EP0496753A1 - 2-bicyclo-benzimidazoles, procede pour leur fabrication et medicaments les contenant - Google Patents

2-bicyclo-benzimidazoles, procede pour leur fabrication et medicaments les contenant

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Publication number
EP0496753A1
EP0496753A1 EP90914918A EP90914918A EP0496753A1 EP 0496753 A1 EP0496753 A1 EP 0496753A1 EP 90914918 A EP90914918 A EP 90914918A EP 90914918 A EP90914918 A EP 90914918A EP 0496753 A1 EP0496753 A1 EP 0496753A1
Authority
EP
European Patent Office
Prior art keywords
group
alkyl
alkoxy
oxo
alkylamino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP90914918A
Other languages
German (de)
English (en)
Inventor
Wolfgang Von Der Saal
Harald Zilch
Erwin BÖHM
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Roche Diagnostics GmbH
Original Assignee
Roche Diagnostics GmbH
Boehringer Mannheim GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Roche Diagnostics GmbH, Boehringer Mannheim GmbH filed Critical Roche Diagnostics GmbH
Publication of EP0496753A1 publication Critical patent/EP0496753A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds of the
  • R 1 represents a hydrogen atom, a C 1 -C 6 alkyl, C 2 -C 6 alkenyl or a C 3 -C 7 cycloalkyl group,
  • R 2 is a C 1 -C 6 alkyl, C 2 -C 6 alkenyl or cyano group, one is substituted by a hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, amino, C 1 -C 6 alkylamino, di-C 1 -C 6 alkylamino or hydrazino group substituted carbonyl group, or R 1 and R 2 together represent a C 2 -C 6 alkylidene or C 3 -C 6 cycloalkylidene group represent, or R 1 and R 2 together with the carbon atom to which they are attached form a C 3 -C 7 spirocycle.
  • n can be 0 or 1
  • R 3 is a hydrogen atom, a C 1 -C 8 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 7 cycloalkyl, benzyl, Caürboxy C 1 - C 6 alkyl, C 1 -C 6 alkyloxycarbonyl C 1 -C 6 alkyl or
  • R 4 , R 5 , R 6 may be the same or different and each
  • the compounds of general formula I inhibit or reduce both erythrocyte aggregation and platelet aggregation in low concentrations. Due to these properties, these substances are suitable for the treatment of diseases in which the erythrocyte and platelet aggregation play an important role in the pathogenesis, such as peripheral and cerebral circulatory disorders, shock conditions, degenerative vascular diseases, rheumatic diseases, various types of ulcers, necrotic processes in tumors, degenerative disorders of the retina, nerves and muscles or of various skin diseases. In particular, the treatment of arterial occlusive diseases, ischemic conditions, is more venous
  • JP 86-257720 (Yoshitomi) (C.A. 109 (19); 170432 d) already known. These are not benzimidazoles, but imidazopyridines of the general formula II
  • the compounds of the general formula II have an inhibitory effect on platelet aggregation, are anti-allergic, anti-inflammatory, soothing and vasodilating.
  • the substituents R 4 , R 5 or R 6 can, independently of one another, be in the 4-, 5-, 6- or 7-position of the benzimidazole ring, this in total 1-3, preferably 1 or 2, substituents can carry.
  • the alkyl part of these substituents can contain 1-7 carbon atoms, preferably 1-4 carbon atoms and be straight-chain or branched.
  • R 4 particular preference is given to hydrogen, an alkylsulfonyloxy, trifluoromethylsulfonyloxy, alkylsulfonylmethyl, alkylsulfinylmethyl, alkylsulfonylmethyl, alkylsulfonylamino, N-alkyl-alkylsulfonylamino, trifluoromethylsulfonylamino, N-alkyltronyloxy group, a hydroxylamino group, Amino, alkylamino or dialkylamino group substituted carbonyl group or a sulfonyl group substituted by an amino, dialkylamino or morpholino group, where each of the alkyl parts mentioned above can preferably contain 1-4, in particular 1 or 2 carbon atoms, a nitro, cyano or alkylaminosulfonyl group with 1-4 carbon atoms, an alkylcarbonylamino, alkylcarbonyloxy
  • Trifluoromethyl group the 1-imidazolyl group or a
  • Halogen atom for R 5 hydrogen, a hydroxy group, an alkyl group with 1-3 carbon atoms, an alkoxy or dialkylamino group with preferably 1-4, in particular 1 or 2 carbon atoms in each alkyl part or a halogen atom and for R 6 hydrogen or an alkoxy group, in particular the methoxy group.
  • Preferred monosubstituted benzimidazoles are the hydroxy, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, allyloxy, propargyloxy, cyanomethyloxy, benzyloxy, methoxycarbonylmethyloxy, halogen, nitro, cyano, aminocarbonyl -, Methoxycarbonyl-, amino-, trifluoromethyl-, C 1 -C 3 alkylcarbonyloxy-, C 1 -C 3 dialkylamino-, C 1 -C 3 alkylmercapto-, C 1 -C 3 alkylsulfinyl-, C 1 -C 3 -alkylsulfonyl -, C 1 -C 3 alkylsulfonyloxy and the 1-imidazolyl group where the substituent can preferably be in the 4- or 5-position.
  • Preferred disubstituted benzidimidazoles contain as substituents an alkanesulfonyloxy-, trifluoromethylsulfonyloxy-, alkylsulfonylmethyl-, alkylsulfinylmethyl-, alkylsulfonylmethyl-, alkylsulfonylamino-, N-alkyl-alkylsufonylamino-, trifluoromethylsulfonylamino-auronylamino-methyl-sulfonylamino-a-n-methyl-sulfonylamino-a-methyl-sulfonylamino-a-methyl-sulfonylamino-a-methyl-sulfonylamino-a-trifluoromethyl-sulfonylamino-a-trifluoromethyl-sulfonylamino-a-trifluoromethyl-sulfonylamino-
  • R 1 is an alkyl, alkenyl or cycloalkyl group and R 2 is an alkyl, alkenyl or a carbonyl group substituted by an alkyl, alkoxy, alkylamino or dialkylamino group
  • each of the abovementioned alkyl or alkenyl parts can be straight-chain or branched and 1-6 or 2-6 carbon atoms and said cycloalkyl part contain 3-7 carbon atoms.
  • R 1 is preferably a hydrogen atom, the methyl, ethyl, isopropyl, 3-pentyl, cyclopentyl or cyclohexyl group.
  • R 2 may preferably represent a methyl, ethyl, isopropyl, 3-pentyl, cyano, carboxy, acetyl, propinyl, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl and hydrazinocarbonyl group.
  • R 1 and R 2 form a cycloalkyl ring together with the C atom to which they are attached, this is preferably the spirocyclopropyl, spirocy ⁇ lobutyl, spirocyclopentyl and spirocyclohexyl group. If R 1 and R 2 together form an alkylidene or cycloalkylidene group, the isopropylidene or cyclohexylidene group is preferred.
  • R 3 can be straight-chain or branched and in particular contain 1-4 carbon atoms.
  • R 3 preferably denotes a hydrogen atom or a C 1 -C 8 alkyl or C 2 -C 6 alkenyl group.
  • radicals for R3 are the hydrogen atom, the methyl, ethyl, isopropyl, propyl, tert-butyl, butyl, pentyl, hexyl, heptyl, octyl, allyl, isobutenyl, propargyl -, cyclopropyl, cyclobutyl, carboxymethyl, carboxyethyl, carboxypropyl, carboxybutyl, carboxypentyl, ethoxycarbonylmethyl, methoxycabonylmethyl, methoxycarbonylethyl,
  • R 4 is hydrogen, the methanesulfonyloxy-, trifluoromethanesulfonyloxy-, methanesulfonylamino-, trifluoromethanesulfonylamino-, methanesulfonylmethylamino-, trifluoromethanesulfonylmethylamino-, methylsulfinylmethyl-, methylsulfonylmethyl-, aminocarbonyl-, aminosulfonyl-, aminosulfonyl-, aminocarbonyl-, aminosulfonyl- , Methylsulfonyl, hydroxy, allyoxy, methyl, methoxy, propargyloxy, cyanomethyloxy, methoxycarbonylmethyloxy, cyan, chlorine, nitro, amino, dimethylamino, trifluoromethyl or the 1-imidazolyl group,
  • R 5 is hydrogen, which is methyl, methoxy, hydroxyl, dimethylamino or chlorine,
  • R 6 is hydrogen or the methoxy group
  • R 1 represents a hydrogen atom or the methyl group
  • R 2 represents the methyl, ethyl or isopropyl group, or R 1 and R 2 together with the carbon atom to which they are attached represent a spirocyclopentyl ring,
  • R 3 represents the hydrogen atom, the methyl, ethyl, propyl, isopropyl, butyl, isobutenyl, allyl, ethoxycarbonyl or the dimethyloxophosphinylmethyl group.
  • the substances of the general formula I are mixed in a manner known per se with suitable pharmaceutical carriers, flavorings, flavors and colors and are shaped, for example, as tablets or dragées or, with the addition of appropriate auxiliaries, suspended in water or oil, such as, for example, olive oil, or solved.
  • suitable pharmaceutical carriers flavorings, flavors and colors
  • auxiliaries suspended in water or oil, such as, for example, olive oil, or solved.
  • 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.
  • Such additives are e.g. Tartrate and citrate buffers, ethanol, 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. Starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, high molecular fatty acids (such as stearic acid), gelatin, agar, calcium phosphate, magnesium stearate, animal and vegetable fats and solid high molecular polymers (such as polyethylene glycols).
  • Preparations suitable for oral administration can be any suitable for oral administration.
  • 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 1-2 tablets with 20-700 mg of active ingredient only have to be given once a day.
  • the active ingredient can also be given by injection 1-8 times a day or by continuous infusion, with amounts of
  • these are preferably set in an organic solvent with the equivalent amount of an inorganic or organic acid, for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, Tartaric acid, maleic acid, fumaric acid, benzoic acid or cyclohexylsulfamic acid.
  • an inorganic or organic acid for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, Tartaric acid, maleic acid, fumaric acid, benzoic acid or cyclohexylsulfamic acid.
  • the compounds III and IV are reacted with a dehydrating agent.
  • a dehydrating agent primarily polyphosphoric acid comes into consideration, advantageously with the addition of diphosphorus pentoxide.
  • a phosphate of the desired compound usually precipitates out in the aqueous workup.
  • the free base is obtained therefrom by alkalization, preferably with aqueous ammonia.
  • This method can be used not only to convert the acids of the general compound IV, but also by derivatives thereof, such as esters (ethyl or methyl esters), amides and the corresponding nitriles.
  • the reaction can also be carried out entirely without solvent if ar is in the melt works.
  • Solvent mixture such as ethanol, isopropanol, glacial acetic acid, glycol, sulfolane or dimethylformamide at temperatures between 0 ° C and 250 ° C, but preferably at the boiling point of the solvent, optionally in the presence of a condensing agent such as phosphoryl chloride, thionyl chloride, p-toluenesulfanic acid, hydrochloric acid, sulfuric acid, Phosphoric acid, polyphosphoric acid or in the presence of a base such as sodium hydroxide, potassium methylate, instead.
  • a condensing agent such as phosphoryl chloride, thionyl chloride, p-toluenesulfanic acid, hydrochloric acid, sulfuric acid, Phosphoric acid, polyphosphoric acid or in the presence of a base such as sodium hydroxide, potassium methylate, instead.
  • Another preferred process for the preparation of the compounds of the general formula I consists in the reductive ring closure of N- (ortho-nitrophenyl) amides of the general formula V,
  • the reduction of the nitro group is preferably carried out in a solvent such as water, ethanol, glacial acetic acid, ethyl acetate or dimethylformamide with hydrogen in the presence of a catalyst such as Raney nickel, platinum or palladium or with metals such as iron, tin or zinc in the presence of an acid, with salts such as Iron (II) sulfate, tin (II) chloride, sodium sulfate, sodium hydrogen sulfide or with hydrazine in the presence of Raney nickel at temperatures between 0 and 250 ° C., preferably at room temperature, carried out.
  • a catalyst such as Raney nickel, platinum or palladium or with metals such as iron, tin or zinc in the presence of an acid
  • salts such as Iron (II) sulfate, tin (II) chloride, sodium sulfate, sodium hydrogen sulfide or with hydrazine in the presence of Raney nickel at temperatures between 0 and
  • Another preferred process for the preparation of the compounds of the general formula V consists in the nitration of compounds of the general formula VII,
  • R 1 -R 6 and n have the meanings given above.
  • the nitration is preferably carried out using nitric acid in sulfuric acid at temperatures between -20 ° C and + 50 ° C. It can also be carried out without sulfuric acid or in its place in water, glacial acetic acid or acetic anhydride or with N 2 O 5 in CCI 4 in the presence of P 2 O 5 .
  • Anhydrides such as acetyl nitrate or nitryl halides with FeCl 3 , methyl nitrate with BF 3 or sodium salts such as NO 2 BF 4 , NO 2 PF 6 or NO 2 CF 3 SO 3 can also be used.
  • a mixture of nitric acid and nitrous acid, which serves as an N 2 O 4 supplier, can also be used for the nitration.
  • Benzyloxy, alkoxy, alkenyloxy, alkynyloxy, cyanoalkoxy, carboxyalkoxy, phenylalkoxy, or alkoxycarbonylalkoxy group means.
  • This alkylation is preferred in a solvent such as acetone, ether, benzene, toluene or dimethylformamide at temperatures between -30 ° C and + 100 ° C, preferably between room temperature and 100 ° C in the presence of a base such as potassium hydroxide and an alkylating agent such as alkyl halides or alkyl sulfates carried out.
  • the subsequent conversion also relates to the preparation of compounds of the general formula I in which R 4 represents an alkylsulfinyl or alkylsulfonyl group, by subsequent oxidation of a compound in which R 4 is an alkyl mercapto group.
  • Oxidation is preferred as in a solvent or solvent mixture, such as water, water / pyridine, acetone, glacial acetic acid, dilute sulfuric acid or trifluoroacetic acid, depending on the oxidizing agent used, advantageously carried out at temperatures between -80 ° C and 100 ° C.
  • the oxidation is conveniently carried out with one equivalent of the oxidizing agent used, e.g. with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20 ° C or in acetone at 0 to 60 ° C, with a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50 ° C or with m-chloroperbenzoic acid in methylene chloride or chloroform at -20 ° C to 60 ° C, with sodium metaperiodate in aqueous methanol or ethanol at -15 ° C to 25 ° C, with bromine in glacial acetic acid or aqueous acetic acid, with N-bromosuccinimide in ethanol, with tert-butyl hypochlorite in methanol at - 80 ° C to -30 ° C, with iod
  • the thioether-chlorine complex obtained is expediently hydrolyzed with aqueous ethanol.
  • the oxidation is advantageously carried out with two or more equivalents of the oxidizing agent used, for example hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or in formic acid at 20 to 100 ° C. or in acetone at 0 to 60 ° C.; with a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 60 ° C, with nitric acid in glacial acetic acid at 0 to 20 ° C.
  • the oxidizing agent used for example hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or in formic acid at 20 to 100 ° C. or in acetone at 0 to 60 ° C.
  • a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride
  • the subsequent conversion also relates to the preparation of compounds of the general formula I in which R 4 represents an alkanesulfonyloxy, trifluoromethanesulfonyloxy alkanesulfonylamino or trifluoromethanesulfonylamino group by the subsequent reaction of a compound in which R 4 is a hydroxy group with a
  • reaction is conveniently carried out in a solvent or solvent mixture such as methylene chloride, ether, tetrahydrofuran, dioxane or benzene, optionally in the presence of an acid-binding agent such as sodium carbonate, triethylamine or pyridine, the latter two also being able to be used simultaneously as solvents, in the presence of an acid activating or dehydrating agents such as thionyl chloride or phosphorus pentachloride, but preferably with a reactive derivative of a compound of general formula VIII, for example with its anhydride or halide, such as methanesulfonic acid chloride or ethanesulfonic acid chloride, at temperatures between 0 and 100 ° C, preferably at temperatures between room temperature and 50 ° C.
  • a solvent or solvent mixture such as methylene chloride, ether, tetrahydrofuran, dioxane or benzene
  • an acid-binding agent such as sodium carbonate, triethyl
  • the subsequent conversion also relates to the preparation of compounds of the general formula I in which R 4 represents a carbonyl group substituted by an amino, alkylamino or dialkylamino group, by the subsequent reaction of a compound in which R 4 represents a carboxyl group, or one reactive derivative thereof, such as ester or acid chloride an amine of the general formula IX HNR 8 R 9 (IX) in which R 8 and R 9 are the same or different
  • reaction may represent hydrogen atoms or alkyl groups, or with a reactive derivative thereof if R 4 represents the carboxyl group.
  • the reaction is advantageously carried out in a solvent such as methylene chloride, ethanol, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid-activating agent or a dehydrating agent, for example in the presence of ethyl chloroformate, thionyl chloride , Phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide / N-hydroxysuccinimide, N, N'-carbonyldiimidazole or N, N'-thionyldiimidazole or triphenylphosphine / carbon tetrachloride, or an agent which
  • the reaction with a corresponding halide for example the carboxylic acid or sulfonic acid chloride, and a corresponding amine, which can simultaneously serve as a solvent, is carried out particularly advantageously at temperatures between 0 and 50.degree. f)
  • the subsequent conversion also relates to the conversion of compounds of the general formula I in which R 2 is the alkoxycarbonyl group to compounds of the general formula I in which R 2 is the hydrazinocarbonyl group. This is done in a solvent such as ethanol, methanol or glacial acetic acid with a small excess of hydrazine hydrate at temperatures between room temperature and the boiling point of the solvent.
  • the subsequent conversion also relates to the alkylation of compounds of the general formula I in which R 3 is a hydrogen atom, to those in which R 3 is an alkyl, alkenyl, alkynyl, cycloalkyl, benzyl, carboxyalkyl, Alkoxycarbonylalkyl- or the dimethyloxophosphinylmethyl group means.
  • R 3 is a hydrogen atom
  • R 3 is an alkyl, alkenyl, alkynyl, cycloalkyl, benzyl, carboxyalkyl, Alkoxycarbonylalkyl- or the dimethyloxophosphinylmethyl group means.
  • These alkylations are preferably carried out in a solvent such as acetone, methyl ethyl ketone, ether, benzene, toluene, xylene or
  • Dimethylformamide at temperatures between -30 ° C and the boiling point of the solvent, preferably at 0 ° C-80 ° C, in the presence of a base such as sodium hydride, sodium hydroxide or potassium carbonate.
  • a base such as sodium hydride, sodium hydroxide or potassium carbonate.
  • 4,4-Dimethyl-1-ethyl-1,2,3,4-tetrahydro-2-oxo-7-quinolinecarboxylic acid was prepared analogously to the instructions for 4,4-dimethyl-1,2,3,4-tetrahydro -2-oxo-7-quinolinecarboxylic acid (DE-A-3,818,830) as follows: 4,4-dimethyl-1,2,3,4-tetra-hydro-2-oxo-7-quinolinecarbonitrile (2.0 g, 10.0 mmol ), Iodoethane (1 ml, 12.0 mmol) and potassium carbonate (1.70 g, 12.0 mmol) were stirred for one hour at 60 ° C., again iodoethane (2 ml, 24.0 mmol) and potassium carbonate (2.5 g, 25 mmol) were added and the mixture was stirred one hour at 60 ° C.
  • the preliminary stage was obtained as follows:
  • This compound (8.2 g, 28 mmol) was stirred for 2 h at 80 ° C in 2N KOH (150 ml). The mixture was acidified with 2N HCl, the precipitate was filtered off with suction, dried in air and 4, 4-dimethyl-1-dimethyloxophosphinylmethyl-1, 2, 3, 4-tetrahydro-2-oxo-7-quinolinecarboxylic acid (7.7 g, 88 %) with mp. 235-238 ° C.
  • the preliminary stage is made as follows:
  • Determination of the erythrocyte aggregation as a parameter for the hemorheology The determination was carried out using the mini erythrocyte aggregometer from Myrenne, Roetgen 1 ). As a measure, this device specifies a dimensionless index that increases as the tendency to aggregate increases.
  • the tests were carried out with the human blood from healthy donors.
  • the blood adjusted to a hematocrit of 45% was incubated with the controil solution or the substance solutions.
  • the erythrocyte aggregation was then measured.
  • Each substance was examined at a concentration of 10 -5 M.
  • Two tests were carried out for each substance with the blood of different donors. The difference in the aggregation indices between the initial value of the controil solution and the values with the substance solution was calculated. These values are listed in the following table.
  • Venoruton R a mixture of various O- ( ⁇ -hydroxyethl) rutosides, is said to counter the tendency of erythrocyte aggregation inhibit 2) .
  • the aggregation index only changes by -0.4 units.
  • the change is only -3.9 +/- 0.9.
  • the substances mentioned inhibit erythrocyte aggregation significantly more.

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  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

Nouveaux composés de formule générale (I), où R1 est un atome d'hydrogène, un groupe alkyle C1-C6, alkényle C2-C6 ou cycloalkyle C3-C7, R2 est un groupe alkyle C1-C6, akényle C2-C6 ou cyanogène, un groupe carbonyle substitué par un groupe hydroxy, alkyle C1-C6, alcoxy C1-C6, amino, alkylamino C1-C6, dialkylamino C1-C6 ou bien hydrazino, ou encore R1 et R2 représentent ensemble un groupe alkylidène C2-C6 ou cycloalkylidène C3-C6, ou bien R1 et R2 forment, conjointement avec l'atome de carbone auquel ils sont liés, un cycle spirannique C3-C7, n peut être égal à 0 ou 1; R3 est un atome d'hydrogène, un groupe alkyle C1-C8, alkényle C2-C6, alkinyle C2-C6, cycloalkyle C3-C7, benzyle, alkylcarboxy C1-C6, alkyloxycarbonyle C1-C6-alkyle C1-C6 ou dialkyle oxophosphinyle C1-C6-alkyle C1-C6, et les résidus R4-R6 ont les notations définies dans la description. Les composés de formule générale (I) servent à la fabrication de médicaments. En faible concentration, ils inhibent l'agrégation érythrocytaire ainsi que l'agrégation thrombocytaire. En raison de ces caractéristiques, ces substances conviennent au traitement de maladies, dans la pathogénèse desquelles l'agrégation érythrocytaire et thrombocytaire joue un rôle important.
EP90914918A 1989-10-03 1990-10-04 2-bicyclo-benzimidazoles, procede pour leur fabrication et medicaments les contenant Withdrawn EP0496753A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE3932953A DE3932953A1 (de) 1989-10-03 1989-10-03 Neue 2-bicyclo-benzimidazole, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
DE3932953 1989-10-03

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EP0496753A1 true EP0496753A1 (fr) 1992-08-05

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US (1) US5414088A (fr)
EP (1) EP0496753A1 (fr)
JP (1) JPH05501249A (fr)
AU (1) AU6526190A (fr)
CA (1) CA2066690A1 (fr)
DE (1) DE3932953A1 (fr)
WO (1) WO1991004974A1 (fr)

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DE3932953A1 (de) 1991-04-11
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CA2066690A1 (fr) 1991-04-04
WO1991004974A1 (fr) 1991-04-18

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