Oxazolidine derivatives or their pharmaceutically acceptable additive salt, or their stereochemical isomeric form, method of their production and a pharmaceutical composition having anti-allergic activity

 

(57) Abstract:

Usage: in the chemistry of heterocyclic compounds as substances having anti-allergic activity. The inventive product is oxazolidine derivative f-ly I, (given in the text description) where the radicals have the respective meanings or their salt or a stereochemical isomeric form. Getting lead by cyclization of compounds of f-crystals II (given in the text description) by processing its alkylhalogenide, metal oxide or metal salt in an inert solvent. The composition having antiallergic activity contains an effective amount of the compounds. 3 s and 5 C. p. F.-ly.

The invention relates to new oxazolidone derivative having the formula:

to their pharmaceutically acceptable additive salts, and stereochemical isomeric forms, where a1AND2AND3AND4is 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 hydrogen atoms in said radicals (a-1) to(a-7) can be independently substituted by a halogen atom, a C1-C6-as4-alkyl; R1represents hydrogen, C1-C6-alkyl or hydroxy WITH1-C6-alkyl;

m is 1 or 2;

represents a C1-C4-alcander; B is an R2CH2, O, SO or SO2where R2is hydrogen or C1-4-alkyl;

n is 0, 1 or 2;

L represents hydrogen; C1-2-alkyl; C3-6-cycloalkyl; C3-C6alkenyl, optionally substituted by aryl; C1-C6-alkylsulphonyl; C1-C6-allyloxycarbonyl; arylcarbamoyl; aryl WITH1-C6-alkyloxy-carbonyl; or a radical of the formula:

-Al-R3(o-1);

-Al-Y-R4(o-2);

-Al-Z1-C X-2-R5(o-3); or

-CH2-CHOH-CH2-O-R6(o-4); where R3represents cyano, aryl or Het; R4represents hydrogen, aryl, Het, or1-C6-alkyl, optionally substituted aryl or Het; R5represents hydrogen, aryl, Het or1-C6-alkyl, optionally substituted aryl or Het; R6represents aryl or naphthalenyl; Y represents O, S, NR7where R7is hydrogen, C1-C6-alkyl or C1-C6-alkylcarboxylic;

Z1and Z2UB>1-C6-alkyl; X represents O, S or NR9where R9is hydrogen, C1-C6-alkyl or cyano; Al each independently is a C1-C6-Alcantara; each Het 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 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 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 rings containing 1 or 2 heteroatom, selected from oxygen atoms, Casamicciola; 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-C6-alkyl)amino, aryl WITH1-C6-amino, nitro, cyano, aminocarbonyl,1-C6-alkyl, C1-C6alkyloxy,1-C6-alkylthio,1-C6-allyloxycarbonyl,1-6-alkyloxy-FROM1-6-alkyl, C1-6-allyloxycarbonyl1-6-alkyl, hydroxy, mercapto, hydroxy1-C6-alkyl, C1-C6-alkylcarboxylic aryl, Rilc1-C6-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-C6-alkyl, C1-C6-alkyloxy,1-C6-alkylthio, mercapto, amino, mono - and di-(C1-C6-alkyl)amino, carboxyl,1-6-allyloxycarbonyl, and C1-C6-alkylcarboxylic.

In the compounds of formula (I), where R3, R4or R5is Het specified Het may be partially or fully saturated, or unsaturated. Connection Faure also exist in tautomeric forms. While these are not exactly noted above, however, they are also included in the scope of the present invention.

In the above definitions: halogen means fluorine, chlorine, bromine or iodine; WITH1-C4-alkyl refers to straight and branched saturated hydrocarbon radicals, having from 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 1-methylethyl, butyl, 1,2-dimethylethyl, 1-methylpropyl, 2-methylpropyl; the term1-4-alkyl defines the above WITH1-C4-alkalemia radicals and the higher homologues having 5 or 6 carbon atoms; the term1-C12-alkyl defines1With alkalemia radicals mentioned above, and their higher homologues having from 5 to 12 carbon atoms; the term3-C6-cycloalkyl refers to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; the term3-C6alkenyl 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-C6alkenyl is substituted on a heteroatom, then the carbon atom indicated WITH3-C6-alkenyl associated with the specified gets the e straight or branched saturated hydrocarbon radicals, having from 1 to 4 carbon atoms, such as methylene, 1,2-ethandiyl, 1,3-propandiol, 1,4-butandiol and their branched isomers; the term4-C6-alcander defines1-C4-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.

Mentioned pharmaceutically acceptable additive salts are therapeutically active non-toxic acid additive salts, which may form a compound of formula I. These forms salts can be mainly obtained by processing the basic form of the compounds of formula I of the 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-hydroxy-propane, 2-oxopropanal, tanginoa, proportionaly, batandjieva, (Z)-2-batandjieva, (E)-2-batandjieva, 2-hydroxybutanone, 2,3-dihydroxybutyl - Dianova, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, econsultancy, be the benzoic acid, etc., Conversely, the salt form can be converted into the free base by treatment with alkali.

The compounds of formula (I) having acidic properties may be similarly converted into the corresponding therapeutically active, non-toxic primary additive salt. Examples of such basic additive salts are, for example, sodium, potassium, calcium salts, and also salts formed pharmaceutically acceptable amines, such as alkylamines followed, benzathine, ammonia, N-methyl-D - glucamine, geranamine, amino acids, e.g. arginine, lysine.

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 according to the 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 1 can be obtained using well known procedures. The diastereomers can be separated visit to be separated from each other using known techniques permissions 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 include using mainly enantiomerically clean and raw materials. Stereochemical isomeric forms of the compounds of formula I are also included in the scope of the invention.

In particular, certain 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-C6-alkyl)amino, aryl-C1-C6-alkylamino, nitro, cyano, aminocarbonyl,1-C6-alkyl, C1-C6-alkyloxy,1-C6-al - kiltie,1-C6-allyloxycarbonyl, hydroxy, C1-C6-alkylcarboxylic, arils1-C6-alkyl and carboxyl; peridiniaceae, neoba is which is independently selected from halogen, amino, C1-C6-alkylamino, arils1-C6-alkyl - amino, hydroxy, C1-C6-alkyl, C1-C6-alkyloxy,1-C6-alkylthio and arils1-C6-alkyl; Peradeniya, optionally substituted C1-C6-alkyl or halogen; pyridinyl, optionally substituted with halogen, amino, or1-C6-alkyl; tanila, optionally substituted with halogen or1-C6-alkyl; furanyl, optionally substituted C1-C6-alkyl or halogen; pyrrolyl, optionally substituted C1-C6-alkyl; thiazolyl, optionally substituted C1-C6-alkyl, C1-C6-allyloxycarbonyl, aryl or arils1-C6-alkyl; imidazolyl, optionally substituted by one or two substituents, each of which is selected from C1-C6-alkyl, aryls1-C6-alkyl and nitro; tetrazolyl, optionally substituted C1-6-alkyl; 1,3,4-thiadiazolyl, optionally substituted C1-6-alkyl or amino; 5,6-dihydro-4-1,3-thiazin-2-yl, optionally substituted C1-C6-alkyl; 4,5-dihydrothiazolo, optional - tion substituted C1-C6-alkyl; osaamisen1-C6-alkyl; 1,4-dihydro-2,4-dioxo-3(2H)-pyrimidinyl, optionally substituted C1-C6-alkyl; 1,4-dihydro - 4-oxopyrimidine, 3,4-dihydro-4-oxopyrimidine or 4,5-dihydro-4-oxopyrimidine, and these radicals are optionally substituted by 1 to 3 substituents selected from C1-C6-alkyl, amino, C1-C6-alkylaminocarbonyl, arylamino - carbylamine, arils1-C6-alkylamino and C1-C6-alkylamino; 2,3-dihydro-3-oxopyridine, optionally substituted C1-C4-alkyl; 2-(amino - or1-C4-alkylamino)-3,4-dihydro-3,6-dimethyl-4-oxopyrimidine-5-Il a; 2-oxo-3-oxazolidinyl; pyrrolidinyl; piperidinyl; morpholinyl; thiomorpholine; dioxane, optionally substituted C1-C6-alkyl; indolyl, optionally substituted by hydroxy or C1-C6-alkyl; chinoline, optionally substituted by hydroxy or C1-C6-alkyl; hintline, optionally substituted by hydroxy or C1-C6-alkyl; khinoksalinona, optionally substituted C1-C6-alkyl; phthalazine, optionally substituted with halogen; 1,3-dioxo-1-isoindole-2(3H)-Il a; 2,3-dihydro-3-OK what Kilom or halogen; 2-oxo-2-1-benzopyranyl and 4-oxo-4-1-benzopyranyl, both of which can be substituted WITH1-C6-alkyl; 3,7-dihydro-1,3-dimethyl-2,6 - dioxo-1-purine-7-yl, optionally substituted C1-C6-alkyl; 6-purine and bicyclic heterocyclic radical of the formula:

(C-2)

(C-3),

(C-5), (C-6)

(C-7), (C-8)

where: X1and X2each independently is O or S;

each of R10independently continues a hydrogen; C1-C6-alkyl, aryls1-C6-alkyl; C1-C6-alkyloxy1-C6-alkyl; hydraxis1-C6-alkyl; or

WITH1-C6-alkyloxy - carbonyl;

each of R11independently represents hydrogen, C1-C6- alkyl, hydroxy, mercapto, C1-C6-alkyloxy,1-C6-alkylthio, halogen, or C1-C6-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-CH CH-, -CH2-NH(CH2)2-, -S-CH CH-, -S-(CH2)3-, -N-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-;

G5is-CH CH-CH CH-, -N CH-CH CH-, -CH N-CH CH-, -CH CH-N 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 formula (C-2) or (C-3), or one or two hydrogen atoms in the above radicals G1, G2, G3, G4, G5or G6can be substituted C1-C6-alkyl, C1-C6-alkylthio,1-C6-alkyloxy or halogen in the case, if they are linked to the carbon atom; or (C1-C6-alkyl, C1-C6-allyloxycarbonyl, or aryl WITH1-C6-alkyl, in case 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-C6-alkyl, hydroxy or1-C6-alkyloxy; and aryl in the definition of R6represents phenyl optionally substituted with halogen.

Typical compounds of formula (I), where R is hydrogen, m is 1, and R1is hydrogen or C1-C6-alkyl.

AND4represents a bivalent radical of formula (a-1) or (a-2); another characteristic subgroup of compounds of formula (I) are the compounds of formula (I), where a1AND2AND3AND4is a bivalent radical having the formula (a-3)-(a-5), and one or two hydrogen atoms in said radicals (a-1) to(a-5), each may be independently substituted WITH1-C6-alkyloxy or hydroxy.

More specific compounds are compounds of any of the above groups or subgroups in which B represents NR2; O or CH2; and/or L represents hydrogen, C1-C6-alkyl, C1-C6-alkylsulphonyl,1-C6-alkyl, C1-C6-alkyl-carbonyl, C1-6-allyloxycarbonyl, or a radical of formula (b-1), (b-2), (b-3) or (b-4).

More typical compounds are those of the above more specific compounds of formula (I) in which: B represents NH or CH2; and/or n is 1 or 2; and/or part D(R1)mis a (2 - or 4-C1-C4-alkyl-1,3-oxazol-5-yl)1-C4-alkyl; (2 - or 5-C1-C4-alkyl-1,3-oxazol-4-yl)1-C4is alkyl; (4 - or 5-C1-C4-Ala,3-oxazol-5-yl)1-C4-alkyl; (2 - or 5-hydroxy-methyl-1,3-oxazol-4-yl)1-C4is alkyl; (4 - or 5-hydroxymethyl-1,3-oxazol-2-yl)1-C4-alkyl; (2,4-di(C1-C4-alkyl)-1,3-oxazol-5-yl)1-C4-alkyl; (2,5-di(C1-C4-al-

Kyl)-1,3-oxazol-4-yl)1-C4-alkyl or (4,5-di(C1-C4-alkyl)-1,3-oxazol-2-yl)- C1-C4-alkyl.

Of the compounds of the present invention are of interest such compounds of formula (I), where a1AND2AND3AND4is a bivalent radical of formula-CH= CH-CH= CH- (a-1) or-N=CH-CH=CH- (a-2), and, in the specified radical (a-1) a hydrogen atom may be substituted with halogen, C1-C6-alkyloxy or hydroxy; R is hydrogen or stands; R1is hydrogen, stands or hydroxymethyl; m is 1 or 2; D is CH2; B is NH,NCH3CH2, O, S or SO; and n is 0,1 or 2; L is hydrogen; C1-C4-alkyl; cyclohexyl, propanolol, 3-phenylpropanol,1-C4-allyloxycarbonyl; or a radical of the formula

-Al-R3(b-1);

-Al-y-R4(b-2);

-ACC-Z1-C(=X)-Z2-R5(b-3); or

-CH2-CHOH-CH2-O-R6(b-4); where: each Al independently 4-allyloxyphenyl, 3,4,5-trimethoxyphenyl, pyridinyl, thienyl, 2-methyl-5-oxazolyl, 4,5-dihydro-4-ethyl-5-oxo-1-tetrazolyl, 2,3-dihydro-6-methyl-3-oxopyridine, 2-oxo-3-oxazoline, 2-(amino or methylamino)-3,4-dihydro-3,6-dimethyl-4-oxo-5-PI - rimidine, 2-oxo-21-benzopyranyl, 3,7-dihydro-1,3-dimethyl-2,6-dioxo-1-purine - 7-yl, 2,3-dihydro-2-oxo-1-benzimidazolyl, or a radical of the formula:

where G2represents-CH=CH-CH=CH-, -(CH2)4-, -S-(CH2)2-S-(CH2)3-, -S-CH=CH-, -N(CH2)3, -N=C(CH3)-CH2-, -N(CH3)=C(CH3)-, -N(CH3)-C= CH-or CH= C(CH3)-O; Y represents NH, O or S; R4represents hydrogen, C1-C4-alkyl, halogenfree, pyridinyl, halogenopyrimidines, pyrimidinyl, 1,4-dihydro-2,4-dioxo-3(2)-pyrimidinyl, 1,4-dihydro-4-oxo-pyrimidinyl, pyridazinyl, halogenopyrimidines, 1-methylimidazole, thiazolyl, 2-amino-1,3,4-thiadiazolyl, 6-purinol or imidazo (4,5-C)pyridinyl Z1and Z2each independently represents O, NH or a direct bond; X represents O or S: R5represents hydrogen, C1-C4-alkyl, AMINOPHENYL,1-C4-alkylphenyl, pyridinyl, aminopyridines, aminopyrazine, 1-methylpyrrole, furanyl or 1-metalindo the P>1AND2AND3= AND4is a bivalent radical having the formula (a-1) or-N=CH-CH= CH- (a-2), R represents a hydrogen: oxazolidone part has the formula:

CH2OH

B represents NH, S, or CH2; n 1; L represents hydrogen, C1-C4-alkyl, hydroxy1-C4-alkyl, propenyl, 3-phenylpropanol, or a radical of the formula:

-Al-R3(b-1);

-Al-Y-R4(b-2);

-Al-H-C(=O)-R5-a (b-3-a); or

-Al-C(=O)-Z2-R5-b (b-3-b); where each Al independently represents a C1-3-alcander; R3represents phenyl, 4-methoxyphenyl, 4-hydroxyphenyl, pyridinyl, thienyl, 4,5-dihydro-4-ethyl-5-oxo-1-tetrazolyl, 2-oxo-2-1-benzopyranyl, 2-(amino or methylamino)-3,4-dihydro-3,6-dimethyl-4-QA - with-5-pyrimidinyl, 6-pyranyl, or a radical of the formula:

where: G2represents-CH=CH-CH=CH-, -(CH2)4-, -S-(CH2)2-S-(CH2)3-, -S-CH= CH - or-N(CH3)-N= C(CH3)-CH2-; y is NH or O; R4is pyrimidinyl 5-amino-1,3,4-thiadiazolyl, pyridazinyl, imidazo [4,5-c]pyridinyl or 1,4-dihydro-4-oxo-2-pyrimidinyl; R5-arepresents aminophenethyl or furanyl; Z2represents O; azannyh groups of compounds, in which AND1AND2AND3AND4is a bivalent radical of formula-CH= CH-CH=CH- (a-1) or-N=CH-CH=CH- (a-2); and one or two hydrogen atoms in said radicals (a-1) or (a-2) can be independently substituted by halogen, C1-6-alkyloxy or hydroxy; D represents CH2; and oxazolidinyl radical associated with D has the formula (R1)mand/or L represents hydrogen; C1-C6-alkyl; a radical of formula (b-1), where R3is aryl or Het; a radical of formula (b-2), where Y is NH or O, and R4is aryl or Het; a radical of the formula-Al-NH-CO-Het (b-3-a); each Het represents pyridinyl, optionally substituted amino or1-C6-alkyl; pyrimidinyl, optionally substituted amino or1-C6-alkyl; pyrazinyl, optionally substituted amino; furanyl; azolyl, optionally substituted C1-C6-alkyl; imidazolyl, optionally substituted C1-C6-alkyl; tetrazolyl, optionally substituted C1-C6-alkyl; 1,3,4-thiadiazolyl, optionally substituted C1-C6-alkyl or amino; oxazolyl, optionally substituted C1-C6-alkyl; 4,5-dihydro-5-oxo-1-tetrazolyl, long is correctly substituted from 1 to 3 substituents, selected from C1-C6-alkyl, amino and C1-C6-alkylamino; 2-oxo-3-oxazolidinyl; indolyl, optionally substituted C1-C6-alkyl; phthalazine; 2-oxo-2H-1-benzopyranyl; 3,7-dihydro-1,3-dimethyl - 2,6-dioxo-1-purine-7-yl, optionally substituted C1-C6-alkyl; 6-purinol or bicyclic heterocyclic radical of formula (c-1) to(c-8), defined above, where R10and R11independently are hydrogen or C1-C6-alkyl, and the radicals (C-2) and (3) X1is O; and

each aryl is unsubstituted phenyl; phenyl substituted with 1 or 2 substituents, each of which is independently selected from halogen, hydroxy, nitro, cyano, trifloromethyl,1-C6-alkyl and C1-C6-alkyloxy; and in addition, optionally substituted by a third Deputy, selected from halogen, C1-C6-alkyl or C1-C6-alkyloxy.

More preferred are those compounds from the group of the above preferred compounds in which L is hydrogen or C1-C3-alkyl.

Even more preferred compounds are compounds from the group described above, preferred compounds,xifei; thienyl; thiazolyl. optionally substituted C1-C6-alkyl; oxazolyl; 4,5-dihydro-1-tetrazolyl, optionally substituted C1-C6-alkyl; 2,3-dihydro-2-oxopentanoate-1-yl; 1,4-dihydro-2,4-dioxo-3(2)-pyrimidinyl; thienyl; 2-oxo-2-benzopyranyl, or R3represents a radical of the formula

or

where G1, G2and R10defined above.

Other even more preferred compounds are those preferred compounds in which L is the radical of the formula-Al-Y-R4(b-2), where Y is NH or O; and R4represents thiazolyl, pyridinyl, 1,3,4-thiadiazolyl, optionally substituted C1-6-alkyl or amino; pyrimidinyl, optionally substituted amino; 6-pyrenyl; 3,4-dihydro-4-oxopyrimidine; phthalazine; or 3 imidazo 4,5-pyridine-2-yl.

The most preferred compound is 1-[(2-methyl-5-oxazolyl)methyl]-N-(1-methyl-4-piperidinyl)-1H - benzimidazole-2-amine, its solvate and its pharmaceutically acceptable salt additive.

To simplify the structural representation of some compounds of formula (I) and intermediates, in the above description to obtain these compounds, the part containing imide is embalam Q.

-Q

The compounds of formula I mostly can be obtained by reaction of the intermediate compounds of formula (II) with appropriately substituted diamine of formula (III).

+(I)In this and the following reaction schemes, W represents an appropriate reactive leaving group such as halogen group, e.g. chloro-, bromo-, or hodograph; C1-6-alkyloxy; C1-6-alkylthio, aryloxy or allylthiourea; and X1is O, S or NH.

Derivatives of 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 compounds 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, for example, 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 hydrocarbon, for example, trichloromethane, dichloromethane, etc., organic-dimethylformamide, N,N-dimethylacetamide, etc., or a mixture of these solvents. Depending on the nature of the solvent and the reaction mixture may be added to the base, such that is normally used when carrying out 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, the reaction of 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.

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

(I)< / BR>
Similarly, the compounds of formula I can also be obtained by reaction promezhutochnoe VI and then W1is the corresponding leaving group such as halogen group (chloro, bromo, and so on); or sulfonyloxy group, such as methanesulfonate-, 4-methylbenzenesulfonate group, etc.

(I)< / 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 such as an aromatic hydrocarbon, e.g. benzene, methylbenzol, etc., an ether, e.g. 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran, etc., halogenated hydrocarbon, for example, trichloromethane, etc., N,N-dimethylformamide; N, N-dimethylacetamide; nitrobenzene; dimethyl sulfoxide; 1-methyl-2-pyrrolidinone, etc. and if M is hydrogen, such a solvent can also be1-C6-alkanol, for example, methanol, ethanol, 1-butanol, etc., a ketone, e.g. 2-propanone, 2-methyl-2-pentanon, etc. In some of the relevant base for example, such as a carbonate or bicarbonate of an alkali metal, e.g. sodium carbonate, sodium bicarbonate, etc., sodium hydride; or an organic base, such as N,N-diethylethanamine or N-(1-methylethyl)-2-propanamine, and/or can be added salt itestosterone acid, preferably, 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 compounds of formula IV, where B Is M represents H2with reagents of formula V is time - mesheanii 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 a polar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, etc.

The compounds of formula (I), where B is-NR2these compounds are represented by formula (I-b) can also be obtained through the reaction of the intermediate of formula (XII) with an intermediate compound of formula (II), where B M is a radical-NH2-H (a specified compound represented by formula (VII-a), conduct is mainly carried out by mixing the reagents in an appropriate inert solvent with a suitable regenerating agent. Preferably, if the first ketone of formula XII is subjected to reaction with an intermediate compound of formula VII-a, resulting in the formation of the enamine, which can be (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-C6-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., Alternatively, as a reducing agent may be used hydrogen in the presence of an appropriate catalyst, such as palladium carbon, platinized charcoal, etc.

In order to avoid undesirable subsequent hydrogenation of some functional groups in the reactants and reaction products, it may be preferred dobavlennaya formula (I-b), where R2is N (these compounds are represented by formula (I-b-I)), can also be obtained by reaction of collegesuniversities corresponding thiourea of the formula (II-a), where X1is S specified thiourea represented by formula (II-a-I), 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-I) with the appropriate alkylhalides, preferably, iodomethane, in an appropriate inert to the reaction solvent, such as1-C6-alkanol, for example, methanol, ethanol, 2-propanol, etc., Alternatively, this reaction collegesuniversities can also be carried out using a reaction between the compounds (IIa-a-I) with an appropriate metal oxide or salt, for example, 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, to the reaction mixture may be added a small amount of sulfur. As collegesuniversities agents can also be used meantioned is the N-alkylation of the intermediate compounds of formula (XV) with an appropriate alkylating agent of formula (XIV).

< / BR>
The above reaction of N-alkylation is carried out, mainly, in an inert solvent, such as water; aromatic hydrocarbons such as benzene, methylbenzol, xylene, and so forth alkanol, for example, methanol, ethanol, 1-butanol, etc., a ketone, e.g. 2-propanone, 4-methyl-2-pentanon, etc. simple ether, e.g. tetrahydrofuran, 1-dioxane, 1,2-oxybisethane, etc., a polar aprotic solvent, such as 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 amines, e.g. N,N-diethylethanamine, N-(1-methylethyl)-2 - propanamine, 4-ethylmorpholine, pyridine, etc., In some cases, it is preferable to add salt itestosterone acids, especially of alkaline iodide IU is the temperature and under stirring. In addition, it may be preferable to carry out the above reaction of N-alkylation in an inert atmosphere, for example, in an atmosphere of argon or nitrogen, which does not contain oxygen.

Alternatively, the 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 halide, hydroxide, bisulfate of dialkyldimethylammonium, tetraalkylammonium, tetraallylsilane, tetrakisphosphate and similar catalysts.

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

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

With the formula (b-1), (b-2) or (b-3) (these radicals represented by the radical L2H-, and the above compounds represented by formula (I-d-I)) can be also obtained by the reaction of reductive-alkylation of compound (I-e) using the appropriate ketone or aldehyde of formula L2O (XVII), where the specified L2O is an intermediate compound of formula L2H2where two genialnyh hydrogen atoms are replaced by O, a L2is genialny divalent radical comprising FROM3-6-cycloalkylation,1-C12-alkyliden, R3C1-C6-alkyliden, R4-Y1-C6-alkyliden and R5Z2-C(=X)-Z2WITH1-C6-alkyliden.

(I - L2= 0 L2H-BQ

Specified reductive N-alkylation, basically, can be carried out in accordance with the procedures described above for preparing compounds of the formula (I-b) from (VII-a) and (XII), and in particular, in accordance with the procedures catalytic hydrogenation.

The compounds of formula (I), where L is a radical of formula (b-2), and R4is aryl or Het (specified R4denoted by R4-aand these compounds are represented by formula (I-d-2) may be that the Xia hydrogen (these compounds are represented by formula (I-d-3) using a reagent of formula (XVIII).

< / BR>
Similarly, the compounds of formula (I-d-2) can be also obtained by treating the compounds of formula (I-d-4) with a reagent of formula (XIX).

< / BR>
Alkylation reaction of compound (I-d-3) with compound (XVIII) and compound (I-d-4) with compound (XIX) can generally be carried out in an inert organic solvent such as an aromatic hydrocarbon, e.g. benzene, methylbenzol, xylene; a ketone, e.g. 2-propanone, 4-methyl-2-pentanone; simple ether, for example, 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran; and polar aprotic solvent, such as 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 an organic base, such as 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 (b-3), Z1is NH, Z2is not a simple bond, and X is NR9(these 2 and X marked socyanate (X2O) or isothiocyanate (X2S) of formula (XXI) with a reagent of formula (XX).

< / BR>
The compound of formula (I), where I is a radical of formula (b-3). Z2is NH, Z1not a direct bond, and X is NR9(these Z1and X denoted by Z1and X2and these compounds are represented by formula (I-d-6), can be obtained by reaction of isocyanate (X2O) or isothiocyanate (X2S) of the formula (XXII) with a compound of formula (I-d-7).

< / BR>
The reaction of the compound (XX) with the compound (XXI), or 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, e.g. tetrahydrofuran, etc., halogenated hydrocarbon, for example, trichlormethane, etc. To increase the rate of reaction can be used elevated temperatures.

The compounds of formula I, where I is a radical of formula (b-3), Z2is a simple bond, and X is NR9, (the Z1and X denoted by 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 accordance with known procedures for reaction of esterification or amidation. For example, the carboxylic acid can be converted into a reactive derivative, for example, anhydride or carboxylic acid halide, which is then subjected to reaction with (I-d-7); or it may be conducted by reaction of (XXIII) and (I-d-7) with an appropriate reagent capable of forming amides or 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 ester, for example, tetrahydrofuran; halogenated hydrocarbon, e.g. 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 L3C2-6-alcander, where L3is aryl, Het or a radical of the formula R5Z2-C(= X) (these compounds are represented by formula (I-d-9) can also be obtained by reaction of accession, which is subjected to the compound of formula (I-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 (b-4) (indicated what xicom (XXV), where R12is hydrogen, C1-4-alkyl or the radical R6O-CH2-.

< / BR>
The reaction of the compound (I-e) (XXIV) and (XXV), respectively, can be carried out with stirring and, if necessary, by heating, such as a ketone, e.g. 2-propanone, 4-methyl-2-pentanone; simple ether, e.g. tetrahydrofuran, 1,1-oxybisethane; alcohol, e.g. methanol, ethanol, 1-butanol; a polar aprotic solvent, such as 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 4 695 575 in the works referenced in this patent, in particular, in U.S. patents 4 335 127, 4 342 870 and 4 443 451.

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 the formula I containing cyano-Deputy can be excellent hydrogen-containing atmosphere in the presence of an appropriate catalyst, such as platinized carbon, Nickel catalyst of the Raney and similar catalysts. Suitable for this purpose solvents are, for example, methanol, ethanol, etc., 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, for example, 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-C6-allyloxycarbonyl group through reaction with methyl or phenylmethylene derived from1-C6-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 forms is stupid, commonly used for catalytic hydrogenation or hydrolysis in acidic or alkaline depending on the nature L.

In all above - mentioned methods of producing compounds of the reaction products can be isolated from the reaction mixture and, if necessary, purified by standard methods.

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 4 219 559, 4 556 660, 4 634 704, 4 695 569, 4 695 575, 4 588 722, 4 835 161 and 4 897 401 and Europatent ER-0 206 415, 0 282 133, 0 297 661 and 0 307 014.

Intermediate compounds of formula (III) can be obtained from aromatic starting compounds with adjacent halogen and nitro substituents (XXVII) by reaction with a suitable>Intermediate compounds of formulas 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 the benzimidazole, imidazopyridine and/or purines.

The compounds of formula I, their pharmaceutically acceptable acid additive 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 the experiments on rats, Guinea pigs and dogs, for example, in the texts of the "Protection of Rats from Compound 48/80-induced lethality", "PCA (passive cutane an aphylaxls) test in Rats described in Drug Dev Res. 5, 137-145 (1985), "Histamine-induced lethality test om Guninea Pigs" and the "Ascaris Allegry test in Dogs". Two of the last experiment described in Arch. Int. Pharmacology Ther. 251, 39-51 (1981).

Compounds of the present invention find mostly anti-allergic profile of a broad spectrum that can be demonstrated excellent results obtained in different test experiments cited above. The second distinctive feature is rofiles, adaptable to ever-changing conditions antiallergic therapy. In particular, these compounds find rapid onset of response, and are particularly attractive duration, that is, this period is neither too short nor too long.

Thanks antiallergic properties of the compounds of formula I and their acid additive salts, 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 invention an effective amount of a specific compound in the form of basic or acid additive salt, as an active ingredient unite by thorough mixing with a pharmaceutically acceptable carrier, which may take various forms depending on the form of the desired drug. These pharmaceutical compositions polochon, 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., and 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 a large part of it consists of sterile water, although it may contain other ingredients, for example, solubilizing agents. For example, can be obtained injectable solutions, in which the carrier comprises saline solution, glucose solution or a mixture of these solutions. Can also be received injectable suspension containing suitable liquid carriers, suspendresume agents, etc., In compositions intended for intradermal injection, socialstudies 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. These 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 basic forms, are preferred for obtaining water compositions.

For ease of administration and uniformity of dosage, these pharmaceutical compositions are 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, each of which contains a predetermined quantity of active ingredient calculated on producing the desired therapeutic effect, in combination with the required pharmaceutical carrier.

Examples of such single carsresale 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 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. Basically, an effective amount of anti-allergic drugs is from about 0.001 to about 20 mg/kg of body weight, and more preferably from about 0.01 to about 5 mg/kg of body weight. The examples below illustrate the present invention but do not limit its scope in all aspects. In the presented examples, all parts are given by weight, unless otherwise specified particularly.

The experimental part.

A. the production of intermediate compounds.

P R I m e R 1. a) To a suspension of 25.4 hours 2-potassium-1-isoindole-1,3-(2)-dione in 141 including N, N-dimethylformamide, is an increase of 18 hours at room temperature, the reaction mixture is evaporated. The residue was distributed between water and dichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was led from acetonitrile in 2 fractions and received 24,2 hours (79,9%) and 2/(2-methyl-5-oxazolyl)methyl/-1H-isoindole-1,3(2H)-dione (InterMedia. Conn. 1).

b) a Mixture of 12 o'clock intermediate compounds 1 and 100 ml of 7 N. hydrochloric acid was stirred for 4 hours at a distillation temperature and 18 hours at room temperature. The reaction mixture was filtered, and the filtrate was concentrated. The residue was diluted with some water and podslushivaet NaOH. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated, resulting received the 4.3 hours (76,7%) of 2-methyl-5-oxazolidinone (InterMedia. Conn. 2).

(C) To the mixture 5,95 h 2-chloro-3-nitropyridine, 79 including ethanol and 4.3 hours intermediate compound 2 was added 3,78 including sodium bicarbonate. After stirring for 6 h at a temperature of distillation, the reaction mixture is evaporated. The residue was distributed between dichloromethane and water. The organic layer was separated, dried, filtered and evaporated. The residue is evaporated together with methylbenzol, resulting received an 8.4 hours (95,8%) N/(2-methyl-5 - oxazolyl)methyl/-3-NIT is the ethanol (4% ) and 198 hours methanol was hydrogenosomal at normal pressure and room temperature in the presence of 2 hours 10% palladium carbon (catalyst). After calculation of the amount of absorbed hydrogen, the catalyst was filtered, and the filtrate is evaporated, resulting received a 7.6 hours (100% ) N2-/(2-methyl-5-oxazolyl)methyl/-2,3-pyridylamine (InterMedia. Conn. 4).

e) a Mixture of 7.64 including intermediate compounds 4, 165 hours of tetrahydrofuran, 8,04 including ethyl 4-isothiocyanato-1 piperidinecarboxylate and 94 including N,N-dimethylformamide was stirred at 50aboutC for 20 h, the Reaction mixture was used as received for the further synthesis. Theoretical output: 15,7 hours (100% ) of ethyl 4-[[[[2-[[(2-methyl-5-oxazolyl)methyl]amino]-3-pyridinyl]amino] taxometer]amino]-1-piperidinecarboxylate (InterMedia. Conn. 5).

Similarly were obtained: ethyl 4-[[[[4-[[(2-methyl-5-oxazolyl)methyl] amino]-2-pyridinyl]amino] taxometer]amino]-1-piperidinecarboxylate (InterMedia. S. 6), ethyl 4-[[[[4-[[(2-methyl-5-oxazolyl)methyl]amino]-5-pyrimidinyl] amino] taxometer]amino]-1-piperidinecarboxylate (prom. S. 7), ethyl 4-[[[[3-[[(2-methyl-5-oxazolyl)methyl] amino]-4-pyridinyl]amino] taxometer] amino]-1-piperidinyloxy - lat (prom. Conn. 8).

P R I m m e R 2. a) To a mixture of 795 hours su is casola in nitrogen atmosphere. The obtained mixture was stirred for 1 h at the temperature of distillation. After cooling in an ice/salt bath, the reaction mixture was filtered and the filtrate is evaporated, resulting in a received 42,7 hours (99,9%) 5-(bromomethyl)-2,4-dimethyloxazole (InterMedia. Conn. 9).

o) To a mixture of 43 hours in-between. Conn. 9 423 including N,N-dimethylformamide was added in portions 23,75 including N-formyl-N-nutriformance. The resulting mixture was stirred for 1 h at 50aboutC and 18 h at room temperature, then the reaction mixture is evaporated, resulting in a received 41 PM (100%) N/a(2,4-dimethyl-5-oxazolyl)methyl/-N-formylmorpholine (InterMedia. Conn. 10).

(C) a Mixture of 41 H. InterMedia. Conn. 10, 152 including hydrochloric acid (conc.) and 395 hours of ethanol was stirred for 1 h at the temperature of distillation and 18 h at room temperature. The reaction mixture was filtered, and the precipitate was washed with ethanol. The combined filtrates evaporated, and the residue was placed in cold water. After alkalizing NaOH (water.) the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, resulting in a received 28 PM (98,6%) of 2,4-dimethyl-5-oxazolidinone (InterMedia. Conn. 11).

d) a Mixture of 28 hours in-between. Conn. 11, 395 including ethanol, 37,7 h 2-chloro-3-nitropyridine and 23,85 hours carb the water. The product was extracted with dichloromethane and the extract was dried, filtered and evaporated. The residue was purified by column chromatography (HPLC; silica gel; hexane/CH3COOC2H560:40). Eluent of the desired fraction evaporated and received 27 PM (48,3% ) N/a(2,4-dimethyl-5-oxazolyl)methyl/-3-nitro-2-pyridylamine (InterMedia. Conn. 12).

e) a Mixture of 26.5 hours intermediate compound 12; 3 hours of a solution of thiophene in methanol 4% and 316 hours of methanol was hydrogenosomal at normal pressure and room temperature in the presence of 4 o'clock 5% palladium charcoal. After calculation of the amount of absorbed hydrogen, the catalyst was filtered, the filtrate evaporated, resulting received to 21.8 hours (100%) N2-/(2,4-dimethyl-5-oxazolyl)methyl/-2,3-pyridylamine (InterMedia. Conn. 13).

P R I m e R 3. To a solution of 33,63 including 1-amino-4-methoxy-2-nitrobenzene in 282 including N, N-dimethylformamide, were added to 21.2 including sodium carbonate and a solution of 35.2 hours 5-bromomethyl-2-methoxazole 94 including N,N-dimethylformamide. The resulting mixture was stirred 20 h at 70aboutWith and then evaporated. The residue was dissolved in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2is oduct was filtered and dried, as a result, we received 30 PM (57,0%) of N-(4-methoxy-2-nitrophenyl)-2-methyl-5-oxazolidinone (InterMedia. Conn. 14).

Using the procedure of example 1 (d) and (e) of the intermediate compound 14 was converted into ethyl 4 -[[[[ 5-methoxy-2-[[(2-methyl-5-oxazolyl)methyl]amino]phenyl]amino] taxameter/amino/-1-piperidinyloxy - Silat (InterMedia. Conn. 15).

P R I m e R 4. a) To a stirred mixture of 412 including N,N'-melanterius/cyclohexanamine/ and 2225 hours of tetrahydrofuran was added drop by drop 1092 including carbon disulfide, and after cooling to 10aboutWith added portions 228 hours of 1-methyl-4-piperidylamine. The resulting mixture was stirred 1 h at room temperature and then evaporated. The residue was recrystallized from 2,2-oxybisethane. The product was filtered and dried, resulting in a received 416,6 hours (100%) 4-isothiocyanato-1 methylpiperidine (InterMedia. Conn. 16).

a) To a mixture of 28 hours in-between. Conn. 11 and 395 hours of ethanol was added 37,7 h 2-chloro-3-nitropyridine and 23,85 including sodium carbonate. The resulting mixture was stirred 6 h at a temperature of distillation, and the reaction mixture is evaporated. The residue was dissolved in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated, and the residue was purified by column chromatography dimethyl-4-oxazolyl)-methyl/-3-nitro-2-pyridylamine (InterMedia. Conn. 17).

Using the procedure of Example 1 (a) and (e), InterMedia. Conn. 17 was converted into N-/2-//(2,5-dimethyl-4-oxazolyl)methyl/amino/-3-pyridinyl/-N-(1 - methyl-4-piperidinyl)thiourea (InterMedia. Conn. 18).

Similarly were obtained:

N-/4-methoxy-2-//(2-methyl-5-oxazolyl)methyl/amino/phenyl/N'-(1 - methyl-4-piperidinyl)thiourea (InterMedia. Conn. 19) and N/4, fluorescent-2//(2-methyl-5-oxazolyl)methyl/amino/phenyl/-N-(1-methyl-4 - piperidinyl)thiourea (InterMedia. Conn. 20).

P R I m e R 5. a) To a mixture of 6.2 G. of ethyl 5-methyl-2-oxazolidinone and 191 hours of dry carbon tetrachloride was added to 7.1 ch. N-bromosuccinimide and several parts of benzoyl peroxide in the atmosphere of nitrogen. The resulting mixture was stirred 1 h at the temperature of distillation. After cooling, the reaction mixture was filtered, and the filtrate is evaporated, resulting in received //(2,5-dimethyl-4-oxazolyl)methyl/amino/-3-pyridinyl/-N-(1 - methyl-4-piperidinyl)thiourea (InterMedia. Conn. 18).

Similarly were obtained:

N-/4-methoxy-2-//(2-methyl-5-oxazo - Lil)methyl/amino/phenyl/N'-(1 - methyl-4-piperidinyl)thiourea (InterMedia. Conn. 19) and N/4, fluorescent-2//(2-methyl-5-oxazolyl)methyl/amino/phenyl/-N-(1-methyl-4-piperidin - nil)thiourea (InterMedia. Conn. 20).

P R I m e R 5. a) To a mixture of 6.2 G. of ethyl 5-mantelpiece in nitrogen atmosphere. The resulting mixture was stirred 1 h at the temperature of distillation. After cooling, the reaction mixture was filtered, and the filtrate is evaporated, resulting in a received 11 o'clock (100%) of ethyl 5-(bromomethyl)-2-oxazolidinone (InterMedia. Conn. 21).

o) To the mixture to 11.52 including ethyl 4-/(1N-benzimidazole-2-yl)amino/-1 piperidinecarboxylate and 235 including N,N-dimethylformamide was added in portions 1,92 including dispersion of sodium hydride in mineral oil (50%). After that, the mixture was stirred for 1/2 h and then added drop by drop a solution of 11 hours between. Conn. 21 47 PM N,N-dimethylformamide, cooling while the ice. The resulting mixture was stirred 18 h, slowly warming to room temperature. The reaction mixture is evaporated and the residue was distributed between water and 4-methyl-2-pentanone. The organic layer was dried, filtered and evaporated, and the residue was purified by column chromatography (silica gel; CH2Cl2/CH3OH 95:5). Eluent of the desired fraction evaporated and the residue was then led from 2,2-oxybisethane and acetonitrile. The product was filtered and dried, resulting in received 10 o'clock (56,6%) ethyl 4-//1-//2-(etoxycarbonyl)-5-oxazolyl)methyl/-1-benzimidazole-2 - yl/amino/-1 piperidinecarboxylate; so pl. 132,1about(InterMedia. Conn. 22).

about(InterMedia. Conn. 23).

P R I m e R 6. a) To a mixture of 38.1 hours 2-chloro-1-benzimidazole and 235 including N, N-dimethylformamide was added 44 PM 5-bromomethyl-2-methoxazole, 26,5 including sodium carbonate and a few crystals of potassium iodide. After that, the mixture was stirred for 18 h at 70aboutC, the reaction mixture is evaporated and the residue was distributed between water and dichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was led from 2,2'-oxybisethane (2), resulting in a received 9,01 hours (14,6%) of product. After evaporation of the United uterine solutions, received 10,23 hours (16,5%) of product. Full output: 19,24 hours (31,1% ) 2-chloro-1-/(2-methyl-5-oxazolyl)methyl/-1 benzoni - Gasol; so pl. 101,0about(InterMedia. Conn. 24).

b) a Mixture of 14,73 H. InterMedia. Conn. 24, 5,03 including thiourea and 79 hours of ethanol was stirred 4 h at a temperature of distillation. The reaction mixture is evaporated and the residue was purified by column chromatography (silica gel; CH2Cl2/CH3OH 98: 2). Eluent of the desired fraction evaporated and the residue was led from acetonitrile. The product was filtered and dried, resulting in a received 19,33 PM(99,0%) 1-/(2-methyl-5-oxazolyl)methyl/-1-benzimidazole-2-thiol; so pl. 153,3about(InterMedia. Conn.e 21,1 PM thionyl chloride. After 2 hours stirring at room temperature the reaction mixture is evaporated, and the residue is evaporated together with methylbenzol, resulting received 26,4 hours (100% ) 4-(chloromethyl)-2,5-dimethyloxazolidine - reed (InterMedia. Conn. 26).

P R I m e R 8. a) To a stirred mixture of 2.5 hours of tetrahydroborate sodium and 87 hours of 1,2-dimethoxyethane added 2,82 including lithium chloride, and after 1 h was added drop by drop to 15.5 hours ethyl 2-methyl-4-oxazolidinone. The resulting mixture was stirred for 10 h at 95aboutC and 18 h at room temperature. After this was added ethyl acetate and a certain amount of water and the resulting mixture was completely poured into 120 hours of ice water, acidified with 15 p.m HCl. The aqueous layer was separated and then was extracted with 2,2'-oxybisethanol, podslushivaet NaOH and was extracted with dichloromethane. The last extract was dried, filtered and evaporated. The remainder of the person to distil (133 PA, 75aboutC), resulting in received of 3.7 hours (32,7%) of 2-methyl-4-oxazolidinone (InterMedia. Conn. 27).

o) To a solution of 3.7 hours in-between. Conn. 27 133 hours of dichloromethane was added 4,1 including N,N-diethylethanamine and added drop by drop 4,14 hours of methanesulfonanilide, cooling while the ice. Then the resulting mixture was stirred and cooled in Acevedo, was dried, filtered and evaporated. The residue is evaporated together with methylbenzol, resulting received 5 parts (79,2% ) of 2-methyl-4-oxazolidinecarboxylate (complex ester) (InterMedia. Conn. 28).

In a similar way were obtained: 5-methyl-2-oxazolidinecarboxylate (ester) (InterMedia. Conn. 29) and 5-methyl-4-oxazolidinedione (ester) (InterMedia. Conn. 30).

B. obtain the final compounds.

P R I m e R 9. A mixture of 23 hours 5-(bromomethyl)-2-methoxazole, and 57.6 G. of ethyl 4-/(1-benzimidazole-2-yl)amino/-1-piperidinyl - oxylate, 26,5 including sodium carbonate and 47.0 including N,N-dimethylformamide was stirred 18 hours at 80aboutC. the Reaction mixture was poured into water and the resulting mixture whole was extracted with 4-methyl-2-pentanone. The extract was washed with water, dried, filtered and evaporated. The residue was stirred in acetonitrile. The precipitate was filtered, and the filtrate evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2/CH3OH 90:10). Eluent of the desired fraction is evaporated, resulting in a received 6 parts (11.2 per cent) ethyl 4-//1-/(2-methyl-5-oxazolyl)methyl/-1 benzoni - Gasol-2-yl/amino/1 piperidinyloxy - LVL (Conn. 2).

P R I m e R 10. To a solution of 26 hours 2-//(1-Tria in mineral oil (50%) in nitrogen atmosphere. After 1 hour stirring was added in portions a solution of 15 hours 5-(bromomethyl)-2-methoxazole 47 PM N,N-dimethylformamide while cooling in an ice bath (20aboutC). The resulting mixture was whole was stirred 18 h and was heated to room temperature. The oily layer was separated and discarded. N,N-dimethylformamide layer was poured into water and the whole was extracted with 4-methyl-2-pentanone (3 x). The combined extracts were washed with water, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2/ /CH3OH, 90:10). Eluent of the desired fraction evaporated and the residue was then led from 2,2-oxybisethane and acetonitrile, resulting in a received 14,31 PM(42,0%) 1-/(2-methyl-5-oxazolyl)methyl/-2-//1-(phenylmethyl)-4-piperidinyl/methyl/- 1-benzimidazole; so pl. 108,5aboutWith (Conn. 1).

P R I m e R 11. A mixture of 15.7 hours InterMedia. Conn. (5), 94 including N,N-dimethylformamide, 10,2 including oxide mercury (II) and several parts of sulfur was stirred 3 h at 75aboutC. the Reaction mixture was filtered through diatomaceous earth, which is then washed with N, N-dimethylformamide until then, until the solution becomes colorless. The combined filtrates evaporated and the residue was distributed between water and dichloromethane. The organic is silica gel; CH2Cl2/CH3OH 90: 10). Eluent of the desired fraction is evaporated, resulting in a received 5.5 hours (38,2%) ethyl 4-[[3-[(2-methyl-5-oxazolyl)-methyl]-3 - imidazo[4,5-b]pyridine-2-yl] amino]-1-piperidine-carboxylate (Conn. 94).

P R I m e R 12. To a solution of 21.6 hours in-between. Conn. (13) 235 including N,N-dimethylformamide was added 21,4 including ethyl-4-isothiocyanato-1 piperidinecarboxylate, and after stirring for 20 h at 50aboutWith added 27,1 including oxide mercury (II) and several parts of sulfur. The resulting mixture was stirred for 3.5 h at 75aboutC. the Reaction mixture was filtered through diatomaceous earth and the filtrate evaporated. The residue was distributed between water and dichloromethane. The organic layer was separated, 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 2,2'-oxybis-propane and acetonitrile. The product was filtered and dried, resulting in a received 16,62 hours (41,7% ) ethyl 4-[[3-[(2,4-dimethyl-5-oxazolyl)methyl] -3-imidazo[4,5-b] pyridine - 2-yl] amino]-1-piperidinecarboxylate (Conn. 153).

P R I m e p 13. To a solution of 12,97 including ethyl 4-hydroxy-1-piperidinecarboxylate in 705 including N,N-dimethylformamide, dobavlyali for 1/2 h at room temperature and for 1/2 h at 40aboutC.

After cooling, was added to 18.6 hours in-between. Conn. 24, keeping the temperature below 20aboutC. After it was stirred for another 18 hours, the Reaction mixture was evaporated, and the residue was distributed between water and dichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was treated with activated charcoal in methanol. After filtration, the compound obtained entirely evaporated and the residue was purified by column chromatography (silica gel; CH2Cl2/CH3OH 98:2). Eluent of the desired fraction is evaporated, resulting in a received 23,5 hours (81,5%) ethyl 4-[[1-[(2-methyl-5-oxazolyl)-methyl] -1-benzimidazole-2-yl]oxy]-1 - piperidine-carboxylate (Conn. 63).

P R I m e R 14. (a) the Following reaction was carried out in nitrogen atmosphere. To a mixture of 8.8 hours InterMedia. Conn. (25) (188 h N,N-dimethylformamide, was added 1,92 including dispersion of sodium hydride in mineral oil (50%), and after stirring for 1 1/2 hours at room temperature was added 13,33 including 1-[(4-were)sulfonyl] -4-piperazineethanesulfonic (ester). The resulting mixture was whole was stirred for 18 h and then evaporated. The residue was distributed between water and dichloromethane. The organic layer was separated, dried, filtered and Lipari desired fraction evaporated, resulting received 12,4 PM(71,4%) 4-[[1-[(2-methyl-5-oxazolyl)methyl]- 1-benzimidazole-2-yl]thio]-1-[(4-were)sulfonyl] piperidine (InterMedia. Conn. 31).

b) a Mixture of 10 hours in-between. Conn. (31) and 149 hours Hydrobromic acid (48% ) was stirred 3 h at the temperature of distillation. The reaction mixture is evaporated and the residue was diluted in water. The resulting mixture was podslushivaet entirely NaOH (water.) and then was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2/ /CH3OH(NH3) 90:10). Eluent of the desired fraction evaporated and the residue was converted into cyclohexylsulfamate salt (1:2) in 2-propanone. Salt was filtered and dried, resulting received a cent to 8.85 parts(53,7%) 1-[(2-methyl-5-oxazolyl)methyl] -2-(4-piperidinyl)-1-benzimidazole cyclohexylsulfamate (1:2); so pl. 147,8aboutWith (Conn. 85).

P R I m e R 15. a) To a mixture of 4,7 H. InterMedia. Conn. (23) and 89 hours of tetrahydrofuran was added 3.5 ml of a solution of tetrahydroborate lithium in tetrahydrofuran 2 M in nitrogen atmosphere. The resulting mixture was whole was stirred for 10 hours at a distillation temperature and 24 h at room temperature. After cooling, ice was added ethyl acetate and some quantities of the-oxybisethane and acetonitrile, resulting received 0,92 hours (21,5% ) 1,1-dimethylethyl 4-[[1-[[2-(hydroxymethyl)5 - oxazolyl]-methyl]-1-benzimidazole-2-yl] amino] -1-piperidinecarboxylate (Conn. 141); so pl. 132,3aboutC.

b) a Mixture of 8.3 hours connection (141), 133 hours of 2-propanol saturated with HCl, and 13.4 hours of methanol was heated at the temperature for 1.5 hours, the Reaction mixture was evaporated and the residue was led from 2-propanol. The product was filtered and dried, resulting in a received 6,1 PM(72,0%) 5- [[2-(4-piperidinyl-amino)-1 - benzimidazole-1-yl]methyl]-2 - oxazolidinecarboxylate; so pl. 279,5aboutWith (Conn. 146).

(C) a Mixture of 3,4 o'clock 1-(2-chloroethyl)-4-methoxybenzene, 5,2 including compounds (146), 3,2 including sodium carbonate, a few crystals of potassium iodide and 160 hours 4-methyl-2-pentanone was heated under reflux for 48 hours, 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 led from acetonitrile, resulting in a received 1,24 PM(19,9%) 5-[[2-[[1-[2-(4-methoxyphenyl)-ethyl]-4-piperidinyl]AMI - but]-1-benzimidazole-1-yl]methyl/-2-oxa - zolotonoshameat; so pl. 130,7aboutWith (Conn. 147).

P R I m e R 16. A mixture of 6 hours of compounds (2), 10,22 including potassium hydroxide and 66.3 including Rivoli and the residue evaporated together with water and then distributed among the small amount of water and dichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2/CH3OH(NH3) 85: 15). Eluent of the desired fraction evaporated and the residue was led from acetonitrile in two fractions, resulting in received 2,21 PM(45,4%) 1-[(2-methyl-5-oxazolyl)-methyl]-N-(-4-Piperi - dinyl)-1-benzimidazole - 2-amine; so pl. 227,2aboutWith (Conn. 3).

P R I m e R 17. A mixture of 3.1 hours of compounds (3), 1 h of Polyoxymethylene, 2 hours of a solution of thiophene in methanol (4%) and 119 hours of methanol was hydrogenosomal at normal pressure and room temperature in the presence of 2 hours 5% palladium charcoal. After calculation of the amount of absorbed hydrogen, the catalyst was filtered, and the filtrate evaporated. The residue was purified by column chromatography (silica gel; CH2-Cl2/CH3OH(NH3) 95:5). Eluent of the desired fraction is evaporated, and the residue was led from acetonitrile. The product was filtered and dried, resulting in a received 0,82 part(24,5%) 1-[(2-methyl-5-oxazolyl)methyl] -N-(1-methyl-4-piperidin - nil)-1 - benzimidazole-2-Amenemhet; so pl. 78,2aboutWith (Conn. 9).

P R I m e R 18. A mixture of 2.6 hours 6-(2-chloroethyl)-7-methyl-5-thiazolo[3,2-a] pyrimidine - 5-she manage the com 18 PM 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 1,34 hours (26,7%) 7-methyl-6-[2-[4-[[1-[(2-methyl-5-oxazolyl)methyl]-1-Benzema - Gasol-2 - yl]methyl]-1-piperidinyl]-ethyl]5-thiazolo [3,2-a]pyrimidine-5-it; so pl. 173,8aboutWith (Conn.14).

P R I m e R 19. To a stirred mixture of 11.0 hours of compounds (5), 6,0 hours of triethylamine and 122 including N,N-dimethylformamide was added drop by drop a solution of 3.6 g chloroacetonitrile at 19 o'clock N,N-dimethylformamide. The resulting mixture was stirred for 36 h at room temperature. The reaction mixture was poured into saturated NaCl solution and the whole was extracted with a mixture of ethyl acetate and 4-methyl-2-pentanone (1:1). The organic layer was separated, washed with water, dried, filtered and evaporated. The residue was stirred in (E)-2-potentiator salt (2:3) in 2-propanol, resulting in received of 13.75 hours(72,9% ) 4-[[1-[(2-methyl-5-oxazolyl)methyl]-1-benzimidazole-2-yl] methyl/-1 - piperidinecarbonitrile ammonia, was hydrogenosomal at normal pressure and room temperature in the presence of 3 hours Nickel catalyst Raney. After calculation of the amount of absorbed hydrogen, the catalyst was filtered and the filtrate is evaporated, resulting in a received 9,6 PM(90,5%) 4-[[1-[(2-methyl-5-oxazolyl)methyl] -1-benzimidazole-2-yl]meth - yl]-1 - piperidylamine (Conn.19).

(C) a Mixture of 1,1 h 2-chloropyrimidine, 3,2 including compounds (19), 1,7 including sodium bicarbonate and 119 hours of ethanol, stirred for 20 hours at a temperature of distillation. After cooling, the reaction mixture was filtered through diatomaceous earth. The filtrate is evaporated, and the residue was purified by column chromatography (silica gel; CH2Cl2/ /CH3OH(NH3) 96:2-96:4). Eluent of the desired fraction is evaporated, and the residue was converted into ethiotube salt (1:2) in ethanol. Sol recrystallize from ethanol, resulting in received of 2.7 hours (49,1%) N-[2-[4-[[1-/(2-methyl-5-oxazolyl)methyl] -1-Benzema - Gasol-2-yl]methyl] 1-piperidinyl]ethyl]-2-pyrimidinamine of candiota (1:2); so pl. 173,7aboutWith (Conn.20).

P R I m e R 20. A mixture of 2.2 h 2-ethenylpyridine 3,1 including compounds (3) and 81 h 1-butanol was stirred for 44 h at the temperature of distillation. After cooling, the reaction mixture is evaporated. The residue was purified through to the Lee, and the residue was converted into (E)-2-butenedioate salt (1:1) in ethanol. Then the salt recrystallize from a mixture of 4-methyl-2-pentanone and ethanol, and then from 2-propanol, resulting in received 1,1 PM(20,6%) 1-[(2-methyl-5-oxazolyl)-methyl]-N-[1-[2-(2-pyridinyl)ethyl]-4-Pipa - riginal]-1-benzimidazole-2-amine (E)-2-butenedioate (1:1); so pl. 184,6aboutWith (Conn.21).

P R I m e R 21. a) a Mixture of 6.2 hours of compounds (3) and 119 hours of methanol was stirred for 15 minutes, when barbotirovanie through her ethylene oxide. Stirring was continued for 3 h, and during this period, the ethylene oxide was barbotirovany another 15 minutes, the Reaction mixture was evaporated, and the residue was purified by column chromatography (silica gel; CH2Cl2/CH3OH(NH3) 95:5). Eluent of the desired fraction is evaporated, and the residue was converted into (E)-2-potentiator salt (1:2) in 2-propanol. Then the salt recrystallize from a mixture of 2-propanol, ethanol and 2-propanol, resulting in received 4,06 PM(31,3%) 4-[[1-[(2-methyl-5-oxazolyl)methyl]-1-benzimidazole-2-yl]AMI - but]-1-piperazineethanol (E)-2-butenedioate (1:2) 2-propenoate (1:1); so pl. 201,2aboutWith (Conn.36).

b) To a stirred mixture of 3.6 hours connection (36), 1.2 parts of 2-[di(hydroxyethyl)amino] ethanol and 106,4 including dichloromethane was added drop by drop a solution of 1,3 including means PM The reaction mixture was washed with water (2x), dried, filtered, and evaporated, resulting in a received 3,6 PM(100%) 2-[4-[[1-[(2-methyl-5-oxazolyl)methyl] -1H-gasoline - imidazol-2-yl]-amino]-1-piperidinyl] ethylmethanesulfonate (complex ester) (Conn.32).

(C) a Mixture of 1,1 h 1-methyl-1H-imidazole-2-thiol, 3,5 hours InterMedia.Conn. (32), 1,4 including potassium carbonate and 119 hours 2-propanol was stirred 12 h at a temperature of distillation. The reaction mixture is evaporated, and the residue was distributed between water and dichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2/ /CH3OH 95:5). Eluent of the desired fraction is evaporated, and the residue was converted into ethiotube salt (1:3) in ethanol. Sol recrystallize from ethanol, resulting in a received 1.0 hours (17,1%) N-[1-[2-[(1-methyl-1 - imidazol-2-yl)thio] ethyl] -4-piperidinyl] -1-[(2-methyl-5-OK-benzimidazole-2-AMI - ethanoate (1:3) hemihydrate; so pl. 195,2aboutWith (Conn.68).

P R I m e R 22. A mixture of 0.7 hours isocyanatomethyl, 3,5 hours connection (30) and 134 hours of tetrahydrofuran was stirred 18 h at room temperature. The reaction mixture is evaporated and the residue was purified by column chromatography (silica gel; CH2Cl2/CH3aboutWith (Conn.31).

P R I m e R 23. To a stirred mixture of 2.1 hours 3-amino-2-pyrazinecarboxamide acid, 2,8 h 2-chloro-1-methylpyridine iodide and 266 hours of dichloromethane was added to 1.5 hours N,N-diethylethanamine, and after 15 minutes another 4.6 hours connection (30). Stirring at room temperature was continued for 1 h the Reaction mixture was washed with water, 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 1,79 h (24,2%) 3-amino-N-[2-[4-[[1-[(2-methyl-5-oxazolyl)-methyl]-1N-benzimidazole-2 - yl] amino] -1-piperidinyl] ethyl] -2-pyrazinecarboxamide monohydrate; so pl. 134,2aboutWith (Conn.42).

P R I m e R 24. A mixture of 2.3 hours of 1-methyl-1-indole-2-carbonylchloride, 3,5 hours connection 30, 3 o'clock N,N-diethylethanamine and 298 hours of trichloromethane was stirred 18 h at room temperature. The reaction mixture was washed with water, dried, filtered and evaporated. The residue was purified by column using the crip who had led from 2,2-oxybisethane. The product was filtered and dried, resulting in a received 0,61 hours (11.9%) of 1-methyl-N-[2-[4-[[1-/(2-methyl-5-oxazolyl)methyl/-1-benzimidazole-2 - yl] amino]-1-piperidinyl]ethyl]-1H-indole-2-carboxamide; so pl. 104,0aboutWith (Conn.65).

P R I m e R 25. To a stirred and heated (60about(C) a mixture of 1.6 hours 2-3,1-benzoxazin-2,4(1)-Dion and 37.6 including N,N-dimethyl - formamide was added drop by drop a solution of 3.5 hours connection (30) of 28.2 including N,N-dimethylformamide. Then continued stirring 4 h at 60aboutC and 18 h at room temperature. The reaction mixture was poured into water and the product was extracted with a mixture of 4-methyl-2-pentanone and ethyl acetate (1:1) (3). The combined extracts were washed with NaCl (water.), was dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl/CH3OH(NH3) 95:5). Eluent of the desired fraction is evaporated, the residue was converted into (E)-2-butenedioate salt (1:2) in ethanol. The result that was obtained 4,4 part (62,3%) 2-amino-N-[2-[4-[[1-[(2-methyl-5-oxazolyl)- methyl]-1-benzimidazole - 2-yl]amino]-1-piperidinyl] ethyl]benzamide (E)-2-butenedioate (1:2); so pl. 219,6aboutWith (Conn.57).

P R I m e R 26. a) To a stirred and cooled (-10about(C) a mixture of 18 hours of carbon disulfide, 6,2 including N,N-melanterius(cyclohexanamine) and 134 hours tetrag the resulting mixture is completely brought up to room temperature and stirred for another 1 h The reaction mixture is evaporated and got 12 hours (100%) N-[1-(2-isothiocyanates)-4-piperidinyl]-1-[(2-methyl-5-oxazolyl) methyl]-1-benzimidazole-2-amine (InterMedia.Conn.33).

a) a Mixture of 3,3 including 3,4-pyridylamine, 12 hours elapsed.Conn. (33) and 134 hours of tetrahydrofuran was heated at the temperature of distillation of 18 hours, the Reaction mixture was used as such for further synthesis. Theoretical yield: 15.2 parts (100% ) of N-(4-amino-3-pyridinyl)-N'-[2-[4-1-[(2-methyl-5 - oxazolyl)methyl] -1-benzimidazole-2-yl] amino] -1-piperidinyl] ethyl] thiourea (InterMedia.Conn.34).

(C) a Mixture of 15 hours in-between.Conn. (34), 10,7 including oxide mercury (II), several parts of sulfur, and 134 hours of tetrahydrofuran was heated under reflux for 3 hours, the Reaction mixture was filtered through diatomaceous earth at a high temperature and the filtrate evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2/ /CH3OH(NH3) 90:10). Eluent of the desired fraction is evaporated, and the residue was led from 2,2-oxybisethane. The product was filtered and dried, resulting in a received 0,54 including 3,74% N-[2-[4-[[1-[(2-methyl - 5-oxazolyl)methyl/-1-benzimidazole-2-yl] amino]-1-piperidinyl]ethyl]-1-imidazo- [4,5-c]pyridine-2-amine hemihydrate; so pl. 181,8aboutWith (Conn.83).

P R I m e R 27. To the PE the creation of 6.1 hours compounds (13) 133 including dichloromethane. After stirring for 2 h at room temperature the reaction mixture was poured into NaHCO3(water.). The resulting mixture was completely evaporated, and the residue was dissolved in a mixture of methanol and dichloromethane, (10:90). The mixture was filtered through diatomaceous earth and the filtrate evaporated. The residue was purified twice by column chromatography (silica gel; CH2Cl2/CH3OH(NH3) 90:10) (silica gel; CH2Cl2/CH3OH(NH3) 95:5). Eluent of the desired fraction is evaporated, and the residue was led from acetonitrile. The product was filtered and dried, resulting in a received 4,2 PM(73,3%) 4-[2-[4-[[1-[(2-methyl-5-oxazolyl)methyl] -1-Ben - imidazol-2-yl] amino]-1-piperidinyl]ethyl]finalgather; so pl. 212,8aboutWith (Conn.47).

P R I m e R 28. A mixture of 5.8 hours of compound (163) and 149 hours Hydrobromic acid (48%) was stirred for 1 h at the temperature of distillation. After cooling, the reaction mixture was filtered, and the filtrate evaporated. The residue is evaporated together with methylbenzol and then pereirae in 2-propanol, resulting in received 4,8 PM(53,2%) 4-[2-[4-[[1-[(2,5-dimethyl-4-oxazolyl)methyl]-1-benzimidazole-2 - yl]amino]-1-piperidinyl/ethyl/fertigator - MFA-sesquihydrate; so pl. > 280, the. oxide of calcium and 119 hours of methanol was hydrogenosomal 18 h at normal pressure and room temperature in the presence of 2 hours 10% palladium charcoal. After calculation of the amount of absorbed hydrogen, the catalyst was filtered and the filtrate evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2/CH3OH(NH3) 95:5). Eluent of the desired fraction is evaporated, and the residue was converted into cyclohexylsulfamate salt (1:2) in 2-propanone. Salt was filtered and dried, resulting in a received 5,0 PM(63,3% ) 1-[(2-methyl-5-oxazolyl)methyl/-N-[1-[2-(2-pyridinylamino)ethyl] 4-piperidinyl]-1-benzimidazole-2-aminocyclopent - calcultate (1: 2); so pl. 212,3aboutWith (Conn.71).

P R I m e R 30. To 5,4 including connections (89) was added a solution of 0.52 g of sodium hydroxide in 100 hours of water. After stirring for 3 h at 40aboutWith added 1,27 including HCl (conc. ). The resulting mixture was whole was extracted with trichloromethane. The organic layer is discarded, and the aqueous layer was evaporated. The residue was dissolved in trichloromethane and this solution was dried, filtered and evaporated. Then the residue was converted into cyclo-hexylamino salt (1:2) in 2-propanol. The product was filtered and dried, resulting in a received 0,92 including the Amata; (1:2) so pl. 182,5aboutWith (Conn.91).

P R I m e R 31. To a mixture of 2.5 hours of compounds (9) and 70,5 including N,N-dimethylformamide under nitrogen atmosphere was added 0,384 including dispersion of sodium hydride in mineral oil (50%) and after stirring for 1/2 h at room temperature and 1/2 hours at 40aboutWith that added to 1.14 o'clock iodomethane. Stirring was continued for 18 h at room temperature. Then add a certain amount of ethanol, and the resulting mixture is completely evaporated. The residue was distributed between water and dichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2/CH3OH(NH3) 90:10). Eluent of the desired fraction is evaporated, and the residue was converted into ethiotube salt (1:2) in 2-propanol. The product was filtered and dried, resulting in a received 0,92 hours (23,0%) N-methyl-1-[(2-methyl-5-oxazolyl)methyl] -N-(1-methyl-4-piperidin - nil)- 1-benzimidazole-2-aminoethanoic (1:2); so pl. 149,7aboutWith (Conn.54).

P R I m e R 32. a) To a solution of 3,3 including compounds (85) 133 hours of dichloromethane was added 2,18 hours anhydride bis(1,1-dimethylmethoxy)formic acid. After 2 hours stirring at room temperature the reaction mixture was diluted th chromatography (silica gel; CH2Cl2/CH3OH 90:10). Eluent of the desired fraction evaporated, and received 3.4 part (79,3%) 1,1-dimethylethyl 4-[[1-[(2-methyl-5-oxazolyl)- methyl]-1-benzimidazole-2-yl]thio]-1-Pipa - reincorporate (Conn.86).

b) To a cooled (ice/salt bath) solution of 3,4 o'clock compounds (86) 133 including dichloromethane, was added to 1.38 including 3-chlorobenzalmalononitrile. The resulting mixture was whole was stirred 1.5 h, cooling at the same time, and then brought to room temperature. The reaction mixture was washed with NaHCO3(waters. and water, and then dried, filtered and evaporated, resulting received a 4.1 hours (100% ) 1,2-dimethylethyl 4-[[1-[(2-methyl-5-oxazolyl)methyl] -1-benzimidazole-2-yl] sulfinil] 1 piperidinecarboxylate (Conn. 87).

P R I m e R 33. a) a Mixture of 14.2 hours of compounds (3), 2 h of a solution of thiophene in methanol 4% 5 CH polyoximethylene and 198 hours of methanol was hydrogenosomal at normal pressure and 50aboutIn the presence of 2 hours 10% palladium charcoal. After calculation of the amount of absorbed hydrogen, the catalyst was filtered and the filtrate evaporated. The residue was distributed between dichloromethane and NH4OH (rasb. ). The organic layer was separated, dried, filtered and evaporated. The residue was purified by column chromatography (who in trihydrochloride salt in a mixture of 2-propanone and ethanol by adding 2-propanone, saturated HCl. Salt was filtered and dried, resulting in a received 12,3 PM(56,8%) 1-[(2-methyl-5-oxazolyl)methyl]-N-(1-methyl-4-piperidine - yl)-1H-benzimidazole-2-lentiviralmediated; so pl. 177,1aboutWith (Conn.24).

b) 3 hours of compounds (9) and 3 hours [R-(R*,R*)]-2,3-dihydroxy-1,4-butandione acid, separately boiled in 119 hours and 23.7 hours of acetonitrile, respectively.

Two mixtures were combined and the whole was left for crystallization. The product was filtered and dried, resulting in a received 4,53 PM(77,5%) (+)-1-[(2-methyl-5-oxazolyl)-methyl] -N-(1-methyl-4-piperidin - nil)- 1 - benzimidazole-2-amine[R-(R*, R*)]-2,3-dihydroxybutanedioate (1:2) hemihydrate; so pl. 155,9aboutC []D20+ of 14.76about(conc. 1% in methanol) (Conn.26).

(C) To a stirred and heated under reflux a mixture consisting of 3 hours of compounds (9), 39,5 including ethanol and 79 hours 2-propanol, was added in portions to 4.5 hours cyclohexylsulfamic acid. Then continued stirring and the resulting mixture was left for crystallization during cooling. The product was filtered and recrystallize from 2-propanol, resulting in received 3,1 PM(49,7%) 1-[(2-methyl-5-oxazolyl)methyl]-N-(1-methyl-4-Pipa - riginal)-1-benzimidazole-2-amine, cyclo - hexylsilane (1:2) hemihydrous acid in 39 PM 2-propanol was added a solution of 2.6 hours of compound (9) in 156 hours 2-propanol. The residue was filtered, dried under vacuum at room temperature and was stirred 156 hours 2-propanol. Then the solid substance was dissolved in 156 hours 2-propanol, and the solution was added 1 h 2-hydroxy-1,2,3-propanetricarboxylic acid in 2-propanol. Salt was filtered and stirred in 156 hours 2-propanol, resulting in received 2,95 PM(49,2% ) 1-[(2-methyl-5-oxazolyl)-methyl]-N-(1-methyl-4-piperidinyl)-1-gasoline - imidazol-2-Amin-hemihydrate-2-propanol (2: 1)-2-hydroxy-1,2-3-propanetricarboxylate (1:2); so pl. 85,2aboutWith (Conn.51).

e) 0,294 including the compound (9) was led from a mixture of acetonitrile and water (9:1). The product was filtered and dried, resulting in a received 0,193 PM(56,2% ) 1-[(2-methyl-5-oxazolyl)methyl] -N-(1-methyl - 4-piperidinyl)-1-benzimidazole-2-amine - three-hydrate; so pl. 94,5aboutWith (Conn.84).

P R I m e R 34. To a solution of 13 hours of compounds (1) 266 hours of dichloromethane was added drop by drop to 5.45 hours of ethylchloride and 5.7 h N,N-diethylethanamine. The resulting mixture was completely mixed and heated under reflux for 17 hours, the Reaction mixture was washed with water, dried, filtered and evaporated. The remainder PTS evaporated, as a result, we received 11 o'clock (89,9%) ethyl-4-[[1-[(2-methyl-5-oxazol)methyl]-1-benzimidazole-2-yl]me - til] 1 piperidinecarboxylate (Conn.4).

P R I m e R 35. A mixture consisting of 17 hours of methyl(CIS+TRANS)-4-amino-3-methyl-1-piperidinecarboxylate, 25 hours in-between.Conn.24 and 7 o'clock copper was stirred 6 h at 150aboutC. After cooling, the reaction mixture was diluted in dichloromethane and the whole was filtered through diatomaceous earth. The filtrate was washed with NaOH (rasb. and water, then dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl/CH3OH(NH3) 98:2). Eluent of the desired fraction is evaporated, resulting in received of 15.6 hours (40,7%) ( N)-methyl (CIS+TRANS)-3-methyl-4-[[1-[(2-methyl-5-oxazolyl)methyl]- 1-benzimidazole-2-yl]am(Conn.143).

All compounds are given in table.1-6 were obtained by the methods described in the examples 13-35.

C. Pharmacological examples.

P R I m e R 36. Valuable antiallergic and antihistaminic properties of the compounds of formula I can be demonstrated, for example, in the experiment "Protection of rats from death induced by compound 48/80" ("Protection pf rats from compo 48/80-induced lethality"), described in U.S. patent 4 556 660 introduced in the present description porini (mg/kg) for connections 3;9;12;14;15;16; or 17 was of the order of from 0.01 mg/kg and 0.04 mg/kg

D. Examples of compositions.

The following forms of drugs illustrate examples of typical pharmaceutical composition in the form of unit dosages suitable for systemic or topical purpose of warm-blooded animals, in accordance with the invention.

"Active ingredient" (A. 1) used in these examples relates to a compound of formula I, its pharmaceutically acceptable acid additive salt or a stereochemical isomeric form.

P R I m e R 37. Drops for admission through the mouth (oral drops).

500g A. 1. dissolved in 0.5 l of 2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol at 60-80aboutC. After cooling to 30-40aboutWith added 35 l of polyethylene glycol and the mixture is thoroughly mixed. Then added a solution of 1750 g of sodium saccharin and 2.5 l of purified water and while stirring, is added 2.5 l kayokyoku additives and polyethylene glycol in an amount necessary to 50 l, giving a solution, oral drops, containing 10 mg/ml A. 1. The resulting solution is filled into suitable containers.

P R I m e R 38. The capsule.

20 g of the active ingredient, 6 g laurilsulfate together. The resulting mixture is subsequently filled into 1000 suitable hardened gelatin capsules, each includes 20 mg of the active ingredient.

P R I m e R 39. Injectable solutions.

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

P R I m e R 40. Suppositories (medical candles).

3 g A. 1. dissolved in a solution of 3 g of 2,3-dihydroxypentanoic acid in 25 ml of polyethylene glycol 400. Together melted 12 g surfactants and triglycerides in the amount necessary to 300, the resulting mixture was well mixed with the first solution. Thus obtained mixture is poured into molds at 37-38aboutWith education 100 suppositories each containing 30 mg A. 1.

1. Oxazolidine derivatives of General formula
< (a 3), -CHCH-N=CH=(a-4), or-N=CH-N=CH-(a-6),

where one or two hydrogen atoms in said radicals (a-1) to(a-6) each independently may be substituted with halogen, C1-C6-alkyloxy - or hydroxy-group;

R is hydrogen or C1-C4-alkyl;

R1hydrogen, C1-C6-alkyl or hydroxy-C1-C6-alkyl;

m is 1 or 2;

D C1-C4-alcander;

B NR2CH2, O, S or SO, where R2hydrogen or C1-C4-alkyl;

n is 0, 1 or 2;

L is hydrogen, C1-C4-alkyl, cyclohexyl; propenyl, 3-phenylpropanol, C1-C4-allyloxycarbonyl or a radical of General formula-Alk-R3(b-1), -alk-Y-R4(b-2), -Alk-Z1-C(=X)-Z2-R5(b-3) or-CH2-CHOH-CH2-O-R6(b-4), where each Alk is independently represents a C1-C4-alcander; R3is cyano, phenyl, hydroxyphenyl, C1-C4-allyloxyphenyl, 3,4,5-trimethoxyphenyl, pyridinyl, thienyl, 2-methyl-5-oxazolyl, 4,5-dihydro-4-ethyl-5-oxo-1H-tetrazolyl, 2,3-dihydro-6-methyl-3-oxopyridine, 2-oxo-3-oxazolidinyl, 2-(amino or methyl-amino)-3,4-dihydro-3,6-dimethyl-4-oxo-5-pyridinyl, 2-oxo-2H-1-benzopyranyl, 3,7-dihydro-1,3-dimethyl-2,6 - dioxo-1H-purine-7-yl, 1,2,3,4-tetrahydro-2,4-dioxoimidazolidin, 2,3-dihydro-2-oxo-1-benim the2)2-, -S-(CH2)3, -S-CH=CH-, -N(CH2)3N=C(CH3)-CH2-, -N(CH3)-N=C(CH3)-, -N(CH3)-N= C(CH3)-CH2-, N(CH3)-CH=CH - or-CH=C(CH3)-O-, Y is NH, O or S, R4is hydrogen, C1-C4-alkyl, haloethanol, pyridinyl, kalaidjian, pyrimidinyl, 1,4-dihydro-2,4-dioxo-3(2H)-pyrimidinyl, 1,4-dihydro-4-oxopyrimidine, pyridazinyl, kalaidjian, 1-methylimidazole, thiazolyl, (2-amino or 2-methyl)-1,3,4-thiadiazolyl, 6-purinol or imidazo(4,5-c)-pyridinyl, Z1and Z2each independently O, NH or a direct bond, X is O or S, R5hydrogen, C1-C4-alkyl, AMINOPHENYL, C1-C4-alkyl, AMINOPHENYL, C1-C4-alkylphenyl, pyridinyl, pyrimidinyl, aminopyridines, aminopyrazine, 1-methylpyrrole, furanyl or 1-methylindolin, R6phenyl

or their pharmaceutically acceptable additive salt in their stereochemical isomeric form.

2. Connection on p. 1, where R is hydrogen, m is 1, R1hydrogen or C1-C6-alkyl.

3. Connection on p. 1, where-A1A2A3A4- bivalent radical having the formula (a-1) or (a-2), and one hydrogen atom in the specified radical (a-1) may be substituted with halogen, C1-C6-alkoxy Il CH2, O, S or SO, n is 0,1 or 2, L is hydrogen, C1-C4-alkyl, cyclohexyl, propenyl, 3-phenylpropanol, C1-C4-allyloxycarbonyl, or the radical of a specified formula (b 1), (b 4), where each Alk is independently represents a C1-C4-alcander, R3phenyl, hydroxyphenyl, C1-C4-allyloxyphenyl, -3,4,5-trimethoxyphenyl, pyridinyl, thienyl, 2-methyl-5-oxazolyl, 4,5-dihydro-4-ethyl-5-oxo-1H-tetrazolyl, 2,3-dihydro-6-methyl-3-oxopyridine, 2-oxo-3-oxazolidinyl, 2-(amino or methyl-amino)-3,4-dihydro - 3,6-dimethyl-4-oxo-5-pyridinyl, 2-oxo-2H-1-benzopyranyl, 3,7-dihydro-1,3-dimethyl-2,6-dioxo-1H-purine-7-yl, 2,3-dihydro-2-oxo-1-benzimidazolyl or a radical of the formula

< / BR>
where G2represents-CH= CH-CH= CH-, -(CH2)4-, -S-(CH2)2, -S-(CH2)3-, -S-CH= CH-N(CH2)3, -N=C(CH3)-CH2-, -N(CH3)-N=C(CH3)-, N(CH3)-CH= CH - or CH=C(CH3)-O-, Y is NH, O or S; R4hydrogen, C1-C4-alkyl, haloethanol, pyridinyl, kalaidjian, pyrimidinyl, 1,4-dihydro-2,4-dioxo-3(2H)-pyrimidinyl, 1,4-dihydro-4-oxo-pyridinyl, pyridazinyl, kalaidjian, 1-methylimidazole, thiazolyl, 2-amino-1,3,4-thiadiazolyl, 6-purinol or imidazo(4,5-c)pyridinyl; Z1and Z2each independently p is4-alkylphenyl, pyridinyl, aminopyridines, aminopyrazine, 1-methylpyrrole, furanyl or 1-methylindolin; R6.

4. Connection on p. 3, where-A1=A2-A3=A4- bivalent radical having the above formula (a-1) or (a-2), R is hydrogen; oxazolidine part has the formula

< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
< / BR>
B NH, S, or CH2, n 1, L is hydrogen, C1-C4-alkyl, propenyl, 3-phenylpropyl or a radical of formula (b-1), (b-2), -Alk-NH-C (O)-R5-a(b-3-a) or-Alk-C (O)-Z2-R5-b(b-3-b), where each Alk is independently represents a C1-C3-alcander, R3- phenyl, 4-methoxyphenyl, 4-hydroxyphenyl, pyridinyl, thienyl, 4,5-dihydro-4-ethyl-5-oxo-1H-tetrazolyl, 2-oxo-2H-1-benzopyranyl, 2-(amino - or methylamino)-3,4-dihydro-3,6-dimethyl-4-oxo-5-pyrimidinyl or a radical of the formula

< / BR>
where G2-CH= CH-CH=CH-, -(CH2)4, -S-(CH2)2S-(CH2)3, -S-CH=CH - or-N(CH3)-N= C(CH3)-CH2, Y is NH or O, R4pyrimidinyl, pyridazinyl, imidazo(4,5-c)pyridinyl or 1,4-dihydro-4-oxo-2-pyrimidinyl, R5-aaminopyrazine or furanyl, Z2O; R5-bhydrogen

5. Connection on p. 1, which is 1-[2-m is integral additive salt.

6. The compound according to any one of paragraphs.1 5, having antiallergic activity.

7. Pharmaceutical composition having anti-allergic activity, including an active ingredient and a pharmaceutically acceptable carrier, characterized in that as the active ingredient it contains anti-allergic effective amount of the compounds of formula I according to any one of paragraphs.1 6.

8. The method of obtaining oxazolidine derivatives of General formula

< / BR>
where A1= A2-A3=A4bivalent radical of formula-CH=CH-CH=CH- (a-1), -N= CH-CH= CH-(a-2), -CH=N-CH-CH=CH-(a-3), -CH=CH-N=CH-(a-4), or-N=CH-N=CH-(a-6), where one or two hydrogen atoms in said radicals (a-1)(a 6) each independently may be substituted with halogen, C1-C6-alkoxy or hydroxy-group, R is hydrogen or C1-C4-alkyl; R1hydrogen, C1-C6-alkyl or hydroxy-C1-C6-alkyl, m is 1 or 2, D - C1-C4-alcander; B NR2CH2, O, S or So, where R2hydrogen or C1-C4-alkyl, n is 0,1 or 2, L is hydrogen, C1-C4-alkyl, cyclohexyl; propenyl, 3-phenylpropanol, C1-C4-allyloxycarbonyl, or a radical of formula-Alk-R3(b - 1), -Alk-Y-R4(b-2), Alk-Z1-C(=X)-Z2-R5(b-3) the sludge is3cyano, phenyl, hydroxyphenyl,1-C4-allyloxyphenyl, 3,4,5-trimethoxyphenyl, pyridinyl, thienyl, 2-methyl-5-oxazolyl, 4,5-dihydro-4-ethyl-5-oxo-1H-tetrazolyl, 2,3-dihydro-6-methyl-3-oxopyridine, 2-oxo-3-oxazolidinyl, 2-(amino or methylamino)-3,4-dihydro-3,6-dimethyl-4-oxo-5-pyrimidinyl, 2-oxo-2H-1-benzopyranyl, 3,7-dihydro-1,3-dimethyl-2,6-dioxo-1H-purine-7-yl, 1,2,3,4-tetrahydro-2,4-dioxoimidazolidin, 2,3-dihydro-2-oxo-1-benzimidazolyl or a radical of the formula

< / BR>
where G2represents-CH=CH-CH=CH, -(CH2)4-, -S=(CH2)2, -S-(CH2)3-, -S-CH=CH-, -N(CH2)3, -N=C(CH3)-CH2-, -N(CH3)-N=C(CH3)-, -N(CH3)-N= C(CH3)-CH2-, N(CH3)-CH=CH - or-CH=C(CH3)-O-, Y is NH, O or S, R4is hydrogen, C1-C4-alkyl, haloethanol, pyridinyl, kalaidjian, pyridinyl, 1,4-dihydro-2,4-dioxo-3(2H)-pyridinyl, 1,4-dihydro-4-oxopyrimidine, pyridazinyl, kalaidjian, 1-methylimidazole, thiazolyl, (2-amino or 2-methyl)-1,3,4-thiadiazolyl, 6-purinol or imidazo [4,5-c] pyridinyl, Z1and Z2each independently O, NH or a direct bond, X is O or S, R5C1-C4-alkyl, AMINOPHENYL, C1-C4-alkylphenyl, pyridinyl, pyrimidinyl, aminopyridines, aminopyrazine, 1-met>/BR>where L, R, R1, -A1=A2=A3=A4- A, B, D, m and n have the above meanings;

X1O, S or NH,

or their pharmaceutical acceptable salt additive, or stoichiometric isomeric form is subjected to cyclization by treatment with alkylhalogenide, metal oxide or metal salt in an inert solvent.

 

Same patents:

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 a compact, crystalline 3-cyan - 2-morpholino-5-(pyrid-4-yl)-pyridine with high apparent (bulk) density and method thereof

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):

N-(CH2)mR2(A) or -(CH2)p, dioxolane, furan, tetrahydrofuran, methylfuran or thiophene, m is an integer from 1 to 3; R3is lower alkyl; R4is phenyl or a radical of dioxolane, furan or thiophene, p = 1, provided that when R1radical 1,2,3,4-tetrahydrobenzo-2-or 1,2,3,4-tetrahydroquinazoline-2,4-dione, R2and R4are not phenyl or substituted by a halogen phenyl, or their pharmacologically acceptable salts with antiacetylcholinesterase activity

The invention relates to new derivatives of pyrazole and their pharmaceutically acceptable salts

The invention relates to medicine, specifically to antisecretory and antiulcer drug

The invention relates to new derivatives of 1-phenyl-3-azabicycloalkanes-2-ones, to a method for producing them, to pharmaceutical compositions containing them and to their use as therapeutic agents

The invention relates to medicine and relates to a pharmaceutical composition inhibiting tumor growth

The invention relates to new derivatives of benzimidazole, possessing valuable pharmacological properties, in particular a derivative of benzimidazole of General formula I

< / BR>
(I) where R1in position 4 means fluorine atom, chlorine or bromine, alkyl with 1-4 carbon atoms, cycloalkyl, vermeil, deformity or trifluoromethyl;

R2alkoxyl with 3-5 carbon atoms, substituted imidazolium in position 3, 4 or 5, alkoxyl with 2-5 carbon atoms, a substituted benzimidazole or tetrahydroimidazo in position 2, 3, 4 or 5, 2-(imidazol-1-yl)-ethoxyl provided that R4means 1H-tetrazolyl, alkylsulfonate with 1-4 carbon atoms, benzosulfimide or generalconclusions, unsubstituted or substituted at the nitrogen atom by alkyl with 1-6 carbon atoms, phenyl, cycloalkyl, phenylalkyl, cycloalkylation, bicyclohexyl or the biphenyl alluminare, in which the acyl radical is alkanoyl with 1-7 carbon atoms, alkoxycarbonyl with a total of 2-4 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, benzoyl, benzazolyl, generalkonsulin, naphthalenesulfonyl, cycloalkylcarbonyl, phenylalkanoic or Central electoral commissions substituents from the group includes fluorine atom, chlorine or bromine, methyl, methoxy, phthalimido, hemophthalmia, 2-carboxymethylamino or 2-carboxymethylamino, and one carbonyl group in phthalimidopropyl replaced by methylene, alkylamino or dialkylamino, one methylene group in hoofdlijnen may be substituted by one or two alkyl groups, and the phenyl nucleus may be optionally mono - or tizamidine the alkyl or alkoxyl, and the substituents may be the same or different and are wholly or partially gidrirovanny, unsubstituted or substituted by one or two alkyl groups or one tetramethylenebis or pentamethylene group 5-, 6 - or 7-membered, alkylamino or alkenylamine in which one methylene group may be replaced by a carbonyl or sulfonyl, imides bicycloalkyl-2,3-dicarboxylic acid and imine bicycloalkyl-2,3-dicarboxylic acid, where bicycloalkanes and bicycloalkanes part can contain 9 or 10 carbon atoms can be substituted by 1, 2 or 3 methyl groups, and endometrioma group may be replaced by oxygen atom, amidinopropane, unsubstituted or substituted by one or two alkyl groups is whether the two alkyl groups or tetramethylene or pentamethylene, maleinimide, unsubstituted or mono - or disubstituted by identical or different substituents from among alkyl and phenyl, linked through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup, oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and mentioned heteroaromatic rings in the carbon skeleton may be substituted by alkyl with 1-6 carbon atoms or phenylalkyl to 5-membered and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methylene group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom of the formed pyridine ring with the sulfur atom, or formed anilinophenol phenyl ring by one or two methyl groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroalkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene bridge, and available if needed in the imidazole ring NH group may be substituted by an alkyl group with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl, imidazolidinedione group, unsubstituted or substituted alkyl, phenylalkyl, tetramethylene, pentamethylene or hexamethylene, pyridazin-3-one and dihydropyridin-3-one, which is in position 2 can be substituted and,

the group R7-NR6CO NR5where R5a hydrogen atom, alkyl with 1-8 carbon atoms, cycloalkyl with 5-7 carbon atoms or phenylalkyl;

R6a hydrogen atom, alkyl with 1-8 carbon atoms, alkenyl with 3-5 carbon atoms, phenyl, phenylalkyl or cycloalkyl with 5-7 carbon atoms,

R7a hydrogen atom or alkyl with 1-6 carbon atoms,

one of the radicals R5, R6or R7may mean bicyclohexyl or diphenylol, R6and R7together with the enclosed nitrogen atoms means the unbranched alkalinising with 4-6 carbon atoms, or R5and R6ashamed mean alkylen with 2-4 carbon atoms, 1H, 3H-hinzelin-2,4-Dion-3-yl, pentamethylene-oxazoline-2-yl, or R1a hydrogen atom or is in position 5, 6 or 7 atoms fluorine, chlorine or bromine, an alkyl group with 1-4 carbon atoms, vermeil, deformity or trifluoromethyl; R2bound through a carbon atom or aminogroup 5-membered heteroaromatic ring containing aminogroup and the oxygen atom or sulfur, or aminogroup and atom oxygen, sulfur or nitrogen, or bound via a carbon atom of the 6-membered heteroaromatic ring containing 1 or 2 nitrogen atom, and said heteroaromatics and 6-membered heteroaromatic ring connected n-propylene, n-butylene or 1,3-butadienyl group via two adjacent carbon atom, or n-propylene or n-butylene group through aminogroup and the adjacent carbon atom, resulting anilinophenol pyridine ring one methine group may be replaced by a nitrogen atom, venelinova group in position 3 or 4 to the nitrogen atom formed piperidino ring sulfur atom, or formed anilinophenol phenyl ring, one or two methine groups may be replaced by nitrogen atoms, and mentioned precondensation aromatic or heteroaromatic rings in the carbon skeleton may additionally be monogamist fluorine atom, chlorine or bromine, the alkyl, alkoxyl, hydroxyl, phenyl, nitro, amino, alkylamino, dialkylamino, alkanolamine, cyano, carboxyla, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl, formation, deformation, trifluoromethyl, alkanoyl, aminosulfonyl, alkylaminocarbonyl or dialkylaminoalkyl, or tizamidine fluorine atoms or chlorine, stands, metaxylem or hydroxyl, and two methyl substituent can be connected to each other in position 1,2 via a methylene or ethylene my with 1-6 carbon atoms, phenylalkyl or cycloalkyl; bound through a carbon atom pyrolidine, piperidine or pyridine ring, and the pyridine ring via two adjacent carbon atoms may be precondensation phenyl, and the neighboring nitrogen atom of the methylene group in pyrolidine or piperidinium the ring may be replaced by carbonyl,

R3a hydrogen atom, an alkyl group with 1-5 carbon atoms in which one methylene group may be replaced by oxygen atom or sulfur, or cycloalkyl with 3-5 carbon atoms,

R4carboxyl, cyano, 1H-tetrazolyl, 1-triphenyl-methyl-tetrazolyl, alkoxycarbonyl with the total number of carbon atoms 2-5, alkanesulfonyl, arylsulfonamides, triftormetilfullerenov, and if nothing else is specified, then the above alcoolica, alkyl and CNS part can contain 1-3 carbon atoms, and cycloalkyl part of 3-7 carbon atoms, and moreover, if (a) R1a hydrogen atom, R3N-propyl and R4carboxyl, R2in position 6 does not mean 3-methylimidazo[4,5-b]pyridine-2-yl or 3-n-hexyl-imidazo[4,5-b]pyridine-2-yl, or if (b) R1a hydrogen atom, R3n-propyl or n-butyl and R41H-tetraza the sawdust and R4carboxyl, R2in position 5 or 6 does not mean 1-methylbenzimidazole-2-yl or 6 position 1H-butylbenzothiazole-2-yl, 1,5-dimethylbenzimidazole-2-yl or 1-methyl-5-trifluoromethyl-benzimidazole-2-yl, or if g) R1a hydrogen atom, R3n-butyl and R4carboxy or 1H-tetrazolyl, R2in position 6 does not mean 1-methylbenzimidazole-2-yl, or if d) R1a hydrogen atom, R3n-butyl and R4carboxyl, R2in position 6 does not mean benzimidazole-2-yl, mixtures of them 1-, 3-isomers or individual isomers and hydrates and salts, in particular their physiologically tolerated salts with inorganic or organic acids or bases which are used, for example, as antagonists of angiotensin II, the method of obtaining derivatives of benzimidazole containing the substances, medicinal product and method of its production

The invention relates to medicine, in particular to pharmacology and Oncology

FIELD: medicine, oncology.

SUBSTANCE: the present innovation deals with treating patients with uterine cervix cancer with relapses in parametral fiber and in case of no possibility for radical operative interference and effect of previous radiation therapy. During the 1st d of therapy one should intravenously inject 30 mg platidiam incubated for 1 h at 37 C with 150 ml autoblood, during the next 3 d comes external irradiation per 2.6 G-r. During the 5th d of therapy one should introduce the following composition into presacral space: 60 ml 0.5%-novocaine solution, 1 ml hydrocortisone suspension, 2 ml 50%-analgin solution, 1 ml 0.01%-vitamin B12 solution, 1.6 g gentamycine, 800 mg cyclophosphan, 10 mg metothrexate. These curative impacts should be repeated at mentioned sequence four times. The method enables to decrease radiation loading and toxic manifestations of anti-tumor therapy at achieving increased percent of tumor regression.

EFFECT: higher efficiency of therapy.

1 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new 1-(p-thienylbenzyl)-imidazoles of the formula (I): , wherein indicated residues represent the following values: R(1) means halogen atom, (C1-C4)-alkoxyl, (C1-C8)-alkoxyl wherein one carbon atom can be replaced with heteroatom oxygen atom (O); R(2) means CHO; R(3) means aryl; R(4) means hydrogen halogen atom; X means oxygen atom; Y means oxygen atom or -NH-; R(5) means (C1-C6)-alkyl; R(6) means (C1-C5)-alkyl in their any stereoisomeric forms and their mixtures taken in any ratios, and their physiologically acceptable salts. Compounds are strong agonists of angiotensin-(1-7) receptors and therefore they can be used as a drug for treatment and prophylaxis of arterial hypertension, heart hypertrophy, cardiac insufficiency, coronary diseases such as stenocardia, heart infarction, vascular restenosis after angioplasty, cardiomyopathy, endothelial dysfunction or endothelial injures, for example, as result of atherosclerosis processes, or in diabetes mellitus, and arterial and venous thrombosis also. Invention describes a pharmaceutical composition based on above said compounds and a method for their applying also.

EFFECT: valuable medicinal properties of compounds and composition.

10 cl, 19 ex

FIELD: organic chemistry and pharmaceutical compositions.

SUBSTANCE: invention relates to new 3-(5)-heteroaryl-substituted pyrazoles of formula I , tautomers or pharmaceutically acceptable salt of compounds and tautomers. In formula R1 is hydride, piperidinyl substituted with methyl, lower alkyl optionally substituted with halogen, hydroxyl, lower alkylanimo or morpholino; R2 is hydride, lower alkyl, amino, aminocarbonylamino, lower alkylaminocarbonylamino, lower alkylsulfonylamino, aminosulfonylamino, lower alkylaminosulfonylamino; Ar1 is phenyl optionally substituted with one or more independently selected halogen; HetAr2 is pyridinyl with the proviso that R2 is not amino or n-propyl when HetAr2 is pyridinyl; and HetAr2 is not 2-pyriridinyl when R2 is hydrogen or lower alkyl. Compounds of formula I have kinase p38 inhibitor activity and are useful in pharmaceutical compositions for treatment of various diseases.

EFFECT: new effective kinase p38 inhibitors.

23 cl, 6 dwg, 1 tbl, 1 ex

FIELD: veterinary science.

SUBSTANCE: a dog should be introduced with 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazole-1-il]benzene sulfonamide or its pharmaceutically acceptable salt at daily dosage ranged about 0.1-10 mg/kg body weight.

EFFECT: higher efficiency of therapy.

4 cl,262 ex, 12 tbl

Up!