AU682026B2 - New 4-aminopyridines, process for preparing the same and medicaments containing the same - Google Patents
New 4-aminopyridines, process for preparing the same and medicaments containing the same Download PDFInfo
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- AU682026B2 AU682026B2 AU62574/94A AU6257494A AU682026B2 AU 682026 B2 AU682026 B2 AU 682026B2 AU 62574/94 A AU62574/94 A AU 62574/94A AU 6257494 A AU6257494 A AU 6257494A AU 682026 B2 AU682026 B2 AU 682026B2
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/72—Nitrogen atoms
- C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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
I Boehringer Mannheim GmbH 3790/OA/ New 4-aminopyridines, processes for their production as well as pharmaceutical agents containing these compounds The invention concerns new 4-aminopyridines of the general formula I s r o r r a o S-
R
3 X CH 2 N N R4
I
in which
R
1 denotes a R 6
-SO-NR
7
R
6 -S0 2
-NR
7
R
6
-NR
7
-SO-,
R
6
-NR
7 -S0 2
R
6
R
6 -S0 2
R
6 -O-SO- or .6-Q-SO2- gr up,
R
2 denotes a hydrogen or halogen atom, a cyano, alkyl, alkoxy or haloalkyl group, X denotes an oxygen atom, a sulphur atom or a NH group,
R
3 and R 4 are the same or different and denote hydrogen atoms or alkyl groups,
I-U
r I- -2-
R
5 denotes a hydrogen atom, an alkyl group or an aralkyl group,
R
6 denotes an alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl group in which the aryl or heteroaryl residues can be substituted once or several times by nitro, halogen, nitrile, hydroxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aralkoxycarbonyl, alkyl, cycloalkyl, alkenyl, alkynyl, cyanoalkyl, alkoxy, alkenyloxy, alkynyloxy, aralkyloxy, cyarNoalkyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, aralkylamino, di-aralkylamino, alkylsulfonylamino, alkylcarbonylamino, formylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl or by one or several of the groups -Y-C0 2
R
8 -S-Y-C0 2
R
8 -O-Y-C0 2
R
8 *-NH-Y-C0 2
R
8
-S-Y-CONR
8
R
9
-O-Y-CO-NR
8
R
9 or
-NH-Y-CONRBR
9 in which the alkyl, alkenyl or alkynyl fragments can be substituted once or several times by halogen, hydroxy, alkoxy, alkylcarbonyloxy, amino or carboxy groups,
R
7 denotes a hydrogen atom, an alkyl, cycloalkyl, alkenyl or alkynyl residue wherein these residues can be substituted once or several times by halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkylcarbonyl or alkoxycarbonyl, or deno e an alkoxycarbonyl, cyanoalkyl, heteroaryl, aryl, -ralkyl or heteroarylalkyl group in which case aryl or heteroaryl residue can be substituted once or several times by halogen, nitrile, alkyl, alkenyl, alkyyl, trifluoromethyl, alkoxy, alkenyloxy, alkynyloxy, alkylthio, alkyl- 7~j77. sulfinyl, alkylsulfonyl, haloalkoxy, trifluoroaPI LL ~el L C-~ I I- I I r- 3 methoxy, hydroxy, carboxy, hydroxyalkyl, carboxyalkyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, alkylsulfonylamino, alkylcarbonylamino, formylamino, aminocarbonyl or phenyl, or denotes a -Y-C0 2
R
8 or -Y-CONR 8
R
9 group, Y denotes a linear or branched alkylene chain,
R
8 and R 9 are the same or different and denote hydrogen atoms, aralkyl, cycloalkyl or alkyl groups, which can be substituted once or several times by halogen, hydroxy, alkoxy, alkylcarbonyloxy, amine or carboxy, or R 8 and R 9 together with the N atom to which they are bound, form a saturated ring which can contain an additional oxygen, sulphur or nitrogen atom, as well as hydrates, solvates and physiologically tolerated salts thereof. The invention also concerns the optically active forms, racemates and mixtures of diastereomers of these compounds.
In addition the invention also concerns processes for the production of the above-mentioned compounds, pharmaceutical agents that contain such compounds as well as the use of these compounds in the production of pharmaceutical agents.
The aminopyridines of the general formula I, their solvates and their salts inhibit thrombin-induced coagulation of fibrinogen in blood as well as thrombininduced aggregation of blood platelets. Thus they prevent formation of hyaline thrombi and platelet-rich .thrombi and can be used to combat and prevent diseases VT V 7 L- 4 such as thrombosis, apoplexy, coronary infarction, inflammations and arteriosclerosis. Furthermore, these compounds have an effect on tumour cells and prevent formation of metastases. As a result they can be used as anti-tumour agents.
Thrombin, the last enzyme of the coagulation cascade, cleaves fibrinogen to form fibrin which is cross-linked by factor XIIIa and becomes an insoluble gel which forms the matrix for a thrombus. Thrombin activates platelet aggregation by proteolysis of its receptor on the blood platelets and in this way also contributes to thrombus formation. When a blood vessel is damaged these processes are necessary in order to stop bleeding. No measurable thrombin concentrations are present in blood plasma under normal circumstances. Increases in the thrombin concentration can lead io the formation of thrombi and hence to thromboembolic diseases which occur very frequently and above all in industrial countries.
Thrombin in plasma is kept ready in the form of prothrombin and is released from it by factor Xa.
Thrombin activates factors V, VIII and XI by which means factor X is then converted into factor Xa. By this means thrombin catalyzes its own release which is why very rapid increases in thrombin concentrations can occur.
Thrombin inhibitors can therefore inhibit the release of thrombin, the platelet-induced and plasmatic blood coagulation.
There is a whole series of serine proteases apart from thrombin that cleave peptide substrates next to a basic amino acid. In order to limit side-effects, the thrombin LI, I l L I •r 5 inhibitors should be selective i.e. they should inhibit other serine proteases only slightly or not at all.
Trypsin in particular being the least specific serine protease, can be easily inhibited by the various inhibitors. Trypsin inhibition can lead to pancreatic stimulation and to pancreatic hypertrophy Geratz, Am. J. Physiol. 216, (1969) p. 812).
Plasma contains the protein plasminogen which is converted into plasmin by activators. Plasmin is a proteolytic enzyme whose activity is similar to that of trypsin. It serves to dissolve thrombi by degrading fibrin. Inhibition of plasmin would thus have the opposite effect to that which one would like to achieve by inhibiting thrombin.
Synthetic thrombin inhibitors have already been known for a long time. Substances of the (D)-Phe-Pro-Arg type were synthesized from fibrinogen the natural substrate of thrombin. Such tripeptides imitate the amino acid sequence before the cleavage site on fibrinogen. In order to obtain good inhibitors the carboxylate group of the arginine was changed in such a way that the hydroxy group of serine 195 in the active site of thrombin can react with it. This can for example be achieved by replacing the carboxylate group by an aldehyde group.
Corresponding (D)-Phe-Pro-arginals are described in the Patent Application EP-A 185390.
Benzamidine, a known trypsin inhibitor, was used as the basis for a second type of thrombin inhibitor. The inhibitors obtained in this way do not only differ from the (D)-Phe-Pro-Arg types in their chemical structure but also in the way they inhibit: serine 195 of thrombin IIIIIPII I r I _1 I I S- 6 does not bind to these inhibitors. This clearly follows from X-ray examinations of the structure Bode, D.
Turk, J. Stirzebecher, Eur. J. Biochem. 193, 175-182 (1990)). Nc-(2-naphthylsulfonylglycyl)-4-amidino-(R,S)phenylalanine-piperidide ("NAPAP", DD 235866) belongs to this second class of thrombin inhibitors.
It was now surprisingly found that compounds of the general formula I which do not have any structural features in common with known thrombin inhibitors, are selective thrombin inhibitors.
The alkyl or alkoxy fragments mentioned in the definitions of R 1
R
9 contain 1-6 carbon atoms wherein these fragments can be straight-chained or branched. The same applies to the corresponding alkenyl or alkinyl fragments. Cycloalkyl groups are rings with three to seven carbon atoms. In the case of a haloalkyl or haloalkoxy group, the alkyl or alkoxy group can be substituted once, twice or three times by halogen. A trifluoromethyl or trifluoromethoxy group preferably comes into consideration in the case of groups substituted three times by halogen. In all cases halogen denotes fluorine, chlorine, bromine or iodine. Aralkyl and aralkoxy-groups are preferably understood as a benzyl or benzyloxy group. In those cases in which the stated groups can be substituted once or several times, a single, double or triple substitution comes into particular consideration. In the case of the sixmembered rings in aryl or heteroaryl groups, the substituents can independently be in the ortho, meta or para position.
If one of the substituents R 2
R
9 in the general L, I I I 7 formula I denotes an alkyl group, or R 6 denotes an aryl or heteroaryl group substituted by one or several alkyl groups, then the alkyl groups are to be understood as straight-chained or branched alkyl groups with 1 to 6 carbon atoms and preferably a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.butyl, pentyl and hexyl group. The halogen atoms as substituents on the alkyl groups are understood as fluorine, chlorine, bromine or iodine and preferably fluorine and chlorine. The trifluoromethyl, chloromethyl, 2-chloroethyl and 3-chloropropyl group are preferred. If the alkyl groups are substituted by hydroxy groups, then the hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, 1,2-dihydroxyethyl and 2,3-dihydroxypropyl group are preferred. If the alkyl groups are substituted by alkoxy groups, then the methoxymethyl, ethoxymethyl, methoxyethyl and ethoxyethyl group are preferred. If the alkyl groups are substituted by amino groups, then the aminomethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl and pentyl group are preferred. If the alkyl groups are substituted by carboxy groups, then the carboxymethyl, l-carboxyethyl, 2-carboxyethyl and 2-methyl-l-carboxyethyl group are particularly preferred.
If R 6
R
7
R
8 or R 9 in the general formula I denote a cycloalkyl group or if R 6 denotes an aryl or heteroaryl group substituted with a cycloalkyl group, then the cycloalkyl groups are to be understood as rings with 3 to 7 members and preferably a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl group. In all cases the cycloalkyl group can also be linked via an alkyl group so that a cycloalkyl-alkyl .roup results as a substituent. In this case a cyclopropylmethyl or cyclohexylmethyl groun are particularly preferred.
I I I 8 If R 6 in the general formula I denotes an aryl or heteroaryl group substituted with an alkenyl residue or if R 7 denotes an alkenyl residue, then these are to be understood as straight-chained or branched residues with 3 to 6 members and preferably an allyl, butenyl or isobutenyl residue.
If R 6 in the general formula I denotes an aryl or heteroaryl group substituted with an alkynyl residue or if R 7 denotes an alkynyl residue, then these are to be understood as straight-chained or branched residues with 3 to 6 members and preferably a propargyl residue.
If R 6 in the general formula I denotes an aryl or heteroaryl group substituted with an alkoxycarbonyl, alkenyloxycarbonyl or alkynyloxycarbonyl residue, then these are to be understood as straight-chained or ,e branched residues with 2 to 6 carbon atoms and preferably a methoxycarbonyl, ethoxycarbonyl or allyloxycarbonyl group.
i If R 6 in the general formula I denotes an aryl or heteroaryl group substituted with an alkoxy residue, then this is to be understood as a straight-chained or branched residue with 1 to 6 carbon atoms and preferably V' a methoxy, ethoxy, propyloxy, butyloxy or pentyloxy group. If the alkoxy groups are substituted by hydroxy groups, then a 2-hydroxyethoxy, 3-hydroxypropyloxy and 2,3-dihydroxypropyloxy group are preferred. If the alkoxy groups are substituted by alkoxy groups, then a methoxyethoxy or ethoxyethoxy group is preferred. If the alkoxy groups are substituted by amino groups, then a 2-aminoethoxy and 3-aminopropyloxy group are preferred.
k4 1 h -n t' I 9 If R 6 in the general formula I denotes an aryl or heteroaryl group substituted with an alkenyloxy residue, then this is to be understood as a straight-chained or branched residue with 3 to 6 carbon atoms and preferably an allyloxy group.
If R 6 in the general formula I denotes an aryl or heteroaryl group substituted with an alkynyloxy residue, then this is to be understood as a straight-chained or branched residue with 1 to 6 carbon atoms and preferably a propargyloxy group.
If R 6 in the general formula I denotes an aryl or heteroaryl group substituted by an alkylthio, alkylsulfinyl or alkylsulfonyl residue, then these are to be understood as straight-chained or branched residues with 1 to 6 carbon atoms and preferably a methylthio, methylsulfinyl or methylsulfonyl group.
If R 6 in the general formula I denotes an aryl or heteroaryl group substituted with an alkylamino or dialkylamino residue, then these are to be understood as straight-chained or branched residues with 1 to 6 carbon atoms and preferably a methylamino, dimethylamino or diethylamino group.
If R 6 in the general formula I denotes an aryl or heteroaryl group substituted with an alkylsulfonylamino residue, then this is to be understood as a straightchained or branched residue with 1 to 6 carbon atoms and preferably a methylsulfonylamino group.
If R 6 in the general formula I denotes an aryl or heteroaryl group substituted with an alkylcarbonylamino S- r y
-I
10 residue, then this is to be understood as a straightchained or branched residue with 1 to 6 carbon atoms and preferably an acetylamino group.
If R 6 in the general formula I denotes an aryl or heteroaryl group substituted with an alkylaminocarbonyl or dialkylaminocarbonyl residue, then these are to be understood as straight-chained or branched residues with 1 to 6 carbon atoms and preferably a methylaminocarbonyl, dimethylaminocarbonyl or diethylaminocarbonyl group.
The benzyl group is particularly preferred among the aralkyl groups for R 6 and R 7 The aryl residues R 6 or R 7 either alone or linked to an alkyl chain, are to be understood as aromatic hydrocarbons with 6-14 C atoms, in particular a phenyl, biphenyl, naphthyl, tetrahydronaphthyl, indanyl or fluorenyl residue.
The heteroaryl residue for R6 is to be understood as a monocyclic, bicyclic or tricyclic aromatic with heteroatoms such as nitrogen, oxygen and sulphur, such as a furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazine, tetrazine, benzothiophene, dibenzothiophene, benzimidazole, carbazole, benzofuran, benzoturazan, benzo-2,1,3-thiadiazole, quinoline, isoquinoline, quinazoline.
The alkylene group Y in the general formula I is to be understood as a linear or branched carbon chain with 1 I^^P t, 11 to 6 carbon atoms and preferably a methylene, ethylene or propylene group.
If the substituents R 8 and R 9 together with the nitrogen atom to which they are bound, form a ring, then this is to be understood as a ring with 4 to 7 members and especially a pyrrolidine, piperidine or homopiperidine ring. If this ring contains additional heteroatoms, then among these the morpholine, thiomorpholine and piperazine ring are preferred.
The residue R 2 on the phenyl ring in the general formula I can be in any desired positions in relation to the fragment X (oxygen atom or NH group). However, a configuration is particularly preferred in which all three substituents of the phenyl ring in the general formula I are in a meta position to Sone another.
R
1 denotes in particular the groups R 6
-SO
2
-NR
7
R
6
-NR
7 -S0 2
R
6 -S0 2 or R 6 -O-S0 2
R
2 denotes in particular a hydrogen, chlorine or bromine atom, or a Cl-C 6 alkyl group such as e.g. a methyl or ethyl group, or a C 1 -Cg alkoxy group such as a methoxy group or trifluoromethyl group.
X is in particular an oxygen atom or a NH group.
R
3 and R 4 can be the same or different and preferably denote hydrogen atoms or C 1
-C
6 alkyl groups, in particular hydrogen atoms or a methyl group.
I .S 12
R
5 is in particular a hydrogen atom, a C 1 -Cg alkyl group (such as a methyl group) or a benzyl group.
R
6 is in particular a C 1
-C
6 alkyl group (such as an isopropyl group), a C 3
-C
7 cycloalkyl group (such as a cyclopentyl or cyclohexyl group), a phenyl group substituted once or several times by fluorine, chlorine,
C
1
-C
6 alkyl (such as e.g. methyl, ethyl, tert.butyl),
C
1
-C
6 alkoxy (such as methoxy), nitro, amino, hydroxy, carboxy, benzyloxycarbonyl, C 1
-C
6 -alkoxycarbonyl (such as e.g. methoxycarbonyl), trifluoromethyl or the group
-O-Y-CO
2
R
8 a naphthyl, tetrahydronaphthyl, biphenyl or indanyl group, a thienyl, pyrazolyl or pyridyl group, a benzthienyl or benzothiadiazinyl group or a benzyl group.
R
7 is in particular a hydrogen atom, a C1-C6 alkyl or
C
2
-C
6 alkenyl group (such as e.g. a methyl, ethyl, n-propyl, allyl, i-propyl group) or an aralkyl group (such as e.g. a benzyl group), a C 1 -Cg alkoxycarbonyl group (such as e.g. an ethoxycarbonyl group), a cyanoalkyl group (such as e.g. a cyanomethyl group), a hydroxyalkyl group (such as e.g. a hydroxyethyl or dihydroxypropyl group), or an aminoalkyl group (such as e.g. an aminoethyl group), a -Y-CO 2
R
8 group or a
-Y-CONR
8
R
9 group.
Y is in particular a methylene, propylene, butylene or pentylene group.
R
8 is in particular a hydrogen atom or an alkyl group (such as e.g. a methyl or ethyl group), a hydroxyalkyl group (such as e.g. a hydroxyethyi, hydroxypropyl or dihydroxypropyl group) or an aminoalkyl group (such as III~ II L Jt-- ~I 13 e.g. an aminoethyl group).
R
9 is in particular a hydrogen atom or an alkyl group (such as e.g. a methyl group).
Compounds of the general formula I are preferred
R
2
-R
3 S CH 2
(I)
\N
R4 Go a
R
in which a
R
1 denotes the groups R6-SO2-NR7- R6-NR7-S02
R
6 -S0 2 or R 6
-O-SO
2
R
2 deibtes a hydrogen, chlorine or bromine atom, a methyl, ethyl, methoxy or a trifluoromethyl group, atoms or methyl groups,
R
5 denotes a hydrogen atom, a methyl or benzyl group,
R
6 denotes an isopropyl, cyclopentyl or cyclohexyl *i i Is- 14 group, an unsubstituted phenyl group or a phenyl group substituted once or several times by fluorine, chlorine, methyl, ethyl, tert.butyl, methoxy, nitro, amino, hydroxy, carboxy, benzyloxycarbonyl, methoxycarbonyl, trifluoromethyl or the group -O-Y-CO 2
R
8 a naphthyl, tetrahydronaphthyl, biphenyl or indanyl group, a thienyl, pyrazolyl or pyridyl group, a benzthienyl or benzothiadiazinyl group or a benzyl group,
R
7 denotes a hydrogen atom, a methyl, ethyl, n-propyl, allyl, i-propyl or benzyl group, an ethoxycarbonyl, hydroxyethyl, dihydroxypropyl, cyanomethyl or aminoethyl group, a -Y-COR 8 group or -Y-CONR 8
R
9 group, Y denotes a methylene, propylene, butylene or pentylene group,
R
8 denotes a hydrogen atom or a methyl, ethyl, hydroxyethyl, hydroxypropyl, dihydroxypropyl or aminoethyl group,
R
9 denotes a hydrogen atom or a methyl group.
The compounds of the general formula I are produced according to well-known methods.
One starts with compounds of the general formula II, Ir i 7 'C 15
(II)
R
3 0
~R
4 1 which are reduced according to conventional methods.
Complex boron and aluminium hydrides, complexes of boron hydride, aluminium hydride which is prepared in situ by reacting LiAlH 4 with AlC1 3 or H 2
SO
4 or a mixture of A1C13 and NaBH 4 come into consideration as the reducing agent.
Compounds of the general formula II are produced by reacting compounds of the general formula III o a a a a. a *e
PI
(III)
X COOH with 4-aminopyridine whose amino N atom carries the residue R 5 This reaction is carried out by reacting equimolar amounts of 4-aminopyridine and the carboxylic acid of the general formula III in the presence of a dehydrating agent,such as polyphoshoric acid, an acid cation exchanger, sulphuric acid halogenide, 2-halopyridinium salt, dicyclohexyl-carbodiimide or N,N'carbonyldiimidazole. This reaction can also proceed in two steps whereby the carboxylic acid is firstly converted into a reactive derivative e.g. an acid chloride, an acid azide or imidazolide and then reacted with the 4-aminopyridine.
II
16 The carboxylic acids of the general formula III are produced from esters of the general formula IV
R
2
(IV)
a COOR 1 0
R
4 in which R 10 denotes an alkyl or benzyl group. Depending on the type of this group, the reaction is carried out either with the aid of bases or acids or hydrogenolytically. If R 10 is a methyl or ethyl group, then the reaction is preferably carried out with sodium hydroxide or potassium hydroxide in methanol, ethanol or in water. If R 10 is a tert.butyl group, then the reaction is carried out with an acid and preferably hydrochloric acid, formic acid or trifluoroacetic acid.
If R 1 0 is a benzyl group the reaction is preferably carried out hydrogenolytically in the presence of a o.catalyst such as palladium on carbon or with platinum.
Another compound of the general formula IV in which R 1 denotes a R 6
-NR
7
R
6
-NR
7 '-S0 2
R
6
-SO-NR
7 or
:R
6
-SO
2
-NR
7 group can be produced by alkylation from compounds of the general formula IV in which R 1 denotes a R 6 -NH-SO-, R 6 -NH-S0 2
R
6 -SO-NH- or R 6 -S0 2 -NH- group.
Compounds of the general formula R 7 are used as alkylating agents, in which R 7 has the same meaning as
R
7 with the exception of the hydrogen atom, the phenyl and heteroaryl group and Z denotes a reactive grouplsuch as halogen and preferably bromine, chlorine or a sulfate. These reactions are preferably carried out in a solvent,such as acetone, ether, toluene or dimethyl- *i -i 'i rr 17 formamide,at temperatures between -30 0 C and 100 0
C,
preferably at room temperature in the presence of a base, such as sodium hydride or calcium carbonate.
The compounds of the general formula IV are prepared from compounds of the general formula V
S
S
which are reacted with a-halogen esters of the general formula Hal-CR 3
R
4 -C0 2
R
1 0 Hal denotes a halogen atom, preferably chlorine and bromine. These reactions are preferably carried out in a solvent such as acetone, ether, toluene or dimethylformamide,at temperatures between -30 0 C and 100°C, preferably at room temperature in the presence of a base such as sodium hydride or calcium carbonate.
The compounds of the general formula IV in which R 1 denotes a R 6
R
6 -S0 2
R
6 -SO-NH- or R 6 -S0 2
-NH-
group are prepared from compounds of the general formula
VI
R
2
A'R
3 X COOR'O
(VI)
r i ~-i la 1 4 C 18 by reacting them with a sulfinyl chloride R 6 -SOCl or sulfonyl chloride R 6
-SO
2 C1. In this case A denotes a hydroxy or amino group NHR 7 It is expedient to carry out the reaction by adding an acid-binding agentsuch as e.g. alkali acetate, alkali hydroxide, calcium oxide, calcium carbonate, magnesium carbonate or with organic bases,such as pyridine, triethylamine, N-methylmorpholine or diisopropylmethylamine wherein for example ether, methylene chloride, dioxane, toluene or an excess of the tertiary amine serve as an inert solvent.
When inorganic acid binding agents are employed, one uses for example water, aqueous ethanol or aqueous dioxane as a reaction medium.
The compounds of the general formula IV in which R 1 denotes the group R 6
R
6 -0-S0 2
R
6
-NR
7 -SO- or
R
6
-NR
7 -S0 2 can be produced from compounds of the general formula VII (VII) Cln- R 3 X COOR 1 0 R4 in which n equals one (sulfinyl chlorides) or 2 (sulfonyl chlorides). They are reacted with compounds of the general formula R 6 -OH or R 6
-NH-R
7 It is expedient to add an acid-binding agent in the reaction,such as e.g. alkali acetate, alkali hydroxide, calcium oxide,
I
19 calcium carbonate, magnesium carbonate or to use organic bases,such as pyridine, triethylamine, N-methylmorpholine or diisopropylmethylamine wherein ether, methylene chloride, dioxane, toluene or an excess of the tertiary amine serve for example as an inert solvent.
When inorganic acid-binding agents are employed, one uses for example water, aqueous ethan9l or aqueous dioxane as a reaction medium.
The compounds of the general formula V and VII are known in the literature ("Methoden der Organischen Chemie (Houben-Weyl), Thieme Verlag, Stuttgart" 1955, p. 285; M. Quaedvlieg, "Aliphatische Sulfinsauren", p. 299; F. Muth, "Aromatische Sulfinsiuren", p. 343; M. Quaedvlieg, "Aliphatische Sulfonsauren", p. 429; F. Muth, "Aromatische Sulfonsauren", p. 599; F. Muth, a "Funktionelle N-Derivate der Arylsulfonsauren", p. 659; F. Muth, "Aromatische Sulfonsdureester") or they can be produced according to the methods described there. The compounds of the general formula VI are known from the literature (Sobotka, Austin, J. Am. Chem. Soc. 74, 3813 (1952)) or they can be produced according to methods described there.
A further process for the production of compounds of the general formula I is to react compounds of the general S• formula VIII R2 R T (VIII)
R
3 X
CH
2
N-H
R4
N
R
Ii 1 1 ,rS 20 with a pyridine derivative which has a nucleofugal group which can be removed in position 4. Halogens, preferably bromine, chlorine and fluorine, as well as nitro, alkoxy and phenoxy groups come into consideration as such groups which can be removed.
In order to facilitate the reaction, the 4-aminopyridine derivative can contain further halogen atoms and preferably chlorine. Preferred derivatives are pentachloropyridine and 4-nitro-tetrachloropyridine.
This reaction is preferably carried out in an inert solvent,such as e.g. toluene, dioxane, dimethylformamide, dimethylacetamide, methylene chloride or ethanol, at temperatures between room temperature and the boiling point of the solvent, preferably between 20 and 0 C. If the pyridine derivative contains further chlorine atoms, then the nucleophilic reaction is followed by a dehalogenation reaction, e.g. by catalytic *0.
so hydrogenation.
The compounds of the general formula VIII are produced by reducing compounds of the general formula IX
SR
2 (I R3
SR
4 in which R 11 denotes a nitrile group or an amide group
CONHR
5 Complex boron and aluminium hydrides, boron hydride complexes, aluminium hydride which is produced by in situ reaction of LiAlH 4 with AlC1 3 or sulphuric acid, or a mixture of A1C1 3 and NaBH 4 come into consideration as the reducing agent.
A i 21 The compounds of the general formula IX are prepared from compounds of the general formula III. This reaction is carried out by reacting equimolar amounts of an amine
H
2
NR
5 and a carboxylic acid of the general formula III in the presence of a dehydrating agent such as polyphosphoric acid, an acid cation exchanger, sulphuric acid halogenide, 2-halopyridinium salt, dicyclohexylcarbodiimide or N,N'-carbonyldiimidazole. This reaction can also be allowed to proceed in two steps whereby the carboxylic acid is firstly converted into a reactive derivative, e.g. an acid chloride or an acid azide and then reacted with ammonia.
A further process for the production of compounds of the general formula I starts with compounds of the general formula X R3 SC Cl HO N N
R
4
R
5 CI
CI
which are obtained according to methods known from the literature Boudakian, in Heterocyclic Compounds, Vol. 14, Suppl. Part. 2, Abramovitch, Wiley, New York 1974, page 407) by reacting the commercially available aminoethanols HO-CR 3
R
4
-CH
2
-NHR
5 with pentachloropyridine or 4-nitrotetrachloropyridine in an inert solvent such as dioxane, tetrahydrofuran, methylene chloride or ethanol at temperatures between 0 C and the boiling temperature of the solvent. The hydroxy group of compounds of the general formula X is 22 converted into a leaving group W and by this means compounds of the general formula XI are obtained
R
3 Cl Cl1 (XI) w 1N N N
R
4
R
Cl
CI
in which W denotes a halogen atom such as chlorine or bromine or a sulfonic acid ester such as tosyloxy. The conversion of the hydroxy group into a halogen atom is carried out with a halogenation agent such as thionyl chloride or phosphoryl chloride, conversion into a sulfonic acid ester is carried out by reaction with a sulfonyl chloride such as tosyl chloride.
The compounds of the general formula XI are then reacted with compounds of the general formula V' 2
R
2
XH
in which R 1 has the same meaning as R 1 but in addition can also be a protected hydroxy group or amino group. A protected hydroxy group is understood as a benzyloxy group or acetyloxy group. A protected amino group is 1 i 9 i a 23 preferably understood as the tert.butyloxycarbamoyl group, benzyloxycarbamoyl group, dibenzylamino group or phthalimido group. The compounds of the general formula XII are formed in this process. Reaction of compounds of the general formula V' with compounds of the general formula X instead of XI according to Mitsunobu in the presence of triphenylphosphine and diazodicarboxylic acid diethyl ester or piperidide also leads to compounds of the general formula XII.
R
R
R
3 Cl Cl (XII) N N
R
4
R/
R
5 C1 CI If R1 in compounds of the general formula XII is a protected hydroxy group or a protected amino group then the protecting group is removed in the next step. This is carried out by hydrogenolysis in the presence of a catalyst such as palladium on carbon,for the benzyl protecting group, by a strong acid,such as trifluoroacetic acidfor the tert.butylcarbamoyl group and by a base,such as sodium hydroxide,for the acetyl group. In this process compounds of the general formula XIII are formed R2 (XIII) A' R3 NCI C
R
R5 Cl Cl i IOrvllj rr 24 which are converted into compounds of the general formula XIV by reaction with sulfinyl chlorides or sulfonyl chlorides
R
2
R
6 -S (XIV)
R
3 L< _C C Cl x N
N
R
4 CI Cl in which n can equal 1 or 2 and X' denotes an oxygen atom or an imino group NH. If X' denotes an imino group, then compounds of the general formula XIV are converted into compounds of the general formula XV
R
2
R
6 -SOn-NRL-
R
R
6
SO
SCl Cl
R
4 R CI Cl in which R 7 has the same meaning as R 7 with the exception of the hydrogen atom. This is achieved by reaction with alkylating agents R 7 as described for alkylations of the general formula IV.
I es 25 Finally compounds of the general formula I are obtained from compounds of the general formula XII in which R 1 has the same meaning as R 1 from compounds of the general formula XIV or from compounds of the general formula XV by removing the chlorine atoms of the pyridine ring. This is carried out by catalytic hydrogenation in the presence of a catalyst, such as Raney nickel or palladium on carbon,in the presence of a basesuch as potassium carbonate, sodium bicarbonate or sodium methylate.
Another synthetic pathway for the production of compounds of the general formula I in which R 1 denotes a
R
6
-SO-NR
7
R
6 -S0 2
-NR
7
R
6 -SO-O or R 6 -S0 2 -0 group is to react compounds of the general formula XVI (XVI) 3 R with a sulfinyl chloride R 6 -SOCi or a sulfonyl chloride
R
6 -S0 2 -Cl. The reaction is carried out as described for the reaction with compounds of the general formula VI.
In this case A denotes a hydroxy group or an amino group
NHR
7 Compounds of the general formula XVI are produced from compounds of the general formula XVII, i 26
R
2 B-A (XVII) B R 3 N- N
R
4
R
in which B denotes a protecting group which is cleaved off to produce compounds of the general formula XVI.
Groups which come into consideration as protecting groups B are a benzyl group which is removed by hydrogenolysis in the presence of a catalystsuch as palladium on carbon, a tert.butyloxycarbonyl group which is removed by the action of acids,such as trifluoroacetic acid. formic acid or hydrochloric acid, or an "aromatic sulfonyl group,such as a benzenesulfonyl or tosyl groupwhich is removed by the action of an alkali S: such as sodium hydroxide or potassium hydroxide.
Compounds of the general formula XVII are produced according to the same principles as compounds of the general formula I. It is preferable to start with compounds of the general formula XVIII, B .A o° R2 (XVIII) B-A-
XH
1 27 which are reacted with halogen esters of the general formula Hal-CR 3
R
4
-CO
2
R
1 0 as described for reactions with compounds of the general formula V. In this process compounds of the general formula XIX are formed,
R
2 (XIX) B-A-
R
B-A 4 R 3 X COOR' 0
R
4 which, after saponification of the ester and activation of the acidic functional group are reacted with 4-aminopyridine or N-R 5 -4-aminopyridine to form compounds of the general formula XVI as described for compounds of the general formula III.
Certain compounds of the general formula I can be subsequently converted into other compounds of the general formula I.
o: This applies to compounds of the general formula I in which the group R 5
R
6 or R 7 denotes a benzyl group or in which R 6 denotes an aryl or heteroaryl group which carry one or several benzyloxy, benzylamino or benzyloxycarbonyl groups as substituents. In this process the benzyl group is replaced by a hydrogen atom by catalytic hydrogenation in the presence of a catalyst, preferably palladium on carbon. The benzyl -c I 28 group can also be removed by reaction with a strong acid such as trifluoroacetic acid in the presence of mesitylene, anisole or thioanisole.
This also applies to compounds of the general formula I in which R 6 denotes an aryl cr heteroaryl group which carry one or several chlorine atoms as substituents. In this process the chlorine atom is replaced by a hydrogen atom by catalytic hydrogenation in the presence of a catalyst, preferably palladium on carbon.
This also applies to compounds of the general formula I in which R 6 denotes an aryl or heteroaryl group which carry one or several nitro groups as substituents. In this process the nitro group is replaced by an amino group by catalytic hydrogenation in the presence of a catalyst, preferably palladium on carbon.
This also applies to compounds of the general formula I.
in which R 6 denotes an aryl or heteroaryl group which carry an alkyloxycarbonyl, alkyloxycarbonylalkyl or alkyloxycarbonylalkyloxy group as substituents or the group R 7 denotes an alkoxycarbonylalkyl group. In this case the free carboxylic acids can be produced from the alkoxycarbonyl groups by reaction with acids such as hydrochloric acid, or bases such as sodium hydroxide. If these alkoxycarbonyl groups are reacted with an amine of the general formula NHR 8
R
9 then a CONR 8
R
9 group is formed from the alkoxycarbonyl group. If these alkoxycarbonyl groups are treated with a reducing agent such as LiAlH 4 then the corresponding hydroxymethyl groups are formed from this.
1 1 1 I 29 This also applies to compounds of the general formula I in which R 6 denotes an aryl or heteroaryl group which carry one or several nitriles, cyanoalkyl, cyanoalkyloxy, formylamino, alkylcarbonylamino, aminocarbonyl, alkylaminocarbonyl groups or a -S-Y-CONHR 8
-O-Y-CONHR
8
-NH-Y-CONHR
8 group as substituents or in which R 7 denotes a cyanoalkyl, aminocarbonylalkyl or the group -Y-CONHR 8 These groups can be reduced preferably with LiAlH 4 to form the corresponding aminomethyl compounds.
Examples of salts of compounds of formula I which can be used physiologically are salts with physiologically tolerated mineral acids such as hydrochloric acid, sulphuric acid, sulphurous acid or phosphoric acid; or with organic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The compounds of formula I with a free carboxy group can also form salts with physiologically tolerated bases. Examples of such salts are alkaline metal, alkaline-earth metal, ammonium and alkylammonium salts such as a sodium, potassium, calcium or tetramethylammonium salt.
The compounds of formula I can be solvated and in particular hydrated. The hydration can be achieved in the course of the production process or gradually occur as a result of hygroscopic properties of a compound of formula I which is firstly anhydrous.
Pure enantiomers of compounds of formula I can either be obtained by racemate resolution (by formation of salts I YI I~ I 30 with optically active bases) or by using optically active starting materials in the synthesis.
For the production of pharmaceutical agents, the substances of the general formula I are mixed with suitable pharmaceutical carrier substances, aromatics, flavourings and dyes and are for example formed into tablets or coated tablets or are suspended or dissolved in water or oil e.g. olive oil with the addition of appropriate auxiliary substances.
The substances of the general formula I and their salts can be administered enterally or parenterally in a liquid or solid form. Water is preferably used as an injection medium which contains the usual additives in injection solutions such as stabilizers, solubilizers or buffers. Such additives are e.g. tartrate and citrate buffer, complexing agents (such as ethylenediaminetetraacetic acid and their non-toxic salts) and high molecular polymers such as liquid polyethyloxide in order to regulate viscosity. Solid carrier materials are for example starch, lactose, mannitol, methylcellulose, talcum, highly dispersed silicic acids, high molecular fatty acids (such as stearic acid), animal and vegetable fats and solid high molecular polymers (such as polyethylene glycols). Preparations suitable for oral administration can, if desired, contain flavourings and sweeteners.
The compounds are usually administered in amounts of 1500 mg per day in relation to 75 kg body weight. It is preferable to administer 1-2 tablets with a content of active substance of 5-500 mg, 2-3 times per day. The tablets can also be retarded _s a result of which only LI~ I i 31 1-2 tablets have to be administered per day with 700 mg active substance. The active substance can also be administered by injection 1-8 times per day or by continuous infusion in which case 50-2000 mg per day are usually sufficient.
The following compounds are preferred within the sense of the invention in addition to those mentioned in the examples: 1. Benzenesulfinic acid-3-methyl-5- (pyridin-4ylamino) -ethoxy]-phenyl ester 2. (Pyridin-4-ylamino) -ethoxy]-phenyl}benzenesulf inamide 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 }-phenoxy-acetic acid 3-{3-Methyl-5-[2- (pyridin-4-ylamino) -ethoxy]phenylaminosulfonyl }-phenoxy-acetamide 6. N-(2-Hydroxyethyl) -3-{3-xe'tyl-5-[2-(pyridin-4ylamino) -ethoxy] -phenylaminosulfonyl}-phenoxyacetamide 7. N'-(2,3-Dihydroxypropyl)-3-3-methyl-5-[2-(pyridin- 4-ylainino) -ethoxy] -phenylaminosulfonyl}-r/henoxyacetamide 32 8. N-(2-Hydroxyethyl) -3-{3-methyl-5-[2-(pyridin-4ylamino) -ethoxy] -phenyloxysulfonyl }-phenoxyacetamide 9. 3-{3-Methyl-5-[2-(pyridin-4-ylamino) -ethoxy]phenylaminosulfonyl} phenoxy--acetic acid-morpholide Acetic acid 2-[2-(benzenesulfonyl-{3-methyl-5-[2pyridin-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-{3methyl-5-[2- (pyridin-4-ylamino) -ethoxy] -phenyl}ami.no-acetylamino] -ethyl ester 13. N-{3-Cyano-5-(2-(pyridin-4-ylamino) -ethoxy]phenyll}-benz enesulfonamide
I
0 33- Example 1 N-{3-[2-(Pyridin-4-ylamino)-ethoxy -phenyl}-2naphthalene-sulfonamide a) 6.3 g (L2 mmol) naphthalene-2-sulfonyl chloride in ml methylene chloride was added dropwise at 10 0
C
to 5.9 g (25 mmol) 3-aminophenoxyacetic acid ethyl ester and 6.9 ml triethylamine in 100 ml methylene chloride while cooling on ice. It was stirred for 1 hour at room temperature, extracted with water and the organic phase was dried over sodium sulfate. The solvent was removed in a vacuum and 9.6 g N-{3-[(ethoxycarbonyl)-methoxy]-phenyl}-2naphthalene-sulfonamide was obtained as an oil.
MS m/e 385.
b) 4.2 g (75 mmol) potassium hydroxide was added to 9.6 g (25 mmol) of this compound in 100 ml ethanol and it was stirred for 1 hour at 70 0 C. It was filtered, the precipitate was dissolved in water, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The solvent was removed in a vacuum, the residue was dissolved in 2 N sodium hydroxide solution, acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in a vacuum. The oily residue crystallizes on standing. 7.6 g (85 N-{3-[(carboxy)-methoxy]phenyl}-2-naphthalene-sulfonamide was obtained. Fp.
153 1550C. FAB-MS: M+H 358.
I 1 1 1 PI I 1 t I S- 34c) 2.7 g (16.8 mmol) 1,1-carbonyldiimidazole was added to 3 g (8.4 mmol) of this compound in 30 ml tetrahydrofuran at 450C and it was stirred for minutes. 0.8 g (8.4 mmol) 4-aminopyridine was added to this and stirred for 6 hours at 60 0 C. Then 2.7 g (16.8 mmol) 1,l-carbonyldiimidazole and 0.8 g (8.4 mmol) 4-aminopyridine was again added and it was stirred for a further 6 hours at 60 0 C. The solvent was removed in a vacuum, the residue was taken up in ethyl acetate and extracted with aqueous sodium bicarbonate and with phosphate buffer, pH 7.0. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in a vacuum. 2.5 g (69 N-{3-[(pyridin-4ylaminocarbonyl)-methoxy]-phenyl}-2-naphthalenesulfonamide was obtained. Fp. 204 2070C.
MS m/e 433.
d) 2.0 g (4.6 mmol) of this compound was added under nitrogen to 1.0 g (20.4 mmol) lithium aluminium hydride in 20 ml tetrahydrofuran and it was boiled for 1 hour under reflux. Excess LiAlH 4 was decomposed with water, filtered and the filtrate was concentrated by evaporation in a vacuum. The residue was taken up in ethyl acetate, extracted with water, the organic phase was dried with sodium sulfate, filtered and the solvent was removed in a vacuum. The oily residue was separated on a reverse-phase column (RP-18; mobile solvent: methanol/water pH 6.8, The desired fraction was evaporated to dryness in a vacuum and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in a vacuum. 0.3 g (16 of the title
IN:~
t, compound was obtained of Fp. 90 91 0
C.
MS m/e 419.
Example 2 N-f 3-r2-[Pyridin-4-vamino) -ethoxv1I-pheny1 -1naphthalene-sulfonamide The production was carried out analogously to example 1 except that in step a) l-naphthalenesulfonyl chloride was used inste.- of 2-naphthalenesulfonyl chloride.
Intermediate steps: a) N-1{3- [(Ethoxycarbonyl) -methoxy3 -phenyl}-lnaphthalenesulfonamide as an oil. MS m/e =385.
b) Ni-{3-L (Carboxy) -methoxy] -phenyl}-I ,aphthalenesulfonamide. Fp. 147 149c'C. FAB-MS: M+H 358.
C) 3-[E(Pyridin-4-ylaminocarbonyl) -methoxy] -phenyl}l-naphthalenesulfonamide. Fp. 210 211 0
C
(decomp.). MS m/e =433.
d) Title compound. Yield 38 Fp. 239 -241 0
C
(decomp.). MS: pos. LSIMS m/e =419 t 36- Example 3 4-Methyl-N-{ 3-f2- (pyridin-4-vlamino) -ethoxyl -phenl benzenesulfonanide The production was carried out analogously to example 1 except that in step a) 4-toluenesulfonyl chloride was used instead of 2-naphthalenesulfonyl chloride.
Intermediate steps: a) 4-Methyl-N-{ 3- [(ethoxycarbonyl) -methoxy] -phenyl} benzenesulfonamide. Fp. 100 102 0 C. MS m/e 349.
b) 4-Methyl-N-{ 3- [(carboxy) -methoxy] -phenyl}-benzenesulfonamide. Fp. 170 173 0 C. FAB-MS: M+H =322.
c) 4-Metllyl-N-{3-[ (pyridin-4-ylaminocarbonyl)methoxyl -phenyl}-benzenesulfonamide as an oil.
MS m/e 397.
d) Title compound. Yield 26 Fp. 165 1670C.
MS m/e 383.
Example 4 4-Fluoro-T3-f2- (Pvridin-4-vlamino) -ethoxyl -phenyllbenzenesulfonamide-hvdrochloride The production was carried out analogously to example 1 except that in step a) 4-f luorot 37 benzenesulfonyl chloride was used instead of 2-naphthalenesulfonyl chloride.
Interme~diate steps: a) 4-Fluoro-N-{3-[ (ethoxycarbonyl) -methoxy] -phenyl}benzenesulfonanide Fp. 94 96 0 C. MS m/e 353.
b) 4-Fluoro-N-{3-[ (carboxy) -methoxy] -phenyl}benzenesulfonamide. Fp. 154 15611C. FAB-MS: M+H 326.
c) 4-Fluoro-N-{3-[ (pyridin-4.-ylaminocarboniyl) methoxy] -phenyl} -benzenesul fonamide. MS m/e =401.
d) Title compound. The base was ground with hydrochloric acid in ether: Yield 21 Fp. 203- 2050C. MS m/e 387.
Examp le 4-Chloro-N-13-f2- (iyridin-4-ylamino) -ethoxyl -phenvilbenzenesulfonamide hydrochloride The production was carried out analogously to example 1 except that in step a) 4-chlorobenzenesulfonyl chloride was used instead of 2 -naphthalenesulfonyl chloride.
Intermediate steps: 38 a) 4-Chloro-N-1{3- ((ethoxycarbonyl) -methoxy] -phenyl}benzenesulfonamide. MS m/e =369.
b) 4-Chloro-N-{3-1 (carboxy) -methoxy] -phenyl}benzenesulfonamide. Fp. 190 1920C. FAB-MS: M+H 342.
C) 4-Chloro-N-{3-[ (pyridin -4-ylaminocarbonyl) methoxy] -phenyl} -benzenesulfonamide. Fp. 168- 171 0 C. MS m/e =417.
d) 1.79 ml (3.53 mmol) 2 M borane dimethylsulfide in tetrahydrofuran was added, to 0.65 g (1.55 mmol) from step c) in 15 ml dry tetrahydrofuran. It was stirred for 3 hours at 60 0 C and 10 ml methanol was then added in an ice bath. 5 ml hydrogen chloride in ether was added. The solvent was removed in a vacuum and the residue was ground with warm water.
0.13 g of the title compound was obtained of Fp.
241 243 0 C. MS m/e =403.
Example 6 4-Trifluoromethvl-N-{3-r2-(pvridin-4-vlamino) -ethoxylphenvl1 -benzenesulfonamide It was produced analogously to example 1 except that in step a) 4-trifluoromethyl-benzenesulfony~l chloride was used instead of 2-naphthalenesulfonyl chlc'ride.
Intermediate steps: 39 a) 4-Trifluoromethyl-N-{ 3-1(ethoxycarbonyl) -methoxyl phenyl}-benzenesulfonamide. MS m/e =403.
b) 4-Trifluoromethyl-N-{ 3- [(carboxy) -methoxy] -phenyl} benzenesulfonamide. Fp. 155 158 0 C. FAB-MS: 14+H 375.
c) 4-Trifluoromethyl-N-{3-[ (pyridin-4-ylaminocarbonyl) -methoxy] -phenyl} -benzenesulfonamide.
Fp. 66 68 0 C. MS m/e 451.
d) Title compound Fp. 145 148 0 C. MS m/e 437.
Example 7 3-Trif luoromethvl-N-13- F2- (pyridin-4-vYlamino) -ethoxyphenyllI-benz enesulfonamide It was produced analogously to example l'except that 3-trifluoromethyl-benzenesulfonyl chloride was used instead of 2-naphthalenesulfonyl chloride.
Intermediate steps: a) 3-Trif luoromethyl-N-{3-[1 (ethoxycarbonyl) -methoxy] phenyl}-benzenesulfonamide. MS m/e =403.
b) 3-Trif luoromethyl-N- {3-11 (carboxy) -methoxy I -phenylybenzenesulfonami~fe. Fp. 147 -149 0 C. FAB-MS: M+H 375.
40 c) 3-Trifluoroinethyl-N-{3-[ (pyridin-4-ylaminocarbonyl) -methoxy]-phenyl}-benzenesulfonamide as an oil. MS m/e 451.
d) Title compound. Fp. 185 187 0 C. MS m/e 437.
EmPLP N-43- 2- (Pvridin-4-vlamino' -ethoxyl -phenvyii-cyclohexanesulfonamide It was produced analogously to example 1 except that in step a) cyclohexyl-sulfonyl chloride was used instead of 2-naphthalenesulfonyl chloride.
Intermediate steps: a) 3- [(Ethoxycarbonyl) -methoxy] -phenyl}cyclohexanesulfonamide. MS m/e 341.
b) 3- [(Carboxy) -methoxy] -phenyl} -cyclohexanesulfonamide. Fp. 1320C. FAB-MS: M+H 313.
C) 3- [(Pyridin-4-ylaminocarbonyl) -methoxy] -phenyl} cyclohexanesulfonamide as an oil. MS ni/e 389.
d) Title compound. MS m/e =375.
4,& 41 Example 9 N-{3-r2-(Pyridin-4-ylamino) -ethoxyl-phenyllbenz enesul foriamide It was produced analogously to example 1 except that in step a) benzenesulfonyl chloride was used instead of 2-naphthalenesulfonyl chloride.
Intermediate steps: a) [(Ethoxycarbonyl) -methoxy] -phenyl} benzenesulfonamide as an oil. MS m/e 335.
b) 3-[(Carboxy) -methoxy] -phenyl} -benzenesulfonamide. Fp. 160 161 0 C. FAB-MS: M+H 307 c) (Pyridin-4-ylaminocarbonyl) -methoxy] -phenyl}benzenesulfonamide. Fp. 151 156 0 C. MS m/e =383.
d) Title compound. Yiel.d 26 Fp. 182 184 0
C.
MS m/e =369.
Example I0 N-f3-[r -Methyl-2- (pvridin-4-vlamino) -ethoxyl-phenyllbenz enesul fonamide a) 5.6 ml (44 mmol) benzenesulfonyl chloride was added dropwise at lOWC to 8.4 g (40 mmol) 2-(3-aminophenoxy)-propionic acid ethyl ester and 6.1 ml (44 inmol) triethylamine in 50 ml methylene chloride 42 while cooling on ice. It was stirred for 1 hour at room temperature, extracted with water, the organic phase was dried with sodium sulfate, filtered and thu solvent was removed in a vacuum. 14 g (ethoxycarbonyl)-ethoxy]-phenyl}-benzenesulfonamide was obtained as an oil. MS m/e 349.
b) 14 g (40 mmol) of this compound and 6.7 g (120 mmol) potassium hydroxide in 100 ml ethanol were stirred for 1 hour at 70 0 C. It was extracted twice with ethyl acetate, acidified with halfconcentrated hydrochloric acid and again extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and the solvent was removed in a vacuum. 9.2 g (72 N-{3- [1-(carboxy)-ethoxy]-phenyl}-benzenesulfonamide was obtained an oil. MS m/e 321.
c) 3.4 g (57 N-{3-[l-(pyridin-4-ylaminocarbonyl)ethoxy]-phenyl}-benzenesulfonamide (Fp. 142 1440C. MS m/e 397) was produced as in example 1, step c) from 4.8 g (15 mmol) of this compound, 2.1 g (22.5 mmol) 4-aminopyridine and 3.2 g (19.5 mmol) l,1-carbonyl-diimidazole in 40 ml tetrahydrofuran.
d) 0.6 g (37 of the title compound (Fp. 162 163 0 C. MS m/e 383) was produced from 1.7 g (4.3 mmol) of this compound and 0.65 g (17.2 mmol) lithium aluminium hydride in 20 ml tetrahydrofuran as in example 1, step d).
r 1 *r IP~ I -43 Example 11.
N-{3-F1. l-Dimethyl-2-(-Pyridin-4-ylamino) -ethoxyl- ]phenyllI-benzenesulfonamide The compound was produced analogously to example 2-methyl-2-(3-aminophenoxy) -propionic acid ethyl ester was used in step a) instead of 2-(3aminophenoxy)-propionic acid ethyl ester.
a) [1-Methyl-i- (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-[l-Methyl- (pyridin-4-ylaminocarbonyl) -ethoxy] phenyl}-benzenesulfonamide. Fp. 141 143 0
C.
MS m/e 411.
d) Title compound as an oil. MS m/e =397.
Example 12 benzenesulfonamide hydrochloride a) A solution of 1.6 ml (25 mmol) iodomethane in 10 ml dimethylformamide was added dropwise at 80 90 0
C
to 8.4 g (25 mmol) N-{3-[(ethoxycarbonyl)-methoxy]phenyl}-benzenesulfonamide (example 9, step a) and g potassium carbonate in 10 ml dimethyl- 44 formamide. It was stirred for a further 2 h at this temperature, allowed to cool to room temperature, filtered and the filtrate was concentrated in a vacuum. The residue was taken up in ethyl acetate and extracted with water. It was dried over sodium sulfate, filtered and the solvent was removed in a vacuum. 8.6 g N-methyl-N-{3-[(ethoxycarbonyl)methoxy]-phenyl}-benzenesulfonamide was obtained as an oil. MS m/e 349.
b) The further reaction was carried out as in example 1; step b. N-methyl-N-{3-[(carboxy)-methoxy]phenyl}-benzenesulfonamide was obtained. Fp.: 110 111 0 C. MS m/e 321.
c) N-Methyl-N-{3-[(pyridin-4-ylaminocarbonyl)methoxy]-phenyl}-benzenesulfonamide. Fp.: 76 780C. MS m/e 397.
d) Title compound. 2 N hydrochloric acid was added to the free base, it was extracted with ethyl acetate and the aqueous phase was evaporated to dryness. An oil was obtained which crystallized after grinding with isopropanol. Yield 46 Fp.: 174 176 0
C.
Example 13 N-Ethyl-N-{3-r2-(pyridin-4-ylamino)-ethoxy]-phenyl}benzenesulfonamide It was produced analogously to example 12 except that iodoethane was used instead of iodomethane in step a).
i' ti I I IM M MW 45 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. Fp.: 122 0 C. MS m/e =335.
c) N-Ethyl-N-{3-[ (pyridin-4-ylaminocarbonyl) -methoxy] phenyl}-benzenesulfonamide. MS m/e 411.
d) Title compound as an oil. MS m/e 397.
Example 14 N-Propyl-N-{3-F2-(pyridin-4-ylamino) -ethoxyl-phenyl,benzenesulfonamide It was produced analogously to example 12 except that iodopropane was used instead of iodomethane in step a).
a) N-Propyl-N- (ethoxycarbonyl) -methoxy] -phenyl} benzenesulfonamide as an oil. MS m/e 377.
b) N-Propy2.-N-{3-( (carboxy) -methoxy] -phenyl}benzenesulfonamide. Fp.: 147 0 C. MS m/e =349.
c) N-Propyl-N-{ 3-f (pyridin-4-ylaminocarbonyl) methoxy] -phenyl}-benzenesulfonamide. Fp. 105 0
C.
MS m/e 425.
d) Title compound as an oil. MS m/e =411.
46 Example N-Benzvl-N-13-r2- (pyridin-4-ylamino) -ethoxyl -phenyl}benzenesulfonamide It was produced analogously to example 12 except that benzyl bromide was used instead of iodomethane in step a).
a) N-Benzyl-N-{ 3- [(ethoxycarbonyl) -methoxy] -phenyl} benzenesulfonamide as an oil. MS m/e 425.
b) N-Benzyl-1-1-3-[ (carboxy) -methoxy] -phenyl}benzenesulfonamide. Fp.: 190 0 C. MS m/e 397.
c) N-Benzyl-N-{3- [(pyridin-4-ylaminocarbonyl) methoxy] -phenyl}-benzenesulfonamide. Fp. 140 0
C.
MS m/e =473.
d) Title compound. Fp.: 128 0 C. MS m/e 459.
Example 16 N-Allvl-N-O 3- (pyridin-4-vlamino) -ethoxvl -phenyllbenz enesul fonamide It was produced analogously to example 12 except that allyl bromide was used instead of iodomethane in step a).
a) N-Allyl-N-{3-[ (ethoxycarbonyl) -methoxy] -phenyl}benzenesulfonamide as an oil. MS m/e 375.
I -47b) N-Allyl-N-{ 3- [(carboxy) -methoxy] -phenyl} benzenesulfonamide. MS m/e 347.
c) N-Allyl-N-{3-[ (pyridin-4-ylaminocarbonyl) -methoxy] phenyl}-benzenesulfonamide. MS m/e =423.
d) Title compound as an oil. MS m/e =409.
Example 17 N-f 5-Methyl-3- F2- (Pyridin-4-vlamino) -ethoxyl -phenyllbenzenesulfonamide hydrochloride It was produced analogously to example 12 except that in step a) benzenesulfonyl chloride was used instead of 2-naphthalenesulfonyl chloride and phenoxyacetic acid ethyl ester insteaa of 3-aminophenoxyacetic acid ethyl ester.
Intermediate steps: 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. Fp.: 156 159 0 C. FAB-MS: M+H 322.
c) N-{5-Methyl-3-[ (pyridin-4-ylaminocarbonyl) methoxy] -phenyl}-benzenesulfonamide. Fp.: 193- 196 0 C. MS m/e =397.
48 d) Title compound. Yield 56 Fp. 170 0
C.
MS m/e 383.
Example 18 Benzenesulfonic acid-3-r2-(pyridin-4-ylamino)-ethoxylphenyl ester a) 0.44 g (u.011 mol) sodium hydride (60 in white oil) is added to 2.5 g (0.01 mol) benzenesulfonic acid-3-hydroxyphenyl ester in 30 ml acetonitrile while cooling at 10 0 C and it is stirred for 1 hour at this temperature. 2.2 ml (0.02 mol) ethyl bromoacetate in 10 ml acetonitrile is added dropwise within 30 minutes and it is stirred for 3 hours at room temperature. After addition of 5 ml isopropanol, the solvent is removed in a vacuum.
ml ethanol, 50 ml water and 0.8 g (0.015 mol) potassium hydroxide are added to the residue. After 16 hours at room temperature, the ethanol is removed in a vacuum and the aqueous solution is extracted three times with ether. The aqueous phase is acidified with hydrochloric acid and extracted with ether. The ether is removed in a vacuum and g (48 2-[3-(phenylsulfonyloxy)-phenyloxy]acetic acid with a Fp. of 152 155 0 C is obtained.
b) 1.4 g (4.5 mmol) of this compound and 958 mg (5.9 mmol) carbonyldiimidazole are stirred for minutes at 45 0 C. 0.64 g (6.8 mmol) 4-aminopyridine is added and it is stirred for two days at 0 C. The solvent is removed in a vacuum and the resid e is dissolved in ethyl acetate which contained 0.5 acetic acid. The organic phase is -v 49 dried, filtered and the solvent is removed in a vacuum. The residue is ground with ether, filtered and 1.8 g (94 N-(4-pyridinyl)-2-[3-(phenylsulfonyloxy)-phenyloxy]-acetamide of Fp. 127 130 0 C is obtained.
c) 2.23 ml (18 mmol) chlorotrimethylsilane is added at 0 C to 192 mg (8.8 mmol) lithium borohydride in ml dry tetrahydrofuran while cooling in an ice bath. After 30 minutes 1.7 g (4.4 mmol) of the compound from step b) is slowly added at 5 0 C. After 16 hours at room temperature it is decomposed with 3 ml methanol and the solvent is removed in a vacuum. The residue is taken up in ethyl acetate and bicarbonate solution. The ethyl acetate phase is purified on a silica gel column (ethyl acetate /methanol The solvent is removed in a vacuum and 1.3 g of the title compound (80 is obtained as a viscous oil. FAB-MS: M+H 371.
Example 19 N-Methvl-N-phenyl-3-[2-(pyridin-4-ylamino)-ethoxy]benzenesulfonamide a) 3-Nitrobenzenesulfonic acid-N-methyl-anilide g 3-nitrobenzenesulfonic acid-chloride is dissolved in 20 ml absolute pyridine and 2.7 ml N-methylaniline is added while cooling on ice and stirring. It is stirred for a further 2 hours at room temperature, the reaction mixture is poured onto ice water and acidified with dilute hydrochloric acid. The aqueous phase is extracted with ethyl acetate, the ethyl acetate phase is
I
50 dried over sodium sulfate and evaporated. The residue is recrystallized from alcohol. Yield: 6.3 g. Fp. 90 0
C.
b) 3-Aminobenzenesulfonic acid-N-methyl-anilide 6 g 3-nitrobenzenesulfonic acid-N-methylanilide is dissolved in 100 ml absolute tetrahydrofuran and hydrogenated after addition of 0.5 g Pd/C (10 catalyst. After the calculated amount of hydrogen has been taken up, it is filtered from the catalyst and the filtrate is concentrated by evaporation.
Yield: 5.5 g. Fp. 104 0
C.
c) 3-Hydroxybenzenesulfonic acid-N-methyl-anilide g 3-aminobenzenesulfonic acid-N-methylanilide is dissolved in 20 ml 50 sulphuric acid. A solution of 1.75 g sodium nitrite in 5 ml water is added dropwise to this while cooling on ice and stirring.
When the diazotization is completed, the reaction mixture is heated for 20 minutes to 100 0 C, it is allowed to cool and extracted with ethyl acetate.
The ethyl acetate phase is dried over sodium sulfate and evaporated. The residue is sufficiently pure for further processing.
d) [3-(Methyl-phenvl-sulfamoyl)-phenoxyl-acetic acid ethyl ester g 3-hydroxybenzenesulfonic acid-N-methylanilide is dissolved in 20 ml absolute dimethylformamide.
2 g potassium carbonate and 1.9 ml ethyl bromoacetate are added to this and the mixture is heated for 3 hours to 100 0 C. It is cooled and the solvent is removed by distillation in a vacuum. The i I- 51 residue obtained (4.3 g) is sufficiently pure for further processing.
e) [3-[Methyl-phenyl-sulfamoyl)-phenoxy]-acetic acid 4.2 g [3-[methyl-phenyl-sulfamoyl)-phenoxy]-acetic acid ethyl ester is dissolved in 40 ml ethanol. 1 g potassium hydroxide is added to this and the mixture is stirred for one hour at 90 0 C. It is cooled to room temperature, acidified with dilute hydrochloric acid and extracted with methylene chloride. The methylene chloride phase is dried over sodium sulfate and evaporated. 4 g [3-[methylphenyl-sulfamoyl)-phenoxy]-acetic acid is obtained as an amorphous solid.
f) 2-r3-(Methyl-phenyl-sulfamoyl)-phenoxyl-N-pyridin- 4-yl-acetamide 2 g [3-(methyl-phenyl-sulfamoyl)-phenoxy]-acetic acid is dissolved in 20 ml absolute tetrahydrofuran. 1.35 g carbonyldiimidazole is added to this and the mixture is heated for 20 minutes to 45 0
C.
It is cooled to room temperature, 900 mg 4-aminopyridine is added and it is stirred for a further 3 hours at 600C. The solvent is removed by distillation, the residue is dissolved in ethyl acetate and extracted by shaking with water. The ethyl acetate phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column for purification (eluting agent: methylene chloride/ methanol After evaporating the column fractions, 1.5 g of the title compound is obtained as an amorphous solid.
FAB-MS: M+H 398.
4 k r v -1 i i- I i r I -52 g) N-Methyl-N-phenyl-3- 2-(pyridin-4-ylamino-ethoxy]benzenesulfonamide 800 mg 2-[3-(methyl-phenyl-sulfamoyl)-phenoxy]-Npyridin-4-yl-acetamide is dissolved in 15 ml absolute tetrahydrofuran. 320 mg lithium aluminium hydride is added under nitrogen and the mixture is subsequently heated for one hour to reflux temperature. It is cooled and saturated ammonium sulfate solution is added to the reaction mixture.
Insoluble material is removed by suction filtration, the filter residue is washed with ether, the filtrate is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column for purification (eluting agent: methylene chloride/methanol After evaporating the column fractions, 420 mg of the title compound is obtained as an amorphous substance. FAB-MS: M+H 384.
Example N-Benzyl-N-phenyl-3-r2-(pyridin-4-vlamino)-ethoxy]benzenesulfonamide The title compound was prepared analogously to example 19 except that N-benzylaniline was used in step a) instead N-methylaniline. Amorphous substance. FAB-Mb; 4+H 460.
T P T ISr 53 Example 21 N-Phenyl-3- F2- (pyridin-4-vlamino) -ethoxyl benz enesulfonamide 300 mg N-benzyl-N-phenyl-3-[2- (pyridin-4-ylamino) ethoxy]-benzenesulfonamide (example 20) is dissolved in 20 ml methanol and hydrogenated after addition of 100 mg pd/c (10 catalyst. After the uptake of hydrogen has ceased, the catalyst is removed by filtration and it is evaporated. 240 mg of the title compound is obtained as an amorphous substance. FAB-MS: M+H 370.
Example 22 N-IMethyl-N-pyridin-2-yl-3-rF2- (pvridin--4-ylamino) ethoxv 1-benz enesulfonamide The title compound was prepared analogously to example 19 except that N-methyl-2-aminopyridine was used in step a) instead of N-methylaniline.
Amorphous substance. FAB-MS: M+H 385.
Example 23 N-13-[2-(Pvridin-4-ylamingi -ethoxyl-phenyll-2- Propanesulfonamide hydrochloride 2.88 ml (22.9 mmol) chlorotrimethylsilane was added dropwise to 0.26 g (11.4 mmol) LiBH 4 in 50 ml tetrahydrofuran, it was stirred for 5 minutes at room temperature and 2.00 g (5.72 mmol) N-13- I I 54 [(pyridin-4-ylaminocarbonyl)-methoxy]-phenyl}-2propanesulfonamide was added in portions which had been prepared analogously to example 1. It was boiled for 30 minutes under reflux, 20 ml methanol is carefully added dropwise after cooling followed by 30 ml 2 N sodium hydroxide solution. The solvent was mostly removed in a vacuum and it was extracted with methylene chloride. It was dried, the solvent was removed in a vacuum and ethereal hydrochloric acid was added to the residue. The solvent was removed in a vacuum, the residue was ground with tert.butylmethyl ether and 1.5 g (70 of the title compound was obtained of Fp. 204 207 0
C.
Example 24 N-{3-r2-(Pyridin-4-ylamino)-ethoxy]-phenvl}cyclopentanesulfonaimide hydrochloride was produced analogously to example 23. Fp. 129 134 0
C.
Example N-Methvl-N-{3-[2-(pyridin-4-ylamino)-ethoxy]-phenyl}-4fluorophenylsulfonamide hydrochloride was produced analogously to example 23. Fp. 140 1430C.
t 1 55 Example 26 N-j3-F2- (Pyridin-4-y1 mino) -ethoxyl -phenyllbenz enesul fonamide was produced analogously to example 1. Oil;- MS: [El] 383.
Example 27 N-13 -r2- (Pyv idin-4 ilamino)-ethoxyl-phenl 1tert .butylbenzenesulfonamide was produced analogously to example 1. oil.
MS: [EI] 425.
Example 28 N-1 -[2-(Pvridin-4-ylamino)-ethoxyl-phenyll-l.2,3,4tetrahvdronaphthalene-6-sulfo-hamide was produced analogously to example 23. Fp. 235 237 0
C.
Extample 29 N-{3-rF2- (Pvridin-4-vlamino) -ethoxyl sulfonamide was produced analogously to example 23 as a free base.
Fp. 140 0 C (decomp.).
/2 ri I 56 Example N-13- r2- (Pvridin-4-vlamino) -ethoxyl -phenyl}-2biphenylsulfonamide was produced analogously to example 23 as a free base.
Fp. 214 2l6 0
C.
Example 31.
N-Methyl -N-{5-methyl-3-F2- (Pyridin-4-ylamino) -ethoxyl pheiijz-l-4fluorobenzenesulfonamide hydrochloride was produced analogously to example 23. Fp. 122 12900.
The starting material N-{5-methyl-3-[ (pyridin-4-ylaminocarbonyl) -methoxy] -phenyl} -4-f luorobenzene-sulfonamide (MS m/e 429) was produced analogously to example 17.
Example 32 N-T 5-Methvl-3- r 2- Drdn4yaio-ehxlpeyl2 chloro-4-fluorobenzenesulfonamide hydrochloride was produced analogously to example 23. Fp. 198 2000C.
The starting material N-{5-methyl-3-[ (pyridin-4--ylaminocarbonyl) -methoxy] -phenyl} -2-chloro-4-fluorobenzenesulfonamide (MS m/e =449) was produced analogously to example 17.
.0 57 Example 33 5-methyl-3-r2- (pridin-4-ylamino) -ethoxyl Phenvl I-2-trifluorobenzenesulfonamide hydrochloride was produced analogously to example 23. Fp. 203 207 0
C.
The starting material N-{5-methyl-3-f (pyridin-4-ylaminocarbonyl) -methoxy] -phenyl}-2-chloro-4-fluorobenzenesulfonamide (MS m/e 479) WdS, produced analogously to example 17.
Example 34 N-f 5-Methyl-3- r2- (pyridin-4-ylamino) -ethoxyl -phenyll-2-.
methylbenzenesulfonamide hydrochloride was produced analogously to example 23. Fp. 135 0
C
(decomp.). The starting material N-{5-methyl-3- (pyridin-4-ylaminocarbonyl) -methoxy]-pheniyl}-2methylbenzene-sulfonamide (MS m/e 411) was produced analogously to example 17.
Example 1ZS 5-methyl-3-r2- (pyridin-4-ylamino) -ethoxyl phenyll -2-methyl-4-fluorobenzenesuloflamide hydrochloride was produced analogously to example 23. Fp. 1460C. The starting material N-methyl-N-{5-methyl-3-[(pyridin-4ylaminocarbonyl) -methoxy] -phenyl} -2-methyl-4-fluorobenzenesulfonamide (MS m/e 443) was produced analogously to example 17.
58 Example 36 N-{5-Methvl-3-r2-(pyridin-4-ylamino) -ethoxyl-phenvll.-2methyl-4-fluorobenzenesulfonamide hydrochloride was produced analogously to example 23. Fp. 193 0 C. The starting material N-{5-methyl-3-[ (pyridin-4-ylaminocarbonyl) -methoxy] -phenyl} -2-methyl-4-fluorobenzenesulfonamide (MS m/e =429) was produced analogously to example 17.
Example 37 N-15-Methyl-3-r2-(pvridin-4-vlamino) -ethoxyl-phenvl -2luorobenzenesulfonamide hydrochloride was produced analogously to example 23. Fp. 246 247 0
C.
The starting material N'-{-methyl-3-[ (pyridin-4-ylaminocarbonyl) -methoxy] -phenyl} -2-methyl-5-f luorobenzenesulfonamide (MS m/e 429; Fp. 211 213 0 C) was produced analogously to example 17.
Example 38 N-Methyl-N-f S-methyl-3-[2- (Pyridin-4-vlamino) -ethoxyl iphenvll~-2-methyl-S-f luorobenzenesulfonamide hydrocloride was produced analogously to example 23. Fp. 165 1660C.
The starting material N-methyl-N-{5-methyl-3-[ (pyridin- 4-ylaminocarbonyl) -methoxy] -phenyl} -2-methyl-S-f luorobenzenesulfonamide (MS m/e =443) was produced analogously to example 17.
59 Example 39 N-f 5-Methyl-3-r2-(pyridin-4-yvlaminio) -ethoxyl-phenyl- 2,4-difluorobenzenesulfonamide hydrochlo:ride was produced analogously to example 23. Fp. 227 228 0
C.
The starting material N-{5-methyl-3- [(pyridin-4-ylaminocarbonyl) -methoxy] -phenyl} 4-difluorobenzenesulfonamide (MS m/e 433; Fp. 194 0 C) was produced analogously to example 17.
Example N-f 5-Methvl-3-r2-(pvridin-4-vlamino) -ethoxvl-pohenlr- 3,.5-dimethyl-4-pyrazolesulfonamide was produced analogously to example 23 as a free base.
Fp. 121 0 C. The starting material N-{5-inethyl-3- (pyridin-4-ylaminocarbonyl) -methoxy] -phenyl}-3 dimethyl-4-pyrazolesulfonamide (MS m/e 415) was produced analogously to example 17.
Example 41.
N-f5-Methyl-3-r2-(pvridin-4-vlamino) -ethoxyl-pohenylr-4fluorobenzenesulfonamide hydrochloride was produced analogously to example 23. Fp. 232 0 C. The starting material N-{5-methyl-3-[ (pyridin-4-ylaminocarbonyl) -methoxy] -phenyl}-4-fluorobenzenesulfonamide (MS m/e =415; Fp. 156 159 0 C was produced analogously to example 17.
60 Example 42 N-{5-Methyl-3-f2-(poyridin-4-ylamino) -ethoxvl-phenvUl-2fluorobenzenesulfonamide hydrochloride was produced analogously to example 23. Fp. 2630C. The starting material N-{5-methyl-3-[ (pyridin-4-ylaminocarbonyl) -methoxy] -phenyl}-2-fluorobenzenesulfonamide (MS m/e =415) was produced analogously to example 17.
Example 43 N-{5-Methvl-3-r2-(pyridin-4-vlamino) -ethoxvl-phenvJ--2trifluoromethylbenzenesulfonamide hydrochloride was produced analogously to example 23. Fp. 217 222 0
C.
The starting material N-{5-methyl-3-[ (pyridin-4-ylaminocarbonyl) -methoxy] -phenyl} -2-trifluoromethylbenzenesulfonamide (MS m/e =465) was produced analogously to example 17.
Example 44 N-Methvl-N-{ 5-methyl-3-rF2- (Dvridin-4-ylamino) -ethoxyl Phenvl} -4-methylbenzenesulfonamide hydrochloride was produced analogously to example 23. Fp. 1800C. The starting material N-methyl-N-{5-methyl-3-[ (pyridin-4ylaminocarbonyl) -methoxy] -phenyl} -4-methylbenzenesulfonamide (MS m/e =425) was produced analogously to example 17.
4 4 61 Example N-15-Methvl-3-[2- (]yridin-4-vlamino) -ethoxvl-phenyll- 2,6-difluorobenzenesulfonamide hydrochloride was produced analogously to example 23. Fp. 263 0 C. The starting material N-{5-methyl-3-[ (pyridin-4-ylaminocarbonyl) -methoxy] -phenyl}-2, 6-difluorobenzenesulfonamide (MS m/e =433; Fp. 234 242 0 C) was produced analogously to example 17.
Example 46 N-15-Methvl-3-r2- (pyridin-4-vlamino) -ethoxyl-phenyl) -2hvydroxv-3-ter-t. hydrochloride a) 50 ml (100 mmol) 2 N sodium hydroxide solution was added to 27.2 g (87.0 mmiol) (3-tert.butyloxy- -acetic acid ethyl ester (example 57b) in 300 ml methanol and stirred for 3 clays at room temperature. The solvent was partially removed in a vacuum, it was extracted with ethyl acetate, the aqueous phase was acidified with hydrochloric acid and extracted with ether. It was dried ai-- the solvent was removed in a vacuum.
15.6 g (3-tert. phenoxy) -acetic acid is obtained of Fp. 120- 122 0
C.
b) This compound was reacted with 4-aminopyridine as described in example lc) and one obtained N-(4- -62 pyridinyl) phenoxy)-acetamide of Fp. 204 205 0
C.
c) 25 ml trifluoroacetic acid was added to 5.00 g (14.0 mmol) of this compound, stirred for minutes at room temperature, it was made alkaline with sodium hydroxide solution and the precipitate was filtered by suction. 2.93 g (78 N-(4-pyridinyl)-3-.(amino-5-methylphenoxy)-acetamide of Fp. 163 0 C was obtained.
d) This compound was reduced as described in example 23 and 3-[2-(pyridin-4-ylamino)-ethoxy]-5-methylaniline was obtained in a 50 yield of Fp. 208 0
C.
e) This compound was reacted with 2-hydroxy-3chloride as described in example la) and the title compound was obtained. Amorphous. MS FAB: 470.
Example 47 N-{5-Methyl-3- f2-(pvridin-4-ylamino)-ethoxyl -phenyll-3benzothiophene-sulfonamide hydrochloride was produced analogously to example 46. For this the compound obtained in example 46d) was reacted with benzothiophene-3-sulfonyl chloride. Fp. 130 0 C (decomp.).
'4i- 63 Example 48 N-{5-Methyl-3-r2-(pyridin-4-vlamino)-ethoxy -phenyl}benzo-2,3,l-thiadiazole-4-sulfonamide hydrochloride was produced analogously to example 46. For this the compound obtained in example 46d) was reacted with benzo-2,3,l-thiadiazole-4-sulfonyl chloride. Fp. 110 0
C.
Example 49 N-f5-Methoxy-3-F2-(pyridin-4-vlamino)-ethoxy -phenyl}-4fluorobenzenesulfonamide hydrochloride a) 16.0 g (115 mmol) 3-hydroxy-5-methoxyphenol (G.
Rodighiero, C. Antonello, Il Farmaco, Ed. Sci. 889 896, (1955)), 3.7 g ammonium chloride, 13.8 ml water and 24 ml concentrated ammonia were heated in a 100 ml autoclave for 12 hours to 130 0
C.
After cooling, the contents of the autoclave were rinsed out with methanol, the solvent was removed in a vacuum, the residue was triturated with ethyl acetate, insoluble material (6.5 g) was removed by filtration, the solvent was removed in a vacuum, the oily residue was applied to a nutsch filter with silica gel and rewashed with heptane/ethyl acetate 1:1. The solvent of the filtrate was removed and 10.4 g 3-hydroxy-5-methoxyaniline was obtained as a red oil.
b) This compound (10.4 g, 75.0 mmol) was acetylated in 100 ml methylene chloride in the presence of 0.1 g 4-dimethylaminopyridine with 100 ml acetic ol j 11 1 ID_ I_ S. 64anhydride for 12 hours at room temperature. The solvent was removed in a vacuum, 200 ml methanol and 20 ml saturated sodium carbonate solution was added to the residue (mainly diacetyl compound) and it was stirred for 3 hours at room temperature. The solvent was removed in a vacuum, 250 ml water was added, it was acidified with concentrated hydrochloric acid and extracted with ethyl acetate.
Removal of the solvent yielded 11 g (81 N-(3of Fp. 126°C.
c) This compound (11.0 g, 61.0 mmol) was alkylated in 100 ml dry dimethylformamide in the presence of 9.1 g (65 mmol) potassium carbonate with 6.9 ml mmol) ethyl chloroacetate for 8 hours at 60 0
C.
It was diluted with water, acidified with hydrochloric acid and extracted with ethyl acetate.
The organic phase was extracted with water, the organic phase was dried over magnesium sulfate, filtered and the solvent was removed in a vacuum.
10.8 g (66 2-(3-acetamido-5-methoxy-phenoxy)acetic acid ethyl ester was obtained as an oil.
d) This compound (10.8 g, 40 mmol) in 70 ml ethanol was stirred for 4 hours with 30 ml 2 N sodium hydroxide solution, the solvent was removed in a vacuum, water was added and it was acidified. The precipitate (5.5 g carboxylic acid) was filtered by suction, dissolved in 50 ml ethanol, 50 ml 10 N sodium hydroxide solution was added and boiled for 8 hours under reflux. It was acidified with concentrated hydrochloric acid, the solvent was removed in a vacuum, 100 ml methanol was added and it was stirred for 12 hours at room temperature.
The solvent was removed in a vacuum, it was m I I' 'f 65 digested with ethyl acetate, filtered by suction and 5.6 g 2-(3-amino-5-methoxy-phenoxy)-acetic acid methyl ester was obtained (MS, m/e 211).
e) 2-[3-(4-Fluorobenzenesulfonylamino)-5-methoxyphenoxy)-acetic acid methyl ester (MS m/e 369) was obtained from this as an oil by reaction with 4-fluorobenzenesulfonyl chloride as described in example la).
f) 2-[3-(4-Fluorobenzenesulfonylamino)-5-methoxyphenoxy)-acetic acid of Fp. 161 0 C was obtained from this in a yield of 95 as described in example Ib).
g) N-(4-Pyridinyl)-2-[3-(4-fluorobenzenesulfonylof Fp. 1610C was obtained from this in a yield of 58 as described in example Ic).
h) The title compound of Fp. 62 0 C was obtained from this in a yield of 76 as described in example 23.
Example N-{3-r2-(Pyridin-4-ylamino)-ethoxyl-phenyll-2chlorobenzenesulfonamide was produced analogously to example 1 in a yield of 58 Melting point 221 223 0
C.
I- I 66 Example 51.
N-Methyl-N-3-f2- (pvridin-4-ylamino) -ethoxyl -phenyll-2chlorobenz enesul fonamide was produced analogously to example 12 in a yield of 22 Melting point 188 190 0
C.
ExaMple 52 N-2-Propyl-N-{3-r2- (Pvridin-4-vlamino)-ethoxyl-phenyllbenzenesulfonamide was produced analogously to example 12 in a yield of 47 Oil. MS 411.
Example 53 N-Methyl-N-f3-[2- (pvridin-4-ylamino) -ethoxyl-phenvll-2thiophenesulfonamide was produced analogously to example 12 in a yield of 12 Melting point 179 181 0
C.
Examp1e 54 N-{5-Methyl-3-r2-(pyridin-4-lamino)-ethoxyl-P-henyll-lnaphthalenesulfonamide hydrochloride was produced analogously to example 17 in a yield of 14 Melting point 215 218 0
C.
67- Example N-{5-Methyvl-3-F2- (pridi-4ylanino) -ethoxyl -phenyll-2thiophenesulfonamide hydrochloride was produced analogously to example 17 in a yield of 24 Melting point 252 254 0
C.
Example 56 N-{5-Methyl-3-F2-(pyridin-4-vlamino -ethoxyl-phenvll-2chlorobenzenesulfonamide hydrochloride was produced analogously to example 17 in a yield of 42 Melting point 254 2580C.
Example 57 N-Methyl-N-{5-methyl-3-F2- (pvridin-4-vlamino) -ethoxyl Phenyl}-l-chlorobenzenesulfonamide hydrochloride a) 96 g (0.78 mol) 3-hydroxy-5-methyl-aniline (F.
Wessely, H. Eibel, G. Friedrich, "Monatshefte Chem.
83, 24 30, (1952)) in 1.2 1 diLuxane and 840 ml water was admixed with 420 ml 2 N sodium hydroxide solution and with 171 g (0.78 mol) ditert.butyldicarbonate while cooling on ice. It was stirred for 12 hours at room temperature, the solvent was removed in a vacuum, it was acidified to pH 2 3 while cooling on ice and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered and the solvent was removed in a vacuum. 174 g (quantitative) N-(tert.butyloxy-
L
68 was obtained as an oil. MS 223.
b) 132 g (0,59 mol) of this compound in 400 ml dry dimethylformamide, 90 g (0.65 mol) potassium carbonate and 69 ml (0.65 mol) ethyl chloroacetate were heated for 3 hours to 70 0 C. It was poured into 1 1 ice water, extracted wi'oh ethyl acetate, the organic phase was dried over sodium sulfate, filtered and the solvent was removed in a vacuum.
174 g (95 2-(3-tert.butyloxycarbonyl-amino-5methyl-phenoxy)-acetic acid ethyl ester was obtained as an oil. MS 309.
c) 174 g (0.562 mol) of this compound was admixed with 200 ml trifluoroacetic acid while cooling on ice, it was stirred for 2 hours at room temperature and the solvent was removed in a vacuum. 2 N hydrochloric acid was added to the residue, it was extracted with ethyl acetate, the aqueous phase was made alkaline with sodium hydroxide solution and it was extracted with ethyl acetate. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in a vacuum. 87.5 g (74 2-(3-amino-5-methyl-phenyloxy)-acetic acid ethyl ester was obtained as an oil. MS 209.
d) As described in example 17a), this compound was reacted with 2-chlorobenzenesulfonyl chloride and 2-[3-(2-chlorobenzenesulfonylamino)-5-methylphenoxy]-acetic acid ethyl ester of Fp. 133 137 0
C
was obtained in a yield of 56 r r I I 69 e) This compound was methylated as described in example 12a) and N-methyl-2-[3-(2-chlorobenzeneacid ethyl ester was obtained in a quantitative yield. Oil.
MS 398, f) This compound was saponified as described in example Ib) and N-methyl-2-[3-(2-chlorobenzeneacid was obtained in a quantitative yield. Fp. 113 115 0
C.
g) This compound was reacted with 4-aminopyridine as described in example Ic) and 2-{3-[(2-chloropyridin-4-yl-acetamide was obtained as an oil in a yield of 68 h) This compound was reduced a= described in example Id) and the title compound was obtained in a yield of 41 Fp. 213 215 0
C.
Example 58 N-Methyl-N--5-methyl-3-F2-(pyridin-4-ylamino)-ethoxy]phenyl}-benzenesulfonamide hydrochloride The compound from example 57 (0.86 g, 2 mmol) was hydrogenated in 30 ml ethanol in the presence of 0.3 g palladium on carbon at room temperature and normal pressure. Hydrogen uptake 55 ml. It was filtered and the solvent was removed in a vacuum. It was digested with ether and 0.75 g (86 of the title compound was obtained of Fp. 182 184 0
C.
70 Example 59 N-{2-Methoxy-5-[2-(pyridin-4-vlamino)-ethoxy]-phenyl}benzenesulfonamide a) 8.4 g (50 mmol) ethyl bromoacetate was added dropwise in an ice bath to 8.5 g (50 mmol) 2-hydroxy-4-nitroanisole and 13.8 g (100 mmol) potassium carbonate in 120 ml acetonitrile. It was stirred for 12 hours at room temperature, the solvent was removed in a vacuum, water was added to the residue and it was extracted with ethyl acetate. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in a vacuum. 12.7 g (quantitative) 2-(2-methoxy-5-nitrophenoxy)-acetic acid ethyl ester was obtained as an oil. MS 255.
b) This compound (12.1 g, 47 mmol) was hydrogenated in 300 ml methanol in the presence of 5 g Raney nickel at normal pressure and room temperature. When 3.4 1 hydrogen had been taken up, it was filtered and the solvent was removed in a vacuum. 10.7 g (quantitative) 2-(2-methoxy-5-amino-phenoxy)-acetic acid ethyl ester was obtained as an oil. MS 225.
c) This compound (10.7 g, 47 mmol) was reacted with benzenesulfonyl chloride as described in example la) and 17.2 g (quantitative) 2-(2-methoxy-5benzenes;ulfonylamino-phenoxy)-acetic acid ethyl ester was obtained. MS 413.
t l i 1 1 1 yrg 1 1 _I 71 d) Following the instructions of example Ib), 11.8 g (74 2-(2-methoxy-5-benzenesulfonylaminophenoxy)-acetic acid was obtained from this compound. MS 337.
e) Following the instructions of example Ic), 5 g N-(4-pyridinyl)-2-(2-methoxy-5benzenesulfonylamino-phenoxy)-acetamide of Fp. 179 0 C was obtained from this compound.
f) Following the instructions of example 23, the title compound of Fp. 188 189 0 C was obtained from this compound.
Example N-f2-Methyl-5-[2-(pyridin-4-ylamino)-ethoxyl-phenyl}benzenesulfonamide was produced analogously to example 59 except that in step a) 2-hydroxy-4-nitrotoluene was used instead of 2-hydroxy-4-nitroanisole. This precursor was prepared as follows: 100 g 2-amino-4-nitrotoluene was stirred into 300 ml concentrated sulphuric acid at 50 0 C, until it was all dissolved (30 min), 2.5 kg ice was added, it was cooled to -15 0 C and a solution of 50 g sodium nitrite in 200 ml water was added dropwise in such a way that the temperature did not exceed 0 C. This solution was added to a mixture of 500 ml concentrated sulphuric acid and 1 1 water which was boiling under reflux. It was boiled for 1 hour under reflux, allowed to stand for 12 hours and the precipitate was filtered by suction. 87.1 g (87 2-hydroxy-4-nitrotoluene of Fp. 117-120 0 C was obtained.
I I LI l I sl I I- 72 a) 2-(2-Methyl-5-nitro-phenoxy)-acetic acid ethyl ester as an oil. MS 239.
b) 2-(2-Methyl-5-amino-phenoxy)-acetic acid ethyl ester as an oil. MS 209.
c) 2-(2-Methyl-5-benzenesulfonylamino-phenoxy)-acetic acid ethyl ester. Fp. 78 83 0
C.
d) 2-(2-Methyl-5-benzenesulfonylamino-phenoxy)-acetic acid. Fp. 157 160 0
C.
e) N-(4-Pyridinyl)-2-(2-methyl-5-benzenesulfonylaminophenoxy)-acetamide of Fp. 157 161 0
C.
f) Title compound of Fp. 179 180 0
C.
Example 61 Benzenesulfonic acid-5-methyl-3- 2-(pyridin--4-vlamino)ethoxy]-phenyl ester a) 7.1 g (50 mmol) 5-methyl-resorcinol, 10 g (100 mmol) potassium bicarbonate and 12.6 g mmol) benzyl bromoacetate were boiled in 70 ml acetonitrile for 24 hours under reflux. The solvent was removed in a vacuum, water was added to the residue and it was extracted with ether, the ether phase was extracted three times with 0.1 N sodium hydroxide solution, the ether phase was dried over sodium sulfate, filtered and the solvent was removed in a vacuum. The residue (7.75 g) was separated on silica gel with isohexane/ethyl 73 acetate and 4.0 g (29 2-(3-hydroxy-5methyl-phenoxy)-acetic acid benzyl ester was obtained as an oil. MS 272.
b) 2.0 g (7.5 mmol) of this compound was reacted with benzenesulfonyl chloride analogously to example la) and 2.1 g (68 2-(3-benzenesulfonyloxy-5-methylphenoxy)-acetic acid benzyl ester was obtained as an oil. MS 412.
c) 2.0 g (5 mmol) of this compound in 150 ml methanol was hydrogenated in the presence of 0.5 g 10 palladium on carbon for 1 hour at room temperature and normal pressure until 140 ml hydrogen had been taken up. It was filtered, ether was added and extracted three times with a sodium bicarbonate solution. The sodium bicarbonate solution was acidified with 2 N sulphuric acid, extracted with ether, dried, the solvent was removed in a vacuum and 600 mg (38 2-(3-benzenesulfonyloxy-5-methylphenoxy)-acetic acid was obtained. MS 322.
d) 0.6 g (2 mmol) of this compound was reacted with 4-aminopyridine analogously to example Ic) and N-(pyridin-4-yl)-2-(3-benzenesulfonyloxy-5-methylphenoxy)-acetamide was obtained (16 MS 392.
e) The title compound was obtained from this analogously to example 23. Fp. 144 1460C.
74 EXaMple 62 2-Chlorobenzenesulfonic acid-5-methvl-3-[2- (pyridin-4vlamino) -ethoxyl--phenVi ester was produced analogously to example 61. Fp. 156 158WC.
Intermediate steps: 2- (2-Chlorobenzenesulfonyloxy) methyl-phenoxy]-acetic acid: Fp. 157 1610C.
N-(Pyridin-4-yl) -2-[3-(2-chlorobenzenesulfonyloxy) methyl-plhenoxy]-acetamide. MS 432.
Example 63 4-Fluorobenzenesulfonic acid-5-methyl-3-rF2- (pvridin-4viamino) -ethoxvl -phanvl ester was produced analogously to example 61 except that in step b) 4-fluorobenzenesulfonyl chloride was used.
Fp. 161 1630C.
Example 64 1-Naphthalenesulfonic acid-5-methyl-3-r2- (Pvridin-4ylamino)J-ethoxyl -phenyl ester was produced analogously to example 61 except that in step b) 1-naphthalenesulfonyl chloride was used.
Fp. 95 99WC.
75 Example 2-Thiophenesulfonic acid-5-methyl-3-[2-(pyridin-4vlamino)-ethoxyl-phenyl ester a) 24.8 g (200 mmol) 5-methylresorcinol, 43.8 g (240 mmol) 2-thiophenesulfonyl chloride and 1.5 q solid sodium bicarbonate in 200 ml water were covered with a layer of 100 ml ether and the pH was kept constant at 7.2 with a dosing apparatus using saturated sodium bicarbonate solution. It was stirred for 12 hours -t room temperature at pH 7.2, the water plase was separated, the etaitr phase was dried with sodium sulfate, it was filtered and the solvent was removed in a vacuum.
Thiophenesulfonic ester was obtained in a quantitative yield as an oil. MS 270.
b) This compound was reacted with ethyl bromoacetate analogously to example 18a and 2-[3-(2-thiopheneacid ethyl ester was obtained. MS 356.
c) 2-[3-(2-Thiophenesulfonyloxy)-5-methyl-phenoxy]acetic acid was obtained from this compound analogously to example ib) of Yp. 142 143 0
C.
d) N-(Pyridin-4-yl)-2-[3-(2-thiophenesulfonyloxy)-5methyl-phenoxy]-acetamide was obtained from this compound analogously to example Ic). Fp. 136 138 0
C.
-;191 i 7 I 76 e) The title compound of Fp. 176 0 C was obtained from this compound.
Example 66 (2-Benzyloxvcarbonyl-benzenesulfonic acid)-5-methyl-3- [2-Cpyridin-4-ylamino)-ethoxyl-phenyl ester a) 5-Methylresorcinol was reacted analogously to example 61a) with ethyl bromoacetate and 2-(3acid ethyl ester was obtained as an oil. MS 210.
b) Analogously to example 61b), 2-[3-(2-benzyloxyacetic acid ethyl ester (MS 484) was obtained from this as an oil by reaction with 2-benzyloxy-carbonyl-benzenesulfonyl chloride.
c) This compound was saponified for 4 h at room temperature analogously to example Ib) and 63 2-[3-(2-benzyloxycarbonyl-benzenesulfonyloxy)-5methyl-phenoxy]-acetic acid was obtained.
MS 456.
d) N-(Pyridin-4-yl)-2-[3-(2-benzyloxycarbonylwas obtained from this. MS 532.
e) The title compound was obtained from this analogously to example 23. MS 518.
77 Example 67 (2-Carboxy-benzenesulfonic acid) -5-methyl-3-f2- (pyridin- 4-viamino) -ethoxyl -phenyl ester g (I mmol) of the compound from example 66 was hydrogenated in 100 ml methanolic ammonia solution in the presence of 1 g 10 palladium on carbon at normal pressure and room temperature. It was filtered, the solvent was removed in a vacuum, the residue was triturated with isopropanol, .it was filtered by suction and recrystallized from ethanol. 0.4 g (14 of the title compound of Fp. 189 0 C was obtained.
Example 68 (2-Methvl-benzenesulfonic acid) -5-methvl-3-f 2-(pvridin- 4-vlamino) -ethoxyl -phenyl ester was produced analogously to example 61. Fp. 152 1540C.
Precursor: N- (pyridin-4-yl) (2-methyl-benzenesulfonyloxy) -5-methyl-phenoxy] -acetamide. Fp. 158- 160 0
C.
Example 69 (2-Methoxy-benzenesulfonic acid) -5-methvyl-3-F2- (pvridin- 4-ylamino) -ethoxyl -phenyl ester was produced analogously to example 61. Fp. 116 119 0
C.
Precursor: N- (pyridin-4-yl) (2-methoxy-benzenesulfonyloxy) -5-methyl-phenoxy]-acetamide. Fp. 156- 159 0
C.
78 Example (2-Nitro-benzenesulfonic acid) -5-methvl-3-r2- (lovridin-4ylamino) -ethoxyl -phenyl ester was produced analogously to example 61. Fp. 137 140 0
C.
Precursor: N- (pyridin-4-yl) (2-nitrobenzenesulfonyloxy) -5-methyl-phenoxy] -acetamide.
MS 453.
Examp~le 71 (2-Axino-benzenesulfonic acid) -5-methyl-3- F2- (pyridin-4viamino) -ethoxyl -phenyl ester g (2.33 mmol) of the compound from example 70 was hydrogenated in 40 ml methanol in the presence of 1 g Raney nickel for 1.5 hours at room temperature and normal pressure. It was filtered, the solvent was removed in a vacuum, the residue was admixed with 25 ml tetrahydrofuran and 25 ml ether, extracted with 0.05 M sodium hydroxide solution, the organic phase was dried, filtered and t'.ie solvent was removed in a vacuum. 0.5 g (54 of the title compound of Fp. 168 171 0 C was obtained.
Example 72 2-Chlorobenzenesulfonic acid-5-methyl-3- r2- (N-methylpyridin-4-vlamino) -ethoxv] -phenyl ester a) N-Methyl-N- (pyridin-4-yl) (2-chlorobenzenesulfonyloxy) -5-methyl-phenoxy] -acetamide (MS (m/e) 79 447) was obtained by reacting acid with 4-methylamino-pyridine according to example 62.
b) The title compound of Fp. 152 161 0 C was obtained from this analogously to example 23.
Example 73 Benzenesulfonic acid-5-chloro-3-[2-(pyridin-4-vlamino)ethoxyl-phenyl ester a) 98.8 g (0.57 mol) 5-chlororesorcinol dimethyl ether and 108 ml (1.14 mol) boron tribromide in 400 ml methylene chloride were stirred for 72 hours at room temperature. It was extracted with water, the aqueous phase was extracted with n-butanol, most of the n-butanol was removed in a vacuum and it was allowed to crystallize for 12 hours at 4°C. 19.5 g (24 5-chlororesorcinol of Fp. 70 71 0 C was obtained.
b) 3.0 g (21 mmol) of this compound in 50 ml water was covered with a layer of 20 ml ether, saturated sodium bicarbonate solution was added until a pH of 5.2 was reached. 8.6 ml (21 mmol) benzenesulfonyl chloride was slowly added while keeping the pH constant, the pH was increased to 7.0 and it was stirred for 48 hours at room temperature while keeping the pH value constant. It was extracted with ether, the ether phase was extracted with 0.1 N sodium hydroxide solution, the sodium hydroxide solution was acidified with 2 N sulphuric I II l 80 acid and extracted three times with ether. The solvent was removed in a vacuum and 1.7 g (28 benzene-sulfonic ester was obtained. MS 284.
c) This compound was reacted with ethyl bromoacetate analogously to example 18a) and 2-[3-chloro-5- (phenylsulfonyloxy)-phenoxy]-acetic acid ethyl ester was obtained in a yield of 95 MS 370.
d) This compound was saponified analogously to example Ib) to obtain 2-[3-chloro-5-(phenylsulfonyloxy)phenoxy]-acetic acid of Fp. 136 138 0 C in a yield of 80 e) This compound was reacted with 4-aminopyridine analogously to example Ic) and N-(pyridin-4-yl)-2of Fp. 173 176 0 C was obtained in a yield of 70 f) This compound was reduced analogously to example 23) and the title compound of Fp. 144 146 0 C was obtained. Hydrochloride: Fp. 173 176 0
C.
Example 74 2-Chlorobenzenesulfonic acid-5-chloro-3-[2-(pyridin-4ylamino)-ethoxyl-phenyl ester was produced analogously to example 73. Intermediate steps: 81 b) 2-Chlorobenzenesulfonic phenyl ester. Fp. 99 105 0
C.
C) 2-[3--Chloro-5-(2-chloro-phenylsulfonyloxy) phenoxcy]-acetic acid ethyl ester as an oil.
MS 405.
d) 2- [3-Chloro-5- (2-chloro-phenylsulfonyloxy) phenoxy]-acetic acid. Fp. 140 1420C.
e) N-(Pyridin-4-yl)-2-[3-chloro-5-(2-chlorophaenylsulfonyloxy) -phenoxy]-acetamide. Fp. 153 15000.
f) Title compound. Fp. 149 1500C.
Bz-IL~le Benzenesulfonic acid-3- r2- (pvridin-4-ylamino) ethylaminol -Phenyl ester a) 15 g (54 mmol) benzenesulfonic acid-(3-nitro-phenyl ester) in 200 ml methanol was hydrogenated in the presence of 2.5 g 10 palladium on carbon at normal pressure and room temperature. It was filtered and the solvent was removed in a vacuum.
The residue (13 g benzenesulfonic acid-(3-aminophenyl ester)), 4.3 g sodium acetate and 8.7 g ethyl bromoacetate in 10 ml ethanol were boiled for 12 hours under ref lux. Water was added and it was extracted with ether. The ether was removnd in a vacuum and 17.3 g (99 2-[3-(phenyl-sulfop~yloxy)phenylamino]-acetic acid ethyl ester was obtained as an oil. NIS =335.
82 b) This compound was saponified analogously to example Ib) to form 2-[3-(phenylsulfonyloxy)-phenylamino]acetic acid. Yield 65 MS 307.
c) This compound was reacted with 4-aminopyridine analogously to example ic) to form N-(pyridin-4yl)-2-[3-(phenylsulfonyloxy)-phenylamino]acetamide. Oil. MS 383.
d) The title compound was obtained from this analogously to example 23. 0.6 g of the compound which formed as an oil was dissolved in 10 ml ethyl acetate and a solution of 220 mg cyclohexanesulfamic acid in 10 ml ethyl acetate was added. A few drops of isopropanol were added and it was allowed to crystallize. 0.3 g of the cyclaminate of the title compound of Fp. 106 111 0 C was obtained.
Example 76 Benzenesulfonic acid-3-methyl-5- 2-(pyridin-4-ylamino)ethylamino]-phenyl ester a) 12.3 g (100 mmol) 3-hydroxy-5-methylaniline (see example 57) and 25.1 g (170 mmol) phthalic acid anhydride in 250 ml acetic acid were boiled for 1 hour under reflux. 250 ml water was added, it was filtered while hot, 250 ml water was added to the filtrate and it was allowed to crystallize. It was filtered, the precipitate was dissolved in 400 ml hot methanol, admixed with active charcoal, the water was removed in a vacuum and 21.7 g (86 of Fp. 170 175 0
C
was obtained.
p* r 'i-l' 83 b) Benzenesulfonic ester was obtained from this analogously to example la). MS 393.
c) 3.9 g (10 mmol) of this compound and 0.7 ml mmol) hydrazine hydrate in 10 ml ethanol and ml methylene chloride were stirred for 12 hours at room temperature, 4 ml concentrated hydrochloric acid was added, stirred for 2 hours at room temperature, filtered, the solvent was removed in a vacuum, 2 N sodium hydroxide solution was added to the residue and it was extracted with ether, the ether phase was washed with water and with saturated saline solution, the ether was removed in a vacuum and 2.5 g (96 benzenesulfonic acid-3ester was obtained.
MS 263.
d) 2.5 g (9.5 mmol) of this compound was reacted with tosyl chloride analogously to example la) an1 benzenesulfonic acid-3-methyl-5-(4-methylphenylsulfonylamino)-phenyl ester was obtained in a quantitative yield. MS 417.
e) This compound was alkylated with ethyl bromoacetate analogously to example 18a) and 5 g (quantitative yield) [4-methylbenzenesulfonyl-(3-benzeneacid ethyl ester was obtained. MS 503.
f) 5 g (10 mmol) of this compound in 60 ml 6 N hydrochloric acid was boiled for 6 hours under reflux. The solvent was removed in a vacuum, water was added, it was neutralized with sodium 1 1 1 K M M
~I_
84 bicarbonate, extracted with ethyl acetate, the aqueous phase was adjusted to pH 3 wi 2 N hydrochloric acid and extracted wit .hyl acetate.
The ethyl acetate was removed in a vicuum and 2 g (62 amino-acetic acid was obtained. MS 321.
g) This compound was reacted analogously to example Ic) and methyl-phenyl)-amino-acetamide was obtained in a yield of 12 MS 397.
h) The title compound was obtained from this compound analogously to example 23) as an oil.
MS 383.
Example 77 2-(Pyridin-4-ylamino)-ethylamino]-phenyl}benzenesulfonamide a) 13.8 g (100 mmol) 3-nitroaniline, 12.3 g sodium acetate (150 mmol) and 25 g (150 mmol) ethyl bromoacetate in 5 ml dimethylsulfoxide were heated for 48 hours to 80 0 C. It was poured onto 400 ml N hydrochloric acid, 15 ml isohexane and 10 ml ether were added and it was allowed to crystallize.
It was filtered and 18.7 g (84 3-nitro-phenylamino-acetic acid ethyl ester was obtained.
Fp. 92 0
C.
iR
I
85 b) 3-Nitro-phenylamino-acetic acid was obtained from this analogously to example ib) in a yield of 90 Fp. 159 1620C.
c) N-(Pyridin-4-yl)-3-nitro-phenylamino-acetamide was obtained from this analogously to example lc) in a yield of 89 Fp. 196 198 0
C.
d) 10.4 g (38 mmol) of this compound wais hydrogenated in 200 ml methanol and 100 ml ethyl acetate in the presence of 10 g Raney nickel at normal pressure and at room temperature. It was filtered, the solvent was removed in a vacuum and 7.7 g (82 N-(pyridin-4-yl)-(3-aminophenylamino)-acetamide was obtained. MS 292.
e) N-(Pyridin-4-yl)-(3-phenylsulfonylaminophenylamino)-acetamide was obtained from this compound analogously to example la).
MS 382.
f) The title compound was obtained from this analogously to example 23) in a yield of 40 MS 368.
Example 78 N-{3-[2-(Pyridin-4-vimino)-ethylaminol-phenyl}thiophene-2-sulfor ide a) N-(Pyridin-4-yl)-[3-(thiophene-2-ylsulfonylamino)phenylamino]-acetamide (MS 388) was obtained in a yield of 59 by reaction of the II e rl -3 111 I I 86 compound from example 77d) with 2-thiophenesulfonyl chloride analogously to example la).
b) The title compound was obtained from this analogously to example 23) in a yield of 24 Fp. 196 198 0
C.
Example 79 N-{3-F2-(Pyridin-4-ylamino)-ethylamino]-5-trifluoromethyl-phenyl}-benzenesulfonamide a) 15 g (270 mmol) iron powder was added in portions to 24.5 g (100 mmol) in 180 ml boiling glacial acetic acid. It was poured onto water, extracted with ethyl acetate and the ethyl acetate phase was neutralized with solid sodium bicarbonate. It was filtered, the solvent was removed in a vacuum, the residue (26.3 g) was applied to silica gel and eluted with isohexane/ethyl acetate 13.0 g (63 of Fp. 80 84 0
C
was obtained.
b) 5.0 g (24 mmol) of this compound was dissolved in ml sulphuric acid and 17 ml water, it was cooled to 0°C and a solution of 1.9 g (27 mmol) sodium nitrite in 10 ml water was added. The cold solution was added to 250 ml boiling, concentrated copper sulphate solution. When the formation of nitrogen had ceased, it was extracted with ether. The ether phase was extracted with 0.05 N sodium hydroxide solution, the aqueous phase was acidified with dilute sulphuric acid and it was extracted with I I I I I I I 87 ether. The ether was removed in a vacuum and 3.4 g (68 3-nitro-5-trifluoromethyl-phenol of Fp. 82 84°C was obtained.
c) 36.7 g (600 mmol) ethanolamine and 80.7 g (550 mmol) phthalic acid anhydride in 290 ml toluene were heated for 2 hours under reflux on a water separator. After separating 9.3 ml water it was allowed to cool, filtered and 95.1 g (90 N-(2-hydroxyethyl)-phthalimide of Fp. 128 132 0
C
was obtained.
d) 28.8 g (150 mmol) of this compound and 42.9 g (225 mmol) tosyl chloride in 200 ml pyridine were stirred for 3 hours at room temperature, acidified with 2 N hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was removed in a vacuum and 48.3 g (85 4-toluenesulfonic acid-(2phthalimidoethyl)-ester of Fp. 144 1480C was obtained.
e) 1.7 g (12.5 mmol) of this compound, 2.6 g (12.5 mmol) of compound 79c) and 4.1 g potassium carbonate in 80 ml dimethylsulfoxide were stirred for 12 hours at 500C. It was poured onto ice, extracted with ethyl acetate, the ethyl acetate was washed with 0.01 N sodium hydroxide and saturated saline solution, the ethyl acetate was removed in a vacuum and 1.9 g (40 N-{2-[2-(3-nitro-5trifluoromethylphenoxy)-ethyl]}-phthalimide of Fp. 146 148 0 C was obtained.
L IL IL r' L~ I 88 f) 2-(3-Nitro-5-trifluoromethyl-phenoxy)-ethylamine was obtained quantitatively from this analogously to example 76c). MS 250.
g) 1.0 g (4 mmol) of this compound, 1.15 g (4.4 mmol) 4-nitro-tetrachloropyridine Roberts, H.
Suschitzky, J..Chem. Soc. C 1968, 2844 2848) and 0.48 ml (4.4 mmol) N-methylmorpholine in 20 ml dioxane were stirred for 3 hours at room temperature. Water was added, it was extracted with ethyl acetate, the ethyl acetate was washed with water and saturated saline solution, the ethyl acetate was removed in a vacuum and 1.4 g (75 N-(tetrachloropyridin-4-yl)-2-(3-nitro-5-trifluoromethylphenoxy)-ethylamine of Fp. 126 129 0 C was obtained.
h) This compound was reduced analogously to step a) and N-(tetrachloropyridin-4-yl)-2-(3-amino-5trifluoromethylphenoxy)-ethylamine of Fp. 144 146 0 C was obtained.
i) 0.4 g (0.92 mmol) of this compound and 0.12 ml (0.92 mmol) benzenesulfonyl chloride in 5 ml pyridine were stirred for 3 hours at room temperature, acidified with 2 N hydrochloric acid, extracted with ethyl acetate, washed with saturated saline solution, the ethyl acetate was removed in a vacuum and 0.4 g N-{3-[2-(tetrachloro-pyridin-4benzenesulfonamide of Fp. 139 143 0 C was obtained.
j) 0.4 g (0.7 mmol) of this compound was hydrogenated in 50 ml methanol in the presence of 3.5 mmol -:a 1 1 gW 89sodium methylate and 0.5 g 10 palladium on carbon at room temperature and normal pressure. It was filtered, water was added and it was extracted with ethyl acetate. The ethyl acetate was removed in a vacuum and 0.2 g of the title compound of Fp. 140 144 0 C was obtained.
Example 2-(pyridin-4-ylamino)ethoxy]-benzenesulfonamide a) 92 g (0.4 mmol) 3,5-dinitrobenzoyl chloride and 28.4 g (0.44 mol) sodium azide in 240 ml glacial acetic acid were stirred for 8 hours at room temperature, 400 ml water was added, the precipitate was filtered and 80.8 g (85 azide of Fp. 105 0 C (decomp.) was obtained.
b) 80.8 g (0.34 mol) of this compound in 500 ml acetic anhydride was carefully heated until generation of gas starts (90 100C and it was kept at this temperature for 4 hours. The solvent was removed in a vacuum, the residue was digested with water and 136 g (quantitative) acetamide of Fp. 163 0 C was obtained.
c) 136 g (0.34 mol) of this compound was boiled for 3 h under reflux in 500 ml ethanol and 500 ml concentrated hydrochloric acid, undissolved material was removed by filtration, the filtrate was poured into 2 1 water, the yellow precipitate was filtered by suction and 41.4 g (66 -1 90 was obtained. Fp. 1400C (decomp.).
d) 25 g (137 mmol) of this compound was dissolved in ml glacial acetic acid and 100 ml concentrated hydrochloric acid, 10.4 g (155 mmol) sodium nitrite in 20 ml water was added dropwise within 5 minutes, it was stirred for a further 15 minutes at this temperature, the brown suspension was cooled to -200C and it was added within 15 minutes to a solution of 2.7 g copper dichloride dihydrate in 200 ml glacial acetic acid which was saturated with sulphur dioxide and cooled to 0 C. It was extracted with ethyl acetate, the ethyl acetate was removed in a vacuum and dried at 10 2 torr. 35.4 g (97 dinitro-benzenesulfonyl chloride was obtained as a brown solid which was used without further purification.
e) 4.9 g (38 sulfonamide (Fp. 175 178 0 C) was obtained analogously to example 79i) from 10.2 g (38.2 mmol) of this compound and 4.5 ml (42 mmol) N-methylaniline.
f) 3.5 g (10.4 mmol) of this compound in 31 ml 0.4 molar methanolic sodium methylate solution was boiled for 1 hour under reflux. The solvent was removed in a vacuum, the residue was digested with ethyl acetate and it was purified over a silica gel column (100 g silica gel). It was eluted with isohexane/ethyl acetate 2:1 and 2.5 g (75 sulfonamide of 2p. 112 0 C was obtained.
91 g) This compound was hydrogenated analogously to example 58) and 2.3 g N-methyl-N-phenyl-3-methoxywas obtained as an oil.
MS 292.
h) A solution of 630 mg (9 mmol) sodium nitrite in 2 ml water was added dropwise to a suspension of 2.3 g (7.8 mmol) of this compound in 10 ml water and 5 ml concentrated sulphuric acid which had been cooled to 0 C, it was stirred for 2 hours at this temperature, urea was added, it was heated for minutes to 1100C, extracted with ethyl acetate, the ethyl acetate was washed with 2 N sodium hydroxide solution, the solvent was removed in a vacuum and 300 mg (13 N-methyl-N-phenyl-3was obtained as an oil. MS 293.
i) 250 mg (0.85 mmol) of this compound was alkylated with 0.14 ml ethyl bromoacetate analogously to example 18a) and 360 mg (quantitative) [3-methoxyacid ethyl ester was obtained as an oil. MS 379.
j) This compound was saponified analogously to example Ib) and 300 mg sulfamoyl)-phenoxy]-acetic acid was obtained as a viscous substance. MS 351.
k) 120 mg (33 N-(pyridin-4-yl)-[3-methoxy-5- (methyl-phenyl-sulfamoyl)-phenoxy]-acetamide was obtained from this compound analogously to example Ic). Fp. 1050C.
'I
i 1 l j -92- 1) 45 mg (46 of the title compound was obtained from 100 mg of this compound analogously to example 1d). MS (mfe) 413.
ExaMle 81 3-Methox y-N-benzvl-N-phenyl-5- F2- (Pyridin-4-vlamino) ethoxyl1-benzenesulfonamide a) N-Benzyl-N-phenyl-3, 5-dinitrobenzenesulfonamide was obtained from compound 90c) and N-benzylaniline in, a yield of 65 analogously to example Fp. 200 0
C.
b) sulfonamide was obtained from this in a quantitative yield analogously to example Fp. 142 0
C.
c) sulfonamide was obtained from this analogously to 79a) in a 56 yield as a viscous substance.
MS 368.
d) N-Ben~yl-N-phenyl-3-methoxy-5-hydroxy-benzene- sulf~onamide was obtained from this analogously to example 80g). MS =369.
e) [3-Methoxy-5- (benzyl-phenyl-sulfamoyl) -phenoxy] acetic acid ethyl ester was obtained from this analogously to example 18a) in a yield of 30 MS 455.
L
93 f) acetic acid was obtained quantitatively from this analogously to example Ib). MS 427.
g) N-(Pyridin-4-yl)-[3-methoxy-5-(methyl-phenylsulfamoyl)-phenoxy]-acetamide was obtained from this analogously to example Ic) in a yield of 42 Fp. 1750C.
h) The title compound was obtained from this analogously to example Id) in a 50 yield as an amorphous powder. MS 489.
Example 82 3-Methoxy-N-phenyl-5-[2-(pyridin-4-ylamino)-ethoxy]benzenesulfonamide mg (0.12 mmol) of the compound from example 81) was hydrogenated analogously to example 58) and 20 mg (40 of the title compound was obtained as an amorphous powder. MS 399.
Example 83 N-Methyl-N-{3-[2-(pyridin-4-ylamino)-ethoxy]-5-methoxyphenyll-benzenesulfonamide a) 18.3 g (100 mmol) of the compound from 80c) was reacted with 14.3 g (110 mmol) benzenesulfonyl chloride analogously to example 79i) and 32.5 g (quant.) was obtained. Fp. 1650C.
I I 94 b) 44 g (136 mmol) of this compound was methylated analogously to example 12a) and 25.1 g (54 was obtained. Fp. 125 0
C.
c) 6.8 g (20 mmol) of this compound was reduced analogously to 79a) and 6.1 g (quant.) N-methyl-Nwas obtained as an amorphous powder. MS 307.
d) 1.8 g (30 benzenesulfonamide was obtained from 6.1 g mmol) of this compound as an amorphous powder analogously to example 80g). MS 308.
(380 after silylation).
e) 1.2 g (4 mmol) of this compound, 6 ml 1 N sodium hydroxide solution, 1.3 g tetrabutylammonium bromide, 6 ml dichloromethane and 0.4 ml iodomethane were stirred for 12 hours at room temperature. The organic phase was separated, the solvent was removed in a vacuum and the residue was purified on silica gel (150 It was eluted with isohexane/ethyl acetate 2:1 and 240 mg (18 sulfonamide was obtained. Fp. 1360C.
f) This compound was hydrogenated analogously to example 58 and aminophenyl)-benzenesulfonamide was obtained quantitatively as an amorphous powder.
MS 292.
L~ LL~ L I s I J 95 g) sulfonamide was obtained from this analogously to example 80g) in a 74 yield as an amorphous powder. MS 293.
h) phenoxy]-acetic acid ethyl ester was obtained from this in a yield of 89 as an amorphous powder analogously to example 18a). MS 379.
i) phenoxy]-acetic acid (74 MS 351), N-(pyridin- 4-yl)-[3-methoxy-5-(N-methyl-phenylsulfonyl-amino)phenoxy]-acetamide (34 MS 427) and the title compound (MS 413) as an amorphous powder were obtained from this analogoUsly to examples 81f) to 81h).
Example 84 3-Chloro-N-methyl-N-phenyl-5-[2-(pyridin-4-ylamino)ethoxyl-benzenesulfonamide a) The compound 80e) was reduced analogously to example 79a) and benzenesulfonamide was obtained in a 50 yield.
Fp. 175 0
C.
b) A solution of 760 mg (11 mmol) sodium nitrite in 2 ml water was added dropwise to 3.5 g (10 mmol) of this compound in 40 ml 6 N hydrochloric acid at 0 0
C
and then the suspension obtained was poured into a solution which had been prepared as follows: 3.75 g I I ~cr;rcuw 96 copper sulfate pentahydrate and 1.35 g sodium chloride were dissolved in 12 ml warm water, a solution of 950 mg (7.5 mmol) sodium sulfite in 3 ml water was added dropwise, the precipitate was rapidly filtered and it was dissolved in 6 ml concentrated hydrochloric acid. It was slowly heated to 1000C, cooled, extracted with ethyl acetate and filtered over a silicic acid gel (100 g silica gel). It was eluted with isohexane/ethyl acetate and 1.45 g (43 N-methyl-N-phenyl-3was obtained.
Fp. 143 0
C.
c) This compound was reduced quantitatively analogously to example 79a) to form N-methyl-N- Amorphous powder. MS 296.
d) The following were produced from this analogously to examples 83g) to 83i): N-methyl-N-phenyl-3- (69 amorphous, MS 297); sulfamoyl)-phenoxy]-acetic acid ethyl ester (92 amorphous, MS 383); sulfamoyl)-phenoxy]-acetic acid (quant., amorphous, MS 355); N-(pyridin-4-yl)-[3-chloro-5-(methylphenyl-sulfamoyl)-phenoxy]-acetamide (32 amorphous, MS 431); title compound (40 amorphous MS 417).
-r .j 1 I -I I ~r l 97 Example 3-Chloro-N-benzyl-N-phenyl-5-Fr2- (pyridin-4-vlamino) ethoxyl -benzenesulfonamide a) 12.3 g (46 mmol) of compound 80d) was reacted with 9.2 g (50 mmol) benzylamine analogously to example 79i) and 31.3 g (83 dinitrobenzenesulfonamide was obtained. Fp. 205 0
C.
b) This compound was reduced anialogously to example 79a) and sulfonamide was obtained quantitatively. Fp. 170 0
C.
c) N-Benzyl-N-phenyl-3 sulfonamide was obtained from this analogously to example 84b). Fp. 160 0
C.
d) The following compounds were produced analogously to examples 84c) to 84d): N-benzyl-N-phenyl-3- (quant., amorphous, MS 372); hydroxy-benzenesulfonamide (quant., amorphous, MS =373); phenoxy]-acetic acid ethyl ester (15 oil, MS 459; phenoxy]-acetic acid (50 amorphous, MS 431); N- (pyridin-4-yl) -[3-chloro-5- (benzyl-phenylsulfamoyl)-phenoxy]-acetamide (44 amorphous, MS 507); title compound (40 amorphous, MS =493).
98 ExaMple 86 3-Chloro-N-benzyl-N-phenyl-5-Lr2- (pyridin-4-vylamino) ethylaminol1-benzenesulfonamide The following compounds were produced from N-benzyl-N-phenyl-3 sulfonamide (example 85d) analogously t'o examples 83h) to 83i): sulfamoyl) -phenylamino] -acetic acid ethyl ester (18 t, oil, MS 458); sulfamoyl)-phenylamino]-acetic acid (quant., amorphous, MS 430); N-(pyridin-4-yl) -[3-chlor: (benzyl-phenyl-sulf amoyl) -phenylamino -acetamide amorphous, MS 506); title compound (50 amorphous, MS 492).
Example 87 N-Methyl-N-13-f2- (pyridin-4-ylamino) -ethoxyl -phenyllbenzenesulfonamide a) N-Methyl-N- (3-amino-5-nitro-phenyl) -benzenesulfonamide (example 83c) was reacted analogously to example 84b) to form nitrophenyl) -benzenesulfonamide (52 amorphous, MS 326).
b) This compound was reduced analogously to example 79a) to form N-mnethyl-N- (3-chloro-5-aminophenyl) benzenesulfonamide (42 oil, MS 296); (N-methyl-phenylsulfonylamino) phenoxy]-acetic acid ethyl ester (89 amorphous, 99 MS =383); [3-chloro-5- (N-methyl-phenylsulfonyl-amino)-phenoxy]-acetic acid (88 MS =355); N-(pyridin-4-yl)-[3-chloro-5-(N-methylphenylsulfonyl-amino) -phenoxy]-acetamide (28 MS 431) and the title compound (56 as an amorphous powder-. MS =417.
Example 88 N-Benzvl-N-13-r2- (pvridin-4-vlamino)-ethoxyl Phenvl1 -benz enesulfonamide a) The compound of example 83a) was benzylated with benzyl bromide analogously to example 92c) and N-benzyl-N- 5-dinitrophenyl) -benzenesulfonamide was obtained (quant.). Fp. 1700C.
b) This compound was reduced analogously to 79a) and 27 N-benzyl-N- (3-amino-5-nitrophenyl) -benzenesulfonamide was obtained as an amorphous powder.
MS =383.
c) N-Benzyl-N-(3-chloro-5-nitrophenyl) -benzenesulfonamide was obtained from this compound analogously to example 84b) in a 45 yield.
Fp. 148 0
C.
d) This compound was reduced analogously to example 79a) and 34 benzenesu]Atonamide was obtained. Fp. 1450C.
e) The following compounds were obtained from this analogously to examples 83g) to 83i): N-benzyl-N- 100 (quant., amorphous, MS 373); (N-benzyl-phenylsulfonyl-amino)-phenoxy]-acetic acid ethyl ester (quant., amorphous, MS 459); phenoxy]-acetic acid (82 Fp. 180 0 C (decomp.)); N-(pyridin-4-yl)-[3-chloro-5-(N-benzyl-phenylsulfonyl-amino)-phenoxy]-acetamide (54 Fp.
178 0 C) and the title compound as an amorphous powder. MS 493.
Example 89 N-{3-[2-Pyridin-4-vlamino)-ethylamino-5-bromophenyl}benzenesulfonamide a) A solution of 7.6 g (110 mmol) sodium nitrite in ml water was added dropwise within 15 minutes to 18.3 g (100 mmol) 3,5-dinitroaniline (example in 100 ml glacial acetic acid and 100 ml 47 aqueous hydrobromic acid at 0 C and the further procedure was as described in example 84b). 21.7 g (88 3,5-dinitrobromobenzene was obtained.
Fp. 65 0
C.
b) This compound was reduced analogously to example 79a) and 17.4 g (91 3-bromo-5-nitroaniline was obtained. Fp. 105 0
C.
c) This compound was alkylated analogously to example 18a) and 3-bromo-5-nitrophenylamino-acetic acid ethyl ester was obtained quantitatively. Amorphous MS 303.
l 101 d) This compound was saponified analogously to example Ib) and bromo-5-nitro-phenylamino acetic acid was obtained (22 amorphous, MS 274).
e) This compound was reacted analogously to example Ic) and N-(pyridin-4-yl)-(3-bromo-5-nitro-phenylamino)-acetamide was obtained in a 29 yield.
Fp. 2400C.
f) This compound was hydrogenated analogously to example 58) and N-(pyridin-4-yl)-(3-bromo-5-aminophenyl-amino)-acetamide was obtained quantitatively. Amorphous. MS 321.
g) N-(Pyridin-4-yl)-[3-bromo-5-banzenesulfonylaminophenyl-amino)-acetamide was obtained from this.
Amorphous. MS 460.
h) The title compound was obtained from this analogously to example Id). Amorphous.
MS 446.
Example Benzenesulfonic acid-3-ethyl-5-r2-(pyridin-4-vlamino)ethoxyl-phenyl ester a) 20 g 3,5-dimethoxybenzoic acid (110 mmol) in 80 ml thionyl chloride was boiled for 1 hour under reflux. The solvent was removed in a vacuum, the residue was taken up in 500 ml dry methylene chloride and dry ammonia was passed for 90 min over the ice-cooled solution. It was stirred for a vt f-y p..
I S- 102 further 2 hours at room temperature, the solvent was removed in a vacuum, the residue was stirred for 12 hours in 200 ml water and 50 ml saturated sodium bicarbonate solution, filtered, the precipitate was dissolved in ethyl acetate, filtered over active charcoal and the ethyl acetate was removed until crystallization begun. 10.8 g was obtained. Fp. 145 0
C.
b) 19.5 ml (310 mmol) iodomethane in 30 ml ether was added dropwise to 7.6 g (310 mmol) magnesium in ml dry ether, it was boiled for 30 min under reflux and then 11.6 g (63 mmol) benzamide was added in portions. It was boiled for 22 h under reflux, 125 ml 6 N hydrochloric acid was added dropwise while cooling on ice, it was stirred for 16 hours at room temperature, the organic phase was washed with water, the solvent was removed in a vacuum and 9.4 g 3,5-dimethoxyacetophenone was obtained as an oil. MS 180.
c) 9.4 g (52 mmol) of this compound in 150 ml ethanol and 2 ml concentrated hydrochloric acid was hydrogenated in the presence of 1 g palladium at 0 C and 5 bar pressure. It was filtered, the solvent was removed in a vacuum and 6.8 g (78 was obtained as an oil.
MS 166.
d) 6.8 g (41 mmol) of this compound in 65 ml glacial acetic acid and 25 ml concentrated 47 hydrobromic acid were boiled for 4 hours under reflux. The solvent was removed in a vacuum, water was added to the residue, it was extracted with ethyl acetate, c N~d II -I .1 S- 103 the ethyl acetate was washed with water, the solvent was removed in a vacuum and the residue was filtered over silica gel (isohexane/ethyl acetate 3.9 g (69 5-ethyl-resorcinol was obtained as an oil. MS 138.
e) 3.9 g (28 mmol) of this compound and 4.3 ml (33 mmol) benzenesulfonyl chloride in 30 ml ether and 60 ml saturated sodium bicarbonate solution were stirred for 48 hours at room temperature. The ether phase was separated, the solvent was removed in a vacuum, the residue was filtered over silica gel (isohexane/ethyl acetate 3:1) and 5.4 g (69 benzenesulfonic acid-3-hydroxy-5-ethyl-phenyl ester was obtained as an oil. MS 278.
f) The following compounds were obtained from this analogously to examples 81e) to 81h): (3-benzeneacid ethyl ester (77 oil, MS 364); (3-benzeneacid (59 amorphous, US 336); N-(pyridin-4-yl)-(3amorphous, MS 412); title compound Fp. 136 0
C).
Example 91 N-Benzyl-N-{3-[2-(pyridin-4-ylamino)-ethoxy]-5-methylphenyl}-benzenesulfonamide a) 107 g (1 mol) para-toluidine was reacted with p-tosyl chloride analogously to example 79i) and 280 g (quant.) N-(4-methylphenyl)-4-methyl-benzenev
II
104 sulfonamide was obtained as an oil which was reacted without further purification. Crystals from ether of Fp. 105 0
C.
b) 21 g (80 mmol) of this compound was added to 56 ml fuming nitric acid, 32 ml concentrated sulphuric acid was slowly added dropwise, it was poured onto ice, the precipitate was washed with water and 46.6 g (73 yellow solid of Fp. 1700C was obtained which was heated for 10 minutes to 10 0
C
in 80 ml concentrated sulphuric acid, it was poured onto ice water and extracted with ethyl acetate.
The solvent was removed in a vacuum and 20 g (88 2,6-dinitro-4-methylaniline of Fp. 171 0 C was obtained.
c) 800 ml glacial acetic acid was added to 20.5 g (300 mmol) sodium nitrite in 220 ml sulphuric acid and 53.5 g (270 mmol) 2,6-dinitro-4-methylaniline was added in portions, it was stirred for 3 hours at 400C until all had dissolved and this solution was added dropwise to an ice-cooled suspension of g copper oxide in ethanol, the solvent was removed in a vacuum, water was added and it was extracted with ethyl acetate. This preparation was carried out again for a second time and a total of 88 g (88 3,5-dinitrotoluene was obtained as an amorphous powder.
d) 88 g (480 mmol) of this compound in 520 ml methanol was saturated with 53 g ammonia and hydrogen sulphide was passed in for 15 minutes during which the temperature increased to 52 0 C. It was boiled for 30 minutes under reflux, 1 1 water was added 1 i s t k 105 and 60.5 g (82 3-methyl-5-nitroaniline was obtained. Fp. 97*C.
e) N- (3-Methyl-5-'nitrophenyl) -benzenesulfonamide (quantitative) was obtained from this analogously to example 79i). Fp. 1650C.
f) N-Benzyl-N- (3-methyl-5-nitrophenyl) -benzenesulfonamide (83 Fp. 154 0 C and N-benzyl-N-(3- -benzenesulfonamide (34 amorphous, MS 352) were obtained from this analogously to examples 88a) to 88b).
g) The following-,compounds were obtained from this analogously to examples 81e) to 81h): [3-(benzenesulfonyl-benzyl-amino) -5-methyl-phenylamino 3-acetic acid ethyl ester (quant., oil, MS =438); (benzenesulfonyl-benzyl-amino) amino) -acetic acid (90 amorphous, MS (m/e) 410); N- (pyridin-4-yl) -[3-(benzenesulfonyl-benzyl-, amino) -5-methyl-phenylamino) -acetamide (10 amorphous, MS =486); title compound (47 amorphous, MS 472).
Example 92 (Benzenesulfonyl-{3-methyl-5-12-(Pyridin-4-vlamino) ethoxyl -phenyll-amino) -acetic acid ethyl ester a) 100 g 4-nitrotetrachioropyridine and 50.6 ml ethanolamine in 1.2 1 dioxane were stirred for minutes at room temperature, the solvent was removed in a vacuum, water was added to the 106 residue, it was extracted with ethyl acetate, the ethyl acetate was washed with water, the solvent was removed in a vacuum and 105 g (72 4-(2hvdroxyethylamino)-tetrachloropyridine was obtained. Fp. 131 1330C.
b) 36.3 g (130 mmol) of this compound and 12.1 ml (170 mmol) acetyl chloride in 450 ml glacial acetic acid were stirred for 12 -urs at room temperature, poured onto ice, neutralized with concentrated ammonia, extracted with ethyl acetate, the ethyl acetate was washed with water, the solvent was removed in a vacuum and 41.6 g (99 acetic acid- 2-(tetrach3)ropyridin-4-ylamino)-ethyl ester was obtained. Fp. 72 75 0
C.
c) I suspension of 10.8 g sodium hydride in 150 mi dimethylformamide was added to 109 g (340 mmol) of this compound in 700 ml dry dimethylformamide and subsequently a solution of 54 ml benzyl bromide in 350 ml dimethylformamide was added dropwise at It was stirred for 2 hours at room temperature, poured onto 7 1 ice water, filtered, the precipitate was washed with water, dissolved in 800 ml methanol and 200 ml dichloromethane, it was concentrated until crystallization began and allowed to crystallize. 120 g acetic acid-2- (benzyl-tetrachloropyridin-4-ylamino)-ethyl ester was obtained. Fp. 97 100 0
C.
d) Enough dimethylformamide was added to 108 g (260 mmol) of this compound in 1.2 1 ethanol and 390 ml 2 N sodium hydroxide solution to dissolve it all (ca. 0.5 It was stirred for 12 hours at p 107 room temperature, the solvent was removed in a vacuum (finally at 10- 2 torr), 3 1 water was added to the residue and it was extracted with 1 1 ethyl acetate, the ethyl acetate was washed with 3 1 water, the solvent was removed in a vacuum and 99 g (quant.) N-benzyl-N-(2-hydroxyethyl)-N-(tetrachloropyridin-4-yl)-amine was obtained as an oil.
MS 366.
e) 73 ml (520 mmol) triethylamine was added to 107 g (290 mmol) of this compound in 800 ml dichloromethane, it was cooled to 0°C and a solution of 67.1 g (350 mmol) 4-toluenesulfonyl chloride in 500 ml dichloromethane was added dropwise. The solution was stored for 16 hours at 40C, water was added, the organic phase was separated and the solvent was removed in a vacuum. 90.6 g (64 4-toluenesulfonic acid-2-(benzyl-tetrachloropyridin-4-ylamino)-ethyl ester was obtained.
Fp. 114 116°C.
f) 57.2 g (240 mmol) of this compound, 64.8 g (260 mmol) 3-phthalimido-5-methylphenol (example 76a) and 66.2 g (480 mmol) potassium carbonate in 1.15 1 dimethylsulfoxide were stirred for 72 hours at room temperature, poured onto 3 1 water, filtered, the residue was digested with diisopropyl ether and 63 g (38 N-benzyl-N-(tetrachloropyridin-4-yl)-N-[2-(3-phthalimido-5-methylphenoxy)-ethyl]-amine was obtained. Fp. 142 144oC.
g) 19.1 g (31.8 mmol) of this compound, 2.3 ml (47.6 mmol) hydrazine hydrate and 50 ml ethanol in I- I i' I 108 100 ml dichloromethane were stirred for 12 hours at room temperature, the solvent was removed in a vacuum, the residue was suspended in 150 ml 2 N sodium hydroxide solution, extracted with dichloromethane, the organic phase was washed with water, the solvent was removed in a vacuum, the residue was digested with methanol and 11.5 g (77 N-benzyl-N-(tetrachloropyridin-4-yl)-N-[2-(3-aminowas obtained.
Fp. 91 930C.
h) 11.5 g (25.5 mmol) of this compound was reacted analogously to example 79i) with 3.51 ml (27.0 mmol) benzenesulfonyl chloride and 13.7 g (91 N-{3-[2-(benzyl-tetrachloropyridin-4sulfonamide was obtained. Fp. 147 149 0
C.
i) 3.0 g (4.00 mmol) of this compound in 15 ml dry dimethylformamide was added to 147 mg (6.3G mmol) sodium hydride in 2 ml dimethylformamide and 0.6 ml (5.4 mmol) ethyl bromoacetate was added dropwise.
It was poured onto 300 ml water, extracted with ethyl acetate, the organic phase was washed with water, the solvent was removed in a vacuum and 3.15 g (91 (benzenesulfonyl-{3-methyl-5-[2- (benzyl-tetrachloropyridin-4-ylamino)-ethoxy]phenyl}-amino)-acetic acid ethyl ester was obtained. Fp. 141 1420C.
j) 3.15 g (4.5 mmol) of this compound, 50 ml trifluoroacetic acid and 6.8 ml 1,2,3-trimethylbenzene were stirred for 12 hours at room temperature, poured onto ice water, neutralized I- L, I I I .1 I 109 with concentrated ammonia, extracted with ether, the ether phase was washed with water, the solvent was removed in a vacuum, the residue was filtered over silica gel (ethyl acetate/isohexane 1:2.5) and 2.50 g (91 (benzenesulfonyl-{3-methyl-5-[2- (tetrachloropyridin-4-ylamino)-ethoxy]-phenyl}amino)-acetic acid ethyl ester was obtained as an oil. MS 605.
k) 3.5 g (5.76 mmol) of this compound and 4.0 g potassium carbonate in 40 ml tetrahydrofuran and ml methanol were hydrogenated in the presence of g 10 palladium on carbon at 4 bar pressure.
It was filtered after 48 hours, the solvent was removed in a vacuum, it was filtered over silica gel (methylene chloride/methanol 4:1) and 2.1 g (78 of the title compound was obtained.
Amorphous. MS 469.
Example 93 (Benzenesulfonyl-{3-methyl-5-f2-(pyridin-4-ylamino)ethoxy]-phenyll-amino)-acetic acid 1.20 g (2.55 mmol) of the compound of example 92) was saponified in 20 ml ethanol with 5.1 ml 1 N sodium hydroxide solution for 2 hours at 450C..It was neutralized with 1 N hydrochloric acid, the solvent was removed in a vacuum, the residue was taken up in 20 ml water and it was allowed to crystallize. 0.97 g (86 of the title compound was obtained. Fp. 100 1020C (decomp.) 110 Example 94 (Benzenesulfonvl-f3-methvl-5-r2-(pyridin-4-vlamino) ethoxv 1-phenyl I-amino)-acetamide g (3.2 mnol) of the compound of example 92) was dissolved in 12 ml concentrated ammonia and 30 ml methanol. After 12 hours at room temperature, it was filtered and 0.99 g (70 of the title compound was obtained. Fp. 163 1650C.
Examqle N-(2-Hydroxvethyl) -(benzenesulfonyl-{3-methyl-5-r2- (pvridin-4-vlamino) -ethoxyl -phenyl I-amino)-acetamide was obtained in a yield of 60 analogously to example 94 using ethanolamine instead of ammonia. Fp. 169 170 0
C.
Example 96 N- (3-Hydroxyethyl) -(benzenesulfonyl-{3-methvl-5- [2- (pyridin-4-ylamino) -ethoxyl -phenyll-amino) -acetamide was obtained in a yield of 70 analogously to example 94 using 3-propanolamine instead of ammonia. Fp. 148 152 0
C.
Example 97 N-Methvl- (benzenesulfonyl-{3-methyl-5-r2- (pyridin-4ylanino)-ethoxyl -phenyl).-amino) -acetamide was obtained in a yield of 58 analogously to example 94 using a 25 ethanolic methylamine solution instead of ammonia. Fp. 136 140 0
C.
Example 98 F2- (Pyridin-4- ].amino) -ethoxyl -phenvil-amin -acetamide was obtained in a yield of 38 analogously to example 94 using a 41 ethanolic dimethylamine solution instead of ammonia. Amorphous. MS =468.
Example 99 N-(2-Aminoethvl) -(benzenesulfonvl-{3-methvl-5-r2- (pvridin-4-ylamino) -ethoxyl -phenyvll-amino) -ace' amide was obtained in a yield of 45 analogously to example 94 using ethylenediamine instead of ammonia. Amorphous.
MS 483.
112 Example 100 N- (2 -Aminoethyl) f2- (pyridin-4 -vlamino) -ethoxy methyl-phenvl.-amino) -benzenesulfonamide The compound of example 94) was reduced analogously to example 18c) and the title compound was obtained in a yield of 34 Amorphous MS 426.
Exae~ple 101 N-(2,.3-Dihydroxypropyl) -(benzenesulfonyl-{3-methvl-5-r2- (pyridin-4-vlamino) -ethoxyl -phenvll-amino) -acetamide was obtained in a yield of 40 analogously to example 94 using 2,3-dihydroxypropylamine instead of ammonia.
Fp. 148 151 0
C.
Example 102 N- (2.3-Dihvdroxypropyl) -N-T3-[2-pvridin-4-vlamino) I-benzenesulfonamide a) 10.0 g (75.7 nunol) 2,2-dimethyl-4-hydroxymethyl- 1,3-dioxolane and 14.3 g (75 inmol) 4-toluenesulfonic acid chloride in 7 ml pyridine were stirred for 16 hours at room temperature, poured onto 200 ml water, extracted with ethyl acetate and the solvent was removed in a vacuum. It was crystallized from isohexane and 10.3 g (48 4-methylbenzenesulfonic acid- 2-dimethyl-l, 3diaxolan-4-yl-methyl) ester was obtained. Fp. 47 0
C.
113 b) 0.24 g (0.83 mmol) of this compound was added to a solution of 23 mg sodium hydride and 0.46 g (0.75 mmol) of the compound of example 92h) in 3 ml dimethylformamide, it was stirred for 8 hours at 110 0 C, poured onto water, extracted with ethyl acetate, the solvent was removed in a vacuum and 300 mg (55 N-(2,2-dimethyl-l,3-dioxolan-4-ylmethyl)-N-{3-[2-(benzyl-tetrachloropyridin-4sulfonamide was obtained as an oil. MS 725.
c) N-(2,3-Dihydroxypropyl)-N-{3-[2-(benzylphenyl}-benzene-sulfonamide (38 Fp. 133 136 0
C)
was obtained from this compound analogously to example 92j).
d) The title compound (66 amorphous, MS 457) was obtained from this compound analogously to example 96k).
Example 103 4-(Benzenesulfonyl-{3-methyl-5-[2-(pyridin-4-ylamino)ethoxy]-phenyl}-amino)-butyric acid ethyl ester The following compounds were obtained analogously to examples 92i) to 92k) by using ethyl 4-bromobutyrate in example 92i) instead of ethyl bromoacetate: 4-(benzenesulfonyl-{3-methyl-5-[2-(benzyl-tetrachloropyridin-4ylamino)-ethoxy]-phenyl}-amino-butyric acid ethyl ester (78 Fp. 106 1080C); 4-(benzenesulfonyl)-{3-methyl- 5-[2-(tetrachloropyridin-4-yr amino)-ethoxy]-phenyl}amino)-butyric acid ethyl ester (oil, MS 633); 114 title compound (75 amorphous, MS =497).
Example 104 5-(Benzenesulfonvl-3-methl-5-2-(pridin-4-vlamilo) ethoxyl-phenyll-amino)-pentanoic acid ethyl ester The following compounds were obtained analogously to examples 92i) to 92k) by using ethyl in example 92i) instead of ethyl bromoacetate: (benzenesulfonyl- {3-methyl-5- (benzyl-tetrachloropyridin-4--ylamino) -ethoxy] -phenyl}-amino) -pentanoic acid ethyl ester (72 Fp. 90 91 0 {3-methyl-5--[2-(tetrachloropyridin-4-ylamino) -ethoxy]phenyl}-amino)-pentanoic acid ethyl ester (86 oil, MS 647); title compound (78 amorphous, MS 511).
Example 105 6-(Benzenesulfonyl-f3-methyl-5-f2-(Pvridin-4ylamilo) ethoxvl -phenyll -amino)-hexanoic acid ethyl ester The following compounds were obtained analogously to examples 92i) to 92k) by using ethyl 6-bromohexanoate in example 92i) instead of ethyi bromoacetate: 6-(benzenesulfonyl-{ 3-methyl-5- (ben7- -tetrachloro-pyridin-4ylamino) -ethoxy] -phenyl}-amino) -hexanoic acid ethyl ester (75 oil, MS 751); 6-(benzene-sulfonyl- {3-methyl-5-[2- (tetrachloro-pyridin-4-ylamino) -ethoxy] phenyl}-amino)-hexanoic acid ethyl ester (49 oil, MS 661); title compound (56 amorphous, MS 525).
115 Example 106 4-(Benzenesulfonyl-{3-methyl-5-f2-(pvridin-4-vlaminio) ethoxyl -phenyll-amino) -butyric acid was obtained analogously to example 93) from the compound of example 103). 65 yield, amorphous, MS 469.
Example. 107 5-(Benzenesulfonyl-T3-methl-5 2-(pvridi-4-vlamilo) ethoxvl -phenyl}-amino) -pentanoic acid was obtained analogously to erample 93) from the compound of example 104). 53 yield, Fp. 117 120 0
C.
Example 108 6-(Benzenesulfonv1- 3-methv1-5-r2-(pridin-4-ylamino)ethoxyl-phenvll-amino) -hexanoic acid was obtained analogously to example 93) from the compound of example 105). 53 yield, amorphous, MS 498.
Example 109 2-Methoxv-benzenesulfonyl-{3-methyl-5-r2- (pvridin-4viamino) -ethoxyl -phenyll-amino) -acetic acid ethyl ester The following compounds were obtained analogously to
I
-116 examples 92h) to 92k) by using 2-methoxybenzenesulfonyl chloride in step 92h) instead of benzenesulfonyl1 chloride: 2-methoxy-N-{ 3- [2-benzyl-tetrachloropyridin-4ylamino) -ethoxy] Fp, 175-C); (2-methoxy-benzene-sulfonyl-{3- (benzyl-tetrachloropyridin-4-ylamino) ethoxy]-pht- iyl}-,amino]-acetic acid ethyl ester (91 Fp. 128 130 0 (2-mnethoxybenzenesulfonyl-{3-methyl-5- (tetrachloropyridin-4-ylamino) -ethoxy] -phenyl} amino)-acetic acid ethyl ester (89 126 0 title compound (81 58 -630C).
Example 12.0 2-Methoxv-benzenesulfonvl-{3-methvl-5-r2- (pvridin-4vlamino) -ethioxyl -phenyll-amino) -acetic aicid was obtained from the compound of exairple 109) analogously to example 93). 82 218 -2220C.
Example III (2-Methoxv-benzenesulfonvl-{3-methyl-5-r2- (pvridin-4ylamino) -ethoxyl-'Phenyll-amino) -acetamide was obtained an alogously to example 94) from th~e compound of example 109. (63 205 0
C).
117 Example 112 N- (2-Hydroxvethyl) -(2-met hoxy-benzenesulfonvl-{ 3-methyl- 5-r2-(Pvridin-4-ylamino) -ethoxyl-phenylI-anino) acetamide was obtained in a yield' of 93 analogously to example from the compound of example 109. Fp. 175 0
C.
Example 113 N- (3-Hydroxypropi) (2-methoxy-benzenesulfonyl-{ 3- F2- (pvridin-4-ylamino) -ethoxyl -phenvl}-amino) acetamide was obtained in a yield of 95 analogously to example 96 from the compound of example 109. Fp. 1I65 167 0
C.
Example 114 N-Methyl- (2-methoxy-benzenesulfonyl-{3-methyl-5- r2- (Pvridin-4 -ylamino) -ethoxy -phenyl I-amino) -acetamide was obtained in a yield of 96 analogously to example 97 from the compound of example 109. Amorphous.
MS 484.
-118- Example 115 NN-Dimethvl- (2-methoxv-benzenesulfonyl-f3-methvl-5-r2- (pvridin-4-vlamino) -ethoxy -phenyll-amino) -acetamide was obtained in a yield of 73 analogously to example 98 from the compound of example 109. Amorphous, MS 498.
Example 116 N- (2-Aminoethvl)-( 2-methoxy-benzenesulfonvl-f3-methvl-5r2- (Pvridin-4-vlamino) -ethoxyl -phenvlL-amino' -acetamide was obtained in a yield of 93 analogously to example 99 from the compound of example 109. Amorphous, MS 513.
Exaftple 117 N-(2,3-Dlihvdroxvpropvl)-(2-methoxv-bE-nzenesulfonvl-{3r2- (pvridin-4-vlamino) -ethoxyl -phenvl"-amino) acetamide was obtained in a yield of 75 analogously to example 101 from the compound of example 109. Amorphous, MS 544.
119 Example 118 (2-Methoxv-benzenesulfonvl-{3-methvl-5-f2- (pvridin-4ylamino)i-ethoxyl -phenvil-amino) -acetonitrile 250 gl trichloroacetyl chloride in 0.5 ml dichloromethane was added at 0 0 C to 94 mg (0.2 mmol) of the compound of example 111) in 0.5 ml dichioromethane and gl triethylamine. After 5 minutes it was neutralized with triethylamine, the solvent was removed in a vacuum, and the residue was filtered over silica gel (ethyl acetate/ methanol ammonia 60 mg of the title compound was obtained as an amorphous substance.
MS =452.
Example 119 N- (2-Aminoethvl) (pvridin-4-vlamino) -ethoxyl methvl-phenvl }-2-methoxv-benzenesulfonamide (2-Methoxy-benzenesulfonyl-{3-methyl-5-[2- (benzyltetrachloropyridin-4 -ylamino) -ethoxy] -phenyl }-amino) acetonitrile (92 Fp. 154 0 C) was obtained by reacting 2-methoxy-N-{ 3- (benzyl-te trachloropyridin-4-ylamino) ethoxy] -5-methyl-phenyl}-benzenesulfonamide (example 109) with chioroacetonitrile analogously to example 92i), from which (2-methoxy-benzenesulfonyl-{3-methyl-5- (tetrachloropyridin-4-ylamino) -ethoxy] -phenyl} amino) -acetonitrile was obtained analogously to example 92j) (85 amorphous, MS 588) which was reactad to form the title compound analogously to example 92k) amorphous, MS 456).
120 Example 120 2-T3-f2- (Benzvl-pvridin-4-lamino),-ethoxvl phenyl-sulfamoyll-benzoic acid methyl ester a) 4--Toluenesulfonic acid-2-(benzyl-tetrachloropyridin-4-ylamino) -ethyl ester (example 92e) was reacted with 3-nitrophenol analogously to example 92f) and N-benzyl-N- (tetrachloropyridin-4-yl) [2- (3-nitro-phenoxy) -ethyl 1-amine was obtained. (61 Fp. 120 122 0
C).
b) This compound was reduced analogously to example 79a) and N-benzyl-N- (tetrachloropyridin-4-yl) (3-aminophenoxy)-ethyl]-amine was obtained (41 Fp. 105 1070C).
c) This compound was reacted analogously to example 92h) to form (benzyl-tetrachloropyridin-4ylamino) -ethoxy] -phenyl}-benzenesulfonamide. (78 Fp. 120 122-C).
d) This compound was hydrogenated analogously to example 92k) and the title compound was obtained (63 amorphous, MS =517).
Example 121 r2- (Methyl-{ 3-methvl-5-rF2- (pyridin-4-ylamino) -ethoxy- Phenyll-sulfamoyl) -phenoxyl -acetic acid ethyl ester a) N-Benzyl-N-(tetrachloropyridin-4-yl) (3-amino- -ethyl 1-amine (example 92g) was 121 reacted analogously to example 92h) with 2-benzyloxy-benzenesulfonyl chloride to obtain methyl-phenyl}-2-benzyloxy-benzenesulfonamide.
Fp. 176 0
C).
b) This compound was methylated analogously to example 12) and N-methyl-N-{3-[2-(benzyl-tetrachloropyridin-4-ylamino)-ethoxy]-5-methyl-phenyl}-2benzyloxy-benzenesulfonamide was obtained (78 amorphous, MS 729).
c) N-Methyl-N-{3-[2-(tetrachloropyridin-4-ylamino)ethoxy]-5-methyl-phenyl}-2-hydroxy-benzenesulfonamide was obtained from this compound analogously to example 92j) (87 amorphous, MS 549).
d) This compound was reacted analogously to example 18) to form [2-(methyl-{3-methyl-5-[2-(tetrachloropyridin-4-ylamino)-ethoxy-phenyl}-sulfamoyl)phenoxy]-acetic acid ethyl ester (quant. oil, MS 635).
e) This compound was hydrogenated analogously to example 92k) and the title compound was obtained amorphous, MS 499).
122 Exam le 122 r2- (pvridin-4-vlamino) -ethoxyl -phenyll-2hydroxy-benz enesulfonamide a) (Benzyl-tetrachloropyridin-4-ylamino) ethoxy] -5-methyl-phenyl} -2-benzyloxybenzenesulfonamide (example 121a) was reacted analogously to example 92j) to form N-{3-[2-(tetrachloropyridin-4-ylamino) -ethoxy] -5-methyl-phenyl}-2hydroxy-benzenesulfonamide (70 amorphous, MS 535).
b) The title compound was obtained from this analogously to example 92k). (81 %,amorphous, MS 399).
Exa~nle 123 N-Methyl-N-{3-methvl-5-r2- (pyridin-4-vlamino) -ethoxyl phenyl -hvdroxy-benzenesulfonamide N-Methyl-N-{3-[2- (benzyl-tetrachloropyridin-4-ylamino) ethoxy] -5-methyl-phenyl} -2-benzyloxy-benzenesulfonamide (example 121b) was reacted analogously to example 122) to obtain N-methyl-N-{3-[2- (tetrachloropyridin-4ylamino) -ethoxy] -5-methyl-phenyl}-2-hydroxy-benzene-.
sulfonamide (65 amorphous, MS 549) and the title compound (27 %,amorphous, MS =413).
123 Example 124 r2-(Methv1-3-meth1-5-2-(pvridi-4-vlaUifo)-ethoxyl- Phenvl}-sulfamovl) -phenoxvl -acetic acid a) (Methyl-{3-methyl-5-[2- (tetrachloropyridin-4ylamino) -ethoxy-phenyl} -sulfamoyl) -phenoxy] -acetic acid ethyl ester (example 121d) was saponified analogously to example 93) to obtain (2-(methyl-{3- (tetrachloropyridin-4-ylamino) -ethoxyphenyl}-sulfamoyl) -phenoxy] -acetic acid (94 amorphous, MS =607).
b) The title compound was obtained from this analogously to example 92k) (75 amorphous, MS 471).
Examnple 125 N-Ethoxvcarbonvl-N-{3-methvl-5-[F2- (pyridin-4-vlamino) ethoxyl -phenyll'-2-methoxv-benzenesulfonamide a) 2-Methoxy-N-{3-[2- (benzyl-tetrachloropyridin-4ylamino) -ethoxy] -5-met1hyl-phenyl }-benz enesulfonamide (example 109) was reacted analogously to example 92i) with ethyl chloroformate to obtain N-ethoxycarbonyl-N-{ 3- (benzyl-tetrachloropyridin-4-ylamino) -ethoxy] -5-methyl-pheryl}-2methoxy-benzenesulfonamide was obtained (quant.
amorphous, MS 711).
b) N-Ethoxycarbonyl-N-{3-[2- (tetrachloro-pyridin-4ylamino) -ethoxy] -5-methyl-phenyl -methoxy- 124 benzenesulfonamide was obtained from this analogously to example 92j) (80 Fp. 156 0
C).
c) The title compound was obtained from this analogously to example 92k) (66 amorphous, MS 485).
Example 126 N-(2-Hydrovethyl)-N-{3-methvl-5-[2-(pyridin-4-vlamino)ethoxyv-phenyl}-2-methoxy-benzenesulfonamide 24 mg (0.6 mmol) lithium aluminium hydride was added to 150 mg (0.3 mmol) (2-methoxy-benzenesulfonyl-{3-methyl- 5-[2-(pyridin-4-ylamino)-ethoxy]-phenyl}-amino)-acetic acid ethyl ester (example 109) in 5 ml dry tetrahydrofuran and it was boiled for 2 hours under reflux. 1 drop of water and 3 drops of 2 N hydrochloric acid were added, it was filtered and the solvent was removed in a vacuum. The residue was filtered over 50 g silica gel (methylene chloride/methanol 4:1) and 50 mg (36 of the title compound was obtained as an amorphous solid.
MS 457.
Example 127 N-f3-Methyl-5-r2-(pyridin-4-vlamino)-ethoxy]-phenyl}pyridin-3-sulfonamide was obtained analogously to example 57) by using 3-pyridinesulfonyl chloride in step 57d). Amorphous.
MS 385.
i 125 Example 128 Description of pharmacological experiments Thrombin time The thrombin time is a conventional test in clinical coagulation diagnostics. This parameter measures the action of thrombin on fibrinogen and the formation of clots. Inhibitors of thrombin result in an extended thrombin time.
In order to obtain plasma, 9 parts of fresh blood from healthy donors was mixed with one part of sodium citrate solution (0.11 mol/1) and centrifuged for 10 minutes at room temperature at ca. 3000 The plasma was pipetted off and can be stored at room temperature for ca. 8 hours.
200 il citrate plasma was incubated for 2 minutes at 37 0 C in a ball coagulometer (KC10 from the Amelung Company). 10 Al dimethylsulfoxide (DMSO) or a solution of the active substance in DMSO was added to 190 gl preheated thrombin reagent (Boehringer Mannheim GmbH; contains ca. 3 U/ml horse thrombin and 0.0125 M On addition of 200 il of this solution to the plasma a stopwatch was started and the time at which coaglQoion starts was determined. The thrombin time was ca. 24 sec.
in control measurements and was substantially increased by the active substances.
The measured thrombin times in seconds are given in the following table as a difference to the control. The
CLL
126 concentrations of the active substances in the final volume were 250 AM (TT250), 25 MM (TT25) and 2.5 AM Thrombin inhibition The kinetic measurements were carried out in 0.1 M phosphate buffer that contained 0.2 M sodium chloride and 0.5 polyethylene glycol 6000 at a pH 7.5 and 0 C with the substrate H-(D)-Phe-Pro-Arg-pNA (S-2238 Kabi) and human a thrombin (Sigma, specific activity 2150 NIH units/mg) in polystyrene semi-microcuvettes in a total volume of 1 ml.
In a preliminary test each active substance was tested whether it inhibits thrombin rapidly or slowly. For this the reaction was firstly started by adding 0.03 NIH units thrombin to a 100 AM solution of the substrate and the active substance. In a second experiment, substrate was added to a solution of thrombin and the active substance which had been incubated for 5 minutes. The increase in the concentration of p-nitroaniline with time was monitored spectroscopically (UV-VIS spectrophotometer Lambda-2 from the Perkin-Elmer Company) at 405 nm for 12 min. Since the measured curves obtained in both experiments were linear and parallel, the active substances of the following table are rapid thrombin inhibitors. The inhibition constants Ki were then determined as follows. The substrate was used at concentrations of 100 MM, 50 pM, 30 AM, 20 MM and at each substrate concentration a measurement was carried out without inhibitor and three measurements were carried out in the presence of various concentrations of the inhibitors listed in the following table. The
I
127 reactions were started by addition of thrombin. The increase in absorbance at 405 nm due to the formation of p-nitroaniline was monitored over a time period of 12 minutes. Measurement points (time versus absorbance) were transferred to a PC at intervals of 20 seconds. The rates V o (change in absorbance per second; measurements without inhibitor) and V i (measurements with inhibitor) were determined by linear regression. Only that part of the measurement was used in which the substrate concentration had decreased by less than 15 Km and Vmax were determined from a measurement series (constant inhibitor concentration, variable substrate concentrations) by a non-linear fit to the equation Vmax*[S] V Km Finally Ki was calculated from the entire series of measurements by non-linear fitting to the equation Vmax*[S] V Km*(l [S] The Michaelis constant Km was 3.8 2 gM in all measurements.
The inhibition constants Ki of the active substances are stated in the following table in units of gM.
I 1 I r~lr sieiicll 128 Inhibition of trypsin and plasmin mg bovine pancreatic trypsin (Sigma) was dissolved in 100 ml 1 mM hydrochloric acid and stored in a refrigerator. 20 Al of this was admixed with 980 gl 1 mM hydrochloric acid. 25 Il thereof was used for each measurement. The measurement was carried out as described for thrombin. Km 45 AM. The substances listed in the following table do not inhibit trypsin (Ki 400 AM).
The measurements with human plasmin (Sigma, 10 units) were carried out as described for thrombin using the substrate S-2251 (H-(D)-Val-Leu-Lys-pNA, Kabi). 0.01 units plasmin were used for each measurement. Km 250 AM. The substances listed in the following table do not inhibit plasmin (Ki 400 AM).
c 129
I.
1 T Example No.
2 8 48 59 72 79 83 86 89 100 108 124 125 thrombin 0.300 1.000 3 .000 0.130 0.600 6.000 0.600 0. 024 5. 000 0. 150 0.100 0.040 1.000 0.024 0.083 0.055 0.250 0.150 TT250 150 288 157 270 300 53 137 300 30 300 300 300 132 300 300 300 300 300 TT2 5 40 58 43 144 238 8 62 300 8 213 192 167 38 300 300 300 300 273 I I TT2 6 13 7 46 0 13 159 0 44 48 11 6 125 186 62 104 73
Claims (10)
1. 4-Amninopyridines of the general formula I ~C ClI' -C N 4N 1* S
06.00* *0 090 to in which R 1 denotes a R 6 -SO-NR 7 R 6 -SO 2 -NR 7 R 6 -NR 7 -SO-, R 6 -NR 7 S0 2 R 6 R 6 S0 2 R 6 -O-SO- or R 6 -O-S0 2 group, R 2 denotes a hydrogen or halogen atom, a cyano, alkyl, alkoxy or haloalkyl group, X denotes an oxygen atom, a sulphur atom or a NH group, R 3 and R 4 are the same or different and denote hydrogen atoms or alkyl groups, R 5 denotes a hydrogen atom, an alkyl group or an aralkyl group, U. 131 R 6 denotes an alkyl, cycloalkyl, aryl, heteroaryl, aralkyl or heteroarylalkyl group in which the aryl or heteroaryl residues can be substituted once or several times by nitro, halogen, nitrile, hydroxy, carboxy, alkoxy- carbonyl, alkenyloxycarbonyl, alkynyloxy- carbonyl, aralkoxycarbonyl, alkyl, cycloalkyl, alkenyl, aJkynyl, cyanoalkyl, alkoxy, alkenyl- oxy, alkynyloxy, aralkyloxy, cyanoalkyloxy, alk,thio, alkylsulfinyl, alkylsulfonyl, amino, alkylamino, dialkylamino, aralkylamino, di- aralkylamino, alkylsulfonylamino, alkylcarbonyl- amino, formylamino, aminocarbonyl, alkylamino- carbonyl, dialkylaminocarbonyl or by one or several of the groups -Y-C0 2 R 8 -S-Y-C0 2 R 8 -O-Y-C0 2 R 8 -NH-Y-C0 2 R, -S-Y-C'ONR 8 R 9 -O-Y-CO-NR 8 R 9 or -NH-Y-CONR 8 R 9 in which the alkyl, alkenyl or alkynyl fragments can be substituted once or several times by halogen, i:i .hydroxy, alkoxy, alkylcarbonyloxy, amino or carboxy groups, R 7 denotes a hydrogen atom, an alkyl, cycloalkyl, alkenyl or alkynyl residue wherein these residues can be substituted once or several times by halogen, hydroxy, alkoxy, amino, alkylamino, dialkylamino, carboxy, alkylcarbonyl or alkoxycarbonyl, or denote an alkoxycarbonyl, cyanoalkyl, heteroaryl, aryl, aralkyl or heteroarylalkyl group in which case the aryl or heteroaryl residue can be substituted once or several times by halogen, nitrile, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkenyloxy, alkynyloxy, alkylthio, alkylsulfinyl, alkyl- sulfonyl., haloalkoxy, hydroxy, carboxy, hydroxy- r I- 132 alkyl, carboxyalkyl, alkoxycarbonyl, amino, alkylamino, dialkylamino, alkylsulfonylamino, alkylcarbonylamino, formylamino, aminocarbonyl or phenyl, or denotes a -Y-C0 2 R 8 or -Y-CONR 8 R 9 group, Y denotes a linear or branched alkylene chain, R 8 and R 9 are the same or different and denote hydrogen atoms, aralkyl, cycloalkyl or alkyl groups, which can be substituted once or several times by halogen, hydroxy, alkoxy, alkyl- carbonyloxy, amine or carboxy, or R 8 and R 9 together with the N atom to which they are bound, form a saturated ring which can contain an additional oxygen, sulphur or nitrogen atom, as well as hydrates, solvates and physiologically tolerated salts thereof, and the optically active forms, racemates and mixtures of diastereomers of these compounds. 2. 4-Aminopyridines of formula I as claimed in claim 1, wherein R 1 denotes R 6 -SO-NR 7 R 6 -NR 7 -S0 2 R 6 -S0 2 or R 6 -0-S0 2 3. 4-Aminopyridines of formula I as claimed in claim 1 or 2, wherein R 2 denotes a hydrogen, chlorine or bromine atom, or a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group or a trifluoromethyl group. ~llli~ll~ le1 i r i .CI 133 4. 4-Aminopyridines of formula I as claimed in one of the claims 1 to 3, wherein X denotes an oxygen atom or a NH group. 4-Aminopyridines of formula I as claimed in one of the claims 1 to 4, wherein R 3 and R 4 are the same or different and represent hydrogen atoms or C1-C 6 alkyl groups. 6. 4-Aminopyridines of formula I as claimed in one of the claims 1 to 5, wherein R 5 represents a hydrogen atom, a Cl-C 6 alkyl group or a benzyl group.
7. 4-Aminopyridines of formula I as claimed in one of the claims 1 to 6, wherein R 6 denotes a C 1 -C 6 alkyl group, a C 3 -C 7 cycloalkyl group, an unsubstituted phenyl or benzyl group or a phenyl or benzyl group 'substituted once or several times by fluorine, chlorine, Cl-C 6 alkyl, Cl-C 6 alkoxy, nitro, amino, hydroxy, carboxy, benzyloxycarbonyl, CI-C 6 alkoxy- carbonyl, trifluoromethyl or a -O-Y-CO2R 8 group; a naphthyl, tetrahydronaphthyl, biphenyl or indanyl group, a thienyl, pyrazolyl or pyridyl, benzthienyl or benzothiadiazinyl group. g*
8. 4-Aminopyridines of formula I as claimed in one of the claims 1 to 7, wherein R 7 denotes a hydrogen atom, a C 1 -C 6 alkyl group, C 2 -C 6 alkenyl group or an aralkyl group, a Cl-Cg alkoxycarbonyl group, a cyanoalkyl group, a hydroxyalkyl group or an aminoalkyl group, a -Y-C0 2 R 8 group or a -Y-CONR 8 R 9 group. I -r e~r 1 I I 134
9. 4-Aminopyridines of formula I as claimed in one of the claims 1 to 8, wherein Y denotes a methylene, propylene, butylene or pentylene group. 4-Aminopyridines of formula I as claimed in one of the claims 1 to 9, wherein R 8 denotes a hydrogen atom or an alkyl group, a hydroxyalkyl group or an aminoalkyl group.
11. 4-Aminopyridines of formula I as claimed in one of the claims 1 to 10, wherein R 9 denotes a hydrogen atom or an alkyl group.
12. 'Process for the production of compounds of formula I as claimed in one of the claims 1 to 11, wherein either S: a) a compound of formula IV R2 R R 3 i(IV), X COOR 1 0 R4 in which R 1 -R 4 and X have the stated meanings and R 1 0 denotes an alkyl or benzyl group, is saponified and the free acid is reacted with 4-aminopyridine to form a compound of formula II ,-sr Ct rl I 1 135 (11), -0C- and the compound of formula II is reduced, or b) a compound of formula IX 4. 444 4* 4 4* 444 *4 *4 4 4 4 4044 .4 4*. 4 4* 4 e 4 *44* 4* 44 4 4 4 R 3 (IX) I in which R 1 -R 4 and X have the stated meanings and R 11 denotes a nitrile group or an amide group -CONHR 5 in which R 5 has the stated meaning, is reduced to a compound~ of the general formula VIII R 3 (VIII) XC Cl-I 2 +N-H I 136 and the compound obtained is reacted with a pyridine derivative which has a nucleofugal group which can be removed in position 4, or c) the chlorine atoms of the pyridine ring are removed by catalytic hydrogenation from a compound of the general formula XII R 3 CI R 5 C1 (XII) 9999 999 9 4 9 49 9 9 9~ 99 4 9 9 9 9,99 9. 9, 999 .9.9 99 9. 9. 9 9 .9 9 9 9 9*99 .9 9. .9 9 9 9 in which R 2 -R 5 and X have the stated meanings and Rl' has the same meaning as R or from a compound of the general formula XIV R 6 -SO n-Xv R 3 (XIV), Cl C1 R 4 C1 C1 I, L I 137 in which R 2 -R 6 and X have the stated meanings, n is 1 or 2 and X' denotes oxygen or an imino group NH or from a compound of the general formula XV R 2 R 6SO, NR' Cl Cl (XV), R 5 CI C1 4 B A S *0e A BB S B in which R 2 -R 6 and X have the stated meanings and R 7 has the same meaning as R 7 with the exception of the hydrogen atom, and if desired the compounds obtained are subsequently converted into physiologically tolerated salts, hydrates, solvates or optical isomers.
13. Process for the production of compounds of the general formula I as claimed in claim 1, wherein R 1 in the general formula I denotes a R 6 -SO-NR 7 R 6 -S0 2 -NR 7 R 6 -SO-O- or R 6 -S0 2 group, wherein compounds of the general formula XVI i I I t 138 R2 R 3 (XVI) K '-N N N R 4 I R in which R 2 -R 5 and X have the stated meanings and A denotes a hydroxy group or an amino group -NHR 7 is reacted with a sulfinyl chloride R 6 -SOCl or a sulfonyl chloride R 6 -S0 2 -Cl in which R 6 and R 7 have the stated meanings.
14. Pharmaceutical agents containing at least one compound of formula I as claimed in one of the claims 1 to 11 in addition to pharmaceutical carrier and auxiliary substances.
15. Use of compounds of formula I as claimed in one of the claims 1 to 11 for the production of pharmaceutical agents for the treatment of thromboembolic diseases. S** a r-r rl' I i 139 Abs t ra ct The invention concerns new 4-aminopyridines of the general formula I XC CH 2 +N N R4 I/ (I),I o *0 S in which Rl denotes a R 6 -SO-NR 7 R 6 -S0 2 -NR 7 R 6 -NR 7 -SO-, R 6 -NR 7 -S0 2 R 6 R 6 -S0 2 R 6 -O-SO- or R 6 -O-S0 2 group, R 2 denotes a hydrogen or halogen atom, a cyano, alkyl, alkoxy or haloalkyl group, X denotes an oxygen atom, a sulphur atom or a NH group, R 3 and R 4 are the same or different and denote hydrogen atoms or alkyl groups, R 5 denotes a hydrogen atom, an alkyl group or an aralkyl group, INTER NATIONAAER RECIIEPCHENh.BERICI-T Intematiomiaos Ptezeichan PCT/EP 94/000 RRIGIERTE FASSU G 12 07.1994 i A. KtASSIVILILRUNC; DES ANM l:l.l)UNGCS("GGNSTAND:S C 07 D 213/74,A 61 K 31/44 Nach der Intcrnationalen 'aten~dawafikation (1IPK) Oder nach der nationalcn Klawikatuon und der 111K B3. KlIUEHRCHIERTE GIWIE~T Recherchicrtcr MindlestprUstoff (Klamikatiorauystm und Klas filkitionmsqyibole) C 07 D 213/00,A 61 K 31/00 Recherchiertc: aber rucht zum, Mindestprsifstoff gehotrendc Verdffentlichungen. soweit diese Linter die recherckuerten Gebiete fallen Wihrend der intemationaien Recherche konsulticrtcecektronische Dateanbank (Namne der Datenbank und evi. verwendete Suchbegrilte) C. ALS WESENTLICH ANGESEHENEUINTERLAGEN Kategone' ezeichnung der Verdfllencichung, soweit erforderlich unte trigabc der in Bctracht komnmenden Tole Bet. Anqpruch Nr. X EP, Al, 0 359 389 1-14 (PFIZER) 21 M&rz 1990 (21.03.90), Ansprache 1-5,8,12,13. A EP, Al, 0 356 176 1-14 (HAMARI CHEMICALS) 28 Februar 1990 (28.02.90), Anspr(tche 1,6,7,9. Alp WO, Al, 93/09 133 14,15 (SMITHKLINE BEECHAM) 13 Ma~i 1993 (13.05.93), Ansprt~che 8-10. AlP EP, A2, 0 565 896 14,15 (CASSELLA) Oktaber 1993 (20.10.93), Ansprache 8-10. Weitere Ver~frentlichungen snd der Fortiemung von Feld C zu Siehe Anhang Patentfatruie entihxnen 1 S esondere Katcgoncn von arigegebenen Verdrrenilichungen .T SItre Ven~fentlichung, die nact, dem internaouonalen Ansnilcd"Mm Verdffentlichung, die den aligemeinen Stand der Techtik deiut od=r dem Pnont~isdatumn verdfrntliclfl warden iat und nut der abet rucht als besonders bcdeumsm anuce s Anmeldung nicht kollidiert, sondem~ nut zwnVers~indnis des der .E Aters Doumet, as jdoc ert si odr nah dm iternoonleninug zugrundeUegenden Prnizips Oder der thr .igruftdeliegenden Arnidedatumn verorrlenticht wordcn tst W Votdfentchun~o besonderer BedcUtung. dic beanspruchte Erfinduri VU Vcrorfenclichung, die geecgnec tit, cinen Pnontatsanspruch zweafelhaft cr- kan= alein aurgm diewe Verdffenllichung nicht ala rieu Oder auf ichecinen zu lasien, aOder durch die dase Verorrfendichungsdawan ciner crfindenscher 1'Itigkeit beruhend bewrachtet werden anderen im Rechcrchenbencht genannten Vcrdffentlichung telcgt werden Verdffendichung von besondercr Bcdeutung; die beansptuchte Erfindung loll Oder die aus elnemn anderen besondereni Grund angegeben iat (mie kann nicht als auf erinderucher Titilkcit bes-uhend beurachtet au. gefstr) werden, wcnn die Veroffentlichung mit ciner Oder mchreren anderen .(Verdttentlichung, die aact auf einc mutndlichec Offnbarung. Verdftentltehungen dieser KAteone in Verbinduniggebrachtwird und oine Bcnutzung, etne Ausstellung Odet andere Maflnahnien bezzeht diese Verbindung fu-r amnen Fait=an naheliegend it Veroffentlichung, die var dem intemationalen Ananicdedaturm. abet nach ~Vrtecihn.deMtie etle aetami a dem bean. pruchten Piontatsclatm vcroffentltcht warden it VrfetihndeMtht csle aetaii s Datum dces Abschlu&sses der intemnatonaleni Recherche Absendedatumn des intemationalen Recherchenbenchts 16 Jurli 1994 30, 05. 94 Name und l'ostanschrift der Intcrnationalc Rcchcrchcnbch~rde BevoilrniAchtigter Bedienisteter Europinches Patentaant. P.D. 5818 Patenilsan 2 NL 2280 HV RijswikSCA F eh Tel. (31.70) 34.0.2040, Tx. 31 651 epa rSCAF h Faxc( 31-70) 34.0-3016 Foambin. PCT/ISA.?212 (BLiLI. 2) (Juli 1991) ~Iflternfltionales Aktenzeictni PC /P 4 000 II. EINSCHLAGIGE VEROFFENTLICHUNGEN lFortsetzung veon Blatt 2) At! Ketinzeichnung der VerTfteteluichunfg, soweit erforderlich unter Angabe der ma~lgblichen Teile IBetr. Anspruch Nr. A,P EP, A2, 0 542 363 14,15 (GLAXO GROUP) 19 Mai 1993 (19.05.93), Ansprfiche 14-17. I F OrMblatl PCT/IS A/21o0 (Zusarzbogefll (JanUar 1985) zum internationalen Recherchen- to the International Search au rapport de recherche inter- bericht Ubar die internationale Report to the International Patent national relatif A la demande de brevet Patentanmelduna Kr. Application No. international n' PCT/EP 94/0060E3 SAE 67017 dpiesem Anhanp sind die Mitqlieder This Annex lists the patent family La prisente annexe indioue les der Patentfamilien der im obehqe- members relatinq to the patent dobuments membres de la famille d6 brevets nannten internationalen Racherchenbericht cited in the ab6ve-mentibned inter- relatifs auy documents de brevets citts anqef~hrten Patentdakumente anqege-ben. national search report. The Office is dans le raoport de recherche inter- Diise Angaben dienen nur zur Ukiter- in no way liable for these particulars national vis~e ci-dessus. Les reseigne- richtung und erfolgen~ ohne Gewihr. which are given merely for the purpose ment, fournis sont donn~s A titre indica- of information. tif eA n'engagent pas la responsibilitt de l'Office. Im Recherchenbericht Datum der Iitglied(er) der Datum der angef~ihrtes Patentookument Yerdffentlichung Patentfamilie Verbffentlichunq Patenit document cited Publication Patent family Publication in search report date member(s) date Document de brevet citi Date de Membre(s) de la Date de dans le rapport de rechorche publication famille de brevets publication EF, Al1 3593789 21-03--90 1) A (1 3944/89 1 1-08-89 D K A 3944/89 1 r:i, AO 893g808 I1 1-0Q-89 FIA B 9:r 30S 14-02-90) 6GB A0 8819307 14-0)9-SB J P A 2 2083369 23-03-90 FT A 9 1439 80-9 US A 496G704 06-:11-90 L9 A 5 0 575!ji26 15- 10-9 1 EF' Al1 356176 28-02-90 CA Al1 1322755 05- 10-9:3 DE CC0 68909353 2G-1.0-93 DE 'T2 68B90 935 3 13-0 1 -94 EP R 11 3561J.76 22-09-93 JP A2 2056465 26-02-90 US A 4950667 2 1-08-90 W0 AlJ 9309 133 13-05--93 keine none i-ien EF- A2 565896 20)- AU Al1 368636/93 14--10--9:3 CA AA 2093770 14-10-93' DE Al 4212304 14-10-93 ER A3 565896 12-01--94 EP A3 565896 20-04--94 HU Ao 9:30o107 1 26-06-93 HU A2 64016 29-11-93 1.L A0 105355 18--08-93 EP A2 542363 19-05-93 AP AO 9200447 731-O0-9 AU Al 29158/92 15-0'6-93 CNI A 1073169 16-06-93 EP A3 542363 14-07-93 (7)B AC) 9 20 C-05:)r'2 1 1-03-92 1:L 1 0:'7 16 04-04-93 MlX A:L 9206541 '14-06-93 WO A2 9 3100()91. 27--0'5-93 WO A3 9 13110()9 :1 2 4- 0 6- GS3 A0 9124221 (0-0 1- I I I. INTERNATIONAL SEARCH REPORT International application No. PCT/EP 94/00608 a A. CLASSIFICATION OF SUBJECT MATTER C07D213/74, A61K31/44 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) C07D213/00, A61K31/00 Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. X EP, Al, 0 359 389 (PFIZER) 1-14 21 March 1990 (21.03.90), claims 1-5,8,12,13 A EP, Al, 0 356 176 (HAMARI CHEMICALS) 1-14 28 February 1990 (28.02.90), claims 1,6,7,9 A,P WO, Al, 93/09 133 (SMITHKLINE BEECHAM) 14,15 13 May 1993 (13.05.93), claims 8-10 A,P EP, A2, 0 565 896 (CASSELLA) 14,15 October 1993 (20.10.93), claims 8-10 Further documents are listed in the continuation of Box C. See patent family annex. Special categories of cited documents: laterdocumentpublishedaftertheinternational filing dateorpriority document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or heory underlying the invention earlier document but published on or after the international filing date document of particular relevance; the claimed invention cannot be considered novel or cannot be considered to involve an inventive document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation cr other special reason (as specified) document of particular relevance; the claimed invention cannot be document referring to an oral disclosure, use, exhibition or other considered to involve an inventive step when the document is means combinedwith oneormoreothersuch documents,suchcombination being obvious to a person skilled in the art document published prior to the international filing date but later than the priority date claimed document member of the same patent family Date of the actual completion of the international search Date of mailing of the international search report 16 June 1994 (16.06.94) 30 June 1994 (30.06.94) Name and mailing address of the ISA/ Authorized officer EUROPEAN PATENT OFFICE Facsimile No. Telephone No. Form PCT/ISA/210 (second sheet) (July 1992)
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE4306506A DE4306506A1 (en) | 1993-03-03 | 1993-03-03 | Novel 4-alkylaminopyridines - processes for their preparation and medicaments containing these compounds |
| DE4306506 | 1993-03-03 | ||
| DE4312966 | 1993-04-21 | ||
| DE19934312966 DE4312966A1 (en) | 1993-04-21 | 1993-04-21 | Novel 4-aminopyridines - process for their preparation and medicaments containing these compounds |
| PCT/EP1994/000608 WO1994020467A1 (en) | 1993-03-03 | 1994-03-02 | New 4-aminopyridines, process for preparing the same and medicaments containing the same |
Publications (2)
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| AU6257494A AU6257494A (en) | 1994-09-26 |
| AU682026B2 true AU682026B2 (en) | 1997-09-18 |
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| AU62574/94A Ceased AU682026B2 (en) | 1993-03-03 | 1994-03-02 | New 4-aminopyridines, process for preparing the same and medicaments containing the same |
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| JP (1) | JPH08507503A (en) |
| KR (1) | KR100252551B1 (en) |
| CN (1) | CN1046710C (en) |
| AT (1) | ATE174590T1 (en) |
| AU (1) | AU682026B2 (en) |
| CA (1) | CA2156729A1 (en) |
| CZ (1) | CZ225495A3 (en) |
| DE (1) | DE59407494D1 (en) |
| DK (1) | DK0687253T3 (en) |
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| SK (1) | SK108295A3 (en) |
| TW (1) | TW257757B (en) |
| WO (1) | WO1994020467A1 (en) |
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| DE4430755A1 (en) * | 1994-08-30 | 1996-03-07 | Boehringer Mannheim Gmbh | New phosphine oxides, processes for their preparation and medicaments containing these compounds |
| IL115420A0 (en) | 1994-09-26 | 1995-12-31 | Zeneca Ltd | Aminoheterocyclic derivatives |
| US5792769A (en) * | 1995-09-29 | 1998-08-11 | 3-Dimensional Pharmaceuticals, Inc. | Guanidino protease inhibitors |
| GB9525620D0 (en) | 1995-12-15 | 1996-02-14 | Glaxo Group Ltd | Chemical compounds |
| BR9612360A (en) | 1995-12-29 | 1999-07-13 | Dimensional Pharm Inc | Amidino protease inhibitors |
| GB9602166D0 (en) | 1996-02-02 | 1996-04-03 | Zeneca Ltd | Aminoheterocyclic derivatives |
| AU1608397A (en) | 1996-02-02 | 1997-08-22 | Zeneca Limited | Heterocyclic compounds useful as pharmaceutical agents |
| SE9602646D0 (en) | 1996-07-04 | 1996-07-04 | Astra Ab | Pharmaceutically useful compounds |
| CA2260872A1 (en) * | 1996-08-14 | 1998-02-19 | Elaine Sophie Elizabeth Stokes | Substituted pyrimidine derivatives and their pharmaceutical use |
| JP2001500864A (en) * | 1996-09-13 | 2001-01-23 | メルク エンド カンパニー インコーポレーテッド | Thrombin inhibitors |
| GB9821483D0 (en) | 1998-10-03 | 1998-11-25 | Glaxo Group Ltd | Chemical compounds |
| UA56197C2 (en) | 1996-11-08 | 2003-05-15 | Зенека Лімітед | Heterocyclic derivatives |
| TW499412B (en) | 1996-11-26 | 2002-08-21 | Dimensional Pharm Inc | Aminoguanidines and alkoxyguanidines as protease inhibitors |
| WO1998024760A1 (en) * | 1996-12-03 | 1998-06-11 | Graybill Todd L | Aminobenzenedicarboxylic acid-based combinatorial libraries |
| DE69815509T2 (en) | 1997-02-13 | 2004-05-13 | Astrazeneca Ab | HETEROCYCLIC COMPOUNDS THAT APPLY AS OXIDO-SQUALEN-CYCLASE INHIBITORS |
| US6440972B1 (en) | 1997-02-13 | 2002-08-27 | Zeneca Limited | Heterocyclic compounds useful as oxido-squalene cyclase inhibitors |
| GB9715895D0 (en) | 1997-07-29 | 1997-10-01 | Zeneca Ltd | Heterocyclic compounds |
| JP4327915B2 (en) * | 1998-03-30 | 2009-09-09 | 株式会社デ・ウエスタン・セラピテクス研究所 | Sulfonamide derivatives |
| AU754253B2 (en) | 1998-10-06 | 2002-11-07 | Dainippon Pharmaceutical Co. Ltd. | 2,3-disubstituted pyridine derivatives, processes for the preparation thereof, pharmaceutical compositions containing the same and intermediates therefor |
| GB9902989D0 (en) | 1999-02-11 | 1999-03-31 | Zeneca Ltd | Heterocyclic derivatives |
| AR023510A1 (en) | 1999-04-21 | 2002-09-04 | Astrazeneca Ab | A TEAM OF PARTS, PHARMACEUTICAL FORMULATION AND USE OF A THROMBIN INHIBITOR. |
| EP1307432A1 (en) | 2000-08-04 | 2003-05-07 | 3-Dimensional Pharmaceuticals, Inc. | Cyclic oxyguanidine protease inhibitors |
| WO2002089740A2 (en) * | 2001-05-07 | 2002-11-14 | Smithkline Beecham Corporation | Sulfonamides |
| US6849635B2 (en) * | 2001-05-07 | 2005-02-01 | Smithkline Beecham Corporation | Sulfonamides |
| US7476683B2 (en) | 2002-08-27 | 2009-01-13 | Merck Patent Gmbh | Glycinamide derivatives as raf-kinase inhibitors |
| BR0314126A (en) | 2002-09-20 | 2005-06-28 | Pfizer Prod Inc | Acyclic Amide and Sulphonamide Ligands for Estrogen Receptor |
| RU2374230C2 (en) | 2003-11-05 | 2009-11-27 | Ф.Хоффманн-Ля Рош Аг | Phenyl derivatives as ppar agonists |
| WO2008104994A2 (en) * | 2007-02-28 | 2008-09-04 | Advinus Therapeutics Private Limited | 2,2,2-tri-substituted acetamide derivatives as glucokinase activators, their process and pharmaceutical application |
| RU2354647C2 (en) * | 2007-06-28 | 2009-05-10 | Общество С Ограниченной Ответственностью "Бионика" | New compounds with thrombin inhibiting function, and based pharmaceutical compositions |
| RU2353619C2 (en) * | 2007-06-28 | 2009-04-27 | Общество С Ограниченной Ответственностью "Бионика" | Novel compounds possessing anticoagulant function, based on them pharmaceutical compositions for treatment of thrombotic conditions and plasma-substituting solution for correction of hypercoagulation disorders in hemodilution |
| GB0815784D0 (en) * | 2008-08-29 | 2008-10-08 | Xention Ltd | Novel potassium channel blockers |
| GB0815781D0 (en) | 2008-08-29 | 2008-10-08 | Xention Ltd | Novel potassium channel blockers |
| GB0815782D0 (en) | 2008-08-29 | 2008-10-08 | Xention Ltd | Novel potassium channel blockers |
| US8265575B2 (en) * | 2009-06-16 | 2012-09-11 | Mediatek Inc. | Methods for handling a transmitting process and communication apparatuses utilizing the same |
| US8207639B2 (en) | 2009-10-23 | 2012-06-26 | Sunonwealth Electric Machine Industry Co., Ltd. | Motor and heating dissipating fan including motor having an annular balancing member |
| RU2685261C1 (en) * | 2018-04-05 | 2019-04-17 | Общество с ограниченной ответственностью "ФК ЛАБОРАТОРИЗ" | 4-amino-1-{2-[3-methyl-5-(benzenesulfonyloxy]phenoxy]ethyl}-pyridium chloride substance, having the biologically active agent properties, influencing the mammals blood coagulability naturally running processes, anticoagulant on its basis and its obtaining method by chemical synthesis |
| CN109172573B (en) * | 2018-09-12 | 2021-01-26 | 黑龙江中桂制药有限公司 | Oral antithrombotic drug and application thereof |
| CN110669337B (en) * | 2019-07-08 | 2020-09-25 | 中国科学院长春应用化学研究所 | Aromatic diamine monomer and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0359389A1 (en) * | 1988-08-13 | 1990-03-21 | Pfizer Limited | Antiarrhythmic agents |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH0256465A (en) * | 1988-08-22 | 1990-02-26 | Hamari Yakuhin Kogyo Kk | Acetamide compound |
| JPH07501057A (en) * | 1991-10-31 | 1995-02-02 | スミスクライン・ビーチャム・コーポレイション | C8-cyclic peptide mimetics for fibrinogen antagonists |
| WO1993010091A2 (en) * | 1991-11-14 | 1993-05-27 | Glaxo Group Limited | Piperidine acetic acid derivatives as inhibitors of fibrinogen-dependent blood platelet aggregation |
| DE4212304A1 (en) * | 1992-04-13 | 1993-10-14 | Cassella Ag | Aspartic acid derivatives, their preparation and use |
-
1994
- 1994-02-22 TW TW083101504A patent/TW257757B/zh active
- 1994-02-28 IL IL10878694A patent/IL108786A/en not_active IP Right Cessation
- 1994-03-02 AT AT94909909T patent/ATE174590T1/en not_active IP Right Cessation
- 1994-03-02 DK DK94909909T patent/DK0687253T3/en active
- 1994-03-02 WO PCT/EP1994/000608 patent/WO1994020467A1/en not_active Application Discontinuation
- 1994-03-02 HU HU9502568A patent/HUT72898A/en unknown
- 1994-03-02 CZ CZ952254A patent/CZ225495A3/en unknown
- 1994-03-02 AU AU62574/94A patent/AU682026B2/en not_active Ceased
- 1994-03-02 RU RU95122612A patent/RU2126388C1/en active
- 1994-03-02 DE DE59407494T patent/DE59407494D1/en not_active Expired - Fee Related
- 1994-03-02 SK SK1082-95A patent/SK108295A3/en unknown
- 1994-03-02 CN CN94191554A patent/CN1046710C/en not_active Expired - Fee Related
- 1994-03-02 JP JP6519556A patent/JPH08507503A/en active Pending
- 1994-03-02 NZ NZ262725A patent/NZ262725A/en unknown
- 1994-03-02 EP EP94909909A patent/EP0687253B1/en not_active Expired - Lifetime
- 1994-03-02 CA CA002156729A patent/CA2156729A1/en not_active Abandoned
- 1994-03-02 PL PL94310520A patent/PL176455B1/en unknown
- 1994-03-02 ES ES94909909T patent/ES2127919T3/en not_active Expired - Lifetime
- 1994-03-02 KR KR1019950703694A patent/KR100252551B1/en not_active IP Right Cessation
-
1995
- 1995-09-01 FI FI954105A patent/FI954105A/en unknown
- 1995-09-01 NO NO953447A patent/NO953447L/en unknown
-
1999
- 1999-03-16 GR GR990400775T patent/GR3029691T3/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0359389A1 (en) * | 1988-08-13 | 1990-03-21 | Pfizer Limited | Antiarrhythmic agents |
Also Published As
| Publication number | Publication date |
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| GR3029691T3 (en) | 1999-06-30 |
| KR100252551B1 (en) | 2000-05-01 |
| DE59407494D1 (en) | 1999-01-28 |
| DK0687253T3 (en) | 1999-08-23 |
| EP0687253B1 (en) | 1998-12-16 |
| FI954105A0 (en) | 1995-09-01 |
| HU9502568D0 (en) | 1995-11-28 |
| TW257757B (en) | 1995-09-21 |
| EP0687253A1 (en) | 1995-12-20 |
| NZ262725A (en) | 1997-05-26 |
| NO953447D0 (en) | 1995-09-01 |
| CN1119858A (en) | 1996-04-03 |
| IL108786A (en) | 1999-04-11 |
| HUT72898A (en) | 1996-06-28 |
| ES2127919T3 (en) | 1999-05-01 |
| AU6257494A (en) | 1994-09-26 |
| CA2156729A1 (en) | 1994-09-15 |
| CZ225495A3 (en) | 1996-01-17 |
| WO1994020467A1 (en) | 1994-09-15 |
| FI954105A (en) | 1995-09-01 |
| RU2126388C1 (en) | 1999-02-20 |
| SK108295A3 (en) | 1996-06-05 |
| CN1046710C (en) | 1999-11-24 |
| NO953447L (en) | 1995-09-01 |
| PL310520A1 (en) | 1995-12-27 |
| IL108786A0 (en) | 1994-06-24 |
| PL176455B1 (en) | 1999-05-31 |
| KR960701019A (en) | 1996-02-24 |
| JPH08507503A (en) | 1996-08-13 |
| ATE174590T1 (en) | 1999-01-15 |
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| MK14 | Patent ceased section 143(a) (annual fees not paid) or expired |