4-aminopyridines and pharmaceutical composition

 

(57) Abstract:

The invention relates to new 4-aminopyridine General formula I

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in which R1denotes a group R6-SO2-NR7-; R6-NR7-SO2-; R6-SO2-O-; R6-O-SO2-;

R2denotes a hydrogen atom or halogen, cyano, alkyl, CNS or halogenation group;

X denotes an oxygen atom, a sulfur atom or NH group;

R3and R4are identical or different and denote hydrogen atoms or alkyl groups;

R5denotes a hydrogen atom, alkyl group or aracelio group;

R6denotes alkyl, cycloalkyl, aryl, heteroaryl, aracelio or heteroallyl group, with aryl or heteroaryl group of one or. repeatedly can be substituted by a nitro-group, halogen, hydroxyl, amino, carboxyla, halogenation, alkoxycarbonyl, alcoxycarbenium, alkyl, cycloalkyl, alkoxyl, alkylamino or one or more groups-Y-CO2R8-O-Y-CO2R8while alkyl groups may be substituted one or more times by halogen;

R7obosnovat be substituted with halogen, by hydroxyl, alkoxyl, amino group or alkylcarboxylic, or denotes cyanoaniline, heteroaryl, aryl or Uralkaliy residues, while the aryl or heteroaryl residues of one or many times can be replaced by carboxypropyl, carboxialkilnuyu or alkoxycarbonyl groups, or denotes a residue-Y-CO2R8or-Y-CONR8R9where Y denotes a linear or branched alkylenes chain, R8and R9are the same or. different and represent hydrogen or alkyl groups, which may be single or multiply substituted by hydroxyl, alkoxyl, amino group or carboxyla, or R8and R9together with N-atom to which they are linked, form a saturated ring which may optionally contain an oxygen atom, sulfur or nitrogen,

and their physiologically acceptable salts.

4-Aminopyridines of formula (I) under item 1, in which R1denotes a group R6-SO2-O-; R6-0-SO2-; R6-NR7-SO2-, R2denotes the hydrogen atom or the halogen, alkyl, CNS or triptorelin group, X denotes an oxygen atom or N, N-group, R3and R4are the same or different and abannalealley, aryl, heteroaryl or aracelio group, with aryl or heteroaryl group of one or multiple can be substituted with halogen, alkyl, trifluoromethyl, alkoxyl, hydroxyl, carboxyla, hydroxyalkyl, carboxylation, alkoxycarbonyl, amino group, alkylamino, R7denotes hydrogen, alkyl, cycloalkyl, alkanniny, carboxialkilnuyu, heteroaryl, allyloxycarbonyl, aryl or Uralkaliy residues, while the aryl residue of one or many times can be replaced by the CNS, carboxyl, carboxialkilnuyu, alkoxycarbonyl groups, alkylcarboxylic or formylamino, as well as their physiologically acceptable salts and pharmaceutical compositions based on them. These compounds are biologically active and possess properties of inhibition of platelets. 2 C. and 12 C. p. F.-ly, 1 table.

The invention relates to new 4-aminopyridine General formula (I)

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in which R1denotes a group R6-SO-NR7-; R6-SO2-NR7-; R6-NR7-SO-; R6-NR7-SO2-; R6SO-O-; R6-SO2-O-; R6-O-SO -, or R6-O-SO2-;

R2oboznachaetto oxygen, a sulfur atom or NH group;

R3and R4are identical or different and denote hydrogen atoms or alkyl groups;

R5denotes a hydrogen atom, alkyl group or aracelio group;

R6denotes alkyl, cycloalkyl, aryl, heteroaryl, aracelio or heteroallyl group, and the aryl or heteroaryl residues may be single or multiply substituted by a nitro-group, halogen, nitrile, hydroxyl, carboxyla, alkoxycarbonyl, alkanolammonium, alkyloxyaryl, alcoxycarbenium, alkyl, cycloalkyl, alkenyl, quinil, lanakila, alkoxyl, alkenylacyl, alkynylamino, aralkylamines, canalcaracol, alkylthiol, alkylsulfonyl, alkylsulfonyl, amino, alkylamino, dialkylamino, aralkylamines-, di-aralkyl-amino-, alkylsulfonate, alkylcarboxylic, formylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminoalkyl or one or more groups-Y - CO2R8; -S-Y-CO2R8; -O-Y-CO2R8; -NH-Y-CO2R8; -S-Y-CONR8R9; -O-Y-CONR8R9or-NH-Y,-CONR8R9and alkyl, alkeline maximinoi, alkylcarboxylic-, amino - or carboxyl groups;

R7denotes a hydrogen atom; alkyl, cycloalkyl, alkanniny or alkynylaryl residue, these residues can be single - or multi-substituted with halogen, hydroxyl, alkoxyl, amino, alkylamino, dialkylamino, carboxyla, alkylcarboxylic or alkoxycarbonyl; or denotes alkoxycarbonyl, lanakila, heteroaryl, aryl, aracelio or heteroallyl group, with aryl or heteroaryl residue may be single or multiply substituted with halogen, nitrile, alkyl, alkenyl, quinil, trifluoromethyl, alkoxyl, alkenylacyl, alkyloxy, alkylthiol, alkylsulfonyl, alkylsulfonyl, halogenation, cryptomaterial, by hydroxyl, carboxyla, hydroxyalkyl, carboxylation, alkoxycarbonyl, amino, alkylamino, dialkylamino, alkylsulfonyl, alkylcarboxylic, formylamino; aminocarbonyl or phenyl; or represents a group-Y-CO2R8or-Y-CONR8R9;

Y denotes a linear or branched alkylenes chain;

R8and R9are identical or different and denote hydrogen atoms, Araki what oxyl, alkoxyl, alkylcarboxylic, amine or carboxyla, or R8and R9together with N-atom to which they are linked, form a saturated ring which may contain an additional oxygen, sulfur atoms or nitrogen;

and their hydrates, solvate and physiologically acceptable salts.

The subject invention are also optically active forms, racemates and mixtures of diastereomers of these compounds.

The invention relates also to a method for producing the above-mentioned compounds containing such compounds medicines, as well as to the use of these compounds in the preparation of medicines.

Aminopyridines of General formula (I), a solvate and their salts inhibit both thrombin-induced clotting of fibrinogen in the blood, and thrombin-induced platelet aggregation. Thus, they prevent the occurrence of obtenerse of blood clots and platelet-rich thrombi and can be used in the treatment and prevention of diseases such as thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis. Further, these compounds have effects on tumor cells and prevent the occurrence of metastasis. Tudni enzyme cascade coagulation, cleaves fibrinogen to fibrin, which is then attached by factor XIIIa and becomes insoluble in the gel, forming a matrix of the thrombus. Thrombin by proteolysis of its receptor on platelets activates platelet aggregation and thus promotes the formation of a blood clot. When damaged blood vessel these processes are needed to stop the bleeding. Under normal circumstances in plasma no measurable concentrations of thrombin. Increasing the concentration of thrombin may lead to thrombus formation and thus to thromboembolic diseases, which often occur primarily in industrialized countries.

Thrombin is formed in the plasma in the form of prothrombin and is released from it by factor Xa. Thrombin activates factors V, VIII and XI, making then the factor X is converted into factor Xa. As a consequence, the thrombin catalyzes its own release, which can come in very quickly increasing concentrations of thrombin.

The thrombin inhibitors can therefore suppress the release of thrombin-induced platelet, and plasma clotting of blood.

Along with thrombin sushestvuet to support minor side effects, thrombin inhibitors should be selective, i.e. they should only slightly or not to inhibit other semipretioase. Especially trypsin, as the nonspecific semipretioase can easily be suppressed in a variety of inhibitors. Inhibition of trypsin can lead to stimulation and hypertrophy of the pancreas (J. D. Geratz, Am. J. Physiol, 216 (1969), S. 12).

Plasma contains a protein plasminogen, which is due activators converted into plasmin. The plasmin is a proteolytic enzyme, whose activity is similar to that of trypsin. It is used to dissolve the blood clot that he destroys fibrin. The inhibition of plasmin, therefore, has the opposite effect to that which can be achieved through the inhibition of thrombin.

Synthetic thrombin inhibitors known for a long time. Based on fibrinogen, the natural substrate of thrombin, synthesize substances (D)-Phe-Pro-Arg-type. These tripeptides similar amino acid sequence to the restriction site of fibrinogen. In order to get good inhibitors, the carboxyl group of arginine with this change so that the hydroxyl group of serine-195 active site of thrombin can reagire is relevant (D)-Phe-Pro-arginal described in European patent application EP-A-185390.

The second type of inhibitors of thrombin belongs is known as trypsin inhibitor, benzamidine. Thus, these inhibitors differ from (D)-Phe-Pro-Arg-type not only by the chemical structure, but also comes inhibition: the serine-195 thrombin is not associated with these inhibitors. It clearly follows from x-ray structural studies (W. Bode, D., TurK, J. Sturzwbecher, Eur. J. Biochem., 193, 175-182 (1990)). To this second class of thrombin inhibitors include N- (2-attilalongoria)-4-amidino-(R, S)-phenyl-alanine-piperidin ("NAPAP", patent GDR N 235866).

Now unexpectedly found that compounds of General formula (I), in which there are no structural similarities with known thrombin inhibitors are selective inhibitors of thrombin.

Specified in the definitions of the radicals R1- R9alkyl or CNS fragments contain 1-6 carbon atoms, and these fragments can be linear or branched. This equally applies to the respective alkenyl or alkynylaryl fragments. Cycloalkyl groups have a ring of 3-7 carbon atoms. If halogenoalkanes or halogenosilanes alkyl group or CNS group can be one, two or t is thinking triptorelin or cryptometer. Halogen in all cases refer to fluorine, chlorine, bromine or iodine. Under Uralkalij and alcoxylate groups preferably understand benzoyloxy or benzoyloxy. In those cases in which these groups can be single - or multi-substituted, in particular taking into account one-, two - or three-fold substitution. In the case of six-membered rings in the aryl or heteroaryl groups in the substituents, independently of one another, may be in ortho-, meta - or paraprotein. If in the General formula (I) one of the substituents R2- R9denotes alkyl group, or R6denotes substituted by one or more alkyl groups, aryl or heteroaryl group, alkyl groups can be understood linear or branched alkyl group with 1-6 carbon atoms, preferably methyl, ethyl, sawn, ISO-propyl, boutelou, isobutylene, tert-boutelou, pentelow and hexoloy group. Under the halogen atoms as substituents alkyl groups understand fluorine, chlorine, bromine or iodine, preferably fluorine and chlorine. Preferred cryptomeria, chlormethine, 2-chloraniline and 3-chloropropylene group. If alkyl groups substituted hydroxyl g is th, 1,2-dihydroxyethylene and 2,3-dihydroxypropyl group. If alkyl groups substituted CNS groups, the preferred ethoxymethylene, ethoxyethylene, methoxyaniline and amoxicilina group. If alkyl groups substituted by amino groups, it is preferred aminomethyl, 2-aminoaniline, 3-aminopropyl, 4-aminobutyl and 5-aminopentyl group. If alkyl groups substituted by carboxyl groups, it is particularly preferred carboxymethyl, 1-carboxyaniline, 2-carboxyaniline and 2-methyl-1-carboxyaniline group.

If in the General formula (I) R6, R7, R8or R9denote cycloalkyl group, or R6denotes a substituted cycloalkyl aryl group or heteroaryl group, then under cycloalkenyl groups need to understand 3-7-membered ring, preferably cyclopropyl, cyclobutyl, cyclopentyl, tsiklogeksilnogo and cycloheptyl group. In all cases cycloalkyl group can also be linked through alkyl group, so as Deputy obtained cycloalkyl is an alkyl group. It is particularly preferred cyclopropylmethyl group and cyclohexylaniline heteroaryl group, or R7means alkanniny balance, it is necessary to understand 3-6-membered, linear or branched residues, preferably allyl, butonly and isobutylenes the rest.

If in the General formula (I) R6denotes a substituted alkynylaryl balance aryl or heteroaryl group, or R7means alkynylaryl balance, it is necessary to understand 3-6-membered, linear or branched residues, preferably propargyl the rest.

If in the General formula (I) R6denotes a substituted alkoxycarbonyl, alkanolammonium or alkyloxyalkyl balance aryl or heteroaryl group, then under it you need to understand linear or branched residues with 2 to 6 carbon atoms, preferably methoxycarbonyl, ethoxycarbonyl and allyloxycarbonyl group.

If in the General formula (I) R6denotes a substituted CNS balance aryl or heteroaryl group, then under it you need to understand linear or branched residue with 1-6 carbon atoms, preferably methoxy, ethoxy, propyloxy, bucalossi and pentyloxy. If CNS group substituted with hydroxyl groups, predpochtitelnye CNS groups, the preferred methoxyethoxide and ethoxyethoxy. If CNS group, substituted amino groups, the preferred 2-aminoethoxy and 3-aminopropoxy.

If in the General formula (I) R6denotes substituted alkenylacyl the remainder of the aryl or heteroaryl group, then under it you need to understand linear or branched residues with 3-6 carbon atoms, preferably alliancegroup.

If in the General formula (I) R6denotes substituted alkyloxy the remainder of the aryl or heteroaryl group, then under it you need to understand linear or branched residue with 1-6 carbon atoms, preferably of propargyloxy group.

If in the General formula (I) R6denotes substituted alkylthio-, alkylsulfonyl or alkylsulfonyl balance aryl or heteroaryl group, then under it you need to understand linear or branched residue with 1-6 carbon atoms, preferably methylthio-, methylsulfinyl and methylsulfonyl group.

If in the General formula (I) R6denotes substituted alkylamino or dialkylamino the remainder of the aryl or heteroaryl group, then under it you need to understand linear or branched astatke the formula (I) R6denotes substituted alkylsulfonyl the remainder of the aryl or heteroaryl group, then under it you need to understand linear or branched residue with 1-6 carbon atoms, preferably methylsulfonylamino.

If in the General formula (I) R6denotes substituted alkylcarboxylic the remainder of the aryl or heteroaryl group, then under it you need to understand linear or branched residue with 1-6 carbon atoms, preferably acetylamino.

If in the General formula (I) R6denotes a substituted alkylaminocarbonyl or dialkylaminoalkyl balance aryl or heteroaryl group, then under it you need to understand linear or branched residue with 1-6 carbon atoms, preferably methylaminoethanol, dimethylaminoethanol and Diethylaminoethanol group.

From kalkilya groups R6or R7especially preferred benzyl group.

As the aryl residue R6or R7individually or in combination with alkyl chain, you need to understand aromatic hydrocarbons with 6-14 carbon atoms, in particular phenyl, biphenylyl, nattily, tetrahydronaphthalene, indaily or f is ilycheskie aromatic hydrocarbons with heteroatoms, as nitrogen, oxygen and sulfur, such as furan, thiophene, pyrrole, oxazole, isoxazol, thiazole, isothiazol, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrazin, pyrimidine, pyridazine, triazine, tetrazine, benzothiophen, dibenzothiophen, benzimidazole, carbazole, benzofuran, benzofurazan, benzo-2,1,3-thiadiazole, quinoline, isoquinoline, hinzelin.

Under alkalinous group in the formula (I) understand linear or branched hydrocarbon chain with 1-6 carbon atoms, preferably methylene, ethylene or propylene group.

If the substituents R8and R9together with the nitrogen atom to which they are linked, form a ring under it you need to understand 4-7-membered ring, especially pyrolidine, piperidine and homopiperazine ring. If this cycle contains additional heteroatoms, among these cycles preferred morpholine, thiomorpholine and pieperazinove ring.

The remainder R2phenyl ring of General formula (I) can be in any position to the fragment X (an oxygen atom or NH group). However, particularly preferred arrangement, in which all three substituent of the phenyl ring of General formula (I) are in meta-position to each other.

R1common/SUP>-O-SO2-.

R2in particular, denotes a hydrogen atom, chlorine or bromine; or C1-C6is an alkyl group, such as methyl or ethyl group, or a C1-C6-CNS group, as, for example, a methoxy group or triptorelin group.

X denotes, in particular, an oxygen atom or NH group.

R3and R4may be the same or different and preferably represent hydrogen atoms or C1-C6is an alkyl group, particularly a hydrogen atom or methyl group.

R5in particular, denotes a hydrogen atom, a C1-C6is an alkyl group (e.g. methyl group) or a benzyl group.

R6in particular represents C1-C6is an alkyl group (for example, ISO-propyl group); C3-C7-cycloalkyl group (as, for example, cyclopentene or tsiklogeksilnogo group); unsubstituted or mono - or multiply substituted with fluorine, chlorine, C1-C6the alkyl (such as methyl, ethyl, tert-butyl), C1-C6-alkoxyl (as, for example, methoxy group), nitro, amino, hydroxyl, carboxyla, benzyloxycarbonyl, C1-C6-Aleppo, naftalina, tetrahydronaphthalene, biphenylene or indenolol group, thienyl, parasailing or pyridyloxy group, bastianello or benzothiadiazole group or benzyl group.

R7in particular, denotes a hydrogen atom, a C1-C6-alkyl or C2-C6-alkenylphenol group (as, for example, methyl, ethyl, n-sawn, allyl, ISO-propyl group) or aracelio group (such as benzyl group), C1-C6-alkoxycarbonyl group (as, for example, ethoxycarbonyl group), cyanoaniline group (as, for example, cyanomethylene group), a hydroxyalkyl group (for example, hydroxyethylene or dihydroxypropyl group) or aminoalkyl group (as, for example, aminoaniline group), group-Y-COR8or a group-Y-CONR8R9.

Y, in particular, denotes a methylene, propylene, butylene or Panteleeva group.

R8in particular, denotes a hydrogen atom or alkyl group (e.g. methyl or ethyl group), a hydroxyalkyl group (for example, hydroxyethylene, hydroxiproline or dihydroxypropyl group) or aminoalkyl group (eg( for example, a methyl group).

Preferred compounds of General formula (I)

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in which R1denotes a group R6-SO2-NR7-, R6-NR7-SO2-; R6-SO2-O - or R6-O-SO2-;

R2denotes a hydrogen atom, chlorine or bromine; methyl, ethyl, methoxy or triptorelin group;

X denotes an oxygen atom or NH group;

R3and R4are identical or different and denote hydrogen atoms or a methyl group;

R5denotes a hydrogen atom, methyl group or benzyl group;

R6represents ISO-propyl, cyclopentyl or tsiklogeksilnogo group; unsubstituted or mono - or multiply substituted with fluorine, chlorine, stands, ethyl, tert-bootrom, methoxy-, nitro-, amino, hydroxyl, carboxyla, benzyloxycarbonyl, methoxycarbonyl, cryptomeria or a group-O-Y-CO2R8phenyl group; naftalina, tetrahydronaphthalene, biphenylene or indenolol group; thienyl, parasailing or pyridinyl group; bastianello or benzothiazolyl group or benzyl group;

R7denotes a hydrogen atom; methyl, ethyl, n-propyl is inuu, cyanomethylene or aminoethyl group; a group-Y-COR8or a group-Y-CONR8R9;

Y denotes a methylene, propylene, butylene or Panteleeva group;

R8denotes a hydrogen atom or a methyl, ethyl, hydroxyethylene, hydroxypropyl, dihydroxypropyl or aminoethyl group;

R9denotes a hydrogen atom or methyl group.

Obtaining compounds of General formula (I) carry out itself by known methods.

Proceed from compounds of General formula (II)

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that restores the usual ways. As the reductant take into account the complex hydrides of boron and aluminum complexes barbadoro, aluminum hydride, which is produced in situ by interaction of LiAlH4with AlCl3or H2SO4or a mixture of AlCl3and NaBH4.

Compounds of General formula (II) are obtained by reacting compounds of General formula (III)

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with 4-aminopyridine, amino N-atom which contains the remainder R5. This interaction is carried out by reaction of equimolar quantities of 4-aminopyridine with a carboxylic acid of General formula (III) in the presence of dehydrating means, RH, dicyclohexylcarbodiimide or N,N'-carbonyldiimidazole. This reaction can also be carried out in two stages, with the carboxylic acid is first converted into a reactive derivative, for example the acid chloride, azide or imidazole, and then injected into the interaction with 4-aminopyridine.

Carboxylic acids of General formula (III) derived from esters of General formula (IV)

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in which R10denotes alkyl or benzyl group. Depending on the kind of this group, the reaction is carried out either using bases or acids, or hydrogenations. If R10denotes a methyl or ethyl group, the interaction is preferably carried out with sodium hydroxide or potassium hydroxide in methanol, ethanol or water. If R10denotes tert-boutelou group, the reaction is carried out with acid, preferably hydrochloric acid, formic acid or triperoxonane acid. If R10denotes a benzyl group, the reaction is carried out preferably hydrogenations in the presence of a catalyst like palladium on coal or platinum.

Of the compounds of General formula (IV) in which R1denotes a group R6-NH-SO-; R6-NH-SO2-; R61denotes a group R6-NR7'-SO-; R6-NR7'-SO2-; R6-SO-NR7'or R6-SO2-NR7'-. As alkylating funds are used compounds of the General formula R7'-Z, and R7'has the same meaning as R7with the exception of the hydrogen atom, the phenyl and heteroaryl groups, and Z represents a reactive group, as a halogen, preferably bromine, chlorine or sulfate. These reactions are carried out preferably in a solvent, such as acetone, ether, toluene or dimethylformamide, at temperatures from -30oC to 100oC, preferably at room temperature, in the presence of a base like sodium hydride or calcium carbonate.

Compounds of General formula (IV) are obtained from compounds of General formula (V)

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which enter into interaction with complex - halogenation General formula

Gal-CR3R4-CO2R10.

Under "Gal" you have to understand halogen atom, preferably chlorine and bromine. These reactions are preferably carried out in a solvent, such as acetone, ether, toluene or dimethylformamide, at temperatures from -30oC to 100oC, preferably at room temperature, in the presence of a base, as Geri6SO IS O; R6-SO2-O-; R6-SONH - or R6-SO2-NH-, derived from compounds of General formula (VI)

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the fact that they enter into interaction with sulphonylchloride R6-SOCl, respectively sulphonylchloride R6-SO2Cl. "A" in this case denotes a hydroxyl or amino group with other7. Interaction is expedient to carry out, with the addition of cyclotosaurus means, as, for example, alkali metal acetate, alkali metal hydroxide, calcium oxide, calcium carbonate, magnesium carbonate, or organic bases as pyridine, triethylamine, N-methylmorpholine or diisopropylethylamine, and as inert solvents are, for example, ether, methylene chloride, dioxane, toluene or an excess of the tertiary amine. When using inorganic ciclofosfamida means as a reaction medium is used, for example, water, aqueous ethanol or aqueous dioxane.

Compounds of General formula (IV) in which R1denotes a group R6-O-SO-; R6-O-SO2; R6-NR7-SO -, or R6-NR7-SO2- can be obtained from compounds of General formula (VII)

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in which n = 1 (sulphonylchloride) or 2 (sulphonylchloride), and these compounds enter solesource carried out with the addition of cyclotosaurus means, as, for example, alkali metal acetate, alkali metal hydroxide, calcium oxide, calcium carbonate, magnesium carbonate, or organic bases as pyridine, triethylamine, N-methylmorpholine or diisopropylethylamine, and as inert solvents are, for example, ether, methylene chloride, dioxane, toluene or an excess of the tertiary amine. When using inorganic ciclofosfamida means as a reaction medium is used, for example, water, aqueous ethanol or aqueous dioxane.

Compounds of General formula (V) and the General formula (VII) are known from the literature (Methods der Organischen Chemil (Honben-Weyl), Thieme Verlag, Stuttgart, 1955: 285 S. - M. Quaedvlieg, Aliphatische Sulfinsauren; S. 299 - F. Muth, Aromatische Sulfinsauren; S. 343 - M. Quaedvlieg, Aliphatische Sulfonsauren; S. 429 - F. Muth, Aromatische Sulfonsauren S. 599 F. Muth, Funktionelle N-Derivate der Aryisulfonsauren; S. 659 F. Muth, Aromatische Sulfonsanreester) or they can be obtained according to the methods described there. Compounds of General formula (VI) are known from the literature (Sobotka. Austin. J. Am. Chem. Soc, 74, 3813 (1952)) or they can be obtained according to the methods described there.

Another method of obtaining compounds of General formula (I) consists in the introduction into the interaction of compounds of General formula (VIII)

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with a derivative of pyridine, which is in position 4 contains nucleofuge Walter, as well as nitro-, alkoxy - and fenoxaprop. To facilitate the reaction of a derivative of 4-aminopyridine may contain other atoms by halogen, preferably chlorine. Preferred derivatives are pentachloropyridine and 4-nitroacetanilide. This reaction is preferably carried out in an inert solvent, such as toluene, dioxane, dimethylformamide, dimethylacetamide, methylene chloride or ethanol, at temperatures from room temperature up to the boiling point of the solvent, preferably at 20-40oC. If the pyridine derivative contains other atoms of chlorine for the nucleophilic reaction should be reaction dehalogenase, for example, by catalytic hydrogenation.

Compounds of General formula (VIII) are obtained by the reduction of compounds of General formula (IX)

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in which R11denotes a nitrile group or amide group CONHR5. As the reductant take into account the complex hydrides of boron and aluminum, bromodiolone complexes, aluminum hydride, which is produced in situ by interaction of LiAlH4with AlCl3or sulfuric acid, or a mixture of AlCl3and NaBH4.

Compounds of General formula (IX) are obtained from compounds of General formula (III). This is the General formula (III) in the presence of dehydrating means, as polyphosphoric acid, acidic cation-exchanger, galoyanized sulfuric acid, 2-halogen-pyridinium salt, dicyclohexylcarbodiimide or N,N'-carbonyldiimidazole. This reaction can also be carried out in two stages, with the first carboxylic acid is converted into a reactive derivative, for example an acid chloride or azide, and then injected into the interaction with ammonia.

The following method of obtaining compounds of General formula (I) originate from compounds of General formula (X)

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receive by known literature methods (M. M. Bondakian, Heterocyclic Componnds, T. 14, supplementary, part 2 (R. A. Abramvitch, ed.), Wiley, New York, 1974, S. 407) by introducing into the interaction sales aminoethanol HO-CR3R4-CH2-OTHER5with pentachloropyridine or 4-nitrotyrosination in an inert solvent like dioxane, tetrahydrofuran, methylene chloride or ethanol, at temperatures from -10oC to the boiling point of the solvent. Hydroxyl group of compounds of General formula (X) is transformed into a group to delete W and so are the compounds of General formula (XI)

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in which W represents a halogen atom such as chlorine or bromine, or an ester of sulfonic acids, as tailorshop. Turning hydroxylated; conversion into an ester of sulfonic acids is carried out by introducing the interaction with sulphonylchloride as taillored.

The compound of General formula (XI) now enter into an interaction with compounds of General formula (V')

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in which R1'has the same meaning as R1but additionally can refer to a protected hydroxyl group, or amino group. Protected hydroxyl group understand benzyloxy or acetyloxy. Protected amino group understands preferably tert-butyloxycarbonyl group, benzyloxycarbonyloxy group, dibenzylamino or phthalimidopropyl. The formation of compounds of General formula (XII). The interaction of compounds of General formula (V') with compounds of General formula (X) instead of General formula (XI) under Mitsunobu, in the presence of triphenylphosphine and diethyl ether complex or piperidine diazocarbonyl acid also lead to compounds of General formula (XII)

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If R1'in the compounds of General formula (XII) represents a protected hydroxyl group or a protected amino group, now in the nearest stage to remove the protective group. This is carried out for benzyl basicgroup, thanks to strong acid, as triperoxonane acid, and acetyl groups, thanks to the Foundation, as the sodium hydroxide solution. The formation of compounds of General formula (XIII)

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that by entering into interaction with sulphonylchloride or sulphonylchloride transferred to compounds of General formula (XIV)

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in which n = 1 or 2 and X' represents an oxygen atom or aminogroup NH. If X' denotes aminogroup, the compounds of General formula (XIV) is now transformed into compounds of General formula (XV)

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in which R7'has the same meaning as R7except for the values of the hydrogen atom. This transformation is carried out by introducing into interaction with alkylating means R7'- Y, as described in alkilirovanija compounds of General formula (IV).

Compounds of General formula (I), finally, are obtained from compounds of General formula (XII) in which R1'has the same meaning as R1from compounds of General formula (XIV) or from compounds of General formula (XV) by removing the chlorine atoms of the pyridine ring. This is carried out by catalytic hydrogenation in the presence of a catalyst like Raney Nickel or palladium-on-charcoal, in the presence of the basis of the second formula (I), in which R1denotes a group R6-SO-NR7-; R6-SO2-NR7-; R6SO-O - or R6-SO2-O-, the future path of synthesis consists in the introduction into the interaction of compounds of General formula (XVI)

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with sulphonylchloride R6-SOCl, respectively, with sulphonylchloride R6-SO2Cl. The interaction is carried out as described for interaction with compounds of General formula (VI). "A" in this case denotes a hydroxyl group, or amino group with other7.

Compounds of General formula (XVI) are obtained from compounds of General formula (XVII)

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where "B" denotes a protective group, tsepliaeva to obtain the compounds of General formula (XVI). As the protective group "B" take into account the benzyl group, which removes hydrogenations in the presence of a catalyst like palladium on coal; tert-butyloxycarbonyl group, which is removed by acids, as triperoxonane acid, formic acid or hydrochloric acid; or aromatic sulfonyloxy group, as benzolsulfonat or Casilina group, which is removed by exposure to alkali, as sodium hydroxide or potassium.

Compounds of General formula (XVII) receive the same is
which enter into interaction with complex halide esters of General formula

Gal-C R3R4-CO2R10,

as described to interact with the compounds of General formula (V). The formation of compounds of General formula (XIX)

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which, after saponification of ester and activation of the acid function, as described in the case of compounds of General formula (III) enter into interaction with 4-aminopyridine or N - R5-4-aminopyridine with obtaining compounds of General formula (XVI).

Known compounds of General formula (I) can then be converted into other compounds of General formula (I).

This relates to compounds of General formula (I) in which R5, R6or R7denotes a benzyl group or in which R6denotes aryl or heteroaryl group, which as substituents contain one or more benzyloxy, benzylamino or benzyloxycarbonyl groups. By catalytic hydrogenation in the presence of a catalyst, preferably palladium-on-charcoal, at this benzyl group substituted by a hydrogen atom. Removal of benzyl groups are also carried out by introducing into the interaction with a strong acid, as the compounds of General formula (I), in which R6denotes aryl or heteroaryl group, which as substituents contain one or more chlorine atoms. By catalytic hydrogenation in the presence of a catalyst, preferably palladium-on-charcoal, while the chlorine atom is replaced by a hydrogen atom.

This also applies to the compounds of General formula (I) in which R6denotes aryl or heteroaryl group, which as substituents contain one or more nitro groups. By catalytic hydrogenation in the presence of a catalyst, preferably palladium-on-charcoal, while the nitro-group is replaced by an amino group.

This also applies to the compounds of General formula (I) in which R6denotes aryl or heteroaryl group, which as substituents contain allyloxycarbonyl, allyloxycarbonyl or alkiloksikarbonilalkilamidov, or R7means alkoxycarbonylmethyl group. Here, by entering into interaction with the acid as hydrochloric acid, or bases as sodium hydroxide, alkoxycarbonyl groups you can get free carboxylic acid. If these alkoxycarbonyl group enter P>8R9-group. If these alkoxycarbonyl group is treated with a reducing agent, as LiAlH4then of them are formed corresponding hydroxymethylene group.

This also applies to the compounds of General formula (I) in which R6denotes aryl or heteroaryl group, which as substituents contain one or more nitrile, lanakila, coanalgesics, formylamino, alkylcarboxylic-, aminocarbonyl, alkylaminocarbonyl groups or a group-S-Y-CONHR8-O-Y-CONHR8, -NH-Y,-CONHR8or where R7means lanakila, aminocarbonylmethyl group or a group-Y-CONHR8. These groups can be restored, preferably using LiAlH4, and formed the corresponding aminomethyl compound.

Examples of physiologically acceptable salts of the compounds of formula I are salts with physiologically acceptable inorganic acids as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid, or with organic acids, as methanesulfonate, p-toluensulfonate, acetic acid, triperoxonane acid, citric acid, fumaric acid, maleic acid, tartaric can also form salts with physiologically acceptable bases. Examples of such salts are salts of alkali metals, salts of alkaline earth metals, ammonium and alkylammonium salts, such as sodium, potassium, calcium or Tetramethylammonium salt.

The compounds of formula (I) can be solvated, especially gidratirovana. Hydrating can be implemented in the retrieval process, or it can occur gradually as a consequence of hygroscopic properties initially anhydrous compound of formula (I).

Pure enantiomers of compounds of formula (I) are given either by splitting of the racemate (via salt formation with optically active acids or bases), or the fact that in the synthesis using optically active educt.

To obtain drugs substances of General formula (I) is mixed with suitable pharmaceutical carriers, perfumes, improves the taste of chemicals and dyes, and, for example, molded in the form of tablets or pills, or with the addition of appropriate assistive devices are suspended or dissolved in water or oil, for example olive oil.

Substances of General formula (I) or their salts can be introduced in liquid or solid form, intestinal or parenteral. In cachectic supplements as a stabilizer, a dissolving agent or a buffer. Such additives are, for example, tartrate and citrate buffer, complexing agents (as ethylenediaminetetraacetic acid and its non-toxic salts and high molecular weight polymers such as liquid polyethylene oxide, to control viscosity. Solid carriers are, for example, starch, lactose, mannitol, methylcellulose, talc, highly dispersed silicic acids, high molecular weight fatty acid (as stearic acid), animal and vegetable fats and solid high molecular weight polymers (such as polyethylene glycols). Suitable for oral administration the compositions may contain desirable in the case of sweetening and gives taste substances.

The compounds are usually administered in amounts of 10 to 1500 mg per day, based on body weight 75 kg, Preferably administered 2 to 3 times a day 1 - 2 tablets with a content of biologically active substances 5 to 500 mg. Tablets can also be prolonged action, allowing you to enter only once a day 1 to 2 tablets containing biologically active substances 20 - 700 mg of the Biologically active substance can be administered by injection 1 to 8 times per day or by continuous infusion, and impactfully the following connections:

1. 3-methyl-5-[2-(pyridin-4-yl-amino)ethoxy] phenyl ether benzosulfimide acid;

2. N-{3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}benzosulfimide;

3. 3-{3-methyl-5-[2-(pyridin-4-yl-amino)ethoxy]phenylenesulfonyl}- venexiana acid;

4. 2-{3-methyl-5-[2-(pyridin-4-yl-amino)ethoxy]phenylamino - sulfonyl}venexiana acid;

5. 3-{3-methyl-5-[2-(pyridin-4-yl-amino)ethoxy]phenylamino - sulfonyl}-phenoxyacetamide;

6. N-(2-hydroxyethyl)-3-{3-methyl-5-[2-(pyridin-4-yl-amino)- ethoxy]phenylenesulfonyl}phenoxyacetamide;

7. N-(2,3-dihydroxypropyl)-3-{3-methyl-5-[2-(pyridin-4-yl - amino)ethoxy] phenylenesulfonyl}phenoxyacetamide;

8. N-(2-hydroxyethyl)-3-{3-methyl-5-[2-(pyridin-4-yl - amino)-ethoxy]phenylenesulfonyl}phenoxyacetamide;

9. morpholin 3-{ 3-methyl-5-[2-(pyridin-4-yl-amino)ethoxy] - phenylenesulfonyl}phenoxyalkanoic acid;

10. 2-[2-(benzazolyl-{3-methyl-5-[2-(pyridin-4-yl-amino)- ethoxy]-phenyl}aminoethylamino]ethyl ester of acetic acid;

11. 3-[2-(benzazolyl-{3-methyl-5-[2-(pyridin-4-yl-amino)- ethoxy]phenyl}aminoethylamino]propyl ester acetic acid;

12. 2-[2-(2-methoxybenzenesulfonyl-{ 3-methyl-5-[2-(pyridin-4 - yl-amino)ethoxy]phenyl}aminoethylamino]ethyl ester acetic Ki is n-4-yl-amino)ethoxy]-phenyl}-2-naphthalenesulfonate.

a) To 5.9 g (25 mmol) of ethyl ester of 3-aminophenoxyethanol acid and 6.9 ml of triethylamine in 100 ml of methylene chloride under ice cooling at 10oC was added dropwise 6.3 g (28 mmol) of naphthalene-2-sulphonylchloride in 30 ml of methylene chloride. Stirred for 1 hour at room temperature, extracted with water and the organic phase is dried over sodium sulfate. The solvent is removed in vacuum and obtain 9.6 g of N-{3-[(etoxycarbonyl)methoxy]phenyl}-2-naphthalenesulfonate in the form of oil. Mass spectrum: m/e = 385.

b) To 9.6 g (25 mmol) of this compound in 100 ml of ethanol is added to 4.2 g (75 mmol) of potassium hydroxide and stirred for 1 hour at 70oC. is Filtered off, dissolved in water, acidified with conc. hydrochloric acid and extracted with ethyl acetate. The solvent is removed in vacuum, the residue is dissolved in 2 BC, the sodium hydroxide solution, acidified with conc. hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and the solvent is removed in vacuum. The oily residue crystallizes upon standing. Obtain 7.6 g (85%) of N-{ 3-[(carboxy)methoxy]phenyl}-2-naphthalenesulfonate. So pl. 153 to 155oC. FAB-mass spectrum: M+H = 358.

in) To 3 is of indimidate and stirred for 20 minutes. To the obtained mixture is added 0.8 g (8.4 mmol) of 4-aminopyridine and stirred at 60oC for 6 hours. Then add again 2.7 g (16,8 mmol) 1,1-carbonyldiimidazole and 0.8 g (8.4 mmol) of 4-aminopyridine and mix the next 6 hours at 60oC. the Solvent is removed in vacuum, the residue is treated with ethyl acetate and extracted with aqueous sodium bicarbonate solution and phosphate buffer, pH 7.0. The organic phase is dried over sodium sulfate, filtered and the solvent is removed in vacuum. Obtain 2.5 g (69%) of N-{3-[(pyridine-4-yl-aminocarbonyl)methoxy]phenyl}-2 - naphthalenesulfonate. So pl. 204-207oC. Mass spectrum: m/e = 433.

g) In a nitrogen atmosphere to 1.0 g (to 20.4 mmol) sociallyengaged in 20 ml of tetrahydrofuran, add 2.0 g (4.6 mmol) videolounge connection and within 1 hour and refluxed. Excess LiAlH4decompose water, filtered and the filtrate is evaporated in vacuum. The residue is treated with ethyl acetate, extracted with water, the organic phase is dried over sodium sulfate, filtered and the solvent is removed in vacuum. Oily residue separated through a column of reversed phase (RP-18; eluting agent: methanol-water in the ratio 7:3; pH of 6.8). Preferably francillia and the solvent is removed in vacuum. Obtain 0.3 g (16%) of target compound with so pl. 90-91oC. Mass spectrum: m/e = 419.

Example 2. N-{3-[2-Pyridine-4-yl-amino)ethoxy]-phenyl}-1-naphthalenesulfonate.

Obtaining carried out as described in example 1, except that in stage (a) instead of 2-naphthalenesulfonate using 1-naphthalenesulfonate.

Intermediate stage:

a) N-{3-[(etoxycarbonyl)methoxy]phenyl}-1-naphthalenesulfonate in the form of oil. Mass spectrum: m/e = 385.

b) N-{ 3-[(carboxy)methoxy] phenyl} -1-naphthalenesulfonate, so pl. 147-149oC. FAB-mass spectrum: M+H = 358.

C) N-{3-[(pyridine-4-yl-aminocarbonyl)methoxy]phenyl}-1 - naphthalenesulfonate. So pl. 210-211oC (decomposition), mass spectrum: m/e = 433.

g) of the target compound, yield = 38%, so pl. 239-241oC (decomposition), mass spectrum: pos. LSIMS : m/e = 419.

Example 3. 4-Methyl-N-{ 3-[2-pyridine-4-yl-amino)-ethoxy] phenyl}benzosulfimide.

Obtaining carried out as described in example 1, except that in stage (a) instead of 2-naphthalenesulfonate using 4-toluensulfonate.

Intermediate stage:

a) 4-methyl-N-{3-[(etoxycarbonyl)methoxy]phenyl}benzosulfimide, so pl. 100-102oC; mass spectrum: m/e = 349.

b) 4-methyl-N-{3-[(carboxy-aminocarbonyl)methoxy] -phenyl} benzosulfimide in the form of oil; mass spectrum: m/e = 397.

g) of the target compound; yield = 26%, so pl. 165-167oC; mass spectrum: m/e = 383.

Example 4. 4-Fluoro-N-{ 3-[2-(pyridin-4-yl-amino)-ethoxy] phenyl} benzensulfonamidelor.

Obtaining carried out as described in example 1, except that in stage (a) instead of 2-naphthalenesulfonate using 4-forbindelsesfaneblad.

Intermediate stage:

a) 4-fluoro-N-{ 3-[(etoxycarbonyl)methoxy]phenyl}benzosulfimide; so pl. 94-96oC; mass spectrum: m/e = 353.

b) 4-fluoro-N-{ 3-[(carboxy)methoxy] phenyl}benzosulfimide so pl. 154-156oC; FAB-mass spectrum: M+H = 326.

b) 4-fluoro-N-{3-[(pyridine-4-yl-aminocarbonyl)methoxy]-phenyl}- benzosulfimide; mass spectrum: m/e = 401.

d) the target connection. The base is ground with hydrochloric acid in ether; yield = 21%; so pl. 203-205oC; mass spectrum: m/e = 387.

Example 5. 4-Chloro-N-{3-[2-pyridine-4-yl-amino)-ethoxy]phenyl}benzosulfimide hydrochloride.

Obtaining carried out as described in example 1, except that in stage (a) instead of 2-naphthalenesulfonate using 4-chlorobenzenesulfonamide.

Intermediate stage.

a) 4-chloro-N-{ 3-[(etoxycarbonyl)methoxy] phenyl}of benzolsulfonat-mass spectrum: M+H = 342.

b) 4-chloro-N-{3-[(pyridine-4-yl-aminocarbonyl)methoxy]phenyl}benzosulfimide; so pl. 168 - 171oC; mass spectrum: m/e = 417;

g) 0.65 g (1.55 mmol) of the compound from stage b) in 15 ml of anhydrous tetrahydrofuran is mixed with 1,79 ml (3.58 mmol) of a 2 M solution of dimethyl sulfide boron in tetrahydrofuran. Stirred for 3 hours at 60oC and then cooled in an ice bath, add 10 ml of methanol. To the resulting mixture add 5 ml of hydrogen chloride in ether. The solvent is removed in vacuo and the residue triturated with warm water. Gain of 0.13 g of target compound with so pl. 241 to 243oC; mass spectrum: m/e = 403.

Example 6. 4-Trifluoromethyl-N-{3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}benzosulfimide.

Obtaining carried out as described in example 1, except that in stage (a) instead of 2-naphthalenesulfonate using 4-trifluoromethyl-benzosulphochloride.

Intermediate stage.

a) 4-trifluoromethyl-N-{ 3-[(etoxycarbonyl)methoxy]phenyl}-benzosulfimide; mass spectrum: m/e = 403.

b) 4-trifluoromethyl-N-{3-[(carboxy)methoxy]phenyl}benzosulfimide; so pl. 155 - 158oC; FAB-mass spectrum: M+H = 375.

C) 4-trifluoromethyl-N-{3-[(pyridine-4-yl-aminocarbonyl)methoxy] phenyl}benzosulfimide; so pl. 66 - 68oC; mass is iformity-N-{3-[2-pyridine-4-yl-amino)ethoxy]phenyl}benzosulfimide.

Obtaining carried out as described in example 1, except that in stage (a) instead of 2-naphthalenesulfonate used 3-triftoratsetilatsetonom.

Intermediate stage.

a) 3-trifluoromethyl-N-{ 3-[(ethoxycarbonyl)methoxy]phenyl}benzosulfimide; mass spectrum: m/e = 403.

b) 3-trifluoromethyl-N-{3-[(carboxy)methoxy]phenyl}benzosulfimide; so pl. 147 - 149oC; FAB-mass spectrum: M+H = 375.

C) 3-trifluoromethyl-N-{3-[(pyridine-4-yl-aminocarbonyl)methoxy]phenyl} benzosulfimide, in the form of an oil; mass spectrum: m/e = 451.

g) target connection; so pl. 185 - 187oC; mass spectrum: m/e = 437.

Example 8. N-{-3-[2-(Pyridin-4-yl-amino)ethoxy]-phenyl}cyclohexanesulfonic.

Obtaining carried out as described in example 1, except that in stage (a) instead of 2-naphthalenesulfonate apply cyclohexylsulfamate.

Intermediate stage.

a) N-{3-[(etoxycarbonyl)methoxy]phenyl}cyclohexanesulfonic; mass spectrum: m/e = 341.

b) N-{ 3-[(carboxy)methoxy] phenyl}cyclohexanesulfamic, so pl. 132oC; FAB-mass spectrum: M+H = 313.

N-{3-[(pyridine-4-yl-aminocarbonyl)methoxy]phenyl}cyclohexanesulfonic in the form of an oil; mass sector: m/e = 389.<}benzosulfimide.

Obtaining carried out as described in example 1, except that in stage (a) instead of 2-naphthalenesulfonate apply benzosulphochloride.

Intermediate stage.

a) N-{ 3-[(etoxycarbonyl)methoxy]phenyl}benzosulfimide in the form of an oil; mass spectrum: m/e = 335.

b) N-{ 3-[(carboxy)methoxy]phenyl}benzosulfimide, so pl. 160 - 161oC; FAB-mass spectrum: M+H = 307.

C) N-{3-[(pyridine-4-yl-aminocarbonyl)methoxy]phenyl}benzosulfimide, so pl. 151-156oC; mass spectrum: m/e = 383.

g) of the target compound; yield = 26%, so pl. 182 - 184oC; mass spectrum: m/e = 369.

The application 10. N-{3-[1-Methyl-2-(pyridin-4-yl-amino)-ethoxy]phenyl}benzosulfimide.

(a) and 8.4 g (40 mmol) of ethyl ester of 2-(3-aminophenoxy)-propionic acid and 6.1 ml (44 mmol) of triethylamine in 50 ml of methylene chloride under ice cooling at 10oC was added dropwise 5.6 ml (44 mmol) of benzosulfimide. Stirred for 1 hour at room temperature, extracted with water, the organic phase is dried over sodium sulfate, filtered and the solvent is removed in vacuum. Get 14 g of N-{3-[1-(etoxycarbonyl)ethoxy]phenyl}benzosulfimide in the form of butter.

Mass spectrum: m/e = 349.

b) 14 g (40 mmol) is s 1 hour. Extracted twice with ethyl acetate, acidified with policecontributing hydrochloric acid and extracted again with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and the solvent is removed in vacuum. Gain of 9.2 g (72%) of N-{3-[1-carboxy)ethoxy]phenyl}benzosulfimide in the form of oil. Mass spectrum: m/e = 321.

C) According to the method of example 1, stage b), 4.8 g (15 mmol) of the above-mentioned compounds, 2.1 g (to 22.5 mmol) of 4-aminopyridine and 3.2 g (1935 mmol) 1,1-carbonyldiimidazole in 40 ml of tetrahydrofuran obtain 3.4 g (57%) of N-{ 3-[1-(pyridine-4-yl-aminocarbonyl)ethoxy] phenyl}benzosulfimide, so pl. 142 - 144oC; mass spectrum: m/e = 397.

g) According to the method of example 1, step g), 1.7 g (4.3 mmol) videolounge connection and 0.65 g (17,2 mmol) sociallyengaged in 20 ml of tetrahydrofuran obtain 0.6 g (37%) of target compound. So pl. 162 - 163oC; mass spectrum: m/e = 383.

Example 11. N-{ 3-[1,1-Dimethyl-2-(pyridin-4-yl-amino)ethoxy]phenyl}benzosulfimide.

The get connection similar to that described in example 10. In stage a) instead of the ethyl ester of 2-(3-aminophenoxy)propionic acid used ethyl ester of 2-methyl-2-(3-aminophenoxy)propionic acid.

a) N-{3-[1-metalbox)ethoxy]phenyl}benzosulfimide in the form of oil; mass spectrum: m/e = 335.

C) N-{ -3-[1-methyl-(pyridine-4-yl-aminocarbonyl)ethoxy]phenyl}benzosulfimide; so pl. 141 - 143oC; mass spectrum: m/e = 411.

g) of the target compound in the form of an oil; mass spectrum: m/e = 397.

Example 12. N-Methyl-N-{3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}benzosulfimide hydrochloride.

(a) and 8.4 g (25 mmol) of N-{3-[(etoxycarbonyl)methoxy]phenyl}benzosulfimide (example 9, step a)) and 3.5 g of potassium carbonate in 10 ml of dimethylformamide at 80 - 90oC was added dropwise a solution of 1.6 ml (25 mmol) of iodomethane in 10 ml of dimethylformamide. Stirred for further 2 hours at this temperature, allowed to cool to room temperature, filtered and the filtrate concentrated in vacuo. The residue is treated with ethyl acetate and extracted with water. The organic phase is dried over sodium sulfate, filtered and the solvent is removed in vacuum. Obtain 8.6 g of N-methyl-N-}3-[(etoxycarbonyl)methoxy]phenyl}benzosulfimide in the form of oil. Mass spectrum: m/e = 349.

b) Further transformation carried out as described in example 1, stage b). Get N-methyl-N-{3-[(carboxy)methoxy]phenyl}benzosulfimide. So pl. 110 - 111oC; mass spectrum: m/e = 321.

C) N-methyl-N-{ 3-[(pyridine-4-yl-aminocarbonyl)methoxy]phenyl}b is mixed with 2 N. hydrochloric acid, extracted with ethyl acetate and the aqueous phase is evaporated to dryness. Get the oil, which after trituration with isopropanol crystallizes. The output is 46%. So pl. 174 - 176oC.

Example 13. N-Ethyl-N-{3-[2-(pyridin-4-yl-amino)-ethoxy]phenyl}benzosulfimide.

Obtaining carried out as described in example 12, only in stage a) instead of iodomethane apply Iodate.

a) N-ethyl-N-{ 3-[(etoxycarbonyl)methoxy]phenyl}benzosulfimide in the form of an oil; mass spectrum: m/e = 363.

b) N-ethyl-N-{3-[(carboxy)methoxy]phenyl}benzosulfimide; so pl. 122oC; mass spectrum: m/e = 335.

C) N-ethyl-N-{ 3-[(pyridine-4-yl-aminocarbonyl)methoxy] phenyl}benzosulfimide; mass spectrum: m/e = 411.

g) of the target compound in the form of an oil; mass spectrum: m/e = 397.

Example 14. N-Propyl-N-{3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}benzosulfimide.

Get similar to that described in example 12, only in stage a) instead of iodomethane apply improper.

a) N-propyl-N-{3-[(etoxycarbonyl)methoxy]phenyl}benzosulfimide in the form of an oil; mass spectrum: m/e = 377.

b) N-propyl-N-{ 3-[(carboxy)methoxy] phenyl} benzosulfimide; so pl. 147oC; mass spectrum: m/e = 349.

in) N-proper> g) of the target compound in the form of an oil; mass spectrum: m/e = 411.

Example 15. N-Benzyl-N-{3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}benzosulfimide.

Get analogously to example 12, only in stage a) instead of iodomethane use benzylbromide.

a) N-benzyl-N-{3-[(etoxycarbonyl)methoxy]phenyl}benzosulfimide in the form of an oil; mass spectrum: m/e = 425.

b) N-benzyl-N-{ 3-[(carboxy)methoxy] phenyl} benzosulfimide; so pl. 190oC; mass spectrum: m/e = 397.

b) N-benzyl-N-{3-[(pyridine-4-yl-aminocarbonyl)methoxy]phenyl}benzosulfimide; so pl. mass spectrum: m/e = 473.

g) target connection; so pl. 128oC; mass spectrum: m/e = 459.

Example 16. N-Allyl-N-{3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}benzosulfimide.

Get similar to that described in example 12, only in stage a) instead of iodomethane use allylbromide.

a) N-allyl-N-{3-[(etoxycarbonyl)methoxy]phenyl}benzosulfimide in the form of an oil; mass spectrum: m/e = 375.

b) N-allyl-N-{3-[(carboxy)methoxy]phenyl}benzosulfimide; mass spectrum: m/e = 347.

in) N-allyl-N-{3-[(pyridine-4-yl-aminocarbonyl)methoxy]-phenyl}benzosulfimide; mass spectrum: m/e = 423.

g) of the target compound in the form of an oil; mass spectrum: m/e = 409.

Intermediate stage.

a) N-{5-methyl-3-[(etoxycarbonyl)methoxy]phenyl}benzosulfimide in the form of an oil; mass spectrum: m/e = 349.

b) N-{5-methyl-3-[(carboxy)methoxy]phenyl}benzosulfimide; so pl. 156 - 159oC; FAB-mass spectrum: M+H = 322.

C) N-{ 5-methyl-3-[(pyridine-4-yl-aminocarbonyl)methoxy]phenyl}benzosulfimide; so pl. 193 - 196oC; mass spectrum: m/e = 397.

g) of the target compound, yield = 56%; so pl. 170oC; mass spectrum: m/e = 383.

Example 18. 3-[2-(Pyridin-4-yl-amino)ethoxy] phenyl ester benzosulfimide.

To 2.5 g (0.01 mol) of 3-hydroxy-phenyl ester benzosulfimide in 30 ml of acetonitrile under cooling at 10oC type of 0.44 g (0.11 mol) of sodium hydride (60% in mineral oil) and stirred for 1 hour at this temperature. Within 30 minutes was added dropwise 2.2 ml (0.02 mol) of ethyl ether bromoxynil acid in 10 ml of acetonitrile and stirred for 3 hours at room temperature. After addition of 5 ml of isopropanol, the solvent is removed in HAC is 16 hours at room temperature, the ethanol is removed in vacuo and the aqueous solution extracted three times with ether. The aqueous phase is acidified with hydrochloric acid and extracted with ether. The ether is removed in vacuo and get 1.5 g(48%) 2-[3-(phenylsulfonyl]phenyloxy)acetic acid, with so pl. 152 - 155oC.

b) 1.4 g (4.5 mmol) videolounge connection and 958 mg (5.9 mmol) of carbonyldiimidazole stirred for 30 minutes at 45oC. Added 0.64 g (6.8 mmol) of 4-aminopyridine and stirred for 2 days at 60oC. the Solvent is removed in vacuum and the residue is dissolved in ethyl acetate, which contains 0.5% acetic acid. The organic phase is dried, filtered and the solvent is removed in vacuum. The residue is triturated with ether, filtered and obtain 1.8 g (94%) of N-(4-pyridinyl)-2-[3-(phenylsulfonyl)phenyloxy] ndimethylacetamide with so pl. 127 - 130oC.

C) While cooling in an ice bath at 5oC 192 mg (8,8 mmol) literalized in 5 ml of anhydrous tetrahydrofuran is mixed with 2,23 ml (18 mmol) of chlorotrimethylsilane. After 30 minutes with 5oC slowly added 1.7 g (4.4 mmol) of the compound from stage b). After 16 hours of incubation at room temperature the mixture is decomposed with 3 ml of methanol and the solvent is removed in vacuum. The residue is treated with ethyl acetate and the solution of bicarbonate. An ethyl acetate phase is purified by using Kohl (80%) as a viscous oil. FAB-mass spectrum: M+H = 371.

Example 19. N-Methyl-N-phenyl-3-[2-(pyridin-4-yl-amino)ethoxy]benzosulfimide.

a) N-methyl-anilide 3-nitrobenzenesulfonate.

5 g of acid chloride of 3-nitrobenzenesulfonate dissolved in 20 ml of absolute pyridine and while cooling with ice and stirring, mixed with 2.7 ml of N-methylaniline. Stirred for further 2 hours at room temperature, the reaction mixture make iced water and acidified with diluted hydrochloric acid. The aqueous phase is extracted with ethyl acetate, an ethyl acetate phase is dried over sodium sulfate and evaporated. The remainder will recrystallized from alcohol. Yield: 6.3 g, so pl. 90oC.

b) N-methyl-anilide 3-aminobenzenesulfonate.

6 g of N-methyl-anilide 3-nitrobenzenesulfonate dissolved in 100 ml of absolute tetrahydrofuran and after the addition of 0.5 g of 10% palladium-on-coal as a catalyst hydronaut. After absorption of the calculated amount of hydrogen is filtered from the catalyst and the filtrate is evaporated. Yield: 5.5 g, so pl. 104oC.

C) N-methyl-anilide 3-hydroxybenzenesulfonate.

5 g of N-methyl-anilide 3-aminobenzenesulfonate dissolved in 20 ml of 50% sulfuric acid. To the resulting solution at a cooling gap is actionnow the mixture is heated for 10 minutes at 100oC, allowed to cool and extracted with ethyl acetate. An ethyl acetate phase is dried over sodium sulfate and evaporated. The remainder is of sufficient purity for further transformation.

d) Ethyl ester [3-(methyl-phenyl-sulfamoyl)phenoxy]-acetic acid.

3.5 g of N-methylaniline 3-hydroxybenzenesulfonate dissolved in 20 ml of absolute dimethylformamide. To the resulting solution was added 2 g of sodium carbonate and 1.9 ml of ethyl ether bromoxynil acid and the mixture is heated for 3 hours at 100oC. is Cooled and the solvent is removed in vacuum. The obtained residue (4.3 g) is of sufficient purity for further transformation.

d) [3-(Methyl-phenyl-sulfamoyl)phenoxy]acetic acid.

of 4.2 g of ethyl ester of [3-(methyl-phenyl-sulfamoyl)phenoxy]-acetic acid are dissolved in 40 ml of ethanol. To the resulting solution add 1 g of potassium hydroxide and the mixture is stirred for 1 hour at 90oC. Cool to room temperature, acidified with diluted hydrochloric acid and extracted with methylene chloride. Methylenchloride phase is dried over sodium sulfate and evaporated. Get 4 g of [3-(methyl-phenyl-sulfamoyl)phenoxy]acetic acid as an amorphous solid vasectamy)phenoxy]acetic acid was dissolved in 20 ml of absolute tetrahydrofuran. To the resulting solution was added 1.35 g of carbonyldiimidazole and the mixture is heated for 20 minutes at 45oC. Cool to room temperature, add 900 mg 4-aminopyridine and stirred further for 3 hours at 60oC. the Solvent is distilled off, the residue is dissolved in ethyl acetate and shaken out with water. An ethyl acetate phase is dried over sodium sulfate and evaporated. Residue to clean chromatographic on a column of silica gel (eluting agent: methylene chloride/methanol=9:5). After evaporation column fractions receive 1.5 target compound as amorphous solid. FAB-mass spectrum: M+H=398.

g) N-methyl-N-phenyl-3-[2-(pyridin-4-yl-amino)-ethoxy]benzosulfimide.

800 mg of 2-[3-(methyl-phenyl-sulfamoyl)phenoxy] -N-pyridin-4-yl-ndimethylacetamide dissolved in 15 ml of absolute tetrahydrofuran. To the resulting solution under nitrogen atmosphere add 320 mg sociallyengaged and the mixture is then for 1 hour and refluxed. Cooled and the reaction mixture is decomposed with a saturated solution of ammonium sulfate. Sucked off from the insoluble matter, the filter residue is washed with ether, the filtrate is dried over sodium sulfate and evaporated. Residue to clean hronicnih fractions obtain 420 mg of the target compound as an amorphous substance. FAB-mass spectrum: M+H=384.

Example 20. N-Benzyl-N-phenyl-3-[2-(pyridin-4-yl-amino)ethoxy] benzosulfimide.

The target connection receive same way as described in example 19, the method only in stage a) instead of N-methylaniline using N-benzylaniline. Amorphous substance. FAB-mass spectrum: M+H=460.

Example 21. N-Phenyl-3-[2-(pyridin-4-yl-amino)-ethoxy] benzosulfimide.

300 mg of N-benzyl-N-phenyl-3-[2-(pyridin-4-yl-amino)ethoxy] benzosulfimide (example 20) was dissolved in 20 ml of methanol and after the addition of 100 mg of 10% palladium-on-coal as a catalyst hydronaut. After the hydrogen absorption was filtered from the catalyst and the filtrate is evaporated. Obtain 240 mg of the target compound as an amorphous substance. FAB-mass spectrum: M+H=370.

Example 22. N-Methyl-N-pyridin-1-yl-3-[2-(pyridin-4-yl-amino) ethoxy]benzosulfimide.

The target connection receive same way as described in example 19, the method only in stage a) instead of N-methylaniline using N-methyl-2-aminopyridine. Amorphous substance. FAB-mass spectrum: M+H=385.

Example 23. N-{ 3-[2-(Pyridin-4-yl-amino)ethoxy]phenyl}-2 - propanesulfinamide hydrochloride.

To 0.26 g to (11.4 mmol) LiBH4in 50 ml of tetrahydrofuran was added dropwise 2,88 ml (the l) N-{3-[(pyridine-4-yl-aminocarbonyl)methoxy]phenyl}-2 - propanesulfinamide, which was obtained similarly to the method of example 1. Within 30 minutes, refluxed, after cooling, carefully added dropwise 20 ml of methanol, and then 30 ml of 2 n sodium hydroxide solution. The solvent is largely removed in vacuum and carry out the extraction with methylene chloride. The extract is dried, the solvent is removed in vacuum and the residue is mixed with an ethereal solution of hydrogen chloride. The solvent is removed in vacuo, the residue triturated with simple tert-butylmethylamine ether and receive 1.5 g (70%) of target compound with so pl. 204 - 207oC.

Example 24. N-{3-[2-(Pyridin-4-yl-amino)-ethoxy]phenyl} cyclopentanemethanol hydrochloride.

Get analogously to example 23. So pl. 129 - 134oC.

Example 25. N-Methyl-N-{ 3-[2-(pyridin-4-yl-amino)ethoxy]phenyl} -4-fortunaltely hydrochloride.

Get analogously to example 23. So pl. 140 - 143oC.

Example 26. N-{3-[2-(Pyridin-4-yl-amino)ethoxy]phenyl} benzosulfimide.

Get analogously to example 1. Oil. Mass spectrum: [E1]=383.

Example 27. N-{3-[2-(Pyridin-4-yl-amino)ethoxy]phenyl} -4-tert-butylbenzenesulfonamide.

Get analogously to example 1. Oil. Mass spectrum: [E1]=425.

Example 28. N-{3-[2-(Pyridine-imera 23. So pl. 235 - 237oC.

Example 29. N-{3-[2-(Pyridin-4-yl-amine)ethoxy]-phenyl}indan-5 - sulfonamide.

Get analogously to example 23 in the form of free base. So pl. 140oC (decomposition).

Example 30. N-{-[2-(Pyridin-4-yl-amino)ethoxy]-phenyl}-2 - biphenylcarboxylic.

Get analogously to example 23 in the form of free base. So pl. 214 - 216oC.

Example 31. N-Methyl-N-{5-methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl-4 - forbindelsesfaneblad hydrochloride.

Get analogously to example 23. So pl. 122 - 129oC. the starting material N-{ 5-methyl-3-[(pyridine-4-yl-aminocarbonyl)methoxy] phenyl} -4-forbindelsesfaneblad (mass spectrum: m/e=429) are obtained analogously to example 17.

Example 32. N-{5-Methyl-3-[2-(pyridin-4-yl-amino)-ethoxy]phenyl} -2-chloro-4-forbindelsesfaneblad hydrochloride.

Get analogously to example 23. So pl. 198 - 200oC. the starting material N-{ 5-methyl-3-[(pyridine-4-yl-aminocarbonyl)-methoxy] phenyl} -2-chloro-4-forbindelsesfaneblad (mass spectrum: m/e = 449) are obtained analogously to example 17.

Example 33. N-Methyl-N-{5-methyl-3-[2-(pyridin-4-yl-amino)ethoxy] phenyl}-2-tripersonality hydrochloride.

Get analogously to example 23. So pl. 203 - 207oC. the Source of prophetic which are square analogously to example 17.

Example 34. N-{5-Methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}-2 - methyl-benzosulfimide hydrochloride.

Get analogously to example 23. So pl. 135oC (decomposition). Starting material N-{5-methyl-3-[(pyridine-4-yl-aminocarbonyl)methoxy] phenyl}-2-methyl-benzosulfimide (mass spectrum: m/e = 411) are obtained analogously to example 17.

Example 35. N-Methyl-N-{5-Methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}-2 - methyl-forbindelsesfaneblad hydrochloride.

Get analogously to example 23. So pl. 146oC. the starting material N-methyl-N-{ 5-methyl-3-[(pyridine-4-yl-aminocarbonyl)methoxy] phenyl} -2-methyl-forbindelsesfaneblad (mass spectrum: m/e = 443) are obtained analogously to example 17.

Example 36. N-{5-Methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}-2 - methyl-4-forbindelsesfaneblad hydrochloride.

Get analogously to example 23. So pl. 193oC. the starting material N-methyl-N-{ 5-methyl-3-[(pyridine-4-yl-aminocarbonyl)methoxy] phenyl}-2-methyl-4-forbindelsesfaneblad (mass spectrum: m/e = 429) are obtained analogously to example 17.

Example 37. N-{5-Methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}-2 - methyl-5-forbindelsesfaneblad hydrochloride.

Get analogously to example 23. So pl. 246 - 247oC. the starting material N-{ 5-methyl-3-[(pyridine-4-yl-analogice example 17.

Example 38. N-Methyl-N-{5-Methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}-2 - methyl-5-forbindelsesfaneblad hydrochloride.

Get analogously to example 23. So pl. 165 - 166oC. the starting material N-methyl-N-{ 5-methyl-3-[(pyridine-4-yl-aminocarbonyl)methoxy] phenyl}-2-methyl-5-forbindelsesfaneblad (mass spectrum: m/e = 443) are obtained analogously to example 17.

Example 39. N-{5-Methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}-2,4 - diftorbenzofenonom hydrochloride.

Get analogously to example 23. So pl. 227 - 228oC. the starting material N-{ 5-methyl-3-[(pyridine-4-yl-aminocarbonyl)methoxy] phenyl} -2,4-diftorbenzofenonom (mass spectrum: m/e = 443, so pl. 194oC) are obtained analogously to example 17.

Example 40. N-{5-Methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl} - for 3,5 dimethyl-4-pyrazolylborate.

Get analogously to example 23 in the form of free base. So pl. 121oC. the starting material N-{5-methyl-3-[(pyridine-4-yl-aminocarbonyl)methoxy] phenyl} -3,5-dimethyl-4-pyrazolylborate (mass spectrum: m/e = 415) are obtained analogously to example 17.

Example 41. N-{ 5-Methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}-4 - forbindelsesfaneblad hydrochloride.

Get analogously to example 23. So pl. 232oC. the starting material N-{5-methyl-3-[(is>) are obtained analogously to example 17.

Example 42. N-{5-Methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}-2-forbindelsesfaneblad hydrochloride.

Get analogously to example 23. So pl. 263oC. the starting material N-{5-methyl-3-[(pyridine-4-yl-aminocarbonyl)methoxy] phenyl}-2-forbindelsesfaneblad (mass spectrum: m/e = 415) are obtained analogously to example 17.

Example 43. N-{5-Methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}-2 - triftoratsetilatsetonom hydrochloride.

Get analogously to example 23. So pl. 217 - 222oC. the starting material N-{ 5-methyl-3-[(pyridine-4-yl-aminocarbonyl)methoxy] phenyl}-2-trifluoromethyl-benzosulfimide (mass spectrum: m/e = 465) are obtained analogously to example 17.

Example 44. N-Methyl-N-{5-Methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}-4 - methylbenzenesulfonamide hydrochloride.

Get analogously to example 23. So pl. 180oC. the starting material N-methyl-N-{ 5-methyl-3-[(pyridine-4-yl-aminocarbonyl)methoxy] phenyl}-4-methylbenzenesulfonamide (mass spectrum: m/e = 425) are obtained analogously to example 17.

Example 45. N-{5-Methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}-2,6 diftorbenzofenonom hydrochloride.

Get analogously to example 23. So pl. 263oC. the starting material N-{5-methyl-3-[(pyridine-4 - analogously to example 17.

Example 46. N-{ 5-Methyl-3-[2-(pyridin-4-yl-amino)ethoxy] phenyl}-2 - hydroxy-3-tert-butyl-5-methyl-benzosulfimide hydrochloride.

a) of 27.2 g (of 87.0 mmol) ethyl ester (3-tert-butyloxycarbonyl-5-methylphenoxy)acetic acid (example 57 (b) in 300 ml of methanol is mixed with 50 ml (100 mmol) of 2 n sodium hydroxide solution and stirred for 3 hours at room temperature. The solvent was partially removed in vacuo, extracted with ethyl acetate, the aqueous phase is acidified with hydrochloric acid and extracted with ether. Dried and the solvent is removed in vacuum. Obtain 15.6 g (3-tert-butyloxycarbonyl-5-methylphenoxy)acetic acid, with so pl. 120 - 122oC.

b) Videolounge connection enter into interaction with 4-aminopyridine, as described in example 1), and receive amide N-(4-pyridinyl)-(3-tert-butyloxycarbonyl-5-methyl-phenoxy) acetic acid, with so pl. 204 - 205oC.

in) of 5.00 g (14.0 mmol) videolounge compounds mixed with 25 ml triperoxonane acid, stirred for 30 minutes at room temperature, alkalinized with sodium hydroxide solution and the precipitate is sucked off. Gain of 2.93 g (78%) of amide N-(4-pyridinyl)-3-(amino-5-methylphenoxy)acetic acid, with so pl. 163oC.

g) Videolounge what hodom 50%, and so pl. 208oC.

d) This compound is injected into the interaction with 2-hydroxy-3-tert-butyl-5-methyl-benzosulphochloride as described in example 1A), and obtain the target compound in an amorphous state. FAB-mass spectrum: M + H = 470.

Example 47. N-{5-Methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}-3 - benzothiazolesulfonamide hydrochloride.

Get as described in example 46. For this purpose, obtained in example 46 g), the compound is administered in cooperation with benzothiophen-3-sulphonylchloride. So pl. 130oC (decomposition).

Example 48. N-{5-Methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}benzo-2,3,1 - thiadiazole-4-sulfonamide hydrochloride.

Get analogously to example 46. For this purpose, obtained in example 46 g), the compound is administered in cooperation with benzo-2,3,1-thiadiazole-4-sulphonylchloride. So pl. 110oC.

Example 49. N-{5-Methoxy-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}-4-forbindelsesfaneblad hydrochloride.

a) 16.0 g (115 mmol) of 3-hydroxy-5-methoxy-phenol (G. Rodighiero, C. Antonello, II Farmaco, Ed. Sci., 10, 889 - 896 (1955)), 3,7 g of ammonium chloride, to 13.8 ml of water and 24 ml of concentrated ammonia in an autoclave with a capacity of 100 ml are heated for 12 hours at 130oC. After cooling, the contents of the autoclave, washed with methanol, rastvoritelei removed in vacuum, oily residue contribute to the Nooch with silica gel and optionally washed with a mixture of heptane to ethyl acetate in the ratio of 1:1. The solvent is removed from the filtrate and obtain 10.4 g of 3-hydroxy-5-methoxyaniline in the form of oil red.

b) the above compound (10.4 g, 75,0 mmol) in 100 ml of methylene chloride in the presence of 0.1 g of 4-dimethylaminopyridine will acetimidoyl with 100 ml of acetanhydride for 12 hours at room temperature. The solvent is removed in vacuo, to the residue (mainly diacetylene connection) add 200 ml of methanol and 20 ml of a saturated solution of sodium carbonate and stirred for 3 hours at room temperature. The solvent is removed in vacuo, add to the residue in 250 ml of water, acidified with conc. hydrochloric acid and extracted with ethyl acetate. Removal of solvent gives 11 g (81%) of N-(3-hydroxy-5-methoxy-phenyl)ndimethylacetamide with so pl. 126oC.

in) Videolounge connection (11,0 g, 61,0 mmol) in 100 ml of anhydrous dimethylformamide in the presence of 9.1 g (65 mmol) of potassium carbonate alkylate with 6.9 ml (65 mmol) of ethyl ester of Chloroacetic acid for 8 hours at 60oC. Diluted with water, acidified with hydrochloric acid and extracted with ethyl acetate. Organicheskoi Aut in vacuum. Obtain 10.8 g (66%) of ethyl ester of 2-(3-acetamido-5-methoxy-phenoxy)acetic acid in the form of butter.

g) This compound (10.8 g, 40 mmol) together with 30 ml of 2 n sodium hydroxide solution is stirred for 4 hours, the solvent is removed in vacuum, the residue is mixed with water and acidified. The precipitate is sucked off (5.5 g carboxylic acid), dissolved in 50 ml of ethanol, add 50 ml of 10 n sodium hydroxide solution and refluxed for 8 hours. Acidified using conc. hydrochloric acid, the solvent is removed in vacuo, add 100 ml of methanol and stirred for 12 hours at room temperature. The solvent is removed in vacuo, the residue with ethyl acetate, sucked off and obtain 5.6 g of methyl ester of 2-(3-amino-5-methoxy-phenoxy)acetic acid (mass spectrum: m/e = 211).

d) According to the procedure described in example 1A), by interacting videolooking connection with 4-forbindelsesfanebladet get methyl ester 2-[3-(4-forbindelseshandtering)-5-methoxy-phenoxy]acetic acid in the form of oil (mass spectrum: m/e = 369).

e) According to the method described in example 1B), from videolooking connection with the release of 95% receive 2-[3-(4-forbindelseshandtering)-5-IU spolucheni acid with a yield of 5% is given to N-(4-pyridinyl)-2-[3-(4-forbindelseshandtering)-5-methoxy-phenoxy] - the ndimethylacetamide with so pl. 161oC.

C) According to the procedure described in example 23, from videolooking connection get the target connection with the release of 76%, and so pl. 62oC.

Example 50. N-{ 3-[2-Pyridine-4-yl-amino)-ethoxy] phenyl}-2-chlorobenzene-sulfonamide.

Get analogously to example 1 with a yield of 58% So pl. 221-223oC.

Example 51. N-Methyl-N-{3-[2-(pyridin-4-yl-amino)-ethoxy]phenyl}-2-chlorobenzenesulfonamide.

Get analogously to example 12 with the release of 22% So pl. 188 - 190oC

Example 52. N-2-Propyl-N-{3-[2-pyridine-4-yl-amino)ethoxy]phenyl}-benzosulfimide.

Get analogously to example 12 with the release of 47%. Oil. Mass spectrum: m/ = 411.

Example 53. N-Methyl-N-{3-[2-(pyridin-4-yl-amino) ethoxy]phenyl}-2-thiophenesulfonyl.

Get analogously to example 12 with the release of 12%. So pl. 179 - 181oC.

Example 54. N-{5-Methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}-1-naphthalene-sulfonamide hydrochloride.

Get analogously to example 17 with the release of 14%. So pl. 215 - 218oC.

Example 55. N-{5-methyl-3-[2-(pyridin-4-yl-amino)ethoxy]phenyl}-2-thiophene-sulfonamide hydrochloride.

Get analogously to example 17 with the release of 24%. So pl. 252 - 254oC.

Example 56. N-{ 5-Methyl-3-[2-(PI 17 with the release of 42%. So pl. 254 - 258oC.

Example 57. N-Methyl-N-{5-methyl-3-{2-(pyridin-4-yl-amino)ethoxy]phenyl}-1 - chlorobenzenesulfonamide hydrochloride.

a) 96 g (0.78 mol) of 3-hydroxy-5-methylaniline (F. Wessely, H. Eibel, G. Frisdrich, Monatshefte Chem. , 83, 24-30 1952)) in 1.2 l of dioxane and 840 ml of water is mixed with 420 ml of 2 n sodium hydroxide solution and cooled with ice mixed with 171 g (0.78 mol) dicret-BUTYLCARBAMATE. Stirred for 12 hours at room temperature, the solvent is removed in vacuo, acidified with ice cooling to pH 2-3 and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and the solvent is removed in vacuum. Get 174 g (yield quantitative) of N-(tert-butyloxycarbonyl)-3-hydroxy-5-methylaniline in the form of oil. Mass spectrum: m/e = 233.

b) 132 g (0.59 mol) videolounge connection in 400 ml of anhydrous dimethylformamide, 90 g (of 0.65 mol) of potassium carbonate and 69 ml of 0.65 mol) of ethyl ester of Chloroacetic acid is heated at 70oC for 3 hours. Shake with 1 l of ice water, extracted with ethyl acetate, the organic phase is dried over sodium sulfate, filtered and the solvent is removed in vacuum. Get 174 g (95%) ethyl ester of 2-(3-tert-butyloxycarbonyl-5-methyl-phenoxy)acetic sour the m mixed with 200 ml triperoxonane acid, stirred for 2 hours at room temperature and the solvent is removed in vacuum. The residue is mixed with 2n., hydrochloric acid, extracted with ethyl acetate, the aqueous phase is alkalinized with sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and the solvent is removed in vacuum. Get to 87.5 g (74%) of ethyl ester of 2-(3-amino-5-methyl-phenyloxy)acetic acid in the form of oil. Mass spectrum: m/e = 209.

g) as described in example 17A) methodology this compound is injected into the interaction with 2-chlorobenzenesulfonamide and receive the ethyl ester of 2-[3-(2-chlorobenzenesulfonamide)-5-methyl-phenoxy] acetic acid, with a yield of 56%, and so pl. 133 - 137oC.

d) Videolounge the connection was identified in, as described in example 12A), and quantitative output gain ethyl ester of N-methyl-2-[3-(2-chlorobenzenesulfonamide)-5-methyl-phenoxy] acetic acid. Oil. Mass spectrum: m/e = 398.

(e) This compound amyraut as described in example 1B), and are obtained from a quantitative yield of N-methyl-2-[3-(2-chlorobenzenesulfonamide)-5-methyl-phenoxy]acetic acid. So pl. 113 - 115oC.

g) the Above compound is administered in cooperation with 4-aminopyrido the-pyridin-4-yl-ndimethylacetamide in the form of butter.

C) the connection Is restored, as described in example 1G), and obtain the target compound with a yield of 41%. So pl. 213 - 215oC.

Example 58. N-Methyl-N-{5-methyl-3-[2-[pyridin-4-yl-amino)ethoxy]phenyl}-benzosulfimide hydrochloride.

The compound of example 57 (0,86 g, 2 mmol) in 30 ml of ethanol hydronaut in the presence of 0.3 g of 10% palladium-on-coal at room temperature and normal pressure. Absorbed amount of hydrogen is 55 ml. Filtered off and the solvent is removed in vacuum. Insist with ether and obtain 0.75 g (86%) of target compound with so pl. 182-184oC.

Example 59. N-{2-Methoxy-5-[2-(pyridin-4-yl-amino)ethoxy]phenyl}- benzosulfimide.

a) To 8.5 g (50 mmol) 2-hydroxy-4-nitroanisole and 13.8 g (100 mmol) of potassium carbonate in 120 ml of acetonitrile using an ice bath was added dropwise to 8.4 g (50 mmol) of ethyl ether bromoxynil acid. Stirred for 12 hours at room temperature, the solvent is removed in vacuum, the residue is mixed with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and the solvent is removed in vacuum. Obtain 12.7 g (yield quantitative) ethyl ester 2-(2-methoxy-5-nitro-phenoxy)acetic acid in the form of oil.idronaut at normal pressure and room temperature. Once absorbed 3.4 liters of hydrogen, filtered and the solvent is removed in vacuum. Obtain 10.7 g (yield quantitative) ethyl ester 2-(2-methoxy-5-amino-phenoxy)acetic acid in the form of oil. Mass spectrum: m/e = 225.

in) Videolounge compound (10.7 g, 47 mmol) enter into interaction with benzosulphochloride as described in example 1A), and gain of 17.2 g (yield quantitative) ethyl ester 2-(2-methoxy-5-benzosulfimide-phenoxy)acetic acid. Mass spectrum: m/e = 413.

g) Of this compound according to the method of example 1B) gain of 11.8 g (74%) of 2-(2-methoxy-5-benzosulfimide-phenoxy)acetic acid. Mass spectrum: m/e = 337.

d) From videolooking connection, according to the method of example 1B), get 5 g (35%) of N-(4-pyridinyl)-2-(2-methoxy-5-benzosulfimide-phenoxy)ndimethylacetamide with so pl. 179oC.

e) From this compound, according to the method of example 23, to obtain the target compound with so pl. 188-189oC.

Example 60. N-{2-Methyl-5-[2-(pyridin-yl-amino)ethoxy]phenyl}benzosulfimide.

Get analogously to example 59, only in stage a) instead of 2-hydroxy-4-nitroanisole use 2-hydroxy-4-nitrotoluene. This is the original connection was obtained as follows: ua until until all is dissolved (30 minutes), add 2.5 kg of ice, cooled to -15oC and added dropwise a solution of 50 g of sodium nitrite in 200 ml of water so that the temperature did not exceed 0oC. This solution is added to boiling under reflux a mixture of 500 ml of concentrated sulfuric acid and 1 l of water. Refluxed for 1 hour, allowed to stand for 12 hours and the precipitate is sucked off. Get to 87.1 g (87%) of 2-hydroxy-4-nitrotoluene with so pl. 117-120oC.

a) Ethyl ester of 2-(2-methyl-5-nitro-phenoxy)acetic acid in the form of an oil; mass spectrum: m/e = 239.

b) Ethyl ester of 2-(2-methyl-5-amino-phenoxy)acetic acid in the form of an oil; mass spectrum: m/e = 209.

b) Ethyl ester of 2-(2-methyl-5-benzosulfimide-phenoxy)acetic acid, so PL 78-83oC.

g) 2-(2-methyl-5-benzosulfimide-phenoxy)acetic acid, so PL 157-160oC.

g) N-(4-pyridinyl)-2-(2-methyl-5-benzosulfimide-phenoxy)ndimethylacetamide with so PL 157-161oC.

e) target connection so pl. 179-180oC.

Example 61. 5-Methyl-3-[2-(pyridin-4-yl-amino)-ethoxy] phenyl ester benzosulfimide.

a) and 7.1 g (50 mmol) of 5-methylresorcinol, 10 g (100 mmol) of potassium bicarbonate and 12.6 g (55 mmol) of gasoline is the solvent removed in vacuum, to the residue water is added and extracted with ether, the ether phase is shaken out three times with 0.1 G. of sodium hydroxide solution, the ether phase is dried over sodium sulfate, filtered and the solvent is removed in vacuum. The remainder (of 7.75 g) share on silica gel using a mixture of isohexane with ethyl acetate (9: 1) and obtain 4.0 g (29%) of benzyl ester of 2-(3-hydroxy-5-methyl-phenoxy)acetic acid in the form of oil. Mass spectrum: m/e = 272.

b) 2.0 g (7.5 mmol) videolounge compounds enter into interaction with benzosulphochloride, analogously to example 1A), and obtain 2.1 g (68%) of benzyl ester of 2-(3-benzosulfimide-5-methyl-phenoxy)acetic acid in the form of oil. Mass spectrum: m/e = 412.

in) 2.0 g (5 mmol) of the compound from stage b) in 150 ml of methanol hydronaut in the presence of 0.5 g of 10% palladium-on-charcoal, for 1 hour at room temperature and normal pressure until it is absorbed in 140 ml of hydrogen. Filter, add ether and shaken out three times with sodium bicarbonate solution. Contains sodium bicarbonate solution is acidified with 2 N. sulfuric acid, extracted with ether, drying the extract obtained, the solvent is removed in vacuum and receive 600 mg (38%) of 2-(3-benzosulfimide-5-methylphenidate with 4-aminopyridine, analogously to example 1B), and obtain N-(pyridin-4-yl)-2-(3-benzazolyl-5-methyl-phenoxy)ndimethylacetamide (16%). Mass spectrum: m/e = 392.

d) From videolooking of ndimethylacetamide analogously to example 23 to obtain the target compound. So pl. 144-146oC.

Example 62. 5-Methyl-3-[2-(pyridin-4-yl-amino)-ethoxy]phenyl ester 2-chlorobenzenesulfonate.

Get analogously to example 61. So pl. 156-158oC.

Intermediate stage:

2-[3-(2-chlorobenzenesulfonyl)-5-methyl-phenoxy] acetic acid, so pl. 157-161oC;

N-(pyridine-4-yl)-2-[3-(2-chlorobenzenesulfonyl)-5-methyl-phenoxy] ndimethylacetamide, mass spectrum: m/e = 432.

Example 63. 5-Methyl-3-[2-(pyridin-4-yl-amino)-ethoxy]phenyl ether 4-fermentolisate,

Get analogously to example 61, only in stage b) using 4-fluoro-benzosulphochloride, so pl. 161-163oC.

Example 64. 5-Methyl-3-[2-(pyridin-4-yl-amino)-ethoxy]phenyl ether 1-naphthalenesulfonate.

Get analogously to example 61, only in stage b) using 1-naphthalenesulfonate. So pl. 95-99oC.

Example 65. 5-Methyl-3-[2-(pyridin-4-yl-amino)-ethoxy]phenyl ester 2-thiophenesulfonyl.

a) 24.8 g (200 mmol) of 5-methylresorcinol that 43.8 g (240 mmol) of 2-titansoderzhashchego the devices establish a pH of 7.2 with a saturated solution of sodium bicarbonate. Stirred for 12 hours at room temperature at a pH of 7.2, separating the aqueous phase, the ether phase is dried over sodium sulfate, filtered and the solvent is removed in vacuum. Get with a quantitative yield of 3-hydroxy-5-methyl-phenyl ester thiophenesulfonyl in the form of oil. Mass spectrum: m/e = 270.

b) Videolounge connection enter into interaction with ethyl ether bromoxynil acid, analogously to example 18a), and receive the ethyl ester of 2-[3-(2-thiophenesulfonyl)-5-methyl-phenoxy] acetic acid. Mass spectrum: m/e = 356.

From this connection, analogously to example 1B), get 2-[3-(2-thiophenesulfonyl)-5-methyl-phenoxy]acetic acid so pl. 142-143oC.

g) Of the above compounds analogously to example 1B), receive N-(pyridin-4-yl)-2-[3-(2-thiophenesulfonyl)-5-methyl - phenoxy]ndimethylacetamide. So pl. 136-138oC.

d) connection receive target connection so pl. 176oC.

Example 66. 5-Methyl-3-[2-(pyridin-4-yl-amino)-ethoxy]phenyl ester 2-benzyloxycarbonyl-benzosulfimide.

a) Analogously to example a) 5-methylresorcinol enter into interaction with ethyl ether bromoxynil acid and get the ethyl ester of 2-(3-hdroxy-5-methyl-Fogo connection by entering it in the interaction with the 2-benzyloxycarbonylamino receive the ethyl ester of 2-[3-(2-benzyloxycarbonyl)- benzosulfimide-5-methyl-phenoxy] acetic acid in the form of oil. Mass spectrum: m/e = 484.

in This connection omelet for 4 hours at room temperature, analogously to example 1B), and get 2-[3-(2-benzyloxycarbonyl-benzosulfimide)-5-methyl-phenoxy] acetic acid with a yield of 63%. Mass spectrum: m/e = 456.

g) From videolooking connection receive N-(pyridin-4-yl)-2-[3-(2-benzyloxycarbonyl-benzosulfimide)-5-methyl - phenoxy]ndimethylacetamide. Mass spectrum: m/e = 532.

d) Of this compound is analogous to example 23 to obtain the target compound. Mass spectrum: m/e = 518.

Example 67. 5-Methyl-3-[2-(pyridin-4-yl-amino)-ethoxy]phenyl ester of 2-carboxy-benzosulfimide.

2.5 g (1 mmol) of the compound from example 66 in 100 ml of methanolic ammonia solution hydronaut in the presence of 1 g of 10% palladium-on-charcoal, at normal pressure and room temperature. Filtered off, the solvent is removed in vacuo, the residue triturated with isopropanol, is sucked off and recrystallized from ethanol. Obtain 0.4 g (14%) of target compound with so pl. 189oC.

Example 68. 5-Methyl-3-[2-(pyridin-4-yl-amino)-ethoxy]phenyl ester of 2-methyl-benzosulfimide.

Get analogously to example 61. So pl. 152 - 154oC. the Original compound: N-(pyridin-4-yl)-2-[3-(2-methylben is Ino)-ethoxy]phenyl ester 2-methoxy-benzosulfimide.

Get analogously to example 51. So pl. 116 - 119oC. the Original connection (prestage): N-(pyridin-4-yl)-2-[3-(2-methoxy-benzosulfimide)-5-methyl-phenoxy]ndimethylacetamide. So pl. 156 - 159oC.

Example 70. 5-Methyl-3-[2-(pyridin-4-yl-amino)-ethoxy]-phenyl ester 2-nitro-benzosulfimide.

Get analogously to example 61. So pl. 137 - 140oC. the Original connection (prestage): N-(pyridin-4-yl)-2-[3-(2-nitro-benzosulfimide)-5-methyl-phenoxy]ndimethylacetamide; mass spectrum: m/e = 453.

Example 71. 5-Methyl-3-[2-(pyridin-4-yl-amino)-ethoxy]phenyl ester 2-amino-benzosulfimide.

1.0 g (2,33 mmol) of the compound from example 70 in 40 ml of methanol hydronaut in the presence of 1 g of Raney Nickel for 1.5 hours at room temperature and normal pressure. Filtered off, the solvent is removed in vacuum, the residue is mixed with 25 ml of tetrahydrofuran and 25 ml of ether, extracted with the help of 0.05 M sodium hydroxide solution, the organic phase is dried, filtered and the solvent is removed in vacuum. Obtain 0.5 g (54%) of target compound with so pl. 168 - 171oC.

Example 72. 5-Methyl-3-[2-(N-methyl-pyridine-4-yl-amino)ethoxy]phenyl ester 2-chlorobenzenesulfonate.

a) By reacting 2-[3-(2-chlorbenzoyl the DIN-4-yl)-2-[3-(2-chlorobenzenesulfonyl)-5-methyl-phenoxy] ndimethylacetamide. Mass spectrum: m/e = 447.

b) Of this compound is analogous to example 23 to obtain the target compound with so pl. 152 - 161oC.

Example 73. 5-Chloro-3-[2-(pyridin-4-yl-amino)-ethoxy]phenyl ester benzosulfimide.

a) 98,8 g (or 0.57 mmol) simple 5-chlororesorcinol-dimethyl ether and 108 ml (1,14 mmol) tribromide boron in 400 ml of methylene chloride is stirred for 72 hours at room temperature. Extracted with water, the aqueous phase is extracted with n-butanol, n-butanol is removed for the most part under vacuum and left to crystallize for 12 hours at 4oC. Obtain 19.5 g (24%) 5-chloro-resorcinol with so pl. 70 - 71oC.

b) 3.0 g (21 mmol) videolounge compound in 50 ml of water is mixed with 20 ml of ether, add a saturated solution of sodium bicarbonate until pH 5.2. While maintaining this pH-value added slowly to 8.6 ml (21 mmol) of benzosulfimide, increase the pH to 7 and stirred while maintaining a constant pH for 48 hours at room temperature. Extracted with ether, the ether phase is treated with 0.1 G. of sodium hydroxide solution, the solution with sodium liquor is acidified using 2 N. sulfuric acid and extracted three times with ether. The solvent is removed in vacuum and the obtained compound, analogously to example 18a), enter into interaction with ethyl ether bromoxynil acid and obtain ethyl ester 2-[3-chloro-5-(phenylsulfonyl)-phenoxy] acetic acid, with a yield of 95%. Mass spectrum: m/e = 370.

g) This compound omelet analogously to example 1B) to 2-[3-chloro-5-(phenylsulfonyl)phenoxy]acetic acid at the output of the last 80%. So pl. 136 - 138oC.

d) the Above compound analogously to example 1B), enter into interaction with 4-aminopyridine and get with the yield of 70% N-(pyridin-4-yl)-2-[3-chloro-5-(phenylsulfonyl)-phenoxy]ndimethylacetamide with so pl. 173 - 176oC.

e) Videolounge connection, analogously to example 23, restore and get the target connection with so pl. 144-146oC. the Hydrochloride: 173 - 176oC.

Example 74. 5-Chloro-3-[2-(pyridin-4-yl-amino)-ethoxy]phenyl ester 2-chlorobenzenesulfonate.

Get analogously to example 73. Intermediate stage:

b) 3-chloro-5-hydroxy-phenyl ester 2-chlorobenzenesulfonate, so pl. 99 - 105oC;

b) Ethyl ester of 2-[3-chloro-5-(2-chloro-phenylsulfanyl)-phenoxy]acetic acid in the form of oil, mass spectrum: m/e = 405

g) 2-[3-chloro-5-(2-chloro-phenylsulfonyl)phenoxy] acetic acid, so pl. 140 - 142oC;

d) N-(Pius, so pl. 149 - 150oC.

Example 75. 3-[2-(Pyridin-4-yl-amino)ethylamino] -phenyl ester benzosulfimide.

a) 15 g (54 mmol) of 3-nitrophenylamino ether benzosulfimide in 200 ml of methanol hydronaut in the presence of 2.5 g of 10% palladium-on-the angle at normal pressure and room temperature. Filtered off and the solvent is removed in vacuum. The residue (13 g 3-aminophenylamino ether betulifolia), 4.3 g of sodium acetate and 8.7 g of ethyl ether bromoxynil acid in 10 ml of ethanol is refluxed for 12 hours. Add water and extracted with ether. The ether is removed in vacuo and obtain 17.3 g (99%) of ethyl ester of 2-[3-(phenylsulfonyl)phenylamino]acetic acid in the form of oil. Mass spectrum: m/e = 335.

b) Videolounge connection omelet analogously to example 1B) to obtain 2-[3-(phenylsulfonyl)phenylamino] acetic acid. Yield 65%. Mass spectrum: m/e = 307.

C) Obtained in paragraph (b), the compound is administered in cooperation with 4-aminopyridine, analogously to example 1B), with N-(pyridin-4-yl)-2-[3-(phenylsulfonyl)phenylamino]ndimethylacetamide. Oil. Mass spectrum: m/e = 383.

g) connection receive target compound analogously to example 23. 0.6 g formed in videoslatinas acid in 10 ml of ethyl acetate. Add a few drops of isopropanol and left to crystallize. Obtain 0.3 g of ciclamino target connection so pl. 106 - 111oC.

Example 76. 3-Methyl-5-[2-(pyridin-4-yl-amino)-ethylamino] phenyl ester benzosulfimide.

a) 12.3 g (100 mmol) 3-hydroxy-5-methylaniline (see example 57) and 25.1 g (170 mmol) of phthalic anhydride in 250 ml of acetic acid is refluxed for 1 hour. Add 250 ml of water, the solution is filtered hot, the filtrate add 250 ml of water and left to crystallize. Filtered off, the residue is dissolved in 400 ml of hot methanol, mixed with active charcoal, the water is removed in vacuum and get to 21.7 g (86%) of 3-phthalimido-5-METHYLPHENOL with so pl. 170 - 175oC.

b) Analogously to example 1A), from the above-mentioned compounds with a quantitative yield obtained 3-methyl-5-phthalimido-phenyl ester benzosulfimide. Mass spectrum: m/e = 393.

in) of 3.9 g (10 mmol) videolounge connection and 0.7 ml (15 mmol) of hydrazine hydrate is added in 10 ml of ethanol and 30 ml of methylene chloride is stirred for 12 hours at room temperature, add 4 ml of concentrated hydrochloric acid, stirred for 2 hours at room temperature, filtered, the solvent is removed in the th, a saturated solution of sodium chloride, the ether is removed in vacuo and obtain 2.5 g (96%) of 3-methyl-5-amino-phenyl ether benzosulfimide. Mass spectrum: m/e = 263.

g) 2.5 g (9.5 mmol) videolounge in stage C) compounds analogously to example 1A) enter into interaction with mozillateam and get with a quantitative yield of 3-methyl-5-(4-methylphenylsulfonyl)-phenyl ester benzosulfimide. Mass spectrum: m/e = 417.

d) Videolounge connection, analogously to example 18a), alkylate using ethyl ester brauksanas acid and get 5 g (quantitative yield) of the ethyl ester [4-methylbenzenesulfonyl-(3-benzosulfimide-5-methyl-phenyl)amino] acetic acid. Mass spectrum: m/e = 503.

e) 5 g (10 mmol) of the above compound in 60 ml of 6 N. hydrochloric acid for 6 hours refluxed. The solvent is removed in vacuo, water is added, neutralized with sodium bicarbonate, extracted with ethyl acetate, using 2 N. hydrochloric acid in the aqueous phase set pH 3 and extracted with ethyl acetate. The ethyl acetate is removed in vacuo and receive 2 g (62%) (3 benzosulfimide-5-methyl-phenyl)amino-acetic acid. Mass spectrum: m/e = 321.

g) This compound is injected into the MFA with the release of 12%. Mass spectrum: m/e = 397.

C) From videolooking compounds analogously to example 23, to obtain the target compound in the form of oil. Mass spectrum: m/e = 383.

Example 77. N-{3-[2-(Pyridin-4-yl-amino)-ethylamino]phenyl}benzosulfimide.

a) 13.8 g (100 mmol) of 3-nitroaniline, 12.3 g of sodium acetate (150 mmol) and 25 g (150 mmol) of ethyl ether bromoxynil acid in 5 ml of dimethyl sulfoxide is heated at 80oC for 48 hours. Poured into 400 ml of 0.5 N. hydrochloric acid, add 15 ml of isohexane and 10 ml of ether and left to crystallize. Filtered off and get to 18.7 g (84%) of ethyl ester of 3-nitro-phenylamino-acetic acid. So pl. 92oC.

b) Analogously to example 1B), from videolooking connection receive 3-nitro-phenylamino-acetic acid with a yield of 90%. so pl. 159 - 162oC.

C) Analogously to example 1B) obtained in paragraph (b) connection receive N-(pyridin-4-yl)-3-nitrophenylamino-ndimethylacetamide with the release of 89%. So pl. 196 - 198oC.

g) 10,4 (38 mmol) videolounge compound in 200 ml of methanol and 100 ml of ethyl acetate hydronaut in the presence of 10 g of Raney Nickel at normal pressure and room temperature. The reaction mixture is filtered, the solution is removed under vacuum and get to 7.7 g (82%) of N-(pyridine-4-andget N-(pyridin-4-yl)-(3-phenylcarbonylamino-phenylamino)-ndimethylacetamide with yield 68%. Mass spectrum: m/e = 382.

e) From above in p. D.) compounds as in example 23 to obtain the target compound with a yield of 40%. Mass spectrum: m/e = 368.

Example 78. N-{ 3-[2-Pyridine-4-yl-amino)-ethylamino] phenyl}thiophenyl-2-sulfonamide.

a) By reacting the compound from example 77g) 2-thiophenesulfonyl, analogously to example 1A), receive N-(pyridin-4-yl)-[3-(thiophene-2-yl-sulfonylamino)phenylamino] ndimethylacetamide with yield 59%. Mass spectrum: m/e = 388.

b) From videolooking compounds analogously to example 23 to obtain the target compound with a yield of 24%. So pl. 196 - 198oC.

Example 79. N-{3-[2-(pyridin-4-yl-amino)ethylamino]-5-triptoreline} benzosulfimide.

a) To 24.5 g (100 mmol) of 3,5-dinitrobenzotrifluoride in 180 ml of boiling glacial acetic acid are added in several portions 15 g (270 mmol) of iron powder. Pour water, extracted with ethyl acetate and an ethyl acetate phase is neutralized with solid sodium bicarbonate. Filtered off, the solvent is removed in vacuo, the residue (26,3 g) is applied onto silica gel and elute with isohexane with ethyl acetate (8:2). Get 13,0 g (63%) of 3-nitro-5-triptorelin with so pl. 80 - 84oC.

b) 5.0 g (24 mmol) videolounge compounds dissolved water. A cold solution make 250 ml of boiling concentrated solution of copper sulphate. After excretion, the reaction mixture is extracted with ether. The ether phase is extracted with the help of 0.05 n sodium hydroxide solution, the aqueous phase is acidified with dilute sulfuric acid and extracted with ether. The ether is removed in vacuo and obtain 3.4 g (68%) of 3-nitro-5-triptoreline with so Kip. 82 - 84oC.

C) to 36.7 g (600 mmol) of ethanolamine and 80.7 g (550 mmol) of phthalic anhydride in 290 ml of toluene for 2 hours, refluxed when using the water separator. After separation of 9.3 ml of water leave the mixture to cool, filtered and receive 95,1 g (90%) of N-(2-hydroxyethyl)-phthalimide with so pl. 128 - 132oC.

g) 28.8 g (150 mmol) videolounge connection and 42.9 g (225 mmol) of tosylchloramide in 200 ml of pyridine is stirred for 3 hours at room temperature, acidified with 2 N. hydrochloric acid and extracted with ethyl acetate.

The ethyl acetate is removed under vacuum and get to 48.3 g (85%) 2-phthalimido-ethyl ester 4-toluenesulfonic acid with so pl. 144-148oC.

d) 1.7 g (12,5) mmol videolooking connection, 2.6 g (12.5 mmol) of the compound from example V) and 4.1 of potassium carbonate in 80 ml Dima is raybaut with the help of 0.01 N. solution of sodium hydroxide and a saturated solution of sodium chloride, the ethyl acetate is removed in vacuo and gain of 1.9 g (40%) of N-{2-[2-3-nitro-5-trifluoromethyl-phenoxy)ethyl]}phthalimide with so pl. 146 - 148oC.

e) Analogously to example V), videolooking connection quantitatively obtain 2-(3-nitro-5-trifluoromethyl-phenoxy)ethylamine. Mass spectrum: m/e = 250.

g) 10 g (4 mmol) of this compound and 1.15 g (4.4 mmol) of 4-nitrotyrosination (M. Roberts, H. Suschitzky, t.Chem. Soc. 1968, 2844 - 2848) and of 0.48 ml (4.4 mmol) of N-methylmorpholine in 20 ml of dioxane is stirred for 3 hours at room temperature. Add water, extracted with ethyl acetate, an ethyl acetate phase is washed with water and saturated sodium chloride solution, the ethyl acetate is removed under vacuum and obtain 1.4 g (75%) of N-(tetrachloropyridine-4-yl)-2-(3-nitro-5-trifluoromethyl-phenoxy)ethylamine with so pl. 126 - 129oC.

C) This compound is similarly restore stage a) and obtain N-(tetrachloropyridine-4-yl)-2-(3-amino-5-trifluoromethyl-phenoxy)ethylamine with so pl. 144 - 146oC.

and) 0.4 g (0,92 mmol) videolounge connection and 0.12 ml (0,92 mmol) benzosulfimide in 5 ml of pyridine is stirred for 3 hours at room temperature, acidified with 2 N. hydrochloric acid, extracted ethylacetamide-4-yl-amino)ethoxy]-5-triptoreline} benzosulfimide with so pl. 139 - 143oC.

K) 0.4 g (0.7 mmol) videolounge compound in 50 ml of methanol in the presence of 3.5 mmol of sodium methylate and 0.5 g of 10% palladium-on-coal hydronaut at room temperature and normal pressure. The reaction mixture is filtered. Add water and extracted with ethyl acetate. The ethyl acetate is removed under vacuum and obtain 0.2 g of the target compound with so pl. 140 - 144oC.

Example 80. 3-Methoxy-N-methyl-N-phenyl-5-[2-(pyridin-4-yl-amino)-ethoxy] benzosulfimide.

a) 92 g (0.4 mol) of 3,5-dinitrobenzamide and 28.4 g (0.44 mol) of sodium azide in 240 ml of glacial acetic acid is stirred for 8 hours at room temperature, add 400 ml of water, the precipitate is filtered off and get to 80.8 g (85%) of 3,5-dinitrobenzoate with so pl. 105oC (decomposition).

b) to 80.8 g (0.34 mol) of this compound in 500 ml of acetic anhydride gently heated before gassing (90 - 100oC) and incubated for 4 hours at this temperature. The solvent is removed in vacuo, the residue insist with water to give 136 g (yield quantitative) N-(3,5-dinitrophenyl) ndimethylacetamide with so pl. 163oC.

in) 136 g (0.34 mol) obtained in stage b) compounds in 500 ml of ethanol and 500 ml of concentrated hydrochloric acid boiling Trat poured into 2 l of water and sucked off yellow precipitate; get to 41.4 g (66%) of 3,5-dinitroaniline. So pl. 140oC (decomposition).

g) 25 g (137 mmol) obtained in stage C) compounds dissolved in 50 ml of glacial acid and 100 ml of concentrated hydrochloric acid at -5oC was added dropwise 10.4 g (155 mmol) of sodium nitrite in 20 ml water for 5 minutes, stirred for further 15 minutes at this temperature, the brown suspension is cooled to -20oC for 15 minutes, add it to the cooled to 0oC and saturated with sulfur dioxide to a solution of 2.7 g of dihydrate of copper dichloride in 200 ml of glacial acetic acid. Extracted with ethyl acetate, the ethyl acetate is removed in vacuo and the residue is dried at 10-2Torr. Get of 35.4 g (97%) of dinitrobenzenesulfonyl in the form of a brown solid which is used without further purification.

d) Of 10.2 g (38,2 mmol) obtained in stage g) connection and 4.5 ml (42 mmol) of N-methylaniline analogously to example I) obtain 4.9 g (38%) of N-methyl-N-phenyl-3,5-dinitrobenzenesulfonic with so pl. 175-178oC.

e) 3.5 g (10.4 mmol) videolounge in stage d) compounds in 31 ml of 0.4 M methanolic solution of sodium methylate for 1 hour and refluxed. The solvent is removed in vacuo, the residue insist with it in the ratio 2:1 and obtain 2.5 g (75%) of N-methyl-N-phenyl-3-methoxy-5-nitrobenzenesulfonamide. So pl. 112oC.

g) Obtained in stage e) connection hydronaut analogously to example 5% and obtain 2.3 g of N-methyl-N-phenyl-3-methoxy-5-amino-benzosulfimide in the form of oil. Mass spectrum: m/e= 292.

C) To a cooled to 0oC suspension of 2.3 g (7.8 mmol) obtained in stage g) of the compound in 10 ml of water and 5 ml of concentrated sulfuric acid was added dropwise a solution of 630 mg (9 mmol) of sodium nitrite in 2 ml of water, stirred for 2 hours at this temperature, the mixture is decomposed with urea, heated for 15 minutes at 110oC, extracted with ethyl acetate, an ethyl acetate phase is washed with 2 n sodium hydroxide solution, the solvent is removed in vacuum and receive 300 mg (13%) N-methyl-N-phenyl-3-methoxy-5-hydroxy-benzosulfimide in the form of oil. Mass spectrum: m/e = 293.

and) 250 mg (0.85 mmol) obtained in stage C) compounds alkylate with the help of 0.14 ml bromoxynil ether analogously to example 18a) and get 360 g (yield quantitative) ethyl ester [3-methoxy-5-(methyl-phenyl-sulfamoyl)phenoxy] acetic acid in the form of oil. Mass spectrum: m/e = 379.

to This connection omelet analogously to example 1B) and receive 300 mg of [3-methoxy-5-(methyl-phenyl-sulfamoyl)phenoxy] acetic acid as a viscous mass. The mass spectrum of ridin-4-yl)-[3-methoxy-5-(methyl-phenyl-sulfamoyl)phenoxy]ndimethylacetamide. So pl. 105oC.

m) From 100 mg of this compound analogously to example 1G) receive 45 mg (46%) of target compound. Mass spectrum:m/e = 413.

Example 81. 3-Methoxy-N-benzyl-N-phenyl-5-[2-(pyridin-4-yl-amino)ethoxy] benzosulfimide.

a) Analogously to example 80g), from the compound of example 80) and N-benzylaniline get N-benzyl-N-phenyl-3,5-dinitrobenzenesulfonic with the release of 65%, and so pl. 200oC.

b) Analogously to example d), videolooking (stage a)) connection with a quantitative yield of receive N-benzyl-N-phenyl-3-methoxy-5-nitro-benzosulfimide. So pl. 142oC.

b) Of this compound is analogous to example 79A) receive N-benzyl-N-phenyl-3-methoxy-5-amino-benzosulfimide with the release of 56% in the form of a viscous mass. Mass spectrum: m/e = 368.

From videolooking compounds analogously to example I) receive N-benzyl-N-phenyl-3-methoxy-5-hydroxy-benzosulfimide. Mass spectrum: m/e = 369.

d) From this compound analogously to example 1A) are obtained ethyl ester [3-methoxy-5-(benzylpenicilloyl)phenoxy] acetic acid with 30% yield. Mass spectrum: m/e = 455.

e) obtained in stage d) compound analogously to example 1B), quantitatively obtain [3-methoxy-5-(methyl-phenylsulfanyl)-PV) opening 42% receive N-(pyridin-4-yl)-[3-methoxy-5-(methyl-phenyl-sulfamoyl)phenoxy] ndimethylacetamide with so pl. 175oC.

C) From this compound, in turn, analogously to example 1G) get the target connection with the release of 50% in the form of amorphous powder. Mass spectrum: m/e = 489.

Example 82. 3-Methoxy-N-phenyl-5-[2-(pyridin-4-yl-amino) ethoxy] benzosulfimide.

60 g (0.12 mmol) of the compound from example 81 hydronaut analogously to example 58 and receive 20 mg (40%) of target compound as amorphous powder. Mass spectrum:m/e=399.

Example 83. N-Methyl-N-{3-(2-pyridin-4-yl-amino)ethoxy]-5-methoxy-phenyl} -benzosulfimide.

a) to 18.3 g (100 mmol) of the compound from example 80), analogously to example I), enter into interaction with 14.3 g (110 mmol) of benzosulfimide and gain of 32.5 g (yield quantitative) N-(3,5-dinitrophenyl) benzosulfimide. So pl. 165oC.

b) 44 g (136 mmol) of the obtained compound will was identified in analogously to example 12A) and gain of 25.1 g (54%) of N-methyl-N-(3,5-dinitro-phenyl)benzosulfimide with so pl. 125oC.

in) 6.8 g (20 mmol) videolounge connections restore analogously to example 79A) and gain of 6.1 g (yield quantitative) N-methyl-N-(3-amino-5-nitro-phenyl) benzosulfimide in the form of amorphous powder. Mass spectrum: m/e = 307.

g) of 6.1 g (20 mmol) of this compound is analogous p-spectrum: m/e = 308 (380 after sililirovanie).

d) 1.2 g (4 mmol) videolounge connection, 6 ml of 1 n sodium hydroxide solution, 1, 3 tetrabutylammonium, 6 ml of dichloromethane and 0.4 ml of iodomethane stirred for 12 hours at room temperature. The organic phase is separated, the solvent is removed in vacuum and the residue is purified by using silica gel (150 g). Elute with a mixture of isohexane with ethyl acetate in the ratio of 2:1 and receive 240 (18%) of N-methyl-N-(3-methoxy-3-nitrophenyl)-benzosulfimide with so pl. 136oC.

(e) This compound hydronaut analogously to example 58 and quantitatively obtain N-methyl-N-(3-methoxy-5-AMINOPHENYL)benzosulfimide in the form of amorphous powder. Mass spectrum: m/e = 292.

f) Analogously to example I), videolooking connection with the yield 74% receive N-methyl-N-(3-methoxy-5-hydroxyphenyl]benzosulfimide in the form of atmospheric powder. Mass spectrum: m/e = 293.

C) Analogously to example 18a), this connection receive ethyl ester [3-methoxy-5-(N-methylphenylsulfonyl-amino) phenoxy]acetic acid, with a yield of 89% in the form of amorphous powder.

Mass spectrum: m/e = 379.

and) Analogously to example a), videolooking connection receive [3-methoxy-5-(N-methyl-phenylsulphonyl-amino)phenoxy] acetic acid (74%, Mar: m/e = 427) and the target compound in the form of an amorphous powder, mass spectrum: m/e = 413.

Example 84. 3-Chloro-N-methyl-N-phenyl-5-[2-(pyridin-4-yl-amino) ethoxy]-benzosulfimide.

a) Compound of example d) restore analogously to example 79A) and get N-methyl-N-phenyl-3-amino-5-nitrobenzenesulfonamide with the release of 50%, and so pl. 175oC.

b) To 3.5 g (10 mmol) videolounge compound in 40 ml of 6 N. hydrochloric acid at 0oC was added dropwise a solution of 760 mg (11 mmol) of sodium nitrite in 2 ml of water and then the resulting suspension was poured into the solution, which is prepared as follows: 3.75 g of the pentahydrate of copper sulfate and 1.35 g of NaCl dissolved in 12 ml of warm water to the obtained solution was added dropwise a solution of 950 mg (7.5 mmol) of sodium sulfate in 3 ml of water, the residue is quickly filtered and dissolved it in 6 ml of concentrated hydrochloric acid. Slowly heated to 100oC, cooled, extracted with ethyl acetate and filtered through silica gel (100 g of silica gel). Elute with a mixture of isohexane with ethyl acetate and obtain 1.45 g (43%) of N-methyl-N-phenyl-3-chloro-5-nitro-benzosulfimide. So pl. 143oC.

in This connection quantitatively recovered as in example 79A) to obtain N-methyl-N-phenyl-3-chloro-5-amino - benzosulfimide. Amorphous powder. Mass spectrum: m/e = 296.

Example 85. 3-Chloro-N-benzyl-N-phenyl-5-[2-(pyridin-4-yl-amino) ethoxy]-benzosulfimide.

a) 12.3 g (46 mmol) of the compound of example 80g) analogously to example I) enter into interaction with 9.2 g (50 mmol) of benzylamine and get 31,3 g (83%) of N-benzyl-N-phenyl-3,5-dinitrobenzenesulfonic with so pl. 205oC.

b) the connection Is restored as in example 79A) and get quantified N-benzyl-N-phenyl-3-amino-5-nitrobenzenesulfonamide. So pl. 170oC.

C) Analogously to example b), obtained from the last connection receive N-benzyl-N-phenyl-3-chloro-5-nitro-benzosulfimide with the release of 37%. So pl. 160oC.

d) Analogously to example a) - g) receive the following compounds: N-benzyl-N-phenyl-3-chloro-5-amino-benzosulfimide (yield quantitative, and who, amorphous substance, mass spectrum: m/e = 373); ethyl ester of [3-chloro-5-(benzyl-phenyl-sulfamoyl)phenoxy]acetic acid (15%, oil, mass spectrum: m/e = 459); [3-chloro-5-(benzyl-phenyl-sulfamoyl)phenoxy] acetic acid (50%, amorphous substance, mass spectrum: m/e = 431); N-(pyridine-4-yl)- [3-chloro-5-(benzyl-phenyl-sulfamoyl)phenoxy] ndimethylacetamide (44%, amorphous substance, mass spectrum: m/e = 507); the target compound (40%, amorphous substance, mass spectrum: m/e = 493).

Example 86. 3-Chloro-N-benzyl-N-phenyl-5-[2-(pyridin-4-yl-amino) ethylamino] benzosulfimide.

From N-benzyl-N-phenyl-3-chloro-5-amino-benzosulfimide (example 85g)), analogously to example s), obtain the following compounds: ethyl ester of [3-chloro-5-(benzyl-phenyl-sulfamoyl)phenylamino] acetic acid (18%, oil, mass spectrum: m/e = 458); [3-chloro-5-(benzyl-phenyl-sulfamoyl)phenylamino]acetic acid (yield quantitative); amorphous substance, mass spectrum: m/e = 430); N-(pyridine-4-yl)-[3-chloro-5-(benzyl-phenyl-sulfamoyl)phenylamino] ndimethylacetamide (25%, amorphous substance, mass spectrum: m/e = 206); the target connection (50%, amorphous substance, mass spectrum: m/e = 492).

Example 87. N-Methyl-N-{ 3-[2-(pyridin-4-yl-amino)ethoxy] phenyl} benzosulfimide.

a) N-methyl-N-(3-amino-5-nitro-phenyl)benzosulfimide (example V)), analogues of which: m/e = 326).

b) Received last connection restore analogously to example 79A) to obtain N-methyl-N-(3-chloro-5-AMINOPHENYL)benzosulfimide (42%, oil, mass spectrum: m/e = 296). Next get the ethyl ester of [3-chloro-5-(N-methyl-phenylcarbonylamino)phenoxy] acetic acid (89%, amorphous substance, mass spectrum: m/e = 383); [3-chloro-5-(N-methyl-phenylcarbonylamino)phenoxy] acetic acid (88%, mass spectrum: m/e = 355); N-(pyridine-4-yl)-[3-chloro-5-(N-methyl-phenylcarbonylamino) phenoxy] the ndimethylacetamide (28%), mass spectrum: m/e = 431) and the target compound (56% in the form of amorphous powder. Mass spectrum: m/e = 417).

Example 88. N-Benzoyl-N-3-[2-(pyridin-4-yl-amino)ethoxy]-5 - chlorophenyl-benzosulfimide.

a) Analogously to example V), the compound of example 83A) benzilic using benzylbromide and get N-benzyl-N-(3,5-dinitrophenyl)benzosulfimide (yield quantitative); so pl. 170oC.

b) Obtained above connection restore analogously to example 79A) and receive 27% N-benzyl-N-(3-amino-5-nitrophenyl)benzosulfimide in the form of amorphous powder. Mass spectrum: m/e = 383.

in) From videolooking compounds analogously to example b) receive N-benzyl-N-(3-chloro-5-nitrophenyl)benzosulfimide with the release of 45%. So pl. 148oC.

g) Wirepaladin the amide. So pl. 145oC.

d) Analogously to examples I) - I), videolooking connection will receive the following compounds: N-benzyl-N-(3-chloro-5-hydroxyphenyl)benzosulfimide (yield quantitative, amorphous substance, mass spectrum: m/e = 373); ethyl ester of [3-chloro-5-(N-benzyl-phenyl-sulfonyl-amino)phenoxy] acetic acid (yield quantitative, amorphous substance, mass spectrum: m/e = 459); [3-chloro-5-(N-benzyl-phenylsulphonyl-amino)phenoxy] acetic acid (82%, so pl. 180oC (decomposition); N-pyridin-4-yl)-[3-chloro-5-(N-benzylphenylglyoxylamide] phenoxy]ndimethylacetamide (54%, so pl. 178oC) and the target compound in the form of an amorphous powder. Mass spectrum: m/e = 493.

Example 89.

N-{3-[2-(Pyridin-4-yl-amino)-ethylamino]-5-bromo-phenyl}-benzosulfimide.

(a) to 18.3 g (100 mmol) of 3,5-dinitroaniline (example 80) in 100 ml of glacial acetic acid and 100 ml of 47% aqueous Hydrobromic acid at 0oC was added dropwise a solution of 7.6 g (110 mmol) of sodium nitrite in 15 ml of water for 15 minutes and then proceed as described in example b). Gain of 21.7 g (88%) of 3,5-dinitro-bromine benzol. So pl. 65oC.

b) Videolounge connection restore analogously to example 79A) and get to 17.4 g (91%) of 3-bromo-5-nitroaniline. So pl. 105oC.

5-nitrophenylamino-acetic acid as an amorphous substance. Mass spectrum: m/e = 303.

g) Videolounge connection omelet analogously to example 1B) and receive bromo-5-nitrophenylamino-acetic acid (22%, amorphous substance, mass spectrum: m/e = 274).

d) Received last connection transform analogously to example 1B) and get N-(pyridin-4-yl)-(3-bromo-5-nitrophenylamino)-ndimethylacetamide with 29%, and so pl. 240oC.

(e) This compound hydronaut analogously to example 58 and receive with a quantitative yield of N-(pyridine-4-yl)-(3-bromo-5-AMINOPHENYL-amino)ndimethylacetamide. Amorphous substance. Mass spectrum: m/e = 321.

f) Analogously to example I), videolooking connection receive N-(pyridin-4-yl)-[3-bromo-5-benzosulfimide-amino] ndimethylacetamide in the form of an amorphous substance. Mass spectrum: m/e = 460.

C) From this compound analogously to example 1G) get the target compound in the form of an amorphous substance. Mass spectrum: m/e = 446.

Example 90. 3-Ethyl-5-[2-(pyridin-4-yl-amino)ethoxy]phenyl ester benzosulfimide.

a) 20 g of 3,5-dimethoxybenzoic acid (110 mmol) in 80 ml of thionyl chloride for 1 hour and refluxed. The solvent is removed in vacuum, the residue is treated with 500 ml of anhydrous methylene chloride and through the ice dissolve dilaut in vacuum, the residue was stirred for 12 hours in 200 ml of water and 50 ml saturated sodium hydrogen carbonate solution is filtered, the residue is dissolved in ethyl acetate, filtered through activated charcoal and the ethyl acetate removed until the beginning of crystallization. Obtain 10.8 g of 3,5-dimethoxybenzamide. So pl. 145oC.

b) To 7.6 g (310 mmol) of magnesium in 10 ml of anhydrous ether was added dropwise to 19.5 ml (310 mmol) of iodomethane in 30 ml of ether for 30 minutes, refluxed and then added in several portions of 11.6 g (63 mmol) of 3,5-dimethoxybenzamide. For 22 hours refluxed under ice cooling was added dropwise 125 ml 6 N. hydrochloric acid, stirred for 16 hours at room temperature, the organic phase is washed with water, the solvent is removed in vacuum and obtain 9.4 g of 3,5-dimethoxy-acetophenone in the form of oil. Mass spectrum: m/e = 180.

in) 9.4 g (52 mmol) videolounge compound in 150 ml of ethanol and 2 ml of concentrated hydrochloric acid hydronaut in the presence of 1 g of palladium at the 50oC and a pressure of 6 bar. Filtered off, the solvent is removed in vacuum and obtain 6.8 g (7%) 3.5-dimethoxyaniline in the form of oil, mass spectrum: m/e = 166.

g) 6.8 g (41 mmol) of this compound in 65 ml of glacial acetic acid and 25 ml coil removed in vacuum, to the residue water is added, extracted with ethyl acetate, an ethyl acetate phase is washed with water, the solvent is removed in vacuum and the residue is filtered over silica gel (isohexane/ethyl acetate = 3:1). Gain of 3.9 g (69%) 5-ethylresorcinol in the form of oil. Mass spectrum: m/e = 138.

d) of 3.9 g (28 mmol) videolounge connection and 4.3 ml (33 mmol) of benzosulfimide in 30 ml of ether and 60 ml of saturated sodium hydrogen carbonate solution is stirred for 48 hours at room temperature. The ether phase is separated, the solvent is removed in vacuum, the residue is filtered through silica gel (isohexane/ethyl acetate = 3:1) and gain of 5.4 g (69%) of 3-hydroxy-5-metilfenidato ether benzosulfimide in the form of oil. Mass spectrum: m/e = 278.

e) Analogously to examples d) - s), this connection will receive the following connections:

ethyl ether (3 benzosulfimide-5-ethyl-phenyloxy)acetic acid (77%, oil, mass spectrum: m/e = 364);

(3 benzosulfimide-5-ethyl-phenyloxy)acetic acid (59% amorphous substance, mass spectrum: m/e = 336);

N-(pyridine-4-yl)-(3-benzosulfimide-5-ethyl-phenoxy)ndimethylacetamide (70%, amorphous substance, mass spectrum: m/e = 412);

the target compound (10%, so pl. 136oC).

Example 91. N-Benzyl-N-3-[2-(pyridin-4-yl-am the lead in the interaction with p-mozillateam and get 280 g (yield quantitative) of N-(4-were)-4-methyl-benzosulfimide in the form of oil, which enter into interaction further without further purification. Crystals from ether so pl. 105oC.

b) 21 g (80 mmol) of this compound under ice cooling contribute in 56 ml of fuming nitric acid is then slowly added dropwise 32 ml of concentrated sulfuric acid, poured on ice, the precipitate washed with water to give 46.6 g (73%) of yellow solids with so pl. 170oC, which in 80 ml of concentrated sulfuric acid for 10 minutes, heated at 100oC, poured into ice water and extracted with ethyl acetate. The solvent is removed in vacuum and receive a 20 g (88%) of 2,6-dinitro-4-methylaniline with so pl. 171oC.

C) To 20.5 g (300 mmol) of sodium nitrite in 220 ml of sulfuric acid, add 800 ml of glacial acetic acid and portions enter to 53.5 g (270 mmol) of 2,6-dinitro-4-methylaniline, stirred for 3 hours at 40oC until complete dissolution and the solution was added dropwise to ice suspension of 20 g of copper oxide in ethanol, the solvent is removed in vacuo, water is added and extracted with ethyl acetate. This mixture is filtered a second time and get 88 g (88%) of 3,5-dinitrotoluene in the form of amorphous powder.

g) 88 g (480 mmol) of this compound in 520 ml of methanol saturated with 53 g of ammonia and ZAT is Atat under reflux, poured into 1 l of water and get of 60.5 g (82%) of 3-methyl-5-nitroaniline with so pl. 97oC.

d) Analogously to example I), videolooking connection receive N-(3-methyl-5-nitrophenyl)benzosulfimide (yield quantitative) so pl. 165oC.

e) Analogously to examples a) - 88B), obtained in stage d) connection receive N-benzyl-N-(3-methyl-5-nitrophenyl)benzosulfimide (83%) with T. pl. 154oC and N-benzyl-N-(3-methyl-5-AMINOPHENYL)benzosulfimide (34%), amorphous substance, mass spectrum: m/e = 352.

f) Analogously to examples d) - s), videolooking compounds have the following connections:

ethyl ester of [3-(benzazolyl-benzylamino)-5-methyl-phenylamino]acetic acid (yield quantitative, oil, mass spectrum: m/e = 438;

[3-(benzazolyl-benzylamino)-5-methyl-phenylamino] acetic acid (90%, amorphous substance, mass spectrum: m/e = 410);

N-(pyridine-4-yl)-[3-(benzazolyl-benzylamino-5-methyl - phenylamino]ndimethylacetamide (10%, amorphous substance, mass spectrum: m/e = 486);

the target compound (47%, amorphous substance, mass spectrum: m/e = 472).

Example 92. Ethyl ether (benzazolyl-3-methyl-5-[2-(pyridin - 4-yl-amino)-ethoxy]phenyl)amino acetic acid.

a) 100 g of 4-nitro-tetrachloropyridine and 5 is IU, add water to the residue, extracted with ethyl acetate, an ethyl acetate phase is washed with water, remove the solvent in vacuo and get 105 g (72%) of 4-(2-hydroxyethyl-amino)tetrachloropyridine. So pl. 131-133oC.

b) of 36.3 g (130 mmol) of this compound and 12.1 ml (170 mmol) of acetylchloride in 450 ml of glacial acetic acid was stirred for 12 hours at room temperature, poured on ice, neutralized with concentrated ammonia and extracted with ethyl acetate, an ethyl acetate phase is washed with water, the solvent is removed in vacuum and get to 41.6 g (99%) of 2-(tetrachloropyridine-4-yl-amino)ethyl ester of acetic acid. So pl. 72-75oC.

C) To 109 g (340 mmol) of this compound in 700 ml of anhydrous dimethylformamide add a suspension of 10.8 g of sodium hydride in 150 ml of dimethylformamide and then with 10oC was added dropwise a solution of 54 ml of benzylbromide in 350 ml of dimethylformamide. Stirred for 2 hours at room temperature, poured into 7 l of ice water, filtered, the precipitate washed with water, dissolve it in 800 ml of methanol and 200 ml of dichloromethane, concentrated until the beginning of crystallization and left to crystallize. Get 120 g of 2-(benzyl-tetrachloropyridine-4-yl-amino)ethyl ester of acetic acid, so pl. 97-100oC.

-2Torr), to the residue add 3 l of water and extracted with 1 l of ethyl acetate, an ethyl acetate phase is washed with 3 l of water, the solvent is removed in vacuum and get 99 g (quantitative yield) of N-benzyl-N-(2-hydroxyethyl)-N-(tetrachloropyridine-4-yl)amine in the form of oil. Mass spectrum: m/e = 366.

d) and 107 g (290 mmol) videolounge connection in 800 ml of dichloromethane added 73 ml (520 mmol) of triethylamine, cooled to 0oC and added dropwise a solution of 67.1 g (350 mmol) of 4-toluensulfonate in 500 ml of dichloromethane. The solution was incubated for 16 hours at 4oC, add water, the organic phase is separated and the solvent is removed in vacuum. Get 90,6 g (64%) 2-benzylacrylamide-4-yl-amino)-ethyl ester 4-toluenesulfonic acid. So pl. 114-116oC.

e) to 57.2 g (240 mmol) of this compound, to 64.8 g (260 mmol) of 3-phthalimido-5-METHYLPHENOL (example 76A)) versus 66.2 g (480 mmol) of potassium carbonate in 1.15 l of dimethyl sulfoxide is stirred for 72 hours at room temperature, the mixture was poured into 3 l of water, filtered, the residue insist with diisopropyl ether and obtain 63 g (38%) of N-benzyl-N-(tet separating connection 2,3 ml, or 47.6 mmol) of hydrazine hydrate is added and 50 ml of ethanol in 100 ml dichloromethane was stirred for 12 hours at room temperature, the solvent is removed in vacuum, the residue is suspended in 150 ml of 2 n sodium hydroxide solution, extracted with dichloromethane, the organic phase is washed with water, the solvent is removed in vacuo, the residue insist with methanol and gain of 11.5 g (77%) of N-benzyl-N-(tetrachloropyridine-4-yl)-N-[2-(3-amino-5-methyl-phenoxy)ethyl] amine with so pl. 91-93oC.

C) of 11.5 g (25.5 mmol) videolounge compounds analogously to example I) enter into interaction with 3,51 ml (27,0 mmol) benzosulfimide and gain of 13.7 g (91%) of N-{3-[2-(benzylacrylamide-4-yl-amino)ethoxy] -5-methyl-phenyl} benzosulfimide with so pl. 147-149oC.

and) 3.0 g (4.00 mmol) of this compound in 15 ml of anhydrous dimethylformamide is added to 147 mg (6.38 mmol) of sodium hydride in 2 ml of dimethylformamide and then added dropwise 0.6 ml (5.4 mmol) of ethyl ether bromoxynil acid. Poured into 300 ml of water, extracted with ethyl acetate, the organic phase is washed with water, the solvent is removed in vacuum and get 3,15 g (91%) of ethyl ether (benzazolyl-{3-methyl-5-[2-(benzyl-tetrachloropyridine-4-yl-amino) ethoxy]phenyl}amino acetic acid. So pl. 141-142oC.

l) 3,5 (USD 5.76 mmol) of this compound and 4.0 g of potassium carbonate in 40 ml of tetrahydrofuran and 40 ml of methanol hydronaut in the presence of 1.0 g of 10% palladium-on-coal at a pressure of 4 bars. After 48 hours, filtered, the solvent is removed in vacuum, the residue is filtered through silica gel (methylene chloride/methanol=4:1) and obtain 2.1 g (78%) of target compound as an amorphous substance. Mass spectrum: m/e = 469.

Example 93. (Benzazolyl-{3-methyl-5-[2-(pyridin-4-yl-amino)ethoxy] phenyl} amino)acetic acid.

1.20 g (2.55 mmol) of the compound from example 92 in 20 ml of ethanol omelet with the help of 5.1 ml of 1 n sodium hydroxide solution for 2 hours at 45oC. Neutralize 1 N. hydrochloric acid, the solvent is removed in vacuum, the residue is treated with 20 ml of water and left to crystallize. Obtain 0.97 g (86%) of target compound. So pl. mine)ndimethylacetamide.

1.5 g (3.2 mmol) of the compound of example 92 was dissolved in 12 ml of concentrated ammonia and 30 ml of methanol. After incubation for 12 hours at room temperature is filtered off and get 0,99 g (70%) of target compound with so pl. 163 - 165oC.

Example 95. N-(2-Hydroxyethyl)-(benzazolyl-{ 3-methyl-5- [2-(pyridin-4-yl-amino)-ethoxy]phenyl}amino)ndimethylacetamide.

Get analogously to example 94 from the output 60% and when using ethanolamine instead of ammonia. So pl. 169 - 170oC.

Example 96. N-(3-Hydroabietyl)-(benzazolyl-{ 3-methyl-5- [2-(pyridin-4-yl-amino)ethoxy]phenyl}amino)ndimethylacetamide.

Get with the yield of 70% as in example 94 3-propanolamine instead of ammonia. So pl. 148 - 152oC.

Example 97. N-Methyl-(benzazolyl-{ 3-methyl-5-[2- (pyridin-4-yl-amino)-ethoxy]phenyl}amino)ndimethylacetamide.

Get off exit 58% as in example 94 using 25% ethanol solution of methylamine instead of ammonia. So pl. 136 - 140oC.

Example 98. N,N-Dimethyl-(benzazolyl-{3-methyl-5-[2-(pyridin - 4-yl-amino)-ethoxy]phenyl}amino)ndimethylacetamide.

Get with 38% as in example 94 using 41% ethanol solution of dimethylamine along the[2-(pyridin-4-yl-amino)-ethoxy]phenyl}-amino)ndimethylacetamide.

Get with the release of 45% as in example 94 using Ethylenediamine instead of ammonia. Amorphous substance. Mass spectrum: m/e = 483.

Example 100. N-(2-amino-ethyl)-N-{3-[2-(pyridin-4-yl-amino)ethoxy] -5-were}benzosulfimide.

The compound from example 94 restore analogously to example 18b) and get the target connection with the release of 34% in the form of an amorphous substance. Mass spectrum: m/e = 426.

Example 101. N-(2,3-Dihydroxypropyl-(benzazolyl-{ 3-methyl-5-[2-(pyridin-4-yl-amino)ethoxy]phenyl}amino)ndimethylacetamide.

Get with the release of 40% as in example 94 using 2,3-dihydroxypropane instead of ammonia. So pl. 148 151oC.

Example 102. N-(2,3-Dihydroxypropyl)-N-{3-[2-(pyridin-4-yl-amino)ethoxy] - 5-were}benzosulfimide.

a) 10.0 g (75,7 mmol) 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane and 14.3 g (75 mmol) of acid chloride of 4-toluenesulfonic acid in 7 ml of pyridine for 16 hours stirred at room temperature, poured into 200 water, extracted with ethyl acetate and the solvent is removed in vacuum. Will recrystallized from isohexane and obtain 10.3 g (48%) of 2,2-dimethyl-1,3-dioxolane-4-yl-metilenovogo ether 4-meiobenthologists. So pl. 45 - 47oC.

b) 0.24 g (0.83 mmol)malformed, stirred for 8 hours at 110oC, poured into water, extracted with ethyl acetate, the solvent is removed in vacuum and receive 300 mg (55%) of N-(2,2-dimethyl-1,3-dioxolane-4-yl-methyl)-N- { 3-[2-(benzyl-tetrachloropyridine-4-yl-amino)ethoxy] -5-methyl-phenyl} benzosulfimide in the form of oil. Mass spectrum: m/e = 725.

b) Of this compound is analogous to example C) receive N-(2,3-dihydroxypropyl)-N-{ 3-[2-benzyl-tetrachloropyridine-4-yl-amino) ethoxy]-5-methyl-phenyl}benzosulfimide (38%, so pl. 133 - 136oC).

g) From videolooking compounds analogously to example l) obtain the target compound (66%, amorphous substance, mass spectrum: m/e = 457).

Example 103. Ethyl ester of 4-(benzazolyl-{3-methyl-5-[2- (pyridin-4-yl-amino)-ethoxy]phenyl}amino)butyric acid.

Similar examples I) - l) receive the following connections the fact that in the example I) instead of ethyl ether bromoxynil acid using ethyl ester 4-pamakani acid:

ethyl ester of 4-(benzazolyl{3-methyl-5-[2-(benzyl - tetrachloropyridine-4-yl-amino)ethoxy]phenyl}amino)butyric acid (78%, so pl. 106 - 108oC);

ethyl ester of 4-(benzazolyl-{3-methyl-5-[2-tetrachloropyridine-4-yl-amino)ethoxy ]phenyl}amino)butyric acid (oil, mass spectrum: m/e = endolsulfan-{3-methyl-5-[2-(pyridin-4-yl-amino)-ethoxy] phenyl}amino)pentanol acid.

Similar examples I) and l) receive the following connections the fact that in the example I) instead of ethyl ether bromoxynil acid using ethyl ester 5-bromopentanoate acid:

ethyl ester of 5-(benzazolyl- {3-methyl-5-[2-(benzyl - tetrachloropyridine-4-yl-amino)ethoxy]phenyl}amino)pentanol acid (72%, so pl. 90 - 91oC);

ethyl ester of 5-(benzazolyl-{ 3-methyl-5-[2- (tetrachloropyridine-4-yl-amino)ethoxy]phenyl}amino)pentanol acid (86%, oil, mass spectrum: m/e = 647);

the target compound (78%, amorphous substance, mass spectrum: m/e = 511).

Example 105. Ethyl ester of 6-(benzazolyl)-{3-methyl-5-[2- (pyridin-4-yl-amino)-ethoxy]phenyl}amino)hexanoic acid.

Similar examples I) and l) receive the following connections that are used in the example I) instead of ethyl ether bromoxynil acid ethyl ester 6-bromo-hexanoic acid:

ethyl ester of 6-(benzazolyl)-(3-methyl-5-[2-(benzyl - tetrachloropyridine-4-yl-amino)ethoxy] phenyl}amino)hexanoic acid (75%, oil, mass spectrum: m/e = 751);

ethyl ester of 6-(benzazolyl-{ 3-methyl-5-[2-( tetrachloropyridine-4-yl-amino)ethoxy] phenyl}amino)hexanoic acid (49%, oil, mass spectrum:m/e = 661;

the target connection (56%, amorphous wishesto) butyric acid.

The target connection receive analogously to example 93 from the compound of example 103. Yield 65%. Amorphous substance. Mass spectrum: m/e = 469.

Example 107. 5-(Benzazolyl-{3-methyl-5-[2-(pyridin-4-yl-amino)ethoxy] phenyl} amino) pentane acid

The target connection receive analogously to example 93 from the compound of example 104. Yield 53%. So pl. 117 - 120oC.

Example 108. 6-(Benzazolyl-{3-methyl-5-[2-(pyridin-4-yl-amino)ethoxy] phenyl} amino) hexanoic acid.

The target connection receive analogously to example 93 from the compound of example 105. Yield 53%, amorphous substance, mass spectrum: m/e = 498.

Example 109. Ethyl ether (2-methoxy-benzazolyl-{3-methyl-5-[2-(pyridin-4-yl-amino)ethoxy] phenyl}amino) acetic acid.

Similar examples s) - l) receive the following connections that are in the stage s) instead of benzosulfimide use 2-methoxybenzenesulfonamide:

2-methoxy-N-{3-[2-(benzyl-tetrachloropyridine-4-yl-amino)ethoxy] -5-were}benzazolyl (65%, so pl. 175oC);

ethyl ether (2-methoxy-benzosulfimide-{ 3-methyl-5-[2-(benzyl-tetrachloropyridine-4-yl-amino) ethoxy] phenyl} amino)acetic acid (91%, so pl. 128-130oC);

ethyl ether (2-methoxy-benzazolyl-the connection (81%, so pl. 58 - 63oC).

Example 110. (2-Methoxy-benzazolyl-{3-methyl-5-[2-(pyridin-4-yl-amino)ethoxy] phenyl}amino) acetic acid

The target compound is obtained from the compound of example 109 as in example 93. Exit 82% So pl. 218 = 222oC.

Example 111. (2-Methoxy-benzazolyl-{3-methyl-5-[2-(pyridin-4-yl-amino)ethoxy] phenyl}amino) ndimethylacetamide.

The target connection receive analogously to example 94 from the compound of example 109 (yield 63%, so pl. 205oC).

Example 112. N-(2-Hydroxyethyl-(2-methoxy-benzazolyl-{3-methyl-5-[2- (pyridin-4-yl-amino)ethoxy]phenyl}amino) ndimethylacetamide.

Get with the release of 93% as in example 95 from the compound of example 109. So pl. 175oC.

Example 113. N-(3-Hydroxypropyl)- (2-methoxy-benzazolyl-{3-methyl-5-[2-(pyridin-4-yl-amino)ethoxy] phenyl}amino)ndimethylacetamide.

Get off exit 95% analogously to example 96 from compound of example 109. So pl. 165 - 167oC.

Example 114. N-Methyl-(2-methoxy-benzazolyl-{3-methyl-5-[2- (pyridin-4-yl-amino)ethoxy]phenyl}amino)ndimethylacetamide.

Get off exit 96% analogously to example 97 from the compound of example 109. Amorphous substance. Mass spectrum: m/e = 484.

Example 115. N, N-Dimethyl-(2-methoxy-benzazolyl-{ 3-the 98 from the compound of example 109. Amorphous substance, mass spectrum: m/e = 498.

Example 116. N-(2-amino-ethyl)-(2-methoxy-benzazolyl-{3-methyl-5- [2-(pyridin-4-yl-amino)ethoxy]phenyl}amino)ndimethylacetamide.

Get off exit 93% analogously to example 99 from the compound of example 109. Amorphous substance, mass spectrum: m/e = 513.

Example 117. N-(2,3-dihydroxypropyl)-(2-methoxy-benzazolyl-{3-methyl-5- [2-(pyridin-4-yl-amino)ethoxy]phenyl}amino)ndimethylacetamide.

Get analogously to example 101 with 75% yield from the compound of example 109. Amorphous substance, mass spectrum: m/e = 544.

Example 118. (2-Methoxy-benzazolyl-{3-methyl-5-[2- (pyridin-4-yl-amino)ethoxy]phenyl}amino)acetonitrile.

To 94 mg (0.2 mmol) of the compound from example 111 in 0.5 ml of dichloromethane and 60 μl of triethylamine at 0oC add 250 ál of trichloroacetaldehyde in 0.5 ml of dichloromethane. After 5 minutes, neutralized with triethylamine, the solvent is removed in vacuum and the residue filtered through silica gel (ethyl acetate/methanol ammonia solution = 4: 1). Receive 60 mg of target compound as an amorphous mass. Mass spectrum: m/e = 452.

Example 119. N-(2-amino-ethyl)-N-{3-[2-(pyridin-4-yl-amino) ethoxy]-5-methyl-phenyl}amino)-2-methoxy-benzosulfimide.

By reacting 2-methoxy-N-{ analogously to example I), receive (2-methoxy-benzazolyl-{3-methyl-5-[2-(benzylacrylamide - 4-yl-amino)ethoxy] phenyl} amino)acetonitrile (92%, so pl. 154oC) analogously to example C) receive (2-methoxy-benzazolyl-{ 3-methyl-5-[2-(tetrachloro-pyridin-4-yl-amino) ethoxy]phenyl} amino)acetonitrile (85%, amorphous substance mass spectrum: m/e = 588), which, in turn, analogously to example l) converted into the target compound (10% amorphous substance, mass spectrum: m/e = 456).

Example 120. Methyl ester 2-{3-[2-(benzylpyridine-4-yl-amino)ethoxy]-5-were - sulfamoyl}benzoic acid.

a) 2-(Benzyl-tetrachloropyridine-4-yl-amino)ethyl ester of 4-toluenesulfonic acid (example d)) enter into an interaction with 3-NITROPHENOL analogously to example e) and get N-benzyl-N-(tetrachloropyridine-4-yl)-N-[2-(3-nitro-phenoxy)ethyl - amine (61%, so pl. 120 - 122oC).

b) the connection Is restored as in example 79A) and get N-benzyl-N-(tetrachloropyridine-4-yl)-N-[2-(3-aminophenoxy)ethyl] amine (41%, so pl. 105 - 107oC).

in) Videolounge compound analogously to example z) is transformed into N-{ 3-[2-(benzyl-tetrachloropyridine-4-yl-amino)-ethoxy] phenyl} benzosulfimide (78%, so pl. 120 - 122oC).

g) This compound hydronaut analo. Ethyl ester of [2-(methyl-{3-methyl-5-[2-(pyridin-4-yl-amino)ethoxy]phenyl}sulfamoyl phenoxy]acetic acid.

a) N-Benzyl-N-(tetrachloropyridine-4-yl-)-N-[2-(amino-5-methyl-phenoxy)ethyl] amine (example g) analogously to example C) enter into an interaction with 2-benzyloxy-benzosulphochloride and get N-{3-[2- (benzyl-tetrachloropyridine-4-yl-amino)ethoxy] -5-methyl-phenyl-2-benzyloxy-benzosulfimide (55%, so pl. 176oC).

b) This connection was identified in analogously to example 12 and receive N-methyl-N-{ 3-[2-(benzyl-tetrachloropyridine-4-yl-amino)ethoxy] -5-methyl-phenyl}- 2-benzyloxybenzaldehyde (78%, amorphous substance, mass spectrum: m/e = 729).

in) From videolooking compounds analogously to example C) receive N-methyl-N-{ 3-[2-(benzyl-tetrachloropyridine-4-yl-amino)ethoxy] -5-methyl-phenyl}- 2-hydroxy-benzosulfimide (87%, amorphous substance, mass spectrum: m/e = 549). g) This compound is analogous to example 18 in turn ethyl ester [2-(methyl-{ 3-methyl-5-[2-(tetrachloropyridine-4-yl-amino)ethoxy-phenyl} sulfamoyl)phenoxy] acetic acid (yield quantitative, oil, mass spectrum: m/e = 635).

d) Videolounge connection hydronaut analogously to example l) and obtain the target compound (50%, amorphous substance, mass spectrum: m/e = 49 a) N-{ 3-[2-(benzyl-tetrachloropyridine-4-yl-amino)ethoxy]-5 - methyl-phenyl} -2-benzyloxy-benzosulfimide (example 121a)) analogously to example C) is transformed into N-{3-[2-(tetrachloropyridine-4-yl - amino)ethoxy]-5-methyl-phenyl}-2-hydroxy-benzosulfimide (70%, amorphous substance, mass spectrum: m/e = 535).

b) Of this compound is analogous to example l) obtain the target compound (81%, amorphous substance, mass spectrum: m/e = 399).

Example 123. N-3-Methyl-N-{3-methyl-5-[2-(pyridin-4-yl - amino)ethoxy]phenyl} -2-hydroxy-benzosulfimide.

a) N-methyl-N-{3-[2-(benzyl-tetrachloropyridine-4-yl-amino)ethoxy]-5 - methyl-phenyl} -2-benzyloxy-benzosulfimide (example 121B)) transform analogously to example 122 and receive N-methyl-N-{3-[2-(tetrachloropyridine - 4-yl-amino)ethoxy] -5-methyl-phenyl} -2-hydroxy-benzosulfimide (65%, amorphous substance, mass spectrum: m/e = 549) and the target compound (27%, amorphous substance, mass spectrum: m/e = 413).

Example 124. [2-(Methyl-{ 3-methyl-5-[2-(pyridine-4-amino)ethoxy] phenyl} sulfamoyl)-phenoxy]acetic acid.

a) Ethyl ester of [2-(methyl-{3-methyl-5-[2-(tetrachloropyridine-4-yl - amino)ethoxy] -phenyl} sulfamoyl)phenoxy]acetic acid (example 121g) omelet analogously to example 93 and receive [2-(methyl-{3-methyl-5-[2-(tetrachloropyridine-4-yl-amino)ethoxy] - phenyl}sulfamoyl)phenoxy]acetic acid (94%, amorphous substance, mass spectrum: m/e = 607).

b) Of this compound is analogous to example l) obtain the target compound (75%, amorphous substance, mass spectrum: m/e = 471).

a) 2-Methoxy-N-{3-[2-(benzyl-tetrachloropyridine-4-yl - amino)ethoxy]-5-methyl-phenyl} benzosulfimide (example 109) analogously to example I) enter into interaction with ethyl ether of Harborview acid and get N-etoxycarbonyl-N-{3-[2- (benzyl-tetrachloropyridine-4-yl-amino)ethoxy]-5-methyl-phenyl} -2 - methoxy-benzosulfimide (yield quantitative, amorphous substance, mass spectrum: m/e = 711).

b) Analogously to example C) from videolooking connection receive N-etoxycarbonyl-N-{ 3-[2-(tetrachloropyridine-4-yl - amino)ethoxy]-5-methyl-phenyl} -2-methoxy-benzosulfimide (80%, so pl. 156oC).

C) Analogously to example l), obtained in stage b) connection receive the target connection (66%, amorphous substance, mass spectrum: m/e = 485).

Example 126. N-[2-Hydroxyethyl-N-{ 3-methyl-5-[2- (pyridin-4-yl-amino)ethoxy]phenyl}-2-methoxy-benzosulfimide.

To 150 mg (0.3 mmol) of ethyl ether (2-methoxy-benzene - sulfonyl-{3-methyl-5-[2-(pyridin-4-yl-amino)ethoxy] phenyl} amino)acetic acid (example 109) in 5 ml of anhydrous tetrahydrofuran added 24 mg (0.6 mmol) of sociallyengaged and refluxed for 2 hours. The reaction mass is decomposed with 1 drop of water and 3 drops of 2 N. hydrochloric acid, Otti is = 4 : 1) and receive 50 mg (36%) of target compound as amorphous solid. Mass spectrum: m/e = 457.

Example 127. N-{3-Methyl-5-[2-(pyridin-4-yl-amino)ethoxy] phenyl}pyridine-3-sulfonamide.

Get analogously to example 57 the fact that in stage g) use 3-pyridinesulfonamide. Amorphous substance, mass spectrum: m/e = 385.

Example 128. Description of the pharmacological tests.

Thrombin time.

Accepted in clinical diagnosis coagulation test is thrombin time. This option includes the effect of thrombin on fibrinogen and formation of a clot. Thrombin inhibitors contribute to the lengthening of thrombin time.

For plasma 9 parts fresh blood of a healthy donor are mixed with one part of a solution of sodium citrate (0.11 mol/l) and centrifuged at room temperature for 10 minutes with a speed of approximately 3000 rpm, the Plasma is pipetted and can be stored at room temperature for approximately 8 hours.

200 μl of citrate plasma incubated for 2 minutes at 37oC ball coagulator (COP 10 firms Amelung). To 190 ál of pre-thermostated thrombin reagent (Bochringer Mannheim GmbH; contains about 3 IU/ml equine thrombin and 0.0125 mol of Ca++) add 10 ál of dimethyl sulfoxide (Andomar and determine the time until coagulation. Thrombin time test measurements is about 24 seconds, and distinctly longer because of the biologically active substances. If the thrombin time in the presence of the compound of example longer than 5 minutes, the test is interrupted.

The following table indicates the measured thrombin times in seconds as the difference relative to the control. The concentration of biologically active substances are, in a final volume of 250 µmol (CT 250), 25 µm (TT 25) and 2.5 µm (TT 2,5).

Inhibition of thrombin.

Kinetic measurements were carried out in 0.1 M phosphate buffer, containing 0.2 M sodium chloride and 0.5% polyethylene glycol 6000, pH 7.5 and 25oC with the substrate H-(D)-Phe-Pro-Arg-pNa (S-2238 Kabi) and human thrombin (Sigma, specific activity = 2150 NIH u/mg) in polymicrogyria of polystyrene in a total volume of 1 ml.

In the preliminary experience for each biologically active substance, determine: fast or slow it inhibits thrombin. For this purpose the reaction, first, start by adding 0,03 NIH units of thrombin to 100 mcalarney the substrate solution and biologically active substances. In the second experiment, the substrate is added to incubated for 5 the eat control spectral (UV-VIS-spectrophotometer Lambda-2 by Perkin-Elmer) at 405 nm for 12 minutes. As obtained in the case of both experiments curves measure linear and parallel, in the case of biologically active substances in the following table we are talking about fast thrombin inhibitors. The inhibition constants (Kithen determined as follows: the substrate used in concentrations of 100 μm, 50 μm, 30 μm, 20 μm and in the case of each concentration of substrate carry out the measurement without inhibitor and three dimensions in the presence of various concentrations indicated in the table below inhibitors. The reaction initiated by adding thrombin. Monitor the increase in extinction at 405 nm due to the resulting p-nitroaniline in a time interval of 12 minutes. Intervals of 20 seconds of measurement points (time VS extinction) is applied on the PC. From the obtained data to determine the velocity vabout(the change in extinction per second: measurement without inhibitor) and vi(measurement with inhibitor) by linear regression. Use only a portion of each dimension, in the case where the substrate concentration is reduced to less than 15%. From a number of measurements (constant concentration of inhibitor, changing substrate concentration) determine Kmand vmaxby the nonlinear form of the equation

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Of all the number of the Kmall measurements is 3.8 2) microns. The inhibition constants (Kibiologically active substances are listed in the table below in units of microns.

The inhibition of trypsin and plasmin.

10 mg bovine pancreatic trypsin (Sigma) dissolved in 100 ml of 1 mm hydrochloric acid and stored in the refrigerator. 20 μl of this solution are mixed with 980 ál of 1 mm hydrochloric acid. For each dimension, using 25 μl of the last solution. The measurement is carried out, as described for thrombin. Km= 45 µm. Listed in the following table substances do not inhibit trypsin (Ki> 400 μm).

Measurements using human plasmin (Sigma, 10 units) is carried out with the substrate S-2251 (H-(D)-Val-Len-Lys-pNa, Kab;), as described for thrombin. One dimension is used to 0.01 units of plasmin. Km= 250 μm. Listed in the following table substances do not inhibit plasmin (Ki> 400 μm).

1. 4-Aminopyridines of General frmula I

< / BR>
in which R1denotes a group R6-SO2NR7-; R6-NR7-SO2; R6-SO2-O or R6-O-SO2-;

R2denotes a hydrogen atom or halogen, cyano, alkyl, CNS or galag is new or different and denote hydrogen atoms or alkyl groups;

R5denotes a hydrogen atom, alkyl group or aracelio group;

R6means alilou, cycloalkyl, aryl, heteroaryl, aracelio or heteroallyl group, and the aryl or heteroaryl residues may be single or multiply substituted by a nitro-group, halogen, hydroxyl, amino, carboxyla, halogenation, alkoxycarbonyl, alcoxycarbenium, alkyl, cycloalkyl, alkoxyl, amino, alkylamino-, or one or more of the groups-Y-CO2R8-O-Y-CO2R8and alkyl groups can be single - or multi-substituted with halogen;

R7denotes a hydrogen atom, alkyl, cycloalkyl, alkanniny residue, these residues can be single - or multi-substituted with halogen, hydroxyl, alkoxyl, amino group, alkylcarboxylic, or denotes lanakila, heteroaryl, aryl, aracelio group, with aryl or heteroaryl residue may be single or multiply substituted by carboxyla, carboxylation, alkoxycarbonyl, or denotes a group-Y-CO2R8or-Y-CONR8R9;

Y denotes a linear or branched alkylenes chain;

R8and R<ü single or multiply substituted by hydroxyl, alkoxyl, amino group or carboxyla, or R8and R9together with N-atom to which they are linked, form a saturated ring which can additionally contain an oxygen atom, sulfur atoms or nitrogen,

and their physiologically acceptable salts.

2. 4-Aminopyridines of formula (I) under item 1, wherein R1means R6-SO2-O-; R6-O-SO2or R6-NR7-SO2, R2denotes a hydrogen atom or halogen, WITH1- C6-alkyl, C1- C6-CNS group or triptorelin group, X denotes an oxygen atom or NH group, R3and R4identical or different, denote hydrogen atoms or1- C6is an alkyl group, R5is a hydrogen atom, R6stands WITH1- C6-alkyl, C3- C7-cycloalkyl, aryl, heteroaryl or aracelio group, with aryl or heteroaryl residues may be single or multiply substituted with halogen, C1- C6-alkyl, triptorelin group1- C6-CNS group, hydroxyl, carboxyla, hydroxy - C1- C6-alkyl, carboxy - C1- C6-alkyl, C1- C6-alcox>- C6is an alkyl group, a C3- C7-cycloalkyl,2- C6-alkenylphenol, carboxy - C1- C6-alkyl, C1- C6-allyloxycarbonyl - C1- C6-alkyl, heteroaryl, aryl or aracelio group, with aryl residue may be single - or multi-substituted C1- C6-CNS group, carboxyl, carboxy - C1- C6-alkyl, C1- C6-alkoxycarbonyl,1- C6-alkylcarboxylic, formylamino, and their physiologically acceptable salts.

3. 4-Aminopyridines of formula (I) under item 1, wherein R1means R6-SO2-NR7, R2denotes a hydrogen atom or halogen, WITH1- C6-alkyl, C1- C6-CNS group or triptorelin group, X is an oxygen atom, R3and R4identical or different, denote hydrogen atoms or1- C6is an alkyl group, R5is a hydrogen atom, R6stands WITH1- C6-alkyl, C3- C7-cycloalkyl, aryl, heteroaryl or aracelio group, with aryl or heteroaryl residues may be single or repeatedly over the POI, by hydroxyl, carboxyla, carboxy - C1- C6-alkyl, C1- C6-alkoxycarbonyl, R7denotes a hydrogen atom, a C1- C6is an alkyl group, a C3- C7-cycloalkyl,2- C6-alkenylphenol, or aracelio group and their physiologically acceptable salts.

4. 4-Aminopyridines of formula (I) under item 1 or p. 2, wherein R2denotes a hydrogen atom, chlorine or bromine, or WITH1- C6is an alkyl group, a C1- C6-CNS group or triptorelin group.

5. 4-Aminopyridines of formula (I) according to any one of paragraphs.1 to 3, characterized in that X denotes an oxygen atom or NH group.

6. 4-Aminopyridines of formula (I) according to any one of paragraphs.1 to 4, wherein R3and R4are identical or different and denote hydrogen atoms or1- C6is an alkyl group.

7. 4-Aminopyridines of formula (I) according to any one of paragraphs.1 to 5, wherein R5denotes a hydrogen atom, a C1- C6is an alkyl or benzyl group.

8. 4-Aminopyridines of formula (I) according to any one of paragraphs.1 to 6, wherein R6stands WITH1- C6is an alkyl group, a C3- C7-cicila, WITH1- C6-alkoxyl, nitro, amino, hydroxyl, carboxyla, benzyloxycarbonyl,1- C6-alkoxycarbonyl, trifluoromethyl or a group-O-Y-CO2R8, phenyl or benzyl group, denotes naftalina, tetrahydronaphthalene, biphenylene or indenolol group, thienyl, parasailing or pyridyloxy, bastianello or benzothiadiazole group.

9. 4-Aminopyridines of formula (I) according to any one of paragraphs.1 to 7, wherein R7denotes a hydrogen atom, a C1- C6-alkyl, C2- C6-alkenylphenol or aracelio group1- C6-alkoxycarbonyl group, cyanoaniline group, hydroxyalkyl group or aminoalkyl group, the group-Y-COR8or a group-Y-CONR8R9.

10. 4-Aminopyridines of formula (I) according to any one of paragraphs.1 to 8, characterized in that Y represents methylene, propylene, butylene or Panteleeva group.

11. 4-Aminopyridines of formula (I) according to any one of paragraphs.1 to 9, wherein R8denotes a hydrogen atom or a C1- C6-alkyl, hydroxy - C1- C6-alkyl or amino - C1- C6is an alkyl group.

12. 4-Aminopyridois an alkyl group.

13. The pharmaceutical composition inhibiting platelets, characterized in that it contains at least one compound of formula (I) according to any one of paragraphs. 1 - 11 along with pharmaceutical carriers and excipients in an effective amount.

14. 4-Aminopyridines of General formula (I) according to any one of paragraphs.1 - 12, inhibiting platelets.

Priority points:

02.03.94 under item 1;

21.04.93 on p. 2;

03.03.93 on p. 3.

 

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< / BR>
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