Derivatives triazolo-(pyrrolo-thieno - or furano-)-azepine having antiallergic activity, the method of their production, intermediate for their production, pharmaceutical composition and method of reception

 

(57) Abstract:

Derivatives triazole-(pyrrolo-, thieno - or furano-)-asarina General formula I, their pharmaceutically acceptable salt additive and stereochemical isomers, where each dashed line independently represents an optional bond, E - G is a bivalent radical of formula-X-C(R1)=CH - or-CH=C(R2)-, where X denotes O, S or NR3, R1and R2is a hydrogen atom, a C1-4-alkyl, hydroxy-(C1-4-alkyl or formyl; R3- N or C1-6-alkyl,- =D - is a bivalent radical of formula C(R4)= or-N=C(R5)-, where R4and R5is hydrogen; (L - H, C1-6-alkyl, possibly substituted by hydroxyl, alkoxyl, hydroxycarbonyl, aryl or arroceros, C3-6alkenyl, substituted aryl, each aryl denotes a phenyl group possibly substituted with halogen or alkoxygroup, or L is a radical of formula-Alk-Het3where Alk - C1-4-alcander, Het3radical of formula (a), where A-Z represents -(CH2)4- or-CH=CH-CH=CH-. The compounds of formula I possess anti-allergic activity. 13 C. and 4 h.p. f-crystals.

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The present invention relates to thiazole derivative of (pyrrole, Tien or furano)azepine, shows leptogastrinae connection which are useful as antagonists of platelet activating factor, antihistamines and/or anti-inflammatory means.

In J. Med. Chem. Vol.26, 974-980 (1983) describes some 1-methyl-4 - piperidinylidene-9-substituted derivatives pyrrolo [2,1-b]benzazepine with neuroleptic properties.

In international patent publication WO 92/06981 are substituted imidazobenzodiazepine and imidazobenzodiazepine with anti-allergic and anti-inflammatory activity.

The present invention is the creation of new derivatives triazole (pyrrolo, thieno or furano)azepino having antiallergic activity that allows you to create pharmaceutical compositions on their basis for the treatment of allergies.

This goal is achieved by the new compounds of General formula I

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their pharmaceutically acceptable additive salts and their stereochemical isomeric forms,

where each dashed line independently represents an optional bond,

-E-C - denotes a bivalent radical of the formula

-X-C(R1)=CH- (a-1),

or formulas

-CH=C(R2)-X- (a-2);

X denotes O, S or NR3where R3is a hydrogen atom, (C11-C4)-alkyl, halogen atom, Attila group, substituted hydroxycarbonyl group or (C1-C4)-alkoxycarbonyl group, hydroxy(C1-C4)-alkyl, formyl group, hydroxycarbonyl group or hydroxycarbonyl (C4-C4)-alkyl;

- =D - bivalent radical of the formula

-C(R4)=N- (b-1),

or formulas

N=C(R5)- (b-2);

R4denotes a hydrogen atom, (C1-C4)-alkyl, atenolol group, substituted hydroxycarbonyl group or (C1-C4)-alkoxycarbonyl group, (C1-C4)-alkyl, substituted hydroxycarbonyl group or (C1-C4)-alkoxycarbonyl group, hydroxy(C1-C1)-alkyl, formyl group or hydroxycarbonyl group;

R5denotes a hydrogen atom, (C1-C4)-alkyl, atenolol group, substituted hydroxycarbonyl group or (C1-C4)-alkoxycarbonyl group, (C1-C4)-alkyl, substituted hydroxycarbonyl group or (C1-C4)-alkoxycarbonyl group, hydroxy(C1-C4)-alkyl, formyl group, hydroxycarbonyl group, phenyl or pyridinyl group

L oboznachaet the C group, includes a hydroxyl group, (C1-C4)-alkyloxy, hydroxycarbonyl group, (C1-C4)-allyloxycarbonyl group, (C1-C4-allyloxycarbonyl ( C1-C4)-alkoxygroup, hydroxycarbonyl (C1-C4)-alkyloxy, (C1-C4)-alkylaminocarbonyl, (C1-C4)-alkylaminocarbonyl, aryl or alloctype, (C1-C6)-alkyl, substituted as hydrocolloid group and arroceros, (C3-C6)-alkenylphenol group, (C3-C6)-alkenylphenol group, substituted aryl, each aryl denotes a phenyl group or a phenyl group substituted by a halogen atom, a cyano, a hydroxyl group, (C1-C4)-alkyl, (C1-C4-alkyloxy or aminocarbonyl group, or L represents a radical of the formula

-Alk-Y-Het1(C-1),

-Alk-NH-CO-Het2(C-2) or

-Alk-Het3(c-3),

where Alk - (C1-C4)-alcander;

Y is O, S or NH;

Het1, Het2or Het3each denote furanyl, thienyl, oxazolyl, thiazolyl or imidazolyl, each of which is optionally substituted by one or two (C1-C4)-alkyl Deputy who, hydroxycarbonyl group, (C1-C4)-allyloxycarbonyl group, or one or two (C1-C4)-alkyl substituents, thiadiazolyl or oxadiazolyl, optionally substituted amino group or (C1-C4)-alkyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl, each of which is optionally substituted C1-C4)-alkyl, (C1-C4-alkyloxy, amino group, hydroxyl group or halogen atom, Het3can also denote 4,5 - dihydro-5-oxo-1H-tetrazolyl, substituted (C1-C4)-alkyl, 2-oxo-3-oxazolidinyl, 2,3-dihydro-2-oxo-1H-benzimidazole-1-yl or a radical of the formula

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where A-Z represents S-CH=CH, S-CH2-CH2S-CH2-CH2-CH2CH=CH-CH=CH or CH2-CH2-CH2-CH2.

In the above definitions, halogen denotes fluorine, chlorine, bromine or iodine, (C1-C4)-alkyl refers to saturated hydrocarbon radicals with a straight or branched chain, containing from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl, (C1-C6-denotes alkyl (C1-C4)-alkyl radicals mentioned previously, and/SUB>)-alkenyl is a hydrocarbon radical straight or branched chain, containing one double bond and from 3 to 6 carbon atoms, such as, for example, 2 - propenyl, 2-butenyl, 3-butenyl, 2-methyl-3-propenyl, 2-pentenyl, 3 - pentenyl, 3,3-dimethyl-2-propenyl, hexenyl etc., (C1-C4)-alcander denotes a bivalent hydrocarbon radical with a straight or branched chain, containing from 1 to 4 carbon atoms, such as, for example, methylene, 1,1-ethandiol, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol etc.

Compounds of the present invention differ structurally from the compounds known from the technical field, so that the Central 7-membered ring always contains a nitrogen atom in the condensed triazole ring, and the fact that they have favorable anti-allergic activity.

The aforementioned term "pharmaceutically acceptable salt accession" means a non-toxic, therapeutically active salts of adhesion, which may form the compound of formula I. the compounds of formula I, having the properties of the base, can be converted in the usual manner into the corresponding therapeutically active non-toxic acid additive salt by treating the base with, the example halogenation acid, in particular hydrochloric acid, Hydrobromic acid, etc., sulfuric acid, nitric acid, phosphoric acid, etc. or organic acids such as, for example, acetic acid, propanoic acid, hydroxyestra acid, 2-hydroxypropanoic acid, 2 - oxopropanoic acid, tanginoa acid, proportionaly acid, batandjieva acid, (Z)-2-batandjieva acid, (E)-2-batandjieva acid, 2-hydroxybutanone acid, 2,3-dihydroxybutanedioate acid, 2-hydroxy-1,2,3 - propanetricarboxylate acid, methanesulfonate, econsultation, 4-methoxybenzenesulfonamide, benzosulfimide, cyclohexanesulfamic acid, 2-hydroxybenzoic acid, 4-amino-2-hydroxybenzoic acid, etc.

The compounds of formula I having acidic properties, can be similarly converted into the corresponding therapeutically active, non-toxic salts joining the Foundation. Examples of such salts joining bases are, for example, salts of sodium, potassium, calcium and salts with pharmaceutically acceptable amines such as ammonia, alkylamines followed, Benjamin, N-methyl-D-glucamine, geranamine, amino acids, in particular Argut to form compounds of the formula I, in particular hydrates, alcoholate, etc.,

The above term "stereochemical isomeric form" defines the possible different isomeric as well as conformational forms which can form compounds of formula I. Unless specifically specified or not specified, it is the chemical name denotes the mixture of all possible stereochemical and conformational isomeric forms, the mixture containing all diastereomers, enantiomers and/or conformers of the main molecular structure. Assumes that all stereochemical isomeric forms of the compounds of formula I in pure form or in mixture with each other are included in the scope of claims of the present invention.

Some compounds of the present invention may exist in different tautomeric forms, and assumes that all such tautomeric forms are included in the scope of claims of the present invention.

An interesting group of compounds of formula (I) are compounds of formula (I), where R1, R2, R4and R5represent a hydrogen atom.

Another interesting group of compounds of formula I are those in which L - (C1-C4)-alkyl.

Most of predpochtitel the lo[1,5-a]azepin,

10-(1-methyl-4-piperidinylidene)-10H-thieno[3,2-d-1,2,4 - triazolo[4,3]azepin and

6,10-dihydro-10-(1-methyl-4-piperidinylidene)- 5H-thieno[2,3-d] [1,2,4] triazolo[1,5-a] azepin, their stereoisomers and their pharmaceutically acceptable acid additive salt.

The following paragraphs describe the different ways of preparing compounds of formula I. C in order to simplify the structural formulas of the compounds of formula I and the intermediates involved in their synthesis, triazolo(pyrrolo, thieno or furano)againby fragment denoted by the symbol T:

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The compounds of formula I can be obtained by cyclization of the alcohol of formula II or ketone of formula III

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The above cyclization reaction is conveniently carried out, treating the intermediate compound of formula II or III of the corresponding acid, getting reaktsionnosposobnykh intermediate compound, which cyclizes with the formation of compounds of formula I. Suitable acids are, for example, strong acids, in particular supercolony, such as methanesulfonate, triftoratsetata, triperoxonane acid, methansulfonate/boron TRIFLUORIDE, hydrogen fluoride/boron TRIFLUORIDE, or a Lewis acid such as aluminum chloride, tin chloride (IV etc., trimethylsily the s only those compounds of formula I, in which the fragment of L is stable in the reaction conditions. In the case of superacids reaction is mainly carried out in the excess of acid, in the case of a Lewis acid such as, for example, tin chloride IV, the reaction is conveniently carried out in an inert solvent, such as, for example, dialogprompt hydrocarbon, in particular dichloromethane, 1,2-dichloroethane, etc.

In the above and below methods the reaction mixture is produced using techniques known from the field of engineering, and the reaction product is isolated and, if necessary, subjected to further purification.

The compounds of formula I, where the Central ring of the tricyclic fragment does not contain an optional bond, can be obtained by cyclization of an intermediate compound of formula IV

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In the formula IV and below, W represents a suitable leaving group, such as, for example, halogen atom, in particular chlorine, bromine, etc., or sulfonyloxy group, such as, for example, methanesulfonate group, 4-methylbenzenesulfonate group, etc.

The above cyclization reaction is conveniently carried out in an inert solvent, such as, for example, aromatic hydrocarbons, alkanol, ketone, simple ether, dipolar Aper, carbonate, bicarbonate, alkoxide, hydride, hydroxide or oxide of an alkaline or alkaline-earth metal, or an organic base may be used to bind the acid that is released during the reaction. In some cases it is convenient to add iodide, mainly iodide of an alkali metal. The increase of temperature and mixing can accelerate the reaction.

Otherwise the compounds of formula I, where between piperidinium and triazolo(pyrrolo, thieno or furano)azepino fragment has a double bond, i.e. compounds represented by formula I-a can be obtained by dehydration of the alcohol of formula V or VI

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The above dehydration reaction is conveniently performed using conventional dehydrating agents in accordance with techniques known from the field of technology. Suitable dehydrating agents are, for example, acids, in particular sulfuric acid, phosphoric acid, hydrochloric acid, methanesulfonate, carboxylic acid, in particular acetic acid, triperoxonane acid and mixtures of these acids; anhydrides, in particular acetic anhydride, pathiakis phosphorus, etc. , other suitable agents, in particular chloride zinc chloride thionyl, apirat TRIFLUORIDE of ratatsii optional can be carried out in an inert solvent, such as, for example, halogenated hydrocarbons, in particular dichloromethane. In some cases, this dehydration reaction may require heating of the reaction mixture, in particular the boiling point. Again in accordance with the above methods can be obtained only those compounds of formula I-a, where L is stable in the above reaction conditions. It should be noted that when carrying out the last reaction using intermediate compound V, where the dashed bond does not denote an optional connection, in some cases, can be obtained from compounds containing a double bond in the tricyclic fragment and a simple link, which is a bridge of communication between the tricyclic fragment and piperidine:

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The compounds of formula I, where L represents (C1-C6)-alkyl, i.e. compounds represented by formula I-b can be transformed in various ways in the compounds of formula I, where L is a hydrogen atom, i.e. compounds represented by formula I-c. The first method involves dealkylation - carbonylation of compounds of formula I-b with (C1-C4)-alkylphosphonate and subsequent hydrolysis of the compounds of formula VII-a

The
is th compound I-b reagent in an appropriate solvent and in the presence of a suitable base. Suitable solvents are, for example, aromatic hydrocarbons, in particular methylbenzol, xylene, chlorobenzene, ethers, in particular 1,2-dimethoxymethane, and similar solvents. Suitable bases are, for example, carbonates, bicarbonates, hydroxides of alkaline or alkaline earth metals or organic bases, such as N,N-diethylethanamine, N-(1-methylethyl)-2 - propanamine, etc. of Compounds of formula VII-a hydrolyzing in an acidic or alkaline medium, using conventional methods. For example, you can use concentrated acids, such as Hydrobromic, hydrochloric and sulfuric acid, or bases, such as caustic soda, caustic potash, etc., in water, alkanol or a mixture of water/alkanol. Suitable alkanols are methanol, ethanol, 2-propanol, etc. C in order to accelerate the reaction, the reaction mixture is predominantly heated, in particular to the boiling point.

The compounds of formula I-b can also be transformed directly into compounds of the formula l-C under stirring and by heating them with an alpha-halogen (C1- C4-alkylchlorosilanes in a suitable solvent, such as, for example, halogenated hydrocarbons, in particular dichloromethane, aromatics is lastnosti methanol, ethanol, 2-propanol, optionally in the presence of a base, such as, for example, carbonate, bicarbonate, hydroxide of alkali or alkaline land metal or amine, in particular. N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine etc.

The compounds of formula I-c can also be obtained by dibenzylammonium the compounds of formula I-d catalytic hydrogenation in the presence of hydrogen and an appropriate catalyst in an inert solvent

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A suitable catalyst in the above reaction is, for example, platinum on charcoal, palladium on coal, etc. in Suitable inert solvent for the specified reaction dibenzylamine is, for example, alcohols, in particular methanol, ethanol, 2-propanol, etc., esters, in particular ethyl acetate, etc., acid, in particular acetic acid, etc.

The compounds of formula I, where L is different from the hydrogen atom, i.e. compounds represented by formula I-e , a L denoted by L1can be obtained by N-alkylation of compounds of formula I-c reagent of formula L4- W (VIII)

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The above reaction of N-alkylation is conveniently carried out in an inert solvent, such as, for example, aromatic hydrocarbons, alkanol, ketone, dipolar aprotic Rast is such as for example, carbonate, bicarbonate, alkoxide, hydride, hydroxide or oxide of an alkaline or alkaline-earth metal, or an organic base may be used to bind the acid that is released during the reaction. In some cases it is convenient to add iodide, mainly iodide of an alkali metal. The increase of temperature and mixing can accelerate the reaction. Otherwise specified N-alkylation may be performed by applying known from the technical field conditions reactions using catalyst transfer phase.

The compounds of formula I where L is - (C1-C6)-alkyl or substituted (C1-C6)-alkyl can also be obtained reductive N-alkylation of compounds of formula I-c according to the methods known from the field of technology. The compounds of formula I where L is - (C1-C6)alkyl or substituted (C1-C6)alkyl, can also be obtained by the reactions of addition compounds of formula I-c with a suitable alkene according to the methods known from the technical field.

The compounds of formula I where L is - (C1-C6)-alkyl, substituted hydroxyl group, can be obtained by the reaction of compounds of formula I-c with a suitable epoxide according to the methods known from the area tensio between tricyclic fragment and piperidine can be converted into a compound of formula I with a simple relationship, as in one, and both of these provisions by the techniques known from the field of technology.

The compounds of formula I can further be converted into other compounds of formula I, using known from the technical field of methods of mutual transformations of functional groups.

For example, the compounds of formula I, where R1or R2denotes a formyl group, can be obtained by the interaction of the corresponding compounds of formula I, where R1or R2represent a hydrogen atom, and N,N-dimethylformamide in the presence of a suitable agent, in particular chlorine phosphoryla. The compounds of formula I, where R1or R2indicate the formyl group can be further transformed into the corresponding hydroxymethylene derivatives known from the technical field of methods of recovery.

The compounds of formula VII-a, resulting in the implementation of the above transformations, are new compounds and are specifically designed for use as intermediates in these transformations. Thus, the present invention relates to new compounds of the formula VII

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their additive salts and their stereochemical isomeric forms,

where each punny formula I;

Q denotes a (C1-C6)-allyloxycarbonyl group, (C1- C4)-alkylcarboxylic group, or (C1-6)-alkyl, substituted by a halogen atom, a cyano, an amino group or methylsulfonylamino.

The most interesting compounds of formula VII are those where Q denotes (C1-C6)-allyloxycarbonyl group, their additive salts and their stereochemical isomeric form.

The following paragraphs describe several ways of obtaining the source of the compounds used in the above methods.

Intermediate compounds of formula II can be obtained by reduction of the corresponding ketones of formula III:

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The specified recovery can be accomplished by reacting the source of the ketone (III) with hydrogen in a solvent, such as alcohol, in particular methanol, ethanol, acid, in particular acetic acid, complex ether, such as ethyl acetate, in the presence of a hydrogenation catalyst, in particular of palladium on charcoal, platinum on charcoal, Raney Nickel. To expedite the reaction, the reaction mixture can be heated and, if necessary, to increase the hydrogen pressure.

Otherwise Speer is such as, for example, socialogical, sodium borohydride, cyanoborohydride sodium, etc. in a suitable solvent, such as, for example, a simple ester, in particular 1,1'- oxybisethane, tetrahydrofuran, etc., alcohol, in particular methanol, ethanol, etc.

Ketones of formula III, where L is a hydrogen atom, can be prepared by hydrolysis of carbamates of formula III-a in acidic or alkaline medium using the methods listed above to obtain compounds of formula I-c of the compound of formula I-b:

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Intermediate compounds of formula III-a can be obtained by the interaction of the carboxylic acid of formula IX with a triazole derivative of the formula X:

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The above reaction is conveniently carried out with stirring and heating the reactants in the presence of a base, such as, for example, amine, in particular N, N-diethylethanamine, N-methylmorpholine, etc. in a suitable solvent, such as, for example, pyridine, acetonitrile or mixtures thereof.

The intermediate compound III-c can also be obtained from a complex ester of formula XI by interaction with a triazole of the formula X in the presence of a strong base, such as, for example, motility, utility, sodium amide, amide Valkyrie, in particular amide di-ISO-propylite or mixtures thereof in a suitable inertia reaction is conveniently carried out at a low temperature. For example, the reagent (X) can be mixed at a temperature of from about -80oC to about -40oC and to add a strong base. Then add ester and allow the reaction mixture to slowly warm to room temperature

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Intermediate compounds of formula V can be obtained by adding the Grignard reagent XII to the ketone of formula XIII in the presence of an inert solvent, in particular tetrahydrofuran (THF):

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Tricyclic ketones of formula XIII is obtained from intermediates of formula XIV by oxidation with a suitable oxidizing agent in the presence of an inert solvent:

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Suitable oxidizing agents are, for example, manganese dioxide, selenium dioxide, suryamaninagar etc.

Inert solvents are, for example, halogenated hydrocarbons, in particular dichloromethane, trichloromethane, etc., or a dipolar aprotic solvent, particularly N,N - dimethylformamide, N,N-dimethylacetamide, etc., or a mixture of carboxylic acid and water, in particular acetic acid and water.

The compounds of formula XIV, where the dashed line denotes an optional bond, can be obtained from corresponding compounds of formula XIV, where casentinesi, in particular by reaction with hydrogen in the presence of catalytic hydrogenation:

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Intermediate compounds of formula XIV-a, where-B-D - denotes a radical of the formula-N= CH-, i.e., the intermediate compounds represented by formula XIV-a-1, can be obtained from benzazepine formula XV by interaction with an agent of formula XVI, or its derivative in an inert solvent, such as, for example, alcohols, in particular methanol, ethanol, etc.

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Intermediate compounds of formula XV can be obtained by the interaction of the intermediate compounds of formula XVII with hydrazine or its derivative in an inert solvent, such as, for example, alcohols, in particular methanol, ethanol, etc.

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Intermediate compounds of formula XVII can be obtained by the reaction of intermediate compounds of formula XVIII, or its derivative in an acid environment. In the formula XVIII R denotes a (C1-C4)-alkyl or both radicals R together denote (C2-C6)-alcander, in particular 1,2-ethandiyl, 1,3-PROPANEDIOL, 2,2-dimethyl-1,3-propandiol:

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The above condensation reaction can conveniently be, mixing the original compound (XVIII) in a solution of carboxylic acid, such as, for example, acetic acid, propanoic acid, and so pcislot etc.

Intermediate compounds of formula XVIII can be obtained by the interaction of the intermediate compounds of formula XIX or its derivative, where R' denotes a (C1-C4)-alkyl, with a reagent of formula XX inert solvent such as, for example, a simple ester, in particular 1,2-dimethoxyethane, tetrahydrofuran, etc.

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Otherwise, the intermediate compounds of formula XIV-a can be obtained by the interaction of the intermediate compound (XXI) with hydrogen in the presence of a suitable catalyst, in particular Raney Nickel, etc. in an inert solvent, in particular methanol, ethanol, etc.

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Intermediate compounds of formula XXI can be synthesized by cyclization of an intermediate compound of formula XXII in the presence of acid, for example sulfuric acid

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Intermediate compounds of formula XXII can be obtained by S-alkylation of an intermediate of compound XXIII with agent R'-W (XXIV) in an inert solvent, in particular methanol, ethanol, etc., not necessarily in the presence of a base, in particular sodium methoxide

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Intermediate compounds of formula XXIII can be obtained by cyclization of an intermediate compound XXV in the presence of a base, in particular sodium hydroxide

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Between the nom or its derivative in an inert solvent, in particular ethanol. The obtained intermediate compound of formula XXVII further interacts with an agent of formula XXVIII in an inert solvent, in particular benzene, etc.:

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Intermediate compounds of formula XIV can also be obtained by cyclization of an intermediate compound of formula XXIX:

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The above cyclization reaction is conveniently carried out in the presence of a Lewis acid, in particular aluminum chloride, etc. In some cases should be added to the reaction mixture of sodium chloride.

Intermediate compounds of formula V can also be synthesized by cyclization of an intermediate compound of formula III in the presence of an acid in an inert solvent:

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A suitable acid for the above reaction is, for example, a Lewis acid, in particular chloride tin (IV etc. Suitable inert solvent is, for example, halogenated hydrocarbons, in particular dichloromethane, 1,2 - dichloroethane, etc., the Intermediate compounds of formula VI can be obtained by the interaction of the ketone of formula XXX with an intermediate compound of formula XIV in the presence of, in particular, amide di-ISO - properity in an inert solvent, such as tetrahydrofuran

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Compounds of formula V, XIII and XIV, obrazowe Otani for use as intermediates in these reactions. Thus, the present invention relates to new compounds of the formula

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their additive salts and their stereochemical isomeric forms,

where the values of L, -B=D - and-E-G - specified previously for formula I.

The compounds of formula I and some of the compounds of formula VII, their pharmaceutically acceptable additive salts and their stereochemical isomeric forms possess useful pharmacological properties, In particular, they are active antiallergic means, the activity of which can clearly be demonstrated by the test results obtained in a series of demonstration tests. Antihistamine activity can be demonstrated by the results of tests published in the "Protection of Rats from Compound 48/80-induced Lethality" (Arch. Int. Pharmacodyn Ther. Vol. 234, 164-176, 1978). It was found that the value of ED for connections 2, 3, 4, 5, 7, 8, 9, 14, 16, 19, 23, 26, 27, 29 and 31 is not more than 0,31 mg/kg

The advantage of the compounds of the present invention is their excellent oral activity, the compounds of the present invention for oral use are almost the same activity as when used subcutaneously.

An interesting feature of the compounds Nastya.

Thanks to their antiallergic properties, the compounds of formula I, the compounds of formula VII and their additive salts useful in the treatment of a wide spectrum of allergic diseases such as allergic rhinitis, allergic conjunctivitis, chronic urticaria, allergic asthma, etc.

Thanks to their anti-allergic properties of the target compounds of formula I can be part of different prescribed pharmaceuticals. For the preparation of antiallergic compositions of the present invention an effective amount of a specific compound in the form of additive salts with an acid or a base as the active ingredient is prepared as a homogeneous mixture with a pharmaceutically acceptable carrier, and the carrier can have different shapes depending on the shape desired for the purpose of the drug. These pharmaceutical compositions are mostly prepared in the form of a standard dose that is convenient for oral, rectal, percutaneous destination for parenteral injection. For example, in the preparation of oral dosage forms can be used to obtain liquid preparations for oral purposes, such as suspensions, syrups, elixirs ilmerge media such as starch, sugars, kaolin, lubricants, binders, disintegrating agents, etc., in the case of powders, pills, capsules and tablets. Due to the simplicity of the destination tablets and capsules are the most convenient oral dosage forms, and in this case, obviously, are solid pharmaceutical carriers. For parenteral compositions, the carrier is usually a sterile water, at least a large part of the composition, although it can include other ingredients, for example to facilitate solubility. Can be obtained solutions for injection, in which the carrier is a saline solution, glucose solution or a mixture of saline and glucose solution. Can also be prepared suspension for injection, which are used aprotic liquid media, suspendresume agents, etc. In the compositions suitable for percutaneous destination, the carrier typically includes an agent that promotes the penetration of drugs through the skin or a suitable wetting agent, optionally together with a small amount of suitable additives, which have no harmful effects on the skin. These supplements can facilitate application to the skin and/or can facilitate the preparation of t is or ointments. To prepare aqueous compositions, obviously, more convenient additive salts of the compounds according to the invention due to their higher solubility in water as compared with the main form of connection.

It is particularly convenient to make these pharmaceutical compositions in the form of standard doses, which facilitates the introduction and provides a more uniform dosage. The standard dose in the context of the present description and claims refers to physically discrete unit suitable for use as unit doses, each unit dose contains a certain amount of active ingredient calculated to provide the desired therapeutic effect, together with the required pharmaceutical carrier. Examples of such standard doses are tablets (including scored tablets or in the shell), capsules, pills, sachets of powder, pills, solutions or suspensions for injection, dose teaspoon doses for a tablespoon, etc., and their various combinations.

The present invention relates also to a method of treating warm-blooded animals suffering from these allergic diseases, by assigning the specified warm-blooded animals EF is of evich forms.

In the General case it is assumed that an effective antiallergic amount is from about 0.001 mg/kg to about 20 mg/kg body weight, more preferably from about 0.01 mg/kg to about 5 mg/kg body weight.

The purpose of the following examples is to illustrate the invention and not to limit the scope of its claims.

A. the production of intermediate compounds

Example 1.

a) a Mixture of 3-topenetrate ether methanesulfonate (0,286 mol) of 1,2,4-triazole (0,571 mol) and potassium carbonate (39,47 g) in acetonitrile (1100 ml), leave to boil for the night with reflux. The mixture is filtered and the filtrate evaporated. The residue is dissolved in water and extracted with dichloromethane. The organic layer is separated, dried (over magnesium sulfate) and evaporated. The residue (49,08 g) purified column chromatography on silica gel (eluent: dichloromethane/methanol/ammonium hydroxide from 99/1/0,1 to 97/3/0,1) (35-70 μm). Pure fractions are collected and evaporated, getting 42,4 g(83%) 1- (2-(3-thienyl)ethyl)-1H-1,2,4-triazole (intermediate compound 1).

Similarly obtain 1-(2-(1-methyl-1H-pyrrol-2-yl)ethyl-1H-1,2,4-triazole (intermediate compound 2) and 1-(2-(5-methyl-2-furanyl)ethyl-1H-1,2,4-triazole (intermediate with the re of nitrogen to a solution of N-(1 - methylethyl)-2-propanamine (43,4 ml) in tetrahydrofuran (400 ml) and the mixture is stirred for 30 minutes. Added dropwise a solution of intermediate compound 1 (0.236 mol) in tetrahydrofuran (50 ml) and the mixture is stirred at a temperature of minus 70oC for 1 hour. Add a solution of ethyl ester of 1-methyl-4-piperidinecarboxylic acid (0,284 mol) in tetrahydrofuran (50 ml) and the mixture is then stirred at a temperature of minus 70oC for 1 hour. Allow the mixture to slowly warm to room temperature, poured into water and extracted with a mixture of 1,1'-oxybisethane/dichloromethane. The organic layer is separated, dried (over magnesium sulfate) and evaporated. The residue (64,3 g) purified column chromatography on silica gel (eluent, dichloromethane/methanol/ammonium hydroxide from 99/4/0,1 to 90/10/0,1) (35 - 70 microns). Pure fractions are collected and evaporated, getting 29,55 g (41%) (1-methyl-4-piperidinyl)[2-[2-(3-thienyl)ethyl]-2H-1,2,4 - triazole-3-yl]methanone (intermediate compound 3).

Similarly receive (1-methyl-4-piperidinyl) [1-[2-(1-methyl-1H-pyrrol-2-yl)ethyl] -1H-1,2,4-triazole-5-yl]metano (intermediate connection 4), [1-[2-(4-methoxyphenyl)ethyl] -4-piperidinyl][2-[2-(1-methyl - 1H-pyrrol-2-yl)ethyl] -2H-1,2,4-triazole-3-yl] mechanon (intermediate connection 5), [1-[2-(4-methoxyphenyl)ethyl] -4-piperidinyl][2-[2-(3-thienyl)-ethyl)- 2H-1,2,4-triazole-3-yl] metano (intermediate compound 28) and [2-[-(5-METI orig tin (IV) is added dropwise at room temperature to a solution of intermediate compound 3 (0,0985 mol) in dichloroethane (500 ml) and stirred the mixture when heated to 80oC for 1 hour. Cooled mixture was poured on ice, alkalinized with ammonia and extracted with dichloromethane. The organic layer was separated, washed with water, dried (over magnesium sulfate), filtered and evaporated to dryness. The residue is purified column chromatography on silica gel (eluent: dichloromethane/methanol/ammonium hydroxide 92/8/1, then 85/15/1). Pure fractions are collected and evaporated, getting to 16.4 g (55%) of product. Sample (3.2 g) was dissolved in methanol and the mixture is refluxed for several hours with noricum. The mixture is filtered through a layer of celite and the filtrate evaporated in vacuum. The residue is recrystallized from a mixture of 2 - propanol/1,1'-oxybisethane getting 1.44 g () -6,10-dihydro-10- (1-methyl-4-pyridinyl)-5H-thieno 2,3-o - 1,2,4 triazolo 1,5-and azepin-10-ol with so pl. 158,3oC (intermediate compound 6).

Similar to get ()-6,10-dihydro-10-1- 2-(4-methoxyphenyl)ethyl-4-piperidinyl-5H-thieno 2,3-1,2,4 about triazolo 1,5-and azepin-10-ol (intermediate compound 30).

Example 2.

a) of hydrazine Monohydrate (65 ml) is added dropwise to a solution of methyl ester 1-methyl-1H-pyrrole-2-acetic acid (0,326 mol) in ethanol (300 ml) and the mixture refluxed for 4 hours. The mixture is evaporated dorsi layer is separated, dried (over magnesium sulfate) and evaporated. The residue (48,8 g) dissolved in 1,1'-oxybisethane and the precipitate is filtered off, getting 45,3 g (90%) hydrazide 1-methyl-1H-pyrrole-2 - acetic acid (intermediate compound 7).

b) 2-Isothiocyanato-1,1-dimethoxyethane (0,357 mol) is added dropwise to a solution of intermediate compound 7 (0,286 mol) in benzene (500 ml) and stirred the mixture at boiling for 1 hour. Cooled to 0oC. the Precipitate is filtered off and dried 1,1'-oxybisethane, getting to 78.2 g (91%) of hydrazide 2-[[2,2-dimethoxymethyl)amino] toximeter] -1-1H-pyrrole-2-acetic acid (intermediate compound 8).

C) a Mixture of intermediate compound 8 (of 0.26 mol) in 2 N. the solution (524 ml) of potassium hydroxide is refluxed for 2 hours. Cool the mixture in the bath with ice. Add ammonium chloride and the mixture is filtered. The precipitate is washed with water and dried in vacuum, obtaining 61,72 g (84%) of 4-(2,2-dimethoxymethyl)-5-[(1-methyl - 1H-pyrrol-2-yl)- methyl]-4H-1,2,4-triazole-3-thiol (intermediate compound 9)

d) Itmean (15,4 ml) was added to a solution of intermediate compound 9 (rate of 0.193 mol) in a solution of sodium methoxide in methanol (53,2 ml) and methanol (500 ml) and stirred the mixture at room temperature for 2 hours. The mixture is evaporated, estateto magnesium) and evaporated. The residue is treated with 1,1'-oxybisethane and the precipitate is filtered off, receiving 56 g (98%) of 4- (2,2-dimethoxymethyl)-3-[(1-methyl-1H-pyrrol-2-yl)methyl] -6-(methylthio)- 4H-1,2,4-triazole (intermediate compound 10).

d) a Mixture of intermediate compound 10 (0,287 mol) in sulfuric acid (500 ml) is stirred at a temperature of 0oC for 2 hours. Pour mixture into ice-cold water, alkalinized with ammonia and extracted with dichloromethane (+ methanol). The organic layer is separated, dried (over magnesium sulfate) and evaporated. The residue (36,67 g) purified column chromatography on silica gel (eluent:dichloromethane /methanol/ammonium hydroxide from 98/2/0,1 to 97/3/0,1) (35-70 μm). Pure fractions are collected and evaporated, obtaining 25 g (34%) 9,10-dihydro-9-methyl-3-(methylthio)pyrrolo[2,3-d] -1,2,4-triazolo [4,3-a]azepine (intermediate compound 11).

E) an Intermediate compound 11 (to 0.108 mol) is refluxed over Raney Nickel (140 g) (washed with methanol) as a catalyst in ethanol (400 ml) for 24 hours. The mixture is heated for another 24 hours. The catalyst is filtered off and the solvent evaporated. The residue (15 g) purified column chromatography on silica gel (eluent: dichloromethane/methanol/ammonium hydroxide from 98/2/0,1). The clean fractions are collected and evaporated, p is hydro-9-methylpyrrole [2,3-d]-1,2,4-triazolo [4,3-a]azepine with so pl. 177,7oC (intermediate compound 12).

Example 3.

a) a Mixture of the hydrochloride of O-ethyl 3-thienemannimyia (0.14 mol) in 1,2-dimethoxyethane (150 ml) is stirred at a temperature of 15oC. Portions contribute 2,2-dimethoxyethane (0.14 mol) and leave the mixture was mixed overnight. Evaporated, getting monohydrochloride N-(2,2-dimethoxymethyl)-3-thiophenecarbonitrile (intermediate compound 13).

Similarly, but using as the solvent, tetrahydrofuran, get monohydrochloride N-(2,2-dimethoxymethyl)-2-thiophenemethylamine (intermediate compound 14).

b) a Mixture of intermediate compound 13 (0.14 mol) in acetic acid (150 ml) is stirred under nitrogen atmosphere. Portions add methanesulfonate (27 g) and the mixture is left to mix overnight. Poured into ice water and alkalinized with sodium hydroxide. The precipitate is filtered off and the aqueous layer was extracted with a mixture of dichloromethane/methanol and evaporated. The precipitate and the residue from evaporation unite, obtaining 13.8 g (60%) 4H-thieno[2,3 - d]azepin-5-amine (intermediate compound 15).

Similarly, but using a 30% solution of hydrogen bromide in acetic acid instead of methansulfonate receive 8H-thieno[2,3-d]azepin-5-amine (PR is(31.5 ml) and methanol (780 ml) was stirred at room temperature for 30 minutes. The mixture is evaporated in vacuum at a temperature of 40oC to a volume of 200 ml, diluted with water and filtered, obtaining a fraction of 1. The aqueous layer was extracted with dichloromethane. The organic layer was washed with water, dried (over magnesium sulfate), filtered and evaporated, getting faction 2. Both factions unite, receiving fall of 19.88 g (73%) 5-hydrazino-4H-thieno[2,3-d]azepine (intermediate compound 17).

Similarly receive 7 hydrazino-8H-thieno[2,3-d] azepin (intermediate compound 18).

g) a Mixture of intermediate 17 (0,111 mol) and acetate methanimidamide (0,166 mol) in ethanol (1200 ml) boil c reflux for 2 hours and 30 minutes. The cooled solution is filtered and evaporated in vacuum. The residue is dissolved in dichloromethane, washed with water, dried (over magnesium sulfate), filtered and evaporated. The residue is recrystallized from 2,2'-oxybisethane getting 15,58 g (74%) of product. The sample is purified column chromatography on silica gel (eluent: dichloromethane/methanol 97/3). Pure fractions are collected and evaporated. The residue is recrystallized from a mixture of ethyl acetate/2,2'- oxybisethane getting 1,08 g 10H-thieno[3,2-d]-1,2,4 - triazolo[4,3]azepine with so pl. 146,3oC (intermediate compound 19).

Analogines intermediate compound 19 (0,0835 mol) and manganese dioxide (158 g) in N,N-dimethylformamide (840 ml) was rapidly stirred and heated at a temperature of 40oC for 48 hours. The hot mixture is filtered through celite, washed with hot N,N - dimethylformamide and evaporated in vacuum. The residue is treated with a mixture of 2 - propanone/2,2'-oxybisethane and sucked off. The precipitate was washed with 2,2'-oxybisethane and dried, obtaining 9,85 g (58%) 10H-thieno [3,2-d] -1,2,4-triazolo[1,5] azepin-10-she (intermediate compound 21).

Similarly receive 9-methylpyrrole[2,3-d]- 1,2,4-triazolo[4,3]azepin-10(9H)-he (intermediate compound 22).

Similarly, but using a mixture of acetic acid and water as a solvent, obtained 10H-thieno[2,3-d] -1,2,4-triazolo [4,3] azepin-10(9H)-he (intermediate compound 23).

(e) 1,2-Dibromethane (a few drops) is added to a stirred mixture of magnesium turnings (0,105 mol) in tetrahydrofuran (5 ml) under nitrogen atmosphere. After start of the reaction add pure 4-chloro-1 - methylpiperidine (a few drops), and then maintaining the temperature in the range from 40 to 50oC, is added dropwise remaining amount of 4-chloro-1-methylpiperidine (0,115 mol) in tetrahydrofuran (50 ml). Dilute the mixture with tetrahydrofuran (50 ml) and refluxed for 2 hours. Portions at a temperature of 60oC add a suspension of intermediate compounds is mesh, decompose a solution of ammonium chloride and extracted with a mixture of dichloromethane/methanol. The organic layer is separated, dried (over magnesium sulfate), filtered and evaporated. The residue is purified column chromatography on silica gel (eluent 1: dichloromethane/methanol/ammonium hydroxide, 90/10/1 and eluent 2: dichloromethane/methanol/ammonium hydroxide: 50/50/1). Pure fractions are collected and evaporated, getting 2,53 g (17%) 10-(1-methyl-4-piperidinyl)-10H - thieno[3,2-d] -1,2,4-triazolo)[1,5-a] azepin-10-ol (intermediate compound 24).

Similar to get ()-9,10-dihydro-9-methyl-10-(1 - methyl-4-piperidinyl)pyrrolo[2,3-d] -1,2,4-triazolo[4,3-a] azepin - 10-ol (intermediate compound 25) and () -10-(1-methyl-4 - piperidinyl)-10H-thieno[2,3-d][1,2,4]triazolo[4,3-a]azepin-10-ol (intermediate compound 26).

B. obtain the final product

Example 4.

A mixture of intermediate 25 (0,008 mol) in phosphorus oxychloride (96 ml) was stirred at the boil under reflux for 2 hours. Cool the mixture and evaporated in vacuum. The residue is dissolved in water, alkalinized with ammonia, extracted with dichloromethane and washed with water. The organic layer is separated, dried (over magnesium sulfate), filtered and evaporated. The residue (2 g) clear column gramatovich. The residue (1.5 g) is recrystallized from a mixture of 2-butanone/methanol, obtaining 0.8 g (36%) 9,10-dihydro-9-methyl-10-( 1-methyl-4-piperidinylidene)pyrrolo [2,3-d] -1, 2,4-triazolo[4,3-a]azepine with so pl. 262,0oC (compound 1).

Similarly receive 10-(1-methyl-4-piperidinylidene) -10H-thieno[3,2-d]-1,2,4-triazolo[4,3-a] azepin, so pl. 244,9oC (compound 2), 10-(1-methyl-4-piperidinylidene)-10H-thieno [2,3-d] [1,2,4] triazolo[4,3-a] azepin, so pl. 239,5oC (compound 3), 6,10-dihydro-10-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinylidene] -5H-thieno[2,3-d] [1,2,4]triazolo[1,5-a]azepine tandikat (2:3) monohydrate, so pl. 158,6oC (compound 16), and()-10-[1-[2-(4- methoxyphenyl)ethyl] -4-piperidinyl] -10H-thieno[2,3-d][1,2,4]triazolo[1,5-a]azepin, so pl. 170,8oC (compound 17).

Example 5.

Intermediate compound 4 (0,116 mol) is added by portions at 0oC to methansulfonate (210 ml) and the mixture is stirred at a temperature of 80oC for 3 hours. Pour the mixture on ice, alkalinized with sodium hydroxide and extracted with dichloromethane. The organic layer is separated, dried (over magnesium sulfate) and evaporated to dryness. The residue (28 g) purified column chromatography on silica gel (eluent: dichloromethane/methanol/ammonium hydroxide, 95/5/0,2) (15 μm). Pure fractions are collected and evaporated. OST danilidis)pyrrolo[3,2-d] [1,2,4] triazolo[1,5-a] azepine with so pl. 169,1oC (compound 4).

Example 6.

Chloride tin (IV) (12,6 ml) is added dropwise at room temperature to a solution of intermediate compound 5 (0,0285 mol) in 1,2-dichloroethane (300 ml) and the stirred mixture heated to 80oC for 2 hours. Cooled mixture was poured on ice and alkalinized with ammonia. The mixture is filtered through celite and the filtrate is extracted with dichloromethane. The organic layer is separated, dried (over magnesium sulfate) and evaporated. The remainder (to 11.52 g) purified column chromatography on silica gel (eluent: dichloromethane/methanol/ ammonium hydroxide from 97/3/0,1 to 95/5/0,1) (35-70 μm). Pure fractions are collected and evaporated. The residue (4.4 g) is recrystallized from a mixture of 2-butanone and 2,2'- oxybisethane getting 3,19 g (38%) ()-7,10-dihydro-10-[1 -[2-(4-methoxyphenyl)ethyl] -4-piperidinyl] -7-methylpyrrole[3,2-d] - 1,2,4-triazolo[1,5-a] azepine with so pl. 140,1oC (compound 5).

Similar to get ()-8-methyl-10-(1-methyl-4-piperidinyl] -10H-furo[3,2-d]-[1,2,4]triazolo[1,5-a]azepin, so pl. 111,8oC (compound 18 ).

Example 7.

Connection 1 (0,00355 mol) in ethanol (250 ml) hydronaut in a Parr apparatus over 10% palladium on charcoal as the catalyst for 6 hours at room temperature is lit and the filtrate evaporated. The residue (0.9 g) purified column chromatography on silica gel (eluent: dichloromethane/methanol/ammonium hydroxide, 95/5/0,5) (15-40 μm). Pure fractions are collected and evaporated. The residue (0.7 g) is recrystallized from a mixture of 2-butanone/2,2'-oxybisethane getting 0,57 g (70%) 5,6,9,10-tetrahydro-9-methyl-10-(1-methyl-4 - piperidinylidene)pyrrolo[3,2-d]-1,2,4-triazolo[4,3-a]azepine with so pl. 214,1oC (compound 6).

Similar to get ()-5,6,7,10-tetrahydro-10-[1-[2- (4-methoxyphenyl)ethyl]-4-piperidinyl]-7-methylpyrrole[3,2-d] -1,2,4-triazolo[1,5-a]azepin, so pl. 132,1oC (compound 7) and ()-5,6,7,10-tetrahydro-7-methyl-10-(1-methyl-4 - piperidinyl) pyrrolo[3,2-d][1,2,4]-triazolo[1,5-a]azepin, so pl. of 142.8oC (compound 8).

Example 8.

a) a Mixture of intermediate compound 6 (0,034 mol) of 98% phosphoric acid (80 ml) is stirred while heating to 100oC for 6 hours. The mixture is cooled, poured into ice water, alkalinized with ammonia and extracted with dichloromethane. The organic layer is separated, dried (over magnesium sulfate) and evaporated. The residue (10,61 g) purified column chromatography on silica gel (eluent: dichloromethane/methanol/ammonium hydroxide from 95/5/0,1 to 90/10/0,1 and 75/25/0,2) (35-70 μm). Pure fractions are collected and evaporated. The fraction recrystallized from 1 ,2oC (compound 9). Fraction 2 is treated with noricum in methanol and recrystallized from pentane, receiving 1.12 g(12%) ()-10-(1-methyl-4-piperidinyl)-10H-thieno[2,3-d] [1,2,4]triazolo [1,5-a]azepine with so pl. 136,7oC (compound 10).

b) a Mixture of compound 10 (0,00342 mol) and compound 9 (0,00342 mol) leave to gidrirovaniya overnight in a mixture of acetic acid (1.65 ml) and ethanol (150 ml) in a Parr apparatus over palladium on activated carbon (2 g) as a catalyst at a temperature of 50oC and a pressure of 3 bar. The catalyst is filtered off through celite and the filtrate evaporated to dryness. The residue is dissolved in dichloromethane and washed with 10% potassium carbonate solution. The organic layer is separated, dried (over magnesium sulfate), filtered and evaporated. The residue is purified column chromatography on silica gel (eluent: dichloromethane /methanol/ammonium hydroxide, 90/10/1) (15-40 μm). Pure fractions are collected and evaporated. The residue (1.5 g) is recrystallized from 2,2'-oxybisethane getting 0,92 g (76%) () -6,10-dihydro-10-(1-methyl-4-piperidinyl)-5H-thieno[2,3-d][1,2, 4]triazolo[1,5-a]azepine with so pl. 123,4oC (compound 11).

Example 9.

a) Ethyl ester harpalinae acid (14,8 ml) is added dropwise at a temperature of 80oC to a solution of compound 4 is Ivanyi for 3 hours. The mixture is cooled, poured into water, decanted and extracted with ethyl acetate. The organic layer was separated, washed with water, dried (over magnesium sulfate), filtered and evaporated. The residue (9,34 g) purified column chromatography on silica gel (eluent: dichloromethane/methanol/ammonium hydroxide, 97,5/2,5/0,1) (15 μm). Pure fractions are collected and evaporated. The residue is recrystallized from a mixture of 2-butanone/2,2'-oxybisethane, receiving 1.8 g (36%) monohydrate ethyl ester 4-(5,6,7,10-tetrahydro-7-methylpyrrole [3,2-d][1,2,4]triazolo[1,5-a]azepin-10-ilidene)-1 - piperidinecarboxylic acid so pl. 104,1oC (compound 12).

Similarly receive the ethyl ester of 4-(5, 6-dihydro-10H-thieno[2,3-d] [1,2,4] triazolo[1,5-a] azepin-10-ilidene)-1-piperidinecarboxylic acid (compound 13), (a)-ethyl ester 4-(10H-thieno[2,3-d] [1,2,4] triazolo [1,5-a] azepin-10-yl)-10-piperidinecarboxylic acid (compound 19) and ethyl ester of 10-(10H-thieno[2,3-d] -1,2,4-triazolo[4,3-a]azepin-10-ilidene)-1-piperidinecarboxylic acid (compound 20).

b) Compound 12 (0,0205 mol) are heated in a solution of sodium hydroxide (11.5g) in 2-propanol (175 ml) in water (175 ml) for 63 hours. The mixture is cooled and evaporated. The residue was diluted with water (200 ml) and extracted with dichloromethane. The organic layer is separated, dried (over Sul dichloromethane/methanol/ammonium hydroxide from 92/8/0,5 to 80/20/0,5). Pure fractions are collected and evaporated, obtaining 4.1 g (74%) of product. The sample (2 g) is recrystallized from a mixture of 2-butanone/2,2'-oxybisethane, receiving 1.8 g (36%) 5,6,7,10-tetrahydro-7-methyl-10-(4 - piperidinylidene)pyrrolo[3,2-d][1,2,4]triazolo[1,5-a] azepine with so pl. 183,1oC (compound 14).

Similarly, but in acidic conditions, receive 6,10-dihydro-10-(4-piperidinylidene)-5H-thieno[2,3-d] [1,2,4] triazolo[1,5-a] azepin, so pl. 198,8oC (compound 15), hemihydrate ()-10-(4-piperidinyl)-10H-thieno[2,3-d][1,2,4] triazolo [1,5-a] azepin, so pl. 136,3oC (compound 21), 10- (4-piperidinylidene)-10H-thieno[2,3-d]-1,2,4-triazolo[4,3 - a]azepine (compound 22).

Example 10. A mixture of compound 14 (0,0047 mol), 1-(2 - bromacil)-4-methoxybenzene (to 0.007 mol), potassium iodide (0.08 g) and potassium carbonate (1.3 g) in 4-methyl-2-pentanone (50 ml), left overnight to boil under reflux. Cooled and evaporated. The residue is dissolved in dichloromethane. The organic layer was washed with water, dried (over magnesium sulfate), filtered and evaporated. The residue (4 g) purified column chromatography on silica gel (eluent: dichloromethane/methanol/ammonium hydroxide, 97/3/0,2) (15 μm). Pure fractions are collected and evaporated. The residue (1.45 g) is recrystallized from a mixture of ethanol/2,2'-oxybisethane, getting to 1.14 g (55%) 5,6,7,10 - tet is oC (compound 23).

Similarly receive 10-[1-[3-(4-pertenece) propyl]-4-piperidinylidene] -6,10-dihydro-5H-thieno[2,3 - d] [1,2,4] triazolo[1,5-a]azepin, so pl. 131,3oC (compound 24), (a) through(E)-10-[1- (3-phenyl-2-propenyl)-4-piperidinyl)-10H-thieno [2,3-d] [1,2,4] triazolo[1,5-a]azepin, so pl. of 149.0oC (compound 25), 1-ethyl-1,4-dihydro-4-[2-[4-(5,6,7,10-tetrahydro-7-methylpyrrole[3,2-d][1,2,4] triazolo [1,5-a] azepin-10-ilidene)-1-piperidinyl] ethyl] -5H-tetrazol-5-he (connection 26), 10-[1-(2- ethoxyethyl-4-piperidinylidene]-6,10-dihydro-5H-thieno[2,3-d] [1,2,4] triazolo[1,5-a]azepin, so pl. 82,5oC (compound 27) and ()-2-methyl-3-[2-[4-(10H-thieno[2,3-d] [1,2,4]triazolo[1,5-a] azepin-10-yl)-1-piperidinyl]ethyl]-4H-pyrido[1,2-a]pyrimidine - 4-one, so pl. 200,1oC (compound 28).

Example 11.

A mixture of compound 14 (0,0092 mol) and methyl ester 2-propanolol acid (0.018 mol) in methanol (40 ml) and left under stirring overnight to boil under reflux. The mixture is evaporated to dryness. The residue (2.7 g) purified column chromatography on silica gel (eluent: dichloromethane/methanol/ammonium hydroxide, 96/4/0,2). Pure fractions are collected and evaporated. The residue is recrystallized from a mixture of 2-propanone/2,2'-oxybisethane, receiving 1.3 g (52%) of methyl ester of 4-( 5,6,7,10-tetrahydro-7-methylpyrrole- [3,2-d][1,2,4]triazolo [ucaut methyl ester 10-(10H-thieno[3,2-d] -1,2,4-triazolo[1,5-a] azepin-10-ilidene)-1-piperidinemethanol acid, so pl. 128,1oC (compound 30).

Example 12.

Oxiran (of 0.017 mole) is bubbled at 0oC in methanol. The resulting mixture is added dropwise within 30 minutes added at room temperature to a solution of compound 15 (0,00844 mol) in methanol. The mixture is stirred at room temperature for 24 hours, evaporated and the residue is dissolved in dichloromethane. The organic layer was washed with water, dried (over magnesium sulfate), filtered and evaporated. The residue is purified column chromatography on silica gel (eluent: dichloromethane/methanol/ammonium hydroxide, 95/5/0,5) (15-40 μm). Pure fractions are collected and evaporated. The residue (2 g) is recrystallized from 2-propanol, getting to 1.15 g (43%) of 4-(5,6 - dihydro-10H-thieno[2,3-d][1,2,4]triazolo[1,5-a] azepin-10-ilidene)-1 - piperazineethanol with so pl. 149,8oC (compound 31).

Example 13.

a) When 0oC chloride is added dropwise phosphoryl (0,022 mol) of N,N-dimethylformamide (13 ml). The resulting mixture was stirred for 30 minutes. Portions at 0oC add connection 4 (0,0106 mol).

Increase the temperature to 30oC and stirred at the same temperature for 3 hours. Cool the reaction mixture was poured into ice water and the resulting solution Potseluev what hatom magnesium), filtered, treated with activated charcoal, filtered over a hard-shelled earth and the filtrate evaporated. The residue is recrystallized from 2,2'- oxybisethane. The precipitate is filtered off (2.2 g) and recrystallized from acetonitrile. The precipitate is filtered off and dried, obtaining 1.3 g (39%) 5,6,7,10-tetrahydro-7-methyl-10-(1-methyl-4-piperidinylidene] pyrrolo [3,2-d] [1,2,4]triazolo[1,5-a]azepin-8 - carboxaldehyde with so pl. 204,5oC (compound 32).

b) a Mixture of compound 32 (0.018 mol) in methanol (190 ml) is cooled to 0oC, portions add sodium borohydride (5.8 g) and stirred the mixture for one hour. The reaction mixture was poured into ice water and extracted with dichloromethane. The organic layer was separated, washed with water, dried (over magnesium sulfate), filtered and evaporated to dryness. The residue is purified column chromatography on silica gel (eluent: dichloromethane/methanol/ammonium hydroxide, 92/8/0,5). Pure fractions are collected and evaporated. The product is recrystallized from 2,2'-oxybisethane, gaining 1.4 g (24%) 5,6,7,10-tetrahydro-7-methyl-10-(1-methyl-4-piperidinylidene] pyrrolo [3,2-d] [1,2,4] triazolo[1,5-a] azepin-8-methanol with so pl. 201,2oC (compound 33).

C. examples of the compositions.

These compositions represent t is for warm-blooded animals, in accordance with the present invention.

The term "active ingredient", as indicated in these examples relates to a compound of formula I or the compound of formula VII, their pharmaceutically acceptable acid additive salts or their stereochemical isomeric form.

Example 14. Drops for oral purposes.

500 g of Active ingredient are dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol at a temperature of 60-80oC. After cooling to a temperature of 30-40oC add a solution of 1750 g of sodium salt of saccharin in 2.5 l of purified water and while stirring add 2.5 l of odorants cocoa and add a sufficient amount of polyethylene glycol to bring the volume to 50 l getting the solution drops for oral destination with a concentration of 10 mg/ml of active ingredient. The resulting solution fill in appropriate containers.

Example 15. The solution is for oral purpose.

9 g of Methyl ester of 4-hydroxybenzoic acid and 1 g of propyl ester of 4-hydroxybenzoic acid dissolved in 4 l of boiling purified water. In 3 l of the resulting solution initially dissolve 10 g of 2,3 - dihydroxybutanedioate acid, and then 20 g of the active ingredient. This solution Pach the bits. 40 g of sodium salt of saccharin dissolved in 0.5 l of water and add 2 ml of raspberry essences and 2 ml krizovany essences. This solution combined with the previously obtained solution and add enough water to bring the volume up to 20 l, obtaining a solution containing 5 mg of active ingredient in a teaspoon (5 ml). The resulting solution fill in appropriate containers.

Example 16. The capsule.

20 g of the Active ingredient, 6 l lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of magnesium stearate vigorously mixed with each other. The mixture then fill 1000 suitable hard gelatin capsules, each containing 20 mg of active ingredient.

Example 17. Coated tablet.

Cooking stuffing pills.

A mixture of 100 g of the active ingredient, 570 g lactose and 200 g starch are thoroughly mixed in a humidified with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone (trade name Kollidon - K 90) approximately 200 ml of water. The wet mixture of powders sieved, dried, and sift again. Add 100 g microcrystalline cellulose (trade name Avicel) and 15 g hydrogenated vegetable oil (torgah contains 10 mg of active ingredient.

Shell.

To a solution of 10 g methyl cellulose (trade name Methocel 60 HG) in 75 ml of denatured alcohol add a solution of 5 g of ethyl cellulose (trade name Ethocel 22 cps) in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml 1,2,3 - propanetriol, 10 g of polyethylene glycol is melted and dissolved in 75 ml of dichloromethane. This solution is added to the previously obtained solution, and then add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated suspensions of the dye (trade name Opaspray K-1-2109) and homogenized the mixture. Stuffing tablets cover the mixture in a special apparatus.

Example 18. The solution for injection.

1.8 g of Methyl ester of 4-hydroxybenzoic acid and 0.2 g of propyl ester of 4-hydroxybenzoic acid dissolved in approximately 0.5 l of boiling water for injection. After cooling to a temperature of 50oC add with stirring 4 g glacial acetic acid, 0.05 grams propylene glycol and 4 g of active ingredient. The solution is cooled to room temperature and add sufficient water for injection to bring the volume to 1 l, obtaining a solution containing 4 mg of the active ingredient in 1 ml of the Solution is sterilized and

3 g of the Active ingredient is dissolved in a solution of 3 g of 2,3-dihydroxybutanedioate acid in 25 ml of propylene glycol 400. Together straighten 12 g of a surfactant (trade name SPAN) and required up to 300 g quantity of triglyceride (trade name Witepsol 555). The resulting mixture is mixed with the previously obtained solution. The resulting mixture was poured into moulds at a temperature of 37 - 38oC and get 100 suppositories each containing 30 mg of active ingredient.

1. Derivatives triazolo-(pyrrolo-, thieno - or furano-)- azepine General formula I

< / BR>
their pharmaceutically acceptable additive salt and stereochemical isomeric forms,

where each dashed line independently represents an optional bond;

E-G is a bivalent radical of the formula

-X-C(R1) = CH- (a - 1)

or formulas

-CH = C(R2) -X- (a - 2)

where X Is O, S or NR3where R3is a hydrogen atom, a C1- C6-alkyl;

R1and R2each independently represents a hydrogen atom, a C1- C4-alkyl, hydroxy-C1-4-alkyl or formyl group;

-B=D - bivalent radical of the formula

-C(R4) = N- (b - 1)

or formulas

-N = C(R5)- (b - 2)

where R4and what ielem, selected from the group comprising hydroxyl group, a C1- C4-alkyloxy, hydroxycarbonyl group, C1- C4-allyloxycarbonyl group, aryl or alloctype, C3- C6-alkenylphenol group, substituted aryl, each aryl denotes a phenyl group or a phenyl group substituted by a halogen atom or C1- C4-alkyloxy, or L is a radical of the formula

-AlK - Het3,

where AlK - C1- C4-alcander, Het3is a radical of the formula

< / BR>
where A - Z - represents-CH2- CH2- CH2- CH2- or-CH = CH - CH = CH-.

2. Connection on p. 1, where R1and R2denote hydrogen atom, hydroxy-C1-4-alkyl.

3. Connection on p. 1, where X Is S or NCH3.

4. Connection on p. 1, where the specified connection is chosen from the group comprising 5,6,7,10-tetrahydro-7-methyl-10-(1-methyl-4-piperidinylidene)pyrrolo/3,2-d//1,2,4/triazole/1,5-a/azepin; 10-(1-methyl-4-piperidinylidene)-10H-thieno/3,2-d/1,2,4-triazolo/4,3/azepin and 6,10-dihydro-10-(1-methyl-4-piperidinylidene)-5H-thieno/2,3-d//1,2,4/triazole/1,5-a/azepin, their stereoisomers and their pharmaceutically acceptable acid additive salt.

5. Connection on p. 1 having antiallergic the General derived azepine as an active ingredient and a pharmaceutically acceptable carrier, characterized in that the quality of the derived azepine it contains derivatives triazolo-(pyrrolo-, thieno - or furano)azepine under item 1 in a therapeutically effective amount.

7. A method of obtaining a pharmaceutical composition having anti-allergic activity, including mixing derived azepine with a pharmaceutically acceptable carrier, characterized in that the quality of the derived azepine used therapeutically effective amount of the compounds under item 1.

8. The compound of General formula VII

< / BR>
where - E - G - B = D are specified in paragraph 1.

Q represents C1- C6-allyloxycarbonyl group, C1- C4-alkylcarboxylic group or a C1- C6-alkyl.

9. Compounds of General formula VIII

and

the General formula XIV

< / BR>
their additive salt and stereochemical isomeric forms,

where values for the dashed lines, groups E-G and B=D specified in paragraph 1.

10. The method of obtaining compounds of General formula I on p. 1, wherein conducting the cyclization of the alcohol of General formula II

< / BR>
or ketone of General formula III

< / BR>
where L-E-G - B = D are specified in paragraph 1 values

in the presence of acid.

< triaza-(pyrrolo-, thieno - or furano)-azepino fragment, characterized in that carry out the dehydration of the alcohol of General formula V

< / BR>
or the General formula VI

< / BR>
where L-E-G - B = D are specified in paragraph 1 values

using a dehydrating agent.

12. The method of obtaining compounds of General formula I on p. 1, containing a double bond in the tricyclic fragment and a simple link, which is a bridge of communication between the tricyclic fragment and piperidine, wherein the carry out dehydration of the alcohol of General formula V

< / BR>
where the Central ring of the tricyclic fragment does not contain double bonds.

in the presence of a dehydrating agent.

13. The method of obtaining compounds of General formula I on p. 1, where L is a hydrogen atom, characterized in that the compound of General formula I-b

< / BR>
where-E-G - B = D have specified values,

are dialkylamino - carbonyliron with C1- C4- alkylphosphonate in the presence of base, followed by hydrolysis of the compounds of General formula VII-a

< / BR>
14. The method of obtaining compounds of General formula I on p. 1, where L is different from the hydrogen atom, with L denoted by L1different TeV inert solvent, perhaps in the presence of a base.

15. The method of obtaining compounds of General formula I on p. 1, where L - C1-6is alkyl or substituted C1-6-alkyl, wherein the compound of formula I-c is subjected to interaction with the alkene.

16. The method of obtaining compounds of General formula I on p. 1, where L - C1- C6-alkyl, substituted hydroxyl group, characterized in that the compound of General formula I-c on p. 14 is subjected to interaction with the epoxide.

17. The method of obtaining compounds of General formula I on p. 1, where R1or R2denote formyl group, characterized in that the compound of General formula I on p. 1, where R1or R2represent a hydrogen atom, is subjected to the interaction with N, N-dimethylformamide, and, if necessary, turn the compound of General formula I in salt form processing pharmaceutically acceptable acid or base, or, conversely, turn the salt form into the free base or free acid by treatment with alkali or acid, respectively, and/or get it stereochemical isomeric form.

 

Same patents:

The invention relates to new chemical compounds with valuable properties, in particular to derive hinolan and naphthyridinone acid of General formula

< / BR>
in which

A is CH, CF, CCl, C-OCH3C-CH3N;

X1hydrogen, halogen, NH2CH3;

R1alkyl containing 1 to 3 carbon atoms, FCH2CH2- cyclopropyl, phenyl, which can be from one to three times substituted by halogen, or

A and R1together can mean the bridge structure C-O-CH2-CH(CH)3,

R2hydrogen, not substituted or substituted by a hydroxy-group, halogen or amino alkyl containing 1 to 3 carbon atoms, or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl;

B balance formulas

< / BR>
where

Y is O or CH2;

R3oxaalkyl containing 2 to 5 carbon atoms, CH2-CO-C6H5CH2CH2CO2R', R O2C-CH=-CO2R', -CH=CH-CO2R' or CH2CH2-CN, where R' denotes hydrogen or alkyl containing 1 to 3 carbon atoms;

R4hydrogen, alkyl containing 1 to 3 carbon atoms, окMG SRC="http://www.fips.ru/fullimg2/rupat3/19981/010.dwl/2105770-6t.gif" ALIGN="ABSMIDDLE">CH=CH-CO2-R' or CH2CH2-CN or 5-methyl-2-oxo-1,3-dioxol-4-yl-methyl, where R' denotes hydrogen or alkyl containing 1 to 3 carbon atom,

in the form of mixtures of isomers or individual isomers, pharmaceutically applicable hydrates and salts, for example acid additive salts and alkaline, alkaline earth, silver and guanidinium salts of the corresponding carboxylic acids

The invention relates to pharmaceutically active bicyclic heterocyclic amines (XXX) and can be used as pharmaceuticals for the treatment of diseases and injuries

The invention relates to new derivatives of 1,4-diazepine and their pharmacologically acceptable salts, methods for their production and pharmaceutical applications

The invention relates to new triazolo[4,3-a][1,4] benzodiazepine or a thieno[3,2-f][1,2,4]triazolo[4,3-a]benzodiazepines of General formula I

< / BR>
where X is-CH=CH -, or S; R1- lower alkyl or trifluoromethyl; R2is chlorine or fluorine; R3is a radical of the formula R4-(CH2)n-CC - or R5-O-CH2-CC -, where n is an integer of 0,1 or 2; s is 0 or 1; R4is phenyl or mono-, di - or tricyclic 5-7-membered heterocyclic radical containing as heteroatoms O or S and/or 1-3 nitrogen atom, unsubstituted or substituted lower alkoxy, oxo, actigraphy or chlorine; R5is phenyl or pyridyl radical, provided that when n is 0, the radical R4must be attached through a carbon to carbon link, and that R5always attached through carbon to oxygen of communication, and in the presence of at least one asymmetric center, their enantiomers and racemates and pharmaceutically-acceptable salts accession acids exhibiting the properties of antagonists of platelet activating factor (PAF) and, respectively, with angioprotective, immunological, is omposition based on them

The invention relates to a method for producing new derivatives triazolo-[4,3-a](1,4) benzodiazepines General formula I:

I,

where X is-CH=CH -, or S;

R1lower alkyl or trifluoromethyl;

R2chlorine or fluorine;

R3the radical of the formula R4-(CH2)nC or R5-O-CH2-C_C-, where n is the integer 0, 1 or 2;

R4phenyl or mono-, di-, or tricyclic 5-7-membered heterocyclic radical containing as heteroatoms 0 or S, and/or 1-3 nitrogen atom, unsubstituted or substituted lower alkoxy, oxo, actigraphy or chlorine,

R5phenyl or pyridylethyl provided that when n is 0, the radical R4must be attached through a carbon to carbon link, and that R5attached via a carbon to oxygen connection with RAG-antagonistic properties

The invention relates to new azetidinone derived isothiazol-pyridone: 2,3,4,9-tetrahydroindazole[5,4-b]China - in-3,4-dione, 2,3,4,9-tetrahydrothieno [5,4-b] [1,8]-naphthiridine-3,4-dione, 1,2,8,9-tetrahydro-7H-isothiazol-[4',5',5,6]pyrido [1,2,3-de]benzoxazine-7,8-dione and its salts

The invention relates to the field of macrolides

The invention relates to animal husbandry, in particular to methods of breeding cattle with the regulation of the sex of offspring

The invention relates to a new method of treatment of patients, such as people with benign prostatic hyperplasia (BPH), which includes treatment by assigning a therapeutically effective amount of an inhibitor 5- reductase in combination with blocker1- adrenergic receptor

The invention relates to new compounds with dual activity, namely the activity of inhibiting angiotensin converting enzyme, and the activity of inhibiting neutral endopeptidase and to methods of producing these compounds
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