Substituted thiazolidine and substituted pyridinoline derivatives or their pharmaceutically acceptable acid salt additive, the retrieval method and the composition having antiallergic activity

 

(57) Abstract:

Usage: the synthesis of medicinal drugs that have anti-allergic activity. The inventive thiazolidine and pyridinoline derivatives of benzimidazole. Reagent 1: 2-[[(1-(phenylmethyl)-4-piperidinyl]methyl] -1H-benzimidazole. Reagent 2: 2-(chloromethyl)-6-methylenetetrahydrofolate. Reaction conditions: to a solution of dimethylformamide in the presence of a dispersion of sodium hydride in mineral oil at room temperature. 5 table.

In the U.S. patents NN 4556660, 4634704, 4695695, 4588722, 4835161, 4897401 and Europatent EP-A-O and 0297661 reveals the benzimidazole - and imidazopyridines piperidine derivatives as antihistamines and inhibitors of serotonin.

The present invention relates to new substituted thiazolium and substituted pyridinium derived formulas

< / BR>
to their pharmaceutically acceptable additive salts and stereochemical isomeric forms, where

A1A2A3A4is a bivalent radical having the formula

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

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

-CH=N-CH=CH- (a-3)

-CH=CH-N=CH- (a-4),

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

-N=CH-N=CH- (a-6) or

-CH=N-CH=N- (a-7),

where one or two atoms su1-6-alkyloxy, hydroxy or trifluoromethyl;

B represents NR1CH2, O, S, SO or SO2where R1is hydrogen or C1-4-alkyl;

R represents a radical of the formula

< / BR>
where D is a C1-4-Alcantara;

R2represents a C1-6-alkyl;

n is 0, 1 or 2;

L represents hydrogen, C1-12-alkyl, C3-6-cycloalkyl,3-6alkenyl, optionally substituted aryl, C1-6-alkylsulphonyl,1-6-alkoxycarbonyl, arylcarbamoyl, aryl WITH1-6-alkoxycarbonyl or a radical of the formula

-AC-R3(c-1),

-AC-y-R4(c-2),

-AC-Z1-C(=X)-Z2-R5(c-3) or

-CH2-CHOH-CH2-O-R6(c-4),

where R3represents cyano, aryl or et;

R4represents hydrogen, aryl, t or1-6-alkyl, optionally substituted aryl or t;

R5represents hydrogen, aryl, Het or1-6-alkyl, optionally substituted aryl or t;

R6represents aryl or naphthalenyl;

y represents O, S, NR7where R7is hydrogen, C1-6-alkyl or C1-6-alkylcarboxylic;

Z1and Z2each is Kilom;

X represents O, S or NR9where R9is hydrogen, C1-6-alkyl or cyano;

AC each independently is a C1-6-Alcantara;

t each represents

(i) optionally substituted heterocyclic ring with 5 or 6 members containing 1, 2, 3 or 4 heteroatoms selected from oxygen, sulfur and nitrogen, provided that there is not more than 2 oxygen atoms and/or sulfur;

(ii) optionally substituted heterocyclic ring with 5 or 6 members, which contains 1 or 2 heteroatoms selected from oxygen atoms, sulfur and nitrogen and related optionally substituted five - or six-membered ring through 2 carbon atoms or 1 carbon atoms and 1 nitrogen atom, and which in the rest of the condensed ring contains only carbon atoms;

(iii) optionally substituted heterocyclic ring with 5 or 6 members, which contains 1 or 2 heteroatoms selected from oxygen atoms, sulfur and nitrogen and related optionally substituted five - or six-membered ring through 2 carbon atoms or 1 carbon atoms and 1 nitrogen atom, and which in the rest of the condensed ring contains 1 or 2 heteroatoms selected from atoms kiselnyh to have up to 4 substituents, and if Het is a bicyclic ring system, it may not necessarily be up to 6 substituents, which are selected from halogen, amino, mono - and di(C1-6-alkyl)amino, arils1-6-amino, nitro, cyano, aminocarbonyl,1-6-alkyl, C1-6-alkyloxy,1-6-alkylthio,1-6-allyloxycarbonyl,1-6-alkyloxy-C1-6-alkyl, C1-6-allyloxycarbonyl1-6-alkyl, hydroxy, mercapto, hydroxys1-6-alkyl, C1-6-alkylcarboxylic, aryl, arils1-6-alkylaminocarbonyl, arylenecarborane, oxo or thio;

each aryl is optionally substituted by 1, 2 or 3 substituents, each of which is independently selected from halogen, hydroxy, nitro, cyano, trifloromethyl,1-6-alkyl, C1-6-alkyloxy,1-6-alkylthio, mercapto, amino, mono - and di-(C1-6-alkyl)amino, carboxyl,1-6-allyloxycarbonyl and C1-6-alkylcarboxylic.

In the compounds of formula (I), where R3, R4or R5is Het specified Het may be partially or fully saturated or unsaturated. The compound of formula (I), where Het is an unsaturated or partially saturated and substituted hydroxy, mercapto or amino, may also su is asego invention.

In the above definitions, halogen means fluorine, chlorine, bromine or iodine; WITH1-4-alkyl refers to straight and branched saturated hydrocarbon radicals, having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl; the term1-4-alkyl defines the above WITH1-4-alkalemia radicals and the higher homologues having 5 or 6 carbon atoms; the term1-12-alkyl defines1-4-alkalemia radicals mentioned above, and their higher homologues having from 5 to 12 carbon atoms; the term3-6-cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the term3-6alkenyl defines straight and branched hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms, such as 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, etc. and if a3-6alkenyl is substituted on a heteroatom, then the carbon atom indicated WITH3-6-alkenyl associated with the specified heteroatom is preferably saturated; the term1-4-alcander defines bivalent straight or branched saturated hydrocarbon radicalsmainly isomers; the term4-6-alcander defines1-4-alkantiolov radicals, as defined above, and their higher homologues having 5 or 6 carbon atoms, such as 1,5-pentadien, 1,6-hexandiol and their branched isomers.

The above-mentioned pharmaceutically acceptable additive salts are therapeutically active non-toxic acid additive salts, which can form compounds of formula (I). These forms salts can be mainly obtained by processing the basic form of the compounds of formula (I) with an appropriate acid such as an inorganic acid, for example galoidvodorodnykh acid, such as hydrochloric acid, Hydrobromic acid, etc., sulfuric acid, nitric acid, phosphoric acid, etc. or an organic acid such as acetic, hydroxyestra, 2-hydroxypropanoic, 2-oxopropanoic, tanginoa, proportionaly, batandjieva, (Z)-2-batandjieva, (E)-2-batandjieva, 2-hydroxybutanone, 2,3-dihydroxybutanedioate, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, econsultancy, benzolsulfonat, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic acid, etc., And on the Sabbath. The term acid additive salt also applies to the hydrates and solvent additives, which are capable of forming a compound of formula (I). Examples of such forms of the compounds are, for example, hydrates, alcoholate, etc.,

Compounds of the present invention can have several asymmetric carbon atoms in its structure. Each of these chiral centers may be identified by the stereochemical descriptors R and S.

Stereochemical pure isomeric forms of the compounds of formula (I) can be obtained using well known procedures. The diastereomers can be separated by physical methods such as selective crystallization and chromatographic techniques, etc., and enantiomers may be separated from each other using a known technique permits, for example, by selective crystallization of their diastereomeric salts with the use of chiral acids. Pure stereochemical isomeric forms may also be derived from the corresponding pure stereochemical isomeric forms of the appropriate starting materials, provided that the stereospecific reactions take place. If you want to get specific stereoisomer, then this connection, it is preferable to synthesize stereoselective methods. These methods predusmatrivaetsya compounds of formula (I) are also included in the scope of the present invention.

In particular, the above-defined radical Het can be selected from pyridinyl, optionally substituted by one or two substituents, each of which is independently selected from halogen, amino, mono - and di(C1-6-alkyl)amino, aryl WITH1-6-alkylamino, nitro, cyano, aminocarbonyl,1-6-alkyl, C1-6-alkyloxy,1-6-alkylthio,1-6-allyloxycarbonyl, hydroxy, C1-6-alkylcarboxylic, arils1-6-alkyl and carboxyl, pyridyloxy, optionally substituted by nitro, pyrimidinyl, optionally substituted by one or two substituents, each of which is independently selected from halogen, amino, C1-6-alkylamino, arils1-6-alkylamino, hydroxy, C1-6-alkyl, C1-6-alkyloxy,1-6-alkylthio and arils1-6-alkyl; Peradeniya, optionally substituted C1-6-alkyl or halogen; pyridinyl, optionally substituted with halogen, amino or1-6-alkyl; tanila, optionally substituted with halogen or1-6-alkyl; furanyl, optionally substituted C1-6-alkyl or halogen; pyrrolyl, optionally substituted C1-6-alkyl; thiazolyl, optionally substituted C1-6-alkyl, C1-6-alkyloxyalkyl, each of which is selected from C1-6-alkyl, aryls1-6-alkyl and nitro; tetrazolyl, optionally substituted C1-6-alkyl; 1,3,4-thiadiazolyl, optionally substituted C1-6-alkyl or amino; 5,6-dihydro--1,3-thiazin-2-yl, optionally substituted C1-6-alkyl; 4,5-dihydrothiazolo, optionally substituted C1-6-alkyl; oxazolyl, optionally substituted C1-6-alkyl; 4,5-dihydro-5-oxo-1H-tetrazolyl, optionally substituted C1-6-alkyl; 1,4-dihydro-2,4-dioxo--pyrimidinyl, optionally substituted C1-6-alkyl; 3,4-dihydro-4-oxopyrimidine or 4,5-dihydro-4-oxopyrimidine, both of these radicals optionally have up to 3 substituents, which are selected from C1-6-alkyl, amino, C1-6-alkylaminocarbonyl, arylenecarborane, aryl WITH1-6-alkylamino and C1-6-alkylamino; 2,3-dihydro-3-oxopyridine; 2-oxo-3-oxazolidinyl; pyrrolidinyl; piperidinyl; morpholinyl; thiomorpholine; dioxane, optionally substituted C1-6-alkyl, indolyl, optionally substituted by hydroxy or C1-6-alkyl; chinoline, optionally substituted by hydroxy or C1-6-alkyl; hintline, neobyazatel is Alasania, optionally substituted with halogen; 1,3-dioxo-isoindole-2(3H)-yl; 2,3-dihydro-3-oxo-benzoxazine and 2,3-dihydro-1,4-benzodioxane, both of which can be substituted WITH1-6-alkyl or halogen; 2-oxo--1-benzopyranyl and 4-oxo--1-benzopyranyl, both of which can be substituted WITH1-6-alkyl; 3,7-dihydro-1,3-dimethyl-2,6-dioxo-purine-7-yl, optionally substituted C1-6-alkyl; 6-purine and bicyclic heterocyclic radical of the formula

< / BR>
where X1and X2each independently is O or S;

each of R10independently represents hydrogen, C1-6-alkyl, aryls1-6-alkyl, C1-6-alkyloxy1-6-alkyl, hydroxys1-6-alkyl or C1-6-allyloxycarbonyl;

each of R11independently represents hydrogen, C1-6-alkyl, hydroxy, mercapto, C1-6-alkyloxy,1-6-alkylthio, halogen or1-6-allyloxycarbonyl1-6-alkyl;

G1is-CH=CH-CH=CH-, -S-CH=CH - or-N=CH-NH-;

G2is-CH-CH-CH=CH-, -(CH2)4-, -S-(CH2)2-, -S-(CH2)3-, -S-CH=CH-, -CH=CH-O -,- NH-(CH2)2-, -NH-(CH2)3-, -NH-CH=CH-, -NH-N=CH-CH2-, -NH-CH=N - or-NH-N=CH-;

G3is-CH= CH=N-;

G4is-CH=CH-CH=CH-, -CH2NH-(CH2)2-, -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH-, -CH=CH-CHN-, -N=CH-N=CH - or-CH=N-CH=N-;

G5is-CH= CH-CH= CH-, -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH-, -CH=CH-CH=N-, -N=CH-N=CH - or-CH=N-CH=N-;

G6is-CH= CH-CH= CH-, -N=CH-CH=CH-, -CH=N-CH=CH-, -CH=CH-N=CH-, -CH=CH-CH=N-, -N=CH-N=CH - or-CH=N-CH=N-,

where one or two hydrogen atoms in the benzene part of the radicals of formulas (d-2) or (d-3) or one or two hydrogen atoms in the above radicals G1, G2, G3, G4, G5or G6can be overridden WITH the1-6-alkyl, C1-6-alkylthio,1-6-alkyloxy or halogen in the case, if they are linked to the carbon atom; or (C1-6-alkyl, C1-6-allyloxycarbonyl or aryl WITH1-6the alkyl in the case, if they are linked to the nitrogen atom; and aryl is as it was defined above.

In particular, the aryl in the definition of R3, R4and R5represents phenyl, optionally substituted with halogen, C1-6-alkyl, hydroxy or1-6-alkyloxy; and aryl in the definition of R6represents phenyl, optionally substituted with halogen.

A characteristic subgroup of compounds of formula (I) are the compounds of formula (I), where-A1A2-A3A4pre who (I) are compounds of formula (1) are the compounds of formula (I), where-A1A2-A3A4is a bivalent radical having the formula (a-3) (a-5), and one or two hydrogen atoms in said radicals (a-1) (a-5) each may be independently substituted WITH1-6-alkyloxy or hydroxy.

Of particular interest are any compounds of the above groups or subgroups in which B is NR2, O, or CH2; and/or L is hydrogen, C1-6-alkyl, C1-6-alkylcarboxylic,1-6-allyloxycarbonyl or a radical of formula (C-1), (2), (3) or (4).

Compounds of particular interest, more interesting are the compounds of formula (I), where B is NH or CH2; and/or n is 1 or 2; and/or R is a radical of the formula

< / BR>
The preferred compounds are any compounds of the above groups in which-A1A2-A3A4- is a bivalent radical of formula-CH=CH-CH=CH- (a-1) or-N=CH-CH=CH- (a-2), where one or two hydrogen atoms in said radicals (a-1) or (a-2) can be independently substituted WITH1-6-alkyloxy or hydroxy; D is CH2; or/and L is hydrogen, C1-6-alkyl, a radical of formula (C-1), where R3represents aryl or Het is m formula AC-NH-CO-Het (C-3-a), where each Het represents pyridinyl, optionally substituted amino or1-6-alkyl; pyrimidinyl, optionally substituted amino or C1-6-alkyl; pyrazinyl, optionally substituted amino; thienyl; furanyl; thiazolyl, optionally substituted C1-6-alkyl; imidazolyl, optionally substituted C1-6-alkyl; tetrazolyl, optionally substituted C1-6-alkyl; 1,3,4-thiadiazolyl, optionally substituted C1-6-alkyl or amino; oxazolyl, optionally substituted C1-6-alkyl; 4,5-dihydro-5-oxo--tetrazolyl, optionally substituted C1-6-alkyl; 1,4-dihydro-2,4-dioxo--pyrimidinyl; 3,4-dihydro-4-oxopyrimidine, which can have up to 3 substituents selected from C1-6-alkyl, amino and C1-6-alkylamino; 2-oxo-3-oxazolidinyl; indolyl, optionally substituted C1-6-alkyl; phthalazine; 2-oxo--1-benzopyranyl; 3,7-dihydro-1,3-dimethyl-2,6-dioxo-purine-7-yl, optionally substituted C1-6-alkyl; 6-purinol or bicyclic heterocyclic radical of formula (d-1) (d-8) as defined above, where R10and R11each independently is hydrogen or C1-6-alkyl, and the radicals (d-2) and (d-3) X1is About; and

each aryl present is from halogen, hydroxy, nitro, cyano, trifloromethyl,1-6-alkyl and C1-6-alkyloxy, and, in addition, optionally substituted by a third Deputy, which are selected from halogen, C1-6-alkyl or C1-6-alkyloxy.

More preferred compounds are those preferred compounds in which L is hydrogen or C1-3-alkyl.

Even more preferred compounds are those preferred compounds in which L is the radical of the formula-AC-R3(C-1), where R3represents a 4-methoxyphenyl; 4-hydroxyphenyl; thienyl; thiazolyl, optionally substituted C1-6-alkyl; oxazolyl; 4,5-dihydro--tetrazolyl, optionally substituted C1-6-alkyl; 2,3-dihydro-2-oxo-benzimidazole-1-yl; 1,4-dihydro-2,4-dioxo--pyrimidinyl; thienyl; 2-oxo--1-benzopyranyl or R3represents a radical of the formula

< / BR>
where G1, G2and R10are the same as defined above.

Other even more preferred compounds are those preferred compounds in which L is the radical of the formula-AC-y-R4(c-2), where y represents NH or O, and R4represents triazolyl; pyridinyl; 1,3, the Mino; 6-purinol; 3,4-dihydro-4-oxopyrimidine; phthalazines or-imidazo[4,5-c]-pyridine-2-yl.

Of the compounds of the present invention the interest are those compounds of formula (I) in which-A1A2-A3A4- is a bivalent radical of formula-CH= CH-CH=CH- (a-1) or N-CH-CH=CH- (a=2); B is NH, CH2or O; R is a radical of the formula

< / BR>
where R2is1-4-alkyl; N Is 1; L represents hydrogen, C1-4-alkyl, C1-4-allyloxycarbonyl or a radical of the formula-AC-R3(C-1), -AC-y-R4(C-2) or-AC-Z1-C(=X)-Z2-R5(C-3), where AC is a C1-4-Alcantara; R3is phenyl,1-4-allyloxyphenyl or a radical of the formula

< / BR>
where G2represents-CH=CH-CH=CH-, -S(CH2)3)-, -S-(CH2)2)- or-S-CH= CH-; y represents O or NH; R4represents hydrogen, C1-4is alkyl or pyrimidinyl; R5represents a C1-4-alkyl; Z1represents NH; Z2represents O; and X represents O.

From the above interest compounds of particular interest are compounds in which B is NH or CH2; R2is stands; L is the>(C-3); AC is a C2-4-Alcantara; R3is 4-methoxyphenyl or a radical of the formula

< / BR>
where G2is-CH=CH-CH=CH-, -S-(CH2)3-, -S-(CH2)2- or-S-CH=CH-; y is O or NH; and R4is C1-4-alkyl or 2-pyrimidinyl.

From the above interest compounds other particularly interesting compounds are compounds in which B represents NH or CH2; R2represents methyl; L represents hydrogen, C1-4-allyloxycarbonyl, phenylmethyl, hydroxyethyl or aminoethyl.

As described above, are particularly interesting compounds of most interest are compounds in which L is the stands or the radical of the formula-AC-R3(C-1), where AK represents a 1,2-ethandiyl, and R3represents a 4-methoxyphenyl or a radical of the formula

< / BR>
where G2is-CH=CH-CH=CH-, -S-(CH2)3-, -S-(CH2)2- or-S-CH=CH-.

To simplify the structural representation of some compounds of the present invention and intermediates in the description below, the receipt of these compounds part containing imidazole group, fused with benzene, the feast of the main can be obtained by reaction of the intermediate compounds of formula (II) with an appropriately substituted diamine of formula (III):

< / BR>
In this and in the following reaction schemes W represents an appropriate reactive leaving group such as halogen group such as chloro-, bromo - or iodine-group; C1-6-alkyloxy; C1-6-alkylthio, aryloxy or alkyltin group, and X1is O, S or NH.

Derivatives of the formula (II), where B is CH2and W is a halogen group, can be obtained in situ, for example by halogenation of the corresponding carboxylic acid using thionyl chloride, trichloride phosphorus, phosphorylchloride, polyphosphoric acid, etc., the Reaction of the compound (II) and (III) can be carried out in an appropriate inert to the reaction, a solvent such as a hydrocarbon solvent, such as benzene, hexane, etc., an ether, e.g. 1,1'-oxybisethane, tetrahydrofuran, etc., a ketone, e.g. 2-propanone, 2-butanone, etc., an alcohol, for example methanol, ethanol, 2-propanol, 1-butanol, etc., halogenated hydrocarbons such as trichloromethane, dichloromethane, etc., organic acid, for example acetic acid, propanoic acid, etc., a polar aprotic solvent, for example N, N-dimethylformamide, N,N-dimethylacetamide, etc., or a mixture of these solvents. In semicivilized of reactions of N-alkylation, and/or iodide salt, such as alkali metal iodide. The reaction rate can be improved by increasing the reaction temperature and the reaction while stirring.

In some cases, as a result of reaction (II) with (III) first receive intermediate compound of formula (II-a), which can then be cyklinowanie until the desired compounds of formula (I), either in situ or, if necessary, after isolation and purification:

< / BR>
The compounds of formula (I) can be also obtained by the reaction of intermediates of formula (IV) with an intermediate compound of formula (V) in accordance with well known procedures for substitution reactions. In (IV) and then M is hydrogen when B is CH2or M is an alkaline or alkaline-earth metal, such as lithium or magnesium, if B is CH2:

< / BR>
Similarly, compounds of formula (I) can also be obtained by reaction of the intermediate of formula (VI) with an intermediate compound of formula (VII), where M has the values defined above. In the formula (VI) and then W1is the corresponding leaving group such as halogen group, chloro, bromo, etc., or sulfonyl the BR> The compounds of formula (I), where B is-CH2- (these compounds are represented by formula (1-a), can be obtained by reaction of the intermediate of formula (VIII) with an intermediate compound of formula (IX) or alternatively by reaction of the intermediate of formula (X) with an intermediate compound of formula (XI):

< / BR>
The reaction of (IV), (VI), (VIII) and (X) (V), (VII), (IX) and (XI) respectively can be carried out in a suitable inert solvent, for example such as an aromatic hydrocarbon, for example benzene, methylbenzol, etc., an ether such as 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran, etc., halogenated Uglevodorody, such as trichloromethane, etc., N,N-dimethylformamide; N, N-dimethylacetamide; nitrobenzene; dimethylsulfoxide; 1-methyl-2-pyrrolidinone, etc. and if M is hydrogen, such a solvent can also be1-6-alkanol, for example methanol, ethanol, 1-butanol, etc., a ketone, e.g. 2-propanone, 4-methyl-2-pentanon, etc. In some cases, in particular when B is a heteroatom, to the reaction mixture may be added an appropriate base such as a carbonate or bicarbonate of alkali metal, for example sodium carbonate, sodium bicarbonate, etc., sodium hydride; Ile added salt itestosterone acid, preferably the iodide of an alkali metal. The reaction rate can be increased by conducting the reaction at elevated temperature and under stirring. The alternative of carrying out the reaction of the intermediate of formula (IV), where B is M represents-NH2with a reagent of formula (V) is the stirring and heating the reactants in the presence of metallic copper in an inert towards the reaction, the solvent such as the solvents mentioned above, and in particular in the polar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.

The compounds of formula (I), where B is-NR1- mentioned compounds represented by the formula (1-b), can be also obtained by the reaction of intermediate compounds of formula (XII) with an intermediate compound of formula (VII), where B-M is a radical-NR1-H (a specified compound represented by formula (VII-a)) carried out in accordance with known procedures reductive N-alkylation:

< / BR>
The reaction of (XII) with (VII-a) are usually conducted by mixing the reactants in an appropriate inert solvent with a suitable regenerating agent. Preferably, if the first ketone of formula (XII) is subjected to (but not necessarily) isolated and purified, and then spend the reaction of recovery specified enamine. Suitable for this reaction solvents are, for example, water, WITH1-6-alkanols, such as methanol, ethanol, 2-propanol, etc., ethers such as 1,4-dioxane, etc., halogenated hydrocarbons such as trichloromethane, etc., polar aprotic solvents such as N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, etc., or mixtures of these solvents. Suitable reducing agents are, for example, hydrides of metals or hydrides of metal complexes, such as borohydride sodium, cyanoborohydride sodium, alumoweld lithium, etc. Alternative as the reductant may be used hydrogen in the presence of an appropriate catalyst, such as palladium carbon, platinized charcoal, etc. to avoid any unwanted subsequent hydrogenation of some functional groups in the reactants and reaction products may be preferred to add to the reaction mixture of the corresponding catalyst poison, such as thiophene, etc.

The compounds of formula (1-b), where R1is N (these compounds are represented by formula (1-b-1)), can be also p, is shown thiourea represented by formula (II-a-1), which can be obtained in situ by condensation of isothiocyanate formula (XIII) with a diamine of the formula (III).

This reaction collegesuniversities can be carried out using the reaction of compound (II-a-1) with the corresponding alkylhalides, preferably by iodomethane, in an appropriate inert to the reaction solvent, such as1-6-alkanol, for example methanol, ethanol, 2-propanol, etc., specified Alternative reaction collegesuniversities can also be carried out using a reaction between the compound (II-a-1) with an appropriate metal oxide or salt, for example an oxide or salt of Hg (II) or Pb (Ii), such as HgO, HgCl2Hg(OAc)2, PbO or Pb(OAc)2, in a suitable solvent and in accordance with well known procedures. In some cases, the reaction mixture may be added a small amount of sulfur. As collegesuniversities agents can also be used methanediamine, and especially dicyclohexylcarbodiimide.

< / BR>
The compounds of formula (I) can be obtained by N-alkylation of the intermediate compounds of formula (XV) using the appropriate alkiliruushimi, such as water; aromatic hydrocarbons such as benzene, methylbenzol, xylene, etc., alkanol, for example methanol, ethanol, 1-butanol, etc., a ketone, e.g. 2-propanone, 4-methyl-2-pentanon etc. simple ether, for example tetrahydrofuran, 1,4-dioxane, 1,1-oxybisethane, etc., a polar aprotic solvent, for example N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, nitrobenzene, 1-methyl-2-pyrrolidinone, etc. or mixtures of these solvents. To absorb the acid released in the reaction, may be added to the corresponding base such as carbonate, bicarbonate, alkoxide, hydride, amide, hydroxide or oxide of an alkaline or alkaline-earth metal, for example sodium carbonate, sodium bicarbonate, potassium carbonate, sodium methoxide, ethoxide sodium t-piperonyl potassium, sodium hydride, sodium amide, sodium hydroxide, calcium carbonate, calcium oxide, etc., or an organic base such as amine, for example N,N-diethylethanamine, N-1-methylethyl-2-propanamine, 4-ethylmorpholine, pyridine, etc. In some cases it is preferable to add salt idiscovered acid, especially an alkali metal iodide. The reaction rate can be increased by conducting the reaction under slightly elevated temperovane in an inert atmosphere, for example in an atmosphere of argon or nitrogen, which does not contain oxygen.

Alternative specified N-alkylation may be carried out under conditions well known reactions, interfacial catalysis. These conditions include mixing of reagents with the corresponding base and optionally in an inert atmosphere, as described above, in the presence of a phase transfer catalyst, such as a halide, hydroxide, bisulfate of dialkyldimethylammonium, tetraalkylammonium, tetraallylsilane, tetrakisphosphate and similar catalysts.

The compounds of formula (I), where L is not hydrogen (specified L denoted by L1and these compounds indicated by formula (1-d)) can also be obtained by N-alkylation of compounds of formula (I), where L is hydrogen (the specified connection is represented by the formula (1-e)), using an alkylating agent of the formula (XVI):

< / BR>
Specified N-alkylation mostly carried out in accordance with well known procedures N-alkylation described above to obtain (I) from (XIV) and (XV).

The compound of the formula (1-d), where L is a C3-6-cycloalkyl,1-12-alkyl, a radical of formula (c-1), (2) or (3) (specified radicalchange by the reaction of reductive N-alkylation of the compound (1-e) using the appropriate ketone or aldehyde of formula L20 (XVII), where the specified L20 is an intermediate compound of formula L2H2where two genialnyh hydrogen atoms are replaced by O and L2is genialny divalent radical comprising FROM3-6-cycloalkylation,1-12-alkyliden, R3-C1-6-alkyliden, R4-y-C1-6-alkyliden and R5-Z2-C(=X)-Z1-C1-6-alkyliden.

< / BR>
The specified recovery can mainly be conducted in accordance with the procedures described above for preparing compounds of the formula (1-C) from (VII) and (XII), and in particular, in accordance with the procedures catalytic hydrogenation.

The compounds of formula (I), where L is a radical of formula (C-2), and R4is aryl or Het (specified R4denoted by R4-aand these compounds are represented by formula (I-d-2)) can also be obtained by alkylation of compounds of formula (I), where L is a radical of formula (C-2), and R4is hydrogen, these compounds are represented by formula (I-d-3) using a reagent of formula (XVIII)):

< / BR>
Similarly, compounds of formula (I-d-2) can be also obtained by treating the compounds of formula (I-d-4) with a reagent of formula (X the main can be carried out in an inert organic solvent, such as an aromatic hydrocarbon, for example benzene, methylbenzol, xylene; a ketone, e.g. 2-propanone, 4-methyl-2-pentanone; simple ether, e.g. 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran; and polar aprotic solvent, for example N,N-dimethylformamide, N, N-dimethylacetamide, dimethyl sulfoxide, nitrobenzene, 1-methyl-2-pyrrolidinone, etc. To absorb the acid released in the reaction, may be added to the corresponding base such as a carbonate or bicarbonate of alkali metal, sodium hydride, or organic base, for example N, N-diethylethanamine or N-(1-methylethyl)-2-propanamine. Conducting the reaction under slightly elevated temperatures can increase the rate of this reaction.

The compounds of formula (I), where L is a radical of formula (C-3), Z2is NH, Z2is not a simple bond and X is NR9(these Z2and denoted by X Z2-aand X2and these compounds are represented by formula (I-d-5)), can be obtained by reaction of isocyanate (X2O) or isothiocyanate (X2S) of formula (XXI) with a reagent of formula (XX):

< / BR>
The compound of formula (I), where L is a radical of formula (C-3), Z2is NH, Z1is not direct the Oia represented by formula (I-d-6)), can be obtained by reaction of isocyanate (X2=O) or isothiocyanate (X2=S) of formula (XXII) with a compound of formula (I-d-7):

< / BR>
The reaction of the compound (XX) with the compound (XXI) or the compound (XXII) with a compound (I-d-7) can mainly be carried out in a suitable inert to the reaction solvent, such as a simple ether, for example tetrahydrofuran, etc., halogenated hydrocarbons such as trichloromethane, etc. To increase the rate of reaction can be used elevated temperatures.

The compounds of formula (I), where L is a radical of formula (c-3), Z2is a simple bond, and X is NR9(these Z1and denoted by X Z1-aand X2and these compounds are represented by formula (I-d-8)), can be obtained by reaction of the reagent of formula (XXIII) or a reactive functional derivative with the compound of the formula (I-d-7):

< / BR>
The reaction of the compound (XXIII) with the compound (I-d-7) can be carried out in accordance with known procedures for reaction of esterification or amidation. For example, the carboxylic acid can be converted into a reactive derivative, for example an anhydride or carboxylic acid halide, which is then subjected to reaction with (I-d-7), the esters, for example N,N-melanterius(cyclohexamide), 2-chloro-1-methylpyridine iodide, etc., These reactions are mainly carried out in an appropriate solvent, such as a simple ether, for example tetrahydrofuran; halogenated hydrocarbons such as dichloromethane, trichloromethane; polar aprotic solvent, etc. May be preferable to add to the reaction mixture a base, such as, for example, N,N-diethylethanamine etc.

The compounds of formula (I), where L is a radical of the formula L3-C2-6-alcander, where L3is aryl, Het or a radical of the formula R5-Z2-C(= X)- (these compounds are represented by formula (I-d-9)) can be also obtained by reaction of accession, which is subjected to a compound of the formula (1-e) with the corresponding alkene of the formula (XXIV):

< / BR>
The compounds of formula (I), where L is 2-hydroxy-C2-6-alkyl or a radical of formula (C-4) (these compounds are represented by formula (I-d-10)), can be obtained by reaction of compounds of formula (1) with the epoxide (XXV), where R12is hydrogen, C1-4-alkyl or the radical R6-O-CH2:

< / BR>
The reaction of the compound (1-e) (XXIV) and (XXV) can be conducted accordingly when ramashiva is he, for example, 2-propanone, 4-methyl-2-pentanone; simple ether, e.g. tetrahydrofuran, 1,1-oxybisethane; alcohol, for example methanol, ethanol, 1-butanol; a polar aprotic solvent, for example N,N-dimethylformamide, N,N-dimethylacetamide, etc.

The compounds of formula (I), where R3, R4or R5are Het, can also be obtained in accordance with known procedures commonly used to obtain heterocyclic ring systems, or similar ways. Some of these procedures used for carrying out the cyclization, as described, for example, in U.S. patent N 4695575 in the works referenced in this patent, in particular in patents U.S. NN 4335127, 4342870 and 4443451.

The compounds of formula (I) can be converted into each other in accordance with known procedures for transformation of functional groups. Some examples of such procedures are given below. The compound of formula (I) containing a cyano-Deputy, may be converted into the corresponding amines by stirring and, if necessary, heat source cyano compounds in a hydrogen-containing atmosphere in the presence of an appropriate catalyst, such as platinized carbon, Nickel Raney catalyst and the Amino group can be alkylated or etilirovany in accordance with known procedures, for example, by N-alkylation, N-acylation, reductive N-alkylation, etc., the compounds of formula (I) containing an amino group substituted by the radical arylmethyl can be hydrogenation by treating the starting compound with hydrogen in the presence of an appropriate catalyst such as palladium carbon, platinized charcoal, etc., preferably in an alcoholic medium. The compounds of formula (I), where L is the stands or vinylmation, can be converted into compounds of formula (I), where L is a C1-6-allyloxycarbonyl group through reaction with methyl or phenylmethylene derived from1-6-allyloxycarbonyl, for example etelcharge.com, in an appropriate inert to the reaction solvent and in the presence of a base, for example N,N-diethylethanamine. The compounds of formula (I), where L is hydrogen, can be obtained from compounds of formula (I), where L is vinylmation or1-6-alkoxycarbonyl, in accordance with known procedures commonly used for catalytic hydrogenation or hydrolysis in acidic or alkaline depending on the nature L.

In all above - and below ways procedurename ways.

Some intermediate and raw materials used to obtain the above compounds are known compounds and can be obtained in accordance with known techniques to obtain these or similar compounds. But some of the intermediate compounds are new compounds and methods for their preparation will be described in more detail below.

Raw materials, such as intermediate compounds of formula (II), (IV), (VI), (VIII), (X), (XII), (XIII) and (XV), mainly can be obtained in accordance with procedures similar to those described for example in U.S. patents NN 4219559, 4556660, 4634704, 4695569, 4695575, 4588722, 4835161 and 4897401 and Europatent EP-A-0206415, 0282133, 0297661 and 0307014.

Intermediate compounds of formula (III) can be obtained from aromatic starting compounds with adjacent halogen and nitro substituents (XXVII) by reaction with an appropriate amine of the formula (XXVI) in accordance with known reaction for reduction of nitro to amine:

< / BR>
Intermediate compounds of formula (V), (VII), (IX) and (XI) can then be obtained from intermediates of formula (III) in accordance with known procedures for the conversion of aromatics with adjacent amino groups in benzimidazolium salt and stereochemical isomeric forms possess valuable pharmacological properties. In particular, they are active anti-allergic and antihistamines, which activity can be successfully demonstrated, for example, the results obtained in experiments, for example, Protection of Rats from Compaund 48/80 induced lethalty", "PCA (passive cutane anaphylaxis) test in Rats described in Drug Dev. Res. 5, 137-145 (1985), "Histamine induced lethality test in Guinea Pigs" and The "Ascaris Allergy test in Dogs". Two of the last experiment described in Arch. Int. Pharmacodyn. Ther. 251, 39-51 (1981).

Especially attractive distinctive feature of the compounds of the present invention is rapid onset of response and favorable period.

Thanks antiallergic properties of the compounds of formula (I) and their acid additive salts of these compounds can be successfully used for the treatment of allergic diseases of a wide range, such as chronic rhinitis, allergic conjunctivitis, chronic urticaria, allergic asthma, etc.

Due to its valuable anti-allergic properties, these compounds can be included in various pharmaceutical forms for administration to patients. To obtain the antiallergic compositions of the present invention an effective amount denaut by thorough mixing with a pharmaceutically acceptable carrier, which can take various forms depending on the form of the desired drug. These pharmaceutical compositions have preferably in the form of a single dosage forms intended for oral, rectal, subcutaneous or parenteral administration. For example, upon receipt of the compositions for oral dosage forms may be used any of the standard pharmaceutical environment, such as water, glycols, oils, alcohols, etc., in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions; and solid carriers such as starches, sugars, kaolin, sizing, binders, dezintegriruetsja agents, etc. in the case of solid preparations such as powders, pills, capsules and tablets. Based on considerations of ease of introduction, the preferred are disposable oral dosage forms are commonly used in solid pharmaceutical carriers. Parenteral compositions, the carrier or at least most of it consists of sterile water, although it may contain other ingredients, such as solubilizing agents. For example, can be obtained injectable solutions, in which the carrier comprises saline solution, RAS is suitable liquid carriers, suspendresume agents, etc., In compositions intended for percutaneous administration, the carrier may contain a sealing means and/or a suitable wetting agent and can be mixed with appropriate additives of any nature, taken in small quantities, provided that these additives do not have a significant adverse impact on the patient's skin. These supplements can facilitate the introduction of the drug into the skin and/or may be useful in obtaining the desired compositions. The above compositions can be introduced in various ways, for example in the form of transdermal patches, in the form of a point of application on the skin or in the form of ointment. Acid additive salts of compounds (I) due to their increased water solubility compared to the corresponding main forms are preferable for obtaining water compositions.

For ease of administration and uniformity of dosage of the above pharmaceutical composition is preferably made in the form of a single dosage forms. The term "disposable dosage form" as used in this description and the claims, refers to physically discrete form of standardized doses, the Finance desired therapeutic effect, in combination with the required pharmaceutical carrier. Examples of such single dosage forms may include tablets (including tablets with grooves and coated tablets), capsules, pills, powder packaging, wafers, injectable solutions or suspensions, solutions or suspensions, metered quantity of a teaspoon or tablespoon, etc. as well as their split multiple forms.

The present invention also relates to a method of treating warm-blooded animals suffering from allergic diseases, by introducing these animals an effective amount of an antiallergic drug in the form of compound (I) or its pharmaceutically acceptable acid additive salt.

An effective amount of anti-allergic drugs required for introducing animals, can easily be determined from the test results presented below. Mainly effective amount of anti-allergic drugs is from about 0.001 mg/kg to about 20 mg/kg of body weight, and more preferably from about 0.01 mg/kg to about 5 mg/kg body weight.

The following examples illustrate the present invention but do not limit its scope in all presented cases. All listed P> A. the production of intermediate compounds.

Example 1. To a mixture of 15.5 parts of 2-chloro-benzimidazole and 235 parts of N, N-dimethylacetamide, was added 22 parts of 4-(chloromethyl)-2-methylthiazole-monohydrochloride and 25.4 parts of sodium carbonate. The resulting mixture was whole was stirred 18 hours at 75oC and then poured into water. The product was extracted with 4-methyl-2-pentanone and the extract was washed with water, dried, filtered and evaporated. The residue was led from 2,2'-oxybisethane, resulting received 11,3 part (42,8%) 2-chloro-1-[(2-methyl-4-thiazolyl)methyl] - benzimidazole (InterMedia. Conn.1). Were similarly obtained 2-chloro-1-[(6-methyl-2-pyridine)methyl] - benzimidazole (InterMedia. Conn. 2).

Example 2.

a) To a stirred and heated under reflux a mixture consisting of 60 parts of 4-forobulgaria, 93 parts of 1-bromo-3-chloropropane, 100 parts of ethanol and 45 parts of water, was added drop by drop a solution of 19 parts of sodium hydroxide in 80 parts of water. Stirring at a temperature of distillation was continued for 8 hours. After cooling, the organic layer was separated and person to distil under reduced pressure (1,7103PA), respectively, received two fractions of 53 parts (so Kip. 136-140o

b) a Mixture of 67.5 parts InterMedia. Conn. 3, 42.9 parts of 1,4-dioxa-8 azaspiro [4,5]-decane, 47.7 parts sodium carbonate, a few crystals of potassium iodide and 2400 parts of 4-methyl-2-pentanone, stirred for 70 hours at a temperature of distillation. The hot reaction mixture was filtered, the filtrate washed with 1,1'-oxybisethane and evaporated. The residue was pereirae 2,2'-oxybisethane, cooling at -20oC. the First fraction of 4.4 parts of product was obtained by filtration. As the result of evaporation of the mother liquor was awarded a second fraction of 97 parts of the product. Full output: 101,4 parts of 1,4-dioxa-8-[3-[(4-forefeel)thio] -propyl] -8-azaspiro[4,5] decane; so pl. 135,5-140o(InterMedia. Conn. 4).

Example 3.

a) a Mixture of 2.44 parts of 6-methyl-2-pyridylmethylamine, 3.2 parts of 2-chloro-3-nitropyridine, 1.7 parts of sodium bicarbonate and 120 parts of ethanol was stirred for 3 hours at a temperature of distillation. The hot reaction mixture was filtered through diatomaceous earth. After cooling, the precipitate formed in the filtrate, filtered, and dried, resulting in a received 2,5 (51% ) of 6-methyl-N-(3-nitro-2-pyridinyl)-2-pyridinediamine; so pl. 131,7o(InterMedia. Conn.5).

b) a Mixture consisting of 55 parts Prohm is the population and at the 50oWith using 3 parts of 5% palladium charcoal. After calculation of the amount of absorbed hydrogen, the catalyst was filtered through diatomaceous earth and the filter is evaporated, resulting in a received 47 parts (99,7%) N2-[(6-methyl-2-pyridinyl)methyl]-2,3-pyridinediamine (InterMedia. Conn.6).

C) the Mixture consisting of 47 parts of ethyl-4-isothiocyanato-1 piperidinecarboxylate, 47 parts InterMedia. Conn. 6 and 900 parts of tetrahydrofuran was stirred overnight at room temperature. To enhance crystallization was added 2,2-hydroxy-beproven. The product was filtered and dried, resulting in a received 78.5 parts (83,5%) ethyl-4-[[[[2-[[(6-methyl-2-pyridinyl)methyl] amino]-3-pyridinyl] amino]taxometer]amino]-1-piperidinecarboxylate; so pl. 176o(InterMedia. Conn. 7).

B. obtain the final compounds.

Example 4. To a stirred mixture consisting of 45 parts of 2-[[(1-(phenylmethyl)-4-piperidinyl] methyl] - benzimidazole and 376 parts of N,N-dimethylformamide was added in portions to 12.2 parts of a dispersion of sodium hydride in mineral oil (60%) and after stirring 1/2 hour solution was added 28 parts of 2-(chloromethyl)-6-methylenetetrahydrofolate in a quantity of N,N-dimethylformamide. The stirring at couduct were extracted with merenpintaan and the extract was dried, was filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2/CH3HE 95:5). Eluent of the desired fraction is evaporated, and the residue was converted into ethiotube salt (1:5/2) in acetonitrile. The product was filtered and dried, resulting in a received 27.8 parts(29,2%) 1-[(6-methyl-2-pyridinyl)methyl] -2-[[1-(phenylmethyl)-4-piperidinyl] methyl] - benzimidazole-ethanoate (1:5/2); so pl. was 155.3oWith (Conn. 48).

Example 5. To a stirred mixture of 36.7 parts of the connection 48 and 267 parts of tetrahydrofuran, was added 15,68 parts of ethylchloride. Stirring is continued for 6 hours and then added 11.7 parts of N,N-diethylethanamine. After stirring over a period of time from Friday to Monday, the reaction mixture was evaporated and the residue was dissolved in water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2/CH3OH 95: 5). Eluent of the desired fraction evaporated and the residue was led from acetonitrile. The product was filtered and dried, resulting in a received 16.6 parts (44,3% ) ethyl-4-[[1-[(6-methyl-2-pyridinyl)methyl]-benzimidazole-2-yl]methyl] -1-piperidine-yl)amino] -1-piperidinecarboxylate, 1.8 parts of 4-(chloromethyl)-2-methylthiazole-monohydrochloride, 2.12 parts of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred overnight at 70oC. the Reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated, and the residue was led from acetonitrile. The product was filtered and dried, resulting in a received 1.5 parts (37.5%) of ethyl-4-[[1-[(2-methyl-4-thiazolyl)-methyl]-benzimidazole-2-yl] amino] -1-piperidinecarboxylate; so pl. 160oWith (Conn. 12).

Example 7. A mixture consisting of 25 parts of compound 12, 34 parts of potassium hydroxide and 160 parts of 2-propanol was stirred overnight at a temperature of distillation. The reaction mixture is evaporated and the residue was dissolved in water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was converted into trihydrochloride salt in 2-propanol. The product was filtered and dried, resulting in a received 20 parts(71,2% ) 1-[(2-methyl-4-thiazolyl)methyl] -N-(4-piperidinyl)- benzimidazole-2-ametripitline-hemihydrate; so pl. 206,4oWith (Conn. 13).

Example 8. A mixture consisting of 15 parts of compound 58 and 224 parts of Hydrobromic acid (48%), heating the alkalizing solution of sodium hydroxide, the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was led from acetonitrile, resulting in received 5 parts(41,3%) 1-[(4-methyl-2-thiazolyl)methyl]-N-(4-piperidinyl)-benzimidazole-2-amine (Conn. 59).

Example 9. A mixture of 2.3 parts of 6-(2-chloroethyl)-7-methyl--thiazolo [3,2-a] pyrimidine-5-she, 3.3 parts of the connection 13, 1.6 parts of sodium carbonate and 160 parts 4-methyl-2-pentanone, was stirred 48 hours at the temperature of distillation. The reaction mixture is evaporated and the residue was dissolved in water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2/CH3OH(NH3) 95: 5). Eluent of the desired fraction evaporated and the residue was led from acetonitrile. The product was filtered and dried, resulting in a received 1,64 part (31,6%) 7-methyl-6-[2-[4-[[1-[(2-methyl-4-thiazolyl)methyl]-benzimidazole-2-yl]amino]-1-piperidinyl]ethyl] --thiazolo[3,2-a]pyrimidine-5-it, so pl. 129,8oWith (Conn. 18).

Example 10. A mixture of 2.26 parts of 3-(2-chloroethyl)-2-methyl--pyrido[1,2-a] pyrimidine-4-it, 3.2 parts of compounds 2, 1.06 parts of sodium carbonate and 45 parts of N,N-dimethylacetamide was stirred overnight at 70oC. Re is whether and received 2.1 part (41,5%) of 2-methyl-3-[2[-/4-[[3-[(6-methyl-2-pyridinyl)methyl] - imidazo[4,5-b] pyridine-2-yl]amino]-1-piperidinyl]ethyl] - pyridone[1,2-a]pyrimidine-4-it; so pl. 233,1oC (Conn.7).

Example 11. The subsequent reaction was carried out in nitrogen atmosphere. To a mixture consisting of 7.5 parts of ethyl-4-hydroxy-1-piperidinecarboxylate and 94 parts of N, N-dimethylformamide was added in portions 2.1 part dispersion of sodium hydride in mineral oil (50%). After stirring for 1 hour at room temperature and for 20 minutes at 40oWith added drop by drop a solution of 11.3 parts of InterMedia. Conn. 1 in 94 parts of N,N-dimethylformamide. Then continued stirring overnight at room temperature. After adding a certain amount of ethanol, the reaction mixture was evaporated. The residue was poured into ice water and the whole was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2/CH3OH 90:10). Eluent of the desired fraction evaporated and obtained 13 parts (75,5%) ethyl-4-[[1-[(2-methyl-4-thiazolyl)-methyl]-benzimidazole-2-yl]oxy]-1-piperidinecarboxylate (Conn. 20).

Example 12. A mixture consisting of 4.5 parts of the connection 13, 2 parts of Polyoxymethylene, 5 parts of potassium acetate and 120 parts of methanol was hydrogenosomal at normal pressure and at 50oWith using 1 part of 10% palladiana. The filtrate is evaporated and the residue was dissolved in water. After alkalizing with sodium carbonate, the product was extracted with trichloromethane. The extract was dried, filtered and evaporated, and the residue was converted into ethiotube salt (1:2) in methanol. The product was filtered and dried, resulting in a received 3.7 parts (70,9%) of N-(1-methyl-4-piperidinyl)-1-[(2-methyl-4-thiazolyl)methyl] - benzimidazole-2-minatojima (1:2); so pl. 221,3oWith (Conn. 16).

Example 13. A mixture consisting of 78 parts InterMedia. Conn. 7, 58.5 parts of oxide of mercury (II), 1 part of sulfur and 800 parts of ethanol was stirred 2 hours at the temperature of distillation. The reaction mixture was filtered through diatomaceous earth and the filtrate is evaporated, resulting in a received 63.5 parts (88,5%) ethyl-4-[[3-[(6-methyl-2-pyridinyl)methyl] - imidazo[4,5-b] pyridine-2-yl] amino]-1-piperidinecarboxylate (Conn. 1).

Example 14. Through the stirred mixture consisting of 3.23 parts of compounds 2 and 80 parts of methanol, was barbotirovany 0.9 parts of ethylene oxide. Continued stirring overnight at room temperature. The reaction mixture is evaporated and the residue was purified by column chromatography (silica gel; HCl3/CH3OH 96: 4). Eluent of the desired fraction evaporated and the residue crystallizer-2-pyridinyl)methyl] - imidazo[4,5-b] -pyridine-2-yl] amino] -1-piperazineethanol; so pl. 152oWith (Conn. 4).

Example 15. A mixture consisting of 9 parts of compound 5, 11 parts of potassium hydroxide and 120 parts of 2-propanol was stirred 4 hours at a temperature of distillation. The reaction mixture is evaporated and the residue was dissolved in water. The product was extracted with dichloromethane (2x) and the combined extracts were dried, filtered and evaporated, resulting in a received 7.5 parts (100%) N-[1-(2-amino-ethyl)-4-piperidinyl] -3-[(6-methylpyridin)methyl] - imidazo[4,5-b] pyridine-2-amine (Conn. 8).

Example 16. A mixture of 1.2 parts of 2-chloropyrimidine, 3.7 parts of compound 8, 0.9 parts of sodium bicarbonate and 80 parts of ethanol was stirred overnight at a temperature of distillation. The reaction mixture was filtered through diatomaceous earth and the filtrate evaporated. The residue was led from a mixture of acetonitrile and methanol. The product was filtered and dried in vacuum at 130oC during the night, resulting in a received part 1(22,5%) 3-[(6-methyl-2-pyridinyl)methyl-N-[1-[2-[(2-pyrimidinyl)amino]-ethyl] -4-piperidinyl]--imidazo[4,5-b]pyridine-2-amine; so pl. 187,4oC (Conn. 9).

All compounds listed in tables 1, 2, 3, 4 and 5 were obtained by the methods described in examples 4-16, as indicated in column 2.

C. F. the s of the formula (I) can be demonstrated, for example, in the experiment "protection of rats from death induced by compound 48/80" ("Protection of rats brom compaund 48/80 induced lothality"), described in U.S. patent N 4556660. The compounds of formula (I) were introduced to rats subcutaneously and/or oral. Received ED50value (mg/kg) for connections 9, 16, 19, 23, 27, 28, 29, 55, 62, 69 and 70 were 0.04 mg/kg

D. Examples of compositions.

Below are examples of ready-preparative forms illustrate typical pharmaceutical composition in the form of unit dosages suitable for systemic, local or topical purpose of warm-blooded animals in accordance with the present invention.

The term "active ingredient" (and.and.), used in these examples relates to a compound of formula (I), its pharmaceutically acceptable acid additive salt or a stereochemical isomeric form.

Example 18. Oral drops.

50 g and.and. was dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol in the 60-80oC. After cooling to 30-40oWith added 35 l of polyethylene glycol and the mixture is mixed well. Then was added a solution of 1750 g of sodium saccharin in 2.5 l of purified water and while stirring was added 2.5 l flavouring, debakel, comprising 10 mg/ml.and. The resulting solution was filled in suitable containers.

Example 19. The capsule.

20 g and.and. 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 magnesium stearate vigorously mixed together. The resulting mixture is then filled with 1000 suitable hardened gelatin capsules, each containing 20 mg and.and.

Example 20. Injectable solution.

1.8 g of methyl-4-hydroxybenzoate and 0.2 g of propyl-4-hydroxybenzoate was dissolved in about 0.5 l of boiling water for injection. After cooling to approximately the 50oWith added while stirring 4 g lactic acid, 0.05 grams propylene glycol and 4 g and.and. The solution was cooled to room temperature and thereto was added water for injection in an amount necessary to achieve a 1 l, giving a solution comprising 4 mg/ml.and. The solution was sterilized by filtration and filled in sterile containers.

Example 21. Medical candles.

3 g and.and. dissolved in a solution of 3 g of 2,3-dihydroxybutanedioate acid in 25 ml of polyethylene glycol 400. Melt together 12 g of surface-active agent and triglycerides in an amount necessary to achieve the 300, the temperature of 37-38oWith education 100 medical candles, each containing 30 mg of active ingredient. TTT TTT TTT TTT TTT

1. Substituted thiazolidine and substituted pyridinoline derivatives of General formula

< / BR>
where-A1=A2-A3=A4bivalent radical of formula-CH=CH-CH=CH - and-N=CH-CH= CH-;

B NH, CH2ABOUT;

R1the radical of General formula

< / BR>
or

< / BR>
where D1C4-alcander;

R2WITH1C4-alkyl;

L is hydrogen, C1C6-alkyl, C1- C6-allyloxycarbonyl or a radical of General formula-Alk-R3; -Alk Y - R4or Alk Z1C(=O) Z2R5,

where Alk C1C4-alcander;

R3phenyl,1C4-alkoxyphenyl or a radical of General formula

< / BR>
or

< / BR>
where G represents-CH=CH-CH=CH-, -S-(CH2)3-, -S-(CH2)2- or S-CH= CH-;

Y is oxygen or NH;

R4hydrogen, C1C4is alkyl or pyrimidinyl; R5- C1C4-alkyl;

Z1and Z2each independently oxygen or NH,

or their pharmaceutically acceptable acid additive salt.

2. The method of obtaining compounds of General formula I on p. 1, ex is in p. 1 values

N-alkylate agent of the General formula L1W, where L1WITH1C6-alkyl, C1C6-allyloxycarbonyl or a radical of formula-Alk R3, -Alk Y R4or

< / BR>
where Alk C1C4-alcander;

R3R5, Y, Z1and Z2have the values listed in paragraph 1;

W is a reactive leaving group,

in an inert towards the reaction solvent in the presence of a base to obtain the desired compounds in the free form or in pharmaceutically acceptable acid additive salt.

3. The composition having antiallergic activity, including an active ingredient and a pharmaceutically acceptable carrier, characterized in that as the active ingredient it contains a compound of formula I under item 1 in a therapeutically effective amount.

 

Same patents:

The invention relates to the field of organic chemistry and relates to a method of obtaining new derivatives of imidazole

The invention relates to new derivatives carbapenem General formula

where a is a pyrolidine ring;

R1represents a hydrogen atom or methyl;

R2represents a hydrogen atom;

R3represents a hydrogen atom or ion with a negative charge Q represents a group of the formula (I)

-(CH2)pZ+where p is zero or an integer 1 or 2;

Z+means pyridyl, pyrrolidinyl or genocidal, each substituted with one or two1-C4-alkyl groups, and contains a Quaternary nitrogen atom, or a group of formula (2)

-(CH2)p-R6where p is an integer 2;

Ra, Rband Rceach is1-C4-alkyl, or Q and R2together with the nitrogen atom to which they are attached, form a group of formula (3)

-Nwhere m and n are each 2 or 3

R6and R7each represents alkyl with 1-4 carbon atoms or alkyl with 1-4 carbon atoms, substituted Deputy selected from the group comprising hydroxy-, carboxy-, карбам�at2/19962/007.dwl/2059639-7t.gif" ALIGN="ABSMIDDLE">where Rd, Reand Rdeach means hydrogen or C1-C4-alkyl;

R6is1-C4-alkyl, or their salts or esters

The invention relates to new triazine derivative or triazolone series, namely: to heterocyclic compounds of General formula

(I) where R1represents a hydrogen atom, l is 0 or 1; ring a represents hexahydropyridine, tetrahydropyrrole, hexahydroazepin, dihydrothiazolo, tetrahydrooxazolo, tetrahydrothiophene or dihydropyridines; Y represents a substituted lower alkyl or aryl, or unsubstituted alkylenes group containing from 1 to 3 carbon atoms; Q represents a group of the formula

N(II) where R2represents a hydrogen atom, a hydroxyl group or aryl group which may be substituted with halogen; R5represents a hydrogen atom; and R3and R4can have the same or different values, each represents a hydrogen atom, halogen atom or morpholinyl, or Q represents a group of the formula

N(III) where Ar1and Ar2may have about the Ohm halogen or alkyl group, or their acid additive salt

The invention relates to novel 3,5-dihydroimidazo[2,1-b] hinzelin-2 (1H)-it is a derivative of the formula I

O

(I) where R is a hydrogen atom, a C1-6-alkyl, phenyl, possibly substituted by 1-3 substituents, independently from each other selected from halogen atoms, hydroxy - C1-6-alkyloxy-FROM1-6is an alkyl or triptorelin groups, pyridinyl, or thienyl, unsubstituted or substituted with halogen or1-6by alkyl;

R1the atom of hydrogen or C1-6-alkyl;

R2a hydrogen atom, a C1-6-alkyl, hydroxy-C1-6alkyl or phenyl, or R1and R2together can form WITH1-5-alcander;

X is the radical of the formula

0 (a)

N-O-R3(b) or

SN-R4(c);

R3a hydrogen atom, three (C1-6-alkyl)-silyl or1-6-alkyl which may be substituted by COOH, SOOS1-4-alkyl, СОNR5R6or SOON2-CONR7R8;

R4COOH, COOC1-4-alkyl, СОNR5R6, COOCH2CONR7R8or1-6-alkyl which may be substituted by COOH, SOOS1-4-alkyl, CONR5R6or COOCH2CONR7R8;

RIS-C1-4-alkyl, C1-4-algological - Nile-C1-4-alkyl;

R6a hydrogen atom, a C1-5-alkyl, hydroxy-C1-4-alkyl or C3-7-cycloalkyl, or R5and R6together with the nitrogen atom to which they are bound, can form pyrrolidinyl, morpholinyl or piperazinil, which can be substituted at the nitrogen atom WITH1-4-alkyl or hydroxy-C1-4-alkyl;

R7and R8independently from each other mean a hydrogen atom, a C1-4-alkyl or hydroxy-C1-4-alkyl, and their pharmaceutically acceptable salts and stereoisomers

The invention relates to new derivatives of glutamic acid with any abscopal valuable properties on the enzyme, using folic acid and its metabolites as substrates and finds application in medicine, as well as the way they are received

The invention relates to a series of new derivatives griseolus acid and provides the means of obtaining these compounds, and methods and compositions for their use

The invention relates to new derivatives of pyridine and their salts, to a method for their herbicide composition containing a specified derivative as an effective ingredient, and to a method of controlling weeds

The invention relates to new 3[2H]-pyridazinone derived, as well as to receive them, containing their insecticidal acaricide, nematocide, fungicidal compositions for use in agriculture and horticulture; compositions for removing ticks from animals, where these compositions contain these derivatives as the active ingredient

The invention relates to new derivatives of 3(2H)-pyridazinone and to their pharmaceutically acceptable salts, possessing inhibitory activity against the aggregation of platelets, cardiotonic activity, vasodilating activity, anti-SRS-A activity, to processes for their preparation and to pharmaceutical compositions containing them as active ingredient

The invention relates to new biologically active compounds, namely, the derivative of 4-aminophenol of the formula I

XNROR1where R1represents a group WITH/ABOUT/УZ;

Y represents a single bond, 0, NR7or; Z represents hydrogen, pyridyl; phenyl which may be substituted with halogen, nitro, lower alkoxy or carboxy; lower alkyl which may be substituted by hydroxy, lower acyloxy, carboxy, lower alkoxycarbonyl, CONR8R9, phenyl/lower/ alkoxy, phenyl, halogen, cyano or NR10R11;

R2, R3, R5and R6that may be the same or different, represent hydrogen, lower alkyl or alkenyl, lower alkoxy or halogen;

R4and R7that may be the same or different, represent hydrogen or lower alkyl;

X 4.5-dihydropyrazolo or pyrazolyl, which may be substituted WITH3-C6-cycloalkyl or phenyl which can be substituted by trihalomethyl;

R8, R9, R10, R11which may be the same or different, represent hydrogen, lower alkyl or benzyloxycarbonyl, or their N-alkyl
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