Derivative imidazo/1.2 a/thieno/2,3-d/azepino, the retrieval method, intermediate for their production, pharmaceutical composition and method of production thereof

 

(57) Abstract:

Describes the new derivative imidazo/1.2 a/ thieno/2,3-d/-azepino formula I, or their pharmaceutically suitable salt of the merger, or stereochemical isomer, where each of the dashed lines independently represents the possible /optional/ link: R1is hydrogen, C1-4- alkyl; R2is hydrogen, C1-4- alkyl, C1-4- alkyl, substituted hydroxycarbonyl or C1-4-allyloxycarbonyl; R3is hydrogen, C1-4- alkyl, X Is S; L is hydrogen, C1-4- alkyl, C1-6is alkyl having one Deputy selected from the group consisting of hydroxy-group, C1-4- alkyloxy, hydroxycarbonyl, C1-4- allyloxycarbonyl, C1-4- alkylaminocarbonyl, C1-4- allyloxycarbonyl, C1-4- allyloxycarbonyl - C1-4- alkyloxy, hydroxycarbonyl - C1-4- alkyloxy, C1-4- alkylaminocarbonyl, C1-4- alkylaminocarbonyl, C1-4- alkylaminocarbonyl aryl and alloctype; C3-6alkenyl, substituted aryl, where each aryl is phenyl or phenyl substituted by halogen, a hydroxy-group, C1-4- alkyloxy, Il is ar or NH; Het1- pyrimidinyl; Het2- furanyl, Het3- pyrrolyl, substituted C1-4- allyloxycarbonyl, pyridinyl, 4,5-dihydro-5-oxo-1H-tetrazolyl, substituted C1-4- alkyl, 2-oxo-3-oxazolidinyl, 2,3-dihydro-2-oxo-1H-benzimidazol-1-yl or a radical of the formula II, in which Z represents a group S-CH =CH, S-CH-CH2S-CH2-CH2-CH2CH= CH-CH = CH. The compounds possess anti-allergic activity. Describes how to obtain these compounds, pharmaceutical compositions and a method of obtaining a composition for the treatment of allergic diseases. 11 C. and 3 h.p. f-crystals.

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The invention relates to new derivatives of imidazo/1,2-a/ thieno /2,3-d/azepino having antiallergic activity.

In the European patent EP-A-0 339 978 describes (benzo - or pyrido)cycloheptatriene, which are useful as antagonists of PAF (platelet activating factor), antihistaminic funds and/or anti-inflammatory drugs. In J. Med Chem., 26(1983), 974-980 describes some derivatives of 1-methyl-4 - piperidinylidene-9-substituted pyrrolo/2,1-d/3/benzazepine with neuroleptic properties.

In WO 92/06981 describes substituted CLASS="ptx2">

The present invention is the creation of new derivatives of imidazo/1,2-a/(thieno-)/2,3-d/azepine having antiallergic activity that allows you to create a pharmaceutical composition for the treatment of allergic diseases.

This goal is achieved new imidazo/1,2-a/-(thieno-) /2,3-d/azepine formula

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and their pharmaceutically suitable salts connection and stereochemical isomers, which

each dashed line independently denotes possible (additional) communication;

R1represents hydrogen, C1-4-alkyl,

R2represents hydrogen, C1-4-alkyl, C1-4-alkyl, substituted hydroxycarbonyl or1-4-allyloxycarbonyl,

R3represents hydrogen, C1-4-alkyl,

X represents S

L represents hydrogen, C1-6-alkyl, C1-6is alkyl having one Deputy selected from the group consisting of hydroxy-group, WITH1-4-alkyloxy, hydroxycarbonyl,1-4-allyloxycarbonyl,1-4-alkylaminocarbonyl,1-4-allyloxycarbonyl,1-4-allyloxycarbonyl-C1-4-alkyloxy, gidroksilaminami, aryl and alloctype; C3-6alkenyl, substituted aryl; where each aryl is phenyl or phenyl substituted by halogen, a hydroxy-group, WITH1-4-alkyl, C1-4-alkyloxy or L is a radical of the formula

-Alk-Y-t1(a-1)

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

-Alk-Het3(a-3), in which

Alk represents a C1-4-alcander;

Y represents 0 or NH; HET1is pyrimidinium

HET2is TuranAlem HET3each represents pyrrolyl, substituted C1-4-allyloxycarbonyl; pyridinyl, 4,5-dihydro-5-oxo-1H-tetrazolyl, substituted C1-4-alkyl, 2-oxo-3-oxazolidinyl, 2,3-dihydro-2-oxo-1H - benzimidazole-1-yl or a radical of the formula

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in which Z is a group S-CH= CH, S-CH2-CH2S-CH2-CH2-CH2CH=CH-CH=CH

Compounds of the present invention differ structurally from the cited known compounds that Central 7-membered nucleus constantly contains a nitrogen atom condensed imidazole nucleus and their favorable antiallergic activity.

Mentioned above, the term halogen denotes fluorine, chlorine, bromine and iodine; C1-4-alkyl denotes nusapersada, for example, methyl, ethyl, propyl, 1-methylated, butyl, 1-methylpropyl, 2-methylpropyl, and 1,1-dimethylethyl; C1-6-alkyl means the above alkali and higher homologues them, having from 5 to 6 carbon atoms, such as pentyl and hexyl; C3-6alkenyl is a hydrocarbon radicals with a chain of normal or branched structure containing one double bond and having from 3 to 6 carbon atoms, for example 2-propenyl, 2-butenyl, 3-butenyl, 2-methyl-2-propenyl, 2 - pentenyl, 3-pentenyl, 3,3-dimethyl-2-propenyl, hexenyl and the like radicals;1-4-alcander denotes a divalent hydrocarbon radicals with a chain of normal or branched structure containing from 1 to 4 carbon atoms, for example methylene, 1,1-ethandiol, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol and similar radicals.

Used above, the term "suitable pharmaceutical salts accession" means a non-toxic therapeutically suitable salt of adhesion, which can form compounds of formula (I). The compounds of formula (I) having the properties of bases can be converted into the corresponding therapeutically active, non-toxic salts with acids by treatment of the free base with a suitable number correspond to the e as halogenation acid, for example hydrochloric acid, Hydrobromic acid and the like acids, sulfuric acid, nitric acid, phosphoric acid and the like acids, or organic acids such as acetic, propanoic, hydroxyestra, 2-hydroxypropanoic, 2-oxopropanoic, ethicality (oxalic acid), perpendiculat, butanedioate, (Z)-2-butandikislota, (E)-2-butandikislota, 2-hydroxybutyrate, 2,3-dihydroxybutanedioate, 2-hydroxy-1,2,3-propanetricarboxylate acid, metasolv, econsult, baselslt-, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.

The compounds of formula (I) having acidic properties, can be transformed in a similar manner into the corresponding therapeutically active, non-toxic salts of accession with the grounds. Examples of such connections with bases are, for example, salts of sodium, potassium, calcium, and salt with a pharmaceutically suitable amines, such as ammonia, alkylamines followed, benzathine, N-methyl-D-glucamine, geranamine, amino acids, e.g. arginine, lysine. The term "pharmaceutically suitable salt accession also includes a solvate, which can form with stereochemically isomers" means different possible isomers, as well as conformational forms (conformers), which may be of the compounds of formula (I). If not specified or not specified otherwise, the chemical determination of compounds denotes the mixture of all possible stereochemical and conformational isomers, and these mixtures containing all diastereomers, enantiomers and/or conformers of the main molecular structure. All stereochemical isomers of compounds of formula (I), as in the form of a pure isomer, or a mixture of them, is included in the scope of the present invention.

Some compounds of the present invention may exist in different tautomeric forms, all of these tautomeric forms are included within the scope of the present invention.

A special group of compounds are those compounds of formula (I) in which L represents hydrogen; C1-6-alkyl; C1-6is alkyl having one Deputy selected from the group consisting of hydroxy-group, WITH1-4-alkyloxy, hydroxycarbonyl,1-4-allyloxycarbonyl,1-4-allyloxycarbonyl - C1-4-alkyloxy, hydroxycarbonyl-C1-4-alkyloxy, C1-4-alkylaminocarbonyl,1-4-alkylaminocarbonyl, aryl and alloctype; C1-61(a-1), Alk-NH-CO-Het2(a-2) or Alk-Het3(a-3).

Interesting compounds of formula (I) are those compounds in which R1, R2and R3represent hydrogen.

Another group of interesting compounds of formula (I) are those compounds in which X represents s

Another group of interesting compounds of formula (I) are compounds of the formula

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in which the dashed line, X, L, R1, R2and R3have the meanings specified for formula (I).

The preferred compounds are those compounds of formula (I) in which L represents a C1-4-alkyl.

The most preferred compounds are: 6,10-dihydro-10-(1-methyl-4-piperidinylidene)-5H-imidazo/1,2-a/thieno/2,3 - d/azepine and its stereoisomers and pharmaceutically suitable salts of the merger.

The following paragraphs explain the different ways of obtaining compounds of formula (I). To simplify the structural formulas of the compounds of formula (I) and intermediates involved in their preparation, part of imidazo/1,2-a)(pyrrolo-, thieno - or furano) /2,3-d/diazepine will be presented next sign T

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The compounds of formula (I) can be obtained by cyclization of Udachnogo product of formula (II) or (III) a suitable acid with the formation of a reactive intermediate product, which cyclist in the compound of formula (I). Suitable acids are, for example, a strong acid, in particular, systems with excess acid, such as methanesulfonate, triftoratsetata, triperoxonane acid, methansulfonate/boron TRIFLUORIDE, hydrofluoric acid/boron TRIFLUORIDE or a Lewis acid such as aluminium chloride, trimethylsilyl iodide, phosphorylchloride. It is obvious that the above method can be used to obtain only those compounds of formula (I) in which L is stable under the conditions of this reaction.

In the above and subsequent methods of obtaining the reaction mixture is treated with known methods and the reaction product is isolated and, if required, to further purify.

The compounds of formula (I), in which the Central core of tricyclic part does not contain possible (additional) communication, can also be obtained by cyclization of an intermediate of formula (IV)

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In the formula (IV) and subsequent formulas, W is a suitable removable group, such as halogen, for example chlorine, bromine and the like group, or sulfonyloxy, for example, methanesulfonate-, 4-methylbenzenesulfonate and similar groups.

Such realestate, alkanol, ketone, simple ether, dipolar aprotic solvent or mixture of such solvents. For acceptance of the acid that is released during the reaction, it is possible to add a suitable base, such as, for example, carbonate, bicarbonate, alkoxide, hydride, hydroxide or oxide of an alkaline or alkaline earth metal or organic base. In some cases, it is advisable to add iodide salt, preferably the alkali metal iodide. Sometimes the reaction rate can be increased by increasing temperature and stirring of the reaction mixture.

Alternative compounds of formula (I), in which between piperidinium and balance imidazo/1,2-a/(pyrrolo-, thieno - or furano) /2,3-d/azepine there is a double bond, and these compounds are represented by formula (I-a), can be obtained by dehydration of the alcohol of formula (V) or (VI).

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This dehydration reaction can be conveniently performed using conventional dehydrating reagents with known methods. Suitable dehydrating reagents are, for example, acids such as sulfuric acid, phosphoric acid, phosphorous acid, hydrochloric acid, methanesulfonate, carboxylic acid, e.g. acetic acid, trifter the ot suitable reagents, for example, zinc chloride, chloride thionyl, apirat boron TRIFLUORIDE, phosphorylchloride, potassium bisulfate, sodium hydroxide or phosphorylchloride. This cyclization reaction may carried out in inert in the reaction conditions, solvents, such as, for example, halogenated hydrocarbon, e.g. dichloromethane. In some cases, the dehydration reaction may require heating of the reaction mixture, more specifically, to the boiling temperature of the reaction mixture. Again it should be noted that this way you can receive only those compounds of formula (I-a) in which L is stable under the conditions of this reaction.

The compounds of formula (I) in which L represents a C1-6-alkyl, with those compounds represented by formula (I-b), can be converted into compounds of formula (I) in which L represents hydrogen, these compounds are represented by formula (I-c), in a variety of ways. The first method involves dealkylation of the carbonyl compounds of the formula (I-b)1-4-alkylchlorosilanes and subsequent hydrolysis of the thus obtained compounds of formula (VII-a).

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Reaction with1-4-alkylchlorosilanes usually carried out by stirring and heating the starting compound (I-b) with rtsa, for example, aromatic hydrocarbons such as methylbenzol, xylene, chlorobenzene; ethers, such as 1,2-dimethoxyethane, and similar solvents. Suitable bases are, for example, carbonates, bicarbonates and hydroxides of alkaline or alkaline earth metals or organic bases, for example, N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine and similar reasons. The compounds of formula (VII-a) hydrolyzing in acidic or basic medium by conventional methods. For example, you can apply a concentrated acid, such as Hydrobromic acid, hydrochloric acid or sulfuric acid, or bases, such as hydroxides of alkali or alkaline earth metals, such as caustic soda or sodium hydroxide, in water, alkanol or a mixture of water-alkanol. Suitable alkanols are methanol, ethanol, 2-propanol, etc. To increase the reaction rate, it is useful to heat the reaction mixture, in particular, to the boiling temperature of the reaction mixture.

The compounds of formula (I-b) can also be converted into compounds of the formula (1-e) mixing and heating them with - halogen-C1-4-alkylchlorosilanes in a suitable solvent, such as, for example, halogenated hydrocarbon, e.g. dichloromethane, T2-dimethoxyethane; alcohol, for example methanol, ethanol, 2-propanol, possibly in the presence of a base, such as, for example, carbonate, bicarbonate, hydroxide of alkali or alkaline earth metal, or amine, such as N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine and such connection.

The compounds of formula (I-c) can also be obtained by dibenzylammonium the compounds of formula (I-d) by catalytic hydrogenation in the presence of hydrogen and a suitable 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. Suitable solvent, inert under the reaction conditions, for example, is an alcohol, e.g. methanol, ethanol, 2-propanol; esters, e.g. ethyl acetate; acid, e.g. acetic acid and the like solvents.

The compounds of formula (I) in which L represents hydrogen, these compounds are represented by formula (I-e) and L presents L1you can get N-alkylation of compounds of formula (I-c) with a reagent of formula L1-W (VIII).

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This reaction N-alkylation can be carried out in an inert under the reaction conditions solvent, such as, for example, aromatic uglevodah of such hydrocarbons. Adding a suitable base, such as, for example, carbonate, bicarbonate, alkoxide, hydride, amide, hydroxide or oxide of an alkaline or alkaline-earth metal, or an organic base, you can apply for acceptance of the acid that is released during the reaction. In some cases, it is advisable to add iodide salt, preferably the alkali metal iodide. Sometimes elevated temperature and mixing can increase the reaction rate. An alternative is the N-alkylation can be carried out in known conditions of the reactions catalyzed transfer phases.

The compounds of formula (I) in which L represents a C1-6is alkyl or substituted C1-C6-alkyl, you can also get recovery N-alkylation of compounds of formula (I-c) by known methods. The compounds of formula (I) in which L represents a C1-6is alkyl or substituted C1-6-alkyl, can also be obtained by reaction of joining compounds of the formula (I-c) with a suitable alkene by known methods. The compounds of formula (I) in which L represents a C1-6-alkyl, substituted by a hydroxy-group, can be obtained by reaction of compounds of formula (I-c) with a suitable epoxide by known methods. articlecheck radical and piperidine, can be converted into compounds of formula (I) with the single bond in one or both of the above provisions by known methods.

The compounds of formula (I) can also be transformed into each other by known methods of transformation of functional groups.

Some examples of these techniques is given next. The compounds of formula (I), substituted amino group, can be obtained by hydrolysis of the corresponding lidocaine. The amino group can be N-alkilirovanii or N-allievate known methods. In addition, the compounds of formula (I) containing ester groups can be converted to a carboxylic acid by the known methods of hydrolysis. Aromatic ethers can be converted into the corresponding alcohols known methods for the cleavage of ethers. The compounds of formula (I) containing a hydroxy-group as a substituent, can About-to alkilirovanii or About-to allievate known methods.

The compounds of formula (VII-a) participating in the above-described methods of preparation, are new compounds, in particular, their use as intermediates in these sources. Therefore, the present invention relates to new compounds of the formula

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-allyloxycarbonyl,1-4-alkylsulphonyl or1-6-alkyl substituted by halogen, cyano, amino group or methylsulfonylamino.

Particularly interesting compounds of the formula (VII) are those compounds in which Q represents a C1-6-allyloxycarbonyl, their salts connection and stereochemical isomers.

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

Intermediates of formula (II) can be obtained from the corresponding ketones of the formula (III) restoration

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Such reversal is convenient to carry out the initial reaction of ketone (III) with hydrogen in a solvent, such as alcohol, for example methanol, ethanol, acid, for example acetic acid; complex ester, such as ethyl acetate; in the presence of a hydrogenation catalyst, for example palladium on charcoal, platinum on charcoal, Raney Nickel. To increase the speed of the reaction, the reaction mixture can be heated and, if required, you can increase the hydrogen pressure.

Alternative alcohols of the formula (II) can also be obtained restore the reed sodium and the like reducing agents, in a suitable solvent, such as, for example, a simple ester, for example, 1,1'-oxybisethane, tetrahydrofuran; alcohol, e.g. methanol, ethanol and the like alcohol.

Ketones of the formula (III) can be obtained by joining the compounds of formula (IX) to the reagent of formula (X) with known methods.

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Ketones of the formula (III), in which the dotted line is an additional bond, you can get N-alkylation of an intermediate product of the formula (IX) with a reagent of formula (XI) in which W represents the above-mentioned reactive delete the group.

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This reaction N-alkylation can conveniently carry out the methods used to obtain the compounds of formula (I-e) from compounds of formula (I-c).

Intermediates of formula (V) can be obtained by the addition of Grignard reagent of formula (XII) to the ketone of formula (XIII) in an inert under the reaction conditions solvent, e.g. tetrahydrofuran.

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Tricyclic ketones of the formula (XIII), in turn, is obtained from intermediates of formula (XIV) by oxidation with a suitable oxidizing agent in an inert under the reaction conditions solvent.

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Suitable oxidants are, for example, dioxide, magnesium dioxide aprimer, halogenated hydrocarbons such as dichloromethane, trichloromethane.

The compounds of formula (XIV), in which the dotted line does not represent an additional bond, can be obtained from corresponding compounds of formula (XIV), in which the dotted lines indicate the additional relationship, is known hydrogenation methods, for example, by reaction with hydrogen in the presence of a hydrogenation catalyst.

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Intermediates of formula (XIV-a) can be obtained from benzazepine formula (XV) by reaction with a reagent of formula (XVI), followed by cyclization of the thus obtained intermediate product (XVII) in an acid environment. (XVI) R represents a C1-4-alkyl, or two radicals R together form2-6-alcander, for example, 1,2-ethandiyl, 1,3-PROPANEDIOL, 2,2-dimethyl-1,3-propandiol.

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Obtaining compounds of formula (XVII) is usually carried out by stirring and heating the reactants in an inert under the reaction conditions solvent, such as alcohol, for example methanol, ethanol.

The cyclization reaction to obtain intermediates of formula (XIV-a) is conducted by stirring and heating the starting compound of the formula (XVII) in the carboxylic acid, e.g. acetic acid, proprietory formula (XIV) can also be obtained by cyclization of an intermediate of formula (XVIII).

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This cyclization reaction is usually carried out in the presence of a Lewis acid, e.g. aluminum chloride and similar compounds. In some cases it may be appropriate to Supplement the reaction mixture with a suitable amount of sodium chloride.

Intermediates of formula (V) can also be obtained by cyclization of the intermediate products of the formula (III) in the presence of an acid in an inert under the reaction conditions solvent.

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The acid in the above reaction is used, for example, a Lewis acid such as tin chloride (IV) and such connection. As intertrigo under the reaction conditions of the solvent used, for example, halogenated hydrocarbon, e.g. dichloromethane, 1,2-dichloroethane and the like solvents.

Intermediates of formula (VI) can be obtained by reaction of a ketone of formula (XIX) with an intermediate product of the formula (XIV) in the presence of, for example, diisopropylamide lithium in an inert solvent, e.g. tetrahydrofuran.

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The compounds of formula (V) or (VI), in which the dotted line forms a double bond, can be converted into compounds of formula (V) or (VI), in which the dotted line forms a single bond, by known methods in Auda new compounds and, in particular, they are used as intermediate products of these methods of obtaining. Therefore, the present invention relates to new compounds of the formula

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and their salts connection and stereochemical isomers, in which the dotted line, L, R1, R2, R3and X have the meanings indicated for formula (I).

The compounds of formula (I) and some compounds of formula (VII), in particular those in which Q represents a C1-6-allyloxycarbonyl, their salts connection and stereochemical isomers possess suitable pharmacological properties. In particular, they are anti-allergic agents, which activity is clearly possible to demonstrate the results obtained in a series of demonstration tests. Antihistaminew activity can be shown in tests to protect rats from induced compound 48/80 lethality (Arch. Int. Pharmacodyn. Ther. 234, 164-176, 1978). ED50- values for compounds 1, 3, 5, 6, 8-12, 14-19, 21-23, 27, 29-32 and 35-37 equal to or below 0,31 mg/kg

An important feature of the compounds of the present invention is their excellent activity when administered orally; it is shown that these compounds when administered orally almost what is rapid onset of their actions and the appropriate duration of action.

Since the compounds of formula (I) and compounds of formula (VII) and their salts accession possess anti-allergic properties, they are suitable for the treatment of allergic diseases of a wide range, for example, allergic rhinitis, allergic conjunctivitis, chronic urticaria, allergic asthma and related diseases.

Since these compounds have suitable anti-allergic properties, they can be produced in the form of various pharmaceutical preparations for introduction into the body. To obtain anti-allergic preparations of the present invention an effective amount of a specific compound in the form of a base or salt with the acid as an active ingredient is intimately mixed with a pharmaceutically suitable carrier, which may take different forms depending on the form of preparation desired for administration. These pharmaceutical preparations are preferably produced in the form of uniform dose, preferably suitable for administration orally, rectally, through the skin, or parenteral injection. To get drugs, for example, in oral dosage form can be applied with any conventional pharmaceutical environment, for example, water, glycols, oils, alcohols in the and, for example, starches, sugars, kaolin, lubricants, binders, dezintegriruetsja agents and other substances in the form of powders, pills, capsules and tablets. Because of the ease of introduction of tablets and capsules are the most favorable oral standardized dosage forms. Obviously, in this case, use solid pharmaceutical carriers. For parenteral drug carrier is usually a sterile water, at least is more a part of, but may include other components, for example, to increase the solubility. You can get injectable solutions, for example, which carrier is a saline solution, a glucose solution or a mixture of saline and glucose solution. You can also get injectable suspension, in this case, you can apply a suitable liquid carriers, suspendresume funds and similar funds. In preparations suitable for injection through the skin, the carrier may contain a means of enhancing the penetration of the active component inside, and/or a suitable wetting agent, possibly together with suitable additives of any nature in small amounts. These additives must not exert any significant which of these drugs. These drugs can be administered in a number of ways. For example, by applying them to the skin in the form of bandages, patches or ointments. Salt accession of these compounds due to their high solubility in water compared with the corresponding reason, obviously, is more suitable for aqueous preparations.

Particularly beneficial preparation of the above pharmaceutical preparations in the form of uniform doses to facilitate their introduction and unification of dosing. The term dosage form used in the description and the claims refers to physically discrete units suitable as standardized doses, each unit contains a specified quantity of active ingredient calculated to produce the desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such dosage forms are tablets (including tablets with shell and without it), capsules, pills, sachets of powder, wafers, injectable solutions or suspensions, drugs with a measuring teaspoon or tablespoon and segregated part of them.

The present invention relates also to a method of treating warm-blooded animals suffering from such Alla is and the compounds of formula (I) or the compounds of formula (VII) or its salt accession.

Effective antiallergic amount should be 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 of body weight.

The following examples are intended to illustrate and not limit the scope of the invention in all of its features.

The experimental part.

A. Obtaining an intermediate product.

Example 1. a) a Mixture of monohydrochloride ethyl-2-thiophenemethylamine (ether) (0.05 m) in tetrahydrofuran (100 ml) is stirred under nitrogen atmosphere. Upon cooling, the parts add 2,2-dimethoxyethane (0.05 m) and the mixture is stirred over night. After evaporation of the mixture obtain 15.6 g (100%) monohydrochloride N-(2,2-dimethoxymethyl)-2-thiophenemethylamine (intermediate 1).

b) a Mixture of intermediate 1 (0.05 m) in acetic acid (50 ml) and a solution of Hydrobromic acid in acetic acid 30% (50 ml) was stirred at 50oC for 24 hours. The mixture is evaporated and the residue is dissolved in water. The mixture is filtered through hyflo and alkalinized with caustic soda. The residue is separated by filtration, washed with water, dissolved in tetrahydrofuran, discolor Norriton and dried (MgSO4). The mixture of the filter is prohibited/2,3-d/azepin-7-amine (intermediate 2).

(C) a Mixture of intermediate 2 (or 0.027 mole) and 2,2-dimethoxyethane (0,054 mol) in methanol (100 ml) is stirred and refluxed overnight. The mixture is evaporated to give 10 g (100%) of N-(2,2-dimethoxymethyl)-8H-thieno/2,3-d/azepin-7-amine (intermediate 3).

d) a Mixture of intermediate 3 (or 0.027 mol) in acetic acid (95 ml) and hydrochloric acid (12.5 ml) was stirred at 70oC during the night. The mixture is evaporated, the residue is dissolved in water, alkalinized with caustic soda and extracted with dichloromethane. The organic layer is separated, dried and evaporated, obtaining 3.4 g (67%) 10H-imidazo/1,2-a/thieno/2,3-d/azepine (intermediate 4).

e) a Mixture of intermediate 4 (0,018 mol) and manganese dioxide (17 g) in dichloromethane (200 ml) is stirred for 3 days at 40oC. Add trichlormethane (200 ml) and the mixture refluxed for 30 minutes the Mixture is filtered while hot through hyflo, washed with trichloromethane and evaporated. The residue is boiled in acetonitrile and cooled. The residue is separated by filtration and dried, obtaining of 1.53 g (42%) 10H-imidazo/1,2-a/thieno/2,3-d/azepin-10-she (intermediate 5).

f) Iodine (a few crystals) are added under stirring to a mixture of magnesium turnings (0.01 methylpiperidin (0,01 mol), dissolved in tetrahydrofuran (5 ml) and the mixture refluxed for 2 hours. Add tetrahydrofuran (5 ml). In parts add intermediate product 5 (0,0075 mol) (temp. 55-60o) and the mixture refluxed for 1 hour. The mixture is cooled, decomposed with a solution of NH4Cl and extracted with a mixture of dichloromethane/methanol. The organic layer is dried and evaporated. The residue is purified column chromatography on silica gel (eluent: a mixture of CH2Cl2/CH3OH, 95:5, CH2Cl2/(CH3OH/NH3), 95:5). Select the pure fractions and evaporated, obtaining 1.6 g(71%) ()-10-(1-methyl-4-piperidinyl)-10H-imidazo/1,2-a/thieno/2,3-d/ azepin-10-ol (intermediate 6).

g) a Mixture of intermediate 6 (0,01 mol) hydronaut in methanol (100 ml) overnight using as a catalyst of palladium on charcoal (10%) (2 g). The catalyst was removed by filtration and hydronaut later in the night. After uptake of hydrogen (1 EQ.) the catalyst is separated by filtration. The residue is evaporated and purified column chromatography on silica gel (eluent: CH2Cl2/(CH3OH/NH3), 95:5). Pure fractions are taken and evaporated, obtaining 2.3 g of product. The sample (1,15 g) crystallized eroticly product 7).

Example 2. a) a Dispersion of sodium hydride in mineral oil (50%) (0,088 mole) is added in N,N-dimethylformamide (150 ml) under stirring in nitrogen atmosphere. In parts add (1H-imidazo-2-yl)-(1-methyl-4-piperidinyl)methanon (0,08 mol) and the mixture is stirred for 1 hour. Added dropwise methanesulfonate 3-thiopentone (ether) (0,086 mole), dissolved in a small amount of N,N-dimethylformamide, and the mixture is stirred under heating at an oil bath at 60othroughout the night. The mixture is cooled, decomposed with water and extracted with dichloromethane. The organic layer is dried, filtered and evaporated. The residue is purified column chromatography on silica gel (eluent: CH2Cl2/(CH3OH/NH3), 95:5). Pure fractions are taken and evaporated, obtaining 15 g (61,8%) (1-methyl-4-piperidinyl) /1-/2-(3-thienyl)ethyl/- 1H-imidazol-2-yl/methanone (intermediate 8).

b) a Mixture of intermediate 8 (0,02 mol) in 1,2-dichloroethane (100 ml) is stirred under nitrogen atmosphere. At room temperature, added dropwise chloride tin (IV) and the mixture was stirred at 80oC for 2 hours. The mixture is cooled, poured into ice, alkalinized with potassium carbonate, extracted with dichloromethane and ethanol and evaporated. The residue is purified colruyt and evaporated. The residue is crystallized from acetonitrile. The precipitate was separated by filtration and dried, obtaining 2.2 g (36,7%) ()-6,10-dihydro-10-(1-methyl-4-piperidinyl)-5H-imidazo/1,2 - a/thieno-/2,3-d/azepin-10-ol; so pl. 176,6oC (intermediate 7).

C. obtain the final compounds.

Example 3. a) a Mixture of intermediate 6 (0,005 mol) in chloroxine phosphorus (50 ml) stirred at the boil under reflux for 2 hours. The mixture is evaporated and the residue is dissolved in water, alkalinized with caustic soda and extracted with a mixture of dichloromethane/methanol. The organic layer is separated, dried and evaporated. The residue is purified on a glass filter with silica gel (eluent: CH2Cl2/(CH3OH, 95: 5/- CH2Cl2/(CH3OH/NH3, 95:5). Pure fractions are taken and evaporated. The residue (1.2 g) crystallized from acetonitrile, receiving 0.3 g (21%) 10-(1-methyl-4-piperidinylidene)-10H-imidazo/1,2-a/thieno/2,3 - d/azepin; so pl. 152,2oC (compound 1).

Example 4. The intermediate product 7 (0,237 mole) and phosphorous acid 98% (1200 g) was stirred in nitrogen atmosphere for 4 hours at 80oC. the Mixture was poured into ice, alkalinized with caustic soda and extracted with dichloromethane. The organic layer is dried (MgSO4), filtered and evaporated. The residue is purified colonoscopist, getting 3.5 g(5,2%) ()-10-(1-methyl-4-piperidinyl)-10H-imidazo-/1,2-a/thieno/2,3-d/azepine (compound 2).

Similarly get:

ethanolate (2: 1) (E)-2-butenedioate (1:2) 6,10-dihydro-10-(1-methyl-4 - piperidinylidene)-5H-imidazo/1,2-a/thieno/2,3-d/azepine; so pl. 164,7oC (compound 3).

Example 5. a) a Mixture of compound 1 (0,0095 mol) and N,N-diethylethanamine (to 0.19 mol) in methylbenzene (1.5 l) was stirred while boiling under reflux. Added dropwise ethyl ester chlorocarbonic acid (value (0.475) mol) and the mixture is 2 hours and refluxed. The mixture is cooled, add water, alkalinized with potassium carbonate and extracted with methylbenzol. The organic layers separated, dried and evaporated. The residue is purified column chromatography on silica gel (eluent: CH2Cl2/(CH3OH, 95:5). Pure fractions are taken and evaporated. The residue (24 g) was stirred in 2,2'-oxybisethane and filtered. The residue is recrystallized from acetonitrile, receiving 17.3 g (53,3%) ethyl-4-(10H-imidazo/1,2-a/thieno/2,3-d/azepin-10-ilidene)-1-piperidinecarboxylate, so pl. 176,5oC (compound 4).

Similarly get:

ethyl-4-(5,6-dihydro-10H-imidazo/1,2-a/thieno/2,3-d/ azepin-10-ilidene)-1-piperidinecarboxylate; so pl. 181,5oC (southertelecom with stirring for 8 hours. The mixture is evaporated, dissolved in water and extracted with dichloromethane. The organic layer is separated, dried and evaporated. The residue is purified on a glass filter with silica gel (eluent: CH2Cl2/(CH3OH/NH3), 90:10). Pure fractions are taken and evaporated, obtaining 13 g of the product. A sample (3 g) turn into salt with (E)-botanically (2:1) in ethanol, getting 1,77 g (E)-2-butenedioate(2:1) 10-(4-piperidinylidene)-10H-imidazo/1,2 - a/thieno/2,3-d/azepine; so pl. 275,0oC (compound 6).

Similarly get:

(E)-butenedioate (1: 1) 6,10-dihydro-10-(4-piperidinylidene)-5H-imidazo/1,2-a/thieno/2,3-d/azepine; so pl. to 252.7oC connection 7).

Example 6. a) a Mixture of 1-(2-chloroethyl)-4-methoxybenzene (0,012 mol), compound 7 (0,01 mol) and N,N-diethylethanamine (0.05 m) in N,N-dimethylacetamide (50 ml) was stirred at 80oC on an oil bath for 16 h and then at 90oC for 24 hours. The mixture is cooled and evaporated. The residue is dissolved in water, alkalinized with potassium carbonate and extracted with dichloromethane. The organic layer is dried, filtered and evaporated. The residue is purified column chromatography on silica gel (eluent: CH2Cl2/(CH3OH/NH3), 95:5). The appropriate fractions are taken and evaporated. The residue (3 g) clear Saut in salt with ethicality (1:2) in ethanol, obtaining 0.8 g (11.4%) of product. The product is crystallized twice from methanol and dried in a gun under 100oC, receiving 0.6 g (8,5%) of candiota (1:2) 6,10-dihydro-10-/1-/2-(4- methoxyphenyl)ethyl/-4-piperidinylidene/-5H-imidazo/1,2-a/thieno/2,3 - d/azepine; so pl. 172,5oC (compound 8).

Similarly get:

1-ethyl-1,4-dihydro-4-/2-/4-(10H-imidazo/1,2-a/thieno/2,3 - d/azepin-10-ilidene)-1-piperidinyl/ethyl/-5H-tetrazol-5-he; so pl. 181,2oC (compound 9);

3/2-/4-(10H-imidazo/1,2-a/thieno/2,3-d/azepin-10-ilidene)-1 - piperidinyl/ethyl/-2-oxazolidinone; so pl. 189,9oC (compound 10);

(E)-2-butenedioate(2: 3) 3-/2-/4-(10H-imidazo/1,2-a/thieno/2,3-d/- azepin-10-ilidene)-1-piperidinyl/ethyl/-2-methyl-4H-pyrido/1,2 - a/-pyrimidine-4-it; so pl. 222,7oC (compound 11);

(E)-2-butenedioate(2:7) 6-/2-/4-(5,6-dihydro-10H-imidazo/1,2 - a/thieno/2,3-/azepin-10-ilidene)-1-piperidinyl/ethyl/-7-methyl-5H - thiazolo/3,2-pyrimidine-5-it; so pl. 213,1oC (compound 12);

1-/2-/4-(5,6-dihydro-10H-imidazo/1,2-a/thieno/2,3-d/azepin-10-ilidene)-1-piperidinyl/ethyl/-4-ethyl-1,4-dihydro-5H-tetrazol-5-he; so pl. 163,3oC (compound 13);

ethanolate (2:1) cyclohexylsulfamate(1:2) 1-/3-/4-(5,6- dihydro-10H-imidazo/1,2-a/thieno/2,3-d/azepin-10-ilidene)-1 - piperidinyl/-propyl/-1,3-dihydro-2H-benzimidazole-2-it; so pl. 174,7oC (compounds is ethyl/-2 - oxazolidinone; so pl. 171,6oC (compound 15);

cyclohexylsulfamate(1: 3) 10-/1-(2-ethoxyethyl)-4-piperidinylidene/ -6,10-dihydro-5H-imidazo/1,2-a/thieno/2,3-d/azepine; (compound 16);

4-(5,6-dihydro-10H-imidazo/1,2-a/thieno/2,3-d/azepin-10-ilidene) -N-(1-methylethyl)-1-piperidinophenyl; so pl. 175,7oC (compound 17);

3-/2-/4-(5,6-dihydro-10H-imidazo/1,2-a/thieno/2,3-d/azepin-10 - ilidene)-1-piperidinyl/ethyl/-4H-pyrido/1,2-a/pyrimidine-4-one; so pl. 211,1oC (compound 18);

(E)-2-butenedioate(2:3) 6-/2-/4-(5,5-dihydro-10H-imidazo/1,2 - a/thieno/2,3-d/azepin-10-ilidene)-1-piperidinyl/ethyl/-2,3-dihydro - 7-methyl-5H-thiazolo/3,2-pyrimidine-5-it; so pl. 209,1oC (compound 19);

ethyl-/2-/4-(5,6-dihydro-10H-imidazo/1,2-a/thieno/2,3 - d/azepin-10-ilidene)-1-piperidinyl/ethyl/carbamate (compound 20);

cyclohexylsulfamate(1: 3) 10-/1-/3-(4-pertenece)propyl/-4 - piperidinylidene/-6,10-dihydro-5H-imidazo/1,2-a/thieno/2,3-d/- azepine (compound 21);

7-/2-/4-(5,6-dihydro-10H-imidazo/1,2-a/thieno/2,3-d/azepin-10-ilidene)-1-piperidinyl/ethyl/-3,4-dihydro-8-methyl-2N, 6N-pyrimido/2,1 - d//1,3/thiazin-6-he; so pl. 221,8oC (compound 22);

hemihydrate of candiota (1: 2) (E)-6,10-dihydro-10-/1-(3-phenyl-2-propenyl)-4 - piperidinylidene/-5H-imidazo/1,2-a/thieno/2,3-d/-azepine; so pl. 183,7oC (compound 23);

hemihydrate 1-acetyl-4-(5,6-dihydro-ANO/2,3-d/-azepin-10-ilidene)-1-piperidinyl/amoxi/acetate (compound 25).

b) a Mixture of compound 8 (0,01 mol) and sodium sulfite (0.1 g) in a solution of Hydrobromic acid in water 48% (100 ml) is stirred and refluxed for 4 hours. The solvent is then evaporated. The residue is stirred in water and the mixture is alkalinized with potassium carbonate. The mixture is extracted with dichloromethane. The separated organic layer is dried (MgSO4), filtered and evaporated from it solvent. The residue is purified on a glass filter with silica gel (eluent: CH2Cl2/CH3OH, 95:5). Pure fractions are taken and the solvent is evaporated. The residue is crystallized from acetonitrile. The precipitate was separated by filtration and dried, obtaining of 0.53 g (14%) 6,10-dihydro-10-/1-/2-(4- hydroxyphenyl)ethyl/-4-piperidinylidene/-5H-imidazo/1,2-a/-thieno/2,3 - d/azepine, so pl. above 200oC (compound 26).

Example 7. a) a Mixture of methyl-2-propionate (0,024 mol) and compound 7 (0,02 mol) in methanol (100 ml) is stirred for 6 hours at room temperature. The mixture is evaporated and the residue purified on a glass filter with silica gel (eluent: CH2Cl2/CH3OH, 95:5) Pure fractions are taken and evaporated. The residue is crystallized from a mixture of 2,2'-oxybisethane/acetonitrile, receiving 4.5 g (63%) of methyl-4-(5,6-dihydro-10H-imidazo/1,2-a/thieno/2,3-d/azepin-10 - ilidene)-1-piperidin the l)ethyl/-4-piperidinylidene/- 5H-imidazo/1,2-a/thieno/2,3-d/azepin; so pl. 144,4oC (compound 28).

b) a Mixture of compound 27 (0,0031 mole) with sodium hydroxide (0,01 mol), water (50 ml), ethanol (10 ml) and tetrahydrofuran (20 ml) was stirred at room temperature overnight. The mixture is evaporated into water and washed with dichloromethane. Add dropwise 1 N hydrochloric acid (10 ml), the precipitate was separated by filtration and dried, obtaining 0.51 g (48%) hemihydrate 4-(5,6-dihydro-10H-imidazo/1,2 - a/thieno/2,3-d/azepin-10-ilidene)-1-piperidinemethanol acid; so pl. 250,2oC; (compound 29).

Similarly get:

/2-/4-(5,6-dihydro-10H-imidazo/1,2-a/thieno/2,3-d/azepin-10-ilidene)-1-piperidinyl)ethoxy/acetic acid; so pl. KZT 205.7oC (compound 30).

Example 8. a) a Mixture of compound 7 (of 0.017 mol) in methanol (200 ml) was stirred at room temperature. Through the mixture for 3 hours verbatimout oxiran (excess) and the mixture is stirred at room temperature for another 1 hour. The mixture is evaporated and the residue purified on a glass filter with silica gel (eluent: CH2Cl2/(CH3OH/NH3), from 95:5 to 90:10). Pure fractions are taken and evaporated. The residue is crystallized from acetonitrile, receiving 4 g (75%) of 4-(5,6-dihydro-10H-imidazo/1,2-a/thieno/2,3 - d/azepin-1-ilidene)-1-piperazineethanol; so pl. 154,8oC (to connect the 0 ml) is stirred under nitrogen atmosphere at room temperature. Add dropwise a solution of compound 31 (0,008 mol) in N,N-dimethylformamide and the mixture is stirred for 1 hour at room temperature. Add on parts 2-chloropyrimidine (0,012 mol) and the mixture is stirred for 1 hour at room temperature. The mixture is heated to 50oC and stirred at 50oC for 48 hours. The mixture is cooled, decomposed with water, extracted with dichloromethane. The organic layer is dried (MgSO4), filtered and evaporated. The residue is purified on a glass filter with silica gel (eluent: CH2Cl2/- CH3OH, 93:7). Pure fractions are taken and evaporated. The residue is converted into the salt with cyclohexanesulfamic acid (1:3) in 2-propanol, getting 1.27 g (17%) cyclohexylsulfamate (1: 3) 6,10-dihydro-10-/1-/2-(2-pyrimidinone)ethyl/-4-piperidinylidene/-5H-imidazo/1,2-a/thieno/2,3-d/azepine; so pl. 122,1oC (compound 32).

Example 9. A mixture of compound 20 (0,01 mol) and sodium hydroxide (0,1 mol) in 2-propanol (50 ml) is refluxed under stirring for 3 hours. The mixture is evaporated, the residue is dissolved in dichloromethane (300 ml), dried (MgSO4), filtered through hyflo and evaporated. The residue is purified on a glass filter with silica gel (eluent: CH2Cl2/(CH3OH/NH3), 90:10). Pure fractions are taken and the issue is.

Example 10. A mixture of ethyl-(3,5-diethoxyanthracene-2-furanyl)carboxylate (0,02 mol) and compound 33 (of 0.01 mole) in acetic acid (50 ml) is stirred for 2 hours while heating at 80oC in the oil bath. The mixture is evaporated. The residue is dissolved in water, alkalinized with potassium carbonate and extracted with dichloromethane. The organic layer is dried, filtered and evaporated. The residue is purified column chromatography on silica gel (eluent 1: CH2Cl2/CH3OH, 95:5, and eluent 2: CH2Cl2/(CH3OH/NH3), 95:5). Pure fractions are taken and evaporated. The residue is dissolved in 2-propanol, discolor noricum, filtered over hyflo and evaporated. The remainder of the turn (3.7 g) in g with cyclohexanesulfamic acid (1:2) in a mixture of 2-propanol/2-propanone, receiving of 2.36 g (28%) cyclohexylsulfamate (1: 2) 2-propenoate (1:1) ethyl-1/2-/4-(5,6-dihydro-10-imidazo/1,2 - a/thieno/2,3-d/azepin-10-ilidene)-1-piperidinyl)ethyl/-1H-pyrrole-2-carboxylate; so pl. of 112.8oC (compound 34).

Example 11. A mixture of 2-frankenboob acid (0,012 mol) iodide 2-chloro-1-methylpyridine (0,012 mol) and N,N-diethylethanamine (0,024 mol) in dichloromethane (100 ml) is stirred for 1 hour. Added dropwise compound 33 (0,01 mol), dissolved in dichloromethane, and the mixture is stirred during Nochnoi chromatography on silica gel (eluent 1: CH2Cl2/CH3OH, 95:5, eluent 2: CH2Cl2/(CH3OH/NH3), 95:5). Pure fractions are taken and evaporated. The residue (4.4 g) is transformed into a salt with ethicality (1:2) in ethanol. The residue is recrystallized from methanol, obtaining 2.6 g (43%) of the monohydrate of candiota (1: 2) N-/2-/4-(5,6- dihydro-10H-imidazo/1,2-a/thieno/2,3-d/azepin-10-ilidene-1 - piperidinyl/ethyl/-3-furancarboxylic; so pl. 185,9oC (compound 35).

Example 12. A mixture of 2-chloropyrimidine (0,012 mol), compound 33 (0,009 mole) and sodium bicarbonate (0,015 mol) in ethanol (100 ml) is refluxed under stirring for 48 hours. The mixture is evaporated, the residue is dissolved in water and extracted with dichloromethane. The residue is purified column chromatography on silica gel (eluent 1: CH2Cl2/CH3OH, 95:5, eluent 2: CH2Cl2/(CH3OH/NH3), 95: 5), pure fractions are taken and evaporated. The residue is crystallized from acetonitrile, getting 1,72 g (48,9%) of product. The product is recrystallized from acetonitrile, getting 0.64 g (16%) N-/2-/4-(5,6-dihydro-10H-imidazo/1,2-a/thieno/2,3-d/azepin-10-ilidene)-1 - piperidinyl/-ethyl/-2-pyrimidinamine; so pl. 172,6oC (compound 36).

Example 13. The methyl isocyanate (0,012 mol) is added dropwise to stirred mixture of compound 3 is lodochnoy chromatography on silica gel (eluent 1: CH2Cl2/CH3OH, 95:5, eluent 2: CH2Cl2/(CH3OH/NH395: 5). Pure fractions are taken and evaporated. The residue is stirred in 2,2'-oxybisethane. The precipitate was separated by filtration and dried. The residue is crystallized from 2-propanone, receiving of 0.85 g (23%) N-/2-/4-(5,6-dihydro-10H, imidazo/1,2-a/thieno- /2,3-d/azepin-10-ilidene)-1-piperidinyl/ethyl/-N'-methylcarbamate; so pl. 158,9oC (compound 37).

Example 14. A mixture of compound 2 (0,012 mol) in acetic acid (6 ml) and ethanol (150 ml) hydronaut using as a catalyst of palladium on charcoal (7 g) at room temperature for 48 hours. After uptake of hydrogen (1 EQ. ) the catalyst is separated by filtration and the filtrate is evaporated. The residue is dissolved in water, alkalinized with potassium carbonate and extracted with dichloromethane. The organic layer is dried, filtered and evaporated. The residue is purified on a glass filter with silica gel (eluent: CH2Cl2/(CH3OH/NH3), 95: 5), pure fractions are taken and evaporated. The residue is crystallized from 2,2'-oxybisethane, receiving ()-6,10-dihydro-10-(1-methyl-4 - piperidinyl)-5H-imidazo/1,2-a/thieno/2,3-d/azepine; so pl. to 121.0oC (compound 38).

C. Examples of drugs

The following drugs are the spas introduction warm-blooded animal in accordance with the present invention.

The term "active component" (A. K.) used in all of these examples relates to a compound of formula (I) or the compound of formula (VII), their pharmaceutically suitable salts with acids or stereochemical isomers.

Example 15. Oral drops.

500 g A. K. dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol at 60-80oC. After cooling to 30-40oC added 35 l of polyethylene glycol and the mixture well stirred. Then 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 how much glycol to a total volume of 50 l, obtaining a solution for oral administration dropwise containing 10 mg/ml A. K. the resulting solution is poured into suitable containers.

Example 16. Oral solutions.

9 g of Methyl-4-hydroxybenzoate and 1 g of propyl-4-hydroxybenzoate dissolved in 4 l of boiling purified water. In 3 l of this solution are dissolved first 10 g of 2,3-dihydroxybutanedioate and then 20 g A. K. the Latter solution is combined with the remaining part of the first solution and add 12 l 1,2,3-propanetriol and 3 l of 70% aqueous solution of sorbitol. 40 g of sodium salt of saccharin dissolved in 0.5 l of water and add 2 ml asensation to achieve a total volume of 20 l, getting oral solution containing 5 mg A. K. in one teaspoon (5 ml). The resulting solution is poured into suitable containers.

Example 17. The capsule.

20 Mr. A. K., 6 g of lauryl sodium, 56 g of starch, 56 g of lactose, 0.8 g of colloidal silicon dioxide, and 1.2 g of stearine magnesium vigorously stirred together. The mixture is then filled 1000 suitable hard gelatin capsules, each containing 20 mg A. K.

Example 18. Tablets with the shell.

Obtain core tablets.

A mixture of 100 g A. K., 570 g lactose and 200 g starch mix well and then moisturize with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone (Kollidon-K90in about 200 ml of water. The wetted powder mixture is sieved, dried and sieved again. Then add 100 g microcrystalline cellulose (Avieel) and 15 g hydrogenating vegetable oil (Sterotexand all should be well mixed and pressed into tablets, receiving 10,000 tablets each containing 10 mg of the active component.

Floor.

In a solution of 10 g of methyl cellulose (Methocel 60 HG) in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose (Ethoc the ut 10 g of polyethylene glycol and the melt is dissolved in 75 ml of dichloromethane. The last solution is added first and then add in a mixture of 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated color suspension (Opaspray ) and the whole mass is homogenized. Core tablets cover the thus obtained mixture in a device for the formation of shells.

Example 19. Injectable solutions.

1.8 g of Methyl-4-hydroxybenzoate and 0.2 g of propyl-4-hydroxybenzoate dissolved in about 0.5 l of boiling water for injection. After cooling to about 50oC added while stirring 4 g lactic acid, 0.05 grams propylene glycol and 4 g A. K. the Solution is cooled to room temperature and added to water in an amount necessary to achieve a total volume of 1 L. the resulting solution contains 4 mg A. K. 1 ml. of the Solution is sterilized by filtration (U. S. P/VIIh. 811) and poured into sterile containers.

Example 20. Suppositories.

3 Mr. A. K. dissolved in a solution of 3 g of 2,3-dihydroxybutanedioate in 25 ml of polyethylene glycol 400. Together melted 12 g of surfactant (SPANS) and triglycerides (Witepsol 555in number to the number required to obtain 300 g of the total melt. The latter mixture is mixed well with the first solution. each of which contains 30 mg A. K.

1. Derivative imidazo/1,2-a/thieno /2,3-d/azepino formula (I)

< / BR>
or their pharmaceutically suitable salt of the merger, or stereochemical isomer,

where each of the dashed lines independently represents possible (additional) communication;

R1is hydrogen, C1-4- alkyl;

R2is hydrogen, C1-4- alkyl, C1-4-alkyl, substituted hydroxycarbonyl, or C1-4-allyloxycarbonyl;

R3is hydrogen, C1-4- alkyl;

X is sulfur;

L is hydrogen, C1-6- alkyl, C1-6is alkyl having one Deputy selected from the group consisting of hydroxy-group, C1-4-alkyloxy, hydroxycarbonyl, C1-4-allyloxycarbonyl, C1-4-alkylaminocarbonyl, C1-4-allyloxycarbonyl, C1-4-allyloxycarbonyl-C1-4-alkyloxy, hydroxycarbonyl-C1-4-alkyloxy, C1-4-alkylaminocarbonyl, C1-4-alkylaminocarbonyl, aryl and alloctype, C3-6alkenyl, substituted aryl, where each aryl is phenyl or phenyl substituted by halogen, a hydroxy-group, C1-4-alkyloxy, or L is a radical of the formula

-Alk-Y-Het1; (a-1)

-Alk-NH-CO-Het2; (a-2)

or-Alk-Het3- pyrrolyl, substituted C1-4-allyloxycarbonyl, pyridinyl, 4,5-dihydro-5-oxo-IH-tetrazolyl, substituted C1-4-alkyl, 2-oxo-3-oxazolidinyl, 2,3-dihydro-2-oxo-IH-benzimidazole-1-yl or a radical of the formula

< / BR>
in which Z is a group S-CH=CH, S-CH2-CH2S-CH2-CH2-CH2CH=CH-CH=CH.

2. Connection on p. 1, characterized in that it R1, R2and R3- hydrogen.

3. Connection on p. 1, characterized in that it is 6,10-dihydro-10-(1-methyl-4-piperidinylidene)-5H-imidazo(1,2-a)thieno/2,3-d /azepino, its stereoisomers and pharmaceutically suitable salts of the merger.

4. Pharmaceutical composition having anti-allergic activity, comprising an active component and a pharmaceutically suitable carrier, wherein the active component using an effective amount of a derivative of imidazo /1,2-a/ thieno /2,3-d/-azepino under item 1.

5. A method of obtaining a pharmaceutical composition, characterized in that a therapeutically effective amount of the compounds under item 1 are thoroughly mixed with a pharmaceutical carrier.

6. Connection on p. 1 having antiallergic BR> where each of the dotted lines X, R1, R2and R3have the values listed in paragraph 1,

Q - C1-6-allyloxycarbonyl, C1-4-alkylaryl or C1-6-alkyl substituted amino group.

8. The connection formulas

< / BR>
where K is the oxygen (compound XIII) or hydrogen (compound XIV)

< / BR>
< / BR>
salt accession or stereochemical isomer him,

where the dashed line, X, R1, R2and R3matter under item 1.

9. The method of obtaining imidazo/1,2-a/thieno-/2,3-d/azepino under item 1 of General formula Ia

< / BR>
characterized in that the alcohol of General formula V or VI

< / BR>
< / BR>
where R1- R3and L have indicated in paragraph 1 values

subjected to dehydration, dehydrating agent, followed if necessary by conversion of compounds of formula Ia in salt processing pharmaceutically suitable acid.

10. The method of obtaining imidazo/1,2-a/thieno/2,3-d/azepino under item 1 of the General formula Ic

< / BR>
where R1- R3are specified in paragraph 1 values

characterized in that the compound of General formula Ib

< / BR>
subjected to interaction with the connection

< / BR>
in the presence of base, followed by hydrolysis of the compounds obtained fo is th pharmaceutically suitable acid.

11. The method of obtaining imidazo /1,2-a/thieno/2,3-d/azepino General formula I on p. 1, where R1- R3are specified in paragraph 1 values, L1is specified for the L values with the exception of hydrogen, characterized in that compounds of General formula Ic is subjected to N-alkylation with a reagent of formula L1- W, where W is a suitable removable group, in an inert solvent, possibly in the presence of a base, followed, if necessary, conversion of the compounds of formula I in salt processing pharmaceutically suitable acid.

12. The method of obtaining imidazo /1,2-a/thieno/2,3-d/azepino General formula I on p. 1, where R1- R3are specified in paragraph 1 values, L - C1-6is alkyl or substituted C1-6-alkyl, wherein the compound of General formula Ic is subjected to interaction with the corresponding alkene, followed if necessary by conversion of compounds of formula I in salt processing pharmaceutically suitable acid.

13. The method of obtaining imidazo /1,2-a/thieno/2,3-d/azepino General formula I on p. 1, where R1- R3are specified in paragraph 1 values, L - C1-6-alkyl, substituted by a hydroxy-group, characterized in that the compound of the General formula Ic is subjected to interaction with sbojkoj pharmaceutically suitable acid.

14. The method of obtaining imidazo /1,2-a/thieno/2,3-d/azepino General formula I with the single bond in the tricyclic portion and/or the single bond connecting the tricyclic portion with piperidine, where R1- R3and L have indicated in paragraph 1 values, characterized in that the compound of General formula I, having the double bond in one or both of the above provisions, restore, followed if necessary by conversion of compounds of formula I in salt processing pharmaceutically suitable acid.

 

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< / BR>
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I,

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