate solvent, such as dimethylformamide, in the presence of a base, for example potassium carbonate.

The compounds of formula (VIII) can be obtained by oxidation of compounds of formula (XXI), where U represents a methylene group, an appropriate oxidant, such as chlorbromuron pyridinium, or restoring the compounds of formula (XIV), where m represents the number 0, an appropriate reducing agent, such as bis-(2-methoxyethoxy)aluminum hydride, sodium in a solvent, such as toluene.

The compounds of formula (XIV) Mor a bromine atom, and L denotes an alkyl group with the number of carbon atoms of from one to six, with the compound of formula (X) in the presence of a base, for example potassium carbonate.

The compounds of formula (I) in which Q means a group of formula IIA can be obtained by the reaction of compounds of formula (XXVII)

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where D' denotes a hydrogen atom, with a compound of formula (VII) in which Z denotes a leaving group, for example p-toluensulfonate, if necessary, in the presence of a base, for example potassium carbonate, and optionally in a solvent, such as acetonitrile.

The compounds of formula (XXVII), where D' denotes a hydrogen atom, can be obtained by removing the protective group in the compounds of formula (XXVII), where D' denotes a protective group, for example tert.-butoxycarbonyl group, for example, by hydrolysis in the presence of acid, for example triperoxonane acid.

The compounds of formula (XXVII), where D' denotes a protective group, can be obtained by the reaction of compounds of formula (XXVIII)

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where D' denotes a protective group, for example tert.-butoxycarbonyl group, with the compound of the formula X-CO-Het, in which X represents a leaving group such as halogen atom, CNS group, a hydroxyl group for the formation of amide linkages, for example carbonyldiimidazole, in such appropriate solvent like methylene chloride.

The compound of formula (XXVII), where D' denotes a protective group, and Het fragment represented by formula (XXX)

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in which Y means the remainder, the final heteroaromatic cycle, and R means a hydrogen atom or alkyl group, can be obtained by the reaction of compounds of formula (XXIX) with a compound of formula (XXX)

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where Y means the remainder, the final heteroaromatic cycle, and R means a hydrogen atom or alkyl group, in a solvent, such as 1,2-dimethoxyethane.

The compounds of formula (I), where Q denotes a group of formula IIB can be obtained by the reaction of compounds of formula (XXXI)

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where D' denotes a hydrogen atom, with a compound of formula VII, where Z denotes a leaving group, for example p-toluensulfonate, if necessary, in the presence of a base, for example potassium carbonate, and optionally in a solvent, such as acetonitrile.

The compounds of formula (XXXI), where D' denotes a hydrogen atom, can be obtained by removing the protective group from compounds of formula (XXXI), where D' denotes a protective group, for example tert.-butoxycarbonyl group, ptx2">

In addition, the compounds of formula (XXXI), where D' denotes a protective group, can be obtained by the reaction of compounds of formula (XXXII)

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in which D' is a protective group, for example tert.-butoxycarbonyl group, with the compound of the formula X-CO-Het, in which X represents a leaving group such as halogen atom, CNS group, hydroxyl group, or alkoxycarbonylmethyl, in the presence of a base, such as triethylamine, or reagent used for the formation of amide linkages, for example, carbonyldiimidazole, in a suitable solvent such as methylene chloride.

The compounds of formula (XXXI), where D' denotes a protective group, and Het denotes a heterocyclic fragment of the formula (XXIX) in which Y completes the heteroaromatic cycle and R means a hydrogen atom or alkyl group, can be obtained by the reaction of compounds of formula (XXXII) with a compound of formula XXIX in which Y completes the heteroaromatic cycle and R means a hydrogen atom or alkyl group, in a solvent, such as 1,2-dimethoxyethane.

In addition, the compounds of formula (I), where Q denotes a group of formula IIB can be obtained by the reaction of compounds of formula (XXXV)

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with the compound of the formula (XXX), for example with ptx2">

The compounds of formula (XXXIII) can be obtained from compounds of formula (XXXIV)

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in which D denotes a protective group, such as 5-bromo-2-hydroxybenzylidene group, the result is catalyzed by acids or bases hydrolysis.

The compounds of formula (XXXIV) can be obtained by the reaction of compounds of formula (XXXV)

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in which D denotes a protective group, such as 5-bromo-2-hydroxybenzylidene group, with a compound of formula (VII), optionally in the presence of a base, such as triethylamine.

The compounds of formula XXXV can be obtained by the reaction of compounds of formula (XXXVI)

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reagent used to protect the amino group, for example 5-bromo-2-hydroxybenzaldehyde.

The compounds of formula (I), where Q denotes a group of formula IIB can be obtained by the reaction of compounds of formula (XXXIII) with allermuir agent of the formula X-CO-Het, in which X represents a leaving group such as halogen atom, CNS group, hydroxyl group, or alkoxycarbonylmethyl, in the presence of a base, such as triethylamine, or reagent used for the formation of amide linkages, such as carbonyldiimidazole or N, N'-diisopropylcarbodiimide, in this pada, with the ability of inhibitors of 5-HT1Aand/or1and/or2Aand/or2Dand/or D2receptors containing a therapeutically effective amount of the compound of the above formula (I) or its salt together with a pharmaceutically acceptable diluent or carrier.

The compositions may be in the form of any known dosage form for oral, perfectlove, parenteral administration, or as an external tool. Suitable for use in the compositions of pharmaceutically acceptable carriers well known in this field of pharmacology. Corresponding to the invention the composition may contain from 0.1 to 99 wt.% the active substance. Corresponding to the invention the composition is prepared usually in the form of a unitary dosage form. A preferred single dose of the active substance is from 1 to 500 mg Used for preparation of such compositions excipients are well known to pharmacologists excipients.

Compositions for admission through the mouth represent preferred compositions within the invention, and it is a known pharmaceutical forms for such a method of administration, for example tablets, capsules fruit which are known to pharmacologists excipients. Tablets can be prepared by mixing the active compounds with such an inert diluent, as calcium phosphate, in the presence of contributing to the loosening agents such as corn starch, and lubricating agents such as magnesium stearate, followed by pelletizing the mixture by known methods. Formulation of tablets prepared in accordance with the accumulated experience in this field, for example, in such a way as to ensure the prolonged isolation of the relevant invention compounds. If desired, such tablets can be equipped with intersolubility coatings using known methods, for example, with the introduction of their composition phthalate cellulose acetate. The same applies to the capsules, such as capsules of hard or soft gelatin containing the active substance with the addition of excipient or without him. They can be prepared by conventional means and, if desired, provided with disintegrating in the gut coatings using known methods. The optimal concentration of active substance in each individual tablet or capsule comprises from 1 to 500 mg. Other compositions for oral administration include, for example, aqueous suspensions containing the active semimetals, or oil suspensions, containing relevant to the invention compound in a suitable vegetable oil, such as peanut butter.

The active substance may be incorporated into the granules with additional excipients or without them. The patient can directly take these granules inside or you can add them before taking to the liquid medium such as water. To facilitate dispersion in a liquid medium granules can contain dezintegriruetsja additives, such as pharmaceutically acceptable pairs emit gas compounds represented by the acid and the carbonate or bicarbonate.

Corresponding to the invention of a composition intended for insertion through the rectum, are the known pharmaceutical forms for such a method of administration, such as suppositories based on cocoa butter or polyethylene glycol.

Corresponding to the invention compositions intended for parenteral administration, are known pharmaceutical forms for such a method of administration, for example sterile suspensions or sterile solutions in a suitable solvent.

The composition for external use can clustersim, to ensure their contact with the skin for transdermal administration. A suitable composition for the introduction of the active substance through the skin can be prepared by mixing the pharmaceutically active compounds such suitable for external use media, such as mineral oil, petrolatum and/or wax, such as paraffin wax or beeswax, together with accelerating the penetration of substances through the skin dimethylsulfoxide or propylene glycol. The active substance may be dispersed in a pharmaceutically acceptable cream or ointment. The number of active connections intended for external use drug form should be such as to ensure that a therapeutically effective amount of the active substance for the period of time during which assumes the presence of the dosage form on the skin.

It is also possible introduction relevant to the invention of compounds with continuous infusion either from an external source, such as an intravenous infusion through a drip, or from a source within the body. Internal sources are implanted reservoirs containing intended for infusion with the example, in the form of a suspension or solution in a pharmaceutically acceptable oil, pour when the connection is in the form of a poorly water-soluble derivative such as a salt dodecanol acid or the corresponding ester, or b) they are represented by solid material in the form of implanted bases, for example, of synthetic resin or waxy material containing the input thus the connection. Solid implant may include one containing all of the active substance of the body or of a series of several bodies, each of which contains part of the input connections. The amount of active substance in the composition of the internal source should be such as to provide a therapeutically effective amount of the active substance over a long period of time.

In some dosage forms good results are obtained by using the respective invention compounds in the form of particles of very small size, such as that obtained in jet mills.

Relevant to the invention pharmaceutical compositions the active ingredient may be optionally supplemented with other compatible pharmacologically active is likesto pharmaceutical compositions can be used to treat people depressive anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson's disease, obesity, hypertension, Tourette's syndrome, disorders of the sexual sphere, addictions to drugs, withdrawal syndrome, defects of memory, Alzheimer's disease, senile dementia, manic States, panic attacks, phobias social nature, disorders of appetite and anorexia, painful changes in the circulatory system of the heart and brain, non-insulin-dependent diabetes mellitus, hyperglycaemia, constipation, arrhythmia, disorders of the neuro-endocrine system, stress, hypertrophy of the prostate gland and seizures. The exact dosage of the injected active compounds in this treatment depends on several factors, such as the patient's age, physical condition and history of the disease, and it is determined by the attending physician, and the number taken per day of the active substance lies in the range from 1 to 1000 mg, preferably from 5 to 500 mg per day. To take the medicine one dose or dividing it into multiple doses, once or several times a day.

Preferably the compounds of formula (I) or their salts, or including these compounds in effective amounts States, anxiety, psychoses (for example schizophrenia), tardive dyskinesia, Parkinson's disease, hypertension, Tourette's syndrome, manic States, panic attacks, phobias social nature of the pathological changes of the circulatory system of the heart and brain, stress and hypertrophy of the prostate.

The ability of compounds of the formula (I) to interact with the receptors 5-hydroxytryptamine (5-HT) is demonstrated in the following test, which in vitro determine the ability of compounds to inhibit the binding of tritium-labeled ligand 5-HT receptors and, in particular, 5-HT1A-receptors.

The fabric of the hippocampus of the brain of male rats Sprague-doli (from Charles One, weighing from 150 to 250 g) homogenized in ice buffer with a concentration of hydrochloride Tris 50 mmol/l (measured at a temperature of 25oC pH value equal to 7.7, the ratio of weight to volume 1:40) and centrifuged at a temperature of 4oC for 10 minutes at 30000g. The precipitate after centrifugation again suspended in the same buffer, incubated at 37oC for 10 minutes and centrifuged at a temperature of 4oC for 10 minutes at 30000g. Thus obtained precipitate again suspence, of 0.1% L-ascorbic acid and 10 µmol/l hydrochloride of N-methyl-N-propylbenzamide (hydrochloride of pargyline), at the rate of 6.25 mg wet tissue material in 1 ml and immediately used in the experiments for the binding. Aliquot of this suspension with a volume of 400 μl, equivalent to 2.5 mg of wet tissue material in a test tube, add in tubes containing ligand (50 μl; concentration of 2 nmol/l) and distilled water (50 μl for total binding) or 5-hydroxytryptamine (50 µl with a concentration of 10 µmol/l for nonspecific binding) or 50 μl of a solution of the compounds in the same concentrations of 10-6mol/l or ten concentrations from 10-11up to 10-3mol/L. as a ligand is used [3H]8-hydroxy-2-(dipropylamino)tetralin ([3H]8-OH-DPAT). The mixture is incubated at 25oC for 30 minutes and complete the incubation fast for filtering.

The filters are washed with cooled in ice buffer containing Tris hydrochloride and dried. Sediment shook off filter in a jar, add scintillation fluid and determine the radioactivity using a liquid scintillation counter. The degree of displacement of specifically bound tritium-labeled ligand races is to build connections, which at a concentration of 10-6mol/l replace 50% or more of the specific binding of tritium-labeled ligand using to calculate the entire area of the concentrations of this compound. On this curve to determine the concentration at which there is 50% inhibition of specific binding (KI50). Then calculate the ratio of inhibition (Kandthe formula

,

where [ligand] means the concentration used tritium-labeled ligand and Kdmeans the equilibrium constant of dissociation of the ligand.

The ability of compounds of the formula I to interact with adrenoretseptory the binding site is demonstrated in the following test which determines the ability of compounds to inhibit the in vitro binding of tritium-labeled ligand to adrenergic receptors, especially with1-adrenoreceptors.

The entire cortex of male rats from Charles One line CD in weight from 150 to 250 g of homogenized in ice buffer with a concentration of hydrochloride Tris 50 mmol/l (measured at a temperature of 25oC pH value of 7.6, the ratio of weight to volume 1:40) and centrifuged at a temperature of 4oC for 10 minutes at 1000g. The liquid above the precipitate centrifuged at TEI 50 mmol/l Tris hydrochloride pH of 7.6 (the ratio of weight to volume 1: 40) and centrifuged at a temperature of 4oC for 10 minutes at 30000g. Thus obtained precipitate is again suspended in the buffer with a concentration of 50 mmol/l Tris hydrochloride pH of 7.6, the rate of 12.5 mg wet tissue material in 1 ml and immediately used in the experiments for the binding. Aliquot of this suspension in 400 µl, equivalent to 5 mg of wet tissue material in a test tube, add in tubes containing ligand (50 μl; concentration of 0.1 nmol/l) and distilled water (50 μl for total binding) or phentolamine (50 µl with a concentration of 5 µmol/l for nonspecific binding) or 50 μl of a solution of the compounds in the same concentrations of 10-6mol/l or ten concentrations from 10-11up to 10-3mol/L. as a ligand is used [7-methoxy-3H]prazosin. The mixture is incubated at 30oC for 30 minutes and complete the incubation fast for filtering.

The filters are washed with cooled in ice buffer containing Tris hydrochloride and dried. Sediment shook off filter in the cuvette, add scintillation fluid and determine the radioactivity using a liquid scintillation counter. The degree of displacement of specifically bound tritium-labeled ligand, the upper margin of the connections which at a concentration of 10-6mol/l replace 50% or more of the specific binding of tritium-labeled ligand using to calculate the entire area of the concentrations of this compound. On this curve to determine the concentration at which there is 50% inhibition of specific binding (IR50). Then calculate the ratio of inhibition (Kandthe formula

,

where [ligand] means the concentration used tritium-labeled ligand and Kdmeans the equilibrium constant of dissociation of the ligand.

The ability of compounds of the formula I to interact with 2-adrenoreceptor binding sites is demonstrated in the following test, which determine in vitro the ability of compounds to inhibit the binding of tritium-labeled ligand with2-adrenergic receptors, especially with2A-adrenoreceptors.

The cortex of the hemispheres of the human brain post mortem homogenized in a cooled ice sucrose solution with a concentration of 0.25 mol/l (the ratio of weight to volume 1:30) and centrifuged at 1000g at a temperature of 4oC for 12 minutes. The liquid above the sediment stored in ice, and the precipitate is again homogenized in sucrose solution with a concentration of 0.25 the United Fugate diluted with a solution of 5 mmol/l Tris hydrochloride pH of 7.5, containing 5 mmol/l ethylenediaminetetraacetic acid, again set pH 7.5 (25oC) the addition of 1 molar sodium hydroxide solution (ratio of weight to volume 1:80) and centrifuged at 4oC for 10 minutes at 11000 etc. Obtained by centrifugation resuspended in a solution of 50 mmol/l Tris hydrochloride from pH 7.5, containing of 5.68 mmol/l L-ascorbic acid and 0.5 mmol/l ethylenediaminetetraacetic acid, again set pH 7.5 (25oC) the addition of 1 molar sodium hydroxide solution (ratio of weight to volume 1:80) and centrifuged for 10 minutes at 11000g. Obtained by centrifugation stored at a temperature of -80oC. on the day of the experiment, the sediment was thawed, resuspended in a solution of 50 mmol/l Tris hydrochloride from pH 7.5, containing of 5.68 mmol/l L-ascorbic acid and 5 mmol/l ethylenediaminetetraacetic acid (the ratio of weight to volume 1:80) and centrifuged for 10 minutes at 11000g. Thus obtained precipitate is again suspended in a solution of 50 mmol/l Tris hydrochloride from pH 7.5, containing of 5.68 mmol/l L-ascorbic acid and 5 mmol/l ethylenediaminetetraacetic acid (aqueous phase at the rate of 25 mg of wet tissue Mat is mportant fabric material on the tube, add in tubes containing ligand (50 μl; concentration of 0.2 nmol/l) and distilled water (50 μl for total binding) or solution fentolamina (50 ál concentration of 50 µmol/l for nonspecific binding) or 50 μl of a solution of the compounds in the same concentrations of 10-6mol/l or ten concentrations from 10-11up to 10-3mol/L. as a ligand using tritium-labeled RX 821002 (2-(2-methoxy-1,4-[6,7(n)-3H] benzodioxan-2-yl)-2-imidazolin) and incubated the mixture at 0oC for 75 minutes, completing the incubation fast for filtering.

The filters are washed with cooled in ice buffer containing Tris hydrochloride and dried. Sediment shook off filter in the cuvette, add scintillation fluid and determine the radioactivity using a liquid scintillation counter. The degree of displacement of specifically bound tritium-labeled ligand calculated as a percentage for a single concentration (10-6mol/l) of the investigated compounds. Curves eviction build for connections at a concentration of 10-6mol/l replace 50% or more of the specific binding of tritium-labeled ligand using to calculate the entire area of concentration eichische binding (IR50). Then calculate the ratio of inhibition (Kandthe formula

,

where [ligand] means the concentration used tritium-labeled ligand and Kdmeans the equilibrium constant of dissociation of the ligand.

The ability of compounds of the formula I to interact with adrenoreceptor binding sites demonstrates the test, which determine in vitro the ability of compounds to inhibit the binding of tritium-labeled ligand to adrenergic receptors, especially with2D-adrenoreceptors.

The tissue of the cortex of the frontal lobes of the brain of male rats from Charles One line CD in weight from 150 to 250 g of homogenized in a cooled ice sucrose solution with a concentration of 0.25 mol/l (the ratio of weight to volume 1:30) and centrifuged at 1000g at a temperature of 4oC for 12 minutes. The liquid above the sediment stored in ice, and the precipitate is again homogenized in sucrose solution with a concentration of 0.25 mol/l (the ratio of weight to volume 1:15) and centrifuged at 850g at a temperature of 4oC for 12 minutes, United Fugate diluted with a solution of 5 mmol/l Tris hydrochloride from pH 7.5, containing 5 mmol/l ethylenediaminetetraacetic acid, again set pH 7.5 (25oC) doreczenie 10 minutes at 30000g. Obtained by centrifugation resuspended in a solution of 50 mmol/l Tris hydrochloride from pH 7.5, containing of 5.68 mmol/l L-ascorbic acid and 0.5 mmol/l ethylenediaminetetraacetic acid, again set pH 7.5 (25oC) the addition of 1 molar sodium hydroxide solution and centrifuged at 30000g for 10 minutes. Obtained by centrifugation again suspended in a solution of 50 mmol/l Tris hydrochloride from pH 7.5, containing of 5.68 mmol/l L-ascorbic acid and 2 mmol/l ethylenediaminetetraacetic acid (aqueous phase at the rate of 12.5 mg wet tissue material per 1 ml of suspension) and immediately use it in the experiments for the binding. Aliquot of this suspension with a volume of 400 μl, equivalent to 5 mg of wet tissue material in a test tube, add in tubes containing ligand (50 μl; concentration of 1 nmol/l) and distilled water (50 μl for total binding) or solution fentolamina (50 µl with a concentration of 5 µmol/l for nonspecific binding) or 50 μl of a solution of the compounds in the same concentrations of 10-6mol/l or ten concentrations from 10-11up to 10-3mol/L. as a ligand using tritium-labeled idazoxan (hydrochloride (1 is ubytovanie fast for filtering.

The filters are washed with cooled in ice buffer containing Tris hydrochloride and dried. Sediment shook off filter in the cuvette, add scintillation fluid and determine the radioactivity using a liquid scintillation counter. The degree of displacement of specifically bound tritium-labeled ligand calculated as a percentage for a single concentration (10-6mol/l) of the investigated compounds. Curves eviction build for connections at a concentration of 10-6mol/l replace 50% or more of the specific binding of tritium-labeled ligand using to calculate the entire area of the concentrations of this compound. On this curve to determine the concentration at which there is 50% inhibition of specific binding (IR50). Then calculate the ratio of inhibition (Kandthe formula

,

where [ligand] means the concentration used tritium-labeled ligand and Kdmeans the equilibrium constant of dissociation of the ligand.

The ability of compounds of the formula (I) to interact with dopamine receptors is demonstrated in the following test, which determine in vitro the ability of compounds to inhibit the binding mechanic striatum of the brain of male rats from Charles One line CD in weight from 140 to 250 g of homogenized in ice buffer with a concentration of hydrochloride Tris 50 mmol/l (measured at a temperature of 25oC the pH of 7.7) and centrifuged for 10 minutes at 40000g. The precipitate is again suspended in a buffer of Tris hydrochloride and salts (buffer 50 mmol/l Tris hydrochloride, containing 120 mmol/l sodium chloride, 5 mmol/l KCl, 2 mmol/l of calcium chloride and 1 mmol/l of magnesium chloride with the addition of 6 mmol/l ascorbic acid and pH of 7.7, measured at a temperature of 25oC) and again centrifuged for 10 minutes at 40000g. Thus obtained residue stored at a temperature of -80oC. Before each experience the precipitate again suspicious in Tris-buffer with the addition of salt (2 mg wet tissue material 1 ml). Aliquot of this suspension with a volume of 720 μl, which is the equivalent of 1.44 mg wet tissue material in a test tube, add in tubes containing ligand (40 μl; concentration of 1 nmol/l) and Tris-buffer with the addition of salts (40 ál for total binding) or a solution of spiroperidol (40 ml with a concentration of 10 nmol/l for nonspecific binding) or 40 μl of a solution of the compounds in the same concentrations of 10-6mol/l or six concentrations ranging from 10-11up to 10-4mol/L. as a ligand is used trichinopoly (S)-sulpiride. The mixture is incubated at 4oC use the built in ice buffer containing Tris hydrochloride and dried. Sediment shook off filter in the cuvette, add scintillation fluid and leave them for about 20 hours before you start counting in scintillation spectrophotometry. The degree of displacement of specifically bound tritium-labeled ligand calculated as a percentage for a single concentration (10-6mol/l) of the investigated compounds. Curves eviction build for connections at a concentration of 10-6mol/l replace 50% or more of the specific binding of tritium-labeled ligand using to calculate the entire area of the concentrations of this compound. On this curve to determine the concentration at which there is 50% inhibition of specific binding (IR50). Then calculate the ratio of inhibition (Kandthe formula

,

where [ligand] means the concentration used tritium-labeled ligand and Kdmeans the equilibrium constant of dissociation of the ligand.

Values of Kiobtained in the above tests the binding of 5-HT1Aand/or1and/or2Aand/or2Dand/or D2the receptors for each of the final products by the following examples 1 to 29 are given in the table (see the end of the description).

-6mol/L.

"NO" in the column means that the substance in this test has not been studied.

The investigated compounds belong to the category of low-toxic substances.

Obtaining compounds of formula (I) is illustrated by the following examples which are given only as examples. The final product of each of these examples is characterized by one or more of the following methods: gas-liquid chromatography, high performance liquid chromatography, elemental analysis, spectroscopy, nuclear magnetic resonance and infrared spectroscopy.

Example 1

A mixture of 10 g of (R)-glycidyl-p-toluensulfonate, of 8.92 g of 5-chloro-2-hydroxybenzaldehyde and 7,87 g of potassium carbonate in 200 ml of dimethylformamide is heated at 60oC under stirring for 5 hours and leave after 18 hours. Add 200 ml of water and the resulting mixture was extracted with ethyl ether (3 x 150 ml). The combined ether extracts are washed with saturated aqueous sodium chloride (3 x 150 ml), dried over magnesium sulfate and the solvent is distilled off. The remainder, representing oil, purified using flash chromatography on silica gel, elwira a mixture of petroleum ether with so Kip. 40-6 output of 8.1 g of the product, contaminated by the impurity substance of unknown structure with a content of about 10%. Next, the product is used without further purification.

A mixture of 8.1 g obtained in the previous phase of the substance and 9.2 g of 85% 3-chlormadinone acid in 100 ml of methylene chloride is refluxed for 20 hours and then cooled in a bath of ice. The precipitate is filtered off and the filtrate is washed with 100 ml saturated aqueous solution of sodium metabisulfite, saturated aqueous sodium bicarbonate (2 x 100 ml), 100 ml of a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is distilled off and the residue 7.98 g (R)-5-chloro-2-(2,3-epoxypropoxy)performace in the form of an orange oil that has been contaminated by impurity substance of unknown structure in an amount of about 10%. The product is used further without additional purification.

In 20 ml of methanol in a nitrogen atmosphere dissolve 0.25 g of metallic sodium and added dropwise a solution of 2.0 g obtained in the previous phase of the substance in 30 ml of methanol. The resulting mixture was stirred for 1 hour, then 2 hours, refluxed and left for 18 hours at room temperature. The solvent is distilled off in vacuum, magnia. After removal of the solvent receive 1,67 g (S)-7-chloro-1,4-benzodioxan-2-ylcarbinol in the form of a yellow oil.

To 6.0 g obtained by the above method (S)-7-chloro-1,4-benzodioxan-2-ylcarbinol in 40 ml of pyridine was added 5.9 g of n-toluensulfonate and stirred for 4 hours. Add 250 mg of n-toluensulfonate and continue stirring for 2 hours, then add another 250 mg p-toluensulfonate and stirred for further 1 hour. The mixture is then poured into 200 ml of water and extracted with ethyl acetate (2 x 200 ml). The combined extracts are washed with hydrochloric acid (2 times 200 ml, the concentration of 2 M), saturated aqueous sodium bicarbonate (2 x 200 ml) and saturated aqueous sodium chloride (200 ml) and dried over magnesium sulfate. The solvent is distilled off in vacuum and the residue is crystallized from sulphuric ether. Get 7,00 g (R)-7-chloro-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate with so pl. 90-91oC.

At room temperature for 3 hours, stirred mixture of 170 g of 5-bromo-2-hydroxybenzaldehyde and 96.9 g of 4-(aminomethyl)of piperidine in 2.5 l of ethanol. The solvent is distilled off in vacuum, get 267 g of 4-bromo-2-[N-(4-piperidinylmethyl)iminomethyl] phenol in a solid yellow color with so pl. 35-38oC.

In a mixture of 30 ml of 1 M aqueous solution of potassium bisulfate and 5 ml technical methylated alcohol for 5 minutes, heated at a temperature of 70oC 4.0 g obtained in the previous phase of the substance, then 1 hour mix mass at room temperature. The mixture is washed with three portions of 50 ml of sulphuric ether, then add saturated aqueous solution of sodium carbonate to pH 11. The resulting mixture was extracted with methylene chloride (3 times 50 ml), the combined extracts dried over magnesium sulfate and the solvent is distilled off. Gain of 1.94 g (S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2 - ylmethyl)piperidine as a colourless oil.

A mixture of 1.0 g of the obtained in the previous phase of the substance and 0.55 g of pyrido[2,3-d][1,3]oxazin-2,4-(1H)-dione in 30 ml of 1,2-dimethoxyethane boiled for 16 hours with reverse huirua mixture of methylene chloride with methanol first in the ratio of 97:3, then 95:5. Fractions with the desired product are combined and the solvent is distilled off in vacuum. The residue is treated with ether and receive 0,80 g (S)-(-)-2-amino-N-{[1-(7-chloro-1,4-benzo-dioxane-2-ylmethyl)-4 - piperidyl]methyl}pyridine-3-carboxamide with so pl. 150-152oC []D- 50,65o(c = 0,918, in methanol).

Example 2

In 120 ml of dimethylformamide with stirring is heated for 5 hours at a temperature of 60oC 4.4 g of 2-chloro-6-hydroxybenzaldehyde, 5.0 g (R)-glycidyl-p-toluensulfonate and 3.9 g of potassium carbonate and leave at room temperature for 18 hours. The solvent is distilled off in vacuum, add 60 ml of water and extracted with a mixture of ether (3 times 100 ml). The combined extracts are dried over magnesium sulfate and the solvent is distilled off. The residue is purified using flash chromatography on silica gel, elwira first with a mixture of petroleum ether with so Kip. 60-80oC and methylene chloride in the ratio of 1:1, then with a mixture of methylene chloride with technical methylated alcohol in the ratio of 19:1. Containing the target product fractions are combined, the solvent is distilled off in vacuum and receive (R)-2-chloro-6-(2,3-epoxypropoxy)benzaldehyde, yield 2.8 g, so pl. 62-64oC.

A solution of 2.8 g obtained in the previous phase of the substance and 4.8 g of 85% 3-chloro who are still 4.8 g of 3-chlormadinone acid and continue heating for 6 hours. The reaction mass is washed with saturated aqueous sodium bicarbonate (3 times 200 ml) and dried over magnesium sulfate. The solvent is distilled off in vacuum and obtain 2.8 g of (R)-2-chloro-6-(2,3-epoxypropoxy)-phenyl-formate in the form of a solid yellow color.

A mixture of 20 ml of an aqueous solution of sodium hydroxide with a concentration of 2.5 M and 2.8 g obtained at the previous stage of the matter is refluxed under stirring for 1.5 hours. The cooled solution is extracted with methylene chloride (2 times 30 ml), the combined extracts dried over magnesium sulfate and the solvent is distilled off in vacuum. Obtain 1.63 g (S)-8-chloro-1,4-benzodioxan-2-ylcarbinol in the form of a yellow oil.

A solution of 1.7 g of n-toluensulfonate in 10 ml of pyridine are added dropwise to a solution of 1.63 g obtained in the previous phase of the substance in 30 ml of pyridine and stirred at room temperature for 4 hours, then 30 minutes heat the mixture at a temperature of 50oC. the Cooled mixture was poured into 50 ml of 5 M hydrochloric acid and extracted with methylene chloride (3 times 50 ml). The combined extracts are dried over magnesium sulfate and the solvent is distilled off in vacuum. Get 2,33 g (R)-8-chloro-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate the[2,3-d][1,3]oxazin-2,4-(1H)-dione in 30 ml of 1,2-dimethoxyethane stirred at room temperature for 3 hours. The solvent is distilled off in vacuo and purify the residue using flash chromatography on silica gel, elwira first methylene chloride and then with a mixture of methylene chloride with technical methylated alcohol in the ratio of 19:1. Containing the target product fractions are combined and the solvent is distilled off in vacuum, get 2-amino-N-[(1-tert.-butoxycarbonyl-4-piperidyl)methyl]pyridine-3-carboxamide, the output of 1.7 g

To a solution of 2.2 g obtained by analogy with the previous 2-amino-N-[(1-tert. -butoxycarbonyl-4-piperidyl)methyl] pyridine-3-carboxamide in 50 ml of methylene chloride was added 9 ml triperoxonane acid and stirred the reaction mass at room temperature for 1 hour. The solvent is distilled off in vacuum, get raw triptorelin 2-amino-N-(4-piperidyl-methyl)pyridine-3-carboxamide.

The mixture obtained substances, 2.3 g of (R)-8-chloro-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate and 3.6 g of potassium carbonate in 70 ml of acetonitrile is refluxed for 6 hours. The solvent is distilled in vacuo, to the residue was added 50 ml of water and extracted with a mixture of methylene chloride (2 times 30 ml). The combined organic phases are extracted with hydrochloric acid with a concentration of 2.5 M (2 times 30 ml), the combined e the combined organic phases are dried over magnesium sulfate and the solvent is distilled off in vacuum. The residue is purified using flash chromatography on silica gel, elwira mixture of methylene chloride and methanol in the ratio 9: 1. Containing the target product factions unite, the solvent is distilled off in vacuum and obtain 1.0 g (S)-2-amino-N-{[1-(8-chloro-1,4-benzodioxan-2 - ylmethyl)-4-piperidyl] methyl} pyridine-3-carboxamide with so pl. 62-70oC []D-35,47o(c = 0,888, in methanol).

Example 3

At a temperature of -78oC to a solution of 5.0 g of 3-fernicola in 100 ml of dry tetrahydrofuran with stirring was added a solution of utility in hexane (15,9 ml; 2.5 M) and continue stirring for 30 minutes, maintaining the temperature. Then add 3,1 ml of dry dimethylformamide and with stirring, allow the mixture to be heated within 1 hour to room temperature. Add 150 ml of water, the mixture extracted with ethyl acetate (3 x 100 ml), the combined extracts washed with 100 ml saturated aqueous solution of sodium chloride, dried over magnesium sulfate and the solvent is distilled off in vacuum. Distillation of the residue under reduced pressure to obtain 4.6 g of 2-fluoro-6-methoxybenzaldehyde in the form of oil, so Kip. 120oC when 10,66 mbar.

At a temperature of -78oC to a solution of 4.66 g obtained by the previous method 2-fluoro-6-metora in methylene chloride. Mixture is allowed to warm to room temperature, add 150 ml of water and extracted with methylene chloride (3 times 100 ml). The combined extracts are washed with 100 ml water, 100 ml saturated aqueous solution of sodium chloride and the solvent is distilled off. Distillation of the residue under reduced pressure to obtain 2.0 g of 2-fluoro-6-hydroxybenzaldehyde containing 7% source methoxypropanol in the form of impurities. The reaction product constituting the oil so Kip. 60oC at a pressure of 4.66 mbar, used in further transformations without further purification.

A mixture of 1.7 g obtained in the previous phase of matter, 2.1 g (R)-glycidyl-p-toluensulfonate and 1.68 g of potassium carbonate in 50 ml of dimethylformamide is stirred and heated at a temperature of 60oC for 5 hours. After stirring for 18 hours at room temperature the mixture was poured into 150 ml of water and extracted with ethyl acetate (3 times 100 ml). The combined extracts are washed with 100 ml saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is distilled off in a vacuum and ignore the remaining oil through a layer of silica gel using as solvent a mixture of ethyl acetate and petroleum ether with so Kip. 60-80oC in the ratio 1:2. tx2">

A mixture of 0.71 g obtained in the previous phase of the substance and 0.87 g of 85% 3-chlormadinone acid in 100 ml of methylene chloride is refluxed for three days, then add another 0.87 g of 3-chlormadinone acid and continue heating for 18 hours. The reaction was poured into 250 ml of a saturated aqueous solution of sodium carbonate, extracted with methylene chloride (3 times 100 ml), the combined extracts washed with 100 ml saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is distilled off in vacuum and receive (R)-2-(2,3-epoxypropoxy)-6-forperformance, yield 0.34 g of product in the form of butter.

In 100 ml of methanol is dissolved 0,89 g of metallic sodium and the resulting solution was added dropwise 6,56 g obtained by the previous method (R)-2-(2,3-epoxypropoxy)-6-forperformance in 100 ml of methanol. The mixture is stirred for 1 hour at room temperature and then boiled for 3 hours under reflux. After three days leave at room temperature and 4 hours refluxed. Distilled off in vacuum, the solvent, add 100 ml of water and extracted with a mixture of ethyl acetate (4 x 100 ml). The combined extracts washed with saturated Vodnye (S)-8-fluoro-1,4-benzodioxan-2-ylcarbinol, which is used in subsequent transformations without further purification.

To a solution of 3.85 g obtained by the above method the crude product in 50 ml of pyridine was added 4.1 g of p-toluensulfonate and stirred the mass for 18 hours before you pour it into 100 ml of 5 M hydrochloric acid. The mixture is extracted with ethyl acetate (3 times 100 ml). The combined extracts are washed with 100 ml saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is distilled off in vacuum and obtain 4.1 g of crude (R)-8-fluoro-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate in the form of a partially crystallized mass, which is used in subsequent transformations without further purification.

The mixture 7,21 g of crude 2-amino-N-(4-piperidinyl)pyridine-3-carboxamide, obtained by analogy with the procedure outlined in example 2, by the way, 4.15 g of potassium carbonate and 2 g of (R)-8-fluoro-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate in 100 ml of acetonitrile is refluxed for 16 hours. After cooling and filtering distilled off in vacuum, the solvent and purify the residue by chromatographytandem on silica gel, elwira only ethyl acetate. Containing the target product fractions are combined and evaporated in vacuo solvent. The(S)-(-)-2-amino-N-{[1-(8-fluoro-1,4-benzodioxan-2 - ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide, containing 0.5 mol of water and 0.15 moles of ethyl acetate, so pl. 115-116oC []D-39,09o(c = 0,967, in methanol).

Example 4

A mixture of 0.82 g of 1,4-benzodioxan-2-ylmethyl-p-toluensulfonate, 0,905 g trifenatate 2-amino-N-(4-piperidinyl)pyridine-3-carboxamide obtained in analogy with example 2, and 1.4 g of potassium carbonate in 50 ml of acetonitrile is refluxed under stirring for 6 hours. After cooling, the solvent is distilled off in vacuum, add to the residue in 60 ml of water and extracted the product of the reaction with methylene chloride (2 times 30 ml). The extracts are dried over magnesium sulfate and after removal of the solvent receive oil. This oil is purified using flash chromatography on silica gel, elwira mixture of methylene chloride and methanol initially in the ratio of 9:1 and then 1:1. Containing the target product fractions are combined to drive off the solvents in vacuo, and the residue oil from which adding 20 ml of an ethereal solution of maleic acid to obtain a solid white color. The solid is separated by filtration, washed with ether and distilled in vacuum solvent. Obtain 95 mg of salt 0.5 moles of maleic acid with 1 mol of 2-amino-N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl}piring (R)-glycidyl-p-toluensulfonate and of 7.25 g of potassium carbonate in 150 ml of anhydrous 1,2-dimethoxyethane with stirring, heated to 60oC for 5 hours, then leave at room temperature for 18 hours, within 8 hours heated at 60oC and leave to cool for 18 hours. The solvent is distilled off in vacuum and add to the residue in 250 ml of water and 250 ml of sulphuric ether, the mixture is filtered through celite, separate the ether layer is washed with water and dried over magnesium sulfate. The solvent is distilled and purify the residue using flash chromatography on silica gel, elwira a mixture of sulphuric ether with petroleum ether (so Kip. 40-60oC) in a ratio of 1:1. The appropriate fractions are combined and the solvent is distilled off. Get 8,91 g (R)-2-(2,3-epoxypropoxy)-5-methylbenzaldehyde in the form of butter.

The solution 8,91 g obtained at the previous stage of the product and of 19.6 g of 86% 3-chlormadinone acid in 250 ml of methylene chloride is stirred at room temperature for 18 hours. The solution is washed with diluted sodium bicarbonate solution (2 x 200 ml), then water (150 ml) and dried over magnesium sulfate. The solvent is distilled and used without additional purification in further transformations of thus obtained crude (R)-2-(2,3-epoxypropoxy)-5-methylphenylimino, yield 14.0 g, which still contains a number of 3-chlorobenzoyl is her stage crude product and heated with stirring at a temperature of 95-100oC for 1.5 hours. The cooled solution is extracted with methylene chloride (2 times 200 ml), the combined extracts dried over magnesium sulfate and the solvent is distilled off. The residue is distilled chromatographytandem on silica gel with elution with a mixture of sulphuric ether and petroleum ether etc Kip. 40-60oC in a 1:1 ratio. Containing the target product fractions are combined and the solvent is distilled off. Get 4.71 g (S)-7-methyl-1,4-benzodioxan-2-ylcarbinol in the form of butter.

To a solution of 4.7 g obtained in the previous phase of the substance in 50 ml of anhydrous pyridine is added dropwise a solution of 5.5 g of n-toluensulfonate in 50 ml of anhydrous pyridine and stirred the mixture for two hours at room temperature, and then for two hours at 50oC. the Mixture was poured on ice, acidified by addition of 5 M hydrochloric acid, then extracted with methylene chloride (2 times 200 ml), the combined extracts washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent is distilled and purified the residue by chromatographytandem on silica gel with elution with a mixture of sulphuric ether and petroleum ether etc Kip. 40-60oC in a 1:1 ratio. Containing the target product fractions are combined to suppress the CLASS="ptx2">

To a solution of 0.92 g obtained by analogy with example 2 2-amino-N-[(1-tert. -butoxycarbonyl-4-piperidyl)methyl] pyridine-3-carboxamide in 10 ml of methylene chloride was added 5 ml triperoxonane acid, stirred the mixture at room temperature for 2 hours and the solvent is distilled off in vacuum. Thus obtained crude triptorelin 2-amino-N-(4-piperidinyl)pyridine-3-carboxamide are dissolved in 10 ml of anhydrous acetonitrile and added first, 1.5 g of potassium carbonate and then a solution of 0.9 g (R)-7-methyl-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate in 5 ml of anhydrous acetonitrile. The mixture is refluxed for 18 hours, then poured into water and extracted with ethyl ether (2 times 100 ml). The combined extracts washed with water and then 1 M hydrochloric acid in 50 ml. of Acid extracts are washed with 100 ml of sulphuric ether, and then alkalinized with sodium bicarbonate and extracted with ethyl ether (2 times 100 ml). These extracts are combined, washed with water and dried over magnesium sulfate. The solvent is distilled and purify the residue using flash chromatography on silica gel, elwira mixture of methylene chloride and methanol in a ratio of 20:1. Containing the target product fractions are combined evaporated and get 0,solids with so pl. 143-146oC []D-46,23o(c = 0,53, in methanol).

Example 6

A mixture of 2.7 g of pyridine-2-carboxylic acid and 5.0 g of 4-(aminomethyl)-1-tert. -butoxycarbonylamino in 50 ml of dry xylene is boiled for 6 hours under reflux with a nozzle Dean-stark for the Department of water. Ohladivshegosya the solution is diluted with pribivaniem 150 ml of ethyl acetate, washed with 2 M aqueous solution of oxalic acid (2 times 100 ml), then 5 M aqueous solution of sodium bicarbonate (2 times 100 ml) and dried over magnesium sulfate. The solvent is distilled off in vacuum and gain of 2.53 g of N-[(1-tert.-butoxycarbonyl-4-piperidyl)methyl]pyridine-2-carboxamide in the form of butter.

To a solution of 2.5 g obtained at the previous stage of the product in 50 ml of methylene chloride was added 16 ml triperoxonane acid and stirred the mixture at room temperature for 2 hours. The solvent is distilled off in vacuo, dissolve the residue in 25 ml of acetonitrile, added 7.0 g of potassium carbonate and 2.4 g of 1,4-benzodioxan-2-ylmethyl-p-toluensulfonate and boil the mixture under reflux for 18 hours, then cooled and poured into water. The resulting mixture is extracted with methylene chloride (2 times 100 ml), the combined extracts washed with water and dried Irua with ethyl acetate. Containing the target product fractions are combined and the solvent is distilled off in vacuum. Get 2,43 g of N-{[1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl} pyridine-2-carboxamide as colorless solids with so pl. 95-97oC.

Example 7

A mixture of 6.65 g of 2-hydroxy-5-methoxybenzaldehyde, 10.0 g (R)-glycidyl-p-toluensulfonate and 6.1 g of potassium carbonate in 100 ml of dry dimethylformamide is heated with stirring at a temperature of 60oC for five hours. The solvent is distilled off in vacuum, add to the residue water and extracted with a mixture of ethyl ether (2 times 200 ml). The combined extracts washed with water and dried over magnesium sulfate. The solvent is distilled and purify the residue using flash chromatography on silica gel, elwira a mixture of sulphuric ether and petroleum ether with so Kip. 40-60oC in the ratio 2:1. Containing the target product factions unite, the solvent is distilled off and get to 7.25 g (R)-(2,3-epoxypropoxy)-5-methoxybenzaldehyde in the form of a clear oil.

A solution of 7.25 g obtained at the previous stage of the product and 14.85 g 86% 3-chlormadinone acid in 200 ml of methylene chloride is stirred at room temperature for 20 hours. Add 200 ml of water, separate the organic referred distillation of the solvent gain of 7.1 g (R)-2-(2,3-epoxypropoxy)-5-methoxyphenylacetate in the form of a clear oil.

A solution of 7.1 g obtained in the previous phase of the substance in 100 ml of 2.5 M aqueous sodium hydroxide solution is heated at a temperature of 95-100oC for 1.5 hours. Kladusa the mixture is extracted with ether (2 times 200 ml) and dry the combined extracts over magnesium sulfate. The solvent is distilled off and get to 3.64 g (S)-7-methoxy-1,4-benzodioxan-2-ylcarbinol in the form of a solid substance.

A solution of 3.54 g of n-toluensulfonate in 35 ml of dry pyridine was added to a solution of 3.64 g obtained in the previous phase of the substance in 60 ml of dry pyridine, and stirred the reaction mass for 18 hours at room temperature and poured on ice. The mixture is acidified by adding 5 M hydrochloric acid and extracted with 200 ml of methylene chloride. The combined extracts are dried over magnesium sulfate and evaporated the solvent, gain of 5.1 g (R)-7-methoxy-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate in the form of a colorless solid.

To a solution of 2.5 g obtained by analogy with example 2 2-amino-N-[(1-tert. -butoxycarbonyl-4-piperidyl)methyl] pyridine-3-carboxamide in 10 ml of methylene chloride was added 10 ml triperoxonane acid and stirred for 2 hours at room temperature. The solvent is distilled off in vacuo, dissolve the residue is e this boil the mixture under reflux for 20 hours. Kladusa mixture was poured into 200 ml of water and extracted it with methylene chloride (2 times 200 ml). The combined extracts are dried over magnesium sulfate, distilled off the solvent and purify the residue by chromatographytandem on silica gel, elwira first ethyl acetate and then a mixture of ethyl acetate with methanol in the ratio 9:1. Containing the target product fractions are combined and the solvent is distilled off in vacuum. Upon recrystallization of the residue from ethyl acetate get to 1.15 g (S)-2-amino-N-{[1-(7-methoxy-1,4-benzodioxan-2 - ylmethyl)-4-piperidyl] methyl} pyridine-3-carboxamide with so pl. 156-158oC []D-46,5o(c = worn: 0.505, in methanol).

Example 8

A mixture of 0.74 g of the quinoline-8-carboxylic acid and 10 ml of thionyl chloride is heated under stirring at a temperature of 50oC for 2 hours. The excess thionyl chloride is distilled off in vacuo, suspended residue in 20 ml of methylene chloride and add a solution of 0.98 g of 4-(aminomethyl)-1-tert.-butoxycarbonylamino in 10 ml of methylene chloride. The mixture is stirred for 4 hours at room temperature, poured into 50 ml of 1 M aqueous solution of sodium bicarbonate, the organic layer is separated, washed with 2 M aqueous solution of oxalic acid (2 times 50 ml) and dried over magnesium sulfate. After distillation, RA is solid.

To a solution of 1.1 g obtained by analogy with the previous stage N-[(1-tert. -butoxycarbonyl-4-piperidyl)methyl] quinoline-8-carboxamide in 20 ml of methylene chloride was added 5 ml triperoxonane acid and boil the mixture under reflux for 2 hours, then cooled and distilled off the solvent in vacuum. The residue is dissolved in 50 ml of acetonitrile, add 3.0 g of potassium carbonate and 0.92 g of 1,4-benzodioxan-2-ylmethyl-p-toluensulfonate and boil the mixture under reflux with stirring for 20 hours, then cooled and poured into 100 ml of water. The resulting mixture is extracted with methylene chloride (2 times 100 ml), the combined extracts washed with water and dried over magnesium sulfate. The solvent is distilled and purify the residue using flash chromatography on silica gel, elwira with ethyl acetate. Containing the target product fractions are combined and the solvent is distilled off in vacuum. The oil obtained is dissolved in 10 ml of methanol and add 0.4 g of fumaric acid. The solvent is distilled off in vacuum and obtain 1.12 g salt 2.5 moles of fumaric acid with 1 mol of N-{[1-(1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl}quinoline-8-carboxamide with so pl. 117-120oC (soften at 78oC).

Example 9

A mixture of 4.4 g of 2-Hargrave under stirring at a temperature of 60oC for five hours and leave to cool for about 18 hours. The solvent is distilled off in vacuum, add to the residue in 60 ml of water and extracted with a mixture of ethyl ether (3 times 100 ml). The combined extracts are dried over magnesium sulfate, the solvent is distilled off and clean the remaining oil via flash chromatography on silica gel, elwira first with a mixture of petroleum ether with so Kip. 40-60oC and methylene chloride in the ratio of 1: 1, then one with methylene chloride and then with a mixture of methylene chloride with technical methylated alcohol in the ratio of 19:1. Containing the target product factions unite, the solvent is distilled off and obtain 2.8 g of (R)-2-chloro-6-(2,3-epoxypropoxy)benzaldehyde in

the form of a pale yellow solid. From other fractions containing insufficiently purified product when you chromatographicaliy receive an additional 0.5 g of the substance.

A solution of 2.8 g obtained in the previous phase of the substance and 4.8 g 86% 3-chlormadinone acid in 200 ml of methylene chloride is stirred at the boil under reflux for 18 hours. Add 4.8 g 86% 3-chlormadinone acid and refluxed for 6 hours. The mixture was washed with saturated aqueous rastvorom,3 epoxypropoxy)-2-chlorpheniramine in a solid yellow color.

A solution of 2.8 g obtained in the previous phase of the substance in 20 ml of 2.5 M aqueous sodium hydroxide solution is refluxed under stirring for 1.5 hours. Kladusa the mixture is extracted with methylene chloride (2 times 30 ml) and dry the combined extracts over magnesium sulfate. The solvent is distilled off and obtain 1.63 g (S)-8-chloro-1,4-benzodioxan-2-ylcarbinol in a solid yellow color.

A solution of 3.15 g of n-toluensulfonate in 15 ml of dry pyridine was added to a solution of 3.32 g of the obtained similarly to the previous stage (S)-8-chloro-1,4-benzodioxan-2-ylcarbinol in 40 ml of dry pyridine, and stirred the reaction mass for 18 hours at room temperature and poured on ice. To the mixture add dilute hydrochloric acid to pH 4 and extracted with methylene chloride (2 times 200 ml). The combined extracts washed with saturated aqueous sodium chloride, dried over magnesium sulfate and the solvent is distilled off. Get to 5.21 g (R)-8-chloro-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate in the form of a pale yellow solid.

A mixture of 2.5 g obtained in the previous phase of matter, 1.42 g of N-benzylidene-1-(4-piperidyl)of methylamine and 2.0 g of potassium carbonate in 50 ml of anhydrous AC in 100 ml of water and extracted with methylene chloride (2 times 100 ml). The combined extracts washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent is distilled and separated the remainder of polar impurities by passing through a layer of silica gel, elwira ethyl ether. The solvent is distilled off and get partially purified (S)-N-benzylidene-1-[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methylamine in the form of pasty substances, the output 1,72,

In 100 ml of 1 M aqueous solution of potassium bisulfate for 2 hours, stirred at room temperature, 1.7 g obtained in the previous phase of the substance. The solution was washed with 100 ml of sulphuric ether, alkalinized 5 M aqueous solution of sodium hydroxide and extracted with methylene chloride (2 times 200 ml). The combined extracts are washed with 100 ml of water and dried over magnesium sulfate. After distillation of the solvent to obtain 0.65 g (S)-4-amino-methyl-1-(8-chloro-1,4-benzodioxan-2-ylmethyl)piperidine in the form of butter.

To a solution of 0.3 g of 2-methylpyridin-3-carboxylic acid in 20 ml of methylene chloride was added to 0.22 g of triethylamine and then 0.24 g of ethylchloride. The mixture is stirred for 18 hours at room temperature, then added dropwise a solution of 0.65 g obtained in the previous phase of the substance in 10 ml of methyl is water and dried over magnesium sulfate. The solvent is distilled and purify the residue using flash chromatography on silica gel, elwira mixture of methylene chloride and methanol in the ratio of 15:1. Containing the target product fractions are combined and the solvent is distilled off in vacuum. Get 0,37 g (S)-N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl} -2 - methylpyridin-3-carboxamide in the form of a solid substance with so pl. 147-149oC []D-37,9o(c = 1,0035, in methanol).

Example 10

To a solution of 20.9 g of 2'-hydroxy-5'-fortetienne in 20 ml of ethanol under stirring was added 38 g of epichlorohydrin, and then add a solution of 9.5 g of potassium hydroxide in a mixture of 30 ml of ethanol and 5 ml of water and continue stirring for 1 hour. The solvent is distilled off in vacuum and the residue is poured into water and extracted with ethyl acetate. The combined extracts washed with saturated aqueous sodium chloride, dried over magnesium sulfate, the solvent is distilled off in vacuo and purify the residue by chromatographytandem on silica gel, elwira a mixture of petroleum ether with so Kip. 40-60oC and first ethyl acetate in the ratio of 9:1, then 3:2. Containing the target product fractions are combined, the solvent is distilled off in vacuum and obtain 4.68 g of 5'-fluoro-2'-(2,3-epoxypropoxy)acetophenone in the form of Maslow 50 ml of chloroform for 18 hours refluxed. After cooling, the mass of her washed with saturated aqueous sodium bicarbonate, then saturated aqueous sodium chloride and the solvent is distilled off in vacuum. Get 4.44 g of crude 5-fluoro-2-(2,3-epoxypropoxy)phenylacetate, which is used further without additional purification.

Within 5 hours refluxed 4.0 g obtained in the previous phase of the substance in 7.3 ml of 10% aqueous sodium hydroxide solution. The cooled mixture was poured into water and extracted with ethyl acetate, the combined organic phases are washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The solvent is distilled off in vacuum and obtain 2.0 g of 7-fluoro-1,4-benzodioxan-2-ylcarbinol.

To a solution of 2.0 g obtained in the previous phase of the substance in 50 ml of pyridine was added 2.14 g of n-toluensulfonate, stirred the reaction mass for 18 hours at room temperature, poured into dilute hydrochloric acid with ice and extracted with ethyl acetate. The combined organic phases are washed with saturated aqueous sodium chloride and dried over magnesium sulfate. After removal of the solvent get contaminated by a significant number of the source is connected is of waldorfkoolid (2.14 g) in 50 ml of pyridine and similar to the previous process of the reaction mass. Get the crude product, which was purified using flash chromatography on silica gel, elwira mixture of methylene chloride and methanol in a ratio of 20:1. Containing the target product fractions are combined and the solvent is distilled off in vacuum. Get 0,78 g of 7-fluoro-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate in the form of a clear oil.

To a solution 0,78 g obtained by analogy with example 2 2-amino-N-[(1-tert.-butoxycarbonyl-4-piperidyl)methyl]pyridine-3 - carboxamide in 25 ml of methylene chloride was added 5 ml triperoxonane acid and stirred for 2 hours the mixture at room temperature. The solvent is distilled off in vacuum, the residue is dissolved in 20 ml of acetonitrile, add 3.0 g of potassium carbonate and a solution of 0.75 g obtained in the previous phase of the substance in 10 ml of acetonitrile and then boil the mixture under reflux with stirring for 18 hours. Kladusa the mixture is filtered and washed precipitate on the filter with 100 ml of methylene chloride. The filtrate and wash water are combined washed with water (2 times 100 ml) and dried over magnesium sulfate, the solvent is distilled off in vacuo and purify the residue using flash chromatography on silica gel, elwira mixture of methylene chloride with methanol in the ratio of 25:1. Containing the target about is methyl)-4 - piperidyl]methyl}pyridine-3-carboxamide as colorless solids with so pl. 141-143oC.

Example 11

To a solution of 2.5 g obtained by analogy with example 2 2-amino-N-[(1-tert. -butoxycarbonyl-4-piperidyl)methyl] pyridine-3-carboxamide in 50 ml of methylene chloride was added 10 ml triperoxonane acid and stirred for 2 hours at room temperature. The solvent is distilled off in vacuum, the residue is dissolved in 50 ml of acetonitrile, and to this solution was added 3 g of potassium carbonate and a solution of 2.5 g obtained on the International lined with the patent application N 95/07274 8-methoxy-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate in 20 ml of acetonitrile. The resulting suspension is refluxed under stirring for 20 hours, cooled, poured into 100 ml of water and extracted with methylene chloride (2 times 100 ml). The combined extracts washed with water, dried over magnesium sulfate, the solvent is distilled off and clean the remaining oil chromatographytandem on silica gel, elwira a mixture of ethyl acetate with methanol in the ratio 9:1. Containing the target product fractions are combined and the solvent is distilled off in vacuum. Obtain 1.55 g of 2-amino-N-{[1-(8-methoxy-1,4 - benzodioxan-2-ylmethyl)-4-piperidyl] methyl}pyridine-3-carboxamide in the form of MES with 0.4 mol of ethyl acetate and 0.5 mol of water. A colorless solid substance with the 2-carboxamide in 50 ml of methylene chloride was added 25 ml triperoxonane acid and stirred for 2 hours at room temperature. The solvent is distilled off in vacuum, the residue is dissolved in 50 ml of acetonitrile, add 25 g of potassium carbonate and 6.0 g obtained by analogy with example 1 (R)-7-chloro-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate and with stirring, boil the mixture under reflux for 24 hours. The cooled reaction mass is filtered, the solvent is distilled off in vacuum, the residue is dissolved in ethyl acetate, washed with water and dried with magnesium sulfate. The solvent is distilled off in vacuo and purify the residue using flash chromatography on silica gel, elwira first ethyl acetate and then a mixture of ethyl acetate with methanol in a ratio of 20: 1. Containing the target product fractions are combined and the solvent is distilled off in vacuum. Get 4.42 g (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl] methyl} pyridine-2-carboxamide with so pl. 110-112oC []D47,7o(c = 1,005, in methanol).

Example 13

The mixture is 60.0 g of 2-benzyloxy-3-hydroxybenzaldehyde, 60,0 g (R)-glycidyl-p-toluensulfonate and 74 g of potassium carbonate in 600 ml of dry dimethylformamide is stirred and heated at a temperature of 60oC for 14 hours. After cooling, the solvent is distilled off in vacuum, add 250 ml of water and extracted with a mixture of ethyl ether (2 times 200 ml), and the rija (2 times 500 ml), dried over magnesium sulfate, distilled off the solvent in vacuo and purify the residue using flash chromatography on silica gel. To do this, hold a preliminary adsorption on silica gel, pariva the solvent from the mixture of sorbent with a solution of the residue in methylene chloride, and then elute with a mixture of petroleum ether with so Kip. 40-60oC with ethyl ether in a ratio of 3:1. Containing the target product fractions are combined and the solvent is distilled off in vacuum, get 14,22 g (R)-2-benzyloxy-3-(2,3-epoxypropoxy)benzaldehyde. Additionally 33,37 g of the substance obtained after extraction was used for chromatography silica gel with ethyl ether (6 servings 500 ml). The combined extracts are concentrated to a volume of 500 ml, cooled overnight, filtered, washed the precipitate with a mixture of petroleum ether with so Kip. 40-60oC and sulphuric ether in the ratio 1:1. From the filtrate in vacuum distilled off the solvent and purify the residue using flash chromatography as described above. Thus receive a third portion of the mass 9,68 g of the target product. The overall yield of the substance is 57,27,

Combined fractions obtained in the previous phase of the product (57,27 g) of 2.75 g of 10% palladium on charcoal, at 81.4 ml cyclohexanethiol distilled off in vacuum, the residue is dissolved in 1 l of ethyl acetate and filtered through a layer of silica. Distilled off in vacuum, the solvent, the residue representing orange oil, dissolved in a mixture of 500 ml of ethanol, 500 ml of water and 55.2 ml of triethylamine. The mixture is boiled for 3 hours under reflux, after cooling, distilled ethanol in vacuum and extracted the remaining aqueous mixture with ethyl acetate (2 times 250 ml). The combined extracts washed with 1 M hydrochloric acid (2 times 250 ml), then with water and dried over magnesium sulfate. The solvent is distilled off in vacuo and purify the residue using flash chromatography on silica gel, elwira a mixture of petroleum ether with so Kip. 40-60oC and first ethyl acetate in the ratio 3:1, then 1:1 ratio. Containing the target product fractions are combined is distilled off in vacuum, the solvent and receive 8,02 g (S)-2-hydroxymethyl-8-formyl-1,4-benzodioxane.

A mixture of 2.0 g obtained in the previous phase of matter, 0.16 g of potassium hydroxide, 1.0 ml of hydrazine hydrate is added and 50 ml of ethylene glycol under stirring and refluxed for 1 hour. The excess hydrazine hydrate is added distilled off up until the temperature in the cube reaches 185oC. After that, continue boiling under reflux for another 2 0 ml of diluted hydrochloric acid, then 100 ml of saturated aqueous sodium bicarbonate solution and dried over magnesium sulfate. The solvent is distilled off in vacuo and purify the residue by chromatographytandem on silica gel, elwira mixture of methylene chloride with methanol in a ratio of 20:1. Obtain 0.9 g (S)-8-methyl-1,4-benzodioxan-2-ylcarbinol.

A solution of 0.96 g of n-toluensulfonate in 10 ml of dry pyridine was added to a cooled with ice to a solution of 0.9 g obtained at the previous stage of the substances in 40 ml of dry pyridine, the reaction mass is stirred, allow it to warm to room temperature for 18 hours and then poured it into ice. The mixture is acidified with diluted hydrochloric acid, extracted with ethyl ether (2 times 200 ml), the combined extracts washed with water and dried over magnesium sulfate. The solvent is distilled and purified the residue by chromatographytandem on silica gel, elwira a mixture of petroleum ether with so Kip. 40-60oC and sulphuric ether in the ratio of 4:1. Containing the target product fractions are combined and the solvent is distilled off. Gain of 0.91 g (R)-8-methyl-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate.

To a solution of 0.9 g of N-[(1-tert.-butoxycarbonyl-4 - piperidyl)methyl]pyridine-2-carboxamide in 30 ml of methylene chloride was added 5 ml tritc dissolved in 20 ml of acetonitrile, add 0,85 g obtained in the previous phase of the substance and 2.0 g of potassium carbonate and with stirring, boil the mixture under reflux for 24 hours. The cooled reaction mass is filtered, the filtrate is poured to 100 ml of methylene chloride and 100 ml of water, the organic layer washed with water and dried over magnesium sulfate. The solvent is distilled off in vacuo and purify the residue using flash chromatography on silica gel, elwira mixture of methylene chloride with methanol in the ratio 9: 1. Containing the target product fractions are combined and the solvent is distilled off. Get 0,42 g (S)-2-amino-N-{[1-(8-methyl-1,4 - benzodioxan-2-ylmethyl)-4-piperidyl] methyl} pyridine-3-carboxamide with so pl. 56-58oC []D(c = 0,869, in methanol).

Example 14

The mixture 19,75 g 6-methylpyridine-2,3-dicarboxylic acid and 51 ml of acetic anhydride is heated under stirring on an oil bath temperature of 110oC for 5 hours. The solvent is distilled off in vacuum and add a mixture of methylene chloride and sulphuric ether in the ratio 2:1, which is beset from the reaction mass of dark brown solid. The solution of this solid in methylene chloride is passed through a layer of silica gel, elute with methylene chloride, the solvent is distilled off and the floor is g obtained in the previous phase of the substance in 10 ml purified from ethanol chloroform under nitrogen atmosphere was added and 1.63 ml trimethylsilane. Formed suspension of the milk type, which becomes transparent after heating for 10 minutes. The reaction mass is allowed to stand for 1 hour at room temperature, 1 hour and heated at a temperature of 95-100oC, cool and add to 0.72 ml of ethanol, the Mixture is cooled in ice and a separate drop-down yellow precipitate. Obtain 1.2 g of 7-methylpurine[2,3-d][1,3] oxazin-2,4-(1H)-dione.

A mixture of 0.35 g obtained in the previous phase of the substance and of 0.58 g of [1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methylamine in 15 ml of 1,2-dimethoxyethane within 24 hours, stirred at room temperature. The solvent is distilled off in vacuo and purify the residue using flash chromatography on silica gel, elwira mixture of methylene chloride and methanol in the ratio 95:5. Containing the target product factions unite, the solvent is distilled off in vacuum and obtain 0.3 g (S)-2-amino-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl] methyl} -6-methylpyridin-3-carboxamide, so pl. 160-163oC []D-50,7o(c = being 0.036, in methanol).

Example 15

To a solution of 1.0 g of N-[(1-tert.-butoxycarbonyl-4 - piperidyl)methyl]pyridine-2-carboxamide in 50 ml of methylene chloride was added 8 ml triperoxonane acid and one hour and stirred at room temperature g (R)-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate and boil the mixture under reflux with stirring for 4 hours. The solvent is distilled in vacuo, to the residue poured 40 ml water and 40 ml of methylene chloride, the organic layer is extracted with 40 ml of 2 M hydrochloric acid, extracts of alkalinized 5 M aqueous solution of sodium hydroxide, extracted with methylene chloride (3 times 20 ml) and dry the combined extracts over magnesium sulfate. The solvent is distilled off in vacuo and purify the residue using flash chromatography on silica gel, elwira mixture of methylene chloride with technical methylated alcohol in the ratio of 9:1. Containing the target product fractions are combined and the solvent is distilled off in vacuum. Is oil, which is treated with a solution of maleic acid in sulphuric ether. The resulting salt is too hygroscopic, and therefore, it is transferred into a 2 M aqueous solution of sodium hydroxide and extracted with a mixture of methylene chloride. The extracts are dried over magnesium sulfate and the solvent is distilled off in vacuum. Obtain 0.18 g (S)-2-amino-N-{[1-(1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl}pyridine-3-carboxamide as a colourless foam with so pl. 102-105oC []D-29,36o(c = 0,6845, in methanol).

Example 16

A solution of 3.1 g of 2H-thieno[3,2-d][1,3]-oxazin-2,4(1H)-dione and 3.9 g of 4-aminomethyl-1-tert. -butoxycarbonylamino in 50 ml of 1,2-dimethoxyethane of paramashiva the ash-chromatography on silica gel, elwira ethyl ether. Containing the target product fractions are combined and evaporated in vacuo solvent. Get to 2.57 g of 3-amino-N-(1-tert.-butoxycarbonyl-4-piperidinyl)thiophene-2-carboxamide as a colorless solid.

To a suspension of 2.0 g obtained at the previous stage of the product in methylene chloride was added 10 ml triperoxonane acid and stirred for 18 hours at room temperature. The solvent is distilled off in vacuum, the residue is dissolved in 100 ml of acetonitrile, added 3.1 g of potassium carbonate, 2 ml of triethylamine and 1.8 g of 1,4-benzodioxan-2-ylmethyl-p-toluensulfonate. With stirring, boil the mixture under reflux for 6 hours, add 4 ml of triethylamine and continue boiling under reflux for a further 6 hours. The cooled reaction mass is filtered, the solvent is distilled off in vacuum, the residue is dissolved in methylene chloride, the organic layer washed with water (2 times 50 ml) and dried over magnesium sulfate. The solvent is distilled off in vacuo and purify the residue using flash chromatography on silica gel, elwira first methylene chloride and then with a mixture of methylene chloride with methylated technical alcohol in the ratio of 19:1. Containing the target product fractions which have 0,22 g 3-amino-N-{[1-(1,4-benzodioxan-2-ylmethyl)-4 - piperidyl] methyl} thiophene-2-carboxamide in the form of a solid substance with so pl. 144-146oC.

Example 17

To a suspension of 3.8 g of 3-amino-N-(1-tert.-butoxycarbonyl-4 - piperidinyl)thiophene-2-carboxamide in 100 ml of methylene chloride was added 5 ml triperoxonane acid and stirred for 18 hours at room temperature. The solvent is distilled off in vacuum, the residue is dissolved in 100 ml of acetonitrile, add to this a solution of 1.4 g of potassium carbonate, and 4 ml of triethylamine and 3.5 g of (R)-7-chloro-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate. With stirring, boil the mixture under reflux for three days, the cooled reaction mass is filtered, the solvent is distilled off in vacuo, the residue, representing the oil, dissolved in 100 ml of methylene chloride, washed with water (2 times 50 ml) and dried over magnesium sulfate. The solvent is distilled off in vacuo and purify the residue using flash chromatography on silica gel, elwira first methylene chloride and then with a mixture of methylene chloride with methylated technical alcohol in the ratio of 19:1. Containing the target product fractions are combined and the solvent is distilled off in vacuum. Get a yellowish solid, which when handling sulphuric ether get 100 mg of (S)-3-amino-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl]methyl}thiophene-2-carboxamide >/P>Example 18

To suspension and 0.46 g of 2-methylpyridin-3-carboxylic acid in methylene chloride add to 0.47 ml of triethylamine and cooled the mixture in water with ice. With stirring, add 0.33 ml of ethylchloride and with stirring, allow the reaction mass to warm to room temperature and left for 18 hours. Then add 1.0 g (S)-4-aminomethyl-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)of piperidine and continue stirring for 24 hours. The solvent is distilled off and treat the residue with water, the reaction product is separated by filtration and purified using flash chromatography on silica gel, elwira a mixture of ethyl acetate with methanol first in the ratio 3:1, then 2:1 and then 1: 1. Containing the target product factions unite, the solvent is distilled off in vacuum and get enough pure product. It again sent to flash chromatography on silica gel, elwira first with a mixture of methylene chloride and methanol in the ratio of 10:1, then with a mixture of methylene chloride, methanol and triethylamine in the ratio of 18: 1: 1. In the process of evaporation in vacuum of the corresponding fractions obtain 330 mg of (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl}-2 - methylpyridin-3-carboxamide as colorless solids with so pl. 133-136oC []the s and 2.7 ml of 1-methylmorpholine in 100 ml of methylene chloride under nitrogen atmosphere at a temperature of -5oC added dropwise with stirring, 2.4 ml of ethylchloride. After 10 minutes, add a solution of 5.0 g of N-benzylidene-1-(4-piperidyl)of methylamine in 25 ml of methylene chloride, and continue stirring at -5oC for 2 hours, then stirred for 18 hours at room temperature. Distilled off in vacuum, the solvent, the residue is stirred with 1 M solution of potassium bisulfate volume of 250 ml for 5 hours. The mixture is filtered and the filtrate is washed with methylene chloride (2 times 150 ml), then alkalinized water 5 M sodium hydroxide solution and extracted with methylene chloride (3 x 150 ml). The combined extracts are dried over magnesium sulfate, the solvent is distilled off and get to 4.81 g of 4-aminomethyl-1-(2-chloro-3-pyridylcarbonyl)piperidine, contaminated with a small amount of 1-methylmorpholine. This substance is used in the following transformation without further purification.

A mixture of 4.75 g obtained in the previous phase of the crude product, 12,93 g of potassium carbonate and 6,64 g (R)-7-chloro-1,4-benzodioxan-2-ylmethyl-p-toolswhat in 100 ml of acetonitrile with stirring and refluxed for 48 hours. The mixture is cooled, filtered and the solvent is distilled off in vacuum. Get the oil cleaned by f is the wearing of 25: 1. Containing the target product factions unite, the solvent is distilled off in vacuum and get 2,49 g ethanol MES (S)-4-[N-(7-chloro-1,4-benzodioxan-2-ylmethyl)aminomethyl]-1-(2 - chloronicotinoyl)piperidine in the form of koukopoulos mass.

The mixture 2,49 g obtained in the previous phase of the substance, 10 ml technical methylated alcohol, 100 ml of an aqueous solution of ammonia with a density of 0.88 g/cm3and 0.5 g of copper powder is heated at a temperature of 150oC for 18 hours in an apparatus for working under pressure. After cooling, add 400 ml of methylene chloride and 400 ml of water, the mixture is filtered through Selita, washed with water (4 x 50 ml), then methylene chloride (4 times 50 ml). Passed through the filter layers separated, the aqueous layer was extracted with 400 ml of methylene chloride, the combined organic layers are dried over magnesium sulfate. After removal of the solvent receive oil red, which is purified using flash chromatography on silica gel, elwira mixture of methylene chloride and ethanol in the ratio of 9: 1. Containing the target product fractions are combined is distilled off in vacuum, the solvent and receive the red koucouloutou mass. It was dissolved in 20 ml of hot ethanol and added a hot solution of 340 mg of fumaric KIS the cue MES salt of 1-(2-aminonicotinic)-4-[N-(7-chloro-1,4-benzodioxan-2 - ylmethyl)aminomethyl]piperidine, containing 1.6 moles of fumaric acid, and 0.7 mol of water and 0.7 mol of ethanol, the yield of 0.85 g, so pl. 110oC (decomp.).

Example 20

In nitrogen atmosphere for 43 hours with stirring is heated at a temperature of 80oC 25 g of 2-fluoro-6-triftormetilfullerenov in 866 ml of 0.5 M aqueous solution of sodium hydroxide. The cooled solution was washed with ether (2 x 350 ml), acidified with concentrated hydrochloric acid and then extracted with ethyl ether (2 times 500 ml). The combined extracts are dried over magnesium sulfate, the solvent is distilled off in vacuo and purify the residue using flash chromatography on silica gel, elwira mixture of methylene chloride with methanol in the ratio 95:5. Containing the target product fractions are combined and evaporated in vacuo solvent. Obtain 6.2 g of 2-hydroxy-6-triftormetilfullerenov in the form of butter.

The mixture 5,95 g obtained in the previous phase of matter, 6,05 g (R)-glycidyl-p-toluensulfonate and 4.3 g of potassium carbonate in 150 ml of dimethylformamide with stirring and heated for 24 hours at 60oC. the Cooled solution is poured into 600 ml of ice water, extracted with ether (3 x 300 ml), the combined extracts washed with saturated aqueous sodium chloride (2 times pakistanization which 30 ml of sulphuric ether gain of 5.4 g of (R)-2-(2,3-epoxypropoxy)-6-triftormetilfullerenov in the form of a solid substance.

A mixture of 5.4 g obtained in the previous phase of the substance and at 13.84 g 57% 3-chlormadinone acid in 300 ml of chloroform with stirring and refluxed for 18 hours. After that, leave at room temperature for three days and then poured into 400 ml of saturated aqueous sodium bicarbonate solution. The mixture is extracted with 200 ml of methylene chloride, the organic phase is washed with saturated aqueous sodium bicarbonate (3 x 400 ml), dried over magnesium sulfate and evaporated in vacuum solvent. Obtain crude 2-(2,3-epoxypropoxy)-6-triftormetilfosfinov in a solid yellow color, the yield of 6.26 g

A solution of 6.26 g obtained in the previous phase of the substance in 75 ml of methanol are added dropwise to a solution of sodium methylate prepared by dissolving 0,69 g of metallic sodium in 75 ml of methanol, stirred mass at room temperature for 18 hours and leave it for 24 hours at room temperature. The solvent is distilled off in vacuum and transfer the residue in 300 ml of water. The mixture is extracted with ethyl acetate (3 x 200 ml), the combined extracts dried over magnesium sulfate, the solvent is distilled off in vacuum and get a brown oil, which is purified in a 1:1 ratio. Containing the target product factions unite, the solvent is distilled off in vacuum, gain of 1.80 g (S)-8-trifluoromethyl-1,4-benzodioxan-2-ylcarbinol in the form of a yellow oil.

To a solution of 1.26 g obtained at the previous stage of the product in 50 ml of dry pyridine at a temperature of -10oC in an atmosphere of nitrogen was added 1.29 g of n-toluensulfonate and allow the reaction mass to warm to room temperature, stirring her 18 hours. Add 0.7 g of n-toluensulfonate and continue stirring for three days, then pour the mixture into 200 ml of diluted hydrochloric acid, extracted with ethyl acetate (2 x 300 ml), the combined extracts washed with diluted hydrochloric acid (2 times 200 ml), dried over magnesium sulfate and the solvent is distilled off in vacuum. Obtain 1.27 g of crude (R)-8-trifluoromethyl-1,4-benzodioxan-2 - ylmethyl-p-toluensulfonate.

To a solution of 1.5 g obtained by analogy with example 2 2-amino-N-[(1-tert.-butoxycarbonyl-4-piperidyl)methyl]pyridine-3 - carboxamide in 15 ml of methylene chloride was added 15 ml triperoxonane acid and stirred for 3 hours at room temperature. The solvent is distilled off in vacuum, the residue is dissolved in 100 ml of acetonitrile, add 4.5 g of potassium carbonate and 1.27 g Pius 72 hours. The cooled solution is filtered, the solid residue washed with 200 ml of ethyl acetate, the filtrate is evaporated in vacuo and purify the residue using flash chromatography on silica gel, elwira a mixture of ethyl acetate with methanol in the ratio of 3: 1. Containing the target product fractions are combined and the solvent is distilled off in vacuum. Obtain 870 mg of (S)-2-amino-N-{ [1-(8-trifluoromethyl-1,4 - benzodioxan-2-ylmethyl)-4-piperidyl]methyl} pyridine-3-carboxamide as colorless solids with so pl. 101-103oC []D-16,2oC, (c = 0,56, methylene chloride).

Example 21

The mixture 68.75 kilopascals g of 5-bromo-2-hydroxybenzaldehyde, 65 g (R)-glycidyl-p-toluensulfonate and of 47.3 g of potassium carbonate in 1.5 liters of dry dimethylformamide under stirring heated for 24 hours at 60oC in nitrogen atmosphere, then cooled and left at room temperature for 24 hours. The reaction was poured into 2 l of water, extracted with ether (4 x 400 ml), the combined extracts washed with saturated aqueous sodium chloride (4 x 500 ml), dried over magnesium sulfate and the solvent is distilled off in vacuum. Get the oil, which is purified using flash chromatography on silica gel, elwira a mixture of petroleum ether with so Kip. 60-80oC and ethyl acetate shoots which when processed 150 ml of sulphuric ether is allocated to 43.3 g (R)-5-bromo-2-(2,3-epoxypropoxy)benzaldehyde as a colorless solid.

A solution of 42.6 g obtained in the previous phase of the substance and 69.4 g 86% 3-chlormadinone acid in 1.5 l of chloroform is refluxed for 24 hours. After that, leave at room temperature for 48 hours and washed with water (5 times 300 ml), 600 ml of saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride (2 times 500 ml), then dried over magnesium sulfate and evaporated in vacuum solvent. Get crude (R)-5-bromo-2-(2,3-epoxypropoxy)performed in the form of a yellow oil, which crystallizes upon standing, the output of 47.8 g

A solution of 47.8 g obtained in the previous phase of the crude substance in 400 ml of methanol are added dropwise to a solution of sodium methylate prepared by dissolving 5.3 g of metallic sodium in 400 ml of methanol, stirred mass at room temperature for 18 hours, evaporated in vacuum, the solvent and add to the residue water (800 ml). The mixture is extracted with ethyl acetate (4 x 500 ml), the combined extracts dried over magnesium sulfate, the solvent is distilled off in vacuum and get a brown oil, which was purified using flash chromatography on silica gel, elwira a mixture of petroleum ether with so Kip. 60-80

To a cooled with ice to a solution of 7.0 g obtained at the previous stage of the product in 50 ml of pyridine is added 7,63 g p-toluensulfonate and stirred for 20 hours at room temperature, then poured onto a mixture of 200 ml of 1 M hydrochloric acid, extracted with ethyl acetate (3 x 200 ml), the combined extracts washed with 200 ml of 1M hydrochloric acid, dried over magnesium sulfate and the solvent is distilled off in vacuum. Upon recrystallization of the residue from a mixture of sulphuric ether and ethyl acetate (3:1) gain of 6.9 g (R)-7-bromo-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate in the form of a colorless solid.

To a solution of 2.5 g obtained by analogy with example 2 2-amino-N-[(1-tert.-butoxycarbonyl-4-piperidyl)methyl]pyridine-3 - carboxamide in 17 ml of methylene chloride was added 17 ml triperoxonane acid and stirred for 2 hours at room temperature. The solvent is distilled off in vacuum, the residue is dissolved in 170 ml of acetonitrile, added 7.6 g of potassium carbonate and of 2.21 g obtained at the previous stage of the product and boil the mixture under reflux for 24 hours and then leave for 36 hours at room temperature. The reaction was poured the M hydrochloric acid (2 x 300 ml), the combined acidic extracts alkalinized by addition of 200 ml of 5 M aqueous sodium hydroxide solution and extracted with a mixture of ethyl acetate (3 x 200 ml). These combined extracts dried over magnesium sulfate and the solvent is distilled off in vacuum. Obtain 1.3 g of colorless solid, which is recrystallized from 7 ml of a mixture of ethyl acetate with petroleum ether with so Kip. 40-60oC in the ratio of 5:1. Get 0,82 g (S)-2-amino-N-{[1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl] methyl} pyridine-3-carboxamide with so pl. 158-160oC []D-25,5o(c = 0.79, which, in methylene chloride).

Example 22

Solution a 3.87 g of the hydrochloride of the acid chloride pyridine-3-carboxylic acid in 100 ml of methylene chloride was added to a suspension of 5.0 g of 4-(aminomethyl)-1-tert.-butoxycarbonylmethylene and 10 g of potassium carbonate in 100 ml of methylene chloride. The mixture is stirred at room temperature for 2 hours and poured into 500 ml of water. The organic layer was washed with 250 ml of water, dried over magnesium sulfate and the solvent is distilled off. The residue is purified using flash chromatography on silica gel, elwira mixture of methylene chloride and methanol in a ratio of 20:1. Containing the target product fractions are combined is distilled off in vacuum, the solvent and receive 3,22 g of N-[thief 0.95 g obtained in the previous phase of the substance in 25 ml of methylene chloride was added 10 ml triperoxonane acid and stirred for 2 hours. The solvent is distilled off in vacuum, the residue is dissolved in 25 ml of dry acetonitrile, add 5.0 g of potassium carbonate and 1.0 g of (R)-7-chloro-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate and with stirring, boil the mixture under reflux for 24 hours. The cooled reaction mass is filtered, the filtrate is evaporated in vacuo and purify the residue using flash chromatography on silica gel, elwira mixture of methylene chloride with methanol in a ratio of 20: 1. Containing the target product fractions are combined and evaporated the solvent in vacuo. Obtain 0.75 g (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4 - piperidyl] methyl} pyridine-3-carboxamide with so pl. 172-4oC []D-48o(c = 0,9945, in methanol).

Example 23

To a solution of 1.51 g obtained by analogy with example 8 N-[(1-tert.-butoxycarbonyl-4-piperidyl)methyl] quinoline-8-carboxamide in 50 ml of methylene chloride was added 10 ml triperoxonane acid and stirred for 2 hours. The solvent is distilled off in vacuum, the residue is dissolved in 30 ml of dry acetonitrile, add 3.0 g of potassium carbonate and 1.51 g (R)-7-chloro-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate and with stirring, boil the mixture under reflux for 24 hours. The reaction mass is filtered, will tow magnesium sulfate. The solvent is distilled off in vacuo and purify the residue using flash chromatography on silica gel, elwira first with methylene chloride, then with a mixture of methylene chloride with methanol in the ratio of 100:1 and then 20:1. Containing the target product fractions are combined and evaporated the solvent in vacuo. Get 1,33 g (S)-N-{ [1-(7-chloro-1,4 - benzodioxan-2-ylmethyl)-4-piperidyl]methyl}quinoline-8-carboxamide with so pl. 51-54oC []D-39,7o(c = 0,7230, in methanol).

Example 24

To a solution of 1.56 g of N-[(1-tert.-butoxycarbonyl-4 - piperidyl)methyl]pyridine-3-carboxamide in 25 ml of methylene chloride was added 10 ml triperoxonane acid and stirred for 2 hours. The solvent is distilled off in vacuum, the residue is dissolved in 10 ml of dry acetonitrile, add 5.0 g of potassium carbonate, and then a solution of 1.7 g of (R)-7-chloro-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate in 15 ml of dry acetonitrile, and with stirring, boil the mixture under reflux for 6 hours. The cooled reaction was poured into water and extracted with methylene chloride (2 times 100 ml), the combined extracts washed with 100 ml saturated aqueous solution of sodium chloride and dried with magnesium sulfate. The solvent is distilled off in vacuo and purify the residue using flash is the product fractions are combined and evaporated the solvent in vacuo. Obtain 1.04 g (S)-N-{[1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl} pyridine-3 - carboxamide with so pl. 52-54oC []D-35,3o(c = 1,024, in methanol).

Example 25

A mixture of 0.57 g (S)-4-aminomethyl-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)of piperidine and 0.27 g of 6-methylpyridin-2-carboxylic acid in 50 ml of xylene is refluxed with a nozzle Dean-stark for the Department of water for 6 hours. From the cooled reaction mass is distilled off in vacuum, the solvent and dissolve the residue in 100 ml of methylene chloride. The solution was washed with water (2 times 100 ml), dried over magnesium sulfate and the solvent is distilled off. The residue is purified using flash chromatography on silica gel, elwira mixture of methylene chloride with methanol in a ratio of 20:1. Containing the target product fractions are combined and evaporated the solvent in vacuo. Obtain 0.15 g of oil which was dissolved in 10 ml of methanol and added 0.04 g of fumaric acid. The solvent is distilled off in vacuum and get to 0.19 g of difumarat (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-6 - methylpyridin-2-carboxamide in the form of a solid beige color with so pl. 81-3oC []D-39,6o(c = 0,389, in methanol).

Example 26

To 50 ml of thionyl chloride are separate then the research Institute for 2 hours. After cooling, distilled in vacuum the excess thionyl chloride, dissolve the residue in 100 ml of methylene chloride and add a solution of 7.3 g of 4-aminomethyl-1-tert. -butoxycarbonylamino in 100 ml of methylene chloride. The reaction mass is stirred for 4 hours at room temperature, poured into 200 ml water, the organic phase is washed with 100 ml of water, aqueous 2 M solution of oxalic acid (2 times 100 ml), 1 M hydrochloric acid (100 ml), 2 M aqueous sodium bicarbonate solution (2 x 150 ml), then with water and dried over magnesium sulfate. The solvent is distilled off in vacuo and purify the residue using flash chromatography on silica gel, elwira a mixture of ethyl acetate with petroleum ether with so Kip. 60-80oC in a 1:1 ratio. Containing the target product fractions are combined and evaporated the solvent in vacuo. Get to 2.06 g of N-[(1-tert. -butoxycarbonyl-4 - piperidyl)methyl]-2-methoxypyridine-3-carboxamide.

To a solution of 2.06 g obtained in the previous phase of the substance in 25 ml of methylene chloride was added 10 ml triperoxonane acid and stirred for 2.5 hours. The solvent is distilled off in vacuum, the residue is dissolved in 50 ml of dry acetonitrile, added 12.0 g of potassium carbonate, and then a solution of 2.33 g (R)-7-chloro-1,4-benzodioxan-2-ylmethyl-p-is a group of 24 hours. The cooled reaction mass is filtered and the solvent is distilled off in vacuum. The residue is dissolved in 200 ml of methylene chloride, the solution washed with water (2 times 200 ml) and dried with magnesium sulfate. The solvent is distilled off in vacuum and the residue purified using flash chromatography on silica gel, elwira mixture of methylene chloride with methanol in a ratio of 20:1. Containing the target product fractions are combined and evaporated the solvent in vacuo. Get 1,21 g hydrochloric salt (to 0.6 mol of HCl) (S)-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl} -2 - methoxypyridine-3-carboxamide in the form of a hydrate with 0.9 mole of water so pl. 72 -75oC []D-47,3o(c = 0,226, in methanol).

Example 27

From 55,6 ml of 2.5 M solution of utility in hexane at room temperature distilled off in vacuum, the solvent, the resulting viscous oil in a nitrogen atmosphere cooled to -78oC and slowly added pre-cooled solution of 15.6 g of tert.-the butyl potassium in 280 ml of tetrahydrofuran. Then added dropwise to 20.0 g of 3,4-diferente, maintaining the reaction temperature below -60oC. the Resulting brown solution is stirred for 2 hours at a temperature of -78oC add to 10.8 ml of dry dimethylformamide, to give the reaction is a mixture of ethyl ether (3 x 300 ml), the combined extracts are washed with aqueous 40% solution of lithium chloride (100 ml), 200 ml of water and dried over magnesium sulfate. After removal of the solvent receive 23,0 g of an orange oil, which was purified using flash chromatography on silica gel, elwira a mixture of petroleum ether with so Kip. 40-60oC and ethyl acetate in the ratio of 9:1. Containing the target product fractions are combined and evaporated the solvent in vacuo. Receive 2,3-debtor-6-methoxybenzaldehyde in a solid yellow color, output, 10,1

To a solution of 10.4 g of 2,3-debtor-6-methoxybenzaldehyde obtained as described above, in 100 ml of methylene chloride under nitrogen atmosphere at a temperature below -20oC with stirring 197,4 ml of 1 M solution tribromide boron in methylene chloride. The resulting solution allowed to warm to room temperature and leave it overnight. Then add 200 ml of methanol and then 100 ml of water and heat the mixture at 40oC for 2 hours. The aqueous layer was separated and extracted it with methylene chloride (2 x 300 ml), the combined organic phases are extracted with 1 M aqueous sodium hydroxide solution (3 x 400 ml) and acidified with a combined extracts concentrated hydrochloric acid. After this the Ute in the vacuum of the solvent. Get to 8.12 g of 2,3-debtor-6-hydroxybenzaldehyde in the form of a solid substance.

A mixture of 8.1 g obtained in the previous phase of matter, 11.4 g (R)-glycidyl-p-toluensulfonate and 7,03 g of potassium carbonate in 250 ml of dimethylformamide with stirring and heated for three days at a temperature of 60oC in nitrogen atmosphere. Poured 300 ml of water, extracted with a mixture of ether (3 x 400 ml), the combined extracts washed with 40% aqueous solution of lithium chloride (200 ml), 200 ml of water and dried over magnesium sulfate. The solvent is distilled off, the resulting oil is added a mixture of sulphuric ether and petroleum ether etc Kip. 40-60oC in the ratio 1:1 and the resulting solution was decanted orange and dark brown oil. Distilled in vacuum the solvent from the orange solution and obtain 9.0 g of (R)-2,3-debtor-6-(2,3-epoxypropoxy)benzaldehyde in the form of butter.

A solution of 9.0 g obtained in the previous phase of the substance and 26,47 g 57% 3-chlormadinone acid in 500 ml of chloroform is refluxed for 18 hours. Add 300 ml of a saturated aqueous solution of sodium bicarbonate and 500 ml of methylene chloride, the organic layer is separated and washed with saturated aqueous sodium bicarbonate (3 times 300 Mitel and get crude (R)-2,3-debtor-6-(2,3-epoxypropoxy)performed in the form of solids, the output of 11.9 g

A solution of 11.9 g obtained in the previous phase of the crude substance in 140 ml of methanol are added dropwise in a nitrogen atmosphere with stirring to a solution of sodium methylate prepared by dissolving 1.22 g of metallic sodium in 140 ml of methanol, the reaction mass leave at room temperature for 18 hours, evaporated in vacuum, the solvent and add to the residue 500 ml of water. The mixture is extracted with ethyl acetate (3 x 400 ml), the combined extracts washed with saturated aqueous sodium chloride (300 ml), dried over magnesium sulfate and the solvent is distilled off in vacuum. The residue is purified using flash chromatography on silica gel, elwira a mixture of ethyl acetate and petroleum ether with so Kip. 40-60oC in a 1:1 ratio. Containing the target product factions unite, the solvent is distilled off in vacuum, obtain 0.7 g (S)-7,8-debtor-1,4-benzodioxan-2-ylcarbinol in the form of butter.

At a temperature of 0oC to a solution of 0.7 g obtained in the previous phase of the substance and 0.52 g of 4-dimethylaminopyridine in 10 ml of methylene chloride under nitrogen atmosphere was added dropwise a solution of 0.74 g of n-toluensulfonate in 10 ml of methylene chloride. The resulting solution was stirred for 2 hours at a temperature of 0oC C the United extracts are dried over magnesium sulfate and the solvent is distilled off. Obtain 1.1 g of (R)-7,8-debtor-1,4-benzodioxan-2-ylmethyl-p-toluensulfonate in the form of a yellow oil, which crystallizes upon standing.

To a solution of 1.48 g obtained by analogy with example 2 2-amino-N-[(1-tert. -butoxycarbonyl-4-piperidyl)methyl] pyridine-3-carboxamide in 10 ml of methylene chloride was added 10 ml triperoxonane acid and stirred for 5 hours at room temperature. The solvent is distilled off in vacuo, the residue was added to a mixture of 4.3 g of potassium carbonate, 10 mg of potassium iodide and 1.1 g obtained at the previous stage of the product in 100 ml of acetonitrile. This mixture while stirring and refluxed for 16 hours. From the cooled mixture is distilled off in vacuum, the solvent is added to the residue, 300 ml of a saturated aqueous solution of sodium bicarbonate and 300 ml of ethyl acetate. The aqueous layer was additionally extracted with ethyl acetate (3 x 300 ml), the combined organic phases are washed with 400 ml of a saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent is distilled off in vacuo and purify the residue using flash chromatography on silica gel, elwira a mixture of ethyl acetate and methanol in the ratio 9:1. Containing the target product fractions are combined and evaporated in a vacuum process is de MES with 0.2 mol of ethyl acetate. Pale yellow solid, yield of 0.47 g, so pl. 127-128oC []D-25,8o(c = 0,80, methylene chloride).

Example 28

A mixture of 8.2 g of carbonate pyragollole, 5.0 g (S)-epichlorohydrin and 0.2 ml of dry pyridine in 50 ml of dry ethyl acetate is refluxed for 2 hours. The solvent is distilled off in vacuum, add 30 ml of water and boil the mixture under reflux for 30 minutes, then added dropwise a solution of 10 g of potassium hydroxide in 20 ml of water and boil the mixture under reflux in nitrogen atmosphere for 30 minutes. The cooled mixture is poured 100 ml of water, acidified with 5 M hydrochloric acid and extracted with ethyl acetate (3 x 200 ml). The combined extracts washed with water (2 times 100 ml) and dried over magnesium sulfate. The solvent is distilled off in vacuo and purify the residue by chromatographytandem on silica gel, elwira first with a mixture of ethyl acetate and petroleum ether with so Kip. 60-80oC in the ratio 1:1, then one acetate. Containing the target product fractions are combined evaporated in vacuum, the solvent and obtain 0.8 g (S)-8-hydroxy-1,4-benzodioxan-2-ylcarbinol.

To a solution of 0.8 g of the obtained in the previous phase of the substance and 0.64 g of 4-(dimethylamino)pyridine in 50 ml of reed triftoratsetata. Mixture is allowed to warm to room temperature and continue stirring for 18 hours, then washed with 100 ml of water and dried over magnesium sulfate. The solvent is distilled off in vacuo and purify the residue using flash chromatography on silica gel, elwira with methylene chloride. Containing the target product fractions are combined and the solvent is distilled off in vacuum. Obtain 1.10 g of (R)-8-tripterocalyx-1,4 - benzodioxan-2-ylmethyl-triftoratsetata.

To a solution of 0.9 g obtained by analogy with example 2 2-amino-N-[(1-tert. -butoxycarbonyl-4-piperidyl)methyl] pyridine-3-carboxamide in 25 ml of methylene chloride was added 5 ml triperoxonane acid and stirred for 2 hours at room temperature. The solvent is distilled off in vacuum, the residue is dissolved in 25 ml of acetonitrile, was added 5.0 g of potassium carbonate and then a solution of 1.03 g obtained at the previous stage of the product in 10 ml of dry acetonitrile. This mixture while stirring and refluxed for 1.5 hours, cooled, filtered and distilled in a vacuum solvent. The residue is dissolved in 100 ml of methylene chloride, washed with water (2 times 100 ml) and dried over magnesium sulfate. The solvent is distilled off in vacuo and purify the residue by using preoduct fractions are combined and evaporated in vacuo solvent. Receive (S)-2-amino-N-{[1-(8-tripterocalyx-1,4 - benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide in the form of a colorless solid, yield 0.17 g, so pl. 52-55oC []D-21,9o(c = 0,2925, in methanol).

Example 29

To a suspension of 5.0 g of pyridine-2-carboxylic acid in 75 ml of methylene chloride at room temperature under stirring in nitrogen atmosphere add to 6.58 g of N, N'-carbonyldiimidazole and continue stirring until gas evolution stops (about two hours), then add to 8.2 g of N-benzylidene-1-(4-piperidyl)of methylamine and stirred the reaction mass for 18 hours. Evaporated the solvent and obtain a viscous yellow oil which is stirred with 200 ml of 1 M aqueous solution of potassium bisulfate for 18 hours. The mixture is washed with methylene chloride (2 times 250 ml), with 5 M aqueous sodium hydroxide solution set in it is pH 14 and then extracted with methylene chloride (3 times 250 ml). The combined extracts are dried over magnesium sulfate and the solvent is distilled off in vacuum. Receive a 4-(aminomethyl)-1-(2-pyridylcarbonyl)piperidine as a viscous yellow oil, yield of 5.2 g

A mixture of 3.0 g obtained in the previous phase of matter, a 4.86 g (R)-7-chloro-1,4-bentabet refrigerator with stirring for 18 hours. The mixture is cooled, filtered, the solvent is distilled off in vacuo and purify the residue using flash chromatography on silica gel with a mixture of methylene chloride and technical methylated alcohol in a ratio of 20:1. Containing the target product fractions are combined is distilled off in vacuum, the solvent, the remaining viscous yellow oil (2,87 g) dissolved in 10 ml of hot ethanol and mixed with a solution of 0,76 g of fumaric acid in 10 ml of hot ethanol. The solvent is distilled off in vacuum and the residue is treated with 250 ml of sulphuric ether. Get MES salt of 4-[N-(7-chloro-1,4-benzodioxan-2-ylmethyl)aminomethyl] -1-(2 - pyridylcarbonyl)piperidine, in which the mol Foundation necessary to 1.2 mol of fumaric acid, 0.5 moles of water of hydration and 0.4 mol of ethanol solvate. A solid substance, so pl. around 55oC (decomp.), []D-42,9o(c = 0,8135, in methanol).

Examples of dosage forms proposed composition.

a) Capsules

Upon receipt of the capsules grind and mixed 10 parts by weight of active substance of the formula (I) and 240 parts by weight of lactose. The mixture is filled capsules of hard gelatin so that each capsule contained an equal part taken doses of active compounds.

b) Tablets

Pill is/BR> Corn starch - 22

Polyvinylpyrrolidone - 10

Magnesium stearate - 3

The active substance, lactose and part of the starch is ground, mixed and granularit resultant mixture with a solution of polyvinylpyrrolidone in ethanol. The dry granulate is mixed with magnesium stearate and the remainder of the starch. This mixture komprimiert on the machine for tabletting so that each tablet contained an equal part taken doses of active compounds.

in) Tablets with intersolubility coating, disintegrating in the intestine

Tablets produced as described above in paragraph (b) method. In order tablet was dissolved in the intestine, they are the usual way to apply the coating using a solution of ethanol-methylene chloride in a ratio of 1: 1, containing 20% phthalate cellulose acetate and 3% diethylphthalate.

g) Suppositories

For preparing suppositories 1300 weight parts of triglyceride bases for suppositories evenly distribute 100 parts by weight of active substance of the formula (I) and form from this mixture suppositories, each containing a therapeutically effective amount of the active ingredient.

1. Derivatives of amides of carboxylic kisli,

where g denotes the number 0, 1, 2, 3 or 4;

R1means (a) a halogen atom, b) unsubstituted or substituted by one or more atoms of halogen alkyl group with the number of carbon atoms and from one to three, in) CNS group with the number of carbon atoms and from one to three, d) unsubstituted or substituted by one or more halogen atoms alkylsulfonates with the number of carbon atoms and from one to three, and denoted by R1the substituents can be identical or different, provided that g means the number 2, 3 or 4;

U mean alkylenes chain with the number of carbon atoms and from one to three;

Q means biradical formula IIa, or IIB

< / BR>
where

V represents a relationship or alkilinity chain with the number of carbon atoms and from one to three;

X means alkylenes chain with the number of carbon atoms is 0, 1 or 2;

X' means alkylenes chain with the number of carbon atoms one to four, provided that the total number of carbon atoms in X and X' is equal to three or four;

T means the acyl residue of heterocyclic carboxylic acids, heterocyclic fragment (Het) which is represented by the following residues: 2-, 3 - or 4-pyridyl, 2 - or 3-thienyl, 2-, 3-, 4 - or 8-chinoline, each m) alkyl group with the number of carbon atoms and from one to three, C) CNS group with the number of carbon atoms and from one to three, g) alkylthiol group with the number of carbon atoms and from one to three, d) amino group, (e) 1-pyrrolidinyl group.

2. Derivatives of amides of carboxylic acids with heterocyclic substituents of General formula I on p. 1, where g denotes the number 0, 1 or 2; R1means a halogen atom (e.g. fluorine atom, chlorine or bromine), an unsubstituted or substituted by one or more atoms of halogen alkyl group with the number of carbon atoms and from one to three, CNS group with the number of carbon atoms and from one to three, unsubstituted or substituted by one or more halogen atoms alkylsulfonates with the number of carbon atoms and from one to three; U represents a methylene group; Q means a group of formula IIa or IIB; V means a methylene group; X and X' both mean the ethylene group, and a heterocyclic fragment presents 2-, 3 - or 4-pyridium, 8-hyalinella or 2-tanila, and each of these residues can be unsubstituted or substituted by one or more substituents from the group comprising methyl, methoxy group, halogen atom, methylthiophenyl group, 1-pyrrolidinyl group and amino group.

3. Derivatives of carboxylic amides is redstapler 2-pyridium, 3-pyridium, 8-hyalinella or 2-tanila, and each of these residues can be unsubstituted or substituted by amino, methyl, metaxylene, 1-pyrrolidino, methylthiophenol group or a bromine atom.

4. Derivatives of amides of carboxylic acids with heterocyclic substituents of General formula I on PP.1 to 3, in which the heterocyclic fragment presents 2-pyridium or 3-pyridium and each of these residues can be unsubstituted or substituted amino group.

5. Derivatives of amides of carboxylic acids with heterocyclic substituents of General formula I on p. 1, selected from the group including:

2-amino-N-{ [1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{ [1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{ [1-(8-fluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{ [1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl}pyridine-3-carboxamide;

2-amino-N-{[1-(7-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

N-{ [1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl}pyridine-2-carboxamide;

2-amino-N-{ [1-(7-methoxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl} pyridine-3-cardoxan-2-ylmethyl)-4-piperidyl]methyl}-2-methylpyridin-3-carboxamide;

2-amino-N-{[1-(7-fluoro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{ [1-(8-methoxy-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl} pyridine-3-carboxamide;

N-{ [1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-2-carboxamide;

2-amino-N-{[1-(8-methyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

2-amino-N-{ [1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl}-6-methylpyridin-3-carboxamide;

3-amino-N-{ [1-(1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}thiophene-2-carboxamide;

3-amino-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}thiophene-2-carboxamide;

N-{ [1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}-2-methylpyridin-3-carboxamide;

1-(2-aminonicotinic)-4-[N-(7-chloro-1,4-benzodioxan-2-ylmethyl)aminomethyl]piperidine;

2-amino-N-{ [1-(8-trifluoromethyl-1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl}pyridine-3-carboxamide;

2-amino-N-{ [1-(7-bromo-1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl} pyridine-3-carboxamide;

N-{ [1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

N-{ [1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}quinoline-8-carboxamide;

N-{ [1-(8-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}p;

N-{ [1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl] methyl}2-methoxypyridine-3-carboxamide;

2-amino-N-{[1-(7,8-debtor-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl} pyridine-3-carboxamide;

2-amino-N-{ [1-(8-tripterocalyx-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}pyridine-3-carboxamide;

4-[N-(7-chloro-1,4-benzodioxan-2-ylmethyl)aminomethyl] -1-(2-pyridylcarbonyl)piperidine;

as well as pharmaceutically acceptable salts of these compounds in the form of individual enantiomers, racemates, or other mixtures of enantiomers.

6. The composition having the ability of inhibitors of 5-HT1Aand/or 1and/or2Aand/or2Dand/or D2receptors containing a therapeutically effective amount of the compounds of formula I on p. 1, or its salt together with a pharmaceutically acceptable diluent or carrier.

 

Same patents:

The invention relates to novel di - and trivalent small selectin inhibitors of formula II, where X is selected from the group comprising-CN, -(CH2)nCO2H, -(CH2)nCONHOH, -O(CH2)m-CO2H, -(CH2)nCOZ, -(CH2)nZ, -CH(CO2H), (CH2)mCO2H,

-OH; Y = -(CH2)f; R1, R2independently selected from the group including hydrogen, lower alkyl, halogen, -OZ, -NO2, -NH2; R3selected from the group including hydrogen, lower alkyl, hydroxy-lower alkyl, amino-lower alkyl, lower alkyl-carboxylic acid; f = 1 - 6; n = 0 to 2; b = 0 - 2; m = 1 to 3; Z represents lower alkyl, phenyl, or their pharmaceutically acceptable salts, esters, Amida

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The invention relates to new N-substituted piperidinylmethyl f-ly I, their N-oxide forms, isomers, and salts, where R1- halogen, C1-6alkylsulfonamides And divalent radical-CH2-CH2; -CH2-CH2-CH2- or-CH=CH-; R2is hydrogen or C1-6alkyloxy; L is a radical of formula-Alk-R4, -Alk-OR5, -Alk-NR6R7; Alk-C1-12alcander; R4is hydrogen, cyano, C1-6alkylsulphonyl,1-6allyloxycarbonyl, etc

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Neurotropic drug // 2156621
The invention relates to medicine and can be used for the correction of impaired immune homeostasis accompanied by changes psychosomatic functions and/or biological reactions, through a multifaceted impact on the integrative activity of the brain

The invention relates to compounds of General formula I

< / BR>
in which X represents a hydrogen atom or halogen, (C1-C3)alkyl group, one or two (C1-C3)alkoxy group, or triptorelin group, Y is a hydrogen atom or halogen, (C1-C3)alkyl or (C1-C3)alkoxygroup, R represents a hydroxy group, a methoxy group, or a group of the General formula NR2R3in which R2and R3each independently represents a hydrogen atom, (C1-C4)alkyl group, 2-methoxyaniline group, 3-methoxyaniline group, 3-aminopropyl group, group 2-(dimethylamino)ethyl group, 3-(dimethylamino)propyl or 2-piperidine-2-retil, or R2and R3form together with the nitrogen atom to which they are connected, morpholine, pyrolidine or pieperazinove ring which may have in position 4 Deputy in the form of a methyl group or groups (1,1-dimethylmethoxy)carbonyl, in the form of free bases or salts formed by the addition of acid

The invention relates to nitrogen-containing compounds that may constitute the active ingredient of the pharmaceutical composition active as an antagonist neirokinina, and more particularly to a derivative of arylpyrimidines and pharmaceutical compositions containing these compounds
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