SK108295A3 - 4-aminopyridine derivative, process for preparing the same and medicament containing the same - Google Patents

Abstract

New 4-aminopyridines have general formula (I), in which R<1> stands for the groups R<6>-SO-NR<7>, R<6>-SO2-NR<7>, R<6>-NR<7>-SO-, R<6>-NR<7>-SO2-, R<6>-SO-O-, R<6>-SO2-O-, R<6>-O-SO- or R<6>-O-SO2; R<2> stands for a hydrogen or halogen atom, a cyano, alkyl, alkoxy or halogen alkyl group; X stands for an oxygen atom, a sulphur atom or the NH group; R<3> and R<4> are the same or different and stand for hydrogen atoms or alkyl groups; R<5> stands for a hydrogen atom, an alkyl group or the aralkyl group; R<6> stands for an aliphatic or cyclic, if required substituted residue; R<7> stands for a hydrogen atom or an aliphatic or cyclic, if required substituted residue; Y stands for a linear or branched alkylene chain; R<8> and R<9> are the same or different and stand for hydrogen atoms, aralkyl, cycloalkyl or alkyl groups which may be substituted once or several times by halogen, hydroxy, alkoxy, alkylcarbonyloxy, amine or carboxy, or R<8> and R<9> form together with the N atom to which they are bound a saturated ring which may contain an additional oxygen, sulphur or nitrogen atom. Also disclosed are the hydrates, solvates and physiologically acceptable salts of these compounds, their optically active forms, racemates and diastereomer mixtures, a process for preparing said compounds, medicaments containing said compounds and the use of said compounds for producing medicaments.

Description

A 4-aminopyridine derivative, a process for its preparation and a pharmaceutical composition containing it. · R? cp <cn ^& cii · ri. ' t. · I vuv Λ

Technical field

The invention relates to 4-aminopyridine derivatives, solvates and salts thereof, which inhibit both thrombin-induced clotting of fibrinogen in the blood and thrombin-induced platelet aggregation. They thus prevent the formation of precipitated thrombi and platelet-rich thrombi and can be used to treat and prevent diseases such as thrombosis, apoplexia, heart attack, inflammation and arteriosclerosis. In addition, these compounds act on tumor cells and prevent the formation of metastases. They can therefore be used as antitumor agents. The invention therefore also relates to pharmaceutical compositions comprising 4-aminopyridine derivatives and to a process for the preparation of these derivatives.

BACKGROUND OF THE INVENTION

Thrombin, the last enzyme of the blood coagulation cascade, cleaves fibrinogen to fibrin, which is cross-linked with factor XIIa and transforms into an insoluble gel that forms a matrix for the thrombus. Thrombin activates platelet aggregation by proteolysis of its receptor on platelets and thus also contributes to thrombus formation. When blood vessels are injured, these processes are necessary to stop bleeding. Under normal conditions, there are no measurable thrombin concentrations in blood plasma. An increase in thrombin concentration can lead to thrombus formation and thus to thromboembolic diseases, which are particularly numerous in industrialized countries.

Thrombin is maintained in the form of prothrombin in plasma and released from it by factor Xa. Thrombin activates Factors V, VIII, and XI, thereby modifying Factor X and Xa. Thrombin thereby catalyses its own release, whereby a thrombin concentration can increase very rapidly.

Thrombin inhibitors may therefore inhibit the release of thrombin, platelet-induced and plasma clotting.

Besides thrombin, there are a number of serine proteases that cleave peptide substrates at a basic amino acid. To keep the side effects low, thrombin inhibitors should be selective, that is, other serine proteases should have little or no braking. In particular, trypsin, as a non-specific serine protease, can be readily inhibited by various braking agents. Trypsin retention can lead to pancreatic stimulation and pancreatic hypertrophy (J.D. Geratz, Am. J. Physiol. 216, 812, 1969).

Plasma contains a plasminogen protein that is altered by plasmin activators. Plasmin is a proteolytic enzyme whose activity is similar to that of trypsin. It serves to dissolve thrombi, while degrading thrombin. Braking of plasmin would therefore have the opposite effect that could be achieved by braking thrombin.

Synthetic thrombin inhibitors have long been known. Starting from fibrinogen, a natural substrate of thrombin, the (D) -Phe-Pro-Arg-type substances are synthesized. Such tripeptides resemble the amino acid sequence upstream of the fibrinogen cleavage site.

In order to obtain good inhibitors, the carboxylate group of arginine is so changed that the hydroxyl group of the serine-195 active site of the thrombin can react with it. This is possible, for example, in that the carboxylate group is replaced by an aldehyde group. Corresponding (D) -Phe-proarginals are described in European Patent Publication No. EP-A-185390.

In addition to the second type of thrombin inhibitors, the known benzamidines are used as trypsin inhibitors. The inhibitors thus obtained differ from the (D) -Phe-Pro-Arg-types not only by chemical construction but also by a type of inhibition: serine-195 thrombin does not bind to these inhibitors. This is clearly evident from X-ray structural studies (W. Bode, D. Turk, J. Sturzebecher, Eur. J. Biochem. 193, p.

175-182 (1990). This second class of thrombin inhibitors includes Na- (2-naphthylsulfonylglycyl) -4-amidino- (R, S) phenylalanine piperidine (NAPAP, DD 235866).

Surprisingly, it has now been found that the 4-aminopyridine derivatives of the invention which exhibit structurally nothing to do with known thrombin inhibitors are selective thrombin inhibitors.

SUMMARY OF THE INVENTION

The present invention provides a 4-aminopyridine derivative of the Formula I

where it means

R ^{1 is a} group of formula R ⁶ -SO-NR ⁷ -, R ⁶ -SO ₂ -NR ⁷ , R ⁶ -NR ⁷ -SO-,

R ⁶ -NR ⁷ -SO 2, R ⁶ -SO-O-, R ⁶ -SO 2 -O-, R ⁶ -O-SO- or R ⁶ -O-SO ₂ -,

R ² is H or halogen, cyano, alkyl or alkoxy or haloalkyl,

X is an oxygen atom, a sulfur atom or an imino group,

R ³ and R ^4, which are the same or different, independently of one another, are hydrogen or alkyl,

R ( ⁵⁾ is hydrogen, alkyl or aralkyl,

R ⁶ is alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl, wherein aryl or heteroaryl are optionally substituted one or several times substituted with substituents for the group consisting of nitro, halogen, nitrile, hydroxy, amino, carboxy, a group of Al alkoxycarbonic, alkenyloxycarbonyl, alkynyloxycarbonyl, aralkoxycarbonyl, alkyl, cycloalkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy, alkenyloxy, alkynyloxy, aralkoxy, kyanalkyloxyskupinu, alkylthio, alkylsulphinyl, alkylsulphonyl, amino, alkylamino, dialkylamino, aralkylamino, diaralkylaminoskupinu, alkylsulfonylamino, alkylkarbonylaminoformylaminoskupinu, aminocarbonyl, alkylaminocarbonyl a dialkylaminocarbonyl group, or optionally substituted one or more times with substituents from s comprising boron, a group of the formula Y-CO 2 R®-, -SY-CC ^ -R -, -OY-CO-R ⁸ -, -NH-Y-CO 2 R ⁸ -, SY-CONR ⁸ R ^9, -OY-CONR ⁸ R ⁹ , or

Q Q

-NH-Y-CONR R, wherein the alkyl, acenyl or alkynyl group is optionally substituted one or more times with a substituent selected from the group consisting of halogen, hydroxy, alkoxy, alkylcarbonyloxy, amino, and carboxy,

R ( ⁷⁾ is hydrogen, alkyl, cycloalkyl, alkenyl or alkynyl, optionally substituted one or more times with halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkylcarbonyl or alkylcarbonyl; , cyanalkyl, heteroaryl, aryl, aralkyl or heteroarylalkyl, wherein the aryl or heteroaryl group is optionally substituted one or more times with a halogen atom, a nitrile group, an alkyl group, an alkenyl group, an alkynyl group, a haloalkyl group, an alkoxy group, , alkylsulfonyl, haloalkoxy, hydroxy, carboxy, hydroxyalkyl, carboxyalkyl, alkoxycarbonyl, amino, al, cylamino, dialkylamino, alkylsulphonylamino, alkylcarbonylamino, formylamino, aminocarbonyl, or a hunting group or a group of the formula Y-CO ₂ -R ⁸ and Y-CONR ⁸ R ⁹ ,

Y a linear or branched alkylene group,

R ⁸ and R ⁹ which are the same or different, independently of one another, are hydrogen, aralkyl, cycloalkyl or alkyl, optionally substituted one or more times with halogen, hydroxy, alkoxy, alkylcarbonyloxy, amino or carboxy;

R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a saturated ring containing optionally additional oxygen, sulfur or nitrogen atoms, the alkyl, alkoxy, alkenyl and alkynyl moieties each having 1 to 6 carbon atoms and a straight or branched chain and cycloalkyl moieties of 3 to 7 carbon atoms, hydrates thereof, solvates and physiologically acceptable salts thereof.

The invention includes optically active forms, racemates and diastereomeric mixtures of the 4-aminopyridine derivatives of Formula I.

When R ^{@ 1} to R @ ⁹ are alkyl or alkoxy, they have 1 to 6 carbon atoms and a straight or branched chain. The same applies to the corresponding alkenyl and alkynyl moieties. Cycloalkyl groups have 3 to 7 carbon atoms. In the case of haloalkyl and haloalkoxy, the alkyl or alkoxy moiety may be substituted one, two or three times by a halogen atom. Preferred are groups substituted by three halogen atoms, such as trifluoromethyl and trifluoromethoxy. In all cases, halogen is fluorine, chlorine, bromine or iodine. Aralkyl and aralkoxy are in each case preferably benzyl or benzyloxy. In cases where said groups are mono- or polysubstituted, in particular, those groups have one, two or three substituents. In the case of a six-membered ring as aryl or heteroaryl, the substituents may independently be ortho, meta or para.

In the case where one of R and R is alkyl and R ⁶ represents one or more alkyl radicals substituted aryl or heteroaryl radical, means an alkyl group the alkyl group of straight or branched chain of 1 to 6 carbon atoms, preferably a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl groups. Halogen atoms in the meaning of alkyl group substituents means fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine. Preferred are trifluoromethyl, chloromethyl, 2-chloroethyl and 3-chloropropyl. Where alkyl groups are substituted with hydroxyl groups, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl and 2,3-dihydroxypropyl groups are preferred. When alkyl groups are substituted with alkoxy groups, methoxy, methyl, ethoxymethyl, methoxyethyl and ethoxyethyl groups are preferred.

Where the alkyl groups are substituted with amino groups, aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl and 5-aminopentyl are preferred. When alkyl groups are substituted with carboxy groups, carboxymethyl, 1-carboxyethyl, 2-carboxyethyl and 2-methyl-1-carboxyethyl groups are preferred.

Ύ fi

In the case where R, R, R ° or R ^{9 represents a} cycloalkyl group or R ⁶ represents a cycloalkyl substituted aryl or heteroaryl group, a cycloalkyl group of 3 to 7 members, preferably a cyclopropyl, cyclobutyl, cyclopentyl group , cyclohexyl and cycloheptyl. In all cases, the cycloalkyl group may be linked via an alkyl group so that it is a cycloalkylalkyl group. Particularly preferred are the cyclopropylmethyl and cyclohexylmethyl groups.

/ I '

Where in formula I R represents an alkenyl substituted aryl or heteroaryl group, or R ⁷ represents an alkenyl group, it is a straight or branched chain group having 3 to 6 carbon atoms, preferably an allyl, butenyl or iso- butenyl.

In the case of formula (I), when R @ ^{6 is an} alkynyl substituted aryl or heteroaryl group or R @ ⁷ is an alkynyl group, it is a straight or branched chain of 3 to 6 carbon atoms, preferably a propargyl group.

Zr

In the general formula (I), when R is alkoxycarbonyl, alkenyloxycarbonyl or alkynyloxycarbonyl substituted aryl or heteroaryl, it is a straight or branched chain group having 2 to 6 carbon atoms, preferably methoxycarbonyl, ethoxycarbonyl and allyloxycarbonyl.

Zr

When in formula (I), R is an alkoxy substituted aryl or heteroaryl group, it is a straight or branched chain group having 1 to 6 carbon atoms, preferably methoxy, ethoxy, propyloxy, butyloxy and pentyloxy. When alkoxy groups are substituted by hydroxyl groups, 2-hydroxyethoxy, 3-hydroxypropyloxy and 2,3-dihydroxypropyloxy are preferred. When alkoxy groups are substituted by alkoxy groups, methoxyethoxy and ethoxyethoxy are preferred.

When alkoxy groups are substituted with amino groups, 2-aminoethoxy and 3-aminopropyloxy are preferred.

When in formula (I), R ^{6 represents an} alkenyloxy substituted aryl or heteroaryl group, it is a straight or branched chain group having 3 to 6 carbon atoms, preferably an allyloxy group.

ZĽ

In the general formula (I), when R represents an alkynyloxy substituted aryl or heteroaryl group, it is a straight or branched chain group having 1 to 6 carbon atoms, preferably a propargyloxy group.

In the general formula (I), when R @ ^{6 is an} alkylthio, alkylsulfinyl or alkylsulfonyl substituted aryl or heteroaryl group, this is a straight or branched chain of 1 to 6 carbon atoms, preferably methylthio, methylsulfinyl or methylsulfonyl.

In the general formula (I), when R @ ^{6 is an} alkylamino or dialkylamino substituted aryl or heteroaryl group, it is a straight or branched chain group having 1 to 6 carbon atoms, preferably methylamino, dimethylamino or diethylamino.

Zr

In the case of formula (I), when R is an alkylsulfonylamino substituted aryl or heteroaryl group, it is a straight or branched chain group having up to 6 carbon atoms, preferably a methylaminosulfonyl group.

Zr

In the case of formula (I), when R represents an alkyl or carbonyl-substituted aryl or heteroaryl group, it is a straight or branched chain group having 1 to 6 carbon atoms, preferably acetylamino.

zr

When in formula (I), R is an alkylaminocarbonyl or dialkylaminocarbonyl substituted aryl or heteroaryl group, it is a straight or branched chain group having 1 to 6 carbon atoms, preferably methylaminocarbonyl, dimethylaminocarbonyl and diethylaminocarbonyl.

fi 7

Aralkyl groups R &lt; 0 &gt; or R &lt; 2 &gt; are preferably benzyl.

Aryl groups in the definition of R @ ⁶ or R? alone or in conjunction with an alkyl group means aromatic hydrocarbon groups having 6 to 14 carbon atoms, in particular a phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indanyl or fluorenyl group.

Aryl groups R ⁶ are monocyclic, bicyclic and tricyclic aromatic hydrocarbon groups with heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, such as furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, imidazole , triazole, tetrazole, pyridine, pyrazine, pyridine, pyridazine, triazine, tetrazine, benzothiophene, dibenzothiophene, benzimidazole, carbazole, benzofuran, benzofurazane, benzo-2,1,3-thiadiazole, quinoline.

When Y in the formula I is an alkylene group, it is a straight or branched chain group having 1 to 6 carbon atoms, preferably a methylene, ethylene or propylene group.

In the case where R and R together with the nitrogen atom to which they are attached form a ring, this is a ring of 4 to C atoms, preferably a pyrrolidine, piperidine and homopiperidine group. If such a ring contains additional heteroatoms, it is preferably a morpholine, thiomorpholine and piperazine group.

The radicals R ^{@ 1} and R ^{@ 2} on the phenyl ring of a compound of formula (I) may be in any position to each other and to the X group (oxygen atom or NH group). However, it is preferred that all three phenyl ring substituents in the compound of formula I are meta-to each other.

R ^{@ 1} is, in particular, R @ ⁶ --SO2 --NR @ ⁷ R @ ⁶ -NR @ ⁷ --SO2, R @ ⁶ --SO2 --O2 or R @ ⁶ --O - SO2 -.

R @ ² is, in particular, hydrogen, chlorine or bromine, C1 -C6 -alkyl, for example methyl or ethyl or C1 -C6 -alkoxy, for example methoxy or trifluoromethyl.

In particular, X represents an oxygen atom or an imino group.

The radicals R @ ³ and R @ 6 may be the same or different and are preferably a hydrogen atom or a C1-6 alkyl group, in particular a hydrogen atom or a methyl group.

In particular, R @ ⁵ represents a hydrogen atom or a C1 -C6 alkyl group, for example methyl or benzyl.

R @ ⁶ is, in particular, C1 -C6 -alkyl, for example isopropyl, C3 -C7 -cycloalkyl, for example cyclopentyl or cyclohexyl, phenyl unsubstituted or mono- or polysubstituted by fluoro or chloro, alkyl (C 1 -C 6), for example methyl, ethyl or tert-butyl, (C 1 -C 6) alkoxy, for example, methoxy, nitro, amino, hydroxy, carboxy, benzyloxycarbonyl, (C 1 -C 6) alkoxycarbonyl , for example, methoxycarbonyl, trifluoromethyl, and -OY-CO ₂ -R ⁸ , further denotes naphthyl, tetrahydronaphthyl, biphenyl or indanyl, thienyl, pyrazolyl or pyridyl, benzthienyl or benzothiadiazinyl or benzyl groups group.

R @ ⁷ is, in particular, hydrogen, C1 -C6 -alkyl or C2 -C6 -alkenyl, for example methyl, ethyl, n-propyl, allyl, isopropyl, or aralkyl, for example benzyl, alkoxycarbonyl having 1; up to 6 carbon atoms in the alkyl moiety such as ethoxycarbonyl, cyanoalkyl such as cyanomethyl, hydroxyalkyl such as hydroxyethyl or dihydroxypropyl, or amino alkyl such as aminoethyl or Y-CO ₂ -R ⁸ - and Y- CONR ⁸ R ⁹

In particular, the symbol Y represents a methylene, propylene, butylene or pentylene group.

In particular, R @ ⁸ represents a hydrogen atom or a C1 -C6 alkyl group, for example a methyl or ethyl group, a C1 -C6 hydroxyalkyl group, for example a hydroxyethyl, hydroxypropyl, dihydroxypropyl, or C1 -C6 aminoalkyl group, for example aminoethyl group.

In particular, R &lt; ⁹ &gt; represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, for example a methyl group.

Preferred are the 4-aminopyridine derivatives of formula I

where it means

R ¹ is of the formula R ⁶ -SO 2 NR ^7, R ⁶ -NR ⁷ -SO 2 R ⁶ -SO ₂ -O- or R 6 _{O -SO2} -,

R is hydrogen or chlorine or bromine, methyl, ethyl, methoxy or trifluoromethyl,

X is an oxygen atom or an imino group,

R ³ and R ⁴ are the same or different, are each independently hydrogen or methyl;

R ( ⁵⁾ is hydrogen, methyl or benzyl,

R ⁶ « isopropyl, cyclopentyl or cyclohexyl, phenyl optionally substituted one or more times with substituents selected from the group consisting of fluorine or chlorine, methyl, ethyl, tert-butyl, methoxy, nitro, amino, hydroxy, trifluoromethyl, carboxy, benzyloxy, benzyloxy, a group of the formula -OY-CO ₂ -R ⁸ , furthermore represents a naphthyl, tetrahydronaphthyl, biphenyl or indany- a hunting, thienyl, pyrazolyl or pyridyl, benzthienyl or benzothiadiazinyl or benzyl group, R ⁷ a hydrogen atom, a methyl, ethyl, n-propyl, allyl, isopropyl or benzyl, ethoxycarbonyl, hydroxyethyl, dihydroxypropyl, cyanomethyl or aminoethyl group or a group of the formula y-co ₂ -r ⁸ - and Y-CONR ⁸ R ⁹ , Y a methylene, propylene, butylene or pentylene group, 'R ⁸ * a hydrogen atom or a methyl, ethyl, hydroxyethyl, hydroxypropyl, dihydroxypropyl or aminoethyl group, R ⁹ a hydrogen atom or a methyl group.

The 4-aminopyridine derivatives of formula I are prepared by known methods.

The compound of formula II is reduced by known methods

Suitable reducing agents are complex boron-aluminum hydrides, boron complexes, aluminum hydride which is formed in situ by the reaction of lithium aluminum hydride with aluminum chloride or sulfuric acid or a mixture of aluminum chloride and sodium borohydride.

Compounds of formula II are prepared by reacting compounds of formula III

with 4-aminopyridine, the amino nitrogen of which bears the substituent R ⁵ . An equimolar amount of 4-aminopyridine and a carboxylic acid of formula III is reacted in the presence of a water-binding agent such as polyphosphoric acid, cationic acid, sulfuric acid halide, 2-halopyridine salt, dicyclohexylcarbodiimide or Ν, Ν'-carbonyldiimidazole. This reaction can also be carried out in two stages, wherein the carboxylic acid is first reacted with a reactive derivative, for example an acid chloride, an acid azide or an imidazolide, and then the reaction product is reacted with 4-aminopyridine.

The carboxylic acids of formula III are prepared from esters of formula IV

COOR ¹⁰ (IV) wherein R ^{10 represents an} alkyl or benzyl group. Under the kind of this group, the reaction is carried out either with the aid of bases or with acids or with hydrogenolysis. When R ¹⁰ is methyl or ethyl, the reaction is carried out preferably with sodium hydroxide or potassium hydroxide in methanol, ethanol or water. Where R ¹⁰ is tert-butyl group, the reaction is carried out with an acid, preferably of hydrochloric acid, formic acid or trifluoroacetic acid. When R ^{10 is} a benzyl group, the reaction is preferably carried out hydrogenolytically in the presence of a catalyst such as palladium on carbon or platinum.

Compounds of formula IV wherein R ^{1 is} R ⁶ -NH-SO-, R ⁶ -NH-SO 2, R ⁶ -SO-NH- or R ⁶ -SO 2 -NH- can be obtained by η.

alkylation of other compounds of formula IV, wherein R is of formula NR ⁶ R ⁷ '-SO-, R ⁶ -NR ^7' -SO 2 R ⁶ -SO-NR ⁷ '-, or R ^6' -SO 2 NR ⁷ '-. As the alkylating agent, for a compound of the formula R ⁷ 'Z, in which R ⁷ · the same as R ^7, except hydrogen, phenyl, and heteroaryl groups and Z is a reactive group such as halogen, preferably Br, Cl or represents a sulfate group. These reactions are preferably carried out in a solvent such as acetone, ether, toluene or dimethylformamide at temperatures of -30 to 100 ° C, preferably at room temperature, in the presence of a base such as sodium hydride or calcium carbonate.

Compounds of formula IV are prepared from compounds of formula V

(V) which are reacted with α-halogen esters of the general formula Hal-CR ³ R ⁴ -COOR 10. _As halogen is meant halogen, preferably chlorine and bromine. These reactions are preferably carried out in a solvent such as acetone, ether, toluene or dimethylformamide at temperatures of -30 to 100 ° C, preferably at room temperature, in the presence of a base such as sodium hydride or calcium carbonate.

η

The compounds of formula IV, wherein R is of the formula R ⁶ -SO-O-, R ⁶ -SO 2 O-, R ⁶ -SO-NH-, R ⁶ -SO 2 NH- are prepared from compounds of formula VI

COOR ¹⁰ (VI) which is reacted with a sulfinyl chloride of the formula R ⁶ -SO-C1, or sulfonyl chloride of formula R ⁶ -SO ₂ -C 1.

In formula VI, A is hydroxy or amino of formula NHR. The reaction is conveniently carried out with the addition of an acid binding agent, such as, for example, alkali acetate, alkali hydroxide, calcium oxide, calcium carbonate, magnesium carbonate or in the presence of organic bases such as pyridine, triethylamine, N-methylmorpholine or diisopropylmethylamine. using ether, methylene chloride, dioxane, toluene or excess tertiary amine. When using inorganic acid binding agents, for example, water, aqueous ethanol or aqueous dioxane are used as the reaction medium.

> Ί ·

Compounds of formula IV wherein R is R ⁶ -O-SO-, R ⁶ -O-SO 2 -, R ⁶ -NR ⁷ -SO- or R ⁶ -NR ⁷ -SO 2 may be prepared from compounds of formula VII

COOR ¹⁰ (VII) wherein n is 1 (sulfinyl chlorides) or 2 (sulfonyl chlorides), by reaction with compounds of formula R -OH or R -NH-R. The reaction is conveniently carried out with the addition of an acid binding agent such as, for example, alkali acetate, alkali hydroxide, calcium oxide, calcium carbonate, magnesium carbonate or in the presence of organic bases such as pyridine, triethylamine, N-methylmorpholine and diisopropylmethylamine. use, for example, ether, methylene chloride, dioxane, toluene, or an excess of a tertiary amine. When using inorganic acid-binding agents, for example, water, aqueous ethanol or aqueous dioxane are used as the reaction medium.

Compounds of formula (V) and (VII) are described in the literature (Methoden der Organischen Chemie (Houben-Weyl), Thieme Verlag, Stuttgart 1955: p. 285: M. Quaedvlieg, Aliphatische Sulfinsäuren; p. 299: F. Mut, Aromatische Sulfinsäuren; p. 343: M. Quaedvlieg, Aliphatische Sulfonsäuren; page 429: F. Mut, Aromatische Sulfonsäuren; page 599: F. Mut, Funktionelle N-Derivate der Arylsulfonsäuren; page 659: F. Mut, Aromatische Sulfonsäureester), or can be prepared by methods described in this literature. Compounds of formula VI are known in the literature (Sobotka, Austin, J. Am. Chem. Soc. 74, 3813, 1952) or can be prepared by methods described in this literature.

The 4-aminopyridine derivatives of formula I may also be prepared by reacting a compound of formula VIII

(VIII) with a pyridine derivative having at the 4-position a nucleophilic release group. Suitable such released groups are halogen atoms, preferably bromine, chlorine and fluorine, as well as nitro, alkoxy and phenoxy. To facilitate the reaction, the 4-aminopyridine derivative may contain further halogen atoms, preferably chlorine. Preferred pyridine derivatives include pentachloropyridine and 4-nitrotetrachloropyridine. The reaction is preferably carried out in an inert solvent such as toluene, dioxane, dimethylformamide, dimethylacetamide, methylene chloride or ethanol at room temperature to the boiling point of the solvent, preferably at a temperature of 20 to 40 ° C when the pyridine derivative contains additional chlorine atoms , a dehalogenation reaction, such as catalytic hydrogenation, follows the nucleophilic reaction.

Compounds of formula VIII are prepared by reduction of compounds of formula IX

(IX) wherein R ^{11 is a} nitrile or amido group of the formula CONHR ⁵ . Suitable reducing agents are complex borohydrides, aluminum hydrides, hydrogen chloride borohydride complexes, aluminum hydride which is prepared in situ by the reaction of lithium aluminum hydride with aluminum chloride or sulfuric acid, or a mixture of aluminum chloride and sodium borohydride.

Compounds of formula (IX) are prepared from compounds of formula (III). This reaction is carried out by contacting an equimolar amount of an amine of formula H ₂ NR ⁵ and a carboxylic acid of formula III in the presence of water-precipitating agents such as polyphosphoric acid, cationic acid, sulfuric acid halide, 2-halopyridine salt, dicyclohexylcarbodiimide or N, N '-karbonylimidazol. This reaction can also be carried out in two stages, wherein the carboxylic acid is reacted first with a reactive derivative, for example an acid chloride or an acid azide, and then with ammonia.

The 4-aminopyridine derivatives of formula I are also prepared by reacting a compound of formula X

R ³

by a method known in the literature (MM Boudakian, Heterocyclic Compounds, Volume XIV, Supplement Part 2 (RAAbramovitch, Ed.) Wiley, New York 1974, p. 407) by reacting a commercial aminoethanol of the formula HOCR ³ R ⁴ -CH ₂ -NH ⁵ with pentachloropyridine or with 4-nitrotetrachloropyridine in an inert solvent such as dioxane, tetrahydrofuran, methylene chloride or ethanol at -10 ° C to the boiling point of the solvent used. The hydroxy group of the compound of formula X is converted to the released group W to give compounds of formula XI

wherein W is a halogen atom such as chlorine or bromine or a sulfonic acid ester group such as a tosyloxy group. Conversion of the hydroxy group to a halogen atom is carried out with a halogenating agent such as thionyl chloride or phosphoryl chloride, conversion to a sulfonic acid ester by reaction with a sulfonyl chloride, for example tosyl chloride.

Compounds of formula XI are reacted with compounds of formula V

wherein R ¹ 'has the same meaning as R ¹ additional but may also be a protected hydroxyl or amino group. Protected hydroxyl means benzyloxy or acetyloxy Protected amino means preferably tert-butyloxycarbamoyl, benzyloxycarbamoyl, dibenzylamino or phthalimido. In this way, compounds of formula XII are formed. Reaction of compounds of formula V with compounds of formula X instead of XI according to Mitsunobu in the presence of triphenylphosphine and diethyl ester of diazodicarboxylic acid or diazodicarboxylic acid piperide also leads to compounds of formula XII

(XII) * 1

In the case where R 'is a protected hydroxyl group or an amino protected group in the general formula (XII), this protecting group is removed in the next step. The optional benzyl group is removed by hydrogenolysis in the presence of a catalyst such as palladium on carbon, an optional butylcarbamoyl group by treatment with a strong acid such as trifluoroacetic acid, and an optional acetyl group by treatment with a base such as sodium hydroxide. In this way, compounds of formula XIII are formed

which are converted to compounds of formula XIV by reaction with sulfinyl chlorides or sulfonyl chlorides

(XIV) wherein n is 1 or 2 and X 'is oxygen or NH. In the case where X 'is X' in formula XIV, compounds of formula XIV are converted to compounds of formula XV

R ²

(XV) * 7 7 * where R '' has the same meaning as R 'except for the hydrogen atom. For this purpose, a compound of formula (XIV) is reacted with an alkylating agent of formula (R'-Y) as described for alkylating compounds of formula (IV).

The 4-aminopyridine derivatives of formula (I) are finally prepared from a compound of formula (XII) wherein R ¹ 'has the same meaning as R ¹ , from a compound of formula (XIV) or from a compound of formula (XV) by removal of the chlorine atom from the pyridine ring. in the presence of a catalyst such as Raney nickel or palladium on carbon in the presence of a base such as potassium carbonate, sodium bicarbonate and sodium methylate

For the preparation of 4-aminopyridine derivatives of the general formula I, in which R ^{1 is a} group of the formula R ⁶ -SO-NR ⁷ -, R ⁶ -SO ₂ -NR ⁷ , R ⁶ -SO-O- or R-SO ₂ -O- , another possibility of preparing the reaction of compounds of formula XVI (XVI)

R ²

with a sulfinyl chloride of the formula R ⁶ -SOCl, optionally with a sulfonyl chloride of the formula R 6 -SOgCl. The reaction is carried out as described for the reaction with compounds of formula VI. In this case, A is a hydroxyl group or an amino group of the formula NHR.

Compounds of formula XVI are prepared from compounds of formula XVII

(XVII) wherein B is a protecting group that is cleaved to prepare compounds of Formula XVI. Suitable protecting groups for B are benzyl which is cleaved by hydrolysis in the presence of a catalyst such as palladium on carbon, a tert-butoxycarbonyl group which is cleaved by treatment with a strong acid, such as trifluoroacetic acid, formic acid and hydrochloric acid; aromatic sulfonyl groups, such as benzenesulfonyl or tosyl, which are cleaved by treatment with a base such as sodium hydroxide or potassium hydroxide.

Compounds of formula (XVII) are prepared essentially in the same manner as 4-aminopyridine derivatives of formula (I).

(XVIII) which are reacted with halogen esters of formula Hal-CR ³ R ⁴ -COOR ¹⁰ as described for reaction with compounds of formula V. Compounds of formula XIX are obtained.

COOR ¹⁰ (XIX) which, after ester saponification and after activation of the acidic group, as in the case of compounds of formula III, are reacted with 4-aminopyridine or NR ⁵ -4-aminopyridine to give compounds of formula XVI.

Certain 4-aminopyridine derivatives of formula (I) may subsequently be converted to other 4-aminopyridine derivatives of formula (I).

This includes derivatives of 4-aminopyridine of the formula I, c * 7 Zr in which R, R and R a benzyl group, or wherein R ⁸ is aryl or heteroaryl group having as substituents one or more benzyloxy, benzylamino or benzyloxycarbonyl. Catalytic hydrogenation in the presence of the catalyst, preferably palladium on carbon, replaces the benzyl group with a hydrogen atom. Removal of the benzyl group is also accomplished by reaction with strong acids, such as trifluoroacetic acid, in the presence of mesitylene, anisole or thioanisole.

It also relates to derivatives of 4-aminopyridine of the formula I in which R ⁶ aryl or heteroaryl group having as substituents one or more chlorine atoms. By catalytic hydrogenation in the presence of a catalyst, preferably palladium on carbon, the chlorine atom is replaced by a hydrogen atom.

It also relates to derivatives of 4-aminopyridine of the formula I in which R ⁶ aryl or heteroaryl group having as substituents one or more nitro groups. By catalytic hydrogenation in the presence of a catalyst, preferably palladium on carbon, the nitro group is replaced by an amino group.

This also applies to 4-aminopyridine derivatives of formula I wherein R ^{6 is an} aryl or heteroaryl group having as alkyloxycarbonyl, alkyloxycarbonylalkyl or alkyloxycarbonylalkoxy substituents, or R ^{7 is} alkyloxycarbonylalkyl. Free carboxylic acid is prepared from the alkoxycarbonyl group by reaction with acids such as hydrochloric acid or bases such as sodium hydroxide. When these alkoxycarbonyl groups are reacted with an amine of the formula NHR ⁸ R ⁹ , the alkoxycarbonyl group forms a group of the formula CONR ⁸ R ⁹ . When these alkoxycarbonyl groups are reacted with a reducing agent, for example lithium aluminum hydride, the corresponding hydroxymethyl groups are obtained.

It also relates to derivatives of 4-aminopyridine of the formula I in which R ⁶ aryl or heteroaryl group having as substituents one or more groups of nitrile, cyanoalkyl, kyánalkyloxyskupín, formylamino, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl groups, and groups of the formula - SY-CONHR ⁸ , -OY-CONHR ⁸ , -NH-Y-CONHR ⁸ , or R ⁷ is cyanalkyl, aminocarbonylalkyl or -Y-CONHR. These groups can preferably be reduced with lithium aluminum hydride to give the corresponding aminomethyl compounds.

Physiologically acceptable salts of the 4-aminopyridine derivatives of the formula I include salts with physiologically acceptable mineral acids such as hydrochloric, sulfuric, sulfuric or phosphoric acid, or with organic acids such as methanesulfonic, p-toluenesulfonic, acetic, trifluoroacetic, citric acid. , fumaric, maleic, wine, amber or salicylic. The 4-aminopyridine derivatives of formula I with free carboxyl groups can also form salts with physiologically acceptable bases. Examples of such salts include alkali metal, alkaline earth metal, ammonium and alkylammonium salts, for example sodium, potassium, calcium or tetramethylammonium salts.

The 4-aminopyridine derivatives of the formula I can be solvated, in particular hydrated. Hydration can occur during the preparation or, optionally, as a result of the hygroscopic properties of the initially anhydrous 4-aminopyridine derivative of the formula I.

Pure enantiomers of the 4-aminopyridine derivatives of formula I are obtained either by resolution of the racemate (via formation of a salt with optically active acids or bases) or by using optically active starting materials for the preparation.

For the preparation of pharmaceutical compositions, the 4-aminopyridine derivatives of the formula I are mixed with suitable pharmaceutical carriers, flavoring and flavoring agents and coloring agents and, for example, processed into tablets or dragees or added with suitable excipients such as water or oils, for example olive oil, suspend or dissolve.

The 4-aminopyridine derivatives of the formula I can be administered in liquid or solid form enterally or parenterally. For example, water which contains the usual additives for injectable solutions, such as stabilizers, solubilizers or buffers, is used as the injectable medium. Examples of such kits include tartrate and citrate buffers, complexing agents (such as ethylenediaminetetraacetic acid and non-toxic salts thereof), and high molecular weight polymers such as liquid polyethylene oxide to affect viscosity. Solid carriers include, for example, starches, lactose, mannitol, methylcellulose, talc, highly disperse silicic acid, high molecular weight fatty acids (such as stearic acid), animal and vegetable fats, and solid high molecular polymers (such as polyethylene glycols). For oral administration, suitable compositions may optionally contain flavorants and sweeteners.

The 4-aminopyridine derivatives of the formula I are usually administered in an amount of 10 to 1500 mg per day, based on a body weight of 75 kg. Preference is given to administering 2 to 3 times a day one to two tablets with an active ingredient content of 5 to 500 mg. The tablets may also have a delayed action, one to two tablets containing 20 to 700 mg of active ingredient being administered once a day. The active ingredient may also be injected once to eight times a day or administered by continuous infusion, with daily administration of 50-2000 mg per day.

In addition to the exemplified compounds, the following compounds are particularly suitable according to the invention:

1. Benzenesulfinic acid 3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl ester

N- {3- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} -benzénsulfínamid

3. 3- {3-Methyl-5- [2- (pyridin-4-ylamino) -ethoxy] -phenylaminosulfonyl} -phenoxy-acetic acid

4. 2- {3-Methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenylaminosulfonyl} phenoxyacetic acid

5. 3- {3-Methyl-5- [2- (pyridin-4-ylamino) -ethoxy] -phenylaminosulfonyl} -phenoxy-acetamide

6. N- (2-Hydroxyethyl) -3- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenylaminosulfonyl} phenoxyacetamide

7. N- (2,3-Dihydroxypropyl) -3- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenylaminosulfonyl} phenoxyacetamide

8. N- (2-hydroxyethyl) -3- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyloxysulfonyl} phenoxyacetamide

9. Acetic acid 3- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenylaminosulfonyl} phenoxymorpholide

10. Acetic acid 2- [2- (benzenesulfonyl) - {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} aminoacetylamino] ethyl ester

11. Acetic acid 3- [2- (benzenesulfonyl) - {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} aminoacetylamino] propyl ester

12. Acetic acid 2- [2- (2-methoxybenzenesulfonyl) - {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} aminoacetylamino] ethyl ester

13. N- {3-Cyano-5- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} -benzenesulfonamide

The invention is illustrated by the following non-limiting examples.

Examples of the invention

Example 1

N- {3- [2- (pyridin-4-ylamino) -ethoxy] -phenyl) -2-naphthalenesulfonamide

(a) 6.3 g (28 mmol) of naphthalene-2-sulfonyl chloride are added dropwise to 5.9 g (25 mmol) of ethyl 3-aminophenoxyacetic acid and 6.9 ml of triethylamine in 100 ml of methylene chloride, while cooling with ice at 10 ° C. in 30 ml of methylene chloride. Stir for 1 hour at room temperature, extract with water and dry the organic phase over sodium sulfate. The solvent was removed in vacuo to give 9.6 g of N- {3 - [(ethoxycarbonyl) methoxy] phenyl} -2-naphthalenesulfonamide as an oil. MS m / e = 385.

b) To 9.6 g (25 mmol) of this compound in 100 mL of ethanol was added 4.2 g (75 mmol) of potassium hydroxide and stirred for 1 hour at 70 ° C. After filtration, the precipitate is dissolved in water, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The solvent was removed in vacuo, the residue was dissolved in 2 N sodium hydroxide, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and the solvent is removed in vacuo. The oily residue is crystallized by standing. 7.6 g (85%) of N- {3 - [(carboxy) methoxy] phenyl} -2-naphthalenesulfonamide, m.p. 153-155 ° C, are obtained. FAB-MS; M + H = 358.

(c) To 3 g (8.4 mmol) of this compound in 30 ml of tetrahydrofuran is added at 45 ° C 2.7 g (16.8 mmol) of 1,1-carbonylimidazole and stirred for 20 minutes. To this was added 0.8 g (8.4 mmol) of 4-aminopyridine and stirred at 60 ° C for 6 hours. Then, 2.7 g (16.8 mmol) of 1,1-carbonyldiimidazole and 0.8 g (8.4 mmol) of 4-aminopyridine are added once more and stirred for a further 6 hours at 60C. The solvent is removed in vacuo and the residue is taken up in ethyl acetate and extracted with aqueous sodium bicarbonate solution with phosphate buffer, pH = 7.0. The organic phase is dried over sodium sulfate, filtered and the solvent is removed in vacuo. 2.5 g (69%) are obtained.

N- {3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} -2-naphthalenesulfonamide, m.p. 204-207 ° C. MS m / e = 433 (MH +).

d) Under nitrogen, 2.0 g (4.6 mmol) of this compound was added to 1.0 g (20.4 mmol) of lithium aluminum hydride in 20 mL of tetrahydrofuran and the mixture was heated to reflux for 1 h. Excess lithium aluminum hydride is quenched with water, the reaction mixture is filtered and the filtrate is evaporated in vacuo. The residue is taken up in acetic acid ester and extracted with water, the organic phase is dried over sodium sulphate, filtered and the solvent is removed in vacuo. The oily residue was separated on a reverse phase column (RP-18; methanol / water, pH = 6.8, 7: 3). The desired fraction was evaporated to dryness and extracted with acetic acid ester. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in vacuo. 0.3 g (16%) of N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-naphthalenesulfonamide, m.p. 90-91 ° C, is obtained. MS m / e = 419 (MH +).

Example 2

N- {3- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} naphthalenesulfonamide

The preparation proceeds as in Example 1 except that in step a) 1-naphthalenesulfonyl chloride is used instead of 2-naphthalenesulfonyl chloride.

intermediates:

(a) N- {3 - [(ethoxycarbonyl) methoxy] phenyl} naphthalenesulfonamide as an oil, MS: m / e = 385;

(b) N- {3 - [(carboxymethoxy) phenyl} naphthalenesulfonamide, m.p. 147-149 ° C, FAB-MS: M + H = 358;

(c) N- {3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} naphthalenesulfonamide, m.p. 210-211 ° C (dec.),

MS: m / e = 433.

d) N- {3- [2- (pyridin-4-ylamino) methoxy] phenyl} naphthalenesulfonamide. Yield 38%, mp 239-241 ° C (dec.),

MS: LSIMS position m / e = 419;

Example 3

4-methyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide

The preparation proceeds as in Example 1 except that in step a) 4-toluenesulfonyl chloride is used instead of 2-naphthalenesulfonyl chloride.

intermediates:

(a) 4-methyl-N- {3 - [(ethoxycarbonyl) methoxy] phenyl} benzenesulfonamide, m.p. 100-102 ° C, MS: m / e = 349;

b) 4-methyl-N- {3 - [(carboxy) methoxy] phenyl} benzenesulfonamide, m.p. 170-173 ° C, FAB-MS: M + H = 322;

c) 4-methyl-N- {3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} benzenesulfonamide as an oil, MS: m / e = 397,

d) 4-methyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide, yield 26%, mp 165-167 ° C,

MS: m / e = 383 (MH +).

Example 4

4-Fluoro-N- (3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide hydrochloride

The preparation is carried out according to Example 1, except that in step a) 4-fluorobenzenesulfonyl chloride is used instead of 2-naphthalenesulfonyl chloride.

intermediates:

(a) 4-fluoro-N- {3 - [(ethoxycarbonyl) methoxy] phenyl] benzenesulfonamide, m.p. 94-96 ° C, MS: m / e = 353;

b) 4-fluoro-N- {3 - [(carboxy) methoxy] phenyl} benzenesulfonamide, m.p. 154-156 ° C, FAB-MS: M + H = 326;

c) 4-fluoro-N- {3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} benzenesulfonamide, MS: m / e = 401,

d) 4-Fluoro-N- {3- (2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide, The base was triturated with hydrochloric acid in ether (yield 21%), m.p. e = 387.

Example 5

4-Chloro-N- {3- (2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide hydrochloride

The preparation proceeds as in Example 1, except that in step a) 4-chlorobenzenesulfonyl chloride is used instead of 2-naphthalenesulfonyl chloride.

intermediates:

(a) 4-chloro-N- {3 - [(ethoxycarbonyl) methoxy] phenyl} benzenesulfonamide, MS: m / e = 369;

b) 4-chloro-N- {3 - [(carboxy) methoxy] phenyl} benzenesulfonamide, m.p. 190-192 ° C, FAB-MS: M + H = 342;

c) 4-chloro-N- {3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} benzenesulfonamide, m.p. 168-171 ° C, MS: m / e = 417;

d) 0.65 g (1.55 mmol) of the product step c) was reacted in 15 ml of dry tetrahydrofuran with 1.79 ml (3.58 mmol) of 2 M borane dimethylsulfide in tetrahydrofuran. It is stirred for 3 hours at 60 ° C and 10 ml of methanol are added in an ice bath. Add 5 ml of hydrogen chloride in ether. The solvent was evaporated in vacuo and the residue was rubbed in warm water. There was obtained 0.13 g of 4-chloro-N- {3- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} -benzenesulfonamide, m.p. 241-243 ° C. MS: m / e = 403 (MH +).

Example 6

4-trifluoromethyl-N- {3- (2- (pyridin-4-ylamino) -ethoxy] fenyljbenzénsulfónamid

The preparation proceeds according to Example 1, except that in step a) 4-trifluoromethylbenzenesulfonyl chloride is used instead of 2-naphthalinesulfonyl chloride.

intermediates:

(a) 4-trifluoromethyl-N- {3 - [(ethoxycarbonyl) methoxy] phenyl} benzenesulfonamide, MS: m / e = 403;

b) 4-trifluoromethyl-N- {3 - [(carboxymethoxy) phenyl} benzenesulfonamide, m.p. 155-158 ° C, FAB-MS: M + H = 375;

c) 4-trifluoromethyl-N- {3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} benzenesulfonamide, m.p.

MS: m / e = 451.

d) 4-trifluoromethyl-N- {3- (2- (pyridin-4-ylamino) -ethoxy] -phenyl} -benzenesulfonamide, m.p. 145-148 ° C, MS: m / e = 437.

Example 7

3-trifluoromethyl-N- {3- (2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide

The preparation proceeds according to Example 1, except that in step a) 3-trifluoromethylbenzenesulfonyl chloride is used instead of 2-naphthalinesulfonyl chloride.

intermediates:

a) 3-trifluoromethyl-N- {3 - [(ethoxycarbonyl) methoxy] phenyl} benzenesulfonamide, MS: m / e = 403;

b) 3-trifluoromethyl-N- {3 - [(carboxy) methoxy] phenyl] benzenesulfonamide, m.p. 147-149 ° C, FAB-MS: M + H = 375;

c) 3-trifluoromethyl-N- {3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenylbenzenesulfonamide as an oil, MS: m / e = 451,

d) 3-trifluoromethyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide, m.p. 185-187 ° C, MS: m / e = 437

Example 8

N- {3- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} cyclohexanesulfonamide

The preparation proceeds as in Example 1, except that in step a) instead of 2-naphthalinesulfonyl chloride, cyclohexylsulfonyl chloride is used.

intermediates:

(a) N- {3 - [(ethoxycarbonyl) methoxy] phenyl} cyclohexanesulfonamide,

MS: m / e 341;

b) N- {3 - [(carboxy) methoxy] phenyl} cyclohexanesulfonamide, m.p. 132 DEG C., FAB-MS: M + H = 313;

c) N- {3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl | cyclohexanesulfonamide as an oil, MS: m / e = 389,

d) N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} cyclohexanesulfonamide, MS: m / e 375.

Example 9

N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide

The preparation proceeds according to Example 1, except that in step a) benzenesulfonyl chloride is used instead of 2-naphthalenesulfonyl chloride.

intermediates:

(a) N- {3 - [(ethoxycarbonyl) methoxy] phenyl} benzenesulfonamide as an oil, MS: m / e 335,

b) N- {3 - [(carboxy) methoxy] phenyl] benzenesulfonamide, m.p.

Mp 160-161 ° C. FAB-MS: M + H = 307;

c) N- {3 - C (pyridin-4-ylaminocarbonyl) methoxy] phenyl} benzenesulfonamide, m.p. 151-156 ° C, MS: m / e = 383;

d) N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide, yield 26%, mp 182-184 ° C, MS: m / e 369.

Example 10

N- {3- [l-methyl-2- (pyridin-4-ylamino) -ethoxy] -phenyl} -benzolsulfónamid

(a) 5.6 ml (44 mmol) are added dropwise to 8.4 g (40 mmol) of ethyl 2- (3-aminophenoxypropionic acid ester and 6.1 ml (44 mmol) of triethylamine in 50 ml of methylene chloride under ice-cooling at 10 ° C. After stirring at room temperature for 1 hour, extracted with water, the organic phase was dried over sodium sulfate and the solvent removed in vacuo to give 14 g of N- {3- [1- (ethoxycarbonyl) -ethoxy] -phenyl} -benzenesulfonyl. of an amide in the form of an oil.

MS: m / e = 349.

b) 14 g (40 mmol) of this compound and 6.7 g (120 mmol) of potassium hydroxide in 100 ml of ethanol were stirred at 70 ° C for 1 hour.

It is extracted twice with ethyl acetate, acidified with semi-concentrated hydrochloric acid and extracted once more with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in vacuo. 9.2 g (72%) of N- {3- [1- (carboxy) ethoxy] phenyl} benzenesulfonamide are obtained as an oil. MS: m / e = 321 (MH +).

c) As in Example 1, step c) was prepared from 4.8 g (15 mmol) of the product according to b), 2.1 g (22.5 mmol) of 4-aminopyridine and 3.2 g (19.5 mmol). mmol) of 1,1-carbonyldiimidazole in 40 ml of tetrahydrofuran 3.4 g (57%) of N- {3- [1- (pyridin-4-ylaminocarbonyl) ethoxy] phenyl} benzenesulfonamide, m.p. 142-144 ° C. MS m / e = 397.

d) As in Example 1, step d) was prepared from 1.7 g (4.3 mmol) of the product according to c) and 0.65 g (17.2 mmol) of lithium aluminum hydride in 20 ml of tetrahydrofuran 0.6 g ( 37%)

N- {3- [1-methyl-2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide, m.p. 162-163 ° C. MS m / e = 383 (MH +).

Example 11

N- {3- [1, l-dimethyl-2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide

The preparation proceeds analogously to Example 10. In step a), 2- (3-aminophenoxy) propionic acid ethyl ester is replaced by 2-methyl-2- (-3-aminophenoxypropionic acid ethyl ester).

intermediates:

(a) N- {3- [1-methyl-1- (ethoxycarbonyl) ethoxy] phenyl} benzenesulfonamide as an oil, MS: m / e 363;

b) N- {3- [1-methyl- (carboxy) ethoxy] phenyl} benzenesulfonamide as an oil, MS: m / e = 335,

c) N- {3- [1-methyl- (pyridin-4-ylaminocarbonyl) ethoxy] phenyl} benzenesulfonamide, m.p. 141-143 ° C, MS: m / e = 411;

d) N- {3- [1,1-dimethyl-2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide as an oil, MS: m / e 397.

Example 12

N-methyl-N- {3- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} benzénsulfónamidhydrochlorid

a) To 8.4 g (25 mmol) of N- {3 - [(ethoxycarbonyl) methoxy] phenyl} benzenesulfonamide (Example 9, step a) and 3.5 g of potassium carbonate in 10 ml of dimethylformamide is added dropwise at 80-90 A solution of 1.6 mL (25 mmol) of iodomethane in 10 mL of DMF. Stir for a further 2 hours at this temperature, allow to cool to room temperature, filter and concentrate the filtrate in vacuo. The residue is taken up in acetic acid ester and extracted with water. Dry over sodium sulfate and remove the solvent in vacuo. 8.6 g of N-methyl-N- {3 - [(ethoxycarbonylmethoxy) phenyl} benzenesulfonamide are obtained in the form of an oil: MS: m / e = 349.

b) The further reaction proceeds as in Example 1, step b). N-methyl-N- {3 - [(carboxymethoxy) phenyl} benzenesulfonamide, m.p. 110 DEG-111 DEG C. MS: m / e = 321.

c) N-methyl-N- {3 - [(pyridin-4-ylaminocarbonylmethoxy) phenyl} benzenesulfonamide, m.p. 76-78 C. MS: m / e = 397.

d) N-methyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide hydrochloride. The free base is treated with 2N hydrochloric acid, extracted with ethyl acetate and the aqueous phase is evaporated to dryness. An oil is obtained which is crystallized by rubbing with isopropanol. Yield 46%. Melting point 174-176 ° C.

Example 13

N-ethyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide

The preparation is carried out according to Example 12, except that iodoethane is used instead of iodomethane in step a).

intermediates:

(a) N-ethyl-N- {3 - [(ethoxycarbonyl) methoxy] phenyl} benzenesulfonamide as an oil, MS: m / e 363;

b) N-ethyl-N- {3 - [(carboxy) methoxy] phenyl} benzenesulfonamide, mp 122 ° C, MS: m / e = 335,

c) N-ethyl-N- {3 - [(pyridin-4-ylamino-carbonyl) methoxy] phenyl} benzenesulfonamide, MS: m / e = 411,

d) N-ethyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide as an oil, MS: m / e 397.

Example 14

N-propyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide

The preparation is carried out according to Example 12, except that iodopropane is used instead of iodomethane in step a).

intermediates:

(a) N-propyl-N- {3 - [(ethoxycarbonyl) methoxy] phenyl} benzenesulfonamide as an oil, MS: m / e 377

b) N-propyl-N- {3 - [(carboxy) methoxy] phenyl} benzenesulfonamide, m.p. 147 DEG C., MS: m / e = 349;

c) N-propyl-N- {3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} benzenesulfonamide, m.p. 105 DEG C., MS: m / e = 425;

d) N-propyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl] benzenesulfonamide as an oil, MS: m / e 411.

Example 15

N-benzyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide

The preparation proceeds as in Example 12, except that benzyl bromide is used instead of iodomethane in step a).

intermediates:

(a) N-benzyl-N- {3 - [(ethoxycarbonyl) methoxy] phenyl) benzenesulfonamide as an oil, MS: m / e 425,

b) N-benzyl-N- {3 - [(carboxy) methoxy] phenyl} benzenesulfonamide, m.p. 190 DEG C., MS: m / e = 397;

(c) N-benzyl-N- {3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} benzenesulfonamide, m.p. 140 ° C, MS: m / e = 473;

d) N-benzyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide, mp 128 ° C, MS: m / e 459.

Example 16

N-allyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide

The preparation proceeds as in Example 12, except that in step a) allyl bromide is used instead of iodomethane.

intermediates:

(a) N-allyl-N- {3 - [(ethoxycarbonyl) methoxy] phenyl} benzenesulfonamide as an oil, MS: m / e 375,

(b) N-allyl-N- {3 - [(carboxy) methoxy] phenyl} benzenesulfonamide,

MS: m / e = 347.1;

c) N-allyl-N- {3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} benzenesulfonamide, MS: m / e = 423,

d) N-allyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide as an oil, MS: m / e 409.

Example 17

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide hydrochloride

The preparation proceeds as in Example 1, except that in step a) instead of 2-naphthalenesulfonyl chloride, benzenesulfonyl chloride is used and ethyl 3-amino-5-methylphenoxyacetic acid ethyl ester is used instead of ethyl 3-aminophenoxyacetic acid ester.

intermediates:

(a) N- {5-methyl-3 - [(ethoxycarbonyl) methoxy] phenyl} benzenesulfonamide as an oil, MS: m / e = 349

b) N- {5-methyl-3 - [(carboxy) methoxy] phenyl] benzenesulfonamide, m.p. 156-159 ° C, FAB-MS: M + H = 322;

c) N- {5-methyl-3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} benzenesulfonamide, m.p. 193-196 ° C, MS: m / e = 397;

d) N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide hydrochloride, yield 56%, mp 170 ° C,

MS: m / e = 383 (MH +).

Example 18

Benzenesulfonic acid 3- [2- (pyridin-4-ylamino) ethoxy] phenyl ester

a) While cooling to 10 ° C, to 2.5 g (0.01 mol) of benzenesulfonic acid 3-hydroxyphenyl ester in 30 ml of acetonitrile is added 0.44 g (0.011 mol) of sodium hydride (60% in white oil) and stirred 1 hour at this temperature. 2.2 ml (0.02 mol) of ethyl bromoacetate in 10 ml of acetonitrile are added dropwise over 30 minutes and stirred at room temperature for 3 hours. After addition of 5 ml of isopropanol, the solvent is removed in vacuo. 30 ml of ethanol, 50 ml of water and 0.8 g (0.015 mol) of potassium hydroxide are added to the residue. After 16 hours at room temperature, the ethanol was removed in vacuo and the aqueous solution was extracted three times with ether. The aqueous phase was acidified with hydrochloric acid and extracted with ether.

The ether was removed in vacuo to give 1.5 g (48%) of 2- [3- (phenylsulonyloxy) phenyloxy] acetic acid, mp 152-155 ° C.

b) 1.4 g (4.5 mmol) of the product according to a) and 958 mg (5.9 mmol) of carbonyldiimidazole were stirred at 45 ° C for 30 minutes. Add 0.64 g (6.8 mmol) of 4-aminopyridine and stir at 60 ° C for two days. The solvent was removed in vacuo, and the residue was dissolved in ethyl acetate containing 0.5% acetic acid. The organic phase was dried, filtered and the solvent was removed in vacuo. The residue is triturated with ether, filtered and contains 1.8 g (94%) of N- (4-pyridinyl) -2- [3-phenylsulfonyloxy) phenyloxy] acetamide, m.p. 127-130 ° C.

c) While cooling in an ice bath, 192 mg (8.8 mmol) of lithium borohydride in 5 ml of dry tetrahydrofuran at 5 ° C were reacted with 2.23 ml (18 mmol) of chlorotrimethylsilane. After 30 minutes, 1.7 g (4.4 mmol) of the product of step b) was added slowly at 5 ° C. After 16 hours at room temperature, quench with 3 mL of methanol and remove the solvent in vacuo. The residue was taken up in ethyl acetate and sodium bicarbonate solution. The ethyl acetate phase was purified on a diatomaceous earth column (ethyl acetate / methanol = 9: 1). The solvent was removed in vacuo and contained 1.3 g of benzenesulfonic acid 3- [2- (pyridin-4-ylamino) ethoxy] phenyl ester (80%) as a viscous oil.

FAB-MS: M + H 371;

Example 19

N-methyl-N-phenyl-3- [2- (pyridin-4-ylamino) -ethoxy] benzenesulfonamide

(a) 3-Nitrobenzenesulfonic acid N-methylanilide

Dissolve 5 g of 3-nitrobenzenesulfonic acid chloride in 20 ml of absolute pyridine and react with 2.7 ml of N-methylaniline while cooling with ice and stirring. Stirring is continued for 2 hours at room temperature, the reaction mixture is added to ice / water and acidified with dilute hydrochloric acid. The aqueous phase is extracted with ethyl acetate, the ethyl acetate phase is dried over sodium sulphate and evaporated. The residue is recrystallized from alcohol. Yield: 6.3 g. Melting point 90 ° C.

b) 3-Aminobenzenesulfonic acid N-methylanilide

6 g of 3-nitrobenzenesulfonic acid N-methylanilide is dissolved in 100 ml of absolute tetrahydrofuran and hydrogenated after addition of 0.5 g of palladium on carbon (10%) as a catalyst. After receiving the calculated amount of hydrogen, the catalyst was filtered off and the filtrate was evaporated. Yield 5.5 g. Melting point 104 ° C.

c) 3-hydroxybenzenesulfonic acid N-methylanilide

Dissolve 5 g of 3-aminobenzenesulfonic acid N-methylanilide in 20 ml of 50% sulfuric acid. While cooling with ice and stirring, a solution of 1.75 g of sodium nitrite in 5 ml of water is added dropwise. After the diazotization was complete, the reaction mixture was kept at 100 ° C for 20 minutes, allowed to cool and extracted with ethyl acetate. The ethyl acetate phase is dried over sodium sulphate and evaporated. The residue is sufficiently pure for further processing.

d) [3- (Methylphenylsulfamoyl) phenoxy] acetic acid ethyl ester Dissolve 3.5 g of 3-hydroxybenzenesulfonic acid N-methylanilide in 20 ml of absolute dimethylformamide. 2 g of potassium carbonate and 1.9 ml of ethyl bromoacetate are added and the mixture is heated at 100 ° C for three hours. The mixture was cooled and freed from solvent by distillation in vacuo. The residue (4.3 g) obtained is pure enough for further work-up.

e) [3- (Methylphenylsulfamoyl) phenoxy] acetic acid

Dissolve 4.2 g of [3- (methylphenylsulfamoyl) phenoxy] acetic acid ethyl ester in 40 ml of ethanol. 1 g of potassium hydroxide is added and the mixture is stirred for 1 hour at 90 ° C. Cool to room temperature, acidify with dilute hydrochloric acid and extract with methylene chloride. The methylene chloride phase is dried over sodium sulphate and evaporated. 4 g of [3- (methylphenylsulfamoyl) phenoxy] acetic acid are obtained as an amorphous solid.

f) 2- [3- (methylphenylsulfamoyl) phenoxy] -N-pyridin-4-yl acetamide

2 g of [3- (methylphenylsulfamoyl) phenoxy] acetic acid are dissolved in 20 ml of absolute tetrahydrofuran. 1.35 g of carbonylimidazole are added and the mixture is heated to 45 ° C for 20 minutes. Cool to room temperature, add 900 mg of 4-aminopyridine and stir for an additional 3 hours at 60 ° C. The solvent was distilled off, the residue was dissolved in ethyl acetate and shaken with water. The ethyl ester phase is dried over sodium sulphate and evaporated. The residue is chromatographed on silica gel (eluent: methylene chloride / methanol 9: 5) for purification. Evaporation of the fraction from the column gave 1.5 g of 2- [3- (methylphenylsulfamoyl) -phenoxy] -N-pyridin-4-yl-acetamide as an amorphous solid. FAB-MS: M + H 398;

(g) N-methyl-N-phenyl-3- [2- (pyridin-4-ylamino) ethoxy] benzenesulfonamide

800 mg of 2- [3- (methylphenylsulfamoyl) phenoxy] -N-pyridin-4-yl-acetamide are dissolved in 15 ml of absolute tetrahydrofuran. 320 mg of lithium aluminum hydride are added under nitrogen and the mixture is heated to reflux for 1 hour. Cool and quench the reaction with saturated ammonium sulfate. The insoluble matter is filtered off with suction, the filter residue is washed with ether, the filtrate is dried over sodium sulphate and evaporated.

The residue is chromatographed on silica gel (eluent: methylene chloride / methanol 8: 2) for purification. Evaporation of the fraction from the column gave 420 mg of N-methyl-N-phenyl-3- [2- (pyridin-4-ylamino) ethoxy] benzenesulfonamide as an amorphous solid. FAB-MS: M + H 384;

Example 20

N-benzyl-N-phenyl-3- [2- (pyridin-4-ylamino) etoxyJbenzénsulfónamid

The preparation is carried out analogously to Example 19, except that in step a), N-benzylaniline is used instead of N-methylaniline. Amorphous substance. FAB-MS: M + H 460;

Example 21

N-phenyl-3- [2- (pyridin-4-ylamino) -ethoxy] benzenesulfonamide

300 mg of N-benzyl-N-phenyl-3- [2- (pyridin-4-ylamino) ethoxy] benzenesulfonamide (Example 20) are dissolved in 20 ml of methanol and hydrogenated after addition of 100 mg of 10% palladium on carbon catalyst. After uptake of hydrogen, the catalyst was filtered off and the filtrate was evaporated. 240 mg of N-phenyl-3- [2- (pyridin-4-ylamino) ethoxy] benzenesulfonamide are obtained as an amorphous substance. FAB-MS: M + H 370;

Example 22

N-methyl-N-pyridin-2-yl-3- [2- (pyridin-4-ylamino) -ethoxy] benzenesulfonamide

The preparation proceeds analogously to Example 19, except that in step a) N-methyl-2-aminopyridine is used instead of N-methylaniline. Amorphous substance. FAB-MS: M + H 385 (MH +).

Example 23

N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-propanesulfonamide hydrochloride

To 0.26 g (11.4 mmol) of lithium borohydride in 50 ml of tetrahydrofuran was added dropwise 2.88 ml (22.9 mmol) of chlorotrimethylsilane, stirred at room temperature for 5 minutes and 2.00 g (5.72) was added in portions. mmol) of N- {3 - [(pyridin-4-ylaminocarbonyl) methoxy) phenyl} -2-propanesulfonamide, prepared analogously to Example 1. The mixture was heated to reflux for 30 minutes, and after cooling 20 ml of methanol was carefully added dropwise, followed by 30 ml of 2N sodium hydroxide solution. Most of the solvent was removed in vacuo and extracted with methylene chloride. It is dried, the solvent is removed in vacuo and the residue is treated with ethereal hydrochloric acid, the solvent is removed in vacuo and the residue is triturated with tert-butyl methyl ether to give 1.5 g (70%) of N- {3- [2] hydrochloride. - (pyridin-4-ylamino) ethoxy] phenyl} -2-propanesulfonamide, m.p. 204-207 ° C.

Example 24

N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} cyclopentanesulfonamide hydrochloride

N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} cyclopentanesulfonamide hydrochloride was prepared analogously to Example 23. Mp 129-134 ° C.

Example 25

N-methyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} 4-fluorophenylsulfonamide hydrochloride

N-Methyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -4-fluorophenylsulfonamide hydrochloride was prepared analogously to Example 23. Melting point 140-143 ° C.

Example 26

N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide

N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide was prepared analogously to Example 1. Oil. MS: [EI] = 382.

Example 27

N- {3- [2- (pyridin-4-ylamino) -ethoxy] phenyl} -4-butylbenzenesulfonamide

N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -4-tert-butylbenzenesulfonamide was prepared analogously to Example 1 as an oil. MS: [EI] = 425.

Example 28

N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -1,2,3,4-tetrahydrodronaphthalene-6-sulfonamide hydrochloride

N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -1,2,3,4-tetarahydronaphthalene-6-sulfonamide hydrochloride was prepared analogously to Example 23. Mp 235-237 ° C. .

Example 29

N- {3- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} indan-5-sulfonamide

N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} indane-5-sulfonamide was prepared in analogy to Example 23 as the free base. Mp 140 ° C (dec.).

Example 30

N- {3- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} -2-biphenylsulfonamide

N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-biphenylsulfonamide was prepared in analogy to Example 23 as the free base. Mp 214-216 ° C.

Example 31

N-methyl-N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} 4-fluorobenzenesulfonamide hydrochloride

N-methyl-N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -4-fluorobenzenesulfonamide hydrochloride was prepared in analogy to Example 23. Mp 122-129 ° C. Starting material N- {5-methyl-3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} fluorobenzenesulfonamide (MS m / e = 429) was prepared analogously to Example 17.

Example 32

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-chloro-4-fluorobenzenesulfonamide hydrochloride

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-chloro-4-fluorobenzenesulfonamide hydrochloride was prepared analogously to Example 23. Mp 198-200 ° C. Starting material N- {5-methyl-3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} -2-chloro-4-fluorobenzenesulfonamide (MS m / e - 449) was prepared analogously to Example 17.

Example 33

N-methyl-N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-trifluorobenzenesulfonamide hydrochloride

N-Methyl-N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-trifluorobenzenesulfonamide hydrochloride was prepared analogously to Example 23. Mp 203-207 ° C. Starting material N- {5-methyl-3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} -2-chloro-4-fluorobenzenesulfonamide (MS m / e = 479) was prepared analogously to Example 17.

Example 34

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-methylbenzenesulfonamide hydrochloride

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-methylbenzenesulfonamide hydrochloride was prepared analogously to Example 23. Mp 135 ° C (dec.). Starting material N- {5-methyl-3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} -2-methylbenzenesulfonamide (MS m / e = 411) was prepared analogously to Example 17.

Example 35

N-methyl-N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-methyl-4-fluorobenzenesulfonamide hydrochloride

N-methyl-N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-methyl-4-fluorobenzenesulfonamide hydrochloride was prepared in analogy to Example 23. Mp 146 ° C. Starting material N-methyl-N- {5-methyl-3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} -2-methyl-4-fluorobenzenesulfonamide (MS m / e = 443) was prepared analogously to Example 17 .

Example 36

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-methyl-4-fluorobenzenesulfonamide hydrochloride

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-methyl-4-fluorobenzenesulfonamide hydrochloride was prepared analogously to Example 23. Mp 193 ° C. Starting material N- {5-methyl-3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} -2-methyl-4-fluoro benzenesulfonamide (MS m / e = 429) was prepared analogously to Example 17.

Example 37

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-methyl-5-fluorobenzenesulfonamide hydrochloride

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-methyl-5-fluorobenzenesulfonamide hydrochloride was prepared in analogy to Example 23. Mp 246-247 ° C. Starting material N- {5-methyl-3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} -2-methyl-5-fluorobenzenesulfonamide (MS m / e = 429; mp 211-213 ° C) was prepared by according to Example 17.

Example 38

N-methyl-N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-methyl-5-fluorobenzenesulfonamide hydrochloride

N-methyl-N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl) -2-methyl-5-fluorobenzenesulfonamide hydrochloride was prepared in analogy to Example 23. Melting point 165-166 ° C C. Starting material N-methyl-N- {5-methyl-3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} -2-methyl-5-fluorobenzenesulfonamide (MS m / e = 443) was prepared analogously to Example 17 .

Example 39

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} 2,4-difluorobenzenesulfonamide hydrochloride

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2,4-difluorobenzenesulfonamide hydrochloride was prepared in analogy to Example 23. Mp 227-228 ° C. Starting material N- {5-methyl-3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} -2,4-difluorobenzenesulfonamide (MS m / e = 433; mp 194 ° C) was prepared analogously to Example 17 .

Example 40

N- {5-methyl-3- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} -3,5-dimethyl-4-pyrazolsulfónamid

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -3,5-dimethyl-4-pyrazolesulfonamide was prepared in analogy to Example 23 as the free base. Melting point 121 ° C. Starting material N- {5-methyl-3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} -3,5-dimethyl-4-pyrazolesulfonamide (MS m / e = 415) was prepared analogously to Example 17.

Example 41

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -4-fluorobenzenesulfonamide hydrochloride

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -4-fluorobenzenesulfonamide hydrochloride was prepared in analogy to Example 23. Mp 232 ° C. Starting material N- {5-methyl-3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} -4-fluorobenzenesulfonamide (MS m / e = 415; mp 156-159 ° C) was prepared analogously to Example 17.

Example 42

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-fluorobenzenesulfonamide hydrochloride

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-fluorobenzenesulfonamide hydrochloride was prepared analogously to Example 23. Melting point 263C. Starting material N- {5-methyl-3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} -2-fluorobenzenesulfonamide (MS m / e = 415) was prepared analogously to Example 17.

Example 43

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-trifluorobenzenesulfonamide hydrochloride

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-trifluorobenzenesulfonamide hydrochloride was prepared in analogy to Example 23. Melting point 217-222 ° C. Starting material N- {5-methyl-3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} -2-trifluoromethylbenzenesulfonamide (MS m / e = 465) was prepared analogously to Example 17.

Example 44

N-methyl-N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -4-methylbenzenesulfonamide hydrochloride

N-Methyl-N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -4-methylbenzenesulfonamide hydrochloride was prepared analogously to Example 23. Melting point 180 ° C. Starting material N-methyl-N- {5-methyl-3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} 4-methylbenzenesulfonamide (MS m / e = 425) was prepared analogously to Example 17.

Example 45

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} 2,6-difluorobenzenesulfonamide hydrochloride

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2,6-difluorobenzenesulfonamide hydrochloride was prepared in analogy to Example 23. Mp 263 ° C. Starting material N- {5-methyl-3 - [(pyridin-4-ylaminocarbonyl) methoxy] phenyl} -2,6-difluorobenzenesulfonamide (MS m / e = 433; mp 234-242 ° C) was prepared analogously to Example 17 .

Example 46

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-hydroxy-3-tert-butyl-5-methylbenzenesulfonamide hydrochloride

a) 27.2 g (87.0 mmol) of (3-tert-butyloxycarbonylamino-5-methyl-phenoxy) -acetic acid ethyl ester (Example 57) is reacted

b) in 300 ml of methanol with 50 ml (100 mmol) of 2N sodium hydroxide solution and stirred at room temperature for 3 days. The solvent was partially removed in vacuo, extracted with ethyl acetate, the aqueous phase acidified with hydrochloric acid and extracted with ether. Dry and remove the solvent in vacuo. 15.6 g of (3-tert-butyloxycarbonylamino-5-methylphenoxy) acetic acid, m.p. 120 DEG-122 DEG C., are obtained.

b) (3-tert-Butyloxycarbonylamino-5-methylphenoxy) acetic acid was reacted with 4-aminopyridine as in Example 1c) to give N- (4-pyridinyl) - (3-tert-butyloxycarbonylamino-5-methylphenoxy) amide m.p. 204-205 ° C.

c) Allow 5.00 g (14.0 mmol) of N- (4-pyridinyl) - (3-tert-butyloxycarbonylamino-5-methylphenoxy) acetic acid to react with 25 ml of trifluoroacetic acid, stir for 30 minutes at room temperature The mixture was basified with sodium hydroxide solution and the precipitate was filtered off with suction. 2.93 g (78%) of N (4-pyridinyl) -3- (amino-5-methylphenoxy) acetic acid amide, m.p. 163 DEG C., is obtained.

d) N- (4-pyridinyl) -3- (amino-5-methylphenoxy) acetic acid was reduced as described in Example 23 to give a yield of 3- [2- (pyridin-4-ylamino) ethoxy] - in 50% yield. 5-methylaniline, m.p. 208 ° C.

e) 3- [2- (pyridin-4-ylamino) -ethoxy] -5-methylaniline from d) was reacted with 2-hydroxy-3-tert-butyl-5-methylbenzenesulfonyl chloride as described in Example 1a) to give N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-hydroxy-3-tert-butyl-5-methylbenzenesulfonamide hydrochloride as an amorphous mass. MS + FAB: 470.

Example 47

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -3-benzothiophenesulfonamide hydrochloride

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -3-benzothiophenesulfonamide hydrochloride was prepared in analogy to Example 46. Benzothiophene-3-sulfonyl chloride was used in place of Example 46d). . Melting point 130C (dec.).

Example 48

N- {5-methyl-3- (2- (pyridin-4-ylamino) ethoxy] phenyl} benzo-2,3,1-thiadiazole-4-sulfonamide hydrochloride

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzo-2,3,1-thiadiazole-4-sulfonamide hydrochloride was prepared in analogy to Example 46, but instead of Example 46d) benzo-2,3,1-thiadiazole-4-sulfonyl chloride is used. Melting point 110 ° C.

Example 49

N- {5-methoxy-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -4-fluorobenzenesulfonamide hydrochloride

a) In a 100 ml autoclave, 16.0 g (115 mmol) of 3-hydroxy-5-methoxyphenol (G. Rodighiero, C. Antonello II Farmaco, Ed. Sci. (1955), 3.7 g of ammonium chloride, 13.8 ml of water and 24 ml of concentrated ammonia. After cooling, the interior of the autoclave was rinsed with methanol, the solvent was removed in vacuo, the residue was triturated with ethyl acetate, the insoluble (6.5 g) was filtered off, the solvent was removed in vacuo, the oily residue was washed with silica gel and washed with heptane. Ethyl acetate 1: 1. The solvent was filtered off to give 10.4 g of 3-hydroxy-5-methoxyaniline as a red oil.

b) 3-hydroxy-5-methoxyaniline (10.4 g, 75.0 mmol) was acetylated for 12 hours in 100 ml of methylene chloride in the presence of 0.1 g of 4-dimethylaminopyridine with 100 ml of acetic anhydride at room temperature. The solvent is removed in vacuo, 200 ml of methanol and 20 ml of saturated sodium carbonate solution are added to the residue (predominantly the diacetyl compound) and stirred at room temperature for 3 hours. The solvent was removed in vacuo, water (250 ml) was added, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. Removal of the solvent gave 11 g (81%) of N- (3-hydroxy-5-methoxyphenyl) acetamide, mp 126 ° C.

c) N- (3-hydroxy-5-methoxyphenyl) acetamide (11.0 g, 61.0 mmol) is alkylated in dry dimethylformamide in the presence of 9.1 g (65 mmol) of potassium carbonate with 6.9 ml (65 mmol) of ethyl chloroacetate at 60 ° C for 8 hours. Dilute with water, acidify with hydrochloric acid and extract with ethyl acetate. The organic phase is extracted with water, dried over sodium sulfate and the solvent is removed in vacuo. 10.8 g (66%) of acetic acid 2- (3-acetamido-5-methoxyphenoxyethyl ester) are obtained as an oil.

d) Acetic acid 2- (3-acetamido-5-methoxyphenoxyethyl ester (10.8 g 40 mmol) in 70 ml of ethanol is stirred for 4 hours with 30 ml of 2N sodium hydroxide solution, the solvent is removed in vacuo, mixed with water and The precipitate (5.5 g of carboxylic acid) is filtered off with suction, dissolved in 50 ml of ethanol, 50 ml of 10 N sodium hydroxide solution is added and the mixture is heated under reflux for 8 hours. the solvent was removed in vacuo, 100 mL of methanol was added and stirred for 12 hours at room temperature The solvent was removed in vacuo, digested with ethyl acetate, filtered off with suction to give 5.6 g of the methyl ester

2- (3-amino-5-methoxyphenoxy) acetic acid (MS, m / e = 211).

e) According to the method Ia, 2- [3- (4-fluorobenzenesulfonylamino) -5-methoxyphenoxy] acetic acid methyl ester is obtained as an oil from 2- (3-amino-5-methoxyphenoxy) acetic acid methyl ester by treatment with 4-fluorobenzenesulfonyl chloride. (MS (m / e = 369)).

f) 2- [3- (4-Fluorobenzenesulfonylamino) -5-methoxyphenoxy] acetic acid methyl ester was obtained in a yield of 95% 2- [3- (4-fluorobenzenesulfonylamino) -5-methoxyphenoxy] by the method of Example 1b). acetic acid, m.p. 161 ° C.

g) Similar to Example 1c), 2- (3- (4-fluorobenzenesulfonylamino) -5-methoxyphenoxy) acetic acid was obtained in a yield of 58% of acetamide N- (4-pyridyl) -2- [3- ( 4-Fluorobenzenesulfonylamino) -5-methoxyphenoxy] -acetic acid, m.p. 161 ° C.

h) Analogously to Example 23, N- (5-methyl-) - hydrochloride is obtained from N- (4-pyridyl) -2- [3- (4-fluorobenzenesulfonylamino) -5-methoxyphenoxy] acetic acid acetamide in 76% yield. 3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -4-fluoro-benzenesulfonamide, m.p. 62 ° C.

Example 50

N- {3- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} -2-chloro-benzenesulfonamide

N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-chlorobenzenesulfonamide was prepared analogously to Example 1 in 58% yield. Melting point 221-223 ° C.

Example 51

N-methyl-N- {3- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} -2-chloro-benzenesulfonamide

N-methyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-chlorobenzenesulfonamide was prepared analogously to Example 12 in 22% yield. Melting point 188-190 ° C.

Example 52

N-2-propyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide

N-2-propyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide was prepared analogously to Example 12 in 47% yield as an oil. MS (m / e) = 411;

57 Example 53

N-methyl-N- {3- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} -2-thiophenesulfonamide

N-methyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-thiophenesulfonamide was prepared in analogy to Example 12 in 12% yield. Melting point 179-181 ° C.

Example 54

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -1-naphthalenesulfonamide hydrochloride

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -1-naphthalenesulfonamide hydrochloride was prepared in analogy to Example 17 in 14% yield. Melting point 215-218 ° C.

Example 55

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-thiophenesulfonamide hydrochloride

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-thiophenesulfonamide hydrochloride was prepared in analogy to Example 17 in 24% yield. Mp 252-254 ° C.

Example 56

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-chlorobenzenesulfonamide hydrochloride

N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -2-chlorobenzenesulfonamide hydrochloride was prepared analogously to Example 17 in 42% yield. Mp 254-258 ° C.

Example 57

N-methyl-N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -1-chlorobenzenesulfonamide hydrochloride

(a) 96 g (0.78 mol) of 3-hydroxy-5-methylaniline (F. Wessely, H. Eibel, G. Friedrich, Monatshefte Chem. 83, 24-30 (1952)) are reacted in 1, 2 L of dioxane and 840 ml of water with 420 ml of 2N sodium hydroxide solution with ice-cooling with 171 g (0.78 mol) of di-tert-butyl hydrogen carbonate. After stirring for 12 hours at room temperature, the solvent is removed in vacuo under ice-cooling, acidified to pH 2-3 and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and the solvent is removed in vacuo. 174 g of N-tert-butyloxycarbonyl) -3-hydroxy-5-methylaniline are obtained in quantitative form as an oil. MS (m / e) = 223.1.

b) 132 g (0.59 mol) of N-tert-butyloxycarbonyl) -3-hydroxy-5-methylaniline in 400 ml of dry dimethylformamide, 90 g (0.65 mol) of potassium carbonate and 69 ml (0.65 mol) of ethyl ester of chloroacetic acid is heated to 70 ° C for 3 hours. It is taken up in 1 l of ice-water, extracted with ethyl acetate, the organic phase is dried over sodium sulphate, filtered and the solvent is removed in vacuo. 174 g (95%) of 2- (tert-butyloxycarbonylamino-5-methyl-phenoxy) -acetic acid ethyl ester are obtained as an oil. MS (m / e) = 309;

c) 174 g (0.562 mol) of 2- (tert-butyloxycarbonylamino-5-methyl-phenoxy) -acetic acid ethyl ester were reacted with ice-cooling with 200 ml of trifluoroacetic acid, stirred at room temperature for two hours and the solvent was removed in vacuo. The residue was treated with 2N hydrochloric acid, extracted with ethyl ester, the aqueous phase basified with sodium hydroxide solution and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in vacuo. 87.5 g (74%) of 2- (3-amino-5-methyl-phenoxy) -acetic acid ethyl ester are obtained as an oil. MS (m / e) = 209.1.

d) Analogously to Example 17a), 2- (3-amino-5-methyl-phenoxy) -acetic acid ethyl ester was reacted with 2-chlorobenzenesulfonyl chloride to give ethyl 2- [3- (2-chlorobenzenesulfonylamino) ester in 56% yield. (5-methylphenoxy) acetic acid, m.p. 133-137 ° C.

e) Methyl 2- [3- (2-chlorobenzenesulfonylamino) -5-methylphenoxy] -acetic acid ethyl ester according to the method of Example 12a) is obtained in quantitative yield N-methyl-2- [3- (2-chlorobenzenesulfonylamino) -5-methylphenoxy] acetic acid ethyl ester acid as an oil, MS (m / e) = 398.

f) N-Methyl-2- [3- (2-chlorobenzenesulfonylamino) -5-methylphenoxy] acetic acid ethyl ester was saponified according to the method of Example 1b) and N-methyl-2- [3- (2-chlorobenzenesulfonylamino) acid was obtained in quantitative yield. ) -5-methylphenoxy] acetic acid. Melting point 113-115 ° C.

g) N-Methyl-2- [3- (2-chloro-benzenesulfonylamino) -5-methyl-phenoxy] -acetic acid was reacted with 4-aminopyridine as in Example 1c) to give 2- {3 - [(2 -chlorobenzenesulfonyl) methylamino] -5-methylphenoxy} -N-pyridin-4-yl-acetamide as an oil.

h) Reduce 2- {3 - [(2-chlorobenzenesulfonyl) methylamino] -5-methylphenoxy} -N-pyridin-4-yl-acetamide according to Example 1d) and yield N-methyl-N hydrochloride in 41% yield. - {5-methyl-3- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} -1-chlórbenzénlsulfónamidu. Melting point 213-215 ° C.

Example 58

N-methyl-N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide hydrochloride

N-Methyl-N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} -1-chlorobenzenesulfonamide hydrochloride according to Example 57 (0.86 g, mmol) was hydrogenated in 30 mL of ethanol in the presence of 0.3 g of 10% palladium on carbon at room temperature and at ambient pressure. The uptake of hydrogen is 55 ml. Filter, remove the solvent in vacuo. Digest with ether to give 0.75 g (86%) of N-methyl-N- {5-methyl-3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide hydrochloride, m.p. 182-184 ° C. C.

Example 59

N- {2-methoxy-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide

a) To 8.5 g (50 mmol) of 2-hydroxy-4-nitroanisole and 13.8 g (10 mmol) of potassium carbonate in 120 ml of acetonitrile was added dropwise 8.4 g (50 mmol) of ethyl bromoacetate in an ice bath. After stirring at room temperature for 12 hours, the solvent is removed in vacuo, the residue is treated with water and extracted with ethyl acetate. The organic phase is dried over sodium sulfate, filtered and the solvent is removed in vacuo. 12.7 (quantitative) 2- (2-methoxy-5-nitrophenoxy) acetic acid ethyl ester is obtained as an oil. MS (m / e) = 255.

b) 2- (2-Methoxy-5-nitrophenoxy) acetic acid ethyl ester (12.1 g, 47 mmol) was subjected to hydrogenation in 300 ml of methanol in the presence of 5 g of Raney-nickel under pressure and ambient temperature. When 3.4 liters of hydrogen were consumed, it was filtered and the solvent was removed in vacuo. 10.7 g of (quantitative) 2- (2-methoxy-5-aminophenoxy) acetic acid ethyl ester are obtained in the form of an oil. MS (m / h)

225th

c) 2- (2-Methoxy-5-aminophenoxy) acetic acid ethyl ester (10.7 g, 47 mmol) was treated with benzenesulfonyl chloride according to Example 1a) to give 17.2 g (quantitative) of ethyl ester 2 (2-methoxy) -5-benzenesulfonylaminophenoxy) acetic acid.

MS (m / e) = 413;

d) From 2- (2-methoxy-5-benzenesulfonylaminophenoxy) -acetic acid ethyl ester, 11.8 g (74%) of 2- (2-methoxy-5-benzenesulfonylaminophenoxy) -acetic acid was obtained according to Example 1b).

MS (m / e) = 337;

e) From 2- (2-methoxy-5-benzenesulfonylaminophenoxy) acetic acid, as described in Example 1c), 5 g (35%) of N-4-pyridinyl-2- (2-methoxy-5-benzenesulfonylaminophenoxyacetamide), m.p. .

f) From N-4-pyridinyl-2- (2-methoxy-5-benzenesulfonylaminophenoxyacetamide), N- {2-methoxy-5- [2 (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide is obtained as described in Example 23. mp 188-189 ° C.

Example 60

N {2-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide

N- {2-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl] benzenesulfonamide was prepared in analogy to Example 59 except that in step a) instead of 2-hydroxy-4-nitranisole was used 2-hydroxy-4-nitrotoluene. This pre-stage is prepared as follows:

100 g of 2-amino-4-nitrotoluene are mixed into 300 ml of concentrated sulfuric acid at 50 ° C. After complete dissolution (30 minutes), 2.5 kg of ice is added, cooled to -15 ° C and a solution of 50 g of sodium nitrite in 200 ml of water is added dropwise so that the temperature does not exceed 0'C. This solution is added to the refluxing mixture consisting of 500 ml of concentrated sulfuric acid and one liter of water. After refluxing, the mixture is heated at reflux for one hour, allowed to stand for 12 hours and the precipitate is filtered off with suction. 87.1 g (87%) of 2-hydroxy-4-nitrotoluene of melting point 117 DEG-120 DEG C. are obtained.

(a) 2- (2-Methyl-5-nitrophenoxy) acetic acid ethyl ester as an oil. MS (m / e) = 239.

b) 2- (2-Methyl-5-aminophenoxy) acetic acid ethyl ester as an oil. MS (m / e) = 209.1.

c) 2- (2-Methyl-5-benzenesulfonylaminophenoxy) -acetic acid ethyl ester. Mp 78-83 ° C.

d) 2- (2-Methyl-5-benzenesulfonylaminophenoxy) acetic acid. Melting point 157-160 ° C.

e) N- (4-pyridinyl) -2- (2-methyl-5-benzenesulfonylaminophenoxy) acetamide. Mp 157-161 ° C.

f) N- {2-methyl-2- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide, m.p. 179-180 ° C.

Example 61

Benzenesulfonic acid 5-methyl-3- (2-pyridin-4-ylamino) ethoxyphenyl ester

(a) In 70 ml of acetonitrile, reflux for 24 hours

7.1 g (50 mmol) of 5-methylresorcin, 10 g (100 mmol) of potassium bicarbonate and 12.6 g (55 mmol) of bromoacetic acid-free ester. The solvent is removed in vacuo, water is added to the residue and the ether phase is extracted three times with 0.1N sodium hydroxide solution, the ether phase is dried over sodium sulphate, filtered and the solvent is removed in vacuo. The residue (7.75 g) was separated on silica gel with isohexane / ethyl acetate (9: 1) to give 4.0 g (29%) of 2- (3-hydroxy-5-methylphenoxy) acetic acid benzyl ester as an oil MS m / e) = 272.

b) 2.0 g (7.5 mmol) of 2- (3-hydroxy-5-methyl-phenoxy) -acetic acid benzyl ester was reacted with benzenesulfonyl chloride analogously to Example 1a) to give 2.1 g (68%) of 2- (3-hydroxy-5-methyl-phenoxy) -acetic acid benzyl ester. 3-Benzenesulfonyloxy-5-methyl-phenoxy) -acetic acid as an oil. MS (m / e) = 412.

c) Hydrogenated with 2.0 g (5 mmol) of 2- (3-benzenesulfonyloxy-5-methylphenoxy) acetic acid benzyl ester in 150 ml of methanol in the presence of 0.5 g of 10% palladium on carbon for one hour at pressure and ambient temperature until receiving 140 ml of hydrogen. Filter, add ether and extract three times with sodium bicarbonate solution. The sodium bicarbonate solution was acidified with 2N sulfuric acid, extracted with ether, dried, the solvent was removed in vacuo to give 600 mg (38%).

2- (3-benzenesulfonyloxy-5-methylphenoxy) acetic acid.

MS (m / e) = 322.1.

d) Reacting 0.6 g (2 mmol) of 2- (3-benzenesulfonyloxy-5-methylphenoxy) acetic acid with 4-aminopyridine in analogy to Example 1c) to give N- (pyridin-4-yl) -2- ( 3-Benzenesulfonyloxy-5-methyl-phenoxy) -acetamide (16%). MS (m / e) = 392;

e) From N- (pyridin-4-yl) -2- (3-benzenesulfonyloxy-5-methylphenoxy) acetamide, benzenesulfonic acid 5-methyl-3- (2-pyridin-4-ylamino) ethoxyphenyl ester was obtained analogously to Example 23. Mp 144-146 ° C.

Example 62

2-Chlorobenzenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester

2-Chlorobenzenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester was prepared in analogy to Example 61. Mp 156-158 ° C. Intermediate: 2- [3- (2-chlorobenzene sulfonyloxy) -5-methylphenoxy] acetic acid. Mp 157-161 ⁰ C. N- (pyridin-4-y1) -2- [3- (2-chlorobenzenesulfonyloxy) -5- methyl-phenoxy] -acetamide. MS (m / e) = 432;

Example 63

4-Fluorobenzenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester

4-Fluorobenzenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester was prepared in analogy to Example 61 except that 4-fluorobenzenesulfonyl chloride was used in step b). Mp 161-163 ° C.

Example 64

1-Naphthalenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester

1-Naphthalenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester was prepared in analogy to Example 61 except that 1-naphthalenesulfonyl chloride was used in step b). Melting point 95-99 ° C.

Example 65

2-Thiophenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester

(a) 24.8 g (200 mmol) of 5-methyl resorcinol, 43.8 g (240 mmol) of 2-thiophenesulfonyl chloride and 1.5 g of solid sodium bicarbonate are coated in 200 ml of water with 100 ml of ether and dispensed with a saturated sodium bicarbonate solution. maintains pH = 7.2. Stir for 12 hours at room temperature at pH 7.2, the aqueous phase is separated, the ether phase is dried over sodium sulphate, filtered and the solvent is removed in vacuo. Quantitative yield of thiophenesulfonic acid 3-hydroxy-5-methylphenyl ester the form of oil. MS (m / e) = 270.

b) Reacting thiophenesulfonic acid 3-hydroxy-5-methylphenyl ester in analogy to Example 18a) with ethyl bromoacetate to give 2- [3- (2-thiophenesulfonyloxy) -5-methylphenoxy] ethyl acetate. MS m / e) = 356;

c) from 2- [3- (2-thiophenesulfonyloxy) -5-methylphenoxy] ethyl acetate, similar to Example 1b), 2- [3- (2-thiophenesulfonyloxy) -5-methylphenoxy] acetic acid, m.p. to 143 ° C.

d) From 2- [3- (2-thiophenesulfonyloxy) -5-methylphenoxy] acetic acid, analogously to Example 1c), N- (pyridin-4-yl) -2 [3- (2-thiophenesulfonyloxy) -5- methylphenoxy] acetamide, m.p. 136-138 ° C.

e) From N- (pyridin-4-yl) -2- [3- (2-thiophenesulfonyloxy) -5-methylphenoxy] acetamide to give 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester 2-thiophenesulfonic acid, m.p. 176 ° C.

Example 66

2-Benzyloxycarbonylbenzenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester

a) Analogously to Example 61 (a), 5-methylresorecin was reacted with ethyl bromoacetate to give 2- (3-hydroxy-5-methylphenoxy) acetic acid ethyl ester as an oil. MS (m / e) = 210.1.

b) Analogously to Example 61b), 2- [3- (2-benzyloxycarbonyl) benzenesulfonyloxy-5-methylphenoxy] acetic acid ethyl ester is obtained from 2- (3-hydroxy-5-methylphenoxy) acetic acid ethyl ester by reaction with 2-benzyloxy66 carbonylbenzenesulfonyl chloride in the form of oil. MS (m / e) = 484;

c) 2- [3- (2-Benzyloxycarbonyl) benzenesulfonyloxy-5-methylphenoxy] acetic acid ethyl ester was saponified according to Example 1b) for 4 hours at room temperature to give 63% of 2- [3- (2-benzyloxycarbonylbenzenesulfonyloxy) - Of 5-methylphenoxy] acetic acid. MS (m / e) = 456;

d) N- (pyridin-4-yl) -2- [3- (2-benzyloxycarbonylbenzenesulfonyloxy) -5-methylphenoxy] acetamide is obtained from 2- [3- (2-benzyloxycarbonylbenzenesulfonyloxy) -5-methylphenoxy] acetic acid MS (m / m) e): 532

e) From N- (pyridin-4-yl) -2- [3- (2-benzyloxycarbonylbenzenesulfonyloxy) -5-methylphenoxy] acetamide, analogously to Example 23, 5-methyl-3 - [(2-pyridin-4-) was obtained. ylamino) ethoxy] phenyl 2-benzyloxycarbonylbenzenesulfonic acid ester. MS (m / e) = 518;

Example 67

2-Carboxybenzenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester

2.5 g (1 mmol) of 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl 2-benzyloxycarbonylbenzenesulfonic acid ester (compound of Example 66) are hydrogenated in 100 ml of methanolic ammonia solution in the presence of 1 g of 10. % palladium on carbon at room temperature and pressure. The reaction mixture was filtered, the solvent was removed in vacuo, the residue was triturated with isopropanol, filtered off with suction and crystallized from ethanol. 0.4 g (14%) of 2-carboxybenzenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester of melting point 189 &apos; C is obtained.

¢ 1

Example 68

2-Methylbenzenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester

2-Methylbenzenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester was prepared analogously to Example 61. Mp 152-154 ° C. [0332] Preference: N- (pyridin-4-yl) -2- [3- (2-methylbenzenesulfonyloxy) -5-methylphenoxy] acetamide, m.p. 158 DEG-160 DEG.

Example 69

2-Methoxybenzenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester

2-Methoxy-benzenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) -ethoxy] -phenyl ester was prepared analogously to Example 61. Mp 116-119 ° C. Preference: N- (pyridin-4-yl) -2- [3- (2-methoxybenzenesulfonyloxy) -5-methylphenoxy] acetamide, m.p. 156-159 ° C.

Example 70

2-Nitrobenzenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester

2-Nitrobenzenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester was prepared analogously to Example 61. Mp 137-140 ° C. Preference: N- (pyridin-4-yl) -2- [3- (2-nitrobenzenesulfonyloxy) -5-methylphenoxy] -acetamide. MS (m / e)

453rd

Example 71

2-Aminobenzenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester

Hydrogenate 1.0 g (2.23 mmol) of 2-nitrobenzenesulfonic acid 5-methyl-3 - [(2-pyridin-4ylamino) ethoxy] phenyl ester (compound of Example 70) in 40 mL of methanol in the presence of 1 g of Raney nickel 1.5 hours at room temperature and pressure. The reaction mixture is filtered, the solvent is removed in vacuo, the residue is treated with 25 ml of tetrahydrofuran and 25 ml of ether, extracted with 0.05 M sodium hydroxide solution, the organic phase is dried, filtered and the solvent is removed in vacuo. 0.5 g (54%) of 2-aminobenzenesulfonic acid 5-methyl-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester, m.p. 168-171 ° C, is obtained.

Example 72

5-methyl-3 - [(2-N-methylpyridin-4-ylamino) -ethoxy] -phenyl

Of 2-chlorobenzenesulfonic acid

a) Treatment of 2- [3- (2-chlorobenzenesulfonyloxy) -5-methylphenoxy] acetic acid according to Example 62 with 4-methylaminopyridine gives N-methyl-N- (pyridin-4-yl) -2- [3- (2 -chlórbenzénsulfonyloxy) -5metylfenoxy] acetamide. MS (m / e) = 447;

b) From N-methyl-N- (pyridin-4-yl) -2- [3- (2-chlorobenzenesulfonyloxy) -5-methylphenoxy] acetamide, analogously to Example 23, 5-methyl-3 - [(2-N-) was obtained. 2-chlorobenzenesulfonic acid methylpyridin-4-ylamino) ethoxy] phenyl ester, m.p. 152-161 ° C

Example 73

Benzenesulfonic acid 5-chloro-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester

a) 89.8 g (0.57 mol) of 5-chlororesorcinedimethyl ester and 108 ml (1.14 mol) of boron tribromide in 400 ml of methylene chloride were stirred at room temperature for 72 hours. Extract with water, extract the aqueous phase with n-butanol, remove n-butanol for the most part in vacuo and allow to crystallize at 4 ° C for 12 hours.

19.5 g (24%) of 5-chlororesortin with a melting point of 71'C are obtained.

b) 3.0 g (21 mmol) of 5-chlororesortin in 50 ml of water are treated with 20 ml of ether, saturated sodium bicarbonate solution is added until pH = 5.2. While maintaining the pH, 8.6 ml (21 mmol) of benzenesulfonyl chloride is added slowly, the pH is raised to 7.0 and stirred at room temperature for 48 hours while maintaining the pH constant. Extract with ether, extract the ether phase with 0.1 N sodium hydroxide solution, acidify the reaction mixture with 2N sulfuric acid and extract three times with ether. The solvent was removed in vacuo to give benzenesulfonic acid 3-chloro-5-hydroxy-phenyl ester.

MS (m / e) = 284.1.

c) The benzenesulfonic acid 3-chloro-5-hydroxyphenyl ester was reacted analogously to Example 18a) to give 2- [3-chloro-5- (phenylsulfonyl) phenoxy] acetic acid ethyl ester in 95% yield. MS (m / e) = 370.

d) Analogously to Example 1b), 2- [3-chloro-5 (phenylsulfonyl) phenoxy] acetic acid ethyl ester was saponified to give 2- [3-chloro-5- (phenylsulfonyl) phenoxy] acetic acid in 80% yield. mp 136 and 138 ° C.

e) Analogously to Example 1c), 2- [3-chloro-5- (phenylsulfonyl) phenoxy] acetic acid was reacted with 4-aminopyridine to give N- (pyridin-4-yl) -2- (70% yield). [3-Chloro-5 (phenylsulfonyl) -phenoxy] -acetamide, m.p. 173-176 ° C.

f) N- (pyridin-4-yl) -2- [3-chloro-5- (phenylsulfonyl) phenoxy] acetamide was reduced in analogy to Example 23 to give 5-chloro-3 - [(2-pyridin-4-ylamino)]. m.p. 144 DEG -146 DEG C. ethoxy] benzenesulfonic acid phenyl ester. The hydrochloride melts at 173-176 ° C.

Example 74

2-Chlorobenzenesulfonic acid 5-chloro-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester

2-Chlorobenzenesulfonic acid 5-chloro-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester was prepared in analogy to Example 72. Intermediate:

b) 2-chlorobenzenesulfonic acid 3-chloro-5-hydroxyphenyl ester, m.p. 99-105 ° C.

c) 2- [3-Chloro (phenylsulfonyloxy) phenoxy] acetic acid ethyl ester as an oil. MS (m / e) = 405.

d) 2- [3-chloro-5- (2-chlorophenylsulfonyloxy) phenoxy] acetic acid, m.p. 140-142 ° C.

e) N- (pyridin-4-yl) -2- [3-chloro-5- (2-chlorophenylsulfonyloxy) phenoxy] acetamide, m.p. 158-160 ° C.

f) 2-chlorobenzenesulfonic acid 5-chloro-3 - [(2-pyridin-4-ylamino) ethoxy] phenyl ester, m.p. 149-150 ° C

Example 75

Benzenesulfonic acid 3 - [(2-pyridin-4-ylamino) ethylamino] phenyl ester

a) 15 g (54 mmol) of benzenesulfonic acid 3-nitrophenyl ester in 200 ml of methanol are hydrogenated in the presence of 2.5 g of 10% palladium on carbon at room temperature and pressure. The reaction mixture was filtered, the solvent was removed in vacuo. The residue (13 g of 3-nitro71 phenyl benzenesulfonic acid ester), 4.3 g of sodium acetate and 8.7 g of ethyl bromoacetate in 10 ml of ethanol is heated under reflux for 12 hours. Water was added and extracted with ether. The ether was removed in vacuo to give 17.3 g (99%) of 2- [3- (phenylsulfonyloxy) phenylamino] acetic acid ethyl ester as an oil. MS (m / e) = 335.

b) Analogously to Example 1b), 2- [3- (phenylsulfonyloxy) phenylamino] acetic acid ethyl ester is saponified to give 2- [3- (phenylsulfonyloxy) phenylamino] acetic acid in 65% yield. MS (m / e) = 307.

c) Analogously to Example 1c), 2- [3- (phenylsulfonyloxy) phenylamino] acetic acid is reacted with 4-aminopyridine to give N- (pyridin-4-yl) -2- [3- (phenylsulfonyloxy) phenylamino] acetamide in the form of an oil. MS (m / e) = 383;

d) Analogously to Example 23, 3 - [(2-pyridin-4-ylamino) -ethoxy] -phenyl benzenesulfone ester was obtained from N- (pyridin-4-yl) -2- [3- (phenylsulfonyloxy) phenylamino] acetamide. acid. 0.6 g of the oil compound is dissolved in 10 ml of ethyl acetate and treated with a solution of 200 mg of cyclohexanesulfamic acid in 10 ml of ethyl acetate. A few drops of isopropanol are added and allowed to crystallize. 0.3 g of benzenesulfonic acid 3 - [(2-pyridin-4-ylamino) -ethylamino] -phenyl ester is obtained, m.p. 106 DEG-111 DEG.

Example 76

Benzenesulfonic acid 3-methyl-5- [2- (pyridin-4-ylamino) ethylamino] phenyl ester

(a) Heating was maintained at reflux for 12 hours with 12.3 g (100 mmol) of 3-hydroxy-5-methylaniline (see Example 57) and 25.1 g (170 mmol) of phthalic anhydride in 250 ml of acetic acid. 250 ml of water are added, filtered while hot, and 250 ml of water are added to the filtrate and allowed to crystallize. Filter, dissolve the precipitate in hot methanol (400 mL), treat with charcoal and remove the water in vacuo. 21.7 g (86%) of 3-phthalimido-5-methylphenol of melting point 170 DEG-175 DEG C. are obtained.

b) Analogously to Example 1a), benzenesulfonic acid 3-methyl-5-phthalimidophenyl ester is obtained in quantitative yield from 3-phthalimido-5-methylphenol. MS (m / e) = 393;

c) Stir 3.9 g (10 mmol) of 3-methyl-5-phthalimidophenyl benzenesulfonic acid ester and 0.7 ml (15 mmol) of hydrazine hydrate in 10 ml of ethanol and 30 ml of methylene chloride for 12 hours at room temperature, add 4 ml concentrated hydrochloric acid, stirred at room temperature for 2 hours, the compound was filtered, the solvent was removed in vacuo, 2N sodium hydroxide solution was added to the residue and extracted with ether, the ether phase was removed in vacuo to give 2.5 g (96 g). %) Benzenesulfonic acid 3-methyl-5-aminophenyl ester. MS (m / e) = 363;

d) Analogously to Example 1a), 2.5 (9.5 mmol) of 3-methyl-5-aminophenyl benzenesulfonic acid ester was reacted with tosyl chloride to give benzenesulfonic acid 3-methyl-5- (4-methylphenylsulfonylamino) phenyl ester in quantitative yield.

MS (m / e) = 417;

e) Analogously to Example 18a), benzenesulfonic acid 3-methyl-5- (4-methylphenylnylsulfonylamino) phenyl ester was alkylated with ethyl bromoacetate to give 5 g (quantitative yield) of [4-methylbenzenesulfonyl- (3-benzenesulfonyloxy-5-methylphenyl) ethyl ester. amino] acetic acid. MS (m / e) = 503;

f) 5 g (10 mmol) of [4-methyl-benzenesulfonyl- (3-benzene-7-sulfonyloxy-5-methyl-phenyl) -amino] -acetic acid ethyl ester in 60 ml of 6N hydrochloric acid is maintained at reflux for 6 hours. The solvent is removed in vacuo, water is added, neutralized with sodium bicarbonate, extracted with ethyl acetate, the pH of the aqueous phase is adjusted to 3 and extracted with ethyl acetate. The ethyl acetate was removed in vacuo to give 2 g (62%) of (3-benzenesulfonyloxy-5-methylphenyl) aminoacetic acid. MS (m / e) = 321.1.

g) Analogous to Example 1c), (3-benzenesulfonyloxy-5-methylphenyl) aminoacetic acid is reacted. Obtained in 12% yield of N- (pyridin-4-yl) benzenesulfonyloxy-5-methylphenyl) aminoacetamide. MS (m / e) = 397;

h) Analogously to Example 23, benzenesulfonic acid 3-methyl-5- [2- (pyridin-4-ylamino) ethylamino] phenyl ester was obtained from N- (pyridin-4-yl) benzenesulfonyloxy-5-methylphenyl) aminoacetamide as an oil. . MS (m / e) = 383;

Example 77

N- {3- [2- (pyridin-4-ylamino) ethylamino] fenyljbenzénsulfónamid

a) 13.8 g (100 mmol) of 3-nitroaniline, 12.3 g (150 mmol) of sodium acetate and 25 g (150 mmol) of ethyl bromoacetate in 5 ml of dimethylsulfoxide are maintained at 80 DEG C. by heating for 48 hours. Pour into 400 ml of 0.5 N hydrochloric acid, add 15 ml of isohexane and 10 ml of ether and allow to crystallize. The compound was filtered off to give 18.7 g (84%) of 3-nitrophenylamino-acetic acid ethyl ester, m.p. 92 ° C.

b) Analogous to Example 1b), 3-nitrophenylaminoacetic acid, m.p. 159 DEG-162 DEG C., is obtained in 90% yield from ethyl 3-nitrophenylaminoacetic acid ester.

(c) Analogously to Example 1 (c), N- (pyridin-4-yl) -3-nitrophenylaminoacetamide, m.p. 196 DEG-198 DEG C., is obtained in 3% yield from 3-nitrophenylaminoacetic acid.

d) Hydrogenate 10.4 g (38 mmol) of N- (pyridin-4-yl) -3-nitrophenylaminoacetamide in 200 mL of methanol and 100 mL of ethyl acetate in the presence of 10 g of Raney-nickel for 1.5 hours at room temperature and pressure. . The reaction mixture was filtered, the solvent was removed in vacuo to give 7.7 g (82%) of N- (pyridin-4-yl) - (3-aminophenyl amino) acetamide. MS (m / e) = 292.

e) Analogously to Example 1a), N- (pyridin-4-yl) - (3-phenylsulfonylaminophenylamino) acetamide was obtained from N- (pyridin-4-yl) - (3-aminophenylamino) acetamide in 68% yield. MS (m / e) = 382;

f) Analogously to Example 23), N- (3- (2- (pyridin-4-ylamino) ethylamino) phenyl) benzenesulfonamide) was obtained from N- (pyridin-4-yl) - (3-phenylsulfonylaminophenylamino) acetamide in 40% yield. .

MS (m / e) = 368;

Example 78

N- {3- [2- (pyridin-4-ylamino) ethylamino] phenyl} thiophenesulfonamide

a) Reaction of N- (pyridin-4-yl) - (3-aminophenylamino) acetamide (compound of Example 77d) with 2-thiophenesulfonyl chloride in analogy to Example 1a) affords N- (pyridin-4-yl) - [3- (thiophen-2-ylsulfonylamino) phenylamino] acetamide in 59% yield.

MS (m / e) = 388.1.

b) Analogously to Example 23), N- (3- (2- (pyridin-4) -pyridine-4-yl) - [3- (thiophen-2-ylsulfonylamino) phenylamino] acetamide was obtained in 24% yield. m.p. 196-198 ° C; -ylamino) ethylamino] phenyl} thiophenesulfonamide;

75 Example 79

N- {3- [2- (Pyridin-4-ylamino) ethylamino] -5-trifluoromethylphenyl} benzenesulfonamide

a) To 24.5 g (100 mmol) of 3,5 dinitrobenzotrifluoride in 180 ml of boiling glacial acetic acid was added portionwise 15 g (270 mmol) of iron powder. Pour over water, extract with glacial acetic acid ester and neutralize the glacial acetic acid phase with solid sodium bicarbonate. The reaction mixture is filtered, the solvent is removed in vacuo, the residue (26.3

g) was loaded onto silica gel and eluted with isohexane / ethyl acetate (8: 2). 13.0 g (63%) of 3-nitro-5-trifluoromethylaniline of melting point 80 DEG-84 DEG C. are obtained.

b) Dissolve 5.0 g (24 mmol) of 3-nitro-5-trifluoromethylaniline in 20 mL of sulfuric acid and 17 mL of water, cool to 0 ° C and add a solution of 1.9 (27 mmol) of sodium nitrite in 10 mL ml of water. The cold solution was added to 250 ml of boiling concentrated copper sulfate solution. After the evolution of nitrogen was complete, it was extracted with ether. The ether phase is extracted with a 0.05 N sodium hydroxide solution, the aqueous phase is acidified with dilute sulfuric acid and extracted with ether. The ether was removed in vacuo to give 3.4 g (68%).

3-nitro-5-trifluoromethylphenol, m.p. 82-84 ° C.

c) 36.7 g (600 mmol) of ethanolamine and 80.7 g (550 mmol) of phthalic anhydride in 290 ml of toluene are heated under reflux for two hours using a water trap. After separating 9.3 ml of water, the mixture was allowed to cool, filtered to give 95.1 g (90%) of N- (2-hydroxyethyl) phthalimide, mp 128-132 ° C.

d) Stir 28.8 g (150 mmol) of N- (2-hydroxyethyl) phthalimide and 42.9 g (225 mmol) of tosyl chloride in 200 ml of pyridine for three hours at room temperature, acidify with 2N hydrochloric acid76 and extract. ethyl acetate. The ethyl acetate was removed in vacuo to give 48.3 g (85%) of (2-phthalimidoethyl) 4-toluenesulfonic acid ester, m.p. 144-148 ° C.

(e) Stir 1.7 g (12.5 mmol) of (2-phthalimidoethyl) -4-toluenesulfonic acid ester, 2.6 g (12.5 mmol) of N- (2-hydroxyethyl) phthalimide (compound 79c) and 1 g of potassium carbonate in 80 ml of dimethyl sulfoxide for 12 hours at 50 ° C. Pour onto ice, extract with ethyl acetate, wash the ethyl acetate solution with 0.01 N sodium hydroxide solution and saturated sodium chloride solution, remove the ethyl acetate in vacuo to give 1.9 g (40%) of N- {2- [ 2- (3-nitro-5-trifluoromethylphenoxy) ethyl]} phthalimide, m.p. 146-148 ° C.

f) Analogously to Example 76c), quantitatively 2- (3-nitro-5-trifluoromethylphenoxy) ethyl amine was obtained from N- {2- [2- (3-nitro-5-trifluoromethylphenoxy) ethyl]} phthalimide. MS (m / e) = 250.

g) Stir 1.0 g (4 mmol) of 2- (3-nitro-5-trifluoromethylphenoxy) ethylamine, 1.15 g (4.4 mmol) of 4-nitrotetrachloropyridine (M. Roberts, H. Sušický, J. Chem.) Soc., Pp. 2844-272 (1968)) and 0.48 ml (4.4 mmol) of n-methylmorpholine in 20 ml of dioxane for three hours at room temperature. Water was added, extracted with ethyl acetate, the ethyl acetate solution was washed with water and saturated sodium chloride solution, and ethyl acetate was removed in vacuo to give 1.4 g (75%) of N- (tetrachloropyridin-4-yl) -2- ( 126 DEG-129 DEG C. (nitro-5-trifluoromethylphenoxy) ethylamine.

h) Reduce N- (tetrachloropyridin-4-yl) -2- (3-nitro-5-trifluoromethylphenoxy) ethylamine in analogy to step a) to obtain N- (tetrachloropyridin-4-yl) -2- (3) (amino-5-trifluoromethylphenoxy) ethylamine, m.p. 126-129 ° C.

i) Stir 0.4 g (0.92 mmol) of N- (tetrachloropyridin-4-yl) -2- (3-amino-5-trifluoromethylphenoxy) ethylamine and 0.12 mL of benzenesulfonyl chloride in 5 mL of pyridine for 3 hours at room temperature acidified with 2N hydrochloric acid, extracted with ethyl acetate, washed with saturated sodium chloride solution, the ethyl acetate was removed in vacuo to give 0.4 g of N {2- [2- (tetrachloropyridin-4-ylamino) ethoxy]] - 5 - trifluoromethylphenyl] benzenesulonamide, m.p. 139-143 ° C.

j) Hydrogenate 0.4 g (0.7 mmol) of N- {2- [2- (tetrachloropyridin-4-ylamino) ethoxy]] - 5-trifluoromethylphenyl} benzolsulonamide in 50 ml of methanol in the presence of 3.5 mmol of sodium methylate and 0. 5 g of palladium on carbon at room temperature under pressure. The reaction mixture was filtered, water was added and extracted with ethyl acetate. The ethyl acetate was removed in vacuo to give 0.2 g of N- {3- [2- (pyridin-4-ylamino) -ethylamino] -5-trifluoromethyl-phenyl} -benzenesulfonamide, m.p. 140-144 ° C.

Example 80

3-methoxy-N-methyl-N-phenyl-5- [2- (pyridin-4-ylamino) etoxyjbenzénsulfónamid

(a) Mix 92 g (0,4 mol) 3,5 dinitrobenzoyl chloride and 28,4 g (0,44 mol) sodium azide in 240 ml acetic acid for 8 hours at room temperature, add 400 ml water, precipitate The mixture was filtered to give 80.8 g (85%) of 3,5-dinitrobenzoylazide, mp 105 ° C (dec.).

(b) Heat 80,8 g (0,34 mol) of 3,5-dinitrobenzoylazide in 500 ml of acetic anhydride gently until gas evolution (90 to 100 ° C) begins and maintain at this temperature for 4 hours. The solvent was removed in vacuo, the residue was digested with water to give 136 g (quantitative) of N- (3,5-dinitrophenylacetamide, mp 163 ° C).

(c) Heating of 136 g (0.34 mol) of N- (3,5-dinitrophenylacetamide in 500 ml of ethanol and 500 ml of concentrated hydrochloric acid) is maintained at reflux for three hours, the insoluble matter is filtered off, the filtrate is poured into 2 liters water and the yellow precipitate was filtered off with suction to give 41.4 g (66%).

3,5-dinitroaniline, m.p. 140 DEG C. (dec.).

d) Dissolve 25 g (137 mmol) of 3,5-dinitroaniline in 50 ml of glacial acetic acid and 100 ml of concentrated hydrochloric acid, dropwise at -5 ° C 10.4 g (155 mmol) of sodium nitrite in 20 ml of water The mixture is stirred for 5 minutes at this temperature, the brown suspension is cooled to -20 ° C and transferred to a sulfur dioxide-saturated solution of 2.7 g of copper chloride dihydrate, cooled to O'C in 200 ml, over 15 minutes. glacial acetic acid. Extract with ethyl acetate, the ethyl acetate was removed in a vacuum and dried at a pressure of 1.33 ^-2 mbar. 35.4 g (97%) of dinitrobenzolsulfonyl chloride are obtained as a brown solid which can be used without further purification.

e) From 10.2 g (38.2 mmol) of dinitrobenzolsulfonyl chloride and 4.5 ml (42 mmol) of N-methylaniline, analogously to Example 79i), 4.9 g (38%) of N-methyl-N-phenyl- 3,5-dinitrobenzenesulfonamide, m.p. 175-178 ° C.

f) By heating, 3.5 g (10.4 mmol) of N-methyl-N-phenyl-3,5-dinitrobenzenesulfonamide in 31 ml of a 0.4 molar methanolic sodium methylate solution is maintained at reflux for one hour. The solvent was removed in vacuo, the residue was digested in ethyl acetate and purified through a silica gel column (100 g silica gel). Elution with isohexane / ethyl acetate 2: 1 gives 2.5 g (75%) of N-methyl-N-phenyl-3-methoxy-5-nitrobenzenesulfonamide, m.p. 112 ° C.

g) Hydrogenating N-methyl-N-phenyl-3-methoxy-5-nitrobenzenesulfonamide in analogy to Example 58 to give 2.3 g of N-methyl-N-phenyl-3-methoxy-5-aminobenzenesulfonamide as an oil. MS (m / e) = 292.

i) Alkylated with 250 mg (0.85 mmol) of N-methyl-N-phenyl-3-methoxy-5-aminobenzenesulfonamide 0.14 ml of bromoacetic acid ester analogously to Example 18a) to give 360 mg (quantitative) of ethyl ester [3]. -methoxy-5- (methylphenylsulfamoyl) phenoxy] acetic acid as an oil. MS (m / e) = 379;

j) [3-Methoxy-5- (methylphenylsulfamoyl) phenoxy] acetic acid ethyl ester was saponified analogously to Example 1b) to give 300 mg of [3-methoxy-5- (methylphenylsulfamoyl) phenoxy] acetic acid as a solid. MS (m / e) = 351.1.

k) From [3-methoxy-5- (methylphenylsulfamoyl) phenoxy] acetic acid, analogously to Example 1c), 120 mg of N- (pyridin-4-yl) [3-methoxy-5- (methylphenylsulfamoyl) phenoxy] acetamide was obtained with mp 105 ° C.

l) From 100 mg of N- (pyridin-4-yl) - [3-methoxy-5- (methylphenylsulfamoyl) phenoxy] acetamide of this compound, 45 mg of 3-methoxy-N-methyl-N- is obtained analogously to Example 1d). phenyl-5- [2- (pyridin-4-ylamino) -ethoxy] benzenesulfonamide. MS (m / e) = 413;

Example 81

3-methoxy-N-benzyl-N-phenyl-5- [2- (pyridin-4-ylamino) -ethoxy] benzenesulfonamide

a) Analogously to Example 80d), starting from 3,5-dinitroaniline (compound 80c) and N-benzylaniline in 65% yield N-benzyl-N-phenyl-3,5-dinitrobenzenesulfonamide, m.p. 200 ° C.

b) Analogously to Example 80e), N-benzyl-N-phenyl-3-methoxy-5-nitrobenzenesulfonamide, m.p. 142 DEG C., was obtained in quantitative yield from N-benzyl-N-phenyl-3,5-dinitrobenzenesulfonamide.

c) N-Benzyl-N-phenyl-3-methoxy-5-aminobenzenesulfonamide is obtained in 56% yield as a solid from N-benzyl-N-phenyl-3-methoxy-5-nitrobenzenesulfonamide in analogy to Example 79a).

MS (m / e) = 368;

d) N-Benzyl-N-phenyl-3-methoxy-5-hydroxybenzenesulfonamide was obtained analogously to Example 80g from N-benzyl-N-phenyl-3-methoxy-5-aminobenzenesulfonamide. MS (m / e) = 369;

e) From N-benzyl-N-phenyl-3-methoxy-5-hydroxybenzenesulfonamide, [3-methoxy-5- (benzylphenylsulfamoyl) phenoxyacetic acid ethyl ester was obtained in 30% yield in analogy to Example 18a).

MS (m / e) = 455;

f) From [3-methoxy-5- (benzylphenylsulfamoyl) phenoxyacetic acid ethyl ester, analogously to Example 1b), quantitative [3-methoxy-5- (methylphenylsulfamoyl) phenoxyacetic acid was obtained.

MS (m / e) = 427;

g) From [3-methoxy-5- (methylphenylsulfamoyl) phenoxyacetic acid was obtained analogously to Example 1c) in 42% yield N-pyridin-4-yl) - [3-methoxy-5- (methylphenylsulfamoyl) phenoxy] acetamide with m.p. mp 175 ° C.

h) From N-pyridin-4-yl) - [3-methoxy-5- (methylphenylsulfamoyl) phenoxy] acetamide was obtained analogously to Example 1d) in 50% yield of 3-methoxy-N-benzyl-N-phenyl-5. [2- (pyridin-4-ylamino) ethoxy] benzenesulfonamide as an amorphous powder. MS (m / e) = 489;

Example 82

3-Methoxy-N-phenyl-5- [2- (pyridin-4-ylamino) ethoxy] benzenesulfonamide

Hydrogenate 60 mg (0.12 mmol) of 3-methoxy-N-benzyl-N-phenyl-5- [2- (pyridin-4-ylamino) ethoxy] benzenesulfonamide (Example 81) in analogy to Example 58 to give 20 g. mg (40%) of 3-methoxy-N-phenyl-5- [2- (pyridin-4-ylamino) ethoxy] benzenesulfonamide as an amorphous powder. MS (m / e) = 399.

Example 83

N-methyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] -5-methoxyphenyl} benzenesulfonamide

a) 18.3 g (100 mmol) of 3,5-dinitroaniline (Example 80c) analogously to Example 79i) is reacted with 14.3 g (110 mmol) of benzenesulfonal chloride to give 32.5 g (quantitative) N- (3,5-dinitrophenyl) benzenesulfonamide, m.p. 165 ° C.

b) Methylated 44 g (136 mmol) of N- (3,5-dinitrophenyl) benzenesulfonamide analogously to Example 12a) to give 25.1 g (54%) of N-methyl-N- (3,5-dinitrophenyl) of benzenesulfonamide, m.p. 125 ° C.

c) Reduce 6.8 g (20 mmol) of N-methyl-N- (3,5-dinitrophenyl) benzenesulfonamide analogously to Example 79a) to give 6.1 g (quantitative) of N-methyl-N- ( 3-amino-5-nitrophenyl) benzenesulfonamide as an amorphous powder. MS (m / e) = 307.

d) From 6.1 g (20 mmol) of N-methyl-N- (3-amino-5-nitrophenyl) benzenesulfonamide, analogously to Example 80g), 1.8 g (30%) of N-methyl-N- (3-methyl-N- (3-amino-5-nitrophenyl) benzene) were obtained. 3-hydroxy-5-nitrophenyl) benzenesulfonamide as an amorphous powder. MS (m / e) = 308; (380 after silylation).

e) Stir 1.2 g (4 mmol) of N-methyl-N- (3-hydroxy-5-nitrophenyl) benzenesulfonamide, 6 ml of 1 N sodium hydroxide solution, 1.3 g of tetrabutylammonium bromide, 6 ml of dichloromethane and 0.4 ml of iodomethane for 12 hours at room temperature. The organic phase was separated, the solvent was removed in vacuo and the residue was purified on silica gel (150 g). Elution with 2: 1 isohexane / ethyl acetate gave 240 mg (18%) of N-methyl-N- (3-methoxy-5-nitrophenyl) benzenesulfonamide, m.p. 136C.

f) N-methyl-N- (3-methoxy-5-nitrophenyl) benzenesulfonamide was hydrogenated in analogy to Example 58 to obtain quantitatively N-methyl-N- (3-methoxy-5-aminophenyl) benzenesulfonamide as an amorphous powder. MS (m / e) = 292.

g) Analogously to Example 80g), N-methyl N- (3-methoxy-5-hydroxyphenyl) benzenesulfonamide was obtained as an amorphous powder from N-methyl-N- (3-methoxy-5-aminophenyl) -benzenesulfonamide in 74% yield. e) = 293.

h) Analogously to Example 18a), [3-methoxy-5- (N-methylphenylsulfonylamino) phenoxy] acetic acid ethyl ester was obtained in 89% yield as an amorphous powder from N- (3-methoxy-5-hydroxyphenyl) benzenesulfonamide. MS (m / e) = 379;

(i) In analogy to Example 81f) to 81h), the following are obtained from [3-methoxy-5- (N-methylphenylsulfonylamino) phenoxy] acetic acid ethyl ester:

[3-Methoxy-5- (N-methyl-phenylsulfonylamino) -phenoxy] -acetic acid (74%; MS (m / e) = 351),

N- (pyridin-4-yl) - [3-methoxy-5- (N-methylphenylsulfonylamino) phenoxy] acetamide (34%; MS (m / e) = 427);

N-methyl-N- (3- (2- (pyridin-4-ylamino) ethoxy) -5-methoxyphenyl} benzenesulfonamide as an amorphous powder) MS (m / e) = 413.

Example 84

3-chloro-N-methyl-N-phenyl-5- [2- (pyridin-4-ylamino) -ethoxy] benzenesulfonamide

a) Analogously to Example 79a), N-methyl-N-phenyl-3,5-dinitrobenzenesulfonamide (compound 80e) was reduced to give N-methyl-N-phenyl-3-amino-5-nitrobenzenesulfonamide with a melting point of 50%. 175 ° C.

b) To 3.5 g (10 mmol) of N-methyl-N-phenyl-3-amino-5-nitrobenzenesulfonamide in 40 ml of 6N hydrochloric acid was added dropwise a solution of 760 mg (11 mmol) of sodium nitrite in 2 ml at 0 ° C. ml of water and the resulting suspension is poured into a solution of 3.75 g of copper sulphate pentahydrate and 1.35 g of sodium chloride are dissolved in 12 ml of warm water, a solution of 950 mg (7.5 mmol) of sodium sulfite in 3 ml of water is added dropwise. the precipitate is filtered rapidly and dissolved in 6 ml of concentrated hydrochloric acid. Heat slowly to 100 ° C, cool, extract with ethyl acetate and filter through a silica gel column (100 g silica gel). Elution with isohexane / ethyl acetate gave 1.45 g (43%) of N-methyl-N-phenyl-3-chloro-5-nitrobenzenesulfonamide, m.p.

c) N-methyl-N-phenyl-3-chloro-5-nitrobenzenesulfonamide was quantitatively reduced as in Example 79a) to give N-methyl-N-phenyl-3-chloro-5-aminobenzenesulfonamide as an amorphous powder. MS (m / e) = 296.1.

d) In analogy to Examples 83g) to 83i), the following was prepared from N-methyl-N-phenyl-3-chloro-5-aminobenzenesulfonamide:

N-methyl-N-phenyl-3-chloro-5-hydroxybenzenesulfonamide. (69%, amorphous, MS 297);

[3-Chloro-5- (methyl-phenylsulfamoyl) -phenoxy] -acetic acid ethyl ester (92%, amorphous, MS = 383);

[3-chloro-5- (methylphenylsulfamoyl) phenoxy] acetic acid, quantitative, amorphous MS = 355);

N- (pyridin-4-yl) - [3-chloro-5- (methylphenylsulfamoyl) phenoxy] acetamide (32%, amorphous, MS = 431;

3-chloro-N-methyl-N-phenyl-5- [2- (pyridin-4-ylamino) ethoxy] benzenesulfonamide (40%, amorphous, MS = 417).

Example 85

3-chloro-N-benzyl-N-phenyl-5- [2- (pyridin-4-yl-amino) -ethoxy] benzenesulfonamide

a) Reaction of 12.3 g (46 mmol) of dinitrobenzolsulfonyl chloride (compound 80d) analogously to Example 79i) with 9.2 g (50 mmol) of benzylamine yielded 31.3 g (83%) of N-benzyl- N-phenyl-3,5-dinitrobenzenesulfonamide, m.p. 205 ° C.

b) N-Benzyl-N-phenyl-3,5-dinitrobenzenesulfonamide was reduced as in Example 79a) to give N-benzyl-N-phenyl-3-amino-5-nitrobenzenesulfonamide with a melting point of 170 ° C.

c) Analogously to Example 84b), N-benzyl-N-phenyl-3-chloro-5-nitro-benzenesulfonamide with a melting point of 160 ° C was obtained from N-benzyl-N-phenyl-3-amino-5-nitrobenzenesulfonamide in 37% yield.

d) In analogy to Example 84c to 84d), the following compounds were prepared from N-benzyl-N-phenyl-3-chloro-5-nitro-benzenesulfonamide:

N-benzyl-N-phenyl-3-chloro-5-aminobenzenesulfonamide (quantitative, amorphous, MS = 372)

(3-Chloro-5- (benzyl-phenylsulfamoyl) -phenoxy] -acetic acid ethyl ester (15% yield, oil, MS = 459) N-benzyl-N-phenyl-3-chloro-5-hydroxybenzenesulfonamide (quantitative, amorphous, MS = 373) [3-chloro-5- (benzylphenylsulfamoyl) phenoxy] acetic acid (yield 50%, amorphous, MS = 431)

N- (pyridin-4-yl) - [3-chloro-5- (benzylphenylsulfamoyl) phenoxy] acetamide (yield 44%, amorphous, MS = 507)

3-Chloro-N-benzyl-N-phenyl-5- [2- (pyridin-4-yl-amino) ethoxy] benzene sulfonamide

Example 86

3-Chloro-N-benzyl-N-phenyl-5- [2- (pyridin-4-ylamino) ethylamino] benzenesulfonamide

The following compounds were prepared from N-benzyl-N-phenyl-3-chloro-5-aminobenzenesulfonamide (Example 85d) analogously to Examples 83h) to 83i):

[3-Chloro-5- (benzyl-phenyl-sulfamoyl) -phenylamino] -acetic acid ethyl ester (18%, oil, MS = 458);

[3-chloro-5- (benzyl-phenylsulfamoyl) -phenylamino) -acetic acid (quantitative, amorphous, MS = 430);

[N- (pyridin-4-yl) - [3-chloro-5- (benzylphenylsulfamoyl) phenylamino] acetamide (25%, amorphous, MS = 506);

3-chloro-N-benzyl-N-phenyl-5- [2- (pyridin-4-ylamino) ethylamino] benzenesulfonamide (50%), amorphous, MS (m / e) = 492.

Example 87

N-methyl-N- {3- (2- (pyridin-4-ylamino) -ethoxy] fenyljbenzénsulfónamid

a) N-Methyl-N- (3-amino-5-nitro-phenyl) -benzenesulfonamide (Example 83c) was reacted analogously to Example 84b) to give N-methyl-N- (3-chloro-5- nitrophenyl) benzenesulfonamide (52%), amorphous MS (m / e) = 326).

b) N-methyl-N- (3-chloro-5-nitrophenyl) benzolsulfonamide was reduced as in Example 79a) to give:

N-methyl-N- (3-chloro-5-aminophenyl) benzenesulfonamide (42%, oil, MS = 296);

[3-Chloro-5- (N-methyl-phenylsulfonylamino) -phenoxy] -acetic acid ethyl ester (89%, amorphous, MS (m / e) = 383);

[3-chloro-5- (N-methylphenylsulfonylamino) phenoxy] acetic acid (88%, MS = 355);

N- (pyridin-4-yl) - [3-chloro-5- (N-methylphenylsulfonyl) amino) phenoxy] acetamide (28%, MS = 431); and

N-methyl-N- {3- [2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide (56%) as an amorphous powder. MS (m / e) = 417;

Example 88

N-benzyl-N- {3- [2- (pyridin-4-ylamino) -ethoxy] -5-chlórfenylJbenzénsulfónamid

a) Analogously to Example 92c), N- (3,5-dinitrophenyl) benzenesulfonamide (compound of Example 83a) is benzylated with benzyl bromide to give N-benzyl-N- (3,5-dinitrophenyl) benzenesulfonamide (quantitative), m.p. 170 ° C.

b) N-benzyl-N- (3,5-dinitrophenyl) benzenesulfonamide was reduced analogously to Example 79a) to give 27% N-benzyl-N- (3-amino-5-nitrophenyl) benzenesulfonamide as an amorphous MS powder (m (e) = 383.

(c) N-benzyl-N- (3-chloro-5-nitrophenyl) benzenesulfonamide, m.p. 148 ', is obtained in a 45% yield from N-benzyl-N- (3-amino-5-nitrophenyl) benzenesulfonamide in analogy to Example 84b). C.

d) N-benzyl-N- (3-chloro-5-nitrophenyl) benzenesulfonamide was reduced in analogy to Example 79a) to give 34% N-benzyl-N (3-chloro-5-aminophenyl) benzenesulfonamide, m.p. 145 ^e C

(e) In analogy to Examples 83g) to 83i), the following are prepared:

N-benzyl-N- (3-chloro-5-hydroxyphenyl) benzenesulfonamide (quantitative, amorphous, MS = 373;

[3-Chloro-5- (N-benzyl-phenylsulfonylamino) -phenoxy] -acetic acid ethyl ester (quantitative, amorphous, MS (m / e) = 459);

[3-chloro-5- (N-benzylphenylsulfonylamino) phenoxy] acetic acid (82%, m.p. 180 DEG C. (dec.);

N- (pyridin-4-yl) - [3-chloro-5- (N-benzylphenylsulfonylamino) phenoxy] acetamide (54%, mp 178 ° C) and N-benzyl-N- {3- [2- ( pyridin-4-ylamino) ethoxy] -5-chlorophenyl} benzenesulfonamide as an amorphous powder. MS (m / e) = 493;

Example 89

N- {3- [2- (pyridin-4-ylamino) ethylamino] -5-bromo-phenyl} benzenesulfonamide

a) To 18.3 g (100 mmol) of 3,5-dinitroaniline (Example 80c) in 100 ml of glacial acetic acid and 100 ml of 47% hydrobromic acid was added dropwise a solution of 7.6 g (110 mmol) of sodium nitrite at 0 ° C. in 15 ml of water for 15 minutes and then proceed as in Example 84b). 21.7 g (88%) of 3,5-dinitrobromobenzene with a melting point of 65 &apos; C are obtained.

b) 3,5-dinitrobromobenzene was reduced analogously to Example 79a) to give 17.4 g (91%) of 3-bromo-5-nitroaniline with a melting point of 105 ° C.

c) 3-Bromo-5-nitroaniline is alkylated in analogy to Example 18a) to give quantitative 3-bromo-5-nitrophenyl-88-minoacetic acid ethyl ester. Amorphous, MS (m / e) = 303.

d) 3-Bromo-5-nitrophenylaminoacetic acid ethyl ester was saponified in analogy to Example 1b) to give 3-bromo-5-nitrophenylaminoacetic acid (22%, amorphous, MS (m / e) = 274).

e) 3-Bromo-5-nitrophenylaminoacetic acid was reacted analogously to Example 1c) to give in 29% yield N (pyridin-4-yl) -3-bromo-5-nitrophenylamino) acetamide, m.p. 240 ° C. .

f) N- (pyridin-4-yl) -3-bromo-5-nitrophenylamino) acetamide was hydrogenated in analogy to Example 58 and obtained quantitatively

N- (pyridin-4-yl) -3-bromo-5-aminophenylamino) -acetamide. Amorphous.

MS (m / e) = 321.1.

g) Analogously to Example 79i), N- (pyridin-4-yl) - [3-bromo-5-benzenesulfonylaminophenylamino] acetamide was obtained from N- (pyridin-4-yl) -3-bromo-5-aminophenylamino) acetamide. Amorphous. MS (m / e) = 460

h) From N- (pyridin-4-yl) - [3-bromo-5-benzenesulfonylaminophenylamino] acetamide was obtained analogously to Example 1d) N- {3- [2- (pyridin-4-ylamino) ethylamino] -5 bromophenyl} benzenesulfonamide. Amorphous. MS (m / e) = 446;

Example 90

Benzenesulfonic acid 3-ethyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl ester

(a) 20 g of 3,5-dimethoxybenzoic acid (110 mmol) in 80 ml of thionyl chloride are heated to reflux for one hour. The solvent is removed in vacuo, the residue is taken up in 500 ml of dry methylene chloride and dry ammonia is introduced into the ice-cooled solution over 90 minutes. Stirring is continued for another hour at room temperature, the solvent is removed in vacuo, the residue is stirred for 12 hours in 200 ml of water and 50 ml of saturated sodium bicarbonate solution, filtered, the precipitate is dissolved in ethyl acetate, filtered through charcoal and ethyl acetate is removed until to incipient crystallization. 10.8 g of 3,5-dimethoxybenzamide, m.p. 145 DEG C., is obtained.

b) To 7.6 g (310 mmol) of magnesium in 10 ml of dry ether was added dropwise 19.5 ml (310 mmol) of iodomethane in 30 ml of ether, heated to reflux and then added in portions of 11.6 g. (63 mmol) of 3,5-dimethoxybenzamide. Maintaining at reflux for 22 hours, 125 ml of 6N hydrochloric acid is added dropwise under ice-cooling, stirred for 16 hours at room temperature, the organic phase is washed with water, the solvent is removed in vacuo to give 9.4 g of 3, 5 dimethoxy acetophenone as an oil MS (m / e) = 180.

(c) 9.4 g (52 mmol) of dimethoxyacetophenone are hydrogenated in 150 ml of ethanol and 2 ml of concentrated hydrochloric acid in the presence of 1 g of palladium on carbon at a temperature of 50 ° C and a pressure of 5 x 10 ⁵ Pa. Filter, remove the solvent in vacuo to give 6.8 g (78%) of 3,5-dimethoxyethylbenzol as an oil.

MS (m / e) = 166.

d) Heating 6.8 g (41 mmol) of 3,5-dimethoxyethylbenzole in 65 ml of glacial acetic acid and 25 ml of concentrated 47% hydrobromic acid is maintained at reflux for four hours. The solvent was removed in vacuo, water was added to the residue, extracted with ethyl acetate, the ethyl acetate solution was washed with water, the solvent was removed in vacuo and the residue was filtered through diatomaceous earth (isohexane / ethyl acetate = 3: 1). 3.9 g (69%) of 5-ethylresorcinin are obtained as an oil. MS (m / e) = 138.1.

e) Stir 3.9 g (28 mmol) of 5-ethyl resorcinin and 4.3 ml (33 mmol) of benzenesulfonyl chloride in 30 ml of ether and 60 ml of saturated sodium bicarbonate solution for 48 hours at room temperature. The ether phase was separated, the solvent was removed in vacuo, the residue was filtered through silica gel (isohexane / ethyl acetate 3: 1) to give 5.4 g (69%) of bromobenzenesulfonic acid 3-hydroxy-5-ethylphenyl ester as an oil MS (m) (e) = 278.

f) In analogy to Examples 81e) to 81h), the following compounds were obtained from 3-hydroxy-5-ethylphenyl bromobenzenesulfonic acid ester:

(3-Benzenesulfonyloxy-5-ethyl-phenyloxy) -acetic acid ethyl ester (77%, oil, MS (m / e) = 364);

(3-Benzenesulfonyloxy-5-ethyl-phenyloxy) -acetic acid (59%, amorphous, MS (m / e) = 336;

N- (pyridin-4-yl) - (3-benzol-sulfonyloxy-5-ethyl-phenyloxy) -acetamide (70%, amorphous, MS (m / e) = 412) and

Benzenesulfonic acid 3-ethyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl ester (10%, mp 136 ° C).

Example 91

N-benzyl-N- {3- [2- (pyridin-4-ylamino) -ethoxy] -5-methylphenyl} benzenesulfonamide

a) Analogously to Example 79i), 107 g (1 mol) of para-toluidine are reacted with p-tosyl chloride to give 280 g (quantitative) of N- (4-methylphenyl) -4-methylbenzenesulfonamide as an oil, which can be used without further purification. cleaning. After recrystallization from ether, the melting point is 105 ° C.

(b) 21 g (80 mmol) of N- (4-methylphenyl) -4-methylbenzenesulphonamide are added to 56 ml of nitric acid with cooling on ice, 32 ml of concentrated sulfuric acid are slowly added dropwise, poured onto ice, the precipitate is washed with water and to give 46.6 g (73%) of a yellow solid, m.p. 170 [deg.] C., which was heated for 10 minutes in 80 ml of concentrated sulfuric acid at 100 [deg.] C., poured into ice water and extracted with ethyl acetate. The solvent was removed in vacuo to give 20 g (88%) of 2,6-dinitro-4-methylaniline, mp 171 ° C.

c) To 20.5 g (300 mmol) of sodium nitrite in 220 ml of sulfuric acid are added 800 ml of glacial acetic acid and in portions 53.5 g (270 mmol) of 2,6-dinitro-4-methylaniline, stirred for 3 hours at 40 ° C until complete dissolution and this solution was added dropwise to an ice-cooled suspension of 20 g of copper oxide in ethanol, the solvent was removed in vacuo, water was added and extracted with ethyl acetate. The process was repeated to give a total of 88 g (88%) of 3,5-dinitrotoluene as an amorphous powder.

(d) 88 g (480 ml) of 3,5-dinitrotoluene in 520 ml of methanol 53 g of ammonia are saturated, hydrogen sulfide is introduced over 15 minutes, the temperature rising to 52 ° C. The mixture is heated to reflux for 30 minutes and poured onto 1 L of water to give 60.5 g (82%) of 3-methyl-5-nitroaniline, m.p. 97 ° C.

e) Analogously to Example 79i), N- (3-methyl-5-nitrophenyl) benzenesulfonamide (quantitative) was obtained from 3-methyl-5-nitroaniline (quantitative), mp 165 ° C.

(f) Analogously to Examples 88a) to 88b), the following are obtained from N- (3-methyl-5-nitrophenyl) benzenesulfonamide:

N-benzyl-N- (3-methyl-5-nitrophenyl) benzenesulfonamide (83%, mp 154 ° C; and

N-benzyl-N- (3-methyl-5-aminophenyl) benzenesulfonamide (34%, amorphous, MS (m / e) = 352).

(g) Analogously to Examples 81e) to 81h), from N-benzyl-N- (3-methyl-5-nitrophenyl) benzenesulfonamide and from N-benzyl-N- (3-meth yl-5-aminophenyl) benzenesulfonamide:

[3- (Benzenesulfonyloxy-benzylamino) -5-methyl-phenyl-amino] -acetic acid ethyl ester (quantitative, oil, MS (m / e) = 438);

[3- (benzenesulfonylbenzylamino) -5-methylphenylphamino] acetic acid (90%, amorphous, MS (m / e) = 410;

N- (pyridin-4-yl) - [(3-benzenesulfonylbenzylamino) -5-methylphenylphamino] acetamide (10%, amorphous, MS (m / e) = 486 and N-benzyl-N- {3- [2- ( pyridin-4-ylamino) ethoxy] -5-methylphenyl} benzenesulfonamide (47%, amorphous, MS (m / e) = 472).

Example 92

(Benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} -amino) -acetic acid ethyl ester

(a) 100 g of 4-nitro-tetrachloropyridine and 50,6 ml of ethaloamine in 1,2 l dioxane are stirred for 90 minutes at room temperature, the solvent is removed in vacuo, water is added to the residue, extracted with ethyl acetate, washed with water , the solvent was removed in vacuo to give 105 g (72%) of 4- (2-hydroxyethylamino) tetrachloropyridine, mp 131-133 ° C.

b) Stir 36.3 g (130 mmol) of 4- (2-hydroxyethylamino) tetrachloropyridine and 12.1 L (170 mmol) of acetyl chloride in 450 ml of glacial acetic acid for 12 hours at room temperature, pour on ice, neutralize concentrated ammonia, extracted with ethyl acetate, washed with water, the solvent was removed in vacuo to give 41.6 g (99%) of ethyl (2-tetrachloropyridin-4-ylamino) ethyl acetate, mp 72-75 ° C .

c) To 109 g (340 mmol) of ethyl (2-tetrachloropyridin-4-ylamino) ethyl ester in 700 ml of dry dimethylformamide was added a suspension of 10.8 g of sodium hydride in 150 ml of dimethylformamide and a solution of 54 ml of benzyl bromide was added dropwise. in 350 ml of dimethylformamide. It is stirred for two hours at room temperature, poured into 7 l of ice-water, filtered, the precipitate is washed with water, dissolved in 800 ml of methanol and 200 ml of dichloromethane, concentrated to the beginning of crystallization and allowed to crystallize. 120 g of acetic acid (2-benzyltetrachloropyridin-4-ylamino) ethyl ester of melting point 97 DEG-100 DEG C. are obtained.

d) To 108 g (260 mmol) of acetic acid (2-benzyl-tetrachloropyridin-4-ylamino) -ethyl ester in 1.2 l of ethanol and 390 ml of 2N sodium hydroxide solution is added enough dimethylformamide until all is dissolved (approximately 0) , 5 1). Stir for 12 hours at room temperature, remove the solvent in vacuo (finally at 1,33 " ² kPa), add 3 L of water to the residue and extract

1 ethyl acetate, the acetic acid ester is washed with 3 l of water, the solvent is removed in vacuo to give 99 g (quantitative) of N-benzyl-N- (2-hydroxyethyl) -N- (tetrachloropyridin-4-yl) amine as an oil. . MS (m / e) = 366;

e) To 107 g (290 mmol) of N-benzyl-N- (2-hydroxyethyl) -N- (tetrachloropyridin-4-yl) amine in 800 ml of dichloromethane is added 73 ml (520 mmol) of triethylamine, cooled to 0 ° C and a solution of 67.1 g (350 mmol) of 4-toluylsulfonyl chloride in 500 mL of dichloromethane was added dropwise. The solution is left for 16 hours at 4 ° C, water is added, the organic phase is separated and the solvent is removed in vacuo. 90.6 g (64%) of 4-toluylsulphonic acid 2- (benzyltetrachloropyridin-4-ylamino) ethyl ester of melting point 114 DEG-116 DEG C. are obtained.

f) Stir 57.2 g (240 mmol) of 4-toluylsulfonic acid 2- (benzyltetrachloropyridin-4-ylamino) ethyl ester, 64.8 g (260 mmol) of 3-phthalimido-5-methylphenol (Example 76a) and 66.2 g (480 mmol) of potassium carbonate in 1.15 L of dimethylsulfoxide for 72 hours at room temperature, poured into 3 L of water, filtered, digested with diisopropyl ether to give 63 g (38%) of N-benzyl-N- (tetrachloropyridin-4-yl-N- [2- (3-phthalimido-5-methylphenoxy) ethyl] amine, m.p. 142-144C).

g) Stir 19.1 g (31.8 mmol) of N-benzyl-N- (tetrachloropyridin-4-yl-N- [2- (3-phthalimido-5-methylphenoxy) ethyl] amine, 2.3 mL (47, 6 mmol) of hydrazine hydrate and 50 ml of ethanol in 100 ml of dichloromethane for 12 hours at room temperature, the solvent is removed in vacuo, the residue is suspended in 150 ml of 2N sodium hydroxide solution, extracted with dichloromethane, the organic phase is washed with water, under vacuum, the residue was digested with methanol to give 11.5 g (77%) of N-benzyl-N- (tetrachloropyridin-4-yl-N- [2- (3-amino-5-methyl-phenoxy) -ethyl] amine, m.p. 91-93 ° C.

h) Analogously to Example 79i), 11.5 g (25.5 mmol) of N-benzyl-N- (tetrachloropyridin-4-yl-N- [2- (3-amino-5-methyl-phenoxy) ethyl] was reacted. of amine with 3.51 ml (27.0 mmol) of benzenesulfonyl chloride to give 13.7 g (91%) of N- {3- [2- (benzyltetrachloropyridin-4-ylamino) -ethoxy] -5-methylphenyl}. m.p. 147-149 ° C.

i) Add 3.0 g (4.00 mmol) of N- {3- [2- (benzyltetrachloropyridin-4-ylamino) -ethoxy] -5-methylphenyl} benzenesulfonamide in 15 mL of dry dimethylformamide to 147 mg (6.38) mmol) of sodium hydride in 2 ml of dimethylformamide and 0.6 ml (5.4 mmol) of ethyl bromoacetate are added dropwise. Pour into 300 mL of water, extract with ethyl acetate, wash the organic phase with water, remove the solvent in vacuo to give 3.15 g (91%) of (benzenesulfonyl- {3-methyl-5- [2- (benzyltetrachloropyridine-) ethyl ester]. 141 DEG-142 DEG C. 4-Ylamino) ethoxy] phenyl] aminoacetic acid.

(j) Stir 3.15 g (4.5 mmol) of (benzenesulfonyl- {3-methyl-5- [2- (benzyl-tetrahydro-pyridin-4-ylamino) -ethoxy] -phenyl} -amino-acetic acid ethyl ester, 50 ml of trifluoroacetic acid and 6 of ethyl acetate are added. , 8 ml of 1,23-trimethylbenzol is stirred for 12 hours at room temperature, poured into ice water, neutralized with concentrated ammonia, extracted with ether, the ether phase is washed with water, the solvent is removed in vacuo, the residue is filtered through silica gel ( ethyl acetate / isohexane 1: 2.5) to give 2.50 g (91%) (benzolsulfonyl- {3-methyl-5- [2- (tetrachloropyridin-4-ylamino) ethoxy] phenyl} amino) acetic acid ethyl ester as an oil, MS (m / e) = 605.

(k) 3.5 g (5.76 mmol) of (benzolsulfonyl {3-methyl-5- [2- (tetrachloropyridin-4-ylamino) ethoxy] phenyl} amino) acetic acid ethyl ester and 4.0 g of potassium carbonate are hydrogenated 40 ml of tetrahydrofuran and 40 ml of methanol in the presence of 1.0 g of 10% palladium on carbon at 4 x 10 ⁵ Pa. After 48 hours, filter, remove the solvent in vacuo, filter through silica gel (methylene chloride / methanol = 4: 1) to obtain 2.1 g (78%) of ethyl ester (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetic acid as an amorphous mass, MS (m / e) = 469.

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

1.20 g (2.55 mmol) of (benzenesulfonyl {3-methyl-5- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} -amino) -acetic acid ethyl ester (compound of Example 92) are saponified in 20 ml of ethanol. by treatment with 5.1 ml of 1N sodium hydroxide solution for two hours at 45 ° C. Neutralized with 1N hydrochloric acid, the solvent was removed in vacuo, the residue was taken up in 20 ml of water and allowed to crystallize. 0.97 (86%) of (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} -amino) -acetic acid is obtained, m.p. 100-102 ° C (dec.).

Example 94 (Benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide

Dissolve 1.5 g (3.2 mmol) of (benzenesulfonyl {3-methyl-5- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} -amino) -acetic acid ethyl ester (compound of Example 92) in 12 mL of concentrated ammonia and 30 ml of methanol. After 12 hours, it was filtered to give 0.99 g (70%) of (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide, m.p. 163-165. C.

Example 95

N- (2-hydroxyethyl) - (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide

N- (2-hydroxyethyl) - (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide was obtained in 60% yield analogously to Example 94 with ethanolamine instead of ammonia. Melting point 169-170 ° C.

Example 96

N- (3-hydroxyethyl) - (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide

N- (3-hydroxyethyl) - (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide was obtained in 70% yield analogously to Example 94 with 3-propanolamine instead of ammonia . Mp 148-152 ° C.

Example 97

N-Methyl- (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide

N-methyl- (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide was obtained in 58% yield similar to Example 94 with 25% ethanolic methylamine solution instead of ammonia . M.p. 136-140 ° C.

Example 98

N, N-dimethyl- (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) -ethoxy] phenyl} amino) acetamide

N, N-dimethyl- (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl) amino) acetamide was obtained in 38% yield analogously to Example 94 with a 41% ethanol solution of dimethylamine instead of ammonia. Amorphous, MS (m / e) = 468.

Example 99

N- (2-Aminoethyl) - (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide

N- (2-aminoethyl) - (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide was obtained in 45% yield analogously to Example 94 with ethylenediamine instead of ammonia. Amorphous, MS (m / e) = 453.

Example 100

N- (2-Aminoethyl) -N- {3- [2- (pyridin-4-ylamino) -5-methylphenyl} benzenesulfonamide (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] ] phenyl} amino) acetamide (compound of Example 94) was reduced analogously to Example 18c) to give N- (2-aminoethyl) - {3- [2- (pyridin-4-ylamino) -5-methylphenyl] -benzenesulfonamide in 34% yield. . Amorphous, MS (m / e) = 426;

Example 101

N- (2,3-dihydroxypropyl) - (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) -ethoxy] phenyl} amino) acetamide

N- (2,3-Dihydroxypropyl) - (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide was obtained in 40% yield analogously to Example 94 with 2 With 3-dihydroxypropylamine instead of ammonia. Mp 148-151 ° C.

Example 102

N- (2,3-dihydroxypropyl) -N- {3- [2- (pyridin-4-ylamino) ethoxy] -5-methylphenyl} benzenesulfonamide

a) Mix 10.0 g (75.7 mmol) of 2,2-dimethyl-4-hydroxymethyl-1,3-dioxolane and 14.4 g (75 mmol) of 4-toluenesulfonic acid chloride in 7 ml of pyridine for 15 hours at a temperature of The reaction mixture was poured into 200 ml of water, extracted with ethyl acetate and the solvent was removed in vacuo. Recrystallization from isohexane gave 10.3 g (48%) of 4-methylbenzenesulfonic acid (2,2-dimethyl-1,3-dioxolan-4-ylmethyl) ester, m.p. 45-47 ° C.

b) Add 0.24 g (0.83 mmol) of 4-methylbenzenesulfonic acid (2,2-dimethyl-1,3-dioxolan-4-ylmethyl) ester to a solution of 23 mg of sodium hydride and 0.46 g (0, 75 mmol) of N- {3- [2- (benzyltetrachloro-pyridin-4-ylamino) -ethoxy] -5-methyl-phenyl} -benzenesulfonamide (compounds of Example 92h) in 3 ml of dimethylformamide, stirred at 110 ° C for hours , poured into water, extracted with ethyl acetate, the solvent was removed in vacuo to give 30Ô mg (55%) of N- (2,2-dimethyl-1,3-dioxolan-4-ylmethyl) -N- { 3- [2 (Benzyltetrachloropyridin-4-ylamino) ethoxy] -5-methylphenyl) benzene sulfonamide as an oil. MS (m / e) = 725;

c) From N- (2,2-dimethyl-1,3-dioxolan-4-ylmethyl) -N- {3- [2- (benzyltetrachloropyridin-4-ylamino) -ethoxy] -5-methylphenyl) benzenesulfonamide was obtained analogously to Example 92j) N- (2,3-dihydroxypropyl) -N- {3- [2- (benzyltetrachloropyridin-4-ylamino) ethoxy] -5-methylphenyl} benzenesulfonamide (38%, m.p. 136 ° C.

d) Analogously to Example 92k) from N- (2,3-dihydroxypropyl) -N- {3- [2- (benzyltetrachloropyridin-4-ylamino) ethoxy] -5-methylphenyl} benzenesulfonamide, N- (2,3) dihydroxypropyl) -N- {3- [2- (pyridin-4-ylamino) -ethoxy] -5-methyl-phenyl} -benzenesulfonamide. (66%, amorphous, MS (m / e) = 457).

Example 103

4- (Benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) butyric acid ethyl ester

In analogy to Examples 92i) to 92k), the following compounds were obtained except that according to Example 92i) ethyl 4-bromobutyrate was used instead of ethyl bromoacetate:

4- (Benzenesulfonyl- {3-methyl-5- [2- (benzyltetrachloropyridin-4-ylamino) ethoxy] phenyllamino) butyric acid ethyl ester (78%, mp 106-108 ° C);

4- (Benzenesulfonyl- {3-methyl-5- [2- (tetrachloropyridin-4-ylamino) -ethoxy] -phenyl-amino-butyric acid ethyl ester as an oil,

MS (m / e) = 633;

100 4- (Benzenesulfonyl- {3-methyl-5- [2- (tetrachloropyridin-4ylamino) ethoxy] phenyl} amino) butyric acid ethyl ester (75%, amorphous,

MS (m / e) = 497;

Example 104

5- (Benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) pentanoic acid ethyl ester

In analogy to Examples 92i) to 92k), the following compounds were obtained except that in Example 92i) ethyl 5-bromopentanoate was used in place of ethyl bromoacetate:

5- (Benzenesulfonyl- {3-methyl-5- [2- (benzyltetrachloropyridin-4-ylamino) ethoxy] phenyl} amino) pentanoic acid ethyl ester (72%, mp 90-91 ° C);

5- (Benzenesulfonyl- {3-methyl-5- [2- (tetrachloropyridin-4ylamino) ethoxy] phenyl} aminopentanoic acid ethyl ester as an oil,

MS (m / e) = 647 and 5- (benzenesulfonyl- {3-methyl-5- (2- (pyridin-4-ylamino) ethoxy] phenyl} amino) pentanoic acid ethyl ester (78%, amorphous, MS (m / e)) e) = 511.

Example 105

6- (Benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino} hexanoic acid ethyl ester

In analogy to Examples 92i) to 92k), the following compounds were obtained except that, according to Example 92i), ethyl 6-bromohexanoate was used in place of ethyl bromoacetate:

6- (Benzenesulfonyl- {3-methyl-5- [2- (benzyltetrachloropyridin-4-ylamino) ethoxy] phenyl} amino) hexanoic acid ethyl ester (75% oil,

101

MS (m / e) = 751;

6- (Benzenesulfonyl- {3-methyl-5- [2- (tetrachloropyridin-4-ylamino) ethoxy] phenyl} amino) hexanoic acid ethyl ester (49%, oil,

MS (m / e) = 661 and 6- (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) hexanoic acid ethyl ester (56%, amorphous, MS (m / e)) e) = 525.

Example 106

4- (Benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) butyric acid

4- (Benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) butyric acid is obtained analogously to Example 93) from 4- (benzenesulfonyl- {3-methyl- 5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) butyric acid (compound of Example 103), 65% yield, amorphous, MS (m / e) = 469.

Example 107

5- (Benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) pentanoic acid

5- (Benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyllamino) pentanoic acid was obtained in analogy to Example 93) from 5- (benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) pentanoic acid (compound of Example 104), 53% yield, mp 117-120 ° C.

Example 108

6- (Benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxyphenyl] hexanoic acid

102

6- (Benzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) hexanoic acid was obtained in analogy to Example 93) from 6- (benzenesulfonyl- {3-methyl- 5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) hexanoic acid (Example 105), 53% yield, amorphous, MS (m / e) = 498.

Example 109

(2-Methoxybenzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetic acid ethyl ester

In analogy to Example 92h) to 92k), the following compounds are obtained except that in step 92h) 2-methoxybenzenesulfonyl chloride is used in place of benzenesulfonyl chloride:

(2-methoxy-N- {3- [2- (benzyltetrachloropyridin-4-ylamino) ethoxy] -5-methylphenyl) benzenesulfonamide (65%, m.p. 175 ° C); (2-Methoxybenzenesulfonyl- {3-methyl-5- [2- (benzyltetrachloropyridin-4-ylamino) ethoxy] phenyl) amino) acetic acid ethyl ester (91%, mp 128-130 ° C);

(2-Methoxy-benzenesulfonyl- {3-methyl-5- [2- (tetrachloropyridin-4-ylamino) -ethoxy] -phenyl} -amino) -acetic acid ethyl ester (89% mp 126 ° C) and (2-methoxy-benzenesulfonyl- {3-ethyl-3-ethyl ester) methyl 5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetic acid (81%, mp 58-63 ° C).

Example 110 (2-Methoxybenzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetic acid (2-Methoxybenzenesulfonyl- {3-methyl-5- [2- (pyridine- 4-ylamino) ethoxy] phenyl} amino) acetic acid was obtained analogously to Example 93) from (2-methoxybenzenesulfonyl- {3-methyl-5103 [2- (pyridin-4-ylamino) ethoxy] phenyl) amino ethyl ester of acetic acid (Example 109 compound), 82% yield, mp 218-222 ° C.

Example 111 (2-Methoxybenzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] -phenyl} -amino) -acetamide (2-Methoxybenzenesulfonyl- {3-methyl-5- [2- ( pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide was obtained analogously to Example 94 from Example 109. 63% yield, mp 205 ° C.

Example 112

N- (2-hydroxyethyl) - (2-metoxybenzénsulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) -ethoxy] phenyl} amino) acetamide

N- (2-hydroxyethyl) - (2-methoxybenzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide was obtained in 93% yield in analogy to Example 95 from the compound of mp 175 ° C.

Example 113

N- (3-hydroxypropyl) - (2-metoxybenzénsulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) -ethoxy] phenyl} amino) acetamide

N- (3-hydroxypropyl) - (2-methoxybenzenesulfonyl- {3-methyl-5- [2 (pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide was obtained in 95% yield analogously to Example 96 from the compound mp 165-167 ° C.

104

Example 114

N-methyl (2-metoxybenzénsulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) -ethoxy] phenyl} amino) acetamide

N-methyl- (2-methoxybenzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide was obtained in 96% yield analogously to Example 97 from the compound of Example 109. Amorphous, MS (m / e) = 484;

Example 115

N, N-dimethyl- (2-metoxybenzénsulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) -ethoxy] phenyl} amino) acetamide

N, N-Dimethyl- (2-methoxybenzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl) amino) acetamide was obtained in 73% yield analogously to Example 98 from Example Example 109. Amorphous, MS (m / e) = 498.

Example 116

N- (2-aminoethyl) - (2-metoxybenzénsulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) -ethoxy] phenyl} amino) acetamide

N- (2-aminoethyl) - (2-methoxybenzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide was obtained in 93% yield analogously to Example 99 from the compound according to Example 109. Amorphous, MS (m / e) = 513.

Example 117

N- (2,3-dihydroxypropyl) - (2-metoxybenzénsulfonyl- {3-methyl-of 512 (pyridin-4-ylamino) -ethoxy] phenyl} amino) acetamide

105

N- (2,3-dihydroxypropyl) - (2-methoxybenzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetamide was obtained in 75% yield analogously to Example 101 from the compound according to Example 109. Amorphous, MS (m / e) = 544.

Example 118 (2-Methoxybenzenesulfonyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy] phenyl} amino) acetonitrile

To 94 mg (0.2 mmol) of N- {3- [1,1-dimethyl-2- (pyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide (compound of Example 11) in 0.5 ml of dichloromethane and 60 μΐ triethylamine is added at 0 ° C to 250 μΐ of trichloroacetyl chloride in 0.5 ml of dichloromethane. After 5 minutes neutralized with triethylamine, the solvent was removed in vacuo and the residue was filtered through silica gel (ethyl acetate / methanol, ammonia = 4: 1) to give 60 mg of (2-methoxybenzenesulfonyl- {3-methyl 5- [2- (pyridine) -4-ylamino) ethoxy] phenyl} amino) acetonitrile as an amorphous mass. MS (m / e) = 452;

Example 119

N- (2-aminoethyl) -N- {3- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} -2metoxybenzénsulfónamid

Reaction of 2-methoxy-N- {3- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} -2-methoxybenzenesulfonamide (Example 109) with chloroacetonitrile analogously to Example 92i) affords (2-methoxybenzenesulfonyl {3- methyl 5- [2- (benzyltetrachloropyridin-4-ylamino) ethoxy] phenyl} aminoacetonitrile (92%), m.p. 154C, from which, as in Example 92j), (2-methoxybenzosulfonyl {3-methyl-5) is obtained. - [2- (tetrachloropyridin-4-ylamino) ethoxy] phenyl} acetonitrile (85%, amorphous, MS (m / e) = 588), which was reacted analogously to Example 92k) to give N- (2-aminomethyl) 1) -N- {3- [2106 (pyridin-4-ylamino) -ethoxy] -phenyl} -2-methoxy-benzenesulfonamide (10%, amorphous, MS (m / e) = 456).

Example 120

2- {3- [2- (Benzyl-pyridin-4-ylamino) -ethoxy] -5-methyl-phenyl) -sulfamoyl} -benzoic acid methyl ester

a) Reaction of 4-toluenesulfonic acid 2- (benzyltetrachloropyridin-4-ylamino) ethyl ester (compound of Example 92e) with 3-nitrophenol analogously to Example 92f) to give N-benzyl-N- (tetrachloropyridin-4-yl) ) -N- [2- (3-nitrophenoxyethyl) amine, (61%, mp 120-122 ° C).

b) N-benzyl-N- (tetrachloropyridin-4-yl) -N- [2- (3-nitrophenoxyethyl) amine was reduced in analogy to Example 79a) to give N-benzyl-N- (tetrachloropyridin-4-yl) ) -N- [2- (3-aminophenoxyethyl) amine, (41%, mp 105-107 ° C).

c) N-benzyl-N- (tetrachloropyridin-4-yl) -N- [2- (3-aminophenoxyethyl) amine was reacted in analogy to Example 92h) to give N- {3- [2- (benzyltetrachloropyridin-4)] (ylamino) ethoxy] phenyl} benzenesulfonamide (78%, mp 120-122 ° C).

d) N- {3- [2- (benzyltetrachloropyridin-4-ylamino) ethoxy] phenyl} benzenesulfonamide was subjected to hydrogenation in analogy to Example 92k) to give 2- {3- [2- (benzyl-pyridine-4-) methyl ester ylamino) ethoxy] -5-methylphenyl} sulfamoyl} benzoic acid (63%,

MS (m / e) = 517).

Example 121

[2- (Methyl- {3-methyl-5- [2- (pyridin-4-ylamino) -ethoxy-phenyl} -sulfamoyl-phenoxy] -acetic acid ethyl ester

107

a) N-Benzyl-N- (tetrachloropyridin-4-yl) -N- [2- (3-amino-5-methylphenoxy) ethyl] amine (Example 92g) was reacted analogously to Example 92h) with 2-benzyloxy- benzolsulfonium chloride to give N- {3- [2- (benzyltetrachloropyridin-4-ylamino) ethoxy] 5-methylphenyl} -2-benzyloxybenzenesulfonamide (55%, m.p. 176 ° C).

b) N- {3- [2- (benzyltetrachloropyridin-4-ylamino) ethoxy] -5-methylphenyl} -2-benzyloxybenzenesulfonamide was methylated as in Example 12) to give N-methyl-N- {3- [2- (benzyltetrachloropyridin-4-ylamino) ethoxy] -5-methylphenyl} -2-benzyloxybenzenesulfonamide (78%, amorphous MS (m / e) = 729).

c) Analogously to Example 92j) N-methyl-N- {3- [2- (benzyltetrachloropyridin-4-ylamino) ethoxy] -5-methylphenyl} -2-benzyloxybenzenesulfonamide is obtained from N-methyl-N- {3- [2- (benzyltetrachloropyridin-4-yl-amino) -ethoxy] -5-methylphenyl} -2-hydroxybenzenesulfonamide (87%, amorphous, MS (m / e) = 549).

d) Analogously to Example 18), N-methyl-N- {3- [2- (benzyltetrachloropyridin-4-yl-amino) -ethoxy] -5-methylphenyl} -2-hydroxybenzenesulfonamide is reacted to give [2-methyl- {3- (3-) ethyl ester. methyl 5- [2- (tetrachloropyridin-4-ylamino) ethoxyphenyl} sulfamoyl) phenoxy] acetic acid (quantitative, oil,

MS (m / e) = 635).

e) [2-Methyl- {3-methyl-5- [2- (tetrachloro-pyridin-4-ylamino) -ethoxy-phenyl} -sulfamoyl) -phenoxy] -acetic acid ethyl ester was hydrogenated according to the method of Example 92k) to give [2 (methyl- { 3-methyl-5- [2- (pyridin-4-ylamino) ethoxyphenyl} sulfamoylphenoxy] acetic acid (50%, amorphous, MS (m / e) = 499).

108

Example 122

N- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxyphenyl} -2-hydroxybenzenesulfonamide

a) Analogously to Example 92j), N- {3- [2 (benzyltetrachloropyridin-4-ylamino) ethoxy] -5-methylphenyl} -2-benzyloxybenzenesulfonamide (compound of Example 121a) was reacted to give N- {3- [ 2- (tetrachloropyridin-4-ylamino) ethoxy] -5-methylphenyl} -2-hydroxybenzenesulfonamide (70%, amorphous, MS (m / e) = 535).

b) From N- {3- [2- (tetrachloropyridin-4-ylamino) ethoxy] -5-methylphenyl} -2-hydroxybenzenesulfonamide, analogously to Example 92k), N- {3-methyl-5- [2- (pyridine) was obtained. -4-ylamino) ethoxyphenyl} -2-hydroxybenzenesulfonamide (81%, amorphous, MS (m / e) = 399).

Example 123

N-methyl-N- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxyphenyl} -2-hydroxybenzenesulfonamide

Analogously to Example 122), N-methyl-N {3-C2- (benzyl-tetrachloropyridin-4-ylamino) -ethoxy] - (-5-methylphenyl) -2-benzyloxy-benzolsulfonamide (compound according to of Example 121b) to give N-methyl-N- {3- [2- (tetrachloropyridin-4-ylamino) ethoxy] 5-methylphenyl} -2-hydroxybenzenesulfonamide (65%, amorphous, MS (m / e) (549) and the desired N-methyl-N- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxyphenyl} -2-hydroxybenzenesulfonamide (27%, amorphous, MS (m / e) = 413) .

109

Example 124 [2- (methyl- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxyphenyl} sulfamoylphenoxy] acetic acid

a) Analogously to Example 93) [2 (methyl- {3-methyl-5- [2- (tetrachloropyridin-4-ylamino) ethoxyphenyl} sulfamoyl) phenoxy] acetic acid ethyl ester (compound of Example 121d) to give [2-methyl- {3-methyl-5- [2- (tetrachloropyridin-4-ylamino) ethoxyphenyl} sulfamoylphenoxy] acetic acid (94%, amorphous, MS (m / e) = 607).

b) From [2-methyl- {3-methyl-5- [2- (tetrachloro-pyridin-4-ylamino) -ethoxy-phenyl} -sulfamoyl-phenoxy] -acetic acid, analogously to Example 92 k), [N-2 (-methyl- {3- methyl 5- [2- (pyridin-4-ylamino) ethoxyphenyl} sulfamoylphenoxy] acetic acid (75%, amorphous, MS (m / e) = 471).

Example 125

N-ethoxycarbonyl-N- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxyphenyl} -2-methoxy-benzenesulfonamide

a) Analogously to Example 92i), 2-methoxy N- {3- [2- (benzyltetrachloropyridin-4-ylamino) ethoxy] -5-methylphenyl} benzenesulfonamide (compound of Example 109) is reacted with ethyl formate to give N -ethoxycarbonyl-N- {3- [2- (benzyltetrachloropyridin-4-ylamino) ethoxy] -5-methylphenyl} -2-methoxybenzenesulfonamide (quantitative, amorphous, MS (m / e) = 711).

b) Analogously to Example 92j), N-ethoxycarbonyl-N- {3- [2-methoxybenzenesulfonamide] gave N-ethoxycarbonyl-N- (3- [2- (benzyltetrachloropyridin-4-ylamino) ethoxy] -5-methylphenyl} -2-methoxybenzenesulfonamide. - (te110 trachloropyridin-4-ylamino) ethoxy] -5-methylphenyl} -2-methoxybenzenesulfonamide (80%, mp 156 ° C).

c) Analogously to Example 92k), N-ethoxycarbonyl-N- {3-methyl-N- {3 [2- (tetrachloropyridin-4-ylamino) ethoxy] -5-methylphenyl} -2-methoxybenzenesulfonamide gives N-ethoxycarbonyl-N- {3-methyl -5- [2 (pyridin-4-ylamino) -ethoxyphenyl} -2-methoxybenzenesulfonamide (66%, amorphous, MS (m / e) = 485).

Example 126

N- (2-hydroxyethyl) -N- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxyphenyl} -2-methoxy-benzenesulfonamide

To 150 mg (0.3 mmol) of (2-methoxy-benzenesulfonyl {3-methyl-5- [2- (pyridin-4-ylamino) -ethoxy] -phenyl} -amino) -acetic acid ethyl ester (compound of Example 109) in 5 mL of dry tetrahydrofuran 24 mg (0.6 mmol) of lithium aluminum hydride are added and the mixture is heated to reflux for two hours. Decomposition was carried out with one drop of water and three drops of 2N hydrochloric acid, filtered and the solvent was removed in vacuo. The residue was filtered through 50 g of silica gel (methylene chloride / methanol 4: 1) to give 50 mg (36%) of N- (2- hydroxyethyl) -N- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxyphenyl} -2-methoxybenzenesulfonamide, MS (m / e) = 457.

Example 127

N- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxy phenyl} pyridine-3-sulfonamide

N- {3-methyl-5- [2- (pyridin-4-ylamino) ethoxyphenyl} pyridine-3sulfonamide was obtained in analogy to Example 57, using 3-pyridinesulfonyl chloride in step 57d). Amorphous. MS (m / e) = 385

111

Example 128

Pharmacological description of the experiments

Thrombin time

One common clinical trial for clotting diagnosis is the thrombin time test. This parameter expresses the effect of thrombin on fibrinogen and on clot formation. Thrombin inhibitors affect the prolongation of thrombin time.

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

Incubate 200 μΐ of citrate plasma in a spherical coagulometer (VC 10 from Amelung) for two minutes at 31 ° C. Up to 190 μΐ of pre-heated thrombin reagent (Boehringer Mannheim GmbH, containing approximately 3 J / ml horse thrombin and 0.0125 M Ca ^{+ +} ) add 10 μΐ of dimethylsulphoxide (DMSO) or a solution of the active substance in dimethylsulphoxide. After adding 200 μΐ of the solution to the plasma, the stopwatch is started and the time to onset of clotting is measured. Thrombin time in control measurements is approximately 24 seconds and is clearly prolonged by the active ingredients. The assay is discontinued when the thrombin time in the presence of the compound of the Examples exceeds 5 minutes.

The following table shows the measured thrombin times in seconds as a difference from the control. The active substance concentrations are in a final volume of 250 μΜ (TT250), 25 μΜ (TT25) and 2.5 μΜ (TT2.5).

112

Inhibition of thrombin

Kinetic measurements are performed in 0.1 M phosphate buffer containing 0.2 M sodium chloride and 0.5% polyethylene glycol 6000 at pH = 7.5 and 25 ° C with H- (D) -Phe-Pro- Arg-pNA (S-2238 Kabi) and human α-thrombin (Sigma, specific activity = 2150 units NIH / mg) in polystyrene half-flowers with a total content of 1 ml.

In the preliminary test, it is determined for each active substance whether it inhibits thrombin rapidly or slowly. To this end, the reaction is initiated by the single addition of 0.03 units of thrombin NIH to 100 μΜ of substrate and drug solution. In the second assay, the substrate is added to a solution of thrombin incubated for 5 minutes and the drug. The increase in p-nitroaniline concentration over time is monitored by spectroscopy for 12 minutes (UV-VIS-Lambda-2 spectrophotometer from PerkinElmer) at 405 nm. Since the curves obtained in both tests are linear and parallel, the active substances in the following table are rapid thrombin inhibitors. The inhibition constants K ^ are determined as follows: The substrate is seeded at concentrations of 100 μΜ, 50μΜ, 30μΜ, 20 μΜ and at each substrate concentration measurements are taken without inhibitor and then three measurements in the presence of different concentrations of inhibitors shown in the table. The reactions are started by the addition of thrombin. The increment at 405 nm produced by p-nitroaniline was monitored over a period of 12 minutes. Within 20 seconds, the measured points (time depending on extinction) are transferred to the computer. The data were determined by linear regression of velocity V _Q (the change in extinction per second; measurements without inhibitor) and W ^ (measurements with inhibitor). Only parts of the measurement where the substrate concentration is reduced by less than 15% shall be used. From the series of measurements (constant inhibitor concentration, variable substrate concentrations) K _m and V _max are determined by non-linear agreement with the equation

113 in * lsi max ^L ° ^J [S] + K ,,

From all series of measurements, Kg is finally calculated by non-linear agreement with the equation v

ⁱⁿ max [S]

K ^ * (1 + [S] / K + + [S]

The Michaelis constant K ^ of all measurements is 3.8 ± 2 μΜ.

The inhibitor constants Kg of the active substances are given in μΜ in the table below.

Inhibition of trypsin and plasmin

Dissolve 10 mg of bovine pancreatic trypsin (Sigma) in 100 ml of 1 mM hydrochloric acid and store in a refrigerator.

μΐ of this mixture is reacted with 980 μΐ mM hydrochloric acid. 25 μΐ shall be used for each test. The measurement is performed as described for thrombin. K _m = 45 μΜ. The substances listed in the following table do not inhibit trypsin (Kg> 400 μΜ).

Human plasmin measurements (Sigma, 10 units) are performed with S-2251 (H- (D) -Val-Leu-Lys-pNA, Kabi) as described for thrombin. 0.01 units of plasmin are used for measurement.

= 250 μΜ. The substances listed in the table below do not inhibit plasmin (Kg> 400 μΜ).

114

Example # Kí Trombín TT250 TT25 TT2,5 2 0,300 150 40 6 8 1,000 288 58 13 10 3,000 157 43 7 15 0,130 270 144 15 48 0,600 300 238 46 59 6,000 53 8 0 60 0,600 137 62 13 72 0,024 300 300 159 79 5,000 30 8 0 80 0,150 300 213 44 83 0,100 300 192 48 86 0,040 300 167 11 89 1,000 132 38 6 90 0,024 300 300 125 100 0,083 300 300 186 108 0,055 300 300 62 124 0,250 300 300 104 125 0,150 300 273 73

Industrial usability

The 4-aminopyridine derivative of the formula I, its hydrates solvates and physiologically acceptable salts, optically active forms, race mint and diastereomeric mixtures are suitable for the preparation of pharmaceutical compositions for the treatment of thromboembolic diseases.

Claims (15)

(I) a group of the formula R ⁶ -SO-NR ⁷ -, R ⁶ -SO 2 NR ^7, R ⁶ -NR ⁷ -SO-, R ⁶ -NR ⁷ -SO 2 R ⁶ -SO-O-, R ⁶ - SO2-o ~, r ⁶ -O-SO- or r ⁶ -O-SO 2, R 'is hydrogen or halogen, cyano, alkyl or alkoxy or haloalkyl, oxygen, sulfur or NH, R ³ and R ^4, which are the same or different, independently of one another, are hydrogen or alkyl, R ' R ^c is hydrogen, alkyl or aralkyl, alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl, wherein the aryl or heteroaryl group is optionally substituted one or more times with substituents selected from nitro, halogen, nitrile, hydroxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aralkoxycarbonyl, alkyl, cykloalkylo116 HL, alkenyl, alkynyl, cyanoalkyl, alkoxy, alkenyloxy, alkynyloxy, aralkoxy, kyanalkyloxyskupinu, alkylthio, alkylsulphinyl, alkylsulphonyl, amino, alkylamino, dialkylamino, aralkylamino, diaralkylaminoskupinu, alkylsulfonylamino, alkylcarbonylaminoformylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, or optionally a • the or several times substituted by substituents from the group consisting of a group of the formula Y-CO ₂ R ⁸ -, -SY-CO 2 R ⁸ ~ -, -OY-CO-R ⁸ -, -NH-Y-CO 2 R ⁸ -, SY-CONR ⁸ R ⁹ , -OY-CONR ⁸ R ⁹ , or -NH-Y-CONR ⁸ R ⁹ , wherein the alkyl, acenyl or alkynyl group is optionally substituted one or more times with substituents selected from the group consisting of halogen, hydroxy, alkoxy , alkylcarbonyloxy, amino and carboxy, R ( ⁷⁾ is hydrogen, alkyl, cycloalkyl, alkenyl or alkynyl, optionally substituted one or more times with halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkylcarbonyl or alkylcarbonyl; represents an alkoxycarbonyl, cyanalkyl, heteroaryl, aryl, aralkyl or heteroarylalkyl group, the aryl or heteroaryl group being optionally substituted one or more times by halogen, nitrile, alkyl, alkenyl, alkynyl, alkyloxy, alkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkoxy, hydroxy, carboxy, hydroxy, alkyl, carboxyalkyl, alkoxycarbonyl, ami a carrier, alkylamino, dialkylamino, alkylsulfonylamino, alkylcarbonylamino, formylamino, aminocarbonyl, or phenyl group or Y-CO ₂ -R ⁸ and Y-CONR ⁸ R ⁹ , Y a linear or branched alkylene group, R ⁸ and R ^9, which are the same or different, independently of one another, are hydrogen, aralkyl, cycloalkyl or alkyl, optionally substituted one or more times with halogen, hydroxy, alkoxy, alkylcarbonyloxy, amino or carboxy, or R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a saturated ring containing optionally additional oxygen, sulfur or nitrogen atoms, the alkyl, alkoxy, alkenyl and alkynyl moieties in each case having 1 to 6 carbon atoms, straight or branched the chain and cycloalkyl moieties of 3 to 7 carbon atoms, its hydrates, solvates and physiologically acceptable salts, optically active forms, racemates and diastereomeric mixtures. 2. A 4-aminopyridine according to claim 1 of formula I wherein R is of the formula R _-SO2-NR ^7, -NR ⁷ R -SO 2 R ⁸ -SO 2 ~ Oalebo R ⁶ -O-SO ₂ - and the other symbols are as defined in claim 1. 3. A 4-aminopyridine according to claim 1 or 2 of formula I wherein R ² represents a hydrogen atom or a chlorine, bromine, alkyl having 1 to 6 carbon atoms, alkoxy of 1 to And other symbols are as defined in claim 1 or 2. A 4-aminopyridine derivative according to any one of claims 1 to 3, in which it is an oxygen atom or an imino group and the other symbols are as defined in claim 1 to 3. A compound according to any one of claims 1 to 4, wherein R ³ and R ⁴ are the same or different, independently of one another, a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and the other symbols in the claim 1 to 4. 6. A 4-aminopyridine according to claim 1 to 5 of the formula I in which R ⁵ is H, alkyl having 1 to 6 ' carbon atoms or benzyl and the other symbols are as defined in claims 1 to 5. 7. A compound according to claim 1, wherein R is C1 -C6 alkyl, C3 -C6 cycloalkyl, optionally substituted one or more times with substituents selected from fluorine, chlorine, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, nitro, amino, hydroxy, carboxy, benzyloxycarbonyl, (C 1 -C 6) alkoxycarbonyl, trifluoromethyl, and -OY-CO ₂ -R 0 substituted a phenyl or benzyl group, furthermore a naphthyl, tetrahydronaphthyl, biphenyl or iridanyl, thienyl, pyrazolyl or pyridyl, benzothienyl or benzothiadiazines ^{4 group} and the other symbols are as defined in claims 1 to 6. A 4-aminopyridine derivative according to claims 1 to 7 of general n of formula I wherein R is hydrogen, alkyl, alkenyl of 2 to 6 carbon atoms or aralkyl, alkoxycarbonyl, cyanoalkyl, hydroxyalkyl or aminoalkyl of 1 to 6 carbon atoms in the alkyl or alkoxy group or a group of the formula Y-CO ₂ - R ⁸ - and Y-CONR ⁸ R ⁹ and other symbols are as defined in claims 1 to 7. 119 9. A compound according to claim 1, wherein Y is methylene, propylene, butylene or pentylene, and the other symbols are as defined in claim 1. A 4-aminopyridine derivative according to any one of claims 1 to 9, wherein R ⁸ represents a hydrogen atom or an alkyl, hydroxyalkyl or aminoalkyl group having from 1 to 6 carbon atoms in the alkyl moiety and the other symbols have the meaning given in claims 1 to 9. A 4-aminopyridine derivative according to any one of claims 1 to 10, wherein R ⁹ is hydrogen or C 1 -C 6 alkyl and the other symbols are as defined in claims 1 to 10. 12. A process for the preparation of a 4-aminopyridine derivative of the general formula I, wherein the symbols are as defined in claims 1 to 11, according to claims 1 to 11, characterized in that a) saponification of a compound of the general formula IV (IV) wherein R ¹ to R ⁴ and X are as defined above, and wherein R ¹⁰ is an alkyl group of · 1-6 carbon atoms or benzyl. the free acid is reacted with 4-aminopyridine, and reducing the obtained compound of formula II 120 (II) R ⁵ • or b) reduces a compound of formula IX (IX) wherein R ¹ and R ² are as defined above and wherein R ¹¹ is a nitrile or imidino group of formula CONHR ⁵ , wherein R ⁵ is as defined above and the compound obtained of formula VIII R ⁵ (VIII) wherein each symbol is as defined above, is reacted with a pyridine derivative having a 4-liberated group at the 4-position, or 121, the catalytic hydrogenation removes chlorine atoms from the pyridine nucleus of a compound of formula XII (XII) wherein R ² to R ⁶ and X are as defined above and wherein R ¹ has the same _χ η meaning as R · * · or compounds of formula XIV R ² R ⁶ -SO _n —X '(XIV) wherein R to R and X are as defined above and wherein n is 1 or 2 and X' is oxygen or NH, or compounds of formula XV IR ² ' R ⁶ -SO _n -NR ⁷ ' X (XV) 122 wherein R @ ² to R @ ⁶ and X are as defined above and R @ ⁷ 'has the same meaning as R @ ⁷ with the exception of hydrogen, and subsequently the compounds obtained are optionally converted to physiologically acceptable salts, hydrates, solvates or optical isomers. A process for the preparation of a 4-aminopyridine derivative of the Formula I wherein R ¹ is R ⁶ -SO-NR ⁷ -, R ⁶ -SO 2 -NR ⁷ -, R ⁶ -SO-O- or R ⁶ -SO 2 -O and the other symbols are as defined in claim 1 to 11, characterized in that a compound of formula XVI (XVI) is reacted wherein R ² to R ⁵ and X are as defined above and wherein A is a hydroxyl group or an amino group of the formula -NHR ⁷ , wherein R ⁷ is as defined above, with a sulfinyl chloride of the formula R ⁶ -SOC 1 or with a sulfonyl chloride of the formula R ⁶ -SO ₂ Cl, wherein R ⁶ and R ⁷ are as defined above. Pharmaceutical composition for the treatment of thromboembolic diseases, characterized in that it comprises at least one 4-aminopyridine derivative of the formula I according to claims 1 to 11 and a pharmaceutically acceptable carrier and excipients. Use of a 4-aminopyridine derivative of the general formula I according to claims 1 to 11 for the preparation of a pharmaceutical composition for the treatment of thromboembolic diseases.