EP1244636A1 - Benzimidazoles, leur production et leur utilisation comme antithrombotiques - Google Patents

Benzimidazoles, leur production et leur utilisation comme antithrombotiques

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Publication number
EP1244636A1
EP1244636A1 EP00983342A EP00983342A EP1244636A1 EP 1244636 A1 EP1244636 A1 EP 1244636A1 EP 00983342 A EP00983342 A EP 00983342A EP 00983342 A EP00983342 A EP 00983342A EP 1244636 A1 EP1244636 A1 EP 1244636A1
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EP
European Patent Office
Prior art keywords
group
substituted
methyl
alkyl
general formula
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.)
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Application number
EP00983342A
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German (de)
English (en)
Inventor
Uwe Ries
Iris Kauffmann-Hefner
Norbert Hauel
Henning Priepke
Herbert Nar
Jean Marie Stassen
Wolfgang Wienen
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.)
Boehringer Ingelheim Pharma GmbH and Co KG
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Boehringer Ingelheim Pharma GmbH and Co KG
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Application filed by Boehringer Ingelheim Pharma GmbH and Co KG filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1244636A1 publication Critical patent/EP1244636A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • C07D403/06—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 linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C07D403/12—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 linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention relates to benzimidazoles of the general formula
  • R a is a straight-chain C 1 -3 alkyl group which is in the 1-position by an optionally by a C 1 . 3- alkyl group substituted pyrrolidinocarbonyl or 2, 5-dihydropyrrolocarbonyl group and by an amino group which is monosubstituted by a cyano-C ⁇ alkyl group, and / or R c is a cyano group or in the 5-position by a C ⁇ alkyl or Phenyl group substituted 1, 2, 4-oxadiazol-3-yl group, where the phenyl substituent can be substituted by a fluorine, chlorine or bromine atom or by a C ⁇ alkyl group, are valuable intermediates for the preparation of the other compounds of the general Formula I, and the compounds of the general formula I above, in which R c represents one of the following amidino groups, and their tautomers, their stereoisomers, their mixtures, their prodrugs, their derivatives
  • the present application thus relates to the new compounds of the above general formula I and their preparation, the pharmaceutical compositions containing the pharmacologically active compounds, their preparation and use.
  • R a is a straight chain C 1 . 3 alkyl group in which the
  • Hydrogen atoms can be replaced in whole or in part by fluorine atoms and in the 1-position
  • R b is a C ⁇ alkyl group and R c is an amidino group, a cyano group or a 5-position through a C 1 .
  • the carboxy groups mentioned in the definition of the abovementioned radicals can also be replaced by a group which can be converted into a carboxy group in vivo or by a group which is negatively charged under physiological conditions, or
  • a group which can be converted into a carboxy group in vivo is, for example, a hydroxmethyl group, a carboxy group esterified with an alcohol, in which the alcoholic part is preferably one a phenyl C 1 . 3- alkanol, a C 3 _ 5 cycloalkanol, where a C 5 _ 8 cycloalkanol may additionally be substituted by one or two C 1-3 alkyl groups, a C s .
  • R d is a C 1-4 alkyl, C 5 . 7 - cycloalkyl -, phenyl - or phenyl -
  • R e is a hydrogen atom, a C 1 . 3 -alkyl-, C s . 7- cycloalkyl or phenyl group and
  • R f represents a hydrogen atom or a, - alkyl group
  • a group negatively charged under physiological conditions such as a tetrazol-5-yl, phenylcarbonylaminocarbonyl, trifluoromethylcarbonylaminocarbonyl, nylamino, phenylsulfonylamino, benzylsulfonylamino, trifluoromethylsulfonylamino, C- ⁇ g-alkylsulfonylaminocarbonyl, phenylsulfonylaminocarbonyl, benzylsulfonylaminocarbonyl or perfluoro-C ⁇ g-alkylsulfonylaminocarbonyl group
  • an imino or amino group in vivo for example a hydroxyl group, an acyl group such as one optionally by fluorine, chlorine, bromine or iodine atoms, by C 1-3 alkyl or C 1-3 alkoxy groups mono- or disubstituted benzoyl group, where the substituents may be the same or different, a pyridinoyl group or such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3, 3, 3-trichloropropionyl or allyloxycarbonyl group, a C- L .
  • an imino or amino group in vivo for example a hydroxyl group, an acyl group such as one optionally by fluorine, chlorine, bromine or iodine atoms, by C 1-3 alkyl or C 1-3 alkoxy groups mono- or disubstituted benzoyl group, where
  • g -alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethoxycarbonyl or phenylpropoxycarbonyl group, a 3-aminopropionyl group in which the amino group passes through or C 3 .
  • R g and R h which may be the same or different, are hydrogen atoms or C 1 . Represent 3 alkyl groups,
  • saturated alkyl and alkoxy parts which contain more than 2 carbon atoms also include their branched isomers such as the isopropyl, tert-butyl, isobutyl group etc.
  • Preferred compounds of the general formula I mentioned above are those in which
  • R b and R c are as defined above and
  • R a is defined with the proviso that a substituent represents an unbranched C 1-3 alkyl group or a 2,5-dihydropyrrolocarbonyl group which is optionally substituted by a C 1-4 alkyl group, or R a is an ethyl group which is in the 1-position
  • R b is a methyl group
  • R c is an amidino group substituted by a benzoyl, methylbenzoyl, fluorobenzoyl or trifluoromethylbenzoyl group or
  • R a is an ethyl group in the 1-position
  • R b is a methyl group
  • R c is an amidino group
  • R a is an ethyl group in the 1-position
  • methyl group is substituted by a methyl group, the methyl group being substituted by a tetrazolyl, carboxymethoxy, ethoxycarbonylmethoxy, ethoxycarbonylethylamino, N- (2-carboxyethyl) -N-methylamino, N- [2- (C ⁇ -Alkoxycarbonyl) -ethyl] - N-methylamino-, N- (carboxymethylaminocarbonyl) -N-methylamino-, N- (C ⁇ -alkoxycarbonylmethylaminocarbonyl) -N-methylamino-, N- (carboxymethylsulfonyl) -N-methyl- amino or N- (C 1, 3 -alkoxycarbonylmethylsulfonyl) -N-methylamino group is substituted,
  • R b is a methyl group
  • R c represents an amidino group
  • R a is an ethyl group in the 1-position by a 2, 5-dihydropyrrolocarbonyl group optionally substituted by a methyl group and
  • C ⁇ _ 2 alkyl group which is terminated by an N- (carboxy-C 1-4 -alkylaminocarbonyl) amino or N- which is optionally substituted on one or both amine nitrogen atoms by a C 1-3 alkyl group (C 1, 3 -alkoxycarbonyl-C 1, 3 -alkylaminocarbonyl) amino group, by a carboxy-C 1 . 3 -alkoxy-, C 1 _ 3 -alkoxycarbonyl-C 1 _ 3 -alkoxy-, N- (C 1.
  • R b is a methyl group
  • R c is an amidino group which may be substituted by a benzoyl, methylbenzoyl, fluorobenzoyl or trifluoromethylbenzoyl group
  • R a is an ethyl group which is in the 1-position
  • amino group is substituted by an amino group, the amino group by an ethoxycarbonylmethyl group which is substituted in the 2-position by a methoxy, dimethylamino or tolyl group by a carboxymethyl, propyl oxycarbonylmethyl-, Isopropyloxycarbonylmethyl-, oxycarbonylmethyl- isobutyl, cyclohexyloxycarbonylmethyl, 3- (C. 2 3 alkoxycarbonyl) propyl or tetrazolylmethyl group is substituted,
  • R b is a methyl group
  • R c is an amidino group substituted by a benzoyl, methylbenzoyl, fluorobenzoyl or trifluoromethylbenzoyl group or
  • R a is an ethyl group in the 1-position
  • R b is a methyl group
  • R c is an amidino group
  • R a is an ethyl group in the 1-position
  • methyl group is substituted by a methyl group, the methyl group being replaced by a tetrazolyl, carboxymethoxy, ethoxycarbonyl methoxy, ethoxycarbonylmethylamino, N- (2-carboxyethyl) -N-methylamino, N- [2- (C 1 _ 3 -alkoxycarbonyl) -ethyl] - N-methylamino-, N- (carboxymethylaminocarbonyl) -N-methylamino-, N- (C ⁇ -alkoxycarbonylmethylaminocarbonyl) -N-methyl- amino, N- (carboxymethylsulfonyl) -N-methylamino or N- (C ⁇ -alkoxycarbonylmethylsulfonyl) -N-methylamino group is substituted,
  • R b is a methyl group
  • R c represents an amidino group
  • the compounds of general formula I are obtained by processes known per se, for example by the following processes:
  • R a and R b are defined as mentioned at the beginning,
  • R c ' is a cyano group or a 1, 2, 4-oxadiazol-3-yl ⁇ group substituted in the 5-position by a C 1.3 alkyl or phenyl group, the phenyl substituent being substituted by a fluorine, chlorine or bromine atom or by a C ⁇ alkyl group can be substituted,
  • Z x and Z 2 which can be the same or different, optionally substituted by alkyl groups having 1 to 6 carbon atoms, amino, hydroxyl or mercapto groups or Z 1 and Z 2 , together represent an oxygen or sulfur atom, an imino group optionally substituted by an alkyl group having 1 to 3 carbon atoms, an alkylenedioxy or alkylenedithio group each having 2 or 3 carbon atoms.
  • the cyclization is conveniently carried out in a solvent or solvent mixture such as ethanol, isopropanol, glacial acetic acid, benzene, chlorobenzene, toluene, xylene, glycol, glycol monomethyl ether, diethylene glycol dimethyl ether, sulfolane, dimethylformamide, tetralin or in an excess of those used to prepare the compound of the general Formula II used acylating agents, for example in the corresponding nitrile, anhydride, acid halide, ester or amide, for example at temperatures between 0 and 250 ° C., but preferably at the boiling point of the reaction mixture, if appropriate in the presence of a condensing agent such as phosphorus oxychloride, thionyl chloride, sulfonyl chloride, sulfuric acid, p -Toluenesulfonic acid, methanesulfonic acid, hydrochloric acid, phosphoric acid, polyphosphoric acid,
  • Z 4 is an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthio group such as the methylthio, ethylthio represents n-propylthio or benzylthio group, with ammonia or with its salts.
  • the reaction is advantageously carried out in a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, with ammonia or one of its salts such as ammonium carbonate or ammonium acetate ,
  • a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane
  • a compound of the general formula III is obtained, for example, by reacting a corresponding cyano compound with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 50 ° C, but preferably at 20 ° C, or a corresponding nitrile with hydrogen sulfide, advantageously in a solvent such as pyridine or dimethylformamide and in the presence of a base such as Triethylamine and subsequent alkylation of the thioamide formed with an appropriate alkyl or aralkyl halide.
  • a corresponding cyano compound with a corresponding alcohol such as methanol,
  • R b and R c are defined as mentioned at the beginning and
  • R a has the meanings mentioned for R a with the proviso that R a contains a group which can be converted into a carboxy group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis,
  • a group which can be converted into a carboxy group is, for example, a carboxyl group protected by a protective radical, such as its functional derivatives, e.g. B. their unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or imino esters, which are expediently converted into a carboxyl group by means of hydrolysis,
  • a protective radical such as its functional derivatives, e.g. B. their unsubstituted or substituted amides, esters, thioesters, trimethylsilyl esters, orthoesters or imino esters, which are expediently converted into a carboxyl group by means of hydrolysis,
  • esters with tertiary alcohols e.g. the tert-butyl ester, which are expediently converted into a carboxyl group by treatment with an acid or thermolysis, and
  • esters with aralkanols e.g. the benzyl ester, which are expediently converted into a carboxyl group by means of hydrogenolysis.
  • the hydrolysis is advantageously carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or a mixture thereof or in the presence of a base such as lithium hydroxide, Sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, water / ethanol, water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane at temperatures between -10 and 120 ° C, for example at temperatures between room temperature and Boiling temperature of the reaction mixture carried out.
  • an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or a mixture thereof
  • a base such as lithium hydroxide, Sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water /
  • a compound of the formula IV contains, for example, the tert-butyl or tert-butyloxycarbonyly group
  • these can also be treated by treatment with an acid such as trifluoroacetic acid, formic acid, p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid, optionally in an inert solvent such as methylene chloride, Chloroform, benzene, toluene, diethyl ether, tetrahydrofuran or dioxane preferably at temperatures between -10 and 120 ° C, for example at temperatures between 0 and 60 ° C, or also thermally optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid, sulfur
  • a compound of the formula IV contains, for example, the benzyloxy or benzyloxycarbonyl group
  • these can also be hydrogenolytically in the presence of a hydrogenation catalyst such as palladium / carbon in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide preferably at temperatures between 0 and 50 ° C, for example at room temperature and a hydrogen pressure of 1 to 5 bar.
  • a hydrogenation catalyst such as palladium / carbon
  • a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide preferably at temperatures between 0 and 50 ° C, for example at room temperature and a hydrogen pressure of 1 to 5 bar.
  • R a and R b are defined as mentioned above, with a compound of the general formula
  • R 9 is the acyl residue of one of the residues which can be cleaved in vivo and
  • Z 5 is a nucleofugic leaving group such as a halogen atom, for example a chlorine, bromine or iodine atom, or a p-nitrophenyl group.
  • a halogen atom for example a chlorine, bromine or iodine atom, or a p-nitrophenyl group.
  • the reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethylformamide, optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20 ° C. and the boiling point of the solvent used.
  • a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethyl sulfoxide or dimethylformamide
  • a compound of the general formula VII in which Z 5 represents a nucleofugic leaving group, the reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone / water, dimethylformamide or dimethyl sulfoxide, optionally in the presence of a base such as sodium hydride, Potassium carbonate, potassium tert-butoxide or N-ethyl-diisopropylamine at temperatures between 0 and 60 ° C, performed.
  • a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, acetone / water, dimethylformamide or dimethyl sulfoxide
  • a base such as sodium hydride, Potassium carbonate, potassium tert-butoxide or N-ethyl-diisopropylamine at temperatures between 0 and 60 ° C, performed.
  • R a and R b are defined as mentioned at the outset and R c "represents a 1, 2, 4-oxadiazol-3-yl group substituted in the 5-position by a C 1-4 alkyl or phenyl group, in which the phenyl substituent is represented by a Fluorine, chlorine or bromine atom or can be substituted by a C x _ 3 alkyl group, and if necessary subsequent hydrolysis of a compound obtained in this way.
  • the catalytic hydrogenation is preferably carried out in a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethanol / glacial acetic acid, ethyl acetate, dioxane or dimethylformamide in the presence of a hydrogenation catalyst such as palladium / carbon, preferably at temperatures between 0 and 50 ° C, e.g. at room temperature, and a hydrogen pressure of 1 to 5 bar.
  • a suitable solvent such as methanol, ethanol, ethanol / water, glacial acetic acid, ethanol / glacial acetic acid, ethyl acetate, dioxane or dimethylformamide
  • a hydrogenation catalyst such as palladium / carbon
  • the optionally subsequent hydrolysis is expediently carried out either in the presence of an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water / methanol, Water / ethanol, water / isopropanol, methanol, ethanol, water / tetrahydrofuran or water / dioxane at temperatures between -10 and 120 ° C, eg at temperatures between room temperatures rature and the boiling temperature of the reaction mixture.
  • an acid such as hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof
  • a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide
  • a suitable solvent such as water, water
  • R a represents an amino-C 1-3 alkyl group in which the amino group is replaced by a carboxy-C 1 . 4 -alkyl or tetrazolyl- C 1 , i -alkyl group is monosubstituted:
  • R b and R c are defined as mentioned at the beginning and
  • R a represents an amino-C 1-3 alkyl group, with a compound of the general formula
  • R a is a carboxy-C 1. 4, alkyl or tetrazolyl-C 1 _ 4 alkyl group and
  • Z 7 represents a nucleofugic leaving group such as a halogen atom or a sulfonic acid ester residue, for example a chlorine, bromine or iodine atom, or a p-nitrophenyl group.
  • a nucleofugic leaving group such as a halogen atom or a sulfonic acid ester residue, for example a chlorine, bromine or iodine atom, or a p-nitrophenyl group.
  • the alkylation is conveniently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide or acetone, optionally in the presence of a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyl diisopropylamine or N-methyl-morpholine, which can also serve as a solvent at the same time, or optionally in the presence of silver carbonate or silver oxide at temperatures between -30 and 100 ° C, but preferably at temperatures between -10 and 80 ° C.
  • a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethyl sulfoxide, dimethylformamide or acetone
  • a reaction accelerator such as sodium or potassium iodide
  • a base such as sodium carbonate or potassium carbonate
  • the subsequent esterification is conveniently carried out with an appropriate alcohol in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, but preferably in an excess of the alcohol used, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrochloric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-carbodiimide Hydroxysuccinimide, N, N '-carbonyldiimidazole- or N, N'-
  • the subsequent transesterification is advantageously carried out with an appropriate alcohol in a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, but preferably in an excess of the alcohol used, advantageously in the presence of an acid such as hydrochloric acid or in Presence of a compound such as 2, 8, 9-trimethyl-l-phospha- 2, 5, 8, 9-tetraazabicyclo [3.3.3] undecane at temperatures between 0 and 150 ° C, preferably at temperatures between 0 and 80 ° C, carried out.
  • a solvent or solvent mixture such as methylene chloride, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, but preferably in an excess of the alcohol used, advantageously in the presence of an acid
  • the subsequent conversion of a cyano group into a tetrazolyl group is preferably carried out in a solvent such as benzene, toluene or dimethylformamide at temperatures between 80 and 150 ° C., preferably at 120 and 130 ° C.
  • a solvent such as benzene, toluene or dimethylformamide
  • the required hydrochloric acid is expediently released during the reaction from an alkali azide, for example from sodium azide, in the presence of a weak acid such as ammonium chloride.
  • the reaction can also be carried out with another salt or derivative of nitrogenous hydrochloric acid, preferably with aluminum azide or tributyltin azide, in which case the tetrazole compound optionally obtained in this way is obtained from the salt contained in the reaction mixture by acidifies with a dilute acid such as 2N hydrochloric acid or 2N sulfuric acid.
  • any reactive groups present such as carboxy, amino or alkylamino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.
  • the trimethylsilyl, methyl, ethyl, tert-butyl, benzyl or tetrahydropyranyl group comes as a protective radical for a carboxy group
  • a protective radical for an amino or alkylamino group the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.but-oxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2, 4-dimethoxybenzyl group and additionally for the amino group Phthalyl group into consideration.
  • the subsequent subsequent splitting off of a protective residue used takes place, for example, hydrolytically in an aqueous solvent, e.g. in water, isopropanol / water, tetrahydrofuran / water or dioxane / water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or in the presence of an alkali base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by means of ether cleavage, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100 ° C, preferably at temperatures between 10 and 50 ° C.
  • an aqueous solvent e.g. in water, isopropanol / water, tetrahydrofuran / water or dioxane / water
  • an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
  • an alkali base such as lithium hydroxide
  • a benzyl, methoxybenzyl or benzyloxycarbonyl radical is split off, for example by hydrogenolysis, for example using hydrogen in the presence of a catalyst such as palladium / carbon in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid, if appropriate with addition an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, preferably however at room temperature and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • a catalyst such as palladium / carbon
  • a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid
  • an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, preferably however at room temperature and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar
  • a methoxybenzyl group can also be split off in the presence of an oxidizing agent such as cerium (IV) ammonium nitrate in a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
  • an oxidizing agent such as cerium (IV) ammonium nitrate
  • a solvent such as methylene chloride, acetonitrile or acetonitrile / water at temperatures between 0 and 50 ° C., but preferably at room temperature.
  • a 2,4-dimethoxybenzyl radical is preferably cleaved in trifluoroacetic acid in the presence of anisole.
  • a tert-butyl or tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.
  • a phthalyl radical is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene / water or dioxane at temperatures between 20 and 50 ° C.
  • An allyloxycarbonyl radical is split off by treatment with a catalytic amount of tetrakis (triphenylphosphine) palladium (O), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100 ° C, preferably at room temperature and under inert gas, or by treatment with a catalytic amount of tris (triphenylphosphine) rhodium (I) chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo - [2.2.2] octane at temperatures between 20 and 70 ° C.
  • the compounds of general formulas II to X used as starting materials, some of which are known from the literature, are obtained by processes known from the literature, and their preparation is also described in the examples.
  • a compound of the general formula II is obtained by acylation of a corresponding o-diamino compound with a corresponding reactive acyl derivative
  • the compounds of general formula I obtained which occur in racemates can be converted into their optical antipodes and by known methods (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) Separate compounds of the general formula I with at least 2 asymmetric carbon atoms into their diastereomers on the basis of their physicochemical differences by methods known per se, for example by chromatography and / or fractional crystallization, which, if they occur in racemic form, finally, as mentioned above, can be separated into the enantiomers.
  • the separation of enantiomers is preferably carried out by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols, and separation of the diastereomeric salt mixture or derivative thus obtained, e.g. due to different solubilities, it being possible for the free antipodes to be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • a salt or derivative such as e.g. Optically active substance which forms esters or amides, in particular acids and their activated derivatives or alcohols
  • optically active alcohols are, for example, (+) - or (-) menthol
  • optically active acyl radicals in amides are, for example, the (+) - or (-) - menthyloxycarbonyl radicals.
  • the compounds of the formula I obtained can be converted into their salts, in particular for pharmaceutical use into their physiologically tolerable salts with inorganic or organic acids.
  • suitable acids for this are hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of formula I thus obtained if they contain a carboxy group, can, if desired, subsequently be converted into their salts with inorganic or organic bases, in particular for their pharmaceutical use into their physiologically tolerable salts.
  • the bases are, for example, sodium hydroxide, ca lium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the new compounds of the general formula I and their salts have valuable properties.
  • the compounds of general formula I, in which R c represents a cyano group are valuable intermediates for the preparation of the other compounds of general formula I
  • the compounds of general formula I, in which R c represents one of the amidino groups mentioned at the outset, and Their tautomers, their stereoisomers and their physiologically tolerable salts have valuable pharmacological properties, in particular an antithrombotic effect, which is preferably based on an action influencing thrombin or factor Xa, for example on a thrombin-inhibiting or factor Xa-inhibiting action, on one the aPTT time prolonging effect and on an inhibitory effect on related serine proteases such as.
  • A 2- (4-amidinophenylaminomethyl) -1-methyl-5- [1- (ethoxycarbonylmethylamino) -1- (2,5-dihydropyrrolocarbonyl) ethyl] benzimidazole dihydrochloride,
  • the aPTT time was determined using a Biomatic BIO coagulometer from Desaga.
  • test substance was placed in the test vessels prescribed by the manufacturer with 0.1 ml of human citrate plasma and 0.1 ml of PTT reagent. The mixture was incubated at 37 ° C for three minutes. The coagulation reaction was started by adding 0.1 ml of calcium solution. Depending on the device, the calcium solution is measured and the time taken for the batch to clot is measured. Batches in which 0.1 ml of DBA buffer were added served as a control.
  • the effective substance concentration was determined via a dose-response curve, at which the aPTT time was doubled compared to the control.
  • the compounds prepared according to the invention are well tolerated, since no toxic side effects could be observed at therapeutic doses.
  • prodrugs for example the compounds of Examples 1 (6), 2, 3 (2) and 3 (5), have good oral absorption.
  • the new compounds and their physiologically tolerable salts are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as the treatment of deep vein thrombosis, the prevention of reocclusions after bypass surgery or angioplasty (PT ( C) A), as well as occlusion in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, prophylaxis of coronary thrombosis, prophylaxis of stroke and prevention of occlusion of shunts.
  • venous and arterial thrombotic diseases such as the treatment of deep vein thrombosis, the prevention of reocclusions after bypass surgery or angioplasty (PT ( C) A)
  • PT ( C) A) angioplasty
  • peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, prophylaxis of coronary thrombosis, prophylaxis of stroke and prevention of occlusion of shunts.
  • the compounds according to the invention are for antithrombotic support in thrombolytic treatment, such as, for example, with rt-PA or streptokinase, for preventing long-term restosis after PT (C) A, for preventing metastasis and the growth of coagulation-dependent tumors and of fibrin-dependent inflammatory processes , e.g. in the treatment of pulmonary fibrosis.
  • thrombolytic treatment such as, for example, with rt-PA or streptokinase
  • C restosis after PT
  • the dosage required to achieve a corresponding effect is expediently 0.1 to 30 mg / kg, preferably 0.3 to 10 mg / kg for intravenous administration and 0.1 to 50 mg / kg, preferably 0.3 to for oral administration 30 mg / kg, 1 to 4 times a day.
  • the compounds of the formula I prepared according to the invention optionally in combination with other active substances, together with one or more inert customary carriers and / or diluents, for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, Water, water / ethanol, water / glycerin, water / sorbitol, water / polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethyl cellulose or fatty substances such as hard fat or their suitable mixtures, in conventional pharmaceutical preparations such as tablets, Work in coated tablets, capsules, powder, suspensions or suppositories.
  • inert customary carriers and / or diluents for example with corn starch, lactose, cane sugar, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, Water, water /
  • Example 1c Prepared analogously to Example 1c from 4- (5-methyl-1,2,4,4-oxadiazol-3-yl) -phenylamino-acetic acid ethyl ester and di-tert. Butyl-dicarbonate / N-ethyl-diisopropylamine in dioxane.
  • R f value 0.5 (reversed phase RP8; 5% saline / methanol
  • R f value 0.5 (reversed phase RP8; 5% saline / methanol
  • Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for injections.
  • Active ingredient and mannitol are dissolved in water. After filling, freeze-drying.
  • the ready-to-use solution is dissolved with water for injection purposes.
  • composition (1) Active ingredient 50.0 mg
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
  • This powder mixture is filled into size 3 hard gelatin capsules on a capsule filling machine.
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
  • This powder mixture is filled in a size 0 hard gelatin capsule on a capsule filling machine.
  • Suppositories with 100 mg of active ingredient 1 suppository contains:
  • Polyethylene glycol (M.G. 1500) 600.0 mg Polyethylene glycol (M.G. 6000) 460.0 mg Polyethylene sorbitan monostearate 840.0 mg
  • the polyethylene glycol is melted together with polyethylene sorbitan monostearate.
  • the milled active substance is homogeneously dispersed in the melt at 40 ° C. It is cooled to 38 ° C and poured into weakly pre-cooled suppository molds.

Abstract

L'invention concerne de nouveaux benzimidazoles de la formule générale (I) où Ra à Rc ont la définition donnée dans la revendication (1), leurs tautomères, leurs stéréoisomères, leurs mélanges, leurs prodrogues, leurs dérivés qui contiennent un groupe chargé négativement dans des conditions physiologiques à la place d'un groupe carboxy, et leurs sels, notamment leurs sels physiologiquement tolérables avec des acides ou des bases inorganiques ou organiques aux précieuses propriétés. Les composés de la formule générale (I) où Rc ne représente aucun groupe amidino, représentent de précieux produits intermédiaires destinés à la production des composés amidino de la formule générale (I) ayant de précieuses propriétés pharmacologiques, notamment une action antithrombotique.
EP00983342A 1999-12-23 2000-12-16 Benzimidazoles, leur production et leur utilisation comme antithrombotiques Withdrawn EP1244636A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19962329 1999-12-23
DE19962329A DE19962329A1 (de) 1999-12-23 1999-12-23 Benzimidazole, deren Herstellung und deren Verwendung als Arzneimittel
PCT/EP2000/012841 WO2001047896A1 (fr) 1999-12-23 2000-12-16 Benzimidazoles, leur production et leur utilisation comme antithrombotiques

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EP1244636A1 true EP1244636A1 (fr) 2002-10-02

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JP (1) JP2003519129A (fr)
AR (1) AR027050A1 (fr)
AU (1) AU2011501A (fr)
CA (1) CA2393916A1 (fr)
DE (1) DE19962329A1 (fr)
MX (1) MXPA02006299A (fr)
PE (1) PE20010954A1 (fr)
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WO (1) WO2001047896A1 (fr)

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DE10125478A1 (de) * 2001-05-25 2002-11-28 Boehringer Ingelheim Pharma Verwendung bicyclischer Heterocyclen zur Behandlung und Vorbeugung arterieller thrombotischer Erkrankungen
US7169934B2 (en) 2002-06-20 2007-01-30 Boehringer Ingelheim International Gmbh (R) 2-(4-amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1 (pyrrolidinocarbonyl)-ethyl]-benzimidazole, the monohydrochloride thereof, preparation thereof and the use as pharmaceutical composition
DE10227666A1 (de) * 2002-06-20 2004-01-08 Boehringer Ingelheim Pharma Gmbh & Co. Kg (R)-2-(4-Amidinophenylaminomethyl)-1-methyl-5-[1-(carboxymethylamino)-1-(pyrrolidinocarbonyl)- ethyl]-benzimidazol, dessen Monohydrochlorid, Verfahren zu deren Herstellung sowie Verwendung als Arzneimittel
PE20040804A1 (es) 2002-12-19 2004-12-31 Boehringer Ingelheim Pharma DERIVADOS DE CARBOXAMIDAS COMO INHIBIDORES DEL FACTOR Xa
US7371743B2 (en) * 2004-02-28 2008-05-13 Boehringer Ingelheim International Gmbh Carboxylic acid amides, the preparation thereof and their use as medicaments
EP1609784A1 (fr) 2004-06-25 2005-12-28 Boehringer Ingelheim Pharma GmbH & Co.KG Procédé pour la préparation de 4-(benzimidazolylméthylamino)-benzamidines
DE102005061623A1 (de) * 2005-12-21 2007-06-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verbessertes Verfahren zur Herstellung von 4-(Benzimidazolylmethylamino)-Benzamidinen und deren Salzen
DE102005061624A1 (de) * 2005-12-21 2007-06-28 Boehringer Ingelheim Pharma Gmbh & Co. Kg Verbessertes Verfahren zur Herstellung von Salzen von 4-(Benzimidazolylmethylamino)-Benzamidinen
US10077251B2 (en) 2012-10-29 2018-09-18 Biophore India Pharmaceuticals Pvt. Ltd. Process for the synthesis of Dabigatran Etexilate and its intermediates
US9533971B2 (en) 2012-10-29 2017-01-03 Biophore India Pharmaceuticals Pvt. Ltd Process for the synthesis of dabigatran and its intermediates
RU2623439C1 (ru) * 2016-10-14 2017-06-26 федеральное государственное автономное образовательное учреждение высшего образования "Южный федеральный университет" Бромиды 1-замещенных-3-{ [2-(3,5-ди-трет-4-гидроксифенил)-2-оксоэтил]} -2-аминобензимидазолия, обладающие антиагрегантными и антиоксидантными свойствами

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DE4129603A1 (de) * 1991-09-06 1993-03-11 Thomae Gmbh Dr K Kondensierte 5-gliedrige heterocyclen, verfahren zu ihrer herstellung und diese verbindungen enthaltende arzneimittel
EP1060166A1 (fr) * 1998-02-03 2000-12-20 Boehringer Ingelheim Pharma KG Heterocycles benzo condenses a 5 chainons utilises comme agents antithrombotiques
TWI248435B (en) * 1998-07-04 2006-02-01 Boehringer Ingelheim Pharma Benzimidazoles, the preparation thereof and their use as pharmaceutical compositions
DE19829964A1 (de) * 1998-07-04 2000-01-05 Boehringer Ingelheim Pharma Benzimidazole, deren Herstellung und deren Verwendung als Arzneimittel

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MXPA02006299A (es) 2002-12-09
DE19962329A1 (de) 2001-06-28
JP2003519129A (ja) 2003-06-17
WO2001047896A1 (fr) 2001-07-05
UY26492A1 (es) 2001-07-31
PE20010954A1 (es) 2001-10-09
CA2393916A1 (fr) 2001-07-05
AR027050A1 (es) 2003-03-12

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