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WO2008135524A2 - Anthranilamides substitués et analogues, leur fabrication et utilisation en tant que médicaments - Google Patents

Anthranilamides substitués et analogues, leur fabrication et utilisation en tant que médicaments Download PDF

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Publication number
WO2008135524A2
WO2008135524A2 PCT/EP2008/055410 EP2008055410W WO2008135524A2 WO 2008135524 A2 WO2008135524 A2 WO 2008135524A2 EP 2008055410 W EP2008055410 W EP 2008055410W WO 2008135524 A2 WO2008135524 A2 WO 2008135524A2
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group
alkyl
atom
fluorine
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PCT/EP2008/055410
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WO2008135524A3 (fr
Inventor
Henning Priepke
Kai Gerlach
Wolfgang Wienen
Annette Schuler-Metz
Herbert Nar
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Boehringer Ingelheim International Gmbh
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Publication of WO2008135524A3 publication Critical patent/WO2008135524A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to new substituted anthranilamides and the analogues thereof of general formula (I)
  • the compounds of the above general formula (I) as well as the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, and the stereoisomers thereof have valuable pharmacological properties, particularly an antithrombotic activity and a factor Xa-inhibiting activity.
  • the present application relates to new compounds of the above general formula (I), the preparation thereof, the pharmaceutical compositions containing the pharmacologically effective compounds, the preparation and use thereof.
  • a 1 st embodiment of the present invention encompasses those compounds of general formula (I) wherein
  • D denotes one of the following groups Ma or Mb
  • K 1 and K 4 each independently of one another denote a bond, a -CH 2 , -CHR 7a CR 7b R 7c or a -C(O) group, and wherein
  • R 7a /R 7b /R 7c each independently of one another denote a fluorine atom, a hydroxy, Ci -5 -alkyloxy or a Ci -5 -alkyl group which may be substituted by 1 -3 fluorine atoms, while the two groups R 7b /R 7c cannot both simultaneously denote a hydroxy group, or two groups R 7b /R 7c together with the ring carbon atom may form a
  • K z and K 3 each independently of one another denote a -CH 2 , -CHR 8a , -CR 8b R 8c or a -C(O) group, wherein
  • R 8a /R 8b /R 8c each independently of one another denote a Ci -5 -alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-Ci -5 - alkyl, Ci -5 -alkyloxy-Ci- 5 -alkyl, carboxy-Co- 5 -alkyl, Ci -5 - alkyloxycarbonyl-Co- 5 -alkyl, aminocarbonyl-Co- 5 -alkyl, Ci- 5 -alkylaminocarbonyl-C 0 - 5 -alkyl, di-(Ci -5 -alkyl)-aminocarbonyl- Co- 5 -alkyl or a C 4-7 -cycloalkyleneiminocarbonyl-Co- 5 -alkyl group,
  • R 8b /R 8c together with the ring carbon atom may form a 3-, 4-, 5-, 6- or 7-membered saturated carbocyclic group
  • R 1 denotes a hydrogen atom or a Ci -5 -alkyl, C 2-5 -alkenyl-CH 2 , C2-5-alkynyl-CH 2 , Cs-6-cycloalkyl, benzyl group,
  • a 1 denotes either N or CR 10 ,
  • a 2 denotes either N or CR 11 ,
  • a 3 denotes either N or CR 12 ,
  • a 6 denotes either N or CR 13 .
  • a 4 denotes either N or CR 14 ,
  • a 5 denotes either N or CR 15 ,
  • R 10 , R 11 , R 12 , R 13 , R 14 and R 15 each independently of one another denote
  • R 2 denotes a hydrogen atom or a Ci -3 -alkyl group
  • R 3 denotes a hydrogen, fluorine, chlorine or bromine atom or an amino, Ci -3 - alkyloxy, Ci -3 -alkyl or a hydroxy group, while the compounds glucuronidated at the hydroxy group may occur in vivo as active metabolites and
  • R 4 denotes a hydrogen, fluorine, chlorine or bromine atom or a cyano, amino, Ci -3 -alkyloxy, Ci -3 -alkyl or a hydroxy group, and
  • R 6 denotes a hydrogen atom or a Ci -3 -alkyl group
  • M denotes a phenyl or pyridyl ring optionally substituted by R 7 and R 8 , wherein
  • R 7 denotes a fluorine, chlorine, bromine or iodine atom or a methyl, ethyl, vinyl, methoxy, ethynyl, cyano Or -C(O)NH 2 group, and
  • R 8 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom or a hydroxy, methoxy, Ci -3 -alkyl, cyano, amino, or NH 2 C(O) group,
  • alkyl, alkenyl, alkynyl and alkyloxy groups with more than two carbon atoms contained in the previous definitions may be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different,
  • Ci-6-alkyl groups mentioned hereinbefore in the definitions are the methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, sec-butyl, te/t-butyl, 1 -pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,2- dimethyl-3-butyl or 2,3-dimethyl-2-butyl group.
  • Ci -5 -alkyloxy groups mentioned hereinbefore in the definitions are the methyloxy, ethyloxy, 1 -propyloxy, 2-propyloxy, n-butyloxy, sec-butyloxy, te/t-butyloxy, 1 -pentyloxy, 2-pentyloxy, 3-pentyloxy or neo-pentyloxy group.
  • Examples of the C 2-5 -alkenyl groups mentioned hereinbefore in the definitions are the ethenyl, 1 -propen-1 -yl, 2-propen-1 -yl, 1 -buten-1 -yl, 2-buten-1 -yl, 3- buten-1-yl, 1-penten-1-yl, 2-penten-1 -yl, 3-penten-1 -yl, 4-penten-1 -yl, but-1-en- 2-yl, but-2-en-2-yl, but-1 -en-3-yl, 2-methyl-prop-2-en-1 -yl, pent-1 -en-2-yl, pent- 2-en-2-yl, pent-3-en-2-yl, pent-4-en-2-yl, pent-1 -en-3-yl, pent-2-en-3-yl, pent-2-en-3-yl, 2- methyl-but-1-en-1 -yl, 2-methyl-but-2-en-1 -yl, 2-
  • Examples of the C2-5-alkynyl groups mentioned hereinbefore in the definitions are the ethynyl, 1 -propynyl, 2-propynyl, 1-butyn-1 -yl, 1-butyn-3-yl, 2-butyn-1-yl, 3-butyn-1 -yl, 1 -pentyn-1-yl, 1 -pentyn-3-yl, 1 -pentyn-4-yl, 2-pentyn-1 -yl, 2- pentyn-3-yl, 3-pentyn-1 -yl, 4-pentyn-1-yl, 2-methyl-1 -butyn-4-yl, 3-methyl-1 - butyn-1-yl or 3-methyl-1-butyn-3-yl group.
  • a 2nd embodiment of the present invention includes those compounds of general formula (I) wherein M, R 2 -R 6 and A 4 -A 5 are defined as described in embodiment 1 and wherein
  • D denotes one of the following groups Ma or Mb
  • K 1 and K 4 each independently of one another denote a bond, a -CH 2 , -CHR 7a - or a -CR 7b R 7c group, and wherein
  • R 7a /R 7b /R 7c each independently of one another denote a fluorine atom or a methyl group, or two groups R 7b /R 7c together with the ring carbon atom may form a cyclopropyl ring, and
  • K z and K eeaacchh iinnddependently of one another denote a -CH 2 , -CHR 8a or -CR 8b R 8c - group, wherein
  • R 8a /R 8b /R 8c each independently of one another denote a methyl group
  • R 8b /R 8c together with the ring carbon atom may form a cyclopropyl ring
  • R 1 denotes a hydrogen atom or a Ci- 3 -alkyl, or C 3 - 6 -cycloalkyl group
  • a 1 denotes CR 10 ,
  • a 2 denotes CR 11 ,
  • a 3 denotes CR 12 ,
  • a 6 denotes either N or CR 13 ,
  • R 10 , R 11 , R 12 and R 13 each independently of one another denote
  • a 3rd embodiment of the present invention includes those compounds of general formula (I), wherein D and M are defined as described in embodiment 1 or 2 and wherein
  • a 4 denotes CR 14 ,
  • a 5 denotes CR 15 ,
  • R 2 denotes a hydrogen atom
  • R 3 denotes a hydrogen, fluorine, chlorine atom or a methoxy, methyl or a hydroxy group, while the compounds glucuronidated at the hydroxy group may occur in vivo as active metabolites and
  • R 4 denotes a hydrogen, fluorine, chlorine or bromine atom or a cyano, C 1.3- methoxy, methyl or a hydroxy group
  • R 6 denotes a hydrogen atom.
  • a 4th embodiment of the present invention includes those compounds of general formula (I) wherein
  • D denotes one of the following groups Ma or Mb
  • K 1 and K 4 each independently of one another denote a bond, a -CH 2 , -CHR 7a- or a -CR 7b R 7c group, and wherein
  • R 7a /R 7b /R 7c each independently of one another denote a fluorine arom or a methyl group or two groups R 7b /R 7c together with the ring carbon atom may form a cyclopropyl ring, and
  • K 2 and K 3 each independently of one another denote a -CH 2 , -CHR 8a or -CR 8b R 8c - group, wherein
  • R 8a /R 8b /R 8c each independently of one another denote a methyl group, or two groups R 8b /R 8c together with the ring carbon atom may form a cyclopropyl ring, and
  • R 1 denotes a hydrogen atom or a Ci -3 -alkyl, or C 3-6 -cycloalkyl group
  • a 1 denotes CR 10 ,
  • a 3 denotes CR 12 ,
  • a 6 denotes either N or CR 13 ,
  • R 10 , R 11 , R 12 and R 13 each independently of one another denote
  • a 4 denotes CR 14 ,
  • a 5 denotes CR 15 ,
  • R 2 denotes a hydrogen atom
  • R 3 denotes a hydrogen, fluorine, chlorine atom or a methoxy, methyl or a hydroxy group, while the compounds glucuronidated at the hydroxy group may occur in vivo as active metabolites and
  • R 4 denotes a hydrogen, fluorine, chlorine or bromine atom or a cyano, Ci -3 - methoxy, methyl or a hydroxy group, and
  • R 6 denotes a hydrogen atom
  • M denotes a phenyl or pyridyl ring optionally substituted by R 7 and R 8 , wherein
  • R 7 denotes a fluorine, chlorine or bromine atom or an ethynyl group
  • R 8 denotes a hydrogen or fluorine atom.
  • a fifth embodiment of the present invention includes those compounds of general formula (I) which are glucuronidated at a hydroxy group.
  • Q denotes a leaving group or a group which may be converted in-situ into a leaving group, such as for example a halogen atom, a hydroxy,
  • Ci -4 -alkyloxy, alkyloxycarbonyloxy, 4-nitrophenyloxy, a thchloromethyl or acyloxy group, and components III and/or IV may optionally be derivatised at reactive groups by a protective group known from the literature.
  • reaction steps i) -ii) shown in Scheme 1 may be carried out in the manner described in the Examples or according to the conditionsdesc in the literature, for example as follows:
  • the acylation is conveniently carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformannide, dimethylsulphoxide, sodium hydroxide solution or sulpholane, optionally in the presence of an inorganic or organic base at temperatures between -20 and 5 200 0 C, but preferably at temperatures between -10 and
  • the acylation may however also be carried out with the free acid optionally in the presence of an acid-activating agent or io a dehydrating agent, for example in the presence of ethyl-1 - ethoxy-1 ,2-dihydroquinoline-i -carboxylate, isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, is phosphorus pentoxide, propanephosphonic acid cycloanhydride, ⁇ /./V-dicyclohexylcarbodiimide, A/./V-dicyclohexylcarbodiimide/camphorsulphonic acid, ⁇ /, ⁇ /'-dicyclohexylcarbodiimide/ ⁇ /-hydroxysuccinimide or 1 -hydroxy-benzotriazole, ⁇ /.
  • the acylation may also be carried out with a carboxylic acid ester (V) or (Vl) and the amine (IVa) by activation with trimethylal u minium.
  • Any protecting group used may optionally subsequently be cleaved for example by hydrolysis in an aqueous solvent, e.g. In water, isopropanol/water, tetrahydrofuran/water or is dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether splitting, e.g. in the presence of iodotrimethylsilane, at
  • a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved hydrogenolytically, for example, e.g. with
  • a protective group may also be cleaved by the 35 methods described by T.W. Greene, P. G. M. Wuts in
  • D is defined as in embodiments 1 to 4,
  • Q denotes a leaving group or a group which can be converted in-situ into a leaving group, such as for example a halogen atom, a hydroxy, Ci -4 -alkyloxy, alkyloxycarbonyloxy, 4-nitrophenyloxy, a thchloromethyl or acyloxy group, are known from the literature, or their synthesis is described in the Examples, or they may be prepared for example using methods of synthesis known from the literature or analogously to methods of synthesis known from the literature, as described for example in WO2000/09480; S. Komoriya et al. Bioorg. Med. Chem. 2006, 14, 1309,
  • M, A ⁇ 4 , A ⁇ 5 , D R4 , D R3 , n R6 and R z are defined as described in the embodiments, which may optionally be protected at any amino, hydroxy, carboxy or thiol groups present by common protective groups, such as for example those described in T.W. Greene, P. G. M.
  • any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.
  • a suitable protecting group for a hydroxy group may be the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert. butyl, trityl, benzyl or tetrahydropyranyl group.
  • Suitable protecting groups for a carboxyl group might be the trimethylsilyl, methyl, ethyl, tert. butyl, benzyl or tetrahydropyranyl group.
  • Suitable protecting groups for an amino, alkylamino or imino group might be the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, the phthalyl group.
  • a suitable protective group for an ethynyl group may be a trimethylsilyl, diphenylmethylsilyl, tert.butyldimethylsilyl or a 1 -hydroxy- 1 -methyl - ethyl group.
  • any protective group used may optionally subsequently be cleaved for example by hydrolysis 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 sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether splitting, e.g. in the presence of iodothmethylsilane, at temperatures between 0 and 100 0 C, preferably at temperatures between 10 and 50 0 C.
  • an aqueous solvent e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water
  • an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid
  • an alkali metal base such as lithium hydroxide, sodium hydro
  • a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved hydrogenolytically, for example, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal 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 ambient temperature, and at a hydrogen pressure of 1 to 7 bar, preferably, however, 1 to 5 bar.
  • a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid
  • an acid such as hydrochloric acid
  • a methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cehum(IV)ammonium nitrate in a solvent such as methylene chloride, acetonithle or acetonitrile/water at temperatures of between 0 and 50 0 C, but preferably at ambient temperature.
  • an oxidising agent such as cehum(IV)ammonium nitrate
  • a solvent such as methylene chloride, acetonithle or acetonitrile/water at temperatures of between 0 and 50 0 C, but preferably at ambient temperature.
  • a methoxy group is expediently cleaved in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between -35 and -25°C.
  • a 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisol.
  • a te/t.butyl or te/t.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • a solvent such as methylene chloride, dioxane or ether.
  • a phthalyl group 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 group is cleaved by treating with a catalytic amount of tetrakis-(thphenylphosphine)-palladium(0), 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 0 C, preferably at ambient temperature and under an inert gas, or by treating with a catalytic amount of tris-(thphenylphosphine)-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 0 C.
  • a catalytic amount of tetrakis-(thphenylphosphine)-palladium(0) preferably in a solvent such as tetrahydrofuran and
  • the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and ENeI E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971 ) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
  • the enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents.
  • Optically active acids in common use are e.g.
  • an optically active alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides may be a (+)- or (-)-menthyloxycarbonyl, for example.
  • the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids.
  • Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
  • the new compounds of formula I may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof.
  • bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and thethanolamine.
  • the compounds of general formula I as well as the tautomers, the enantiomers, the diastereomers and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an antithrombotic activity, which is preferably based on an effect on thrombin or factor Xa, for example on a thrombin-inhibiting or factor Xa-inhibiting activity, on a prolonging effect on the aPTT time and on an inhibiting effect on related serine proteases such as e.g. urokinase, factor Vila, factor IX, factor Xl and factor XII.
  • an antithrombotic activity which is preferably based on an effect on thrombin or factor Xa, for example on a thrombin-inhibiting or factor Xa-inhibiting activity, on a prolonging effect on the aPTT time and on an inhibiting effect on related serine proteases such as e.g. urokinase, factor Vila, factor
  • Enzyme-kinetic measurement with chromogenic substrate The quantity of p- nitroaniline (pNA) released from the colourless 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 the enzyme activity by the test substance (in relation to the solvent control) is determined at various concentrations of test substance and from this the IC 5 O is calculated, as the concentration which inhibits the factor Xa used by 50 %.
  • pNA p- nitroaniline
  • 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 prepared according to the invention are generally well tolerated.
  • the new compounds and the physiologically acceptable salts thereof are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as for example the prevention and treatment of deep leg vein thrombosis, thrombophlebitis, for preventing reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases, and for preventing and treating pulmonary embolism, disseminated intravascular coagulation and severe sepsis, for preventing and treating DVT in patients with exacerbation of COPD, for treating ulcerative colitis, for treating and preventing coronary thrombosis, for preventing stroke and the occlusion of shunts.
  • venous and arterial thrombotic diseases such as for example the prevention and treatment of deep leg vein thrombosis, thrombophlebitis, for preventing reocclusions after bypass operations or angioplasty (PT(C)A), and
  • the compounds according to the invention are suitable 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 prevention and treatment of ischaemic events in patients with all forms of coronary heart disease, for preventing metastasis and the growth of tumours and inflammatory processes, e.g. in the treatment of pulmonary fibrosis, for preventing and treating rheumatoid arthritis, for preventing and treating fibrin- dependent tissue adhesions and/or the formation of scar tissue and for promoting wound healing processes.
  • the compounds specified may also be used as anticoagulants in connection with the preparation, storage, fractionation or use of whole blood or in invasive therapies, e.g. for coating prostheses, artificial heart valves and catheters for reducing the risk of thrombosis.
  • the new compounds and the physiologically acceptable salts thereof are also suitable for treating Alzheimer's and Parkinson ' s disease.
  • One rationale for this can be seen for example in the following findings, from which it can be concluded that thrombin inhibitors or factor Xa inhibitors, by inhibiting thrombin formation or activity, could be valuable drugs for treating Alzheimer's and Parkinson ' s disease.
  • Clinical and experimental studies indicate that neurotoxic mechanisms, for example the inflammation that accompanies the activation of proteases of the clotting cascade, are involved in the dying off of neurones following brain damage.
  • Various studies indicate an involvement of thrombin in neurodegenerative processes, e.g. following a stroke, repeated bypass operations or traumatic brain injury.
  • thrombin causes neurite retraction and glia proliferation, and apoptosis in primary cultures of neurones and neuroblastoma cells (for an overview see: Neurobiol. Aging, 2004, 25(6), 783-793).
  • various in vitro studies on the brains of patients with Alzheimer's disease indicate that thrombin plays a part in the pathogenesis of this disease (Neurosci. Lett., 1992, 146, 152-54).
  • An accumulation of immunoreactive thrombin has been detected in neurite plaques in the brains of Alzheimer's patients.
  • thrombin also plays a part in the regulation and stimulation of the production of Amyloid Precursor Protein (APP) as well as in the cleaving of APP into fragments which can be detected in the amyloid plaques in the brains of Alzheimer's patients. It has also been shown that thrombin-induced microglial activation in vivo leads to the degeneration of nigral dopaminergic neurones. These findings lead one to conclude that microglial activation, triggered by endogenous substance(s) such as thrombin, for example, are involved in the neuropathological process of the cell death of dopaminergic neurones, such as occurs in patients with Parkinson's disease (J. Neurosci., 2003, 23, 5877-86).
  • endogenous substance(s) such as thrombin
  • the new compounds and the physiologically acceptable salts thereof can also be used for the prevention and treatment of arterial vascular diseases in combination therapy with lipid-lowering active substances such as HMG-CoA reductase inhibitors and vasodilators, particularly ACE inhibitors, angiotensin Il antagonists, renin inhibitors, ⁇ -receptor antagonists, ⁇ -receptor antagonists, diuretics, Ca-channel blockers, or stimulators of soluble guanylate cyclase.
  • lipid-lowering active substances such as HMG-CoA reductase inhibitors and vasodilators, particularly ACE inhibitors, angiotensin Il antagonists, renin inhibitors, ⁇ -receptor antagonists, ⁇ -receptor antagonists, diuretics, Ca-channel blockers, or stimulators of soluble guanylate cyclase.
  • the new compounds and the physiologically acceptable salts thereof can also be used in combination therapy with other anticoagulants such as, for example, unfractionated heparin, low-molecular heparin, fondaparinux or direct thrombin inhibitors, for example recombinant hirudine or "active-site" thrombin inhibitors.
  • other anticoagulants such as, for example, unfractionated heparin, low-molecular heparin, fondaparinux or direct thrombin inhibitors, for example recombinant hirudine or "active-site" thrombin inhibitors.
  • the new compounds and the physiologically acceptable salts thereof may be used therapeutically in conjunction with acetylsalicylic acid, with inhibitors of platelet aggregation such as fibrinogen receptor antagonists (e.g. abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of the clotting system and the recombinant analogues thereof (e.g. protein C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (e.g. clopidogrel, prasugrel, ticlopidine), with P 2 T receptor antagonists (e.g. cangrelor) or with combined thromboxane receptor antagonists/synthetase inhibitors (e.g. terbogrel).
  • fibrinogen receptor antagonists e.g. abciximab, eptifibatide, tirofiban, roxifiban
  • the dosage required to achieve such an effect is appropriately 0.01 to 3 mg/kg, preferably 0.03 to 1.0 mg/kg by intravenous route, and 0.03 to 30 mg/kg, preferably 0.1 to 10 mg/kg by oral route, in each case administered 1 to 4 times a day.
  • the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.
  • inert conventional carriers and/or diluents e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glyce
  • the ratios given for the eluants refer to units by volume of the solvents in question. Chromatographic purification was done using silica gel supplied by Messrs Millipore (MATREXTM, 35-70 ⁇ m). If the configuration is not specified in detail, it is unclear whether the compound in question is a pure stereoisomer or a mixture of enantiomer and diastereomer.
  • Active substance and mannitol are dissolved in water. After packaging the solution is freeze-dried. To produce the solution ready for use for injections, the product is dissolved in water.
  • Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried. To produce the solution ready for use for injections, the product is dissolved in water.
  • Tablet containinq 50 mq of active substance
  • This powder mixture is packed into size 3 hard gelatine capsules in a capsule filling machine.
  • Capsules containin ⁇ 350 mq of active substance
  • This powder mixture is packed into size 0 hard gelatine capsules in a capsule filling machine.
  • Example G Suppositories containing 100 mq of active substance
  • 1 suppository contains:
  • the polyethyleneglycol is melted together with polyethylenesorbitan monostearate. At 40 0 C the ground active substance is homogeneously dispersed in the melt. It is cooled to 38°C and poured into slightly chilled suppository moulds.

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Abstract

La présente invention concerne de nouveaux prolinamides substitués de formule générale (I), D, M, A4, A5, R2, R3, R4 et R6 étant tels que définis dans la description, les tautomères, les énantiomères, les diastéréomères, les mélanges de ceux-ci et les sels de ceux-ci, en particulier les sels acceptables du point de vue pharmaceutique de ceux-ci avec des acides et des bases inorganiques ou organiques, qui ont des propriétés importantes.
PCT/EP2008/055410 2007-05-02 2008-05-02 Anthranilamides substitués et analogues, leur fabrication et utilisation en tant que médicaments WO2008135524A2 (fr)

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US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
EP3078378A1 (fr) 2015-04-08 2016-10-12 Vaiomer Utilisation d'inhibiteurs du facteur xa destinés à réguler la glycémie
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2017192304A1 (fr) * 2016-05-02 2017-11-09 Inception 1, Inc. Arylcarboxamides et leurs utilisations
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
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US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma
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US7504417B2 (en) * 2000-11-22 2009-03-17 Astellas Pharma Inc. Substituted benzene derivatives or salts thereof
JP2004210716A (ja) * 2002-12-27 2004-07-29 Dai Ichi Seiyaku Co Ltd ジアミド誘導体

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US11535614B2 (en) 2014-02-03 2022-12-27 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US10047085B2 (en) 2014-02-03 2018-08-14 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10807980B2 (en) 2014-02-03 2020-10-20 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US10399976B2 (en) 2014-02-03 2019-09-03 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
US9624217B2 (en) 2014-02-03 2017-04-18 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9266886B2 (en) 2014-02-03 2016-02-23 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10087184B2 (en) 2014-10-14 2018-10-02 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of RORγ
US9796710B2 (en) 2014-10-14 2017-10-24 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US11001583B2 (en) 2014-11-05 2021-05-11 Vitae Pharmaceuticals, Llc Dihydropyrrolopyridine inhibitors of ROR-gamma
EP3078378A1 (fr) 2015-04-08 2016-10-12 Vaiomer Utilisation d'inhibiteurs du facteur xa destinés à réguler la glycémie
WO2016162472A1 (fr) 2015-04-08 2016-10-13 Vaiomer Utilisation d'inhibiteurs du facteur xa pour réguler la glycémie
US10301261B2 (en) 2015-08-05 2019-05-28 Vitae Pharmaceuticals, Llc Substituted indoles as modulators of ROR-gamma
US10829448B2 (en) 2015-08-05 2020-11-10 Vitae Pharmaceuticals, Llc Substituted benzoimidazoles as modulators of ROR-γ
US11008340B2 (en) 2015-11-20 2021-05-18 Vitae Pharmaceuticals, Llc Modulators of ROR-gamma
US10829481B2 (en) 2016-01-29 2020-11-10 Vitae Pharmaceuticals, Llc Benzimidazole derivatives as modulators of ROR-gamma
WO2017192304A1 (fr) * 2016-05-02 2017-11-09 Inception 1, Inc. Arylcarboxamides et leurs utilisations
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
US10913739B2 (en) 2017-07-24 2021-02-09 Vitae Pharmaceuticals, LLC (121374) Inhibitors of RORγ
US11186573B2 (en) 2017-07-24 2021-11-30 Vitae Pharmaceuticals, Llc Inhibitors of ROR gamma
US20190270733A1 (en) * 2018-03-01 2019-09-05 Reaction Biology Corp. Quinoline and Isoquinoline Based HDAC Inhibitors and Methods of Use Thereof
US11753413B2 (en) 2020-06-19 2023-09-12 Incyte Corporation Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors
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US11767323B2 (en) 2020-07-02 2023-09-26 Incyte Corporation Tricyclic pyridone compounds as JAK2 V617F inhibitors
US11780840B2 (en) 2020-07-02 2023-10-10 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
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US11661422B2 (en) 2020-08-27 2023-05-30 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
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