Oxyalkylene derivatives or their pharmaceutically acceptable salts accession acids, or their stereochemical isomeric form, having antiallergic activity and antiallergic composition

 

(57) Abstract:

Usage: in medicine as an anti-allergic agent. The inventive product is oxyalkylene derivative f-ly I listed in the description text,- pharmaceutically acceptable salt accession acids him or stereoisomeric compounds, where-A1-A2-A3-A4- bivalent radical having the f-Lu: -CH=CH-CH=CH-(a-1), -N=CH-CH=CH-(a-2), -CH=CH-CH=N-(a-5) or-N= CH-N=CH-(a-6), n-1 or 2B-NR4or CH2, R4-H or C1-C6alkyl, L-H, C1-C6alkyl, C1-C6allyloxycarbonyl, or the radical of f-crystals-Alk-R5(1;) -Alk-Y-R6(b-2), -Alk-Z1-C(-X)-Z2-R7(b-3), or-CH2-CHOH-CH2-O-R8where R5cyano group, phenyl, optionally substituted C1-C6alkyloxy; pyridinyl; 4,5-dihydro-5 - oxo-1-n-tetrazolyl; 2-oxo-3-oxazolidinyl; 2,3-dihydro-2-oxo-1-n-benzimidazolyl; or bicycling radical f-crystals (s-4-a), where G2-CH= CH-CH= CH-, -S-(CH2)3- , -S(CH2)2- -S-CH= CH - or-CH=C(CH3)-O - group, R6-C1-C6alkyl; pyridinyl optionally substituted nitro group; pyrimidinyl; pyrazinyl; pyridazinyl optionally substituted of halogenous 2,3-dihydro-3-oxopentanenitrile; R8-haloethanol, Y Is O or NH, Z1or Z2each independently NH or a direct bond, X Is O, each Alk is independently C1-6alcander. 1 C.p. f-crystals, 8 PL.

The invention relates to compounds of the formula I

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

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

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

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

-CH=CH-CH=N (a-5) or

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

n=1 or 2

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

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

-Alk - R5(b-1),

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

-Alk - Z1- C(=X) - Z2- R7(b-3), or

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

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

R6- C1-C6-alkyl, pyrid is m, 2,3-dihydro-3-oxopyridine; or 9-methyl-6-purinol;

R7- C1-C6-alkyl; halophenol; 1-methyl-1H-pyrrolyl; furanyl, thienyl, or aminopyrazine;

R8- halophenol;

Y is O or NH;

Z1or Z2each independently NH or a direct link X-O

each lk independently - C1-C6alcander.

The above-mentioned pharmaceutically acceptable acid additive salts include therapeutically active non-toxic additive salts, which can form compounds of formula (I). These salts can be obtained by treating compounds of formula (I), in the main form, with suitable acids, for example inorganic, such as halogen, in particular hydrochloric, Hydrobromic, etc., sulphuric, nitric, phosphoric, etc. or organic acids such as acetic, propanoic, oxiana, 2-oxopropanal, 2-oxopropanal, titanova, ditropanbuy, dimetanola (Z)-2-dimetanola, (E)-2-dimetanola, 2-oxydiethanol, 2,3-deoxidization, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, benzolsulfonat, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-oxybenzone, 4-amino-2-oxybenzone, etc. acids. And noadditional salts are meant also hydrates and additive compounds with solvents, which can form compounds of formula (I). Examples of such compounds are, in particular, hydrates, alcoholate, etc.,

Compounds in accordance with the present invention can contain one or more asymmetric carbon atoms. Each of these chiral centers may be indicated by the stereochemical symbols R and s

Individual stereoisomers of compounds of formula (I) can be obtained by known methods. Diastereoisomer can be separated using physical methods such as selective crystallization or chromatographic methods, in particular counter-current separation, liquid chromatography, and so on, the Enantiomers can be separated using known methods of separation, for example by selective crystallization of their diastereomeric salts with chiral acids. Pure stereoisomers can be obtained from the appropriate stereochemical pure source materials provided stereospecific reaction. It is preferable to obtain the pure stereoisomers to synthesize their stereoselective methods. Preferably in the implementation of these methods to use enantiomerically pure starting materials

In order to simplify the writing structural formulas of some of the compounds and intermediates in the following examples, the portion of the molecule containing the imidazole group condensed with a benzene, pyridine or pyrimidine ring, in the future will be denoted by the symbol Q.

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The compounds of formula (I) in the General case can be obtained by reacting the intermediate of formula (II) with an appropriately substituted diamine of formula (III).

_____(I)< / BR>
In this and subsequent schemes reactions W means corresponding useplease group, for example halogen atom, particularly a chlorine atom, bromine or iodine, WITH1-C6-alkyloxy-group1-C6-alkylthio, aryloxy or aaltio-group, and X1Is O, S or NH.

Derivatives of the formula (II), which means CH2and W is a halogen atom, can be obtained in situ, for example by halogenation of the corresponding carboxylic acid with thionyl chloride, phosphorus trichloride, phosphorylchloride, polyphosphoric acid, etc., the Reaction between the compounds of formulae (II) and (III) can be performed in the environment of a suitable inert solvent, for example hydrocarbons, in particular benzene, hexane, etc., simple AA etc., alcohol, in particular methanol, ethanol, 2-propanol, 1-butanol, etc., halogenated hydrocarbons, in particular trichloromethane, dichloromethane, etc., organic acid, in particular acetic, propanoic acid, etc., dipolar aprotic solvent, particularly N,N-dimethylformamide, N,N-dimethylacetamide, etc., or mixtures thereof. Depending on the nature of the solvent and W may be appropriate to add to the reaction mixture a base, for example of those that are commonly used for carrying out reactions of N-alkylation, and/or modestou salt, such as alkali metal iodide. The increase of temperature and mixing can increase the reaction rate. In some cases the result of the reaction between (II) and (III) beginning may form an intermediate compound of the formula (II-a), which can then be cyclosiloxane in the target compound of formula (I) in situ or, if desired, after separation and purification.

_____(I)< / BR>
The compounds of formula (I) can be also obtained by reacting the intermediate of formula (V) with the following known reaction of substitution. In the formula (IV) and then M stands for a hydrogen atom (in the case, if is other than CH2, value) or alkaline or Selim way the compounds of formula (I) can be obtained by reacting the intermediate compounds of formula (VI) with an intermediate compound of formula (VII), in which M has the above definition. In the formula (VI) and then W1means corresponding useplease group, for example halogen atom, particularly a chlorine atom, bromine and so on, or sulfonyloxy group, in particular methansulfonate-, 4-methylbenzenesulfonate groups, etc.

LNW1(I)

The compounds of formula (I), which means-CH2- (these compounds are described by formula (I-a) can also be obtained by interaction between the intermediate compounds of formulas (VIII) and (IX) or between the intermediate compounds of formulas (X) and (XI).

LN LNQ

The reaction between compounds of formulae (IV), (VI), (VIII) and (X) and, accordingly, the compounds of formula (V), (VII), (IX) and (XI) should be carried out in inert under the reaction conditions solvent, for example aromatic hydrocarbons, in particular benzene, methylbenzene etc., simple ester, in particular 1,4-dioxane, 1,1' -oxybisethane, tetrahydrofuran, etc. , halogenated hydrocarbons, in particular trichlormethane etc., N,N-dimethylformamide, N, N-dimethylacetamide, nitrobenzene, dimethyl sulfoxide, 1-methyl-2-pyrrolidone, etc., In that case, if M denotes a hydrogen atom, such a solvent can also be1-C6-alkane what teas, in particular, when the means heteroatom, it may be appropriate to the addition of an appropriate base such as a carbonate or bicarbonate of an alkali metal, in particular carbonate or sodium hydrogen carbonate, etc., sodium hydride, or organic bases, for example N,N-diethylethanamine or N-(1-methylethyl)-2-propanamine, and/or adding modestou salts, preferably the alkali metal iodide. Some of the increase in temperature and the stirring can increase the reaction rate.

The compounds of formula (I), which means-NR4- (such compounds are described by formula (I-b) can be also obtained by reacting the intermediate compounds of formula (XII) and formula (VII), wherein M means a radical-NR4-H- (these intermediate compounds are described by formula (VII-a)) and the following well-known N-alkylation.

LN LNQ

The reaction between the compounds of formulas (XII) and (VII-a) it is expedient to carry out by mixing the reagents in an environment suitable inert under the reaction conditions solvent with an appropriate reducing agent. Preferably first by the interaction of the ketone of formula (XII) with an intermediate compound of formula (VII-a) with the formation of enamine that retelei for carrying out this reaction are, for example, water, WITH1-C6-alkanols, in particular methanol, ethanol, 2-propanol and so on, ethers, in particular 1,4-dioxane, etc., halogenated hydrocarbons, in particular trichlormethane etc., dipolar aprotic solvents, in particular N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, etc., or mixtures thereof. Suitable reducing agents are, for example, metal hydrides or metal complexes, in particular sodium borohydride, cyanoborohydride sodium, sociallyengaged, etc. Can as a reductant to use and hydrogen in the presence of a suitable catalyst, for example palladium or platinum on charcoal, etc. in order to prevent undesirable hydrogenation of some functional groups in the reactants and the reaction products, it may be appropriate to add to the reaction mixture the corresponding analizatory poison, for example thiophene, etc.

The compounds of formula (I-b), which means-NH- (these compounds can be described by the formula (I-b-I) can be also obtained by the reaction of collegesuniversities corresponding urea of the formula (II-a). This urea is described by formula (II-a-I) and can be obtained by condensation isothiocyanate the compounds of formula (II-a-I) with the appropriate halogenation, preferably iodomethane, in an environment suitable inert under the reaction conditions an organic solvent, for example WITH1-C6-alkanol, in particular methanol, ethanol, 2-propanol, etc. By another variant of collegesuniversities can be performed by reacting the compounds of formula (II-a-I) with the appropriate metal oxide or salt, for example an oxide or salt of Hg(II) or Pb(II), in particular HgO, HgCl2Hg(OAc)2, PbO or PB(SLA)2in the presence of a suitable solvent and subsequent well-known procedures. In some cases it may be appropriate to add to the reaction mixture a small amount of sulfur. As collegesuniversities agent can be used, in particular, and methandienone.

< / BR>
< / BR>
The compounds of formula (I) can be obtained by N-alkylation of the intermediate compounds of formula (XV) with the appropriate alkylating agent of formula (XIV).

< / BR>
The above reaction of N-alkylation should be carried out in inert under the reaction conditions solvent, such as water, aromatic hydrocarbons, in particular benzene, methylbenzene, xylene, etc., alkanol, in particular methanol, ethanol, 1-butanol, etc., Xan, 1,1'- oxybisethane etc., dipolar aprotic solvent, e.g. N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, nitrobenzene, 1-methyl-2-pyrrolidone, etc., or mixtures thereof. To bind the acid formed during the reaction, it is expedient to add to the reaction mixture a suitable base such as a carbonate, hydrogen carbonate, alkoxide, hydride, amide, hydroxide or oxide of an alkaline or alkaline-earth metal, in particular sodium carbonate or sodium bicarbonate, sodium carbonate, potassium methoxide or ethoxide sodium tert. piperonyl potassium, sodium hydride, sodium amide, sodium hydroxide, calcium carbonate, calcium oxide, etc. or an organic base such as tertiary amine, in particular N,N-diethylethanamine, N-(1-methylethyl)-2-propanamine, 4-ethylmorpholine, pyridine, etc. In some cases it is preferable to add modestou salt, in particular the alkali metal iodide. Some of the increase in temperature and mixing allow you to increase the reaction rate. In addition, it may be appropriate to carry out the specified N-alkylation of an inert gas, for example not containing oxygen, argon or nitrogen.

Alternatively the N-alkylation can be performed in a known usloviyah a suitable base, if desired, in an atmosphere of inert gas in accordance with the above definition, in the presence of a suitable phase transfer catalyst, for example halogen, hydroxide, hydrosulphate of dialkyldimethylammonium, tetraalkylammonium, tetraallylsilane, tetrakisphosphate and other similar catalysts.

The compounds of formula (I) in which R1means a hydrogen atom (such compounds are described by formula (I-c)) can be obtained by condensation of furan derivative of the formula (XVI) with an aldehyde R2-SNO formula (XVII) in the presence of a suitable acidic or basic catalyst.

< / BR>
These compounds of formula (I-c) can also be obtained by recovering carboxylic acid derivative of the formula (XVIII) in which R means a hydrogen atom, alkyl or aryl, a reducing agent, such as sociallyengaged, lithium borohydride, sodium borohydride, etc., in inert in the reaction conditions solvent, for example a simple ether, in particular tetrahydrofuran, 1,1'-oxybisethane, 1,4-dioxane, etc., or by reacting the specified carboxylic acid of formula (XVIII) or a salt thereof with an ORGANOMETALLIC compound, in particular WITH1-C6

< / BR>
The compounds of formula (I) in which L has a different meaning than the hydrogen atom (L in this case is denoted as L1and these compounds are described by formula (I-d)) can also be obtained by N-alkylation of compounds of formula (I), in which L denotes a hydrogen atom (such compounds are described by formula (I-e)), alkylating agent of the formula (XIX).

HNQ LNQ

The above reaction of N-alkylation is advisable to carry out usual for such cases, as described above, when obtaining the compounds of formula (I) of the parent compounds of formulas (XIV) and (XV).

The compounds of formula (I-d), in which L stands WITH3-C6-cycloalkyl,1-C12-alkyl, a radical of formula (b-1), (b-2) or (b-3) (these radicals can be represented as a radical L2N, and these compounds are described by formula (I-d-I) can also be obtained by reductive N-alkylation of compounds of formula (I-e) a ketone or aldehyde of formula L2=O (XX), with the specified connection formulas of L22represents a divalent radical with two links one carbon atom, including3-C6-cycloalkylation,1-C12-alkyliden, R5-C1-C6-alkyliden, R6-Y-C1-C6-alkyliden and R7- Z2-C(= X) - Z1-C1-C6-alkyliden.

(I-eL2= 0 L2HNQ

The specified reaction reductive N-alkylation of appropriate conduct in the same manner as described in obtaining compounds of formula (I-b) of the parent compounds of formula (VII-a) and (XII), in particular by catalytic hydrogenation.

The compounds of formula (I) in which L is the radical of formula (b-2), and R6-aryl or Het (R6in this case, can be designated as R6-aand these compounds are described by formula (I-d-2) can also be obtained by alkylation of compounds of formula (I) in which L is the radical of formula (b-2), and R6means a hydrogen atom (these compounds can be described by the formula (I-d-3) with a reagent of formula (XXI).

H-Y-AlkNQ R6-a-Y-AlkNQ

Similarly the compounds of formula (I-d-2) can be obtained by treating the compounds of formula (I-d-4) with a reagent of formula (XXII).

W-AlkNQ R

The compounds of formula (I) in which L is the radical of formula (b-3), Z1means NH, Z2has a different meaning than a simple link, and X has a different value than NR11(Z2and X in this case can be denoted, respectively, Z2-aand X2and these compounds are described by formula (I-d-5) can be obtained by reacting isocyanate (X2=O) or isothiocyanate (X2=S) of formula (I-d-6) with the compound of the formula (XXIII).

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The connection is of Rasta communication, and X has a different value than NR11(Z1and X in this case can be denoted as Z1-aand X2), and compounds described by formula (I-d-7), can be obtained by reacting isocyanate (X2=O) or isothiocyanate (X2=S) of formula (XXIV) with a compound of formula (I-d-8).

< / BR>
The reaction between compounds of formulae (XXIII) and (I-d-6) or (XXIV) and (I-d-8), as a rule, can be performed in the environment is suitable, inert under the reaction conditions solvent, for example a simple ether, in particular tetrahydrofuran and so on, halogenated hydrocarbons, in particular trichlormethane, etc., the reaction Rate can be increased by increasing the temperature.

The compounds of formula (1), in which L is the radical of formula (b-3), Z2- a simple link, Z1has a different meaning than a simple link, and X has a different value than NR11(Z1and X in this case denoted respectively Z1-a and X2and these compounds are described by formula (I-d-9), can be obtained by reacting the compounds of formula (XXV) or a reactive functional derivative with the compound of the formula (I-d-8).

HZ1-a-AlkNQ R7-C(=X2)-ZAlkN

The reaction between the compounds of formulae (XXV) and (measures carboxylic acid can be converted to a reactive derivative such as an anhydride or galoyanized, which is then subjected to interaction with the compound of the formula (I-d-8). Alternatively the reaction between (XXV) and (I-d-8) is carried out in the presence of a suitable reagent capable of forming amides or esters. This reagent can be, for example, N,N-melanterius(cyclohexamide), 2-chloro-1-methylpyridinium, etc., These reactions should be carried out in an environment suitable solvent, for example a simple ether, in particular tetrahydrofuran, halogenated hydrocarbons, in particular dichloromethane or trichloromethane, dipolar aprotic solvent, etc. it may be Appropriate to add to the reaction mixture of a base, for example N,N-diethylethanamine etc.

The compounds of formula (I) in which L is the radical of the formula L3-C2-C6-alcander, where L3means aryl, Het, arylsulfonyl or a radical of the formula R7- Z2-C(=X)- (these compounds may be described by formula (I-d-10) can also be obtained by reaction of accession of the compounds of formula (I-e) to the corresponding alkene of the formula (XXVI).

HNQ L3-C2-6acanalonia compounds are described by formula (I-d-11), can be obtained by reacting the compounds of formula (I-n) with an epoxide of the formula (XXVII), where R14means a hydrogen atom, a C1-C4-alkyl or the radical R8-O-CH-2-.

HNQ R14-CHOH-CHN

The reaction between the compound of formula (I-e) and the compound of formula (XXVI) or (XXVII) can be conducted by stirring and, if desired, heating, inert under the reaction conditions solvent such as a ketone, in particular 2-propanone, 4-methyl-2-pentanone, simple ether, in particular tetrahydrofuran, 1,1' -oxybisethane, alcohol, in particular methanol, ethanol, 1-butanol, dipolar aprotic solvent, particularly N,N-dimethylformamide, N,N-dimethylacetamide, and so on

The compounds of formula (I) in which R5, R6or R7mean Het, can be obtained by known methods used to obtain heterocyclic ring systems, or other similar methods. Some of these ways of cyclization is described, for example, in U.S. patent N 4695575 and in these references, in particular in patents U.S. N 4335127, 4342870 and 4443451.

The compounds of formula (I) can also be converted into other compounds of the same formula by known methods of transformation funkcij corresponding amines by stirring and, if desired, heat source cyanoderivatives in a hydrogen-containing atmosphere in the presence of a suitable catalyst, such as platinum on charcoal, Raney Nickel, etc., Suitable solvents are, for example, methanol, ethanol, etc., the Amino group can be converted into the corresponding isocyanate groups by treating the starting compound CS2optionally in the presence of N, N-melanterius(cyclohexamide). Amino groups can be alkylated or etilirovany by known methods, for example by N-alkylation, N-acylation, reductive N-alkylation, etc. of Compounds of formula (I) containing an amino group, a substituted aryl radical-CH2can be subjected to hydrogenolysis by treating the starting compound with hydrogen in the presence of a suitable catalyst, for example palladium or platinum on charcoal, etc., in alcoholic medium.

In the case of all previous and the following procedures, the reaction products can be isolated from the reaction mixture and optionally subjected to additional purification by known methods.

Some of the intermediates and starting materials used for the above-described methods, is the Oia these or similar compounds. Others described compounds are new. Some methods of obtaining these compounds will be described in detail in the following examples.

Raw materials, for example, intermediate compounds of formula (II), (IV), (VI), (VIII), (X), (XII), (XIII), (XV) and (XVI) can be obtained using methods similar to those described, for example, in U.S. patent N 4219559, 4556660, 4634704, 4695569, 4695575, 4588722, 4835161 and 4897401, as well as in European patent A-0206415, 0282133, 0297661 and 0307014.

Intermediates of formula (III) can be obtained from the original aromatic compounds with substituents of a halogen atom and a nitro-group at the neighboring carbon atoms of the formula (XXVIII), by reacting it with an appropriate amine of the formula (XXIX) by the known method of restoring the nitro to the amino group.

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Intermediates of formula (V), (VII), (IX) and (XI) can be obtained from intermediates of formula (III) is known a method of converting aromatic compounds, substituted amino groups at adjacent carbon atoms in the benzimidazole, imidazopyridine and/or purines.

Intermediates of formula (XVIII) can be obtained by N-alkylation of an intermediate of formula (XV) appropriately substituted derived forinclusion compounds of formula (I) from intermediates of formula (XV) and (XIV).

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The compounds of formula (I), their pharmacologically acceptable acid additive salts and stereoisomers possess valuable pharmacological properties. Thus, in particular, they are active antihistamine agents that can be convincingly demonstrated, for example, test results, "Protection of rats from calling their deaths compound 48/80", "Antagonism of histamine in Guinea pigs" and "Ascaric Allergy tests for dogs". In addition to antihistaminic activity of some of the inventive compounds also possess antagonistic activity against serotonin, which can be demonstrated using test gastric diseases in rats induced by compound 48/80".

Due to its antihistamine and serotonine activity of the compounds of formula (I) and their acid salt additive can be used with success for the treatment of allergic diseases, such as, for example, allergic rhinitis, allergic conjunctivitis, allergic contact dermatitis, allergic asthma, etc.

Because the proposed compounds have anti-allergic activity, on their basis it is possible to prepare various pharmaceutical preparations. To obtain the antiallergic compositions in salt additive salt, playing the role of an active component, thoroughly mixed with a pharmaceutically acceptable carrier which can be in very different forms depending on the form of the resulting composition. It is preferable to produce such pharmaceutical compositions in the form of a unit dose which could be administered orally, rectally, through the skin, or parenteral. For example, upon receipt of the compositions for oral administration can use any of the commonly used pharmaceutical ingredients, in particular water, glycols, oils, alcohols, etc. when receiving liquid compositions, such as suspensions, syrups, elixirs and solutions) or solid carriers such as starches, sugars, kaolin, slip additives, binders, dispersing agents, etc. (upon receipt of powders, pills, capsules and tablets). Due to the simplicity of the introduction of tablets and capsules are the most preferred oral single doses, which, of course, apply solid pharmaceutical carriers. In parenteral compositions as the media usually used (at least partially) sterilized water, although, for example, to aid solubility, the carrier can contain other components. For rastvoro mixture of these solutions. On the basis of the proposed compounds can also be obtained suspension for injection containing a suitable liquid carriers, dispersing agents, etc., In compositions for insertion through the skin, the carrier may contain an agent that promotes the penetration of active substances, and/or a suitable wetting agent, optionally in combination with small amounts of suitable additives of any nature, without harmful effects on the skin. These supplements can facilitate the introduction of the compositions through the skin and/or be useful when you receive them. These compositions can be administered in a number of ways, such as percutaneous, by applying in the form of spots or in the form of ointment. Acid additive salts of compounds of formula (I) due to their higher solubility in water than the corresponding basic forms can obviously be used to obtain water compositions.

Preferably, in particular, to manufacture the listed pharmaceutical composition in the form of single doses. This facilitates the taking and dosage. Under used in the description and the claims the term "unit dose" refers prepared in the form physically discrete portions of unit doses, each of which contains tion with an appropriate pharmaceutical carrier. Examples of such unit doses are tablets (including tablets incision or tablet with the shell), capsules, pills, powders, sachets, pills, solutions or suspensions for injection, the liquid dosage compositions of the amount in a teaspoon or tablespoon, as well as segregated packaging, contains many such doses.

The present invention relates also to a method of treating warm-blooded animals suffering from the above allergic diseases, by introducing anti-allergic effective amount of the compounds of formula (I) or its pharmaceutically acceptable acid additive salt.

Specialists in the treatment of allergic diseases in warm-blooded animals can easily determine the effective amount of the following test results. It is assumed that the anti-allergic effective amount of the active substance should be from about 0.001 to about 100, preferably from about 0.01 to about 1 mg/kg body weight.

The following examples illustrate the present invention but in no way limit its scope. If this is not specified, all the above parts are by weight.

A. Obtaining intermediates.

aboutC. the Reaction mixture was then poured into water and the resulting product was extracted with methylbenzol. The extract was washed with water, dried, filtered and evaporated. The residue was subjected to purification using column chromatography on silica gel (mobile phase: a mixture of CHCl3and CH3OH in the ratio 97: 3). The eluate desired fraction was evaporated and the residue was stirred 1,1' -oxybisethane. Dropdown precipitate was filtered and dried. The result has been to 31.2 hours (70,8%) ethyl-4-[[1-[[5-(etoxycarbonyl)-2-furanyl]methyl] -1H-benzimidazole-2-yl] - amino] -2-piperidinecarboxylate. So pl. 136,0about(Intermediate 1).

Similarly 4-(1H-benzimidazole-2-ylamino)hexahydro-1H-azepin-1-carboxylate (obtained in the same manner as described in example 9 of European patent N 0297661 published 4.01.1989) were transferred into ethyl-4-[[1-[[-5- (etoxycarbonyl)-2-furanyl]methyl]-1H-Benzema - Gasol-2-yl] amino]hexahydro-1H-azepin-1-carboxylate (intermediate 2) and ethyl-3-(1H-benzimidazole-2-ylamino)-1-pyrrole - dicarboxylate monohydrochloride (obtained in the same manner as described in example 8 Evropeiskogo] -1-pyrrolidinecarboxylic (intermediate 3).

P R I m m e R 2. To 470 h N,N-dimethylformamide was added in portions to 17.3 hours dispersion of sodium hydride in mineral oil (50% ) and to 91.6 hours 2-[[1-(phenylmethyl)-4-piperidinyl] methyl] -1H-benzimidazole (obtained in the same manner as described in example 16 patent N 4695575), under stirring, in a nitrogen atmosphere. After stirring for one hour to the mixture dropwise, while cooling was added to 67.9 including ethyl-5-chloromethyl-2-furancarboxylic. Stirring was continued for another hour, after which the reaction mixture was added water. The product was extracted with methylbenzol and the extract was washed with water, dried, filtered and evaporated. The residue was dried by azeotropic distillation and methylbenzol (twice). As a result received 119 hours (86,6%) ethyl-5-[[2-[[1-(phenylmethyl)-4-piperidinyl]]methyl-2-furancarboxylic (intermediate 4). In the same way, using the appropriate starting materials, received

methyl-5-[[2-[[1-[2-(4-methoxyphenyl)ethyl]- 4-piperidinyl]amino]-1H-benzimidazole-1- -yl]methyl]-2 - furancarboxylic, so pl. 124,3about(Intermediate 5);

ethyl-5-[[2-[[1-[2-(4-methoxyphenyl)ethyl] -4-piperidinyl-] amino] - 1H-benzimidazole-1-yl] methyl] -3-furancarboxylic, so pl. 121,9about(Intermediate 6);

methyl-5-[[-2-[(1-methyl-4-piperidinyl)-amino]-idini)amino]-1H-benzimidazole-1-yl]methyl] -3-furancarboxylic (E)-2-butenedioate (1:2). So pl. 200,9about(intermediate 8);

ethyl-2-[[2-[[1-[2-(4-methoxyphenyl)ethyl] -4-piperidinyl] amino]-1H - benzimidazole-1-yl] methyl] -3-furancarboxylic (intermediate 9); ethyl-4-[[1-[[3-(etoxycarbonyl)-2-furanyl] methyl] -1H-benzimidazole - 2-yl]amino]- 1-piperidinecarboxylate/ so pl. 162,3about(Intermediate 10);

ethyl-4-[[1-[[2-(methoxycarbonyl)-3-Fura - Neil]methyl]-1H-benzimidazole-2 - yl] amino] -1-piperidinecarboxylate (intermediate 11) and methyl-3-[[2-[[1-[2-(4-methoxyphenyl)ethyl] -4-piperidinyl] amino]-1H - benzimidazole-1-yl]methyl]-2-furancarboxylic (intermediate 12).

P R I m e R 3. a) a Mixture of 55 o'clock N-(2-furylmethyl)-3-nitro-2 - pyridylamino, 2 hours 4% solution of thiophene in methanol and 400 hours of methanol, saturated with ammonia, was subjected to hydrogenation at normal pressure and room temperature in the presence of 4 hours of a 5% platinum catalyst on charcoal. After absorption of the calculated amount of hydrogen the catalyst was filtered and the filtrate was evaporated, resulting in a received 48 hours N2-(2-furylmethyl)-2,3-pyridinediamine (intermediate 13).

C) a Mixture of 54 G. of ethyl-4-isocyanato-1 piperidinecarboxylate, 48 hours of intermediate (13) and 450 parts of tetrahydrofuran was stirred over night while boiling under reflux, after which the result was received 76 hours (75%) of ethyl-4-[[2-[([2-(furylmethyl)amino]-3-pyridinyl]aminothiazol - Tyl]amino] -1-piperidinecarboxylate, so pl. 132,7about(Intermediate 14).

Similarly, atelectasia-4-isothiocyanato-1H-azepin-1 - carboxylate (obtained by the method in accordance with example 9 of European patent N 0297661, published January 4, 1989) translated in ethylhexane-4-[[[[2-[[[5-(oxymethyl)-2-furanyl]methyl]amino]-3 - pyridinyl]amino] taxometer]amino]-1H - azepin-1-carboxylate (intermediate 15).

(C) a Mixture of 74 hours of intermediate (14), 96 hours of oxide of mercury (11), 0,1 including sulfur and 800 hours of ethanol was stirred for 3 h at boiling under reflux. The reaction mixture was then filtered through diatomaceous earth and the filtrate was evaporated. The residue was recrystallized from acetonitrile, to deliver 52,5 h (79%) of ethyl-4-[[3-(2-furylmethyl)-3H-imidazo[4,5-b]pyridine-2-yl]amino]-1 - piperidinecarboxylate. So pl. 149,2about(Intermediate 16).

P R I m e R 4. a) a Mixture of 16.3 hours 4,6-dihydro-5-piperidylamine, 14 hours 5-(aminomethyl)-2-furanmethanol, 12 noon, N,N-diethylethanamine and 200 hours of water was stirred for 10 h at boiling under reflux. The reaction mixture was then evaporated and the residue was subjected to purification using column chromatographyelectrospray 95:5. The eluate fraction containing the target product was evaporated and the residue was recrystallized from acetonitrile. The product was filtered and dried, obtaining the result of 19.5 hours(76,6%) 5-[[(5-amino-6-chloro-4-pyrimidinyl)-amino] methyl] -2-fu - ranmuthugala. So pl. 136,7about(Intermediate 17).

C) a Mixture of 18.5 hours of intermediate (17), 1 PM to 4% of a solution of thiophene in methanol, 119 including methanol and 10 o'clock of calcium oxide was first made at normal pressure and room temperature in the presence of 4 hours 10% palladium catalyst on charcoal. After absorption of the calculated amount of hydrogen the catalyst was filtered and the filtrate was evaporated, receiving the result of 15.9 hours(100%) 5-[[(5-Aino-4-pyrimidinyl)amino]methyl]-2-furan - methanol (intermediate 18).

P R I m e R 5. a) a Mixture of 15.9 hours 4-chloro-3-nitropyridine, 12,7 h 5-(aminomethyl)-2-furanmethanol, 13,3 including N,N-diethylethanamine and 745 hours of trichloromethane was stirred for 3 hours at the boiling temperature under reflux. After cooling, the reaction mixture was washed with an aqueous solution TO a2CO3, dried, filtered and evaporated. The residue was recrystallized from acetonitrile. The target product was filtered and dried. The result has been 17,76 PM(71,3%) 5-[[(3-the nitro-4-pyridi PM 4% solution of thiophene in methanol and 158 hours of methanol was first made at normal pressure and room temperature in the presence of 1 teaspoon of a 5% platinum catalyst on charcoal. After absorption of the calculated amount of hydrogen the catalyst was filtered and the filtrate was evaporated. The residue was recrystallized from acetonitrile. The product was filtered and dried, received in the result of 12.7 hours(83,9% ) 5-[[(3-amino-4-pyridinyl)amino]-methyl]-2-furan - methanol (intermediate 20).

(C) a Mixture of 14.3 hours-ethyl-4-isothiocyanato-1 piperidinecarboxylate, 12,7 hours of intermediate (20) and 188 including N,N-dimethylformamide was stirred overnight at 60aboutS, after which the reaction mixture was evaporated, receiving the result of 25.1 hours (100% ) of ethyl-4-[[[[4-[[[5-(oxymethyl)-2-furanyl]methyl]amino]- 3-pyridinyl] amino]taxometer]amino]-1-piperidinecarboxylate (intermediate 21).

Conducting the process in the same way, intermediate (18) were transferred to 4-[[[[4-[[[5-(oxymethyl)-2-furanyl]methyl]amino]-5-pyrimi-dinyl]amino] taxometer]amino]-1-piperidinecarboxylate (intermediate 22).

P R I m e R 6. a) To a solution of 25 hours 1-(phenylmethyl)-4-piperidinecarbonitrile 178 hours of tetrahydrofuran was added dropwise at room temperature 37,97 scales. part of chlorform rali 90 hours ethyl acetate and the solution washed successively 3 N. HCl, NaHCO3and saturated NaCl solution. The solvent is kept off and the residue was distilled at a temperature of 100-110aboutC and a pressure of 6.7 PA. The result has been to 18.7 hours (81,4%) ethyl-4-(cyanomethyl)-1-piperidinecarboxylate (intermediate 24).

C) a Mixture of 18,32 hours of intermediate (24), 4,30 including ethanol and 74,5 hours of trichloromethane was cooled in an ice bath and cooled was passed through it for 30 min hydrogen chloride. The reaction mixture was then left in the refrigerator for 48 hours, then evaporated. The residue is triturated with 142 hours of 1,1' - oxybisethane. The product was dried in vacuum, the result has been to 14.2 hours (54.1 per cent ) ethyl-4-(2-ethoxy-2-iminoethyl)-1-piperidine - carboxylate of monohydrochloride (intermediate 25).

Conducting the process in the same way, 1-(phenylmethyl)-4-piperidinecarbonitrile translated in Q ethyl-1-(phenylmethyl)-4-piperidineacetate the dihydrochloride (intermediate 26).

C. Obtain the target compounds.

P R I m e R 7. a) To a stirred mixture of 4.4 hours of intermediate (1) and 133,5 hours of tetrahydrofuran was added dropwise in a nitrogen atmosphere, 5 ml of a solution of tetrahydroborate lithium in tetrahydrofuran (2M). Stirring was continued overnight, boiling the mixture with the reverse was built in what was evaporated, the residue was dissolved in water and podslushivaet TO2CO3. The resulting product was extracted with dichloromethane, the extract was dried, filtered and evaporated. The residue was recrystallized from 4-methyl-2-pentanone, receiving the result of 2.08 hours (52,2%) ethyl-4-[[1-[[5-(oxymethyl)-2-furanyl] methyl] -1H-benzimidazole-2 - yl]amino]-1-piperidinecarboxylate. So pl. 141,6about(Connection 3.05).

C) a Mixture 75,7 including compounds (3,05), 106,5 including potassium hydroxide and 390 hours of 2-propanol was stirred over night at the boiling point under reflux. After cooling, the reaction mixture was evaporated and the residue was dissolved in water. The resulting product was extracted with dichloromethane and the extract was filtered through diatomaceous earth, and then was evaporated. The residue was recrystallized from 2-propanone, receiving the result 46,5 h 5-[[2-(4-piperidinylidene)-1H-benzimidazole-1 - yl] methyl]-2-furan-methanol. So pl. 156,3aboutWith (3.11 connection).

(C) a Mixture 4,53 hours of chloroacetonitrile, 16,26 including compounds (3.11), 8 g sodium carbonate and 141 including N,N-dimethylformamide was stirred for 2 h at room temperature. The reaction mixture was then poured into water and the resulting product was extracted with trichloromethane. The extract was dried, filtered and pariva is Uchali 17,71 PM (96,9%) 4-[[1-[[5-(oxymethyl)-2-furanyl]methyl]-1H-benzimidazole-2-yl]-1 - piperidinecarbonitrile. So pl. 209,8about(Connection 3.22).

d) a Mixture of 16.6 hours connection (3.22) and 790 hours of methanol, saturated with ammonia, was first made at normal pressure and room temperature in the presence of 6 hours of Raney Nickel. After absorption of the calculated amount of hydrogen the catalyst was filtered and the filtrate was evaporated. The residue was recrystallized successively from acetonitrile and 2-propanol, receiving the result of 7.4 hours 5-[[2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-1H-benzimidazole-1-yl]- methyl]-2-furanmethanol. So pl. 164,6about(Connection 3.23).

e) To a stirred solution of 1.38 h 1-methyl-1H-2-terracarbon acid, 2,81 h 2-chloro-1-methylpyridinium, 2,2 including N,N-diethylethanamine and 199,5 including dichloromethane was added a solution of 3.7 hours connection (3.23) in a mixture of dichloromethane and N, N-dimethylacetamide. After stirring for 3 h the reaction mixture was poured into water. The resulting product was extracted with dichloromethane, the extract was dried, filtered and evaporated. The residue was subjected to purification using column chromatography on silica gel, using as mobile phase a mixture of CHCl3and CH3OH saturated with ammonia in a ratio of 95 is the result received to 2.25 hours (47.2% ) of N-[2-[4-[[1-[[5-(oxymethyl)-2-furanyl] methyl]-1H-Ben-imidazol-2 - yl] amino] -1-Piperi-dinyl] ethyl]-1-methyl-1H-pyrrol-2-carboxy - Mead. So pl. of 182.2about(Connection 3.24).

P R I m e R 8. To stir the mixture for 12 hours of sociallyengaged and 445 hours of tetrahydrofuran was added at the boiling temperature, under nitrogen atmosphere is added dropwise a solution of 137 hours of intermediate (4) in tetrahydrofuran. Boiling the mixture under reflux continued for a further hour, after which it was cooled and added to it consistently found that 42 PM 15% NaOH solution (dropwise) and 36 hours of water. The resulting mixture was filtered, the filtrate was evaporated and the residue was dissolved in water. The resulting product was extracted with dichloromethane, the extract was dried, filtered and evaporated. The residue was recrystallized from acetonitrile, resulting in a received 64,1 PM(51,4% ) 5-[[2-[[1-(phenylmethyl)-4-piperidinyl]methyl]--1H-benzimidazole-1-yl] methyl]- 2-furanmethanol. So pl. 143,8about(Connection 1.01).

C) To a stirred mixture of 14.1 hours of 2-chloro-1-methylpyridinium, 11,5 including N, N-diethylethanamine and 282 including N,N-dimethylformamide was added dropwise at room temperature, 3.3 parts of acetic acid. After stirring for one hour to the reaction mixture were added 41,5 including what was strayaway dichloromethane, the extract was dried, filtered and evaporated, to deliver 40 PM(87,4%) 5-[[2-[[1-(phenylmethyl)-4-piperidinyl] methyl] -1H-benzimidazole-1-yl] methyl]-2-furanmethanol (ester) (compound 1.02).

(C) To a stirred mixture of 45.8 hours connection (1.02) and 261 hours of methylbenzene was added dropwise at the boiling temperature of 12 hours of ethylchloride. Boiling the mixture under reflux continued for a further hour. After cooling, to the reaction mixture were added water. The resulting product was extracted with methylbenzol. The extract was dried, filtered and evaporated, resulting in the 44,0 hours (100%) of ethyl-4-[[1-[[5-(the atomic charges)methyl]-2-furanyl]methyl]- 1H-benzimidazole-2-yl]methyl]-1 - piperidinecarboxylate (connection 1.03). The compound obtained contained, in addition, some amount of by-product, namely ethyl-4-[[1-[[5-[(phenyl)methoxy] methyl] -2-furanyl] methyl] -1H - benzimidazole-2-yl]methyl]-1-piperidinecarboxylate.

d) a Mixture of 44.0 h compound (1.03), 56 including potassium hydroxide and 234 hours 2-propanole was stirred over night while boiling under reflux. After the reaction mixture was evaporated and the residue was dissolved in water. The resulting product was extracted with dichloromethane and the extract was dried, fiue as mobile phase a mixture of CHCl3and CH3OH saturated with ammonia in a ratio of 95:5 to 80:20). The second eluate fraction was evaporated, receiving the result of 27.5 hours(84,5%) 5-[[2-(4-piperidinylmethyl)-1H-benzimidazole-1-yl]methyl]-2 - furanmethanol (connection 1.04).

After evaporation of the first fraction received 9 o'clock 2-[[5-(phenylmethoxy)methyl]-2-furanyl]methyl]-2-(4-piperidinylmethyl)-1H - benzimidazole (compound 1.05).

e) a Mixture of 3.25 hours connection (2.04), 2 hours of Polyoxymethylene, 2 hours 4% solution of thiophene in methanol and 119 hours of methanol was first made at normal pressure and room temperature in the presence of 2 hours of palladium catalyst on charcoal. After absorption of the calculated amount of hydrogen the catalyst was filtered and the filtrate was evaporated. The residue was dissolved in dichloromethane and the solution was washed with an aqueous solution of NH4OH. The organic layer was dried, filtered and evaporated. The residue successively recrystallized from 4-methyl-2-pentanone and acetonitrile, resulting in the 1,72 PM(50,7%) 5-[[2-[(1-methyl-4-piperidinyl)methyl]-1H-benzimidazole-1-yl]methyl] -2 - furanmethanol. So pl. 158,1about(Connection 1.17).

P R I m e R 9. After stirring a mixture of 8.4 hours of intermediate (16), of 5.05 PM 40% solution of formaldehyde and 4.25 hours of piperidine propulsively in for the weekend, then treated with ammonia. The resulting product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was subjected to purification using column chromatography on silica gel, using as mobile phase a mixture of CHCl3and CH3OH in the ratio of 97:3 98:2. Fractions of the eluate containing the target product was evaporated and the residue was recrystallized from a mixture of 4-methyl-2-pentanone and 2,2'-oxybisethane, receiving the 1.0 part (12.5%) of ethyl-4- [[3-[[5-(oxymethyl)-2-furanyl]methyl]-3H-imidazo-[4,5-b]pyridine-2-yl] amino]-1-piperidinecarboxylate. So pl. 148,3about(Connection 2.01).

P R I m e R 10. The mixture 105,9 hours of intermediate (25), 197,5 including 5-[[(3-amino-2-pyridinyl)amino] methyl] -2-furanmethanol and 470 including N,N-dimethylformamide was stirred for 3 days at room temperature. The reaction mixture was then poured into water, podslushivaet TO2CO3and subjected to extraction with dichloromethane. The extract was dried, filtered and evaporated, and the residue was dissolved in 435 hours of methylbenzol. To the solution was added a small amount of 4-methylbenzenesulfonate and stirring the mixture for 2 hours at boiling point. After cooling and alkalizing water solution TO2CO3product is 0%) ethyl-4-[[3-[[5-(oxymethyl)-2-furanyl] methyl] -3H-imida-zo[4,5-b] pyridine-2-yl] methyl] -1-piperidinecarboxylate (connection 2.13).

P R I m e R 11. A mixture of 20 hours of connection (3.05) and 237 hours of methanol was acidified with sulfuric acid to pH 1 with stirring. Stirring was continued over night at boiling point. After cooling, the reaction mixture was podslushivaet methanol, saturated with ammonia, and evaporated. The residue was dissolved in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was subjected to purification using column chromatography on silica gel, using as mobile phase a mixture of CHCl3and CH3OH in the ratio of 97:3. The fraction of the eluate containing the desired product were evaporated, resulting in the 29 hours (100% ) of ethyl-4-[[1-[[5-(methoxymethyl)-2-furanyl] methyl] -1H-benzimidazole- -2 - yl]amino]-1-piperidinecarboxylate (connection 3.06).

P R I m e R 12. A mixture of 2 hours [(4-pertenece)methyl]oxirane, 3,26 including compounds (3.11) and 39 hours 2-propanol was stirred for 48 h at boiling temperature. The reaction mixture was then evaporated and the residue was subjected to purification using column chromatography on silica gel, using as mobile phase a mixture of CHCl3and CH3OH saturated with ammonia in a ratio of 97: 3. The fraction of the eluate containing the target product was evaporated and the residue precrystallization ethyl)-2-furanyl] methyl] -1H - benzimidazole-2-yl]amino]-1-piperidine-canola. So pl. 136,8about(Connection 3.20).

P R I m e p 13. To a stirred and cooled (0about(C) a mixture of 3,3 including compounds (3.11), 1,01 including 1,1' -oxybisethane and 94 including N,N-dimethylformamide was added dropwise a solution of 0.8 h acetylchloride in N,N'-dimethylformamide. The reaction mixture was allowed to warm to room temperature and was evaporated. The precipitate was boiled 4 times in trichlormethane, decanter after each boiling. The combined liquid phases were dried, filtered and evaporated. The residue was subjected to purification using column chromatography on silica gel, using as mobile phase a mixture of CH2Cl2and CH3OH in the ratio 95:5. The fraction of the eluate containing the target product was evaporated and the residue was recrystallized from methanol, to deliver 0,8 h (21,7%) of 1-acetyl-N-[1-[[5-(oxymethyl)-2-furanyl] methyl]-1H-benzimidazole-2 - yl]-4-piperidylamine. So pl. 213,9about(Connection 3.21).

P R I m e R 14. A mixture of 3.7 hours 7-(2-bromacil)-3,4-dihydro-8-methyl - 2N, 6N-pyrimido-[2,1-b] thiazin-6-he monohydrobromide, 3,2 including compounds (3.11), 2,1 including sodium carbonate and 160 hours 4-methyl-2-pentanone was stirred over night at boiling point. The reaction mixture was then evaporated and the residue was dissolved in water. The product was extracted with dichloro is ographie on silica gel, using as mobile phase a mixture of CH2Cl2and CH3OH in the ratio 95:5. The fraction of the eluate containing the target product was evaporated and the residue was recrystallized from acetonitrile. The product was filtered and dried, resulting in the 1,5 hours (28,0%) of 3,4-dihydro-7-[2-[4-[[1-[[5-(oxymethyl)-2-furanyl] methyl] -1H-benzimidazole - 2-yl] amino]-1-piperidinyl]ethyl]-8-methyl-2N, 6N-pyrimido[2,1 - b][1,3]-thiazin-6-it. So pl. 226,9about(Connection 3.31).

P R I m e R 15. A mixture of 3.3 hours 2-chloroacetonitrile, 13 hours connection (2.03) 5 H. N,N-diethylethanamine and 94 including N,N-dimethylformamide was stirred for 4 h at room temperature. After adding potassium carbonate, the reaction mixture was diluted with water, stirred for a short time and the resulting product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was stirred 1,1' -oxybisethane, filtered and dried, resulting in the 10,85 PM(74%) 4-[[3-[[5-(oxymethyl)-2-furanyl] methyl] -3H-imidazo-[4,5-b]pyridine-2-yl]amino] -1-precontrol (connection 2.26).

P R I m e R 16. A mixture of 3 hours 2-ethenylpyridine, 3,7 including compounds (2.28) and 122 including 1-butanol was stirred over night while boiling under reflux. The reaction mixture C is the number of the mobile phase a mixture of CH2Cl2CH3O H and CH3HE saturated with ammonia at a ratio of 90:10:0 90:8:2. The fraction of the eluate containing the target product was evaporated and the residue was transferred into the (E)-2-butenedioate (2:3) in ethanol. This salt is recrystallized twice from ethanol, semi-tea in the result 2,14 PM(35,3%) 5-[[2-[[1-[2-(2-pyridinyl)ethyl] -4-piperidinyl]methyl]3H - imida-angry[4,5 - b] -pyridine-3-yl] methyl]-2-furanmethanol (E)-2-butenedioate (2:3). So pl. 159,8about(Connection 2.35).

P R I m e R 17. A mixture of 4.5 hours 3,6-dichloropyridazine, 11,1 including compounds (1.14) and 3.2 g sodium carbonate was stirred for half an hour at 150aboutC. After cooling, the reaction mixture was diluted with water. The resulting product was extracted with trichloromethane and the extract was dried, filtered and evaporated. The residue was boiled in acetonitrile. After cooling, the precipitate was filtered and dried, resulting in the 9,72 PM(67,4%) 5-[[2-[[1-[2-[(6-chloro-3-pyridazinyl)amino] ethyl]-4-Piperi - dinyl]methyl]- 1H-benzimidazole-1-yl]methyl]-2-furanmethanol. So pl. EUR 188.4about(Connection 1.21).

P R I m e R 18. A mixture of 1,1 including 4-chloro-3-nitropyridine, 2,5 hours connection (3.23), 1 tsp sodium carbonate and 39.5 hours of ethanol was stirred overnight at room temperature, then added to the reaction mixture water and recrystallization from a mixture of acetonitrile and ethanol, receiving the result of 1.9 PM(56,8%) 5-[[2-[[1-[2-[(3-the nitro-4-pyridinyl)amino] ethyl] -4-piperidinyl]amino]- 1H-benzimidazole-1-yl]methyl] -2-furanmethanol. So pl. 191,0about(Connection 3.26).

P R I m e R 19. A mixture of 1.74 hours 4-chloro-3-nitropyridine, 4,22 including compounds (4.11), 1,11 parts of N,N-diethylethanamine and 149 hours of trichloromethane was stirred over night at room temperature. The reaction mixture was then washed with an aqueous solution TO a2CO3,the aqueous layer was separated and carried out the extraction with dichloromethane. The combined organic layers were dried, filtered and evaporated. The residue was subjected to purification using column chromatography on silica gel, using as eluent a mixture of CH2Cl2CH3OH and CH3OH saturated with ammonia in a ratio of 90:10:1. The fraction of the eluate containing the target product was evaporated and the residue was recrystallized from a mixture of 4-methyl-2-pentanone and ethanol. The product was filtered and dried, resulting in the 1,2 h(21,2%)-5-[[2-[[hexahydro-1-[2-[(3-the nitro-4-pyridinyl)amino] ethyl] -1H - azepin-4-yl]amino]-1H-benzimidazole-1-yl]-methyl] -2-furanmethanol hemihydrate. So pl. 155, 1mmabout(Connection 4.14).

P R I m e R 20. To a solution of 1.3 g sociallyengaged in 89 parts of tetrahydrofuran to the m, the reaction mixture was treated with ethyl acetate, was added thereto dropwise with stirring to 7.9 hours 15% NaOH solution and 4.8 hours water, filtered through diatomaceous earth and the filtrate was evaporated. The residue was subjected to purification using column chromatography on silica gel, using as mobile phase a mixture of CH2Cl2CH3HE and CH3OH saturated with NH3in the ratio of 90:5:5. The fraction of the eluate containing the target product was evaporated and the residue was recrystallized from a mixture of acetonitrile and 2,2'-oxybisethane (twice), receiving the result of 0.65 part(18,4%) -5-[[2-[(hexahydro-1-methyl-1H-azepin-4-yl) amino] -1H-Ben-imidazol-1-yl]methyl]-2 - furanmethanol (connection 4.02).

P R I m e R 21. A mixture of 2.5 hours 3-bromo-N-(1-methylethyl)propanamide, 3,26 connection parts (3.11), 1,26 g sodium bicarbonate and 39.5 hours of ethanol was stirred over night at the boiling point under reflux. The reaction mixture was then evaporated, the residue was dissolved in water, the product was extracted with a mixture of trichloromethane and ethanol, the extract was dried, filtered and evaporated. The residue was recrystallized from acetonitrile, to deliver 3,20 PM(72,8%) 4-[[1-[[5-(oxymethyl)-2-furanyl]methyl]-1H-benzimidazole-2-yl] amino] -N-(1-methylethyl)-1-piperidinophenyl. So pl. 139,7about(Link is 2 hours the calcium oxide was first made at normal pressure and room temperature in the presence of 2 hours of palladium catalyst on charcoal. After absorption of the calculated amount of hydrogen the catalyst was filtered and the filtrate was evaporated. The residue was dissolved in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was subjected to purification using column chromatography on silica gel, using as eluent a mixture of CH2Cl2and CH3OH saturated with NH3in the ratio 95:5. The fraction of the eluate containing the target product was evaporated and the residue was transferred into the salt tandikat (1:3) in a mixture of methanol and ethanol. The product was filtered and dried, resulting in the 4,51 PM(69,9%) 5-[[2-[[1-[2-(3-pyridinylamino)ethyl]-4-PI - pyridinyl]methyl]-1H-benzimidazole-1 - yl]methyl]-2-furanmethanol of candiota (1: 3). So pl. 203,5about(Connection 1.24).

P R I m e R 23. A mixture of 3,4 o'clock compound (1.21), 0,82 including sodium acetate and 73.5 hours vinegar - Noah acid was stirred for 4 hours at the boiling temperature under reflux. The reaction mixture was then evaporated and the residue was dissolved in water. After alkalizing TO2CO3the solution was subjected to extraction dichloromethane and the mixture was stirred for 3 h at the boiling point under reflux, then the solvent drove and was added to the residue water. The resulting product was extracted with 1-butanol and the extract was dried, filtered and evaporated. The residue was subjected to purification using column chromatography on silica gel, using as eluent a mixture of CH2Cl2and CH3OH saturated with NH3in the ratio of 90:10. The fraction of the eluate containing the target product was evaporated and the residue was transferred into the salt tandikat (2:5) in ethanol. The product was filtered and dried, obtaining the result of 2.20 PM(45,6%) 6-[[2-[4-[[1-[[5-(oxymethyl)-2-furanyl] methyl] -1H-benzimida - Zol-2-yl]methyl]-1-piperidinyl] ethyl] amino - 3(2H)-pyridazinone of candiota (2:5). So pl. 210,2about(Connection to 1.25).

P R I m e R 24. A mixture of 22.4 hours of intermediate (15), 13 o'clock oxide mercury (II) a tablespoon of sulfur and 178 hours of tetrahydrofuran was stirred for 3 hours at the boiling temperature under reflux. The reaction mixture is then filtered and the filtrate was evaporated. The residue was distributed between the H2SO4and dichloromethane. The organic layer was dried, filtered and evaporated, and the residue was subjected to purification using column chromatography on silica gel, using as eluent a mixture of CH2Cl2and C2HCOH in the ratio is sagita-4-[[3-[[5-(oxymethyl)-2-furanyl] methyl] -3H-imidazo[4,5-b] - pyridine-2-yl]amino]-1H-azepin-1-carbox-power (connection 4.04).

All new compounds listed in table.1-6 were obtained in the described manner.

C. Pharmacological examples.

P R I m e R 25. Antihistaminic activity of the compounds of formula (I) can be demonstrated in the test "Protection of rats from calling their deaths compound 48/80", described in U.S. patent N 4556660, which is included in the references to this application. The results are shown in table.7. The term (sc) refers to subcutaneous administration. Values U50are given in table.8.

D. Examples of the composition.

P R I m e R 26. Drops for oral administration.

500 hours of active substance was dissolved in 0.5 l of 2-oxopropanoic acid and 1.5 l of the polyethylene glycol at 60-80aboutC. After cooling to 30-40aboutTo the resulting solution were added 35 l of polyethylene glycol and the mixture is thoroughly stirred. Thereafter, thereto was added a solution of 1750 hours saccharin sodium 2.5 l of purified water and while stirring, 2.5 liters of Cocoa flavor and polyethylene glycol to a total volume of 50 L. the result is a solution droplets with active substance 10 mg/ml of the Prepared solution is poured into suitable containers.

P R I m e R 27. RAS is boiling purified water. In 3 l of this solution were dissolved first 10 hours of 2,3-deoxidization acid and then 20 hours of active substance. The prepared solution was combined with the rest of the first solution and added to a mixture of 12 l 1,2,3-propanetriol and 3 l of 70% aqueous solution of sorbitol. 40 hours of saccharin sodium was dissolved in 0.5 l of water and added to the prepared solution of 2 ml of raspberry and 2 ml krajowego extracts. This solution was combined with the previously prepared solution and added water to a total volume of 20 L. the result is a solution for oral administration with the active substance 5 mg per teaspoon (5 ml). The resulting solution was poured into suitable containers.

P R I m e R 28. The capsule.

20 hours of active substance, 6 hours lauryl sodium, 56 g starch, 56 including lactose, 0,8 including colloidal silicon dioxide, and 1.2 g magnesium stearate vigorously mixed, and the resulting mixture was filled in 100 suitably hardened gelatin capsules. The content of the active substance in one capsule was 20 mg.

P R I m e R 29. Tablets with the shell.

Getting the basics tablets

A mixture of 100 parts of active substance, 570 hours of lactose and 200 g starch were thoroughly stirred, and then watered the plants is different, and the mixture was sifted, dried and again sieved. Thereafter, thereto were added 100 parts of microcrystalline cellulose (A vicel) and 15 hours hydrogenated oils (Steretex). The mass was mixed and extruded from her tablet. As a result received 10,000 tablets with content in each tablet of 10 mg of the active substance.

Shell.

To a solution of 10 hours of methyl cellulose (Methocel 60 HG) in 75 ml of denatured ethanol solution was added to 5 hours of ethyl cellulose (Ethocel 22 cps) in 150 ml of dichloromethane, and then 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. Spread 10 hours of polyethylene glycol and dissolved them in 75 ml of dichloroethane. This solution was added to the initially prepared solution and then added to a mixture of 2.5 parts of octadecanoate magnesium, 5 hours of polyvinylpyrrolidone and 30 ml of concentrated colour suspension (Opaspray K-1-2109) and stirred the whole mass. Tablets covered thus prepared mixture in the designated device.

P R I m e R 30. The solution for injection.

1,8 including methyl-4-oxybenzoates and 0.2 hours propyl-4-oxybenzoates was dissolved in approximately 0.5 l intended for injection of boiling water. After cooling to about 50aboutWith the solution under stirring was added 4 h lactic acid, 0.05 to PM propylenglycol for injection, to a total volume of 1 L. the result is a solution with a content of active substance 4 mg/ml Solution sterilized by filtration (u.s.P. XVII, S. 811) and filled them sterile container.

P R I m e R 31. The candles.

3 hours of active substance was dissolved in a solution of 3 o'clock 2,3-deoxidization acid in 25 ml of polyethylene glycol 400. Melted 12 o'clock surfactants (SPAN) and triglyceride (Witepsol 555) up to a total of 300 hours and stirred melt with the previously prepared solution. Thus prepared mixture was poured into moulds at 37-38aboutC. as a result received 100 candles with a content of active substance in each candle 30 mg/ml

P R I m e R 32. Injection

Was stirred for 60 hours active substances and 12 h of benzyl alcohol. To the mixture was added sesame oil to a total volume of 1 L. the result is a solution with a content of active substance 60 mg/ml, sterilized, and filled them sterile containers.

OXYALKYLENE DERIVATIVES OR THEIR PHARMACEUTICALLY ACCEPTABLE SALTS ACCESSION ACIDS, OR THEIR STEREOCHEMICAL ISOMERIC FORM, HAVING ANTIALLERGIC ACTIVITY AND ANTIALLERGIC COMPOSITION.

1. Oxyalkylene the uly

- CH = CH - CH = CH-;

- N = CH - CH = CH-;

- CH = CH - CH = N - or

- N = CH - N = CH-;

n = 1 or 2;

B - NR4or CH2< / BR>
R4is hydrogen or C1- C6-alkyl,

L is hydrogen, C1- C6-alkyl, C1- C6-allyloxycarbonyl or a radical of General formula

- Alk - R5;

- Alk - Y - R6;

- Alk - Z1- C (=X) - Z2- R7< / BR>
or

- CH2- CHOH - CH2- O - R8,

where R5is cyano, phenyl, does not necessarily substituted C1- C6-alkyloxy, pyridinyl, 4,5-dihydro-5-oxo-1H-tetrazolyl, 2-oxo-3-oxazolidinyl, 2,3-dihydro-2-oxo-1H-benzimidazolyl,

or bicyclic radical of General formula

< / BR>
where G2= -CH = CH - CH = CH-, - S - (CH2)3-, - S - (CH2)2-, - S - CH = CH - or - CH = C(CH3)-0-group,

R6- C1- C6-alkyl, pyridinyl, not necessarily substituted by a nitro-group, pyrimidinyl, pyrazinyl, pyridazinyl, not necessarily substituted with halogen, 2,3-dihydro-3-oxopyridine or 9-methyl-6-purinol,

R7- C1- C6- alkyl, haloethanol, 1-methyl-1H-pyrrolyl, furanyl, thienyl or aminopyrazine;

R8- haloethanol;

Y is oxygen or NH;

Z1and Z2each independently NH or prbleme salt accession acids, or stereochemical isomeric form, having antiallergic activity.

2. Anti-allergic composition comprising a pharmaceutically acceptable carrier and an active ingredient, wherein the active ingredient is used as a compound of General formula I in a quantity of 0.05 to 15.0 wt.%

 

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NNAlK where Alk is methyl or ethyl, with improved anthelminthic activity

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

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

The invention relates to new biologically active chemical compounds, namely, to derive a cyclic amide of the formula I

R1-(CH2)n-Z,

where R1group cyclic amide, such as 2H-3,4-dihydro-1,3-benzoxazin-2-she, 2H-3,4-dihydro-1,3-benzoxazin-2,4-dione, and 1,2,3,4-tetrahydroquinazoline-2,4-dione, and 1,2,3,4-tetrahydroquinazolin-2-it, 1,2,3,4-tetrahydropyrido(3,2-d)-pyrimidine-2,4 - dione, and 1,2,3,4-tetrahydropyrido(3,2-d)pyrimidine-2-it, 1,2,3,4-tetrahydropyrimidine-2,4-dione, pyrrolidin-2-it, 1,2,3,4 - tetrahydropyridine-2-it, 5H-6,7,8,9-tetrahydropyrido(3,2-b)azepin-6-she N-5,6,7,8-tetrahydropyrido(2,3-b)azepin - 8-she, 2H-3,4-dihydropyrido(2,3-e)-1, 3-oxazin-2-thione or 2-she pyrrolidine (3,4-b)-pyrazin-5-she 1H-2,3,4,5-tetrahydrothieno(2,3-b)indol-2-it, 8H-4,5,6,7-tetrahydrothieno(2,3-b)thiophene-7-she 4H-pyrazolo(5,4-f)benzazepin-9-it, isoindoline-1,3-dione, benzoxazolyl-2-it, unsubstituted or substituted lower alkyl, lower alkoxy, halogen, the nitro-group, carboxy, benzoyl or benzyl, n is zero or an integer from 1 to 6, Z is a group of formula (A) or (B):

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R2is methylene;

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_where And communication, cycloalkenes and cycloalkylcarbonyl groups, each with 3-4 carbon atoms in which one methylene group can be replaced dichloromethylene group, an unbranched Allenova group with 2 or 3 carbon atoms, which may be single or multiply unsaturated group-R7CR8-, -O-R7CR8- or-NR9where R7is a hydrogen atom, hydroxyl, phenyl or an alkyl group with 1-3 carbon atoms; R8is a hydrogen atom or an alkyl group with 1-3 carbon atoms and R9is a hydrogen atom, an alkyl group with 1-3 carbon atoms or phenyl; X is carbonyl, thiocarbonyl or sulfonylurea group;

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R2is a hydrogen atom or alkyl with 1-4 carbon atoms;

R3- pyridyl;

R4and R5is a hydrogen atom or together denote a further carbon-carbon bond;

R6is hydroxyl or alkoxygroup with 1-3 carbon atoms;

n = 2,3 or 4,

mixtures of their isomers or individual isomers and their physiologically tolerable additive salts (if R6means a hydroxyl group), which have valuable pharmacological properties, particularly an antithrombotic effect

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O__N< / BR>
(I) where R is amino, WITH1-C4-monoalkylamines,1-C4-dialkylamino, amino-C1-C4-alkylamino, di ( C1-C4-alkyl ) - amino-C1-C4-alkylamino, morpholino-C1-C4-alkylamino, hydroxy-C2-C4-alkylamino, di-(hydroxy-C2-C4-alkyl)-amino, C1-C4- alkoxy-C2-C4- alkylamino, morpholino,1-C4-alkoxy, -hydroxy-C2-C4-alkoxy, dioxy-C3-C4-alkoxy, C1-C4-alkoxy-C2-C4-alkoxygroup or chlorine, and their physiologically compatible salts accession acids having cardiotonic and vasodilator activity
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