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WO1994020468A1 - 4-aminopyridines, leur fabrication et leur utilisation comme agents antithrombotiques - Google Patents

4-aminopyridines, leur fabrication et leur utilisation comme agents antithrombotiques Download PDF

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Publication number
WO1994020468A1
WO1994020468A1 PCT/EP1994/000609 EP9400609W WO9420468A1 WO 1994020468 A1 WO1994020468 A1 WO 1994020468A1 EP 9400609 W EP9400609 W EP 9400609W WO 9420468 A1 WO9420468 A1 WO 9420468A1
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compounds
formula
alkyl
acid
general formula
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PCT/EP1994/000609
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German (de)
English (en)
Inventor
Herbert Leinert
Wolfgang Von Der Saal
Karlheinz Stegmeier
Thomas Poll
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Boehringer Mannheim Gmbh
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Application filed by Boehringer Mannheim Gmbh filed Critical Boehringer Mannheim Gmbh
Priority to AU62824/94A priority Critical patent/AU6282494A/en
Priority to JP6519557A priority patent/JPH08509472A/ja
Priority to EP94910360A priority patent/EP0687254A1/fr
Publication of WO1994020468A1 publication Critical patent/WO1994020468A1/fr

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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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to new 4-aminopyridines of the general formula I.
  • R an aryl, a heteroaryl or a cycioalkyl group, which can be substituted if desired
  • n the numbers 0 or 1
  • R 2 and R « are identical or different and form hydrogen atoms, alkyl, carboxyalkyl or alkoxycarbonylalkyl groups or R 2 and R 3 together with the nitrogen atom to which they are attached form a heterocyclyl ring which, if desired, also contains a second hetero atom and can be substituted by alkyl, carboxy or alkoxycarbonyl groups,
  • R 4 and R 5 are identical or different and are hydrogen atoms or alkyl groups, m the numbers 0, 1 or 2,
  • Rg, R7, R ⁇ and Rg are the same or different and denote hydrogen atoms or halogen atoms
  • the invention also relates to the optically active forms, the racemates and the diastereomer mixtures of these compounds.
  • the invention also relates to processes for the preparation of the above compounds, medicaments containing such compounds and the use of these compounds in the production of medicaments.
  • the aminopyridines of the general formula I inhibit both the thrombin-induced clotting of fibrinogen in the blood and the thrombin-induced aggregation of the blood platelets. They prevent the formation of coagulation thrombi and platelet-rich thrombi and can be used to combat and prevent diseases such as thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis. These compounds also have an effect on tumor cells and prevent the formation of metastases. Thus, they can be used as anti-tumor agents.
  • Thrombin the last enzyme in the coagulation cascade, cleaves fibrinogen to fibrin, which is cross-linked by the Xllla factor and becomes an insoluble gel that 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. If a blood vessel is injured, these processes are necessary to stop bleeding. Under normal circumstances, there are no measurable thrombin concentrations in the blood plasma. Increasing thrombin concentration can lead to the formation of thrombi and thus to thromboembolic diseases, which occur very frequently, especially in the industrialized countries.
  • Thrombin is kept in the form of prothrombin in the plasma and released by factor Xa. Thrombin activates factor VIII, which then converts factor X to factor Xa with factor IXa. Thrombin thereby catalyzes its own release, which is why thrombin concentrations can increase very rapidly.
  • Thrombin inhibitors can therefore inhibit the release of thrombin, platelet-induced and plasmatic blood coagulation.
  • thrombin inhibitors In addition to thrombin, there are a whole series of serine proteases that cleave peptide substrates in addition to a basic amino acid. To minimize side effects, the thrombin inhibitors should be selective, i.e. H. they should inhibit other serine proteases only slightly or not at all. Trypsin in particular, as the most unspecific serine protease, can be easily inhibited by a wide variety of inhibitors. Trypsin inhibition can lead to pancreatic stimulation and to pancreatic hypertrophy (J.D. 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 the thrombus by breaking down fibrin. Inhibition of the plasmin would therefore have exactly the opposite effect which one would like to achieve by inhibiting the thrombin.
  • Synthetic thrombin inhibitors have long been known. Starting from fibrinogen, the natural substrate of thrombin, substances of the (D) -Phe-Pro-Arg type were synthesized. Such tripeptides mimic the amino acid sequence before the cleavage site on the fibrinogen. In order to obtain good inhibitors, the carboxylate group of the arginine was changed so that the hydroxyl group of the serine-195 of the active site of the thrombin can react with it. This is possible, for example, by replacing the carboxylate group with the aldehyde function. Corresponding (D) -Phe-Pro-Arginale are described in the patent application EP-A-185390.
  • the benzamidine known as the trypsin inhibitor was used as the basis.
  • the inhibitors obtained in this way differ from the (D) - Phe-Pro-Arg types not only in their chemical structure, but also in the type of inhibition: the serine-195 of thrombin does not bind to these inhibitors. This is clearly evident from X-ray structure examinations. before (W. Bode, D. Turk, J. Sturzbecher, Eur. J. Biochem. 193, 175-182 (1990)).
  • This second class of thrombin inhibitors includes N- (2-naphthylsulfonylglycyl) -4-amidino- (R, S) -phenylalanine piperidide ("NAPAP", DD 235866).
  • a disadvantage of the inhibitors of the (D) -Phe-Pro-Arg class is the lack of selectivity towards other serine proteases (JC Powers, C.-M. Kam, in Thrombin, Structure and Function (LJ Hopkins, editor), plenum , New York 1992, p.117). Selectivity is slightly better with NAPAP.
  • the inhibition constants of NAPAP are as follows (J. Sturzbecher et al., Pharmazie 34 (1988), p. 782): thrombin 6 nM, trypsin 0.69 ⁇ M, plasmin 30 ⁇ M.
  • the selectivity of this inhibitor between thrombin and trypsin, expressed as the quotient of the inhibition constant, is therefore about 1: 100.
  • the phenyl, naphthyl and anthryl group if desired with 1-5 identical or different substituents such as halogen, nitro, nitrile, phenyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, trifluoromethyl, trrfluoromethoxy, C-
  • the phenyl groups can be condensed with a cycloalkyl or heterocyclyl group, the tetrahydronaphthyl, indanyl, chromanyl, methylenedioxyphenyl, ethylenedioxyphenyl and tetrahydroquinolinyl groups being particularly preferred.
  • Heteroaryl for R means five- and six-membered aromatics with 1-4 heteroatoms such as nitrogen, oxygen or sulfur, which can be condensed with one or two phenyl groups and whose carbon atoms, if desired, substituents such as halogen, nitro, nitrile, phenyl , Trifluoromethyl-, C j -Cg-alkyl-, C j -Cg-alkenyl-, C ⁇ Cg-alkynyl-, hydroxy-, C- J -Cg-alkyloxy-, C j -Cg-alkenyloxy-, C j - Cg-alkynyloxy, amino, C ⁇ Cg-alkylamino, C j -CG-alkenylamino, Ci-CSS alkynylamino, di- (C ..- Cg-alkyl) amino, benzylamino, carboxyl, Ci-C ⁇ -alkyl
  • Preferred aromatics are furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazine, tetrazine, benzothiophene, dibenzothiophene, benzimidazole or carbazole.
  • the C.-Cg components mentioned can be straight-chain or branched. These are preferably to be understood as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, vinyl, allyl and propargyl radicals.
  • Cycloalkyl groups for R. are rings with 3-8 C atoms, preferably the cyclopentyl, cyclohexyl and cycloheptyl group.
  • AS means glycine, azaglycine and the amino acids alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophane, serine, threonine, asparagine, aspartic acid, glutamine, glutamic acid, tyrosine , Cysteine, lysine, arginine and histidine, which can be in the D or L form or as a mixture of both forms.
  • R 1 and R 3 form a heterocyclyl ring together with the nitrogen atom to which they are attached, this is preferably understood to mean pyrrolidine, piperidine, homopiperidine, piparazine, morpholine and thiomorpholine. These rings can carry one or two C.-Cg-alkyl, carboxyl or C.-Cg-alkyloxycarbonyl groups.
  • R ⁇ 1 means in particular a phenyl, naphthyl, tetrahydronaphthyl, pyridinyl, thienyl, cyclohexyl or chromanyl ring which can be substituted one or more times by C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or halogen groups .
  • AS means in particular glycine, azaglycine, alanine, glutamine, glutamate, asparagine or aspartate.
  • n means in particular the numbers 0 or 1.
  • R 1 and R 3 can be the same or different and in particular mean a C 1 -C 6 -alkyl group, such as, for example, the ethyl group; a C-
  • R 4 and R 5 can be the same or different and in particular represent hydrogen atoms or C 1 -C 6 -alkyl groups, preferably methyl groups.
  • Rg, R, Rg, R g can be the same or different and in particular represent hydrogen, fluorine or chlorine atoms.
  • R 1 phenyl, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 1-naphthyl,
  • AS means glycine, azaglycine or alanine, glutamine, glutamate, asparagine or aspartate,
  • n can be the numbers 0 or 1
  • R 2 and R 3 are the same or different and are ethyl, ethoxycarbonylmethyl or carboxymethyl or, together with the N atom to which they are bound, a pyrrolidine, piperidine, homopiperidine, morpholine, thiomorpholine or piperazine ring form, optionally one or two methyl, ethyl, propyl, butyl, carboxyl, methoxycarbonyl, ethoxycarbonyl or tert. Can carry butyloxy-carbonyl groups,
  • R. and R c are identical or different and denote hydrogen atoms or methyl groups
  • Rg, R, Rg, Rg are the same or different and denote hydrogen, fluorine or chlorine atoms.
  • physiologically tolerated salts of the compounds of the general formula I are formates, acetates, caproates, oleates, lactates, or salts of carboxylic acids with up to 16 C atoms, hydrochlorides, hydrobromides, hydroiodides, alakanesulfonates with up to 10 C atoms, Salts of dicarboxylic acids and tricarboxylic acids such as citrates, malonates and tartrates.
  • R - j - R e - AS, n and m have the abovementioned meanings and Seh represents a protective group such as the benzyloxycarbonyl, t-butoxycarbonyl or the phthalimido group, with which it reacts with a reagent which splits off the protective groups.
  • the compounds of the general formula IV can be prepared by
  • Y is a halogen atom or an activated radical customary in peptide chemistry and A is a nitrogen atom or an atomic group of the general formula X
  • R 1 Q represents one of the usual amino acid side chain.
  • the compounds of the general formula V are prepared by processes known from the literature.
  • the compounds of general formula I can also be prepared by using a compound of general formula XI,
  • the compounds of general formula XI are prepared by using a compound of general formula XII,
  • R 2 -R g have the meanings given and Seh means a protective group which is customary in peptide chemistry, such as the benzyloxycarbonyl, t-butoxycarbonyl or phthalimide radical, is reacted with a reagent which cleaves the protective groups and is customary in peptide chemistry.
  • the compounds of general formula XIII are prepared by combining the amide group with a compound of general formula XIV, in which R 2 -R c , Seh and m have the meanings given, subject to a Hofmann degradation.
  • the compounds of general formula XIV are prepared by using a compound of general formula XV,
  • the compounds of the general formula -XV are prepared from compounds of the general formula XVI,
  • R 4 and R c have the meanings given, by reaction with a protective group reagent customary in peptide chemistry.
  • the compounds of the general formula XVI are known in the literature.
  • the reactions of a compound of general formula II with a compound of general formula III to a compound of general formula I are carried out in an inert solvent such as dimethylformamide, dioxane, dimethyl sulfoxide or toluene at temperatures between 0 degrees Celsius and boiling point of the solvent , preferably at room temperature in the presence of an auxiliary base such as triethylamine, N-methylmorpholine, pyridine or N-ethyldi-isopropylamine.
  • an inert solvent such as dimethylformamide, dioxane, dimethyl sulfoxide or toluene
  • an auxiliary base such as triethylamine, N-methylmorpholine, pyridine or N-ethyldi-isopropylamine.
  • the compounds of the general formula I in which Rg-Rg are hydrogen, from the compounds of the general formula I in which Rg-Rg are halogen, are obtained from these by catalytic hydrogenation in an inert solvent such as e.g. Methanol or ethanol in the presence of an acid binding agent such as e.g. Sodium methylate or sodium ethylate preferably at room temperature and normal pressure with platinum or palladium as the catalyst.
  • an inert solvent such as e.g. Methanol or ethanol
  • an acid binding agent such as e.g. Sodium methylate or sodium ethylate preferably at room temperature and normal pressure with platinum or palladium as the catalyst.
  • the compounds of the general formula II are prepared by splitting off a protective group from the compounds of the general formula IV in accordance with the methods customary in peptide chemistry by acidic reagents such as e.g. Bromwas ⁇ hydrogen in glacial acetic acid, trifluoroacetic acid or hydrogenolytically or by cleavage with hydrazine.
  • acidic reagents such as e.g. Bromwas ⁇ hydrogen in glacial acetic acid, trifluoroacetic acid or hydrogenolytically or by cleavage with hydrazine.
  • the compounds of the general formula V are prepared by methods known from the literature, e.g. from an amino acid precursor with phosgene in an inert solvent such as e.g. Dioxane.
  • reaction of compounds of general formula V to compounds of general formula IV is also carried out according to methods known in the literature in an inert solvent such as e.g. Dimethylformamide at temperatures between -50 and +50 degrees Celsius.
  • an inert solvent such as e.g. Dimethylformamide at temperatures between -50 and +50 degrees Celsius.
  • reaction of compounds of general formula XI with compounds of general formula VIII to compounds of general formula I is carried out in an inert solvent such as dimethylformamide, methylene chloride or dioxane at temperatures between 0 and 50 degrees Celsius, preferably at room temperature in the presence of an auxiliary base such as Triethylamine, N-methyl-morpholine or N-ethyl-diisopropylamine.
  • an auxiliary base such as Triethylamine, N-methyl-morpholine or N-ethyl-diisopropylamine.
  • the amino protective group is split off from a compound of the general formula XII to a compound of the general formula XI, for example, hydrolytically using a solution of hydrogen bromide in glacial acetic acid, trifluoroacetic acid, hydrogenolytically or by reaction with hydrazine by customary methods known in peptide chemistry.
  • reaction of a compound of general formula XIII with a compound of general formula III to a compound of general formula XII is carried out in an inert solvent such as e.g. Dimethylformamide, dioxane, dimethyl sulfoxide or toluene at temperatures between 0 degrees Celsius and the boiling point of the solvent, preferably at room temperature in the presence of an auxiliary base such as e.g. Triethylamine, N-methyl-morpholine, pyridine or N-ethyl-diisopropylamine.
  • an inert solvent such as e.g. Dimethylformamide, dioxane, dimethyl sulfoxide or toluene at temperatures between 0 degrees Celsius and the boiling point of the solvent, preferably at room temperature in the presence of an auxiliary base such as e.g. Triethylamine, N-methyl-morpholine, pyridine or N-ethyl-diisopropylamine.
  • the conversion of compounds of the general formula XIV into compounds of the general formula XIII is carried out by Hofmann degradation, preferably using [bis (trifluoroacetoxy) iodo] benzene in a mixture of an inert solvent with water, preferably in an acetonitrile / water mixture, preferably at room temperature.
  • the compounds of the general formula XIV are prepared from compounds of the general formula XV by methods customary in peptide chemistry.
  • the compounds of the general formula XV are also prepared from the compounds of the general formula XVI by methods customary in peptide chemistry.
  • physiologically usable salts of the compounds of the formula I are salts with physiologically tolerable mineral acids, such as hydrochloric acid, sulfuric acid, sulfurous 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 compatible bases. Examples of such salts are alkali metal, earth alkali metal, ammonium and alkylammonium salts such as the Na, K, Ca or tetramethylammonium salt.
  • the compounds of the formula I can be solvated, in particular hydrated.
  • the hydration can take place in the course of the production process or can gradually occur as a result of hygroscopic properties of an initially water-free compound of the formula I.
  • Pure enantiomers of the compounds of the formula I are obtained either by racemate resolution (via salt formation with optically active bases) or by using optically active starting materials in the synthesis.
  • the substances of the general formula I are mixed with suitable pharmaceutical carriers, flavoring, flavoring and coloring agents and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, e.g. in olive oil, suspended or dissolved.
  • the substances of the general formula I and their salts can be administered enterally or parenterally in liquid or solid form.
  • Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizing agents, solubilizers or buffers.
  • additives are e.g. Tartrate and citrate buffers, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts) and high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation.
  • Solid carriers are e.g.
  • Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.
  • the compounds are usually applied in amounts of 10-1500 mg per day based on 75 kg of body weight. It is preferred to administer 1-2 tablets with an active substance content of 5-500 mg 2-3 times a day. The tablets can also be delayed, which means that only 1-2 tablets with 20-700 mg of active ingredient have to be given once a day. The active substance can also be injected tion are given 1-8 times a day or by continuous infusion, with 50-2000 mg per day usually being sufficient.
  • the methylene chloride phase is dried over sodium sulfate and evaporated.
  • the crude ⁇ -bromo- ⁇ -phthalimido-valeric acid obtained (53 g) is dissolved in 300 ml of dimethylformamide without further purification. 20.8 g of sodium azide are added to this solution and the mixture is stirred for 24 hours at room temperature. Then the solution i.Vak. evaporated, the residue dissolved in ethyl acetate, the solution washed with water, dried over sodium sulfate and evaporated.
  • the ⁇ -azido- ⁇ -phthalimido-valeric acid obtained is concentrated in a mixture of 240 ml of glacial acetic acid and 30 ml.
  • the titite compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that homopiperidine was used instead of piperidine.
  • Mp 150 degrees Celsius.
  • FAB-MS M + H 524.
  • the titite compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that 2-naphthylsulfonyl- (S) -methyl-asparaginyl chloride was used instead of 2-naphthylsulfonylglycyl chloride.
  • FAB-MS M + H 582.
  • Thrombin time is a test commonly used in clinical coagulation diagnostics. This parameter detects the thrombin effect on fibrinogen and the formation of clot. Thrombin inhibitors cause an increase in thrombin time.
  • ⁇ l of citrate plasma were incubated in a spherical coaguiometer (KC10 from Amelung) at 37 ° C. for 2 minutes.
  • 10 ⁇ l of dimethyl sulfoxide (DMSO) or a solution of the active substance in DMSO were added to 190 ⁇ l of pre-heated thrombin reagent (Boehringer Mannheim GmbH; contains approx. 3 U / ml horse thrombin and 0.0125 M Ca ++ ).
  • a stopwatch was started and the point in time until coagulation started was determined.
  • the thrombin time in the control measurements was approx. 24 seconds and was significantly extended by the active substances.
  • the following table shows the measured thrombin times in seconds as the difference to the control.
  • the concentrations of the active substances in the final volume are 250 ⁇ M (TT250), 25 ⁇ M (TT25) and 2.5 ⁇ M (TT2.5).
  • the reactions were started by adding thrombin.
  • the increase in absorbance at 405 nm by the resulting p-nitroaniline was monitored over a period of 12 minutes.
  • Measuring points time vs. extinction
  • the velocities V 0 (change in extinction per second; measurements without inhibitor) and Vj (measurements with inhibitor) were determined from the data by linear regression. Only the part of each measurement in which the substrate concentration had decreased by less than 15% was used. From a series of measurements (constant inhibitor concentration, variable substrate concentrations), K m " and V max were determined by a nonlinear fit to the equation
  • the inhibition constants Kj of the active substances are given in the following table in the unit ⁇ M.

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Abstract

Composés de formule (I) dans laquelle R1 désigne un groupe aryle, hétéroaryle ou cycloalkyle pouvant être éventuellement substitué; AS désigne un aminoacide; n est égal à 0 ou 1; R2 et R3 sont identiques ou différents et désignent des atomes d'hydrogène, des groupes alkyle, carboxyalkyl ou alcoxycarbonylalkyle, ou bien R2 et R3 forment, conjointement avec l'atome d'azote auquel ils sont liés, un noyau hétérocyclyle pouvant éventuellement renfermer un deuxième hétéroatome et être substitué par des groupes alkyle; carboxy ou alcoxycarbonyle; R4 et R5 sont identiques ou différents et désignent des atomes d'hydrogène ou des groupes alkyle; m est égal à 0, 1 ou 2; R6, R7, R8 et R9 sont identiques ou différents et désignent des atomes d'hydrogène ou des atomes d'halogène; ainsi que hydrates, solvates et sels physiologiquement compatibles de ces composés. L'invention a également pour objet les formes optiquement actives, les racémates et les mélanges diastéréomères de ces composés, leur procédé de fabrication et les médicaments renfermant ces composés, en particulier un procédé de fabrication de médicaments destinés au traitement de maladies thrombo-emboliques.
PCT/EP1994/000609 1993-03-05 1994-03-02 4-aminopyridines, leur fabrication et leur utilisation comme agents antithrombotiques WO1994020468A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU62824/94A AU6282494A (en) 1993-03-05 1994-03-02 4-aminopyridines, their production and use as an antithrombosis agent
JP6519557A JPH08509472A (ja) 1993-03-05 1994-03-02 新規４−アミノピリジン、それらの製造方法およびそれらを含有する薬剤
EP94910360A EP0687254A1 (fr) 1993-03-05 1994-03-02 4-aminopyridines, leur preparation et leur utilisation comme agent antithrombotique

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DEP4306873.1 1993-03-05
DE4306873A DE4306873A1 (de) 1993-03-05 1993-03-05 Neue 4-Aminopyridine-Verfahren zu ihrer Herstellung sowie diese Verbindungen enthaltende Arzneimittel

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Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5559150A (en) * 1995-06-06 1996-09-24 3-Dimensional Pharmaceuticals, Inc. N,N-disulfonylated aminobenzene carboxlic acids and the use thereof as thrombin inhibitors
WO1997028129A1 (fr) * 1996-02-02 1997-08-07 Zeneca Limited Derives aminoheterocycliques en tant qu'agents anti-thrombotiques ou anticoagulants
US5741819A (en) * 1995-06-07 1998-04-21 3-Dimensional Pharmaceuticals, Inc. Arylsulfonylaminobenzene derivatives and the use thereof as factor Xa inhibitors
WO1999009027A1 (fr) * 1997-07-29 1999-02-25 Zeneca Limited Derives de (hetero)aryle-sulfonamide, leur preparation et leur utilisation en tant qu'inhibiteurs du facteur xa
US5965559A (en) * 1994-09-26 1999-10-12 Zeneca Limited Aminoheterocyclic derivatives as antithrombotic or anticoagulant
US6093718A (en) * 1996-08-14 2000-07-25 Zeneca Limited Substituted pyrimidine derivatives and their pharmaceutical use
US6300330B1 (en) 1996-11-08 2001-10-09 Zeneca Limited Heterocycle derivatives which inhibit factor Xa
US6313127B1 (en) 1996-02-02 2001-11-06 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
US6440972B1 (en) 1997-02-13 2002-08-27 Zeneca Limited Heterocyclic compounds useful as oxido-squalene cyclase inhibitors
US6723723B1 (en) 1999-02-11 2004-04-20 Astrazeneca Heterocyclic derivatives as inhibitors of factor Xa
WO2004076434A1 (fr) * 2003-02-28 2004-09-10 Aic Inhibiteurs de dipeptidyl peptidases
WO2018050110A1 (fr) * 2016-09-18 2018-03-22 正大天晴药业集团股份有限公司 Nouvel inhibiteur d'assemblage de protéine capsidique

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US6730672B2 (en) 1994-09-26 2004-05-04 Zeneca Limited Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents
US5965559A (en) * 1994-09-26 1999-10-12 Zeneca Limited Aminoheterocyclic derivatives as antithrombotic or anticoagulant
US6225309B1 (en) 1994-09-26 2001-05-01 Zeneca Limited Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents
US5559150A (en) * 1995-06-06 1996-09-24 3-Dimensional Pharmaceuticals, Inc. N,N-disulfonylated aminobenzene carboxlic acids and the use thereof as thrombin inhibitors
US5741819A (en) * 1995-06-07 1998-04-21 3-Dimensional Pharmaceuticals, Inc. Arylsulfonylaminobenzene derivatives and the use thereof as factor Xa inhibitors
US7173025B1 (en) 1996-02-02 2007-02-06 Zeneca Limited Aminoheterocyclic derivatives as antithrombotic or anticoagulant agents
WO1997028129A1 (fr) * 1996-02-02 1997-08-07 Zeneca Limited Derives aminoheterocycliques en tant qu'agents anti-thrombotiques ou anticoagulants
US6313127B1 (en) 1996-02-02 2001-11-06 Zeneca Limited Heterocyclic compounds useful as pharmaceutical agents
US6093718A (en) * 1996-08-14 2000-07-25 Zeneca Limited Substituted pyrimidine derivatives and their pharmaceutical use
US6300330B1 (en) 1996-11-08 2001-10-09 Zeneca Limited Heterocycle derivatives which inhibit factor Xa
US6936610B2 (en) 1996-11-08 2005-08-30 Astrazeneca Uk Limited Heterocyclic derivatives
US6440972B1 (en) 1997-02-13 2002-08-27 Zeneca Limited Heterocyclic compounds useful as oxido-squalene cyclase inhibitors
US6486154B1 (en) 1997-07-29 2002-11-26 Zeneca Limited (Hetero) aryl-sulfonamide derivatives, their preparation and their use as factor XA inhibitors
WO1999009027A1 (fr) * 1997-07-29 1999-02-25 Zeneca Limited Derives de (hetero)aryle-sulfonamide, leur preparation et leur utilisation en tant qu'inhibiteurs du facteur xa
US6723723B1 (en) 1999-02-11 2004-04-20 Astrazeneca Heterocyclic derivatives as inhibitors of factor Xa
WO2004076434A1 (fr) * 2003-02-28 2004-09-10 Aic Inhibiteurs de dipeptidyl peptidases
WO2018050110A1 (fr) * 2016-09-18 2018-03-22 正大天晴药业集团股份有限公司 Nouvel inhibiteur d'assemblage de protéine capsidique

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IL108847A0 (en) 1994-06-24
ZA941522B (en) 1995-09-04
DE4306873A1 (de) 1994-09-08
EP0687254A1 (fr) 1995-12-20
CA2157215A1 (fr) 1994-09-15
JPH08509472A (ja) 1996-10-08
AU6282494A (en) 1994-09-26

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