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WO1997008165A1 - Nouvelles guanidines cycliques, procede de production correspondant et medicaments - Google Patents

Nouvelles guanidines cycliques, procede de production correspondant et medicaments Download PDF

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Publication number
WO1997008165A1
WO1997008165A1 PCT/EP1996/003679 EP9603679W WO9708165A1 WO 1997008165 A1 WO1997008165 A1 WO 1997008165A1 EP 9603679 W EP9603679 W EP 9603679W WO 9708165 A1 WO9708165 A1 WO 9708165A1
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Prior art keywords
group
yloxy
imino
methyl
amino
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PCT/EP1996/003679
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German (de)
English (en)
Inventor
Ralf Kucznierz
Wolfgang Von Der Saal
Herbert Leinert
Frank Grams
Karlheinz Stegmeier
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Boehringer Mannheim Gmbh
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Application filed by Boehringer Mannheim Gmbh filed Critical Boehringer Mannheim Gmbh
Priority to AU69264/96A priority Critical patent/AU6926496A/en
Priority to EP96930066A priority patent/EP0846115A1/fr
Priority to JP9509817A priority patent/JPH11511445A/ja
Publication of WO1997008165A1 publication Critical patent/WO1997008165A1/fr

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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
    • 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
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates

Definitions

  • the invention relates to new cyclic guanidines of the general formula I.
  • Rl, R2, R3 independently of one another a hydrogen atom, a halogen atom, a
  • X represents a single bond, an alkylene or alkyleneoxy group
  • Y can be a single bond, a chalcogen atom or a carbonyl group
  • Z represents a saturated or unsaturated, optionally substituted, heterocyclic or carbocyclic ring system, an optionally substituted amino group, a hydroxyl group, a carboxyl group, an alkoxycarbonyl group or an alkyl group;
  • n denotes 1 or 2
  • n is an integer between 0 and 4
  • 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 which contain such compounds, and the use of these compounds in the production of medicaments.
  • cyclic guanidines of the general formula I interfere with the process of blood coagulation by reversibly inhibiting factor Xa and thus prevent the formation of coagulation thrombi. They can therefore be used to fight and prevent diseases such as thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis.
  • Factor Xa is a serine protease of the coagulation system that catalyzes the proteolytic conversion of prothrombin to thrombin. Thrombin, the last enzyme in the
  • Coagulation cascade on the one hand splits fibrinogen to fibrin, which after cross-linking using factor XTIIa becomes an insoluble gel and the matrix for a thrombus on the other hand, it activates platelet aggregation by proteolysis of its receptor on the platelets and in this way also contributes to the formation of thrombus.
  • factor XTIIa activates platelet aggregation by proteolysis of its receptor on the platelets and in this way also contributes to the formation of thrombus.
  • 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.
  • Inhibition of factor Xa can prevent the formation of thrombin.
  • amidinoarylpropanoic acid derivatives such as (+) - (2S) -2- [4- [[(3S) -l-acetimidoyl-3-pyrrolidinyl] oxy] phenyl] -3- (7-amidino-2- naphthyl] propanoic acid hydrochloride pentahydrate (DX-9065a; Formula II) are factor Xa inhibitors (J. Med. Chem. 1994, 37, 1200-1207; Thrombosis and Haemostasis 1994, 71, 314-319; EP-0- 540-051-Al).
  • novel cyclic guanidines of the general formula I according to the invention and hydrates, solvates and physiologically tolerable salts thereof are effective factor Xa inhibitors.
  • Halogens as substituents R *, R ⁇ , R3 in the general formula I are fluorine, chlorine, bromine and iodine atoms, but preferably fluorine, chlorine or bromine atoms.
  • R *, R ⁇ , R3 in the general formula I is a hydroxyalkyl group, this can be straight-chain or branched and contain 1 to 6 carbon atoms.
  • Prefers are the hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, hydroxypentyl and the hydroxyhexyl group.
  • R 1, R, R 3 in the general formula I is an alkyl group, this can be straight-chain or branched and contain 1 to 6 carbon atoms.
  • the methyl, ethyl, "-propyl, / ' -propyl,” -butyl, / " -butyl, t-butyl, pentyl and the hexyl group are preferred.
  • Rl, R ⁇ , R 3 in the general formula I is an alkenyl group, this can be straight-chain or branched and contain 2 to 6 carbon atoms.
  • the vinyl, 1-propenyl, 2-propenyl, 2-methyl-2-propenyl, 1-butenyl, 1-pentenyl and the 1-hexenyl groups are preferred.
  • Rl, R ⁇ , R 3 in the general formula I is an alkynyl group, this can be straight-chain or branched and contain 2 to 6 carbon atoms.
  • the ethynyl and propargyl groups are preferred.
  • Alkoxy groups as the substituents Rl, R ⁇ , R 3 i n of the general formula I contain from 1 to 6 carbon atoms and are straight or branched.
  • the methoxy-, ethoxy-, “-propyloxy-, / -propyloxy-,“ -butyloxy-, / -butyloxy-, tert are preferred.
  • R 1, R 1, R 3 in the general formula I is an aralkyloxy group, this contains a phenyl group linked to a straight-chain or branched C 1 -C 6 -alkyl chain.
  • the benzyloxy group is preferred.
  • Alkenyloxy groups as substituents Rl, R2, R 3 i n of the general formula I contain from 2 to 6 carbon atoms and are straight or branched.
  • the vinyl oxy and allyloxy groups are preferred.
  • Alkynyloxy groups as substituents Rl, R, R 3 in the general formula I contain 2 to 6 carbon atoms and are straight-chain or branched.
  • the propargyloxy group is preferred.
  • Alkoxycarbonyl groups as substituents Rl, R ⁇ , R 3 in the general formula I contain straight-chain or branched alkyl chains with 1 to 6 carbon atoms.
  • the methoxycarbonyl and the ethoxycarbonyl group are preferred.
  • R 1, R 3 denotes an alkenyloxycarbonyl group, this contains straight-chain or branched alkenyls having 3 to 6 carbon atoms.
  • the allyloxycarbonyl group is preferred.
  • R 1, R 1, R 3 denotes an alkynyloxycarbonyl group, this contains straight-chain or branched alkynyls having 3 to 6 carbon atoms.
  • the propargyloxycarbonyl group is preferred.
  • Carboxyalkyl groups as substituents Rl, R ⁇ , R 3 in the general formula I contain alkyls with 1 to 6 carbon atoms and are straight-chain or branched. The carboxymethyl, the carboxyethyl and the carboxypropyl group are preferred.
  • R 1 , R 2 , R 3 in the general formula I are an alkyloxycarbonylalkyl group
  • the alkyl radicals are in each case straight-chain or branched alkyl chains with 1 to 6 carbon atoms.
  • the methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl, ethoxycarbonylethyl, methoxycarbonylpropyl and the ethoxycarbonylpropyl group are preferred.
  • R 1 , R 2 , R 3 in the general formula I is an alkenyloxycarbonylalkyl group
  • the alkenyl radicals are straight-chain or branched with 3 to 6 carbon atoms and the alkyl groups are straight-chain or branched with 1 to 6 carbon atoms.
  • the allyloxycarbonylmethyl, allyloxycarbonylethyl and the allyloxycarbonylpropyl groups are preferred.
  • R 1, R 2 , R 3 in the general formula I is an alkynyloxycarbonylalkyl group
  • the alkynyl radicals are straight-chain or branched with 3 to 6 carbon atoms and the alkyl groups are straight-chain or branched with 1 to 6 carbon atoms.
  • the propargyloxycarbonylmethyl, propargyloxycarbonylethyl and the propargyloxycarbonylpropyl group are preferred.
  • the group denoted by A can mean a single bond or a methylene group which can be unsubstituted or substituted by a carboxyl group or alkoxycarbonyl group or a straight-chain or branched alkylene group having 2 to 6 carbon atoms, optionally substituents such as hydroxyl, carboxyl - Can carry alkoxycarbonyl groups or halogen atoms.
  • Alkoxycarbonyl groups as substituents of the methylene or alkylene group of group A contain straight-chain or branched alkoxy radicals having 1 to 6 carbon atoms, the methoxycarbonyl and the ethoxycarbonyl group being preferred.
  • Halogens as substituents of the straight-chain or branched alkylene group of group A can be fluorine, chlorine, bromine and iodine atoms, but preferably chlorine or bromine atoms.
  • the group denoted by X can mean a single bond, an alkylene group with 1 or 2 carbon atoms or a methyleneoxy fragment.
  • Y can mean a single bond, a chalcogen atom, in particular oxygen or a sulfur, or a carbonyl group.
  • group Z in the compounds of the general formula I is a saturated or unsaturated heterocyclic ring system, this is understood to mean a ring system with 5 to 7 ring members which contains one or two identical or different heteroatoms such as nitrogen, oxygen and sulfur, preferably pyrrolidine, piperidine , Piperazine, morpholine, hexahydroazepine, tetrahydrofuran, tetrahydropyran, tetrahydrothiophene, 4,5-dihydroimidazole, pyrrole, imidazole, pyrazine, pyrimidine, pyridazine, lH-azepine, 3H-azepine, 1,2-diazepine, 1,4-diazepine, furan, thiophene, oxazole, isoxazole, thiazole, isothiazole, pyrazole, Pyrollidinone, imidazolidinone, piperidinone
  • group Z in the compounds of the general formula I is a saturated or unsaturated carbocyclic ring system, this is understood to mean a ring system having 3 to 7 carbon atoms, preferably cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl or phenyl.
  • the heterocyclic or carbocyclic radicals Z can have one or two substituents such as nitrile, carboxyl, CJ-C ⁇ -carboxyalkyl, Ci-Cö-alkyloxycarbonyl-Ci-C ⁇ -alkyl, Ci-Cg-alkyl, C3-C6-alkenyl, imino, C j -Cg-alkylimino, carboxylimino, amidino, formimidoyl, Ci-Cg-alkanimidoyl, C3-C6-cycloalkanimidoyl, benzimidoyl (possibly Cl-C6-alkoxy-substituted), Cj-Cg-alkylcarbonyl, Ci-Cg-alkyloxvcarbonyl, C3 -C6-alkenyloxycarbonyl, benzyloxycarbonyl, carbamoyl, mono- or di- (-C-C6) -alkylcarb
  • group Z in the general formula I denotes an amino group
  • this can be substituted, specifically with one or two Ci-Cö-alkyl groups, preferably methyl or ethyl, with one or two aralkyl groups, preferably benzyl, with a Ci-Cg- Alkyloxycarbonyl group, preferably t-butyloxycarbonyl, with a C3-C6-alkenyloxycarbonyl group, preferably allyloxycarbonyl or with an aralkyloxycarbonyl group, preferably benzyloxycarbonyl.
  • (Ci -Cg) here stands for a straight-chain or branched alkyl chain with 1 to 6 carbon atoms, while (C3-C5) optionally denotes a straight-chain or branched alkenyl grouping with 3 to 6 carbon atoms.
  • group Z in the general formula I denotes an alkoxycarbonyl group
  • this can contain straight-chain or branched alkoxy radicals having 1 to 6 carbon atoms, the methoxycarbonyl and the ethoxycarbonyl group being preferred.
  • group Z in the general formula I denotes an alkyl chain, this is straight-chain or branched and contains 1 to 6 carbon atoms which can carry one or more hydroxyl groups, which in turn independently of one another, preferably with C] -C6-alkyl groups Methyl or with aralkyl groups, preferably benzyl or with C3-C6 alkenyl groups, preferably allyl, can be etherified.
  • CJ-C ⁇ stands for a straight-chain or branched alkyl chain with 1 to 6 carbon atoms, while (C3-C6) optionally denotes a straight-chain or branched alkenyl grouping with 3 to 6 carbon atoms.
  • n means 1 or 2 and the number m means an integer between 0 and 4.
  • Rl is a hydrogen atom, a hydroxy group, a methoxy group, a
  • Benzyloxy group a carboxyl group, a methoxycarbonyl or an ethoxycarbonyl group
  • R 2 , R 3 are identical or different and are a hydrogen atom, a hydroxyl group, a methoxy group, a benzyloxy group, a carboxyl group, a carboxymethyl group, a carboxyethyl group, a carboxymethyloxy group, a methoxy or ethoxycarbonyl group, a methoxy or ethoxycarbonylmethyl group, a methoxy or ethoxycarbonylethyl group, a methoxycarbonylmethyloxy or
  • A represents a methylene group, which may optionally contain a carboxy
  • Carboxymethyl, methoxycarbonyl, ethoxycarbonyl, allyloxycarbonyl or hydroxymethyl group can be substituted;
  • X represents a single bond, a methylene group, an ethylene group or the fragment -CH2-O-;
  • Y represents an oxygen atom
  • Z is a 4-tetrahydropyranyl radical, a 2-tetrahydrofuranyi radical is a 3-
  • Tetrahydrofuranylrest an amino group, a hydroxyl group, a methoxy group, a carboxyl group, an ethoxycarbonyl group, a guanidino group, a free or optionally ethylene-bridged amidino group, a 4-imidazolyl radical, a 2-position imino- or ethoxycarbonylimino-substituted 5-dinahydyr means, or a 2-pyrrolidinyl radical unsubstituted or substituted on the nitrogen or one unsubstituted on the nitrogen.
  • physiologically tolerable salts of the general formula I are, for example, formates. Acetates. Caproates, oleates, lactates or salts of carboxylic acids with up to 18 carbon atoms or salts of dicarboxylic acids and tricarboxylic acids such as citrates. Malonates and tartrates or alkanesulfonates with up to 10 carbon atoms or p-toluenesulfonates or salicylates or trifluoroacetates or salts of physiologically compatible mineral acids such as hydrochloric acid. Hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid.
  • the compounds of formula I with a free carboxyl group can also form salts with physiologically compatible bases.
  • salts are alkali metal, alkaline earth metal.
  • Ammonium and alkylammonium salts such as the sodium, potassium, calcium or tetramethylammonium salt.
  • the compounds of the formula I can be solvated, in particular hydrated.
  • the hydration can take place in the course of production or can occur gradually as a result of hygroscopic properties of an initially anhydrous compound of the formula I.
  • the invention also relates to the optically active forms, the racemates and the diastereomer mixtures of compounds of the general formula I.
  • the substances of general formula I are used with suitable pharmaceutical carrier substances.
  • Aromas, flavors and colors are mixed and shaped, for example, as tablets or dragees or with the addition of appropriate auxiliaries in water or oil, e.g. in olive oil, suspended or dissolved.
  • the substances of general formula I and their seeds 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, for example, tartrate and citrate buffers.
  • Complexing agents such as ethylenediaminetetraacetic acid and its non-toxic salts
  • high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation.
  • Solid carriers are, for example, starch. Lactose, mannitol.
  • Preparations suitable for oral administration can optionally contain flavoring and sweetening agents.
  • 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 given by injection 1-8 times a day or by continuous infusion, with 50-2000 mg per day usually being sufficient.
  • the compounds of general formula I are prepared by using a compound of general formula ÜI
  • A, X, Y, Z, n and m have the meanings given above, with a guanylating reagent such as 1H-pyrazole-1-carboxamidine or S-methylthiourea in an inert solvent such as.
  • the compound of general formula III also contains a free amino group at other points, for example in group Z, this is also guanylated under the reaction conditions by the process mentioned above.
  • R 1 -R 3 , A, X, Y, Z, n and m have the meanings given above and PGl denotes a protective group such as the benzyloxycarbonyl group, the t-butyloxycarbonyl group or the allyloxycarbonyl group, with a reagent which splits off the protective groups to react.
  • the deprotection takes place according to the methods customary in peptide chemistry by acidic reagents such as hydrogen bromide in glacial acetic acid or trifluoroacetic acid or ethereal HCl solution or hydrogenolytically or by palladium- or rhodium-catalyzed cleavage.
  • the compound of the general formula IV also contains a group analogous to PG 1 at other points, for example within group Z, this group is also cleaved off under the reaction conditions by the process mentioned above.
  • the compounds of general formula IV are prepared by using a compound of general formula V
  • R 2 , R 3 , A, Y, Z, and m have the meanings given above and R * is halogen, tosylate, mesylate or triflate, in an inert solvent such as dioxane, tetrahydrofuran, dimethylformamide, N-methyl-pyrrolidone or Toluene in the presence of a base such as sodium carbonate, potassium carbonate, 1,5-diazabicyclo [5.4.0] undec-5-ene or ethyldiisopropylamine at temperatures between 0 ° C and boiling point of the solvent, preferably between room temperature and 80 ° C.
  • a base such as sodium carbonate, potassium carbonate, 1,5-diazabicyclo [5.4.0] undec-5-ene or ethyldiisopropylamine at temperatures between 0 ° C and boiling point of the solvent, preferably between room temperature and 80 ° C.
  • the compounds of the general formula V are prepared by the methods customary in peptide chemistry by reacting compounds of type VII,
  • R 1 -R 3 , A, X, Z, n, m and PGl have the meanings given above and V is an oxygen atom can also be prepared by using a compound of the general formula VIII
  • Z and m have the meanings given above in an inert solvent such as dioxane, tetrahydrofuran or toluene in the presence of diethyl azodicarboxylate and trimethyl or triethyl phosphite at temperatures between 0 and 50 ° C., preferably at room temperature.
  • an inert solvent such as dioxane, tetrahydrofuran or toluene
  • diethyl azodicarboxylate and trimethyl or triethyl phosphite at temperatures between 0 and 50 ° C., preferably at room temperature.
  • the compounds of general formula VIII are prepared by using a compound of general formula X
  • Rl-R 3 , A, X, PGl, n have the meanings given above and PG 2 has a further protective group such as, for. B.
  • PG 2 has a further protective group such as, for. B.
  • the deprotection is carried out by customary methods using acidic or Lewis acidic reagents, such as. B.
  • R 2 , R 3 , A, PG 2 have the meanings given above and R ⁇ is a leaving group such as halogen, tosylate, mesylate or triflate, in an inert solvent such as tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone or toluene in the presence a base such as sodium carbonate, potassium carbonate, 1,5-diazabicyclo [5.4.0] undec-5-ene or ethyldiisopropylamine at temperatures between 0 ° C. and the boiling point of the solvent, preferably between room temperature and 100 ° C.
  • an inert solvent such as tetrahydrofuran, dioxane, dimethylformamide, N-methylpyrrolidone or toluene
  • a base such as sodium carbonate, potassium carbonate, 1,5-diazabicyclo [5.4.0] undec-5-ene or ethyldiisopropy
  • R 2 , R 3 , A, PG 2 have the meanings given above, for example by chlorinating an alcohol of the general formula XTJ using phosphorus pentachloride in an inert solvent such as benzene or toluene or mesitylene at temperatures between room temperature and the boiling point of the solvent used, preferably between room temperature and 60 ° C.
  • an inert solvent such as benzene or toluene or mesitylene
  • R 1 -R 3 , X, PGl, PG 2 , n have the meanings given above and A 'is a hydroxymethyl-substituted methylene group can also be prepared by using a compound of the general formula X ",
  • Rl-R 3 X, PGl, PG 2 , n have the meanings given above and A "is a methoxy-, ethoxy- or allyloxycarbonyl-substituted methylene group, by basic or palladium-catalyzed saponification and subsequent reduction of the free carboxyl function with mild reducing agents such as sodium borohydride in inert solvents such as ethanol, tetrahydrofuran, dioxane in the corresponding alcohol.
  • mild reducing agents such as sodium borohydride in inert solvents such as ethanol, tetrahydrofuran, dioxane in the corresponding alcohol.
  • Certain compounds of the general formula I can subsequently be converted into other compounds of the general formula I.
  • This relates to compounds of the general formula I which carry one or more carboxylic ester functions in one or more fragments of R 1 -R 3 , A or Z.
  • standard methods such as B. by aqueous alkaline hydrolysis or by treatment with trimethylsilyl iodide at temperatures between 0 ° C and boiling point of the solvent, preferably at room temperature in inert solvents such as methylene chloride or by enzymatic hydrolysis, for example in the presence of an esterase, these compounds can be used in compounds of general formula I. be converted with free carboxyl groups.
  • the benzyl group can also be removed by reaction with a strong acid such as trifluoroacetic acid in the presence of mesitylene, anisole or thioanisole at temperatures between 0 and 50 ° C., preferably at room temperature, or by treatment with Lewis acids such as BF3 etherate in an inert solvent such as Toluene, acetonitrii, diethyl ether or tetrahydrofuran at temperatures between 0 ° C and boiling point of the solvent, preferably between room temperature and boiling point of the solvent or by treatment with trimethylsilyl iodide at temperatures between 0 ° C and boiling point of the solvent, preferably at room temperature in inert Solvents such as diethyl ether, tetrahydrofuran, methylene chloride or chloroform.
  • a strong acid such as trifluoroacetic acid in the presence of mesitylene, anisole or thioanisole at temperatures between 0 and 50 ° C., preferably at room
  • Pure enantiomers of the compounds of the formula I are obtained either by resolving racemates (via salt formation with optically active acids or bases), or by using optically active starting materials in the synthesis or by hydrolysing enzymatically.
  • Activated partial thromboplastin time (APTT-)
  • APTT reagent Diagnostica Stago / Boehringer Mannheim GmbH; contains lyophilisate cephalin with microcrystalline diatomaceous earth activator
  • DMSO dimethyl sulfoxide
  • KC10 ball coagulometer
  • a stopwatch is started and the point in time until coagulation occurs.
  • the APTT for the control measurements is approx. 28-35 seconds and is extended by active substances.
  • Table 1 shows the measured APTT times in seconds as the difference to the control.
  • concentrations of the active substances in the final volume were 100 ⁇ M (APTT100), 10 ⁇ M (APTTlO), 1 ⁇ M (APTTl).
  • Table 1 shows the measured thrombin times in seconds as the difference to the control.
  • concentrations of the active substances in the final volume were 500 ⁇ M (TT500).
  • the kinetic measurements were carried out in 0.1 M phosphate buffer containing 0.2 M sodium chloride and 0.5% polyethylene glycol 6000 (preparation see below) at pH 7.5 and 25 ° C. in polystyrene semi-micro cuvettes in a total volume of 1 ml.
  • the reactions were started by adding enzyme to preincubated solutions which contained either dimethyl sulfoxide (control) or solutions of the test substance in DMSO (inhibitor stock solutions: 10 mM in DMSO).
  • the increase in absorbance at 405 nm as a result of the release of 4-nitroaniline from the substrate was monitored photometrically over a period of 12 minutes. Measured values (absorbance vs.
  • VMÜX is the maximum rate in the absence of an inhibitor
  • K M is the Michaiis constant
  • [S] is the substrate concentration
  • Table 1 shows the measured Kj values in [ ⁇ M].
  • the entry K ; 999 means that the corresponding enzyme is not inhibited.
  • phosphate buffer solution 990 ⁇ l of phosphate buffer solution (preparation see below) were mixed with 10 ⁇ l of human factor Xa (Boehringer Mannheim GmbH; 10 U; suspension) and stored on ice for a maximum of 4 hours.
  • 850 ⁇ l phosphate buffer with 100 ⁇ l substrate [N-methoxycarbonyl- (D) -norleucyl-glycyl- (L) -arginine-4-nitroaniline acetate; Chromozyme X; Boehringer Mannheim GmbH; used substrate concentrations 800, 600, 400 and 200 ⁇ M; K M 400 ⁇ M] and 25 ⁇ l inhibitor solution or 25 ⁇ l DMSO (control) thermostatted in a photometer (25 ° C). The reaction is started by adding 25 ⁇ l of stock solution.

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Abstract

L'invention concerne des composés de la formule (I) où: R?1, R2, R3¿ représentent indépendamment les uns des autres un atome d'hydrogène, un atome d'halogène, un groupe hydroxy, un groupe hydroxyalkyle, un groupe alkyle, un groupe alcényle, un groupe alkinyle, un groupe alcoxy, un groupe aralkyloxy, un groupe alcényloxy, un groupe alkinyloxy, un groupe carboxyle, un groupe alcoxycarbonyle, un groupe alcényloxycarbonyle, un groupe alkinyloxycarbonyle, un groupe carboxyalkyle, un groupe alkyloxycarbonylalkyle, un groupe alcényloxycarbonylalkyle ou un groupe alkinyloxycarbonylalkyle; A représente un groupe alkylène à chaîne linéaire ou ramifiée qui peut être, si souhaité, doté de substituants tels que des groupes hydroxyle, carboxyle, alcoxy, carbonyle ou des atomes d'halogène; X représente une liaison simple, un groupe alkyle ou alkyloxénoxy; Y peut représenter une liaison simple, un atome de chalcogène ou un groupe carbonyle; Z représente une combinaison hétérocyclique ou carbocyclique saturée ou insaturée, éventuellement substituée, un groupe amino éventuellement substitué, un groupe hydroxyle, un groupe carboxyle, un groupe alcoxycarbonyle ou un groupe alkyle; n vaut 1 ou 2; et m représente un nombre entier compris entre 0 et 4. L'invention concerne également des hydrates, des solvates, les sels physiologiquement tolérables de ces produits et des isomères optiques ainsi que le procédé de production correspondant et les médicaments contenant ces composés et destinés au traitement d'affections thromboemboliques.
PCT/EP1996/003679 1995-08-23 1996-08-21 Nouvelles guanidines cycliques, procede de production correspondant et medicaments WO1997008165A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU69264/96A AU6926496A (en) 1995-08-23 1996-08-21 New cyclic guanidines, process for preparing the same and medicaments
EP96930066A EP0846115A1 (fr) 1995-08-23 1996-08-21 Nouvelles guanidines cycliques, procede de production correspondant et medicaments
JP9509817A JPH11511445A (ja) 1995-08-23 1996-08-21 新規環式グアニジン、それを製造するための方法及び医薬組成物

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DE19530996A DE19530996A1 (de) 1995-08-23 1995-08-23 Cyclische Guanidine, Verfahren zu ihrer Herstellung und Arzneimittel
DE19530996.0 1995-08-23

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WO1997008165A1 true WO1997008165A1 (fr) 1997-03-06

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JP (1) JPH11511445A (fr)
AU (1) AU6926496A (fr)
CA (1) CA2229903A1 (fr)
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WO (1) WO1997008165A1 (fr)

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000012479A1 (fr) * 1998-08-29 2000-03-09 Merck Patent Gmbh Derives de la 2-oxo-2h-choline
WO2000008005A3 (fr) * 1998-08-08 2000-05-18 Merck Patent Gmbh Derives de piperazinone
US6337344B1 (en) 1997-12-24 2002-01-08 Aventis Pharma Deutschland Gmbh Indole derivatives as inhibitors or factor Xa
WO2001056989A3 (fr) * 2000-02-01 2002-02-28 Cor Therapeutics Inc Inhibiteurs du facteur xa contenant du phenylene bivalent
WO2003013531A1 (fr) 2001-08-08 2003-02-20 Merck Patent Gmbh Derives de phenyle en tant qu'inhibiteurs du facteur xa
RU2201927C2 (ru) * 1998-04-10 2003-04-10 Джапан Тобакко Инк. Амидиновые соединения и фармацевтическая композиция, обладающая фактор ха ингибирующим действием
WO2004065369A1 (fr) 2003-01-23 2004-08-05 Merck Patent Gmbh Derives d'amide d'acide carboxylique et utilisation de ces composes en tant qu'inhibiteurs du facteur xa
WO2004076429A1 (fr) 2003-02-28 2004-09-10 Merck Patent Gmbh Derives ethynyl servant d'inhibiteurs du facteur xa
WO2010005087A1 (fr) * 2008-07-11 2010-01-14 味の素株式会社 Dérivé d’amidine
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques

Families Citing this family (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA985247B (en) * 1997-06-19 1999-12-17 Du Pont Merck Pharma Guanidine mimics as factor Xa inhibitors.
EP0937723A1 (fr) * 1998-02-18 1999-08-25 Roche Diagnostics GmbH Nouveaux sulfonamides, procédé pour leur préparation et médicaments les contenant
DE10027024A1 (de) * 2000-05-31 2001-12-06 Merck Patent Gmbh Carbaminsäureester
DE10112768A1 (de) * 2001-03-16 2002-09-19 Merck Patent Gmbh Phenylderivate 3
EP2133340B1 (fr) 2002-12-20 2013-01-16 Glaxo Group Limited Nouveaux dérivés de benzazépine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0528369A2 (fr) * 1991-08-19 1993-02-24 Dr. Karl Thomae GmbH Dérivés à fonction imine cyclique, compositions pharmaceutiques les contenant et procédé pour leur préparation
EP0540051A1 (fr) * 1991-10-31 1993-05-05 Daiichi Pharmaceutical Co., Ltd. Dérivés aromatiques à fonction amidines et leurs sels

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0528369A2 (fr) * 1991-08-19 1993-02-24 Dr. Karl Thomae GmbH Dérivés à fonction imine cyclique, compositions pharmaceutiques les contenant et procédé pour leur préparation
EP0540051A1 (fr) * 1991-10-31 1993-05-05 Daiichi Pharmaceutical Co., Ltd. Dérivés aromatiques à fonction amidines et leurs sels

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NAGAHARA ET AL.: "Dibasic (Amidinoaryl)propanoic Acid Derivatives...", J. MED. CHEM., vol. 37, 1994, pages 1200 - 1207, XP002020157 *

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6337344B1 (en) 1997-12-24 2002-01-08 Aventis Pharma Deutschland Gmbh Indole derivatives as inhibitors or factor Xa
RU2201927C2 (ru) * 1998-04-10 2003-04-10 Джапан Тобакко Инк. Амидиновые соединения и фармацевтическая композиция, обладающая фактор ха ингибирующим действием
US6562828B1 (en) * 1998-04-10 2003-05-13 Japan Tobacco Inc. Amidine compounds
WO2000008005A3 (fr) * 1998-08-08 2000-05-18 Merck Patent Gmbh Derives de piperazinone
WO2000012479A1 (fr) * 1998-08-29 2000-03-09 Merck Patent Gmbh Derives de la 2-oxo-2h-choline
WO2001056989A3 (fr) * 2000-02-01 2002-02-28 Cor Therapeutics Inc Inhibiteurs du facteur xa contenant du phenylene bivalent
WO2003013531A1 (fr) 2001-08-08 2003-02-20 Merck Patent Gmbh Derives de phenyle en tant qu'inhibiteurs du facteur xa
EP2982668A2 (fr) 2002-12-03 2016-02-10 Pharmacyclics LLC Dérivés de 2-(2-hydroxybiphényl-3-yl)-1h-benzoimidazole-5-carboxamidine en tant qu'inhibiteurs du facteur viia inhibitors pour le traitement de maladies thromboemboliques
WO2004065369A1 (fr) 2003-01-23 2004-08-05 Merck Patent Gmbh Derives d'amide d'acide carboxylique et utilisation de ces composes en tant qu'inhibiteurs du facteur xa
WO2004076429A1 (fr) 2003-02-28 2004-09-10 Merck Patent Gmbh Derives ethynyl servant d'inhibiteurs du facteur xa
WO2010005087A1 (fr) * 2008-07-11 2010-01-14 味の素株式会社 Dérivé d’amidine

Also Published As

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CA2229903A1 (fr) 1997-03-06
AU6926496A (en) 1997-03-19
DE19530996A1 (de) 1997-02-27
JPH11511445A (ja) 1999-10-05
EP0846115A1 (fr) 1998-06-10

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