EP1390357A2 - Composes antithrombotiques, leur preparation et leur utilisation comme produits pharmaceutiques - Google Patents

Composes antithrombotiques, leur preparation et leur utilisation comme produits pharmaceutiques

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Publication number
EP1390357A2
EP1390357A2 EP02714118A EP02714118A EP1390357A2 EP 1390357 A2 EP1390357 A2 EP 1390357A2 EP 02714118 A EP02714118 A EP 02714118A EP 02714118 A EP02714118 A EP 02714118A EP 1390357 A2 EP1390357 A2 EP 1390357A2
Authority
EP
European Patent Office
Prior art keywords
group
alkyl
carbonyl
phenyl
methyl
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Withdrawn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
EP02714118A
Other languages
German (de)
English (en)
Inventor
Uwe Jörg RIES
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
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharma GmbH and Co KG
Boehringer Ingelheim Pharmaceuticals Inc
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
Priority claimed from DE10104597A external-priority patent/DE10104597A1/de
Application filed by Boehringer Ingelheim Pharma GmbH and Co KG, Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharma GmbH and Co KG
Publication of EP1390357A2 publication Critical patent/EP1390357A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings

Definitions

  • Antithrombotic compounds their preparation and their use as
  • the present invention relates to the compounds of the general formula
  • 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.
  • one or two hydrogen atoms can each be replaced independently of one another by a C 3 alkyl group or
  • a hydrogen atom can be replaced by the group - (CH 2 ) P -R f , where
  • p is one of the numbers 0, 1, 2 or 3 and
  • R f is a hydroxycarbonyl-, C ⁇ _ 3 -alkoxycarbonyl-, aminocarbonyl-, C ⁇ _ 3 -Alkylaminocarbonyl-, di- (C ⁇ _ 3 -alkyl) -aminocarbonyl-, C 3 . 7 -cycloalkylamino-carbonyl-, N- (C ⁇ _ 3 -alkoxy-carbonylmethyl) -N- (C ⁇ .
  • A a straight-chain C ⁇ . 3 -alkylene group, in which one or two hydrogen atoms can be replaced independently of one another by a C ⁇ - 3 alkyl group, or
  • Ri an amino, C ⁇ . 5 alkylamino, C 3 . 7- Cycloalkylamino- or phenyl-C ⁇ . 3 -alkyl- amino group, each on the amine nitrogen atom by a phenylcarbonyl or phenylsulfonyl group or by a group in the alkyl part optionally by a carboxy group, an in vivo convertible group to a carboxy group, an amino, C 3 alkylamino or di - (. C ⁇ -C3 alkyl) amino-substituted C- ⁇ - 3 alkyl or C ⁇ _ 3 alkyl-carbonyl group may be substituted,
  • C- 3 alkyl amino-C. 3 -alkyl-, C ⁇ _ 3 -alkylamino- C- ⁇ -3-alkyl-, di- (C ⁇ _ 3 -alkyl) -amino-C ⁇ .. 3 -alkyl-, aminocarbonyl-, C ⁇ _ 3 -Alkylamino- carbonyl- or di - (C-
  • . 3 -alkyl-, C ⁇ _ 3 -alkyl carbonyl, phenylcarbonyl or phenylsulfonyl group can be replaced,
  • C ⁇ . 3 -alkyl groups-substituted amidino group can be substituted by a fluorine, chlorine or bromine atom, by a trifluoromethyl, C- ⁇ - 3 alkyl or C ⁇ _ 3 alkoxy group,
  • R 2 is a hydrogen, fluorine, chlorine or bromine atom, a C 3 alkyl group in which the hydrogen atoms can be replaced in whole or in part by fluorine atoms, a C 2 3 alkenyl, C 2 3 alkynyl group , Hydroxy-, C ⁇ _ 3 alkoxy or trifluoromethoxy group,
  • R 3 is a hydrogen atom or a C 3 alkyl group
  • R 4 is a hydrogen atom or a C 3 alkyl group optionally substituted by a carboxy group or a group which can be converted into a carboxy group in vivo and
  • Ar is a phenyl or naphthyl group substituted by the radicals R 5 , R 6 and R 7 , where R 5 is a cyano group, an amidino group which is optionally substituted by one or two d-3-alkyl groups, an amino-C ⁇ _alkyl-, C- ⁇ - 3 -alkyl-amino-C- ⁇ - 3 -alkyl- or di- (C- 3 alkyl) amino-C. 3 -alkyl group,
  • R 6 is a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, C 1 . 3 - alkyl-, hydroxy-, hydroxy-C- ⁇ _ 3 -alkyl-, C ⁇ - 3 -alkoxy-, C ⁇ . 3 -alkoxy-C ⁇ - 3 -alkyl-, carboxy-, carboxy-C ⁇ _ 3 -alkyl-, carboxy-C ⁇ . 3 -alkoxy-, C ⁇ _ 4 -alkoxy-carbonyloxy-, -C ⁇ - 4 -alkoxy-carbonyl-C ⁇ - 3 -alkoxy-, phenyl-C ⁇ . 3 -alkoxy-, amino-, C ⁇ _ 3 -alkylamino- or di- (C ⁇ - 3 -alkyl) amino group and
  • R 7 represents a hydrogen, fluorine, chlorine or bromine atom or a C 1 -C 3 alkyl group
  • an imino group which may be substituted by a C 1-4 alkyl group or an oxygen or sulfur atom and additionally a nitrogen atom,
  • a phenyl ring can be fused to the 5- or 6-membered heteroaryl groups mentioned above via two adjacent carbon atoms and the bicyclic heteroaryl groups thus formed can be bonded via the heteroaromatic or carbocyclic part,
  • the carboxy groups mentioned in the definition of the abovementioned radicals can 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,
  • amino and imino groups mentioned in the definition of the radicals mentioned above can be substituted by a radical which can be split off in vivo.
  • radicals which can be split off in vivo.
  • groups are described, for example, in WO 98/46576 and by N.M. Nielsen et al. in International Journal of Pharmaceutics 39, 75-85 (1987).
  • a convertible in vivo into a carboxy group is, for example, a hydroxymethyl group, an esterified carboxy group with an alcohol in which the alcoholic moiety is preferably a Ct 6 alkanol, a phenyl-C ⁇ _ 3 -alkanol, a C 3-9 -CycloaIkanol , where a C 5 . 8- Cycloalkanol can also be substituted by one or two C 3 alkyl groups, a Cs-s-cycloalkanol in which a methylene group in the 3- or 4-position by an oxygen atom or by a C-
  • 3 -alkoxycarbonyl- or C 2 -6-alkanoyl group substituted imino group is replaced and the cycloalkanol part additionally by one or two C ⁇ .
  • 3 -alkyl groups may be substituted, a C 4 _ 7 cycloalkenol, a C 3 -s-alkenol, a phenyl-C 3 .
  • R a is a Ci- ⁇ -alkyl, C. 5 7- cycloalkyl, phenyl or phenyl-C ⁇ - 3 alkyl group,
  • R b is a hydrogen atom, a C- ⁇ - 3 alkyl, C 5 . Cycloalkyl or phenyl group and
  • R c is a hydrogen atom or a C- ⁇ - represent 3 alkyl 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- ⁇ - 3 alkyl or C-
  • 3 -alkoxy groups mono- or disubstituted phenylcarbonyl group, where the substituents may be the same or different, a pyridinoyl group or a -C 6 alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, a 3rd , 3,3-trichloropropionyl or allyloxycarbonyl group, a C ⁇ _i 6 -alkoxycarbonyl or in which hydrogen atoms can be replaced in whole or in part by fluorine or chlorine atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, Nonyloxycarbonyl, decy
  • R d and R e which may be the same or different, are hydrogen atoms or
  • 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.
  • one or two hydrogen atoms can each be replaced independently of one another by a C 3 alkyl group or a hydrogen atom can be replaced by the group - (CH 2 ) P -R f , where
  • p is one of the numbers 0, 1, 2 or 3 and
  • R f is a hydroxycarbonyl, C 3 alkoxycarbonyl, aminocarbonyl,
  • A is a straight-chain C 3 alkylene group in which one or two hydrogen atoms independently of one another each by a C 1. 3 alkyl group can be replaced,
  • Ri an amino, C ⁇ . 3 alkylamino or C 3 . 7- Cycloalkylamino group, each on the amine nitrogen atom by a C ⁇ " 3 alkyl, C ⁇ - 3 alkylcarbonyl, carboxy-C- ⁇ . 3 -alkyl-, carboxy-C ⁇ _ 3 -alkylcarbonyl-, C ⁇ . 6 -alkoxy-carbonyl-C ⁇ . 3 -alkyl carbonyl or amino -C. 3- alkyl-carbonyl group can be substituted,
  • C ⁇ _ 3 alkyl amino C ⁇ . 3 -alkyl-, C 1 . 3 -alkylamino-C 1 . 3 - alkyl, aminocarbonyl or C ⁇ - 3 alkylamino-carbonyl group substituted 4- to 7-membered cycloalkyleneiminocarbonyl group, wherein
  • a hydrogen atom bonded to a nitrogen atom can be replaced by an acetyl, phenylcarbonyl or tert-butoxycarbonyl group, or a 2,5-dihydropyrrol-1-yl carbonyl group,
  • R 2 is a hydrogen, fluorine, chlorine or bromine atom, a C ⁇ . 3 -alkyl-, C 2 -3-alkenyl-, C - 3 -alkynyl-, trifluoromethyl-, C ⁇ . 3 -alkoxy or trifluoromethoxy group,
  • R 3 is a hydrogen atom or a C ⁇ . 3 -alkyl group
  • R 4 is a hydrogen atom or a C ⁇ _ 3 alkyl group
  • Ar is a phenyl group substituted by the radicals R 5 , R ⁇ and R, where
  • R 5 is a cyano group, an amidino group optionally substituted by one or two C 3 alkyl groups, a hydroxyl, C 6 alkoxy carbonyl, 2,2,2-trichloroethoxycarbonyl or phenyl carbonyl group, an amino C 1 group. 3 -alkyl- or C ⁇ - 3 alkylamino-C ⁇ - 3 alkyl group,
  • R 6 is a hydrogen, fluorine, chlorine or bromine atom, a trifluoromethyl, C 1 . 3 - alkyl, hydroxy, hydroxy -CC. 3 alkyl, C ⁇ alkoxy, carboxy, C ⁇ . 3 -alkoxy carbonyloxy, carboxy C 3 alkoxy or C 1 alkoxy carbonyl C 1 . 3 -alkoxy group and
  • R 7 is a hydrogen atom or a C ⁇ . 3 represents alkyl group
  • one or two hydrogen atoms independently of each other by a C ⁇ . 3 alkyl group can be replaced or
  • a hydrogen atom can be replaced by the group - (CH 2 ) P -R f , where
  • p is one of the numbers 0, 1, 2 or 3 and
  • R f is a hydroxycarbonyl, C ⁇ . 3 -alkoxycarbonyl-, N- (C ⁇ . 3 -alkyl) -amino-carbonyl-, di- (C ⁇ . 3 -alkyl) -aminocarbonyl-, N- (C ⁇ . 3 -alkoxy-carbonyl-methyl) -N- ( C ⁇ . 3 -alkyl) -aminocarbonyl-, N- (carboxymethyl) -N- (C ⁇ . 3 - alkyl) -aminocarbonyl- or a 4- to 7-membered cycloalkyleneimino-carbonyl group
  • A is a -CH 2 -CH 2 group
  • A represents a -CH 2 group
  • R 1 to R are defined as mentioned above, but R 1 is bonded in the 4-position to the phenyl radical contained in formula I and
  • Ar represents a phenyl group disubstituted by the radicals R 5 and RQ, where R 5 is bound in the 3-position when RQ represents a hydrogen atom, or is bound in the 5-position when R 6 takes on a meaning other than that of the hydrogen atom, and one optionally by one or two C ⁇ . 3 -alkyl groups, a hydroxy, C ⁇ _ 6 alkoxy-carbonyl, 2,2,2-trichloroethoxycarbonyl or phenylcarbonyl group substituted amidino group, an amino-C ⁇ . 3 -alkyl- or C ⁇ - 3 alkylamino-C ⁇ . 3 alkyl group and
  • R ⁇ is a hydrogen atom or a hydroxy, C 1 bonded in the 2-position.
  • 3 -AI- koxy-, carboxy-C ⁇ . 3 -alkoxy-, C ⁇ . 3 -alkoxy-carbonyloxy- or C ⁇ _ 4 -alkoxy- carbonyl-C ⁇ - 3 -alkoxy group means
  • a hydrogen atom through a methyl, hydroxycarbonyl, C 3 alkoxy carbonyl, C 1. 3 -AlkylaminocarbonyI-, dimethylaminocarbonyl, pyrrolidin-1-yl-carbonyl-, C ⁇ . 3 -Alkylaminocarbonylmethyl-, N- (hydroxy-carbonyl-methyl) - N- (C ⁇ _ 3 -alkyl) -amino-carbonyl-methyl-, N- (C ⁇ . 3 -alkoxy-carbonyl-methyl) -N- (C ⁇ - 3 -alkyl) -amino-carbonyl-methyl, hydroxycarbonylmethyl, C ⁇ . 3 -alkoxycarbonylmethyl or dimethylaminocarbonylmethyl group can be replaced,
  • Ri is bound in the 4-position of the phenyl radical of the formula I and
  • a C5-7 cycloalkylamino group on the amine nitrogen atom by a C ⁇ _ 3 alkyl, C ⁇ _ 3 alkylcarbonyl, amino-C ⁇ . 3 -alkylcarbonyl-, carboxy-C ⁇ . 3 -alkylcarbonyl- or C ⁇ ⁇ -alkoxy-carbonyl-C ⁇ _ 3 -alkyl-carbonyl group may be substituted, a 4- to 7-membered cycloalkyleneiminocarbonyl group
  • R 2 is a hydrogen atom or a bonded in 3- or, if R 3 represents a C 3 alkyl group, in the 5-position of the phenyl radical in formula I. 3- alkyl, ethenyl, ethynyl, trifluoromethyl or trifluoromethoxy group or a chlorine or bromine atom bonded in the 3-position,
  • R 3 is a hydrogen atom or a C 1 bonded in the 2-position of the phenyl radical in formula I. 3 -alkyl group,
  • R 4 is a hydrogen atom
  • Ar is a phenyl group disubstituted by the radicals R 5 and RQ, where
  • R 5 is bonded in the 3-position if R ⁇ represents a hydrogen atom, or is bonded in the 5-position if R 6 takes on a meaning other than that of the hydrogen atom, and one optionally by a C ⁇ _ 6 -alkoxy-carbonyl-,
  • R 6 represents a hydrogen atom or a hydroxy or C 3 - alkoxy-carbonyloxy group bonded in the 2-position
  • A is a -CH 2 -CH 2 group
  • Ri is a 4- to 7-membered cycloalkyleneiminocarbonyl or 2,5-dihydropyrrol-1-ylcarbonyl group bonded in the 4-position of the phenyl radical of the formula I,
  • R 2 is a hydrogen atom or a substituent bonded in 3- or, if R 3 is a C 3 alkyl group, in the 5 position of the phenyl radical in formula I selected from fluorine, chlorine, bromine, C 3 alkyl and trifluoromethyl,
  • R 3 is a hydrogen atom or a C 3 alkyl group bonded in the 2-position of the phenyl radical in formula I,
  • R is a hydrogen atom
  • Ar is a phenyl group disubstituted by the radicals R 5 and R 6 , where
  • R 5 is bound in the 5-position and one optionally by one or two C ⁇ . 3 alkyl groups, a C ⁇ . 6 -alkoxy-carbonyl or phenylcarbonyl group substituted amidino group and
  • R 6 represents a hydroxy group bonded in the 2-position
  • the compounds of general formula I are obtained by processes known per se, for example by the following processes:
  • a hydrogen atom can be replaced by the group - (CH 2 ) P -R f , where p and R f are defined as mentioned at the outset,
  • Ar is a phenyl or naphthyl group substituted by the radicals R 5 , R ⁇ and R 7 , where R 6 and R 7 are defined as mentioned at the outset and R 5 is an amidino group:
  • A is a straight-chain C ⁇ alkylene group in which one or two hydrogen atoms can be replaced independently of one another by a C ⁇ _ 3 alkyl group or a hydrogen atom can be replaced by the group - (CH 2 ) P -R f , where p and R f are defined as mentioned above, or a bond and
  • Ar is a phenyl or naphthyl group substituted by the radicals R 5 , R ⁇ and R 7 , where
  • R 5 represents a cyano group and R 6 and R 7 are defined as mentioned at the beginning
  • n represents the number 0 or 1
  • X represents a hydroxyl or C 4 alkoxy group or a chlorine atom
  • R 1 to R 3 are defined as mentioned at the outset, or with their reactive derivatives and subsequent conversion of the cyano compound thus obtained into an amidino compound.
  • the acylation is advantageously carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, sodium hydroxide solution or sulfolane, if appropriate in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.
  • a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformamide, sodium hydroxide solution or sulfolane, if appropriate in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160
  • the acylation can also be carried out with the free acid, if appropriate in the presence of an acid-activating agent or a dehydrating agent, for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexyl- carbodiimide / N-hydroxysuccinimide or 1-hydroxy-benzotriazole, N, N'-carbonyldiimidazole, O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyl-uronium tetrafluoroborate / N-methyl-morpholiri , O- (Benzotriazol-1-yl)
  • A is a straight-chain C 3 alkylene group in which one or two hydrogen atoms can each be replaced independently of one another by a C 3 alkyl group, and
  • Ar is a phenyl or naphthyl group substituted by the radicals R 5 , R ⁇ and R 7 , where R 6 and R are defined as mentioned at the outset and R 5 is an amidino group:
  • A is a straight-chain C 3 alkylene group in which one or two hydrogen atoms can be replaced independently of one another by a C 3 alkyl group
  • Ar is a phenyl or naphthyl group substituted by the radicals R 5 , Re and R 7 , where R ⁇ and R 7 are defined as mentioned at the outset and R 5 represents a cyano group
  • Z 1 represents a leaving group such as a halogen atom or a sulfonyloxy group, for example a chlorine, bromine or iodine atom or a trifluoromethylsulfonyloxy group, and subsequent conversion of the thus obtained Cyano compound into an amidino compound.
  • the alkylation is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane, dimethyl sulfoxide or sulfolane with an alkylating agent such as a corresponding halide or sulfonic acid ester, e.g.
  • a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane, dimethyl sulfoxide or sulfolane
  • an alkylating agent such as a corresponding halide or sulfonic acid ester, e.g.
  • methyl iodide ethyl bromide, dimethyl sulfate or benzyl chloride
  • a tertiary organic base preferably at temperatures between 0 and 100 ° C.
  • Ar is a phenyl or naphthyl group substituted by the radicals R 5 , R 6 and R 7 , where R ⁇ and R 7 are defined as mentioned at the outset and R 5 represents an amidino group,
  • n the number 0 and A a straight-chain C ⁇ . 3 -alkylene group in which one or two hydrogen atoms independently of one another each by a C ⁇ . 3 alkyl group can be replaced, or m is 2, n is 0 and A is a bond:
  • A is a straight-chain C 3 alkylene group in which one or two hydrogen atoms independently of one another each by a C 1. 3 alkyl group can be replaced, or a bond, and
  • Ar is a phenyl or naphthyl group substituted by the radicals Rs, R ⁇ and R, where R ⁇ and R 7 are defined as mentioned at the outset and R 5 is a cyano group,
  • R 1 to R 3 are defined as mentioned at the outset
  • m represents the number 1 or 2
  • Z 2 represents a leaving group such as a halogen atom or a sulfonyloxy group, for example a chlorine, bromine or iodine atom or a trifluoromethylsulfonyloxy group, and. subsequent conversion of the cyano compound thus obtained into an amidino compound.
  • the alkylation is optionally in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane, dimethyl sulfoxide or sulfolane with an alkylating agent such as a corresponding halide or sulfonic acid ester, for example with methyl iodide, ethyl bromide, dimethyl sulfate or benzyl chloride, if appropriate in the presence of a tertiary organic base or in the presence of an inorganic base, advantageously at temperatures between 0 and 150 ° C., preferably at temperatures between 0 and 100 ° C.
  • a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene
  • Ar is a phenyl or naphthyl group substituted by the radicals R 5 , R ⁇ and R 7 , where R 6 and R 7 are defined as mentioned at the outset and R 5 is an amidino group,
  • n is the number 0
  • A is a straight-chain C 3 alkylene group in which one or two hydrogen atoms can be replaced independently of one another by a C 3 alkyl group, or
  • R 1 to R 4 are defined as mentioned at the outset and m represents the number 0, 1 or 2, with an aldehyde of the general formula
  • A is a straight-chain C 3 alkylene group in which one or two hydrogen atoms can each be replaced independently of one another by a C 3 alkyl group, or a bond
  • Ar one substituted by the radicals R 5 , R 6 and R 7 Phenyl or naphthyl group, where R ⁇ and R 7 are defined as mentioned at the beginning and R 5 represents a cyano group, and subsequent conversion of the cyano compound thus obtained into an amidino compound.
  • the reductive alkylation is preferably carried out in the presence of a complex metal hydride such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride or borane / pyridine, preferably at a pH of 1-7, optionally in the presence of a dehydrating agent such as molecular sieve or titanium IV isopropylate and at room temperature or with hydrogen in the presence of a hydrogenation catalyst, for example in the presence of palladium / carbon, at a hydrogen pressure of 1 to 5 bar, preferably at temperatures between 20 ° C and the boiling point of the solvent used.
  • a complex metal hydride such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, zinc borohydride, sodium triacetoxyborohydride or borane / pyridine
  • a dehydrating agent such as molecular sieve or titanium IV isopropylate
  • a hydrogenation catalyst for example in the presence
  • Ri to R, m, n and A are defined as mentioned at the beginning
  • Ar is a phenyl or naphthyl group substituted by the radicals R ⁇ and R 7 , where R 6 and R7 are defined as mentioned at the beginning, and
  • Z 3 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 that
  • R 8 and Rg which may be the same or different, each have a hydrogen atom or a C ⁇ . 3 -Alkylou mean, 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 an amine of the general formula IX or with a corresponding acid addition salt such as ammonium carbonate or ammonium acetate.
  • a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane
  • a compound of the general formula VIII 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 tetrafiuorbora.t 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 expediently 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 a corresponding alkyl or aralkyl halide.
  • a corresponding cyano compound with a corresponding alcohol such as
  • Ar represents a phenyl or naphthyl group substituted by the radicals R5, R ⁇ and R 7 , R 1 to R 4 , R 6 , R 7 , A, m and n are defined as mentioned at the outset and R 5 represents a cyano group, and optionally subsequent alkylation with a compound of the formula
  • Z 4 represents a leaving group such as a halogen atom or a sulfonyloxy group, for example a chlorine, bromine or iodine atom or a trifluoromethylsulfonyloxy group.
  • the catalytic hydrogenation is countered with hydrogen in the presence of a catalyst such as palladium / carbon, platinum in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide / acetone or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ° C., but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar, or, for example, with Raney nickel, preferably in methanolic ammonia solution ,
  • the optionally subsequent alkylation is expediently carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane, dimethyl sulfoxide or sulfolane with an alkylating agent such as a corresponding halide or sulfonic acid ester, e.g.
  • a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran, dioxane, dimethyl sulfoxide or sulfolane
  • an alkylating agent such as a corresponding halide or sulfonic acid ester, e.g.
  • methyl iodide ethyl bromide, dimethyl sulfate or benzyl chloride
  • a tertiary organic base preferably at temperatures between 0 and 100 ° C.
  • n the number 0, A is a straight-chain C 3 alkyl group, in which one or two hydrogen atoms can be replaced independently of one another by a C 3 alkyl group, and
  • Ar is a phenyl or naphthyl group substituted by the radicals R 5 , R ⁇ and R 7 , where R 6 and R7 are defined as mentioned at the outset and R 5 is an amidino group:
  • R in the R 1 to R 3 are defined as mentioned at the outset and Z5 represents a leaving group such as a halogen atom or a sulfonyloxy group, for example a chlorine, bromine or iodine atom or a trifluoromethylsulfonyloxy group,
  • A is a straight-chain C 3 alkylene group in which one or two hydrogen atoms can each be replaced independently of one another by a C 3 alkyl group, and
  • Ar is a phenyl or naphthyl group substituted by the radicals R5, R ⁇ and R 7 , where R ⁇ and R7 are defined as mentioned at the beginning and R 5 is a cyano group, and then converting the cyano compound thus obtained into an amidino compound.
  • the coupling reaction is advantageously carried out in a solvent such as toluene, dioxane, dimethoxyethane or tetrahydrofuran using a suitable catalyst, for example bis (tri-o-tolylphosphine) palladium (II) chloride, tris (di-benzylidene acetone) dipalladium ( 0) / tris-o-tolylphosphine, tris (dibenzylidene acetone) - dipalladium (0) / tris- (2-furyl) phosphine, tris (dibenzylidene acetone) dipalladium (0) / 2,2'-bis (diphenylphosphino) -1, 1'-binaphthyl, tetrakis (triphenylphosphine) palladium (0), 1, 1'-bis (diphenylphosphino) ferrocene-palladium dichloride or pal
  • the subsequent acylation is advantageously carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane, if appropriate in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.
  • a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile or sulfolane, if appropriate in the presence of an inorganic or organic base at temperatures between -20 and 200 ° C, but preferably at temperatures between -10 and 160 ° C.
  • an acid activating agent or a dehydrating agent e.
  • the subsequent 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 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 and the subsequent decarboxylation in the presence of an acid as described above at temperatures between -10 and 120 ° C, for example at temperatures between room temperature and the boiling point 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
  • the subsequent esterification 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, optionally in the presence of an acid such as hydrochloric acid or in the presence a dehydrating agent, e.g.
  • 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 a dehydrating agent, e.g.
  • any reactive groups present such as hydroxyl, carboxy, amino, alkylamino or imino groups
  • customary protective groups which are split off again after the reaction.
  • the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydröpyranyl group comes as a protective radical for a hydroxyl group, the trimethylsilyl, methyl, ethyl or , tert-butyl, benzyl or tetrahydröpyranyl distr and
  • a protective radical for an amino, alkylamino or imino group the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group in addition the 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 cleaved off, for example, by hydrogenolysis, e.g. with 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, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50 ° C, but preferably at room temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably of 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, but preferably at room temperature, and at a hydrogen pressure of 1 to
  • 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 methoxy group is advantageously removed in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between -35 and -25 ° C.
  • 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, if appropriate 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 removed 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 (l) 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.
  • 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
  • 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)
  • the enantiomers are separated preferably by column separation on chiral phases or by recrystallization from an optically active solvent or by reaction with an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols, and Separation of the diastereomeric salt mixture or derivative obtained in this way, for example on the basis of 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.
  • an optically active substance which forms salts or derivatives, such as esters or amides, for example esters or amides, in particular acids and their activated derivatives or alcohols
  • optically active acids are, for example, the D and L forms of tartaric acid or dibenzoyl tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.
  • Suitable 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. Examples of 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 contain a carboxy group, they 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.
  • Suitable bases are, for example, sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the new compounds of the general formula I and their salts have valuable properties.
  • the compounds of the general formula I in which Ar is a phenyl or naphthyl group substituted by the radicals R 5 , R 6 and R 7 and R 5 is a cyano group are valuable intermediates for the preparation of the corresponding compounds of the general formula I , in which R5 is an amidino group which is optionally substituted by one or two C 3 alkyl groups.
  • the compounds of the general formula I with the exception of those compounds in which Ar represents a phenyl or naphthyl group substituted by the radicals R 5 , R ⁇ and R 7 and R 5 is a cyano group, and their tautomers, their stereoisomers and their physiologically tolerable salts are valuable pharmacological properties, in particular an antithrombotic effect, which is preferably based on a thrombin or factor Xa influencing effect, for example on a thrombin-inhibiting or factor Xa-inhibiting effect, on an effect which prolongs the aPTT time and on an inhibitory effect on related serine proteases such as, for. B. trypsin, urokinase, factor VIIa, factor IX, factor XI and factor XII.
  • an antithrombotic effect which is preferably based on a thrombin or factor Xa influencing effect, for example on a thrombin-inhibiting or factor Xa-in
  • Methodology Enzyme kinetic measurement with a chromogenic substrate.
  • the amount of p-nitroaniline (pNA) released from the colorless chromogenic substrate by human factor Xa is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used.
  • the inhibition of enzyme activity (relative to the solvent control) is determined by the test substance concentrations of test substance at different therefrom and the IC 5 o calculated as the concentration which inhibits the factor Xa used by 50%.
  • Tris (hydroxymethyl) aminomethane buffer 100 mmol
  • sodium chloride 150 mmol
  • Chromozym X substrate (Röche), final concentration: 200 ⁇ mol / l per reaction mixture
  • Test substance final concentration 100, 30, 10, 3, 1, 0.3, 0.1, 0.03, 0.01, 0.003, 0.001 ⁇ mol / l
  • the compounds produced according to the invention are well tolerated since no toxic side effects could be observed at therapeutic doses.
  • the new compounds are suitable, with the exception of those compounds in which Ar is a phenyl or naphthyl group substituted by the radicals R 5 , R 6 and R 7 and R 5 is a cyano group, and their physiologically tolerable salts for prevention and treatment 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 the occlusion in peripheral arterial diseases such as pulmonary embolism, the 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
  • the compounds according to the invention are for antithrombotic support in thrombolytic treatment, such as, for example, with Alteplase, Reteplase, Tenecteplase, Staphylokinase or Streptokinase, for preventing long-term restenosis after PT (C) A, for the prophylaxis and treatment of ischemic incidents in patients with unstable angina or non-transmural myocardial infarction, to prevent the metastasis and growth of coagulation-dependent tumors and fibrin-dependent inflammatory processes, for example in the treatment of pulmonary fibrosis, for the prophylaxis and treatment of rheumatoid arthritis, for the prevention or prevention of fibrin dependent tissue adhesions and / or scar tissue formation as well as to promote wound healing processes.
  • C PT
  • the new compounds and their physiologically tolerable salts can be used therapeutically in combination with inhibitors of platelet aggregation, such as fibrinogen receptor antagonists (for example abciximab, eptifibatide, tirofiban), with inhibitors for ADP-induced aggregation (for example clopidogrel, ticlopidine), with P 2 T- Receptor antagonists (eg Cangrelor) or with combined thromboxane receptor antagonists / synthetase inhibitors (eg Terbogrel) can be used.
  • fibrinogen receptor antagonists for example abciximab, eptifibatide, tirofiban
  • inhibitors for ADP-induced aggregation for example clopidogrel, ticlopidine
  • P 2 T- Receptor antagonists eg Cangrelor
  • combined thromboxane receptor antagonists / synthetase inhibitors eg Terbogrel
  • the dosage required to achieve a corresponding effect is expediently 3 to 30 mg / kg, preferably 1 to 10, when administered intravenously mg / kg, and in the case of oral administration 5 to 50 mg / kg, preferably 3 to 30 mg / kg, in each case 1 to 4 times a day.
  • the compounds of the formula I prepared according to the invention 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 customary galenical preparations such as tablets, dragees, capsules, powders, Work in suspensions or suppositories.
  • customary galenical preparations such as tablets, dragees, capsules, powders, Work in suspensions or suppositories.
  • N- (5-aminomethyl-2-hydroxy-benzyl) -3-methyl-4- (pyrrolidin-1-yl-carbonyl) benzamide Prepared as in Example 2.b. from N- (5-cyano-2-benzyloxy-benzyl) -3-methyl-4- (pyrrolidin-l-yl-carbonyl) benzamide in methanolic ammonia / Raney-
  • Nickel / hydrogen and subsequent reaction analogous to example 3.g. with hydrogen in methanol with the addition of palladium on activated carbon. Yield: 34% of theory, Rf value: 0.35 (silica gel; dichloromethane / ethanol 8: 2)
  • Half of the combined organic phases are concentrated, with conc.
  • the aqueous phase is by adding conc.
  • the combined organic extracts are washed with saturated saline, dried and evaporated.
  • Active ingredient and mannitol are dissolved in water. After filling, freeze-drying. The ready-to-use solution is dissolved with water for
  • Preparation (1), (2) and (3) are mixed and granulated with an aqueous solution of (4). (5) is added to the dried granulate. Tablets are pressed from this mixture, biplan with a facet on both sides and a partial notch on one side. Tablet diameter: 9 mm.
  • (1) is triturated with (3). This trituration is added to the mixture of (2) and (4) with intensive mixing.
  • (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 0 hard gelatin capsules on a capsule filling machine.
  • 1 suppository contains: active ingredient 100.0 mg
  • Polyethylene glycol (M.G. 1500) 600.0 mg
  • the polyethylene glycol is melted together with polyethylene sorbitan monostearate. At 40 ° C, the ground active substance becomes homogeneous in the melt dispersed. It is cooled to 38 ° C and poured into weakly pre-cooled suppository molds.

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Abstract

La présente invention concerne des composés antithrombotiques de formule générale (1) dans laquelle R1 à R4, Ar, A, m et n sont tels que définis dans la revendication 1, leurs tautomères, leurs stéréoisomères, leurs mélanges, leurs promédicaments et leurs sels, qui ont des propriétés intéressantes. Les composés de la formule 1 indiquée ci-dessus, dans lesquels Ar est un groupe phényle ou naphtyle substitué par les radicaux R5, R6 et R7 et R5 est un groupe cyano, correspondent à des produits intermédiaires intéressants permettant la production de composés correspondants de formule générale 1, dans lesquels R5 est un groupe aminido éventuellement substitué par un ou deux groupes alkyle en C1-3. Les composés de formule générale 1 indiquée ci-dessus, à l'exception des composés dans lesquels Ar est un groupe phényle ou naphtyle substitué par les radicaux R5, R6 et R7 et R5 est un groupe cyano, ont des propriétés pharmacologiques intéressantes, notamment une action antithrombotique et une action d'inhibition de facteur Xa.
EP02714118A 2001-02-02 2002-01-26 Composes antithrombotiques, leur preparation et leur utilisation comme produits pharmaceutiques Withdrawn EP1390357A2 (fr)

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DE10104597A DE10104597A1 (de) 2001-02-02 2001-02-02 Antithrombotische Verbindungen, deren Herstellung und deren Verwendung als Arzneimittel
DE10135435 2001-07-26
DE10135435 2001-07-26
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US20030181488A1 (en) 2002-03-07 2003-09-25 Boehringer Ingelheim Pharma Gmbh & Co. Kg Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1H-benzimidazol-5-carbonyl)-pyridin-2-yl-amino]-propionic acid ethyl ester and the salts thereof
DE10234058A1 (de) * 2002-07-26 2004-02-05 Boehringer Ingelheim Pharma Gmbh & Co. Kg Neue substituierte Benzoesäureamide, deren Herstellung und deren Verwendung als Arzneimittel
AU2003265398A1 (en) * 2002-08-09 2004-02-25 Transtech Pharma, Inc. Aryl and heteroaryl compounds and methods to modulate coagulation
US7247654B2 (en) 2003-06-04 2007-07-24 Bristol-Myers Squibb Company 3,4-disubstituted benzamidines and benzylamines, and analogues thereof, useful as serine protease inhibitors
US7570259B2 (en) 2004-06-01 2009-08-04 Intel Corporation System to manage display power consumption
BRPI0515140A (pt) * 2004-09-06 2008-07-08 Hoffmann La Roche derivados de benzamidina de 4-aminometila e seu emprego como inibidores do fator viia
EP1828152B1 (fr) 2004-12-08 2008-08-20 Bristol-Myers Squibb Company Composes heterocycliques utilises comme inhibiteurs du facteur viia
EP2010493B1 (fr) 2006-04-12 2016-01-27 Merck Sharp & Dohme Corp. Composés de pyridylamide antagonistes des canaux calciques de type t
AU2008317353B2 (en) 2007-10-24 2014-08-07 Merck Sharp & Dohme Llc Heterocycle phenyl amide T-type calcium channel antagonists
MX388871B (es) 2014-06-27 2025-03-20 Nogra Pharma Ltd Moduladores del receptor arilo y metodos para elaborar y usar los mismos.

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DD142804A3 (de) * 1977-11-07 1980-07-16 Wagner Guenter Verfahren zur herstellung von na-alkyl-bzw.na-aryl-sulfonylierten omega-amidinophenyl-alpha-aminoalkylcarbonsaeureamiden
EP0654465A1 (fr) * 1993-11-15 1995-05-24 Ciba-Geigy Ag Polyamino-polyamides
US5741819A (en) * 1995-06-07 1998-04-21 3-Dimensional Pharmaceuticals, Inc. Arylsulfonylaminobenzene derivatives and the use thereof as factor Xa inhibitors
WO2000056707A1 (fr) * 1999-03-24 2000-09-28 Sepracor, Inc. Thioethers de diaryle, compositions et utilisations de ces dernieres
EP1206446B1 (fr) * 1999-08-07 2004-05-26 Boehringer Ingelheim Pharma GmbH & Co.KG Amides d'acide carboxylique, leur production et leur utilisation comme medicaments
DE10033337A1 (de) * 2000-07-08 2002-01-17 Boehringer Ingelheim Pharma Biphenylcarbonsäureamide, ihre Herstellung und ihre Verwendung als Arzneimittel

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* Cited by examiner, † Cited by third party
Title
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