Derived 1,3-dihydro-2h-imidazo/4,5-b/quinoline-2-it as a phosphodiesterase inhibitor, the method of its production, intermediate for him, pharmaceutical composition and method of reception

 

(57) Abstract:

Derivatives of 1,3-dihydro - 2H - imidazo/a 4.5-in/quinoline-2-it formula I, where R is hydrogen, phenyl, possibly substituted by 1-3 substituents selected from halogen, alkyl, or the radical =C=O or =S=N-O-R1; R1- C1-6-alkyl, possibly substituted by COOH, SOOS1-4the alkyl or CONR3R4; R3- C1-4-alkyl, R4- C3-7-alkyl, or R3and R4together with the nitrogen atoms to which they are attached, may form piperazinonyl cycle, or their pharmaceutically acceptable salts, or their stereometria forms have properties to inhibit phosphodiesterase and can be used for treatment of allergic and atopic diseases. 7 C. and 5 C.p. f-crystals, 4 PL.

The present invention relates to new derivatives of 1,2-dihydro-2H-imidazo/4,5 - b/quinoline-2-she formulas (1)

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their pharmaceutically acceptable salts and stereoisomeric forms,

in which R represents hydrogen, phenyl, possibly substituted by 1-3 substituents, each of which is independently selected from halogen, C1-C6-alkoxygroup; pyridinyl;

represents a radical of the formula:

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where R1represents C1-C-C4-alkyl, R4- C3-C7-cycloalkyl, R3and R4together with the nitrogen atom to which they are attached, may form piperazinonyl cycle, and piperidinyloxy cycle possibly substituted at the nitrogen atom WITH1-C4-alkyl, (C3-C7-cycloalkyl) - C1-C4-alkyl.

In the above definitions, the term "halogen" includes fluorine, bromine and iodine; C1-C4-alkyl defines a normal or branched, saturated hydrocarbon radical with 1 to 4 carbon atoms, such as, for example: methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1 - dimethylethyl; C1-C6the alkyl includes in its definition WITH1-C4-alkyl, and its higher homologues, such as, for example: pentyl, hexyl and so on;3-C7-cycloalkyl includes cyclopropyl and cycloheptyl; three (C1-C6-alkyl)silyl can be, in particular, presents trimethylsilanol, triethylsilanol, tert-butyl dimethylsilane etc.

Famous replaced imidazo (4,5-b/quinoline-2-ones/ patent Belgium BE N 904671, the Federal Republic of Germany patent DE 3717291, U.S. patent 4701459, 4943573 as phosphodiesterase inhibitors and inhibitors of platelet aggregation, and therefore they can be the derivative of 3,5-dihydroimidazo /2,1-b/ hinzelin-2(1H)-it as a positive inotropic and lusotropical/U.S. Patent 5043327/.

Compounds according to the invention have properties to inhibit phosphodiesterase.

These compounds of General formula I may exist as salts. The above-mentioned pharmaceutically acceptable salts include therapeutically active non-toxic salts which the compounds of formula (I) can form. Such salts are, as a rule, can be obtained by treating compounds of formula (I) as the Foundation of an appropriate acid such as an inorganic acid, for example: gidrohlorida acid, for example: hydrochloric, Hydrobromic and the like acids, sulfuric acid, nitric acid, phosphoric acid, etc. or an organic acid, such as, for example: acetic, propanoic, hydroxyestra, 2-hydroxypropanoic, 2-oxopropanoic, atindimubona acid, propanediamine acid, butandikislota acid (Z)-2-butandikislota acid, (E)-2-butane-dicarboxylic acid, 2-hydroxybutyrophenone acid, 2,3-dihydroxybutanedioate acid, 2-hydroxy-1,2,3-propanetricarboxylate, methansulfonate, econsultancy, benzolsulfonat, 4-methylbenzenesulfonate, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and analogichnaya formula (I), containing acidic hydrogens, the processing of the appropriate organic or inorganic base can be converted into a therapeutically active non-toxic metal salts or amines. The corresponding basic salts include, for example, ammonium salts, salts of alkali and alkaline earth metals, e.g. , salts of lithium, sodium, potassium, magnesium, calcium, etc., salts of organic bases, e.g. the benzathine, N-methyl-D-glucamine, geranamine and salts with amino acids such as, for example, salts of arginine, lysine, etc.

Definition of salt also includes a hydrate and a solvate, which the compounds of formula (I) can form. Examples of such forms include, for example, hydrates, alcoholate, etc.,

Compounds of the present invention have asymmetric carbon atoms. Each of these chiral centers may be indicated stereochemical designation R and S. the compounds of formula (I), in which the group /C=X represents the radical of formula (b) may exist as a mixture of E - and Z - isomers or in the form of pure E-isomer or a pure Z - isomer.

Stereochemical pure isomeric forms of the compounds of formula (I) can be obtained using what kristallizatsiei and methods chromatography, for example, counter current distribution, liquid chromatography, etc., and enantiomers may be separated by known separation methods, for example, selective crystallization of their diastereomeric salts with chiral acids. Or the enantiomers can be separated by liquid chromatography using a chiral stationary phase. Pure stereoisomeric forms may also be obtained on the basis of pure stereoisomeric forms of the corresponding source products provided stereospetsifichno of reactions. If you want to get specific stereoisomer, this connection is recommended to get stereospecificity methods of synthesis. In such methods can be successfully used enantiomers clean original products. Obviously, stereoisomeric forms of the compounds of formula (I) are also the subject of invention.

To interest compounds include those compounds of formula (I) in which R represents hydrogen, phenyl, possibly substituted by 1 or 2 substituents, each of which is independently selected from halogen, C1-C6- alkoxygroup or C1-C6- alkyl, pyridinyl and group/C=X represents the radical of formula (a) is Sogno substituted by 1 or 2 substituents, each of which is independently selected from fluorine, chlorine, bromine, metoxygroup, cyclopentyloxy or methyl, or pyridinyl, and/C=X represents the radical of formula (a) or (b), where R1is1-C4- alkyl, possibly substituted by a group COOH, COO-C1-C4alkyl or CONR3R4.

Especially interesting are those compounds in which R represents hydrogen or phenyl, possibly substituted by 1 or 2 substituents, each of which is independently selected from fluorine, metoxygroup or methyl, and the group /C=X is represented by a radical of the formula (a) or (b), where R1is1-C4- alkyl, possibly substituted by a COOH group, COOC2H5, SON (CH3) - (cyclo. WITH6H11or

Of most interest are the following compounds:

(E)-N-cyclohexyl-2-/// (2,3-dihydro-2-j imidazo/4,5-b/ - quinoline-7-yl/phenylmethylene/amino/hydroxy/ methylacetamide; 7-benzoyl 1,3-dihydro, imidazo/4,5-b/quinoline-2-he;

(E)-1-(cyclohexylmethyl)-4-////(2,3-dihydro-2-oxo imidazo/4,5-b quinoline-7-yl)methylene/amino/hydroxy/acetyl/piperazine and (E)-N-diclohexal-2-///(2,3-dihydro-2-oxo imidazo/4,5-b/-quinoline-7-yl)methylene/amino/hydroxy/-N-methylacetamide, their pharmaceutically acceptable salts of the x intermediates in the description of the preparative methods the following fragment of 1,3-dihydro-2H-imidazo /4,5-b/quinoline 2-it is denoted by the symbol D

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The compounds of formula (I), as a rule, can be obtained by cyclization of the intermediate compounds of formula (II):

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in an acceptable solvent. such as, for example, dimethylsulfoxide, N, N - dimethylacetamide, tetrahydrothiophene - 1,1 - dioxide, diphenyl ether, etc., in the presence of acid, such as, for example: acetic acid, triperoxonane acid or sulfonic acid, for example, methanesulfonate acid, triftormetilfullerenov acid, 4-methylbenzenesulfonamide or 4-methylbenzenesulfonate pyridinium, etc., In some cases, it may be convenient to apply the solvent excess acid. In addition, to increase the rate of the cyclization reaction can be successfully carried out in the temperature range 130-160oC, preferably at 140-150oC.

The compounds of formula (I) can also be obtained by cyclization of the intermediate compounds of formula (III):

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using the methods described above for the cyclization of the intermediate compounds of formula (II).

However, the conversion of intermediate compounds of formula (III) in a compound of formula (I) includes about the alizatsii in the reaction mixture can be added iodine as oxidant, and adding iodine may be carried out during or, preferably, upon completion of the cyclization reaction. In some cases, the reaction of the intermediate compounds of formula (III) with acid may be formed rich intermediate compound of the following formula:

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Such rich intermediate compound can be oxidized by known methods in the compound of formula (I).

Cyclization of the intermediate compounds of formula (III) in the compound of formula (I) has an important advantage compared to the previously specified methods of cyclization. The fact that cyclization participate only (E) - isomers of compounds of formula (II), and as for compounds of formula (III) such isomers are not specific, the compound of formula (1) can be obtained with much more output.

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Examples of acceptable for the above reaction solvents include halogenated hydrocarbons, for example: dichloromethane, trichloromethane and etc., aromatic hydrocarbons such as benzene, methylbenzol and so on, ethers, for example: 1,1' - oxybisethane, tetrahydrofuran etc., dipolar aprotic solvents such as N, N - dimethylformamide, N, 1 - dimethylacetamide, acetonitrile, etc.

-C4- alkyl, CONR3R4,

can be converted by known methods into each other using, for example, esterification, amidation, interesterification, parametervalue, hydrolysis of ester and similar methods.

For example, compounds in which R1represents C1-C6- alkyl, substituted by COOH, can be converted into an ester in which R1is1-C6- alkyl, substituted COO-C1-C4-alkyl, or can be converted into amide in which R1represents C1-C6- alkyl, substituted CONR3R4processing carboxylic acid alkanol formula1-C4- alkyl - HE or amine of the formula HNR3R4in the presence of an appropriate reagent, contributing to the formation of ester and/or amide. Typical examples of such reagents include: dicyclohexylcarbodiimide, 2-chloro-1-methylpyridinium, pathiakis phosphorus, 1,1'-carbonylbis /1H-imidazole/, 1,1'- sulfanilic-/1H-imidazole/ and similar reagents. Or these carboxylic acids can be converted into their corresponding reactive functional derivatives, such as, for example: acylhomoserine, symmetric spodnie before the reaction with alkanols1-C4- alkyl-OH, or an amine other3R4. Such reactive functional derivative can be synthesized by known methods, for example, by the reaction of carboxylic acid with a halogenation agent, such as, for example thionyl chloride, phosphorus trichloride, polyphosphoric acid, phosphorylchloride, oxalicacid, etc., or by the reaction of carboxylic acids with allogenic, such as acetylchloride, etc. Such reactive derivatives of carboxylic acids can be formed in situ or, if desired, can be isolated and subjected to additional treatment prior to their reaction with alkanols1-C4-alkyl-OH, or an amine HNR3R4.

These reactions of esterification and amidation usually l mixing of reagents, possibly in an inert solvent, such as, for example: halogenated hydrocarbons, for example: dichloromethane; trichlormethane etc., aromatic hydrocarbons, such as benzene, methylbenzol and so on, ethers, for example: 1,1'-oxybisethane, tetrahydrofuran, etc., dipolar aprotic solvents such as N, N - dimethylformamide, N, N-dimethylacetamide, pyridine, etc. In some cases it may be convenient to use an excess of odacchi, remove from the reaction mixture by known methods, such as, for example: azeotropic distillation, complexation, formation of salts and similar methods. In some cases, especially easy can be added acceptable bases, such as, for example: amine, for example: N, N - diethylethanamine, 4-ethylmorpholine, pyridine or N, N - dimethyl-4-pyridylamine. In addition, to improve the speed of response is similar to the acylation reaction can be successfully carried out under slightly elevated temperature, in particular at the boiling temperature of the reaction mixture.

Transesterification can be carried out by reaction of the compound in which R1represents C1-C6- alkyl, substituted COO-C1With alkyl, with other alkanols formula1-C4- alkyl.

The balance of the interesterification reaction can be shifted by known methods, for example, by using an excess of the specified alcohols or distillation of the formed alcohol. Similar by using amine HNR3R4can be made and transamination.

Compounds in which R1represents C1-C6- alkyl, substituted COO-C1-C4the alkyl may be g is H, the hydrolysis is usually carried out by stirring under heating of ester in aqueous and/or alcoholic medium, for example: water, methanol, ethanol, etc. or mixtures thereof in the presence of a base, such as, for example: sodium hydroxide, potassium hydroxide, potassium carbonate, etc., In some cases, for example, in the case of 1,1-dimethylethylene ester hydrolysis can be conducted by stirring and, possibly, by heating the ester in acid aqueous and/or alcoholic medium, described above.

The compounds of formula (1-b) in which R1different from hydrogen, i.e., represented by the symbol R1-aand the compound represented by formula (1-b-1) can also be obtained from compounds of the formula (1-b) in which R1is hydrogen, i.e. compounds of the formula (1-b-2) 0-alkylation or 0-similarobama by using the appropriate alkylating or cilleruelo agent of the formula R1-a-W1.

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In such alkylating or similitude agent W1is off a whole group, such as, for example: halogen, such as chlorine, bromine or sulfonyloxy, for example: 4-methylbenzenesulfonate, benzosulfimide-, 2-naphthalenesulfonate, methanesulfonate, triftormetilfullerenov ywaniem of the reactants with inert under the reaction conditions solvent in the presence of a base. Acceptable solvents include: halogenated hydrocarbons, such as, for example: dichloromethane, trichloromethane and so on, ethers, for example: 1,1'- oxybisethane, tetrahydrofuran, etc., dipolar aprotic solvents such as N, N - dimethylformamide, N, N - dimethylacetamide, pyridine, acetonitrile, etc. To acceptable bases include amines, such as, for example: N, N - diethylethanamine, 4-methylmorpholine, imidazole, pyridine, tetramethylguanidine, etc. or sodium hydride, etc.

In addition, the compounds of formula (1-b-2) that may exist in the form of E - or Z - isomer, or mixtures thereof, can be samaritani of balance in an acidic environment.

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The compounds of formula (1-b-1) in which R1-ais three(C1-C6-alkyl)silyl can be desilicious in oximes of the formula (1-b-2) processing of fluoride salt, such as, for example: potassium fluoride, tetrabutylammonium or by reaction with hydrochloric acid in a solvent such as simple ether, for example: 1,1'- oxybisethane tetrahydrofuran or their aqueous mixtures. With regard to compounds of the formula (1-b-1) in which R1-ais three (C1-C6-alkyl)silyl, such compounds can be easily separated on the E-desilicious in the aforementioned manner. This sequence provides an effective method of obtaining those stereoisomers of the formula (1-b), which cannot be obtained by the aforementioned method of isomerization.

Or compounds of the formula (1-b-1) can be obtained from intermediates of formula (XI) in which W2represents an appropriate reactive waste group, such as, for example: halogen, for example chlorine or acetate, by reaction with a reagent of formula (XII )

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Most of the key intermediates in the above reaction schemes are new compounds, specially created for making the compounds of the present invention.

Intermediate compounds of formula (II) can be obtained from the corresponding nitro-derivatives of the formula (XIII) using known methods of recovery.

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For example, nitro-derivatives of the formula (XIII) can be restored by catalytic hydrogenation in an acceptable solvent such as, for example: alcohol, such as methanol, ethanol, simple ether, such as tetrahydrofuran or 2-methoxyethanol, ester, e.g. ethyl acetate, carboxylic acid, e.g. acetic acid and similar solvents, in the presence of hydrogen is, is icela Raney, etc. and the corresponding catalytic poison, for example, thiophene, possibly at elevated temperatures and/or pressures. Or nitro-derivatives of the formula (XIII) may be reinstated by a reducing agent, such as, for example: sodium sulfide, sodium hydrosulfide, sodium hydrosulphate, titanium trichloride, complex dialkylammonium - palladium on charcoal, iron-ammoniacloridegas etc.

Intermediate compounds of formula (III) can be obtained from intermediates of formula (XIII) by catalytic regeneration as described above, but without the use of catalytic poison. It is obvious that the intermediate compounds of formula (III) can be also obtained additional recovery of intermediate compounds of formula (II), for example, by catalytic hydrogenation in the aforementioned manner.

The intermediate nitro-derivatives of the formula (XIII) can be obtained by reaction of the intermediate of formula (XIV) with ridom phosphorus of the formula (XV) (Wittig reaction) or with ridom formula (XIV) obtained from a phosphonate (reaction Horner-Emmons), where R7represents C1-C6- alkyl.

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Intermediate compounds of formula (XIII) can bildik, for example, processing reagents sodium acetate in acetic anhydride, or by treatment with a base, such as, for example: alkali metal alkoxide, e.g. sodium methoxide, ethoxide sodium tert-piperonyl potassium, etc. in an appropriate solvent, such as alcohol, for example: methanol, ethanol, tert-butanol, etc.

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This condensation reaction is conveniently carried out by stirring and by careful heating of the reaction mixture.

Intermediate compounds of formula (XIV), in which the group/C=X is represented by a radical of the formula (a), i.e., the intermediate compounds of formula (XIV-a) can be obtained from the intermediate compounds of formula (XVIII) in which both R8radical are alkyl group, for example: methyl, ethyl, etc. or both R8together form ascandilwy radical, for example: 1,2-ethandiyl, 1,3-PROPANEDIOL, 2,2 - dimethyl-1,3-propandiol, etc., by hydrolysis in an acidic aqueous medium.

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Intermediate compounds of formula (XVIII) can be obtained from the cyanide of the formula (XIX) using known methods of oxidation, for example, by treating compound of formula (XIX) air in an alkaline environment.

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The cyanides of the formula (XIX) can be easily obtained by the reaction of ar is OLE (XXI) W3is reactive waste group, such as, for example: halogen, such as chlorine or fluorine, a nitro-group, 4-methylbenzenesulfonamide, fenoxaprop, alkyloxy and similar groups, manifesting itself well as outgoing groups known in the aromatic nucleophilic substitution reactions. Similar reaction of aromatic nucleophilic substitution is conveniently carried out by stirring the reactants in the presence of a base in an inert under the reaction conditions solvent, such as, for example, dipolar aprotic solvent, for example N, N - dimethylformamide, N, N - dimethylacetamide, hexamethylphosphorotriamide, pyridine, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone, 1,3-dimethylamine - tolidine, 1,1,3,3-tetramethylrhodamine, 1-methyl-2-pyrrolidinone, nitrobenzene and similar solvents or mixtures thereof. Examples of acceptable bases include sodium hydride, sodium amide, sodium salt sulfanilic-(methane), diisopropylamide lithium and a similar reason. A beneficial effect may have added to the reaction mixture crown ether, for example, 1,4,7,10,13,16 - hexaoxacyclooctadecane, etc. or complexing agent, such as, for example, Tris/2- (2-methoxyethoxy)/ethanamine, etc. N cleophile substitution can be carried out by using known reaction conditions of phase transfer catalyst. Such conditions include mixing of the reagents with the corresponding base in the presence of an appropriate catalyst transfer phases, such as, for example: dialkyldimethylammonium, tetraalkylammonium, tetraalkylammonium, tetraarylporphyrin, -Oh, -hydrosulfate and similar catalysts.

Aldehydes of formula (XIV-a) can also be obtained by hydrolysis in an aqueous environment - amaneciendo formula (XXII).

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In the formula (XXII) and then the group-NR9R9is dialkylamino group or heterocyclic radical, such as, for example, morpholino, piperidino and similar groups.

Intermediate compounds of formula (XXII) in turn can be obtained by the reaction of aromatic nucleophilic substitution in the nitrobenzene of the formula (XXI) the above method to obtain the intermediate compounds of formula (XIX).

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The reagent of formula (XXIII) can be easily obtained from the corresponding aldehyde by its reaction with sodium cyanide, potassium cyanide and the cyanide in the presence of an amine HNR9R9and hydrosulfite sodium. Acceptable solvents include, for example: water, alkanols, such as methanol, ethanol, etc. and mixtures thereof.

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This oxidation reaction is conveniently carried out by mixing the reagent in an inert solvent, such as dimethylsulfoxide, dichloromethane, etc., or mixtures thereof in the presence of an oxidant, such as, for example: magnesium oxide (IV), pyridinium dichromate, etc., the Oxidation can also be carried out by treatment of the alcohol at low temperatures, preferably at -60oC reactive complex, prepared from dimethyl sulfoxide and such a reagent, such as: dicyclohexylcarbodiimide, chlorosulfonylisocyanate, oxalicacid, molybdenum peroxide, 4-methylbenzenesulfonate, anhydride methanesulfonic acid. In another embodiment, the aldehyde is produced by adding to the reaction mixture acceptable bases, such as, for example: N, N - diethylethanamine, pyridine, sodium bicarbonate.

Intermediate compounds of formula (XXIV), in turn, can be obtained by oxidation of the intermediate compounds of formula (XXV).

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This oxidation reaction is conveniently carried out by stirring the reactants in water in the presence of an oxidant, such as hydrogen peroxide and a base such as, for example, potassium hydroxide, etc.

Intermediate compounds of the formula Tabasalu.

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The specified reaction accession convenient to carry by mixing the reagents in an inert under the reaction conditions solvent in the presence of reasonable grounds. Acceptable solvents include, for example: dipolar aprotic solvents such as N, N - dimethyl formamide, N, N-dimethylacetamide, dimethylsulfoxide, pyridine, etc. or alcohols, such as methanol, etc., Examples of appropriate bases include sodium hydroxide, potassium hydroxide, sodium hydride, sodium amide, sodium salt sulfanilic(methane) and a similar reason. Or similar to the reaction of the joining may be carried out by the application of known catalytic reaction conditions of the transfer phase. Such conditions include mixing of reagents in the presence of a base and an acceptable catalyst transfer phases, such as, for example halide, hydroxide, hydrosulphate of dialkyldimethylammonium, tetraalkylammonium, tetraallylsilane and similar catalysts.

Intermediate compounds of formula (XIV), in which the group represented by a radical of the formula (b), i.e., the intermediate compounds of formula (XIV-b), can be obtained by oxidation of the corresponding intermediate alcohols of formula (XXVI-b) according to the above methods, polhena intermediate compounds of formula (XXVI-b), in which R is hydrogen, are disclosed in European patent EP-A-0406958 with a publication date January 9, 1991

The intermediate benzyl alcohols of formula (XXVI-b) can be obtained from the protected alcohols of the formula (XXV-b) using known methods of removal of the protective groups (release).

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In the formula (XXVII-b) R is acceptable protective group such as, for example: tetrahydropyranyl, 2-methoxyethoxymethyl 2-methoxypropyl, 2-acetoxypropionyl, 1-ethoxyethyl etc., trialkylsilyl group, for example: trimethylsilyl, tert-butyldimethylsilyl and similar groups. This reaction is the removal of the protective group can be easily carried out by known methods of hydrolysis of acetals and cyrilovich esters, for example, by acid hydrolysis in the aquatic environment.

Intermediate compounds of formula (XXV-b) in which the group represented by a radical of the formula (b) can easily be obtained from intermediates of formula (XXV-a) in which X is oxygen, using the techniques described above for converting compounds of the formula (1-a) compounds of the formula (1-b)

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The protected intermediate compound of formula (XXV) can be derived from alkanols of the formula (XXIV) using known methods of protection dwarf in an inert solvent and in the presence of an acid catalyst, or to consist of O-alkylation or O-siciliani appropriate alkylating agent such as, for example, trialkylsilyl, for example: trimethylsilyloxy, tert-butyldimethylsilyloxy, and can also be used similar reaction protection.

Intermediate compounds of formula (XXVI-b-1), in which R - pyridinyl, and X is the group NOR1where R1different from hydrogen, i.e., the radical represented by the symbol R1-acan be obtained from intermediates of formula (XXVI-6), in which R - pyridinyl, and X is the group NOH, i.e., from the intermediate compounds of formula (XXVI-b-2) O-alkylation or O-similarobama according to methodology described above to obtain compounds of the formula (1-b-1).

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Intermediate compounds of formula (XXVI-b-2) can be obtained by reduction of the corresponding aldehydes of formula (XIV-b), in which R - pyridinyl, and X is the group NOH, i.e., the intermediate compounds of formula (XIV-b-2) using known methods of recovery.

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The specified reduction is conveniently carried out by mixing reagent or preferably, its salts in alkanol, for example, methanol, etc. in the presence of a reducing agent, such as, for example, sodium borohydride, etc., For p.

Intermediate compounds of formula (XIV-b-2), in turn, can be obtained by hydrolysis of the intermediate compounds of formula (XXVIII) in acidic aqueous environment.

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Intermediate compounds of formula (XXVIII) can be easily obtained from intermediates of formula (XXIX), in which X is oxygen and R is pyridinyl, using methods described above for converting compounds of the formula (1-a) in the compounds of formula (1-b).

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The protected intermediate compound of formula (XXIX) can be selectively prepared from aldehydes of formula (XIV-a), in which R is pyridinyl, i.e., from the intermediate compounds of formula (XIV-a-1) by known methods.

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Usually such reactions protection include the processing of alcohol, e.g. methanol, ethanol, 1,2-ethanediol, etc. in the presence of an acid catalyst, for example, 4-methylbenzenesulfonate.

Or intermediate compounds of formula (XIV-6-1) can be obtained direct O-alkylation of intermediates of formula (XXVIII) using the methods described above to obtain compounds of the formula (1-b-1), followed by hydrolysis acetamino group in the aldehyde in an aqueous acidic environment.

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Intermediate soy is s (XXXI).

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Examples of suitable reducing agents for this reaction include tin chloride (II) in the presence of acid, for example hydrochloric acid, or hydrogen in the presence of a hydrogenation catalyst.

Intermediate compounds of formula (XXXI) can be synthesized by reaction of the intermediate of formula (XXXII) with nitroacetanilide formula (XXXIII) in an inert under the reaction conditions solvent such as an alcohol, e.g. methanol, ethanol, etc.

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Or intermediate compounds of formula (XXXI) can be prepared by reaction of intermediates of formula (XXXIV) with NH3in an inert under the reaction conditions solvent, such as alcohol, for example ethanol, 1-butanol, etc., preferably at elevated temperature, for example at the temperature of boiling or reaction intermediates of formula (XXXIV) with ammonium acetate in acetic acid.

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Another alternative way to obtain the intermediate compounds of formula (XXXI) can be illustrated by the following reaction scheme (see below).

Intermediate compounds of formula (XXXII) can be obtained by reduction of the known methods of the corresponding nitro-derivatives of the formula (XI is the ect or zinc in the presence of acid, for example hydrochloric acid, or hydrogen in the presence of a hydrogenation catalyst.

Intermediate compounds of formula (XXXIV) can be synthesized by reaction of intermediates of formula (XXXII) with 1,1-bis(methylthio)-2-nitroethanol formula (XXXV) in the presence of acid, for example hydrochloric acid, Imanalieva acid, etc.

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The compounds of formula (I), their pharmaceutically acceptable salts and stereoisomeric forms are effective inhibitors as phosphodiesterase (PDE) type III (cGMP - inhibiting type) and type IV (camp - specific type). Used here and below the notation PDE III and PDE IV is consistent with the classification proposed by J. A. v and D. N. Reifsn waed, TIPS Reviews, April 1990, pages 150-155.

Inhibition of isozymes of phosphodiesterase type III and IV leads to increased levels of camp in specific cells, for example: cardiac muscle, certain cells, such as basophils and saintilan and mastocytic. cyclic amp is a key secondary mediator, the concentration of which affect specific cellular activity by activating enzymes, such as kinases. The number of allergic and atopic diseases believed to be associated with more in what I hypersensitivity affected cells to excitatory stimuli. (Examples of such hypersensitivity include excessive release by basophils and mastocytoma histamine or excessive formation by eosinophils supercedes anion radical). Since the compounds of the present invention have pronounced any abscopal phosphodiesterase properties, it can be expected that the compounds will be useful tools to facilitate and/or cure allergic and atomic diseases. The functional effect of inhibitors PDE III and IV is, for example, in the relaxation of smooth muscles of respiratory tract, inhibition of platelet aggregation and inhibition allocation mediator of leukocyte.

Especially important in this context, the discovery that the dual activity of the compounds of the present invention in relation to the PDE as type III, and type IV leads to a fine regulation of the downside of such cells as basophils and Metacity.

Therefore, the target compounds should be considered as valuable therapeutic agents for warm-blooded animals, in particular humans, suffering from allergic disorders, atopic disease and similar disorders. Examples of allergic diseases include: bronchial is s, urticaria, vasculitis, vulva, examples of these disorders include: dermatitis and eczema, winterfat, asthma, allergic rhinitis and similar disorders include, for example: psoriasis and other hyperproteinemia disease.

Due to their useful properties by inhibition of phosphodiesterase these compounds may be formulated into various pharmaceutical forms for administration. For preparing pharmaceutical preparations of the present invention an effective amount of a particular compound (in the form of a base or salt of acid) as an active ingredient uniformly mixed with a pharmaceutically acceptable carrier, which may take a variety of forms, depending on the intended form of administration. It is desirable to have these drugs in a single dosage form suitable for administration orally, rectally, transdermally, or parenterally by injection. For example, upon receipt of the drugs in the form of oral dosage forms may be used any conventional pharmaceutical environment, such as, for example, water, glycols, oils, alcohols, etc., in the case of oral liquid preparations such as suspensions, syrups, alexievitch, structuring additives, etc. in the case of powders, pills, capsules and tablets. Due to the simplicity of their administration tablets and capsules are the most convenient oral unit dosage forms, for the preparation of which, obviously, use solid pharmaceutical carriers. In the case of parenteral preparations carrier is usually sterile water, at least mostly, but the drug may include other components, for example, increase the solubility. For example, can be prepared injectisome solutions containing as a carrier saline solution, glucose solution or a mixture of saline and glucose solution. Can also be prepared injected suspension, and in this case, use the appropriate liquid carriers, suspendresume funds and similar additives. In preparations suitable for percutaneous administration, the carrier may contain reinforcing the penetration of the tool and/or acceptable wetting agent, possibly in a mixture with small amounts of acceptable additives of any nature, provided that such additives do not have appreciable adverse effects on the skin. Such additives may facilitate the penetration into the skin and/or may have the de transdermal patches, in marked spots or in the form of ointment.

Upon receipt of an aqueous salt drugs target compounds, obviously, more suitable, because of their increased solubility in water.

Or the compounds of formula (I) can be mixed with an acceptable carrier, for example, cyclodextrin (CD) or, in particular, derivatives of cyclodextrin, for example, disclosed in U.S. patent US - 3459731, European patent EP-A-149197 or European patent EP-A-197571. Typically, these derivatives are presented,--of the CD, in which one or more hydroxyl groups substituted WITH1-C6- alkyl, in particular: the stands, ethyl or isopropyl; hydroxy-C1-C6- alkyl, in particular: the hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxy - C1-C6- alkyl, in particular: a carboxymethyl or carboxyethyl; C1-C6- alkylcarboxylic, in particular, acetyl, C1-C6-allyloxycarbonyl-C1-C6-alkyl; carboxy-C1-C6-alkyloxy-C1-C6-alkyl, in particular: carboxyphenoxypropane, carboxitherapy or1-C6-alkylcarboxylic-C1-C6-alkyl, in particular 2-acetylaminophenol. Especially notable in ka is -- CD 2-hydroxypropyl -- CD (2 carboxymethoxy)propyl -- CSD, in particular 2-hydroxypropyl -- CSD. In the above-mentioned derivatives of cyclodextrin Sz (degree of substitution, i.e. the average number of substituted hydroxybenzyl on the link glucose) is preferably 0.125 to 3, in particular, 0.2 to 2 0.2 to 1.5. A more preferred range of values of Sz is 0.2 to 0.7, in particular from 0.35 to 0.5, in particular of 0.4. MOH (molar degree of substitution, i.e. the average number of moles of the substituting agent on the level of glucose) is in the range 0,125-10, in particular from 0.3 to 3 0.3 to 1.5. A more preferred range of values of MH is 0.3 to 0.8, in particular, 0,35/0,5, in particular of 0.4. For use in the preparations of the present invention is especially recommended such cyclodextrin derivatives like hydroxypropyl -- cyclodextrin with a value of MZ in the range of 0.35 to 0.5, containing less than 1.5% unsubstituted - cyclodextrin.

These preparations may be prepared by dissolving the cyclodextrin or its ether derivative in water and adding the target compounds as well as other adjuvants and components, such as, for example: sodium chloride, potassium nitrate, glucose, mannitol, sorbitol, xylitol and buffer mixture, such as, for example: phosphate, acetate or citrate is AI or lyophilization. The amount of cyclodextrin or its ether derivative in the final preparation is typically in the range of 1-40 wt.%, in particular 2.5 to 15%, in particular 5-20%.

Be targeted drugs can, for example, in the form of an aerosol, for example, propellants, such as nitrogen, carbon dioxide, freon or without propellant, for example, pumped by spraying, in the form of drops or in semi-solid state, for example, in the form of thickened drug caused by tampon. When a particular type of application usually will be used semi-solid preparations, for example, in the form of healing ointments, creams, jellies, pastes, etc.

Particularly beneficial preparation of the abovementioned pharmaceutical preparations in dosage unit forms, to facilitate their introduction and unifying the dosage. Dosage unit form refers to a physically discrete unit suitable as a single dose, with each unit contains a given number of the active component, designed to create a target therapeutic effect, in a mixture with the required pharmaceutical carrier. Examples of such dosage unit forms include tablets (including the dashed pills and tablets with coating the governmental form.

Because these compounds are suitable for treatment of allergic and atopic diseases, it may be used to treat, so a method of treating warm-blooded animals suffering from allergic and atopic diseases. This method is the systematic introduction of the animal a pharmaceutically effective amount of the compounds of formula (I) or its pharmaceutically acceptable salt in a mixture with a pharmaceutical carrier. Specialist in the treatment of allergic and atopic diseases on the basis of the results presented here can easily determine the effective daily amount. In General, the daily effective amount will be ranges from 0.01 mg/kg of body weight up to 4 mg/kg body weight, more preferably from 0.04 mg/kg of body weight up to 2 mg/kg of body weight.

It is obvious that the effective daily amount may be reduced or increased depending on the reaction being treated object and/or considerations of physician prescribing the compounds of the present invention. Thus, the above intervals daily effective amounts can only serve as a General guide and not intended to limit about is to limit the scope of the present invention.

Experimental part

A. the production of intermediate compounds

Example 1.

a) a Mixture of 114.5 g hydrosulfite sodium and 500 ml of water is stirred for 15 min at room temperature. After cooling in a bath with ice to 5oC added dropwise 100 g of 2-methoxybenzaldehyde, stirred for 15 min and add the 95.8 g of the research. Then add a solution of 39.2 g of sodium cyanide in 100 ml of water and the mixture is stirred for 24 hours at 50oC. the Product is extracted with dichloromethane and the extract is dried, filtered and evaporated. Joint evaporation residue with methylbenzol get 168,2 g (99,2%) - (3-methoxyphenyl)-4-morpholinosydnonimine (prom. Conn. 1).

b) To a stirred mixture of 35 g of sodium hydride in 1000 ml of N, N - dimethylformamide under nitrogen atmosphere was added dropwise a solution of 168,2 g of the intermediate compound (1) in 250 ml of N, N - dimethylformamide and stirring is continued for 3 hours. At 10oC added dropwise a solution of 152,9 g of 3-chloro-2-(dimethoxymethyl)-1-nitrobenzene (obtained as described in 1 655 1 693) in 250 ml of N, N - dimethylformamide. The mixture is stirred for 1 hour at 10oC and about a day at room temperature. The reaction mixture was transferred into ice water and the product extracted with dichloromethane. The extract is dried, the filter is a layer to separate, dried, filtered and evaporated. Washing of the residue with hexane (3 times) get 294,6 g (100%) - 3-dimethoxymethyl)-4-nitrophenyl -- (4-methoxyphenyl)-4-morpholinosydnonimine (prom. Conn. 2).

Similarly obtained also:

- /3-(dimethoxymethyl)-4-nitrophenyl -- (4-forfinal)-4-morpholinylmethyl (prom. Conn. 3);

- /3-(dimethoxymethyl)-4-nitrophenyl/ -- (3,4-acid)-4 - morpholinylmethyl (prom. Conn. 4) and

- /3-(dimethoxymethyl)-4-nitrophenyl -- (4-were)-4-morpholinylmethyl (prom. Conn. 5).

(C) To a stirred mixture of 1200 ml of 2-propanol saturated with NS, and 500 ml of water are added dropwise a solution of 294,6 g of the intermediate compound (2) in 700 ml of 1,4-dioxane. The stirring is continued for 20 hours at boiling temperature. After cooling, the reaction mixture is evaporated and the residue is stirred in water. The entire mixture is neutralized NH4OH and the product is extracted with dichloromethane. The extract is dried, filtered and evaporated. The residue is purified column chromatography (silica gel, CH2Cl2). Eluent target fraction is evaporated and the residue successively stirred in diisopropyl ether and recrystallized from 2-propanol. The product is filtered, washed with diisopropyl ether and after drying are also obtained:

5-(4-perbenzoic)-2-nitrobenzaldehyde, so pl. of 105.2oC (prom. Conn. 7);

5-(3,4-dimethoxybenzoyl)-2-nitrobenzaldehyde, so pl. 169,4oC (prom. Conn. 8) and 5-(4-methylbenzoyl)-2-nitrobenzaldehyde, so pl. 131,7oC (prom. Conn. 9)

Example 2.

a) a Solution of 91 g of the intermediate compound (24), to 41.6 ml trimethoxymethane, to 9.9 ml of sulfuric acid, 0.66 g of 4-methylbenzenesulfonate, 1000 ml of methanol and 50 ml of 2,2-dimethoxypropane boil for about a day. The cooled reaction mixture is transferred into a mixture of 53 g of Na2CO3in methanol with simultaneous stirring and cooling. The entire mixture is filtered and the residue rinsed with dichloromethane. The combined filtrates evaporated and the residue partitioned between water and dichloromethane. The organic layer is separated, dried, filtered and evaporated to obtain 106 g (38,8%) /3-(dimethoxymethyl)-4-nitrophenyl/-(3-pyridinyl) methanone (prom. Conn. 10).

b) To a mixture of 106 g of the intermediate compound (10), 700 ml of pyridine and 36.9 g of sodium bicarbonate add 29,26 g monohydrochloride hydroxylamine. The mixture is heated to about the day when 80-90oC and then evaporated. The residue is evaporated together with ethanol (3 times) and then partitioned between water and dichloromethane. The formed precipitate is sucked off the t and evaporated to obtain a third fraction of the product (27 g). The second and third fractions of the product are combined and recrystallized from acetonitrile. The product is filtered, washed with acetonitrile and after drying in vacuum at 50-60oC get to 44.7 g (40,1%) (E/Z 85:15)- /3-(dimethoxymethyl)-4-nitrophenyl/ (3-pyridinyl)methanone, oxime (prom. Conn. II). The first product fraction is transferred into a mixture of methanol with dichloromethane (90:10). The resulting solution was washed with water, dried, filtered and evaporated. By recrystallization of the residue from acetonitrile obtain 10.6 g (9,5%) of (Z) -/3-(dimethoxymethyl)-4 - nitrophenyl/ (3-pyridinyl)methanone, and oxime, so pl. 183,6oC (prom. Conn. 12).

(C) a Mixture of 177 g of the intermediate compound (II), 400 ml of 2 N. hydrochloric acid and 400 ml of 2-propanol is stirred for approximately day 50oC. After cooling, the precipitate (HCI salt of Z - isomer) is filtered off and the filtrate evaporated. The residue is stirred in water, filtered and after drying gain of 18.1 g (10,5%) (E)-5-/(hydroxyimino)(3-pyridinyl) methyl/-2-1-nitrobenzaldehyde, monohydrochloride, so pl. 230,6oC (prom. Conn. 13).

Similarly obtained also:

ethyl ester of (Z)-5-///(3-formyl-4-nitrophenyl)(3-pyridinyl)methylen/amino/hydroxy/ pentanol acid (prom. Conn. 14).

d) To a mixture of 13.5 g of the intermediate compound (13) in 150 ml VOUT water and drying in vacuum at 60oC get of 11.15 g (93,6%) (E)-5-/(hydroxyimino) (3-pyridinyl)methyl/-2-nitrobenzaldehyde (prom. Conn. 15).

e) To mix the solution to 9.15 g of the intermediate compound (15) in 100 ml of methanol and 35.3 ml of 1 n sodium hydroxide added 0.45 g of sodium borohydride. Stirring is continued at room temperature until completion of the reaction, after which add 2.67 g of ammonium chloride. After 15 min the reaction mixture was evaporated and the residue is stirred in water. The product is filtered, washed with water and dried in vacuum at 60oC gain of 8.75 g (0,7%) of the oxime (E)-/3-(hydroxymethyl)-4-nitrophenyl/(3-pyridinyl)methanone (prom. Conn. 16).

f) To a stirred solution of 8.75 g of the intermediate compound (16) in 150 ml of N, N - dimethylformamide add portions of 1.33 g of sodium hydride and after 10 min added dropwise a solution of 5.4 ml of ethyl ether 5-bromopentanoate acid in 20 ml of N,N-dimethylformamide. The mixture is stirred for about a day at room temperature and then concentrated. The residue is transferred into a mixture of water (+NaCI) with dichloromethane. The product is extracted with dichloromethane and the extract is dried, filtered and evaporated. The residue is purified column chromatography (silica gel, CH2CI2/C2H5OH 97:3). Eluent target fractional)- 4-nitrophenyl/(3-pyridinyl)methylen/amino/hydroxy/pentanol acid (prom. Conn. 17).

Similarly obtained also:

ethyl ester of (E)-2-////3-(hydroxymethyl)-4-nitrophenyl/methylene/ amino /hydroxy/acetic acid, so pl. of 112.8oC (prom. Conn. 18);

ethyl ester of (Z)-5-////3-(dimethoxymethyl)-4-nitrophenyl-/- (3-pyridinyl)methylen/amino/hydroxy/pentanol acid (prom. Conn. 19);

(E)-1-(cyclohexylmethyl)-4-/////3-(hydroxymethyl)-4-nitrophenyl/ methylene/amino/hydroxy/acetyl/piperazine, so pl. 185oC (prom. Conn. 54) and

(E)-11-cyclohexyl-2-////3-(hydroxymethyl)-4-nitrophenyl/- methylene/amino/hydroxy/-11-methylacetamide, so pl. 169, 5mmoC (prom. Conn. 58).

Example 3.

Column chromatography (MicroPrep Si60, CH2CI2CH3OH to 98.5 : 1.5) are 86,2 g (E + Z)-N-cyclohexyl-2-////3- (hydroxymethyl)-4-nitrophenyl/phenylmethyl/amino/hydroxy/-N methylacetamide (obtained by the method of patent application U.S. N 529826) share on its E - and Z-isomer. Eluent first fraction is evaporated and the residue is recrystallized from 2-propanol. The product is filtered, washed with 2-propanol and hexane, and after drying obtain 30.5 g (35.8 per cent) (Z) - isomer, so pl. 153,8oC (prom. Conn. 20). Evaporation of eluent second faction gain of 25.9 g (30.4 per cent) (E)-isomer (prom. Conn. 21).

Example 4.

a) To a solution of 241,3 g of potassium hydroxide in 1400 ml of meth is for 1.5 hours at room temperature, the reaction mixture was concentrated. To the residue add some water and 300 g of acetic acid. The precipitate is filtered off, boiled in dichloromethane and optionally purified column chromatography (silica gel, CHCl3/CH3OH 90:10). Eluent target fraction is evaporated and the residue crystallized from a mixture of acetonitrile with methanol. After evaporation of methanol, the product was filtered, washed with diisopropyl ether and drying get to 67.9 g (25,9%) of (E+Z) - - /4- (hydroxyimino)-3-(hydroxymethyl) 2,5 - cyclohexadienone/-3-pyridine of clonicel, hemihydrate, so pl. 199,7oC (prom. Conn. 22).

b) To a solution of 982 g of potassium hydroxide in 5140 ml of water is added 164, 8mm g of the intermediate compound (22) and then added dropwise a solution of 988,8 ml of hydrogen peroxide in 2400 ml of water. After stirring for 3 hours the precipitate is filtered and washed successively with water, 2-propanol and diisopropyl ether. The product was then purified column chromatography (silica gel, CHCl3/CH3IT is 90:10). Eluent target fraction is evaporated and the residue crystallized from a mixture of acetonitrile with methanol. The product is filtered and after drying receive 53,4 g (31,8%) /3-(hydroxymethyl)-4-nitrophenyl/(3-pyridinyl)methanone, so pl. 184,3oC (prom. Conn. 23).

(C) To a solution of 18 g of intermediate soedinenie day at room temperature the mixture is filtered through diatomaceous earth. The filtrate is again stirred for about a day with the new portion 60 g of manganese oxide (IV) and then boil for 2 weeks. The reaction mixture is filtered through diatomaceous earth and the filtrate concentrated. The residue is twice purified column chromatography (silica gel, CH2CI2/CH3OH 98:2). Evaporation of the eluent of the first and second fractions gain of 13.4 g (74,7%) of 2-nitro-5-(3 - pyridylcarbonyl)benzaldehyde (prom. Conn. 24).

Similarly obtained also:

(Z)-N-cyclohexyl-2-//(3-formyl-4-nitrophenyl)phenylmethylene /amino/hydroxy/-N-methylacetamide (prom. Conn. 25);

(E)-N-cyclohexyl-2-///(3-formyl-4-nitrophenyl)phenylmethylene /amino/ hydroxy/-N-methylacetamide (prom. Conn. 26);

ethyl ester of (E)-2-///(3-formyl-4-nitrophenyl)methylene/amino/ hydroxy/acetic acid, so pl. 105oC (prom. Conn. 27) and ethyl ether (E)-5-///(3-formyl-4-nitrophenyl)(3-pyridinyl)-methylene/amino/ hydroxy/pentanol acid (prom. Conn. 28).

d) a Solution of ethiopiaid (0,042 mole) is stirred in a stream of N2in dichloromethane (20 ml) cooled to -70oC (bath 2-propanol /CO2). Added dropwise a solution of dimethylsulfoxide (of 0.066 mol) in dichloromethane (7 ml). The mixture is diluted with dichloromethane (80 ml). Added in several portions of the intermediate compound (54) (0,0215 elatonin (0,128 mol). The reaction mixture was left to warm to room temperature. Then the reaction mixture is washed once with water and twice with an aqueous solution NaOCI. The organic layer is separated, dried (MgSO4), filtered and the solvent evaporated. To the residue is added toluene, and after re-evaporation of the solvent get 11.7 g (100%) of (E)-1-(cyclohexylmethyl) -4-////(3-formyl-4-nitrophenyl)methylene/amino/ hydroxy/acetyl/piperazine (prom. Conn. 55).

Similarly obtained:

(E)-N-cyclohexyl-2 -///(3-formyl-4-nitrophenyl)methylene/amino/ hydroxy/-N-methylacetamide (prom. Conn. 59).

e) To a stirred solution of 0.73 g of sodium in 200 ml ethanol add 7,49 g diethyl-2,5-dioxoimidazolidin-4-phosphate and after 5 min a solution of 7.4 g of the intermediate compound (24) in a mixture of 60 ml of ethanol and 90 ml of dichloromethane. Stirring at room temperature continued for 0.5 hours. The reaction mixture is evaporated and the residue is stirred in water. The product is filtered, washed with water and after drying in vacuum at 60-80oC get of 6.65 g (66,2%) of (E+Z)-5-//2-nitro-5-(3-pyridylcarbonyl)phenyl/methylene/-2,4 - imidazolidinedione hemihydrate, so pl. 199,4oC (prom. Conn. 29).

Listed in table 1 of the intermediate obtained in a similar way.

Similarly obtained also:

ethyl ether /5/Z 3(E+Z)//-5-////4-amino-3-/(2.5 dioxo-4 - imidazolidinyl)methyl/phenyl/(3-pyridinyl)methylen/amino/-oxy/ pentanol acid (prom. Conn. 42);

2/Z 3(E)//-2-////(4-amino-3-/(2.5 dioxo-4-imidazolidinyl) methyl/phenyl/phenylmethylene/amino/hydroxy/-N-cyclohexyl-N-methylacetamide (prom. Conn. 43);

ethyl ether /2/E, (E+Z)//-2-////4-amino-3-/(2.5 dioxo-4-imidazo - linenlinen)methyl/phenyl/methylene/amino/hydroxy/acetic acid (prom. Conn. 44) and

ethyl ether /5/E, 3(E+Z)//-5-////4-amino-3-/(2.5 dioxo-4 - imidazolidinyl)methyl/phenyl/(3-pyridinyl)methylen/amino/hydroxy/ pentanol acid (prom. Conn. 45).

Example 5.

A mixture of 11.9 g of the intermediate compound (30), 2 ml of a solution of thiophene in methanol (4%) and 250 ml of 2-methoxyethanol hydronaut about a day at normal pressure and room temperature in the presence of 3 g of 5% plates on charcoal as catalyst. After absorption of the calculated amount of hydrogen ka is up in diisopropyl ether. The product is filtered, washed with diisopropyl ether and after drying in vacuum at 80oC obtain 10.8 g (99,6%) of (E+Z)-5-/(2-amino-5-benzoylphenyl) methylene/-2,4-imidazolidinedione (prom. Conn. 46).

Similarly obtained also:

(E+Z)-5-//2-amino-5-(3-methoxybenzoyl)phenyl/methylene/-2,4 - imidazolidinedione (prom. Conn. 47).

In a similar way, but using the solvent methanol is obtained as well:

-2E, (E+Z)/-1-/////4-amino-3-/(2.5 dioxo-4-imidazolidinyl) methyl/phenyl/methylene/amino/hydroxy/acetyl/-4-(cyclohexyl)piperazine (prom. Conn. 57).

In a similar way, but using as the solvent tetrahydrofuran (THF) received:

/2E, (E+Z)/-2-////4-amino-3-/(2.5 dioxo-4-imidazolidinyl) methyl/phenyl/methylene/amino/hydroxy/-N-cyclohexyl-N-methylacetamide (prom Conn. 61).

Example 6.

A mixture of 9.8 g of the intermediate compound (46) and 300 ml of 2-methoxy - ethanol hydronaut 3 days at normal pressure and room temperature in the presence as catalyst of 4 g of 5% platinum on charcoal. The catalyst is filtered off and the filtrate evaporated. The residue is evaporated together with methylbenzol to obtain 9.4 g(95,3%) 5-/(2-amino-5-benzoylphenyl)methyl/-2,4-imidazolidinedione (prom. Conn. igintion (prom. Conn. 49).

Example 7.

A mixture of 8.5 g of the intermediate compound (33), 4.94 g of iron powder, to 4.73 g of ammonium chloride, 150 ml of ethanol, 75 ml of water and 100 ml of tetrahydrofuran boil until the complete disappearance of intermediate compounds. The reaction mixture was filtered hot through diatomaceous earth. The filtrate is evaporated and the residue is transferred into a 250 ml mixture of methanol with dichloromethane (10:90). The precipitate is filtered and washed with a mixture of methanol with dichloromethane. The combined filtrate is filtered through diatomaceous earth, and then washed with water (+NaCl), dried, filtered and evaporation obtain 7.9 g (98,8%) of ethyl ether /5/ (E+Z)//-5-////4-amino-3-/(2.5 dioxo-4-imidazolidinyl/methyl/ phenyl/ (3-pyridinyl)methylen/-amino/hydroxy/pentanol acid (prom. Conn. 50).

Similarly obtained also:

/2/E, 3(E+Z)//-2-////4-amino-3-/(2.5 dioxo-4 - imidazolidinyl)methyl/phenyl/phenylmethylene/amino/hydroxy/-N-cyclohexyl-N-methylacetamide (prom. Conn. 51).

Example 8.

A mixture of 5.3 g of the intermediate compound (38) and 250 ml of 2-methoxy - ethanol hydronaut at normal pressure and room temperature in the presence as catalyst, 2 g of 5% platinum on charcoal. After some time, the catalyst otherthenthat evaporated. Joint evaporation residue with methylbenzol get 5 g(100%) 5-//2-amino-5-(4-perbenzoic)phenyl/methyl/-2,4-imidazolidinedione (prom. Conn. 52).

Similarly obtained also:

5-//2-amino-5-(4-methylbenzoyl)phenyl/methyl/-2,4-imidazolidinedione.

C. obtain the final compounds

Example 9.

A solution of 9.4 g of the intermediate compound (48), 7.6 g of 4-methylben - zolsulphonate and 90 ml of dimethyl sulfoxide is heated for 0.5 hours at 150-160oC. Then the reaction mixture is transferred into 600 ml of ice water. The product is filtered off and stirred in an aqueous solution of NaHCO3. The product is filtered two fractions respectively 6.25 g and 0.28 g combined fractions purified column chromatography (HPLC-aminopropyl, CH2CI2/CH3OH 95:5). Eluent third and fourth fraction is evaporated and the residue is transferred into a mixture of methanol with water. With stirring, add 1 N. NaOH and everything boil for a few minutes with activated carbon. The mixture is filtered hot through diatomaceous earth. To the filtrate with stirring, add 1 N. HCl. The residue is filtered off, washed successively with a mixture of methanol water (1:1), water, methanol and diisopropyl ether, and after drying in vacuum at 70-80°C receive the m obtained:

7-(3,4-dimethoxybenzoyl)-1,3-dihydro-2H-imidazo/4,5-b/quinoline-2 - it, so pl. > 300oC (Conn. 2);

7-(4-perbenzoic)-1,3-dihydro-2H-imidazo/4,5-b/quinoline-2-it, so pl. > 300oC (Conn. 3) and

1,3-dihydro-7-(4-methylbenzoyl)-2H-imidazo/4,5-b/quinoline-2-it, so pl. > 300oC (Conn. 4).

Example 10.

The mixture 5,23 g of the intermediate compound (41), 6.4 g of 4-methylbenzenesulfonate and 100 ml of dimethylsulfoxide is heated for 40 min at 150oC. the Reaction mixture is transferred into ice-cold water and with stirring, added dropwise 10% solution of NaHCO3to pH 5. The precipitate is filtered off, washed with water three times and boiled in a mixture of ethyl acetate with methanol (1:1) (respectively 100 ml, 75 ml and 50 ml). Each time the product is filtered while hot and washed with a mixture of ethyl acetate with methanol and diisopropyl ether. The product is then transferred into a mixture of 50 ml of methanol and 20 ml of water. Mix in full boil with 300 mg of activated charcoal. The mixture is hot filtered through diatomaceous earth and the cooled filtrate with stirring, add 10 ml of 1 N. HCl. The precipitate is filtered off, washed successively with a mixture of water with methanol (1: 1) water, methanol and diisopropyl ether, and after drying in vacuum at 70-80oC get 0,63ptx2">

Compounds shown in table 2, obtained in a similar way.

In a similar way, but using 1-/(4-were - sulfonyl/pyridinium received:

(E)-1-(cyclohexylmethyl)-4-////(2,3-dihydro-2-oxo-1H-imidazo /4,5-b/ quinoline-7-yl)methylene/amino/hydroxy/acetyl/piperazine monohydrate, so pl. > 260oC (Conn. 15) and

(E)-B1-cyclohexyl-2-///(2,3-dihydro-2-oxo-1H-imidazo/4,5-b/- quinoline-7-yl)methylene/amino/hydroxy/-M-methylacetamide hemihydrate, so pl. 263,4oC (Conn. 16).

Example 11.

A mixture of 0.99 g of compound (6) and 6 ml of 1 n sodium hydroxide is stirred for 2.5 hours at room temperature. Then to the reaction mixture add 10 ml of 1 N. HCl. The precipitate is filtered off, washed with water and boiled in methanol. The product is filtered, washed with methanol and vicoprofen ether and after drying in vacuum at 80oC obtain 0.7 g (75,1%) (Z) -5-///(2,3-dihydro-2-oxo-1H - imidazo/4,5-b/quinoline-7-yl)(3-pyridinyl)methylen/amino/hydroxy/pentane acid, so pl. > 300oC (decomp.) (Conn. 13).

Similarly obtained also:

(E+Z)-5-///(2,3-dihydro-2-oxo-1H-imidazo/4,5-b/quinoline-7-yl( (3-pyridinyl)methylen/amino/hydroxy/pentanol acid monohydrate, so pl. 233,5oC (Conn. 14).

(C) Pharmacological examples.

Example 12.

The inhibition of phosphodiesterase type III (PDE III).

Encubierta mixture (pH of 7.1 (200 μl) contains 40 mm Tris, 3.75 mm 2-mercaptoethanol, 6 mm magnesium chloride, 1.2 µm3H-camp (310 MCi/mmol) and phosphodiesterase type III, the number of which depends on the enzymatic activity. The concentration of protein is picked such that the activity of phosphodiesterase increases linearly during the incubation period of 10 minutes at 37oC.

When identifying the effects of various compounds on the activity of phosphodiesterase containing no camp Wednesday, incubated 5 min with connection(s) or its vehicle (DMSO, final concentration 1%). The enzymatic reaction start by adding a3H-camp and stopped 10 min later by keeping the tubes 40 sec in a water bath at 100oC. After cooling to room temperature, add alkaline phosphatase (0.25 microgram/ml) and the mixture is left for 20 min at room temperature. The mixture is then applied Pasteur pipette AI in the eluate determine quantitatively liquid scintillation counter.

The inhibitory activity of the compounds of the present invention on phosphodiesterase PDE III canine and human hearts is determined at various concentrations of compounds. Based on the obtained values of inhibition graphically count value IR50. Table 3 shows the values obtained IR50compounds of the present invention to PDE III canine and human hearts.

Example 13. The inhibition of phosphodiesterase type IV from human managernew lymphocytes (KNEADING)

Human blood obtained from donors suffering from earlier, as the documentary shows, allergic or atopic disease. By venipuncture of the umbilical vein are selected 35 ml of blood and collected in 5 ml 100 mm TO2Add (pH of 7.1). Add 4 ml of 0.6% dextran in saline solution and the mixture is left for 30 min at room temperature. Collect does not contain red blood cells supernatant, gently rasclaat on Lymphoprep solution and centrifuged 15 min at 18oC and 750 q. The interphase is separated, diluted with buffer containing 137 M NaCI, 50 mm KS1 and 100 mm HEPES (pH 7.4), and centrifuged 10 min at 10oC and 900 q. The precipitate is again suspended in the same buffer.

Suspension RUMPLED set is I, the suspension is homogenized at 40oC homogenizer (PT-DA 3020/2 TS ) brand Polytron RTOO (Kinematics AG), operating at 8000 rpm 5x10 sec, followed by treatment at 4oC in the ultrasonic Brunson 250 operating at an output frequency of 20000 Hz, the operating power of 40 W, for 10x30 sec. The homogenate was centrifuged 10 min at 10000 q. The obtained supernatant used as a source for determining the activity of PDE IV. The incubation mixture (pH of 7.1) (200 μl) contains 40 mm Tris, 3.75 mm 2-mercaptoethanol, 6 mm magnesium chloride, 1.2 µm3H-camp (310 MCI/mmol) and phosphodiesterase type IV, the number of which is determined by enzymatic activity. The concentration of protein is picked such that the phosphodiesterase activity during incubation for 10 minutes at 37oC increases linearly and in which less than 10% of the original substrate is hydrolyzed. To block the degradation activity of PDE III activity of PDE IV is determined in the presence of 10-4M cGMP.

When identifying the effect of various compounds on the activity of phosphodiesterase containing no camp Wednesday, incubated 5 min with compound (s) or its vehicle (DMSO, final concentration 1%). The enzymatic reaction start by adding a3-camp and stop SDA is ry add alkaline phosphatase (0.25 microgram/ml) and the mixture is left for 20 min at room temperature. After that, the mixture is transferred Pasteur pipette column with 1 ml DEAE-Sephadex A-25 and washed twice in 3 ml of 20 mm Tris-NC (pH 7,4).3H-labeled reaction products in the eluate determine quantitatively liquid scintillation counter.

The inhibitory activity of the compounds of the present invention on the human phosphodiesterase managernew lymphocytes (PDE IV) determined at various concentrations of compounds. Based on the resulting values of inhibition graphically calculated values IR50. Table 4 shows the values obtained IR50compounds of the present invention to PDE human managernew lymphocytes.

D) Examples of drugs

The following compounds are typical examples of pharmaceutical preparations in dosage unit form suitable for systemic introduction of animals and man in accordance with the present invention.

"Active component" (A. K.) is used in the examples means a compound of formula (I), its pharmaceutically acceptable salt or its stereoisomeric form.

Example 14. Oral drops

In 0.5 l of 2-hydroxypropanoic acid and 1.5 l of the polyethylene glycol restorereplica. Then add a solution of 1750 l saccharin sodium 2.5 l of purified water and while stirring add 2.5 l of cocoa corrigenda and polyethylene glycol in an amount necessary to bring the volume to 50 L. the result is a solution, oral drops containing 10 mg/ml A. K. the resulting solution fill in the appropriate container.

Example 15. Oral solution.

In 4 l of boiling purified water dissolve 9 g of methyl ester of 4-hydroxybenzoic acid and 1 g of propyl ester of 4-hydroxybenzoic acid. In 3 l of the resulting solution is first dissolved 10 g of 2,3-dihydroxybutanedioate acid, and then 20 g A. K. Last solution is mixed with the remaining part of the first solution and added to the mixture 12 l 1,2,3-propanetriol and 3 l of 70% solution of sorbitol. 0.5 l of water dissolve 40 g of saccharin sodium and to the solution add 2 ml of raspberry and 2 ml of gooseberry family essences. The last solution is mixed with the first and add water in an amount necessary to bring the volume to 20 L. the result is an oral solution containing 5 mg A. K. teaspoon (5 ml). The resulting solution fill in the appropriate containers.

Example 16. The capsule.

Intensively stirred for 20 g A. the scientists mixture then fill 1000 suitable hard gelatin capsules, each of which contains 20 mg A. K.

Example 17. The tablets are film-coated.

Receiving the Central part of the tablet.

A mixture of 100 g A. K., 570 g lactose and 200 g starch are thoroughly mixed, then moistened with a solution of 5 g sodium dodecyl sulfate and 10 g polyvinylpyrrolidone (Kollidon-90) in 200 ml of water. Wet powder mixture is sieved, dried, and sift again. Then add 100 g microcrystalline cellulose (Avicel) and 15 g hydrogenated vegetable oil (Sarotex). All are thoroughly mixed and pressed into tablets. The result of 10,000 tablets, each containing 10 mg of the active component.

Coating

To a solution of 10 g methyl cellulose (Methocel 60 HC) in 75 ml of denatured ethanol is added a solution of 5 g of ethyl cellulose (Ethocel 22 SDR) in 150 ml of dichloromethane. Then add 75 ml of dichloromethane and 2.5 ml 1,2,3-propantriol. Melt 10 g of polyethylene glycol and dissolved in 75 ml of dichloromethane. The last solution is added to the first, and then add 2.5 g of octadecanoate magnesium, 5 g of polyvinylpyrrolidone and 30 ml of concentrated suspensions of the dye (Opaspray K-1-ut mixture.

Example 18. Injectable solution.

Approximately 0.5 l of boiling water for injection is dissolved 1.8 g of methyl ester of 4-hydroxybenzoic acid and 0.2 g of propyl ester of 4-hydroxybenzoic acid. After cooling to approximately the 50oC with stirring 4 g lactic acid, 0.05 grams propylene glycol and 4 g A. K. the Solution is cooled to room temperature and added water for injection in an amount necessary to bring the volume to 1 L. the result is a solution containing 4 mg/ml A. K. the Solution is sterilized by filtration (U. S. P. XVII, page 811), after which a solution of fill with sterile container.

Example 19. Suppository.

In the solution of 3 g of 2,3-dihydroxybutanedioate acid in 25 ml of polyethylene glycol 400 dissolve 3 g A. K. a common melt 12 g of surfactant (Span) and triglycerides (Vicenza 555in the quantity necessary to obtain a total mass of 300 g of the Obtained melt is thoroughly mixed with the first solution. The resulting mixture at a temperature of 37-38oC fill in the form with receipt 100 suppositories each containing 30 mg of the active component.

Example 20. 2% cream.

Example 21. 2% gel for application topically.

To a solution of 200 mg of hydroxypropyl -- cyclodextrin in purified water with stirring, add 20 mg A. K. Add hydrochloric acid until dissolved and then add the sodium hydroxide to pH 6. The resulting solution was added with stirring to a dispersion of 10 mg carrageenan P1 50 mg of propylene glycol. The mixture with slow stirring, heated to 50oC and then allowed to cool to approximately 35oC with the simultaneous addition of 50 mg of ethyl alcohol (95 vol.%/vol.). Add the remaining quantity of purified water to a total weight of 1 g and the mixture is stirred until homogeneous.

Example 22. 2% cream topically is added 20 mg A. K. Add hydrochloric acid until dissolved and then add the sodium hydroxide to pH 6. With stirring, add 50 mg of glycerol and 35 mg of Polysorbate 60 and the mixture is heated to 70oC. the resulting mixture with slow stirring add to the mixture of 100 mg of mineral oil, 20 mg stearyl alcohol, 20 mg of cetyl alcohol, 20 mg glycerol monostearate and 15 mg sorbate 60 heated to 70oC. After cooling to a temperature below the 25oC add the remaining quantity of purified water to the total mass of 1 g and the mixture is stirred until homogeneous.

Example 23. 2% liposomal composition.

A mixture of 2 g A. K. in the form of microparticles, 20 g of phosphatidylcholine, 5 g of cholesterol and 10 g of ethyl alcohol was stirred with heating at 55-60oC until dissolved and added with stirring to a solution of 0.2 g of methylparaben, 0.02 g of propyl paraben, 0.15 g of diacrylate and 0.3 g of sodium chloride in purified water. Add 0.15 g hydroxypropylmethylcellulose in purified water to a total mass of 100 g and stirring is continued until complete swelling.

Example 24. 2% liposomal composition. A mixture of 10 g of phosphatidylcholine and 1 g cholesterol 7.5 ethanol is stirred with heating at 40oC to oC. Alcohol solution with stirring slowly for 10 minutes is added to aqueous solution. Add 1.5 g of the hypromellose in purified water under stirring until complete swelling. The addition of 1 n sodium hydroxide in the resulting solution set pH 5 and the solution is diluted with the remaining amount of purified water to total mass in 100 g

Example 25. The aerosol.

a) To a solution of 0.1 g of hydroxypropyl -- cyclodextrin (MOH = 0,43) in 0.7 ml of distilled water add 730 µg in 0.1 n hydrochloric acid solution and 2.5 mg A. K. After stirring 10 minutes at room temperature the resulting solution by the addition of 0.1 n sodium hydroxide solution set pH 5.5. Then add 4 mg of sodium chloride and 0.15 mg acetate finalstate and the mixture is stirred until complete dissolution. Add distilled water to a volume of 1 ml of the Obtained fill a glass bottle, closed with a mechanical supercharger, a feed of 0.1 ml per injection.

b) To a solution of 0.1 g of dimethyl -- cyclodextrin in 0.7 ml of distilled water add 600 mcg of 0.1 n hydrochloric acid solution and 2 mg A. K. After stirring 10 minutes at room temperature in a mixture dissolve 10 mg polyphenylenevinylene add 4 mg of sodium chloride and 2 mg of phenethyl alcohol and the mixture is stirred until complete dissolution. Add distilled water to the full volume of 1 ml and the resulting fill a glass bottle, closed with a mechanical supercharger, a feed of 0.1 ml per injection.

1. Derived 1,3-dihydro-2H-imidazo/4,5-b/-quinoline-2-it General formula I

< / BR>
where R is hydrogen, phenyl, possibly substituted by 1 to 3 substituents, each of which is independently selected from halogen, C1- C6-alkyl or C1- C6-alkoxy; pyridinyl; group

is a radical of the formula

< / BR>
where R1- C1- C6-alkyl, possibly substituted by COOH, SOOS1- C4the alkyl or CONR3R4, R3- C1- C4-alkyl, R4- C3- C7-cycloalkyl or R3and R4together with the nitrogen atom to which they are attached, may form piperazinonyl cycle, and piperidinyloxy cycle possibly substituted at the nitrogen atom of C1- C4-alkyl or (C3- C7-cycloalkyl)- C1- C4-alkyl,

or its pharmaceutically acceptable salt, or its stereoisomeric forms.

2. Connection on p. 1, where R is hydrogen, phenyl, possibly substituted by 1 or 2 substituents, each of which is independently selected from halogen, C1- tx2">

3. Connection on p. 2, where R is hydrogen, phenyl, possibly substituted by 1 or 2 substituents, each of which is independently selected from fluorine, chlorine, bromine, metoxygroup or methyl, pyridinyl and the group represents a radical of formula (a) or (b), where R1- C1- C4-alkyl, possibly substituted by a COOH group, SOOS1- C4the alkyl or CONR3R4.

4. Connection on p. 3, where R is hydrogen or phenyl, possibly substituted by 1 or 2 substituents, each of which is independently selected from fluorine, metoxygroup or methyl, and the group represents a radical of formula (a) or (b), where R1- C1- C4-alkyl, possibly substituted by COOH, COOC2H5, CON(CH3) (cyclo C6H11or

< / BR>
5. Connection on p. 1, selected from the group of (E)-N-cyclohexyl-2-///(2,3-dihydro-2-oxo-1H-imidazo/4,5-b/-quinoline-7-yl)phenyl-methylene/amino/hydroxy/-N methylacetamide; 7-benzoyl-1,3-dihydro-2H-imidazo(4,5-b)quinoline-2-it; (E)-1-(cyclohexylmethyl)-4-////(2,3-dihydro-2-oxo-1H-imidazo/4,5-b)quinoline-7-yl/methylene/amino/hydroxy/acetyl/piperazine or (E)-N-cyclohexyl-2-///(2,3-dihydro-2-oxo-1H-imidazo/4,5-b/-quinoline-7-yl/methylene/amino/hydroxy-N-methylacetamide.

6. The compound according to any one of paragraphs.1 - 5 phosphodiesterase inhibitor.


< / BR>
where R and group are set to p. 1,

in a solvent and in the presence of acid.

8. The method of obtaining the compounds I according to any one of paragraphs.1 to 5, namely, that carry out the cyclization and aromatization of the intermediate compounds of formula III

< / BR>
where R and is defined in paragraph 1,

in the solvent, which also serves as the oxidant in the process of aromatization, and in the presence of acid.

9. The compound of General formula II

< / BR>
or salts thereof, or stereoisomeric forms,

where R and group are set to p. 1.

10. The compound of General formula III

< / BR>
or salts thereof, or stereoisomeric forms,

where R and group are set to p. 1.

11. The pharmaceutical composition inhibiting phosphodiesterase, including derived imidazo(4,5-b)quinoline-2-she and a carrier, wherein the active means it contains a compound of formula I under item 1 in an effective amount.

12. A method of obtaining a pharmaceutical composition by mixing the ingredient with the carrier, wherein the carrier is mixed as an ingredient connection PP.1 - 5.

 

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