WO2005087774A1 - Imidazopyridazindione, sa fabrication et son utilisation comme medicament - Google Patents

Imidazopyridazindione, sa fabrication et son utilisation comme medicament Download PDF

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WO2005087774A1
WO2005087774A1 PCT/EP2005/002524 EP2005002524W WO2005087774A1 WO 2005087774 A1 WO2005087774 A1 WO 2005087774A1 EP 2005002524 W EP2005002524 W EP 2005002524W WO 2005087774 A1 WO2005087774 A1 WO 2005087774A1
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group
ylmethyl
dihydro
ynyl
substituted
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PCT/EP2005/002524
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German (de)
English (en)
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Matthias Eckhardt
Frank Himmelsbach
Elke Langkopf
Iris Kauffmann-Hefner
Mohammad Tadayyon
Leo Thomas
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Boehringer Ingelheim International Gmbh
Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Priority to EP05728980A priority Critical patent/EP1763530A1/fr
Priority to CA002559444A priority patent/CA2559444A1/fr
Priority to JP2007502292A priority patent/JP2007527888A/ja
Publication of WO2005087774A1 publication Critical patent/WO2005087774A1/fr

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Definitions

  • the present invention relates to substituted imidazopyridazinediones of the general formula
  • DPP-IV dipeptidylpeptidase-IV
  • their tautomers, their stereoisomers, their mixtures and their salts, in particular their physiologically tolerable salts with inorganic or organic acids or bases which have valuable pharmacological properties, in particular an inhibitory effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV), their production, their use for the prevention or treatment of diseases or conditions which are associated with increased DPP-IV activity or which can be prevented or alleviated by reducing the DPP-IV activity, in particular of type I or type diabetes meliitus II, the medicament containing a compound of the general formula (I) or a physiologically tolerable salt thereof and process for their preparation.
  • DPP-IV dipeptidylpeptidase-IV
  • R 1 is an arylmethyl group
  • an arylprop-2-enyl or heteroarylprop-2-enyl group in which the propenyl chain with 1 to 4 fluorine atoms or a cyan, C ⁇ . 3 -alkyloxy-carbonyl or nitro group can be substituted
  • R 2 is a C 6 alkyl group
  • a C 6 alkyl group substituted by a group R a where R a is a fluorine, chlorine or bromine atom, a C 3 . 7- Cycloalkyl group, in which one or two methylene groups independently of one another each by an oxygen or sulfur atom or by an - NH or -N (C- ⁇ . 3 alkyl) - group, or by a carbonyl, sulfinyl or sulfonyl group can be replaced, or a trifluoromethyl, aryl, heteroaryl, cyano, carboxy, C 3 alkoxy carbonyl, aminocarbonyl, C 1.
  • R b is isolated from the ring nitrogen atom by at least two carbon atoms and R b is a hydroxy-, C ⁇ -alkoxy-, C ⁇ - 3 -AlkyIsulfanyl-, amino-, cis-alkylamino- or di- (C ⁇ - 3 -alkyl) -amino-, pyrrolidin-1-yl-, piperidin-1 -yl-, morpholin-4-yl, piperazin-1-yl or 4- (C ⁇ - 3 alkyl) -piperazin-1-yl group,
  • R 3 is a C 5 - 7 cycloalkenylmethyl group which is optionally substituted by a C 3 alkyl group,
  • R 4 is a pyrrolidin-1-yl or azetedin-1-yl group which is substituted in the 3-position by an amino or C 3 alkyl alkyl group and can additionally be substituted by one or two C 3 alkyl groups,
  • a piperidin-1-yl or hexahydroazepin-1-yl group which is substituted in the 3-position or in the 4-position by an amino group or C- ⁇ - 3 alkylamino group and additionally by one or two C ⁇ . 3 -alkyl groups can be substituted, a piperazin-1-yl or homopiperazin-1-yl group which is replaced by one or two C 1 . 3 - alkyl groups can be substituted,
  • R 15 is a hydrogen atom, a C 6 alkyl, C 3 . 6 -cycloalkyl-, C3.6-cycloalkyl-C- 1 . 3 - alkyl, aryl or aryl -C 3 alkyl group and
  • R 16 represents an R 17 -C 2 - 3 alkyl group, the C 2 - 3 alkyl part being straight-chain and having 1 to 4 C ⁇ . 3 -alkyl groups, which can be the same or different * , can be substituted and
  • R 7 represents an amino or C 3 alkylamino group
  • R 15 is defined as mentioned above and R 18 is a C 3 substituted by R 19 in the 1-position of the cycloalkyl radical. 6- cycloalkyl-methyl group or a C 3 _ 6 -cycloalkyl group substituted in the 1-position by an R 19 -CH 2 group, where R 19 represents an amino or C 3 alkylamine group,
  • R 15 is as defined above and R 20 is azetidin-3-yl, azetidin-2-ylmethyl-, azetidin-3-ylmethyl-, pyrrolidin-3-yl-, pyrrolidin-2-ylmethyl-, pyrrolidin- 3-ylmethyl -, Piperidin-3-yl, piperidin-4-yl, piperidin-2-ylmethyl, piperidin-3-ylmethyl or piperidin-4-ylmethyl group, the radicals mentioned for R 20 each having one or two C ⁇ 3 alkyl groups can be substituted,
  • R 15 and R 21 an amino group substituted by the radicals R 15 and R 21 , in which R 15 is as hereinbefore defined and R 21 is a 2- or 3-position by an amino or alkylamino group C ⁇ - 3 substituted C 3-7 cycloalkyl group which may additionally be substituted by one or two C ⁇ _ alkyl groups 3, represents,
  • aryl groups mentioned in the definition of the abovementioned radicals are to be understood as meaning phenyl or naphthyl groups which can independently of one another be mono-, di- or tri-substituted by R h , where the substituents can be identical or different and R h is a fluorine, chlorine, bromine or iodine atom, a trifluoromethyl, cyano, nitro, amino, aminocarbonyl, C ⁇ - 3 alkoxycarbonyl, aminosulfonyl, methylsulfonyl, acetylamino, methylsulfonylamino, C 1 - 3 - represents alkyl, cyclopropyl, ethenyl, ethinyl, morpholinyl, hydroxyl, C- ⁇ - 3 alkyloxy, difluoromethoxy or trifluoromethoxy group, and in which each hydrogen atom can be replaced by a fluorine atom,
  • heteroaryl groups mentioned in the definition of the radicals mentioned above mean a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, phenanthridinyl, quinolinyl or isoquinolinyl group,
  • alkyl, alkenyl and alkynyl groups mentioned above can be straight-chain or branched
  • 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 abovementioned radicals can be substituted by a radical which can be split off in vivo.
  • a radical which can be split off in vivo.
  • Such 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 group which can be converted into a carboxy group in vivo is, for example, a hydroxymethyl group, a carboxy group esterified with an alcohol, in which the alcoholic part is preferably a C 6 alkanol, a phenyl C 1. 3- alkanol, a C 3 -g-cycloalkanol, a C 5 . 8- Cycloalkanol additionally by one or two C ⁇ . 3 alkyl groups can be substituted, a C 5 . 8- Cycloalkanol, in which a methylene group in the 3- or 4-position through an oxygen atom or through a optionally by a C 3 alkyl, phenyl C 3 alkyl, phenyl C 1.
  • cycloalkanol part can additionally be substituted by one or two C ⁇ - 3 alkyl groups, a C 4 - 7 cycloalkenol, a C 3 -5-alkenol, a phenyl-C3-5-alkenol C 3 - -Alkinol or phenyl-C 3 - 5 -alkinol with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a C 3 - 8 cycloalkyl-C ⁇ - 3 alkanol , A bicycloalkanol with a total of 8 to 10 carbon atoms, which can be additionally substituted in the bicycloalkyl part by one or two -C 3 alkyl groups, a 1, 3-dihydro-3-oxo-1-isobenz
  • R q is a hydrogen atom, a C ⁇ _ 3 alkyl, Cs-yCycloalkyl- or phenyl group and
  • R r represents a hydrogen atom or a C 3 alkyl group
  • an imino or amino group in vivo for example a hydroxyl group, an acyl group such as, if appropriate, a
  • C 3 . 7- cycloalkyl groups mono- or disubstituted and the substituents may be the same or different, a C ⁇ . 3 -Alkylsulfonyl-C 2 - -alkoxycarbonyl-, -C ⁇ - 3 -alkoxy- C 2 . 4 -alkoxy-C 2 - 4 -alkoxycarbonyl-, R p -CO-O- (R q CR r ) -O-CO-, C ⁇ .
  • R s and R t which may be the same or different, represent hydrogen atoms or C 3 alkyl groups
  • saturated alkyl and alkoxy parts which contain more than 2 carbon atoms and, unless otherwise stated, mentioned in the definitions above and below also include their branched isomers such as the isopropyl, tert-butyl, isobutyl group etc.
  • R 1 comes for example the meaning of a 2-cyanobenzyl, 3-fluorobenzyl, 3-methoxybenzyl, 4-bromo-2-cyanobenzyl, 3-chloro-2-cyanobenzyl, 2-cyan-4-fluorobenzyl, 2-cyan -6-fluorobenzyl, 3,5-dimethoxybenzyl-, 2,6-dicyanbenzyl-, 5-cyanfuranylmethyl-, oxazolylmethyl-, isoxazolylmethyl-, 5-methoxycarbonylthienylmethyl-, pyridinylmethyl-, 3-cyanopyridin-2-ylmethyl-, 3 Cyanopyridin-4-ylmethyl-, 4-cyanopyridin-3-ylmethyl-, 6-cyanopyridin-2-ylmethyl-, 6-fluoropyridin-2-ylmethyl-, pyrimidin-2-ylmethyl-, 4-methyl-pyrimidin- 2-ylmethyl-, 4,6-dimethyl-pyrimidin
  • R 2 is, for example, the meaning of a methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, 2-propen-1-yl, 2-propyne-1 yl, cyclopropylmethyl, benzyl, 2-phenylethyl, phenylcarbonylmethyl, 3-phenylpropyl, 2-hydroxyethyl, 2-
  • aminocarbonyl ethyl, 2- (methylaminocarbonyl) ethyl, 2- (dimethylaminocarbonyl) ethyl, 2- (pyrrolidinocarbonyl) ethyl, 2- (piperidinocarbonyl) ethyl, 2- (morpholino) carbonyl) ethyl, cyanomethyl, 2-cyanoethyl, 2-fluoroethyl, pyridin-3-yimethyl or pyridin-4-ylmethyl group.
  • R 3 for example, the meaning of a 2-propen-1-yl, 2-methyl-2-propen-1-yl, 1-buten-1-y
  • R 4 for example, the meaning of a 3-aminopyrrolidin-1-yI-, 3-amino-piperidin-1-yl-, 3- (methylamino) -piperidin-1-yl-, 3- (ethylamino) -piperidin-1 -yl-, 3-Amino-2-methyl-piperidin-1-yl, 3-amino-3-methyl-piperidin-1-yl, 3-amino-4-methyl-piperidin-1-yl-, 3rd -Amino-5-methyl-piperidin-1-yl-, 3-amino-6-methyl-piperidin-1-yl-, 4-aminopiperidin-1-yl-, 3-amino-hexahydroazepin-1-yl-, 4 -Amino-hexahydroazepine-1-yl, (2-aminocyclopropyl) amino, (2-aminocyclobutyl) amino, (3-aminocyclobutyl, (3
  • R 1 and R 2 are defined as mentioned above,
  • R 3 is 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enylmethyl, furanylmethyl, thienylmethyl, chlorobenzyl, bromobenzyl , iodobenzyl, methoxybenzyl or cyanbenzyl group, and
  • R 4 is an N- (2-aminoethyl) -N-methyl-amino group, which may be substituted in the ethyl part by one or two C 3 alkyl groups, or 3-aminopiperidine-1-yl, piperazin-1-yl or homopiperazin-1-yl group, whilst the abovementioned groups in addition by one or two C 1 respectively - 3 - may be substituted alkyl groups mean
  • R 1 is a phenylmethyl, phenylcarbonylmethyl, phenylprop-2-enyl, pyridinylmethyl, pyrimidinylmethyl, naphthylmethyl, quinolinylmethyl, isoquinolinylmethyl, chinazolinylmethyl, quinoxalinylmethyl, phenanthridinylmethyl, naphthylmethyl, naphthylmethyl, naphthylmethyl, naphthylmethyl, naphthylmethyl, naphthylmethyl, naphthylmethyl groups, naphthylmethyl or naphthylmethyl groups, naphthylmethyl or naphthylmethyl groups, naphthylmethyl or naphthylmethyl groups
  • Aryl and heteroaryl groups can be substituted by one or two fluorine, chlorine, bromine atoms or one or two cyano, nitro, amino, C 3 alkyl, C 3 alkyloxy and morpholinyl groups, the Substit
  • R 2 is a C 6 alkyl group through a fluorine atom or a cyan, carboxy, C 1 . 3 - Alkyloxy-carbonyl, aminocarbonyl, C ⁇ - 3 -Alkylaminocarbonyl-, C ⁇ - 3 alkylsulfonyl, aryl or heteroaryl group may be substituted, wherein the aryl or heteroaryl group is defined as mentioned above,
  • R b is isolated from the ring nitrogen atom by at least two carbon atoms and R is a hydroxy or C 3 alkyloxy group
  • R 3 is a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enylmethyl, furanylmethyl, thienylmethyl, chlorobenzyl, Bromobenzyl, iodobenzyl or cyanobenzyl group and
  • R 4 is N- (2-aminoethyl) -N-methylamino-, N- (2-aminopropyl) -N-methylamino-, 3-aminopiperidin-1-yl-, piperazin-1-yl- or homopiperazin-1 -yl group mean
  • R 1 is a cyanobenzyl, phenylcarbonylmethyl, methylquinazolinylmethyl, methylisoquinolinylmethyl, naphthylmethyl or quinolinylmethyl group,
  • R 2 is a methyl, prop-2-enyl, prop-2-ynyl, 2-fluoroethyl, cyanomethyl, carboxymethyl, aminocarbonylmethyl, pyridinylmethyl or phenylmethyl group,
  • R 3 is a 2-butyn-1-yl group
  • R 4 represents a 3-aminopiperidin-1-yl or piperazin-1-yl group
  • the compounds of the general formula I are obtained by processes known per se, for example by the following processes:
  • R 1 to R 3 are defined as mentioned at the outset and
  • Z 1 represents a leaving group such as a halogen atom, a substituted hydroxy, mercapto-sulfinyl, sulfonyl or sulfonyloxy group such as a chlorine or bromine atom, a methanesulfonyl or methanesulfonyloxy group, with a compound of the general formula
  • R 4 is defined as mentioned at the beginning.
  • reaction is conveniently carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, toluene, chlorobenzene, dimethylformamide, dimethyl sulfoxide, methylene chloride, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane, optionally in the presence of an inorganic or tertiary organic base, e.g. Sodium carbonate or potassium hydroxide, a tertiary organic base, e.g.
  • Triethylamine or in the presence of N-ethyl-diisopropylamine (Hünig base), these organic bases can also serve as solvents at the same time, and optionally in the presence of a reaction accelerator such as an alkali metal halide or a palladium-based catalyst at temperatures between -20 and 180 ° C, but preferably at temperatures between -10 and 120 ° C.
  • a reaction accelerator such as an alkali metal halide or a palladium-based catalyst at temperatures between -20 and 180 ° C, but preferably at temperatures between -10 and 120 ° C.
  • the reaction can also be carried out without a solvent or in an excess of the compound of the general formula IV used.
  • R) 1, R D2 u,, n “d, JR D3 are as defined at the beginning and R 4 'contains an N-tert.-butyloxycarbonylamino group or an N-tert.-butyloxycarbonyl-N-alkylamino group, it being possible for the alkyl part of the N-tert.-butyloxycarbonyl-N-alkylamino group to be substituted as mentioned at the outset.
  • the tert-butyloxycarbonyl radical is preferably cleaved off by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with bromotrimethylsilane or iodotrimethylsilane, optionally using a solvent such as methylene chloride, ethyl acetate, dioxane, methanol, isopropanol or diethyl ether at temperatures between 0 and 80 ° C. ,
  • a compound of the general formula I which contains an amino, alkylamino or imino group, this can be converted into a corresponding acyl or sulfonyl compound of the general formula I by means of acylation or sulfonylation or
  • the subsequent esterification is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene,
  • a Acid such as hydrochloric acid
  • a dehydrating agent for example in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, sulfuric acid, methanesulfonic acid.
  • the subsequent ester formation can also be carried out by reacting a compound containing a carboxy group with an appropriate alkyl halide.
  • the subsequent acylation or sulfonylation is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane with a corresponding acyl or sulfonyl derivative, optionally in the presence of a tertiary organic base or in the presence of an inorganic base or in the presence of a dehydrating agent, e.g.
  • a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane with a corresponding acyl or sulfonyl derivative, optionally in the presence of a tertiary organic base or in the presence of an inorganic base
  • the subsequent alkylation is optionally in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane 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, optionally in Presence of a tertiary organic base or in the presence of an inorganic Base expediently carried out 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 / tetrahydrofuran or diox
  • the subsequent reductive alkylation is advantageously carried out with a corresponding carbonyl compound such as formaldehyde, acetaldehyde, propionaldehyde, acetone or butyraldehyde in the presence of a complex metal hydride such as sodium borohydride, lithium borohydride, sodium triacetoxyborohydride or sodium cyanoborohydride at a pH of 6-7 and at room temperature or in the presence of a hydrogenation catalyst, e.g. with hydrogen in the presence of palladium / coal, at a hydrogen pressure of 1 to 5 bar.
  • the methylation can also be carried out in the presence of formic acid as a reducing agent at elevated temperatures, e.g. at temperatures between 60 and 120 ° C.
  • the subsequent amide formation is carried out by reacting a corresponding reactive carboxylic acid derivative with a corresponding amine, if appropriate in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene / tetrahydrofuran or dioxane, it being possible for the amine used to serve simultaneously as a solvent , if appropriate in the presence of a tertiary organic base or in the presence of an inorganic base or with a corresponding carboxylic acid in
  • a dehydrating agent e.g. in the presence of isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N, N'-dicyclohexylcarbodiimide, N, N'-dicyclohexylcarbodiimide / N-hydroxy-succinimide or 1-hydroxy-benzotriazole and optionally additionally 4-benzotriazole Dimethylamino-pyridine, N.N'-carbonyldiimidazole or triphenylphosphine / carbon tetrachloride, expediently carried out at temperatures between 0 and 150 ° C., preferably at temperatures between 0 and 80 ° C.
  • reactive groups such as hydroxyl, carboxy, amino, alkylamino or
  • Imino groups are protected during the reaction by conventional protective groups, which are split off again after the reaction.
  • the trimethylsilyl, acetyl, benzoyl, methyl, ethyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group comes as a protective radical for a hydroxyl group,
  • protective radicals for an amino, alkylamino or imino group the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, 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, acetic acid / 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 sodium hydroxide or potassium hydroxide or aprotic, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120 ° C, preferably at temperatures between 10 and 100 ° C.
  • an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
  • an alkali base such as sodium hydroxide or potassium hydroxide or aprotic
  • Ethanol, ethyl acetate or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 100 ° C, but preferably at room temperatures between 20 and 60 ° C, and at a hydrogen pressure of 1 to 7 bar, but preferably from 3 to 5 bar.
  • an acid such as hydrochloric acid
  • 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 or by treatment with iodotrimethylsilane, optionally using a solvent such as methylene chloride, dioxane, methanol or diethyl ether.
  • a trifluoroacetyl radical is preferably split off by treatment with an acid such as hydrochloric acid, if appropriate in the presence of a solvent such as acetic acid at temperatures between 50 and 120 ° C. or by treatment with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran at temperatures between 0 and 50 ° C. ,
  • 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.
  • the compounds of general formula I obtained can be separated into their enantiomers and / or diastereomers.
  • cis / trans mixtures can be separated into their ice and trans isomers, and compounds with at least one optically active carbon atom can be separated into their enantiomers.
  • the cis / trans mixtures obtained can be chromatographed into their cis and trans isomers, the compounds of the general formula I obtained which occur in racemates, according to methods known per se
  • 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.
  • Particularly common, optically active acids are, for example, the D and
  • L forms of tartaric acid or dibenzoyltartaric 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, (+) - or (-) - menthyloxycarbonyl.
  • 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 purpose 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 obtained in this way 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.
  • bases which can be used here are sodium hydroxide, potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
  • the compounds of general formulas II and IV used as starting materials are either known from the literature or can be obtained by processes known per se from the literature (see Examples I to VII).
  • the compounds of the general formula I according to the invention and their physiologically tolerable salts have valuable pharmacological properties, in particular an inhibitory effect on the enzyme DPP-IV.
  • the cell extract was obtained from cells solubilized in a buffer (10mM Tris HCl, 0.15M NaCl, 0.04 tiu aprotinin, 0.5% Nonidet-P40, pH 8.0) by centrifugation at 35,000 g for 30 minutes at 4 ° C (to remove cell debris) ,
  • the DPP-IV assay was carried out as follows:
  • AFC amido-4-trifluoromethylcoumarin
  • 20 ⁇ l assay buffer final concentrations 50 mM Tris HCl pH 7.8, 50 mM NaCl, 1% DMSO
  • the reaction was started by adding 30 ⁇ l solubilized Caco-2 protein (final concentration 0.14 ⁇ g protein per well).
  • the test substances to be checked were typically added in 20 ⁇ l pre-diluted, the assay buffer volume then being reduced accordingly. The reaction was carried out at room temperature, the incubation period was 60 minutes.
  • the compounds prepared according to the invention are well tolerated, since no changes in the behavior of the animals could be observed, for example, after oral administration of 10 mg / kg of the compound of Example 1 (1) to rats.
  • the compounds of general formula I according to the invention and their corresponding pharmaceutically acceptable salts are suitable for influencing all those conditions or diseases which can be influenced by inhibiting DPP-IV activity . It is therefore to be expected that the compounds according to the invention for the prevention or treatment of diseases or conditions such as type 1 and type 2 diabetes meliitus, diabetic complications (such as, for example, retinopathy, nephropathy or neuropathies), metabolic acidosis or ketosis, reactive hypoglycemia, insulin resistance, metabolic effects Syndrome, dyslipidemia of various origins, arthritis, atherosclerosis and related diseases, obesity, allograft trans- plantation and osteoporosis caused by calcitonin are suitable.
  • diseases or conditions such as type 1 and type 2 diabetes meliitus, diabetic complications (such as, for example, retinopathy, nephropathy or neuropathies), metabolic acidosis or ketosis, reactive hypoglycemia, insulin resistance, metabolic effects Syndrome, dyslipidemia of various origins, arthritis, atheros
  • these substances are suitable for preventing B cell degeneration such as apoptosis or necrosis of pancreatic B cells.
  • the substances are also suitable for improving or restoring the functionality of pancreatic cells, and also increasing the number and size of pancreatic B cells.
  • the compounds according to the invention are suitable for achieving, among other things, a sedative or anxiolytic effect , to be able to influence catabolic conditions after operations or hormonal stress responses favorably or to reduce mortality and morbidity after myocardial infarction.
  • the compounds according to the invention are suitable for the treatment of all conditions which are related to the above-mentioned effects and are mediated by GLP-1 or GLP-2.
  • the compounds according to the invention can also be used as diuretics or antihypertensives and are suitable for the prevention and treatment of acute kidney failure.
  • the compounds according to the invention can be used to treat inflammatory diseases of the respiratory tract. They are also suitable for the prevention and therapy of chronic inflammatory bowel diseases such as irritable bowel syndrome (IBS), Crohn's disease or ulcerative colitis as well as for pancreatitis.
  • IBS irritable bowel syndrome
  • Crohn's disease Crohn's disease
  • ulcerative colitis as well as for pancreatitis.
  • DPP-IV inhibitors and thus also the compounds according to the invention can be used to treat infertility or to improve fertility in humans or in the mammalian organism, in particular if the infertility in connection with an insulin resistance or with the poly- cystic ovarian syndrome.
  • these substances are suitable for influencing the motility of the sperm and can therefore be used as contraceptives for use in men.
  • the substances are suitable for influencing growth hormone deficiency states that are associated with short stature, and can be used sensibly in all indications in which growth hormone can be used.
  • Compounds according to the invention are also suitable for the treatment of various autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, thyroidoditis and Graves ' disease, etc. due to their inhibitory action against DPP IV.
  • autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, thyroidoditis and Graves ' disease, etc.
  • they can be used for viral diseases, for example for HIV infections, for the stimulation of blood formation, for benign prostatic hyperplasia, for gingivitis as well as for the treatment of neuronal defects and neurodegenerative diseases such as Alzheimer's disease.
  • Compounds described are also to be used for the therapy of tumors, in particular for changing tumor invasion, as well as metastatisation.
  • T-cell lymphomas examples here are the use in T-cell lymphomas, acute lymphoblastic leukemia, cell-based thyroid carcinomas, basal cell carcinomas or breast carcinomas.
  • Other indications are stroke, ischemia of various origins, Parkinson's disease and migraines.
  • further areas of indication include follicular and epidermal hyperkeratosis, increased keratinocyte proliferation, psoriasis, encephalomyelitis, glomerulonephritis, lipodystrophy as well as psychosomatic, depressive and neuropsychiatric diseases of various origins.
  • the compounds according to the invention can also be used in combination with other active ingredients.
  • Therapeutics suitable for such a combination include, for example, antidiabetic agents such as metformin, sulfonylureas (e.g. glibenclamide, tolbutamide, glimepiride), nateglinide, repaglinide, thiazolidinedione (e.g. rosiglitazone, pioglitazone), PPAR-gamma agonists (e.g.
  • Gl 262570 and antagonists, PPAR-gamma / alpha modulators (eg KRP 297), alpha-glucosidase inhibitors (eg acarbose, Voglibose), other DPPIV inhibitors, alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 Analogs (e.g. exendin-4) or amylin.
  • SGLT2 inhibitors such as T-1095 or KGT-1251 (869682), inhibitors of protein tyrosine phosphatase 1, substances which influence deregulated glucose production in the liver, such as inhibitors of glucose-6-phosphatase, or fructose-1, 6- bisphosphatase, glycogen phosphorylase, glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, lipid-lowering agents.
  • HMG-CoA reductase inhibitors e.g. simvastatin, atorvastatin
  • fibrates e.g.
  • a combination with medications to influence high blood pressure such as All antagonists or ACE inhibitors, diuretics, ⁇ -blockers, Ca antagonists and others or combinations thereof are suitable.
  • the dosage required to achieve a corresponding effect is expediently 1 to 100 mg, preferably 1 to 30 mg for intravenous administration, and 1 to 1000 mg, preferably 1 to 100 mg, in each case 1 to 4 times a day for oral administration.
  • the compounds of 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, e.g.
  • reaction solution was worked up with aqueous potassium carbonate solution and the product was purified over silica gel with dichloromethane / methanol
  • reaction solution was worked up with aqueous potassium carbonate solution and the product was purified over silica gel with dichloromethane / methanol
  • 1 coated tablet contains: active substance 75.0 mg calcium phosphate 93.0 mg maize starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethyl cellulose 15.0 mg magnesium stearate 1.5 mq 230.0 mg
  • the active substance is mixed with calcium phosphate, corn starch, polyvinylpyrrolidone, hydroxypropylmethyl cellulose and half of the stated amount of magnesium stearate. Pressings with a diameter of approx. 13 mm are produced on a tabletting machine, these are rubbed on a suitable machine through a sieve with a 1.5 mm mesh size and mixed with the remaining amount of magnesium stearate. This granulate is pressed on a tablet machine into tablets of the desired shape. Core weight: 230 mg stamp: 9 mm, curved
  • the dragee cores thus produced are coated with a film consisting essentially of hydroxypropylmethyl cellulose.
  • the finished film coated tablets are polished with beeswax. Drage weight: 245 mg.
  • 1 tablet contains: Active ingredient 100.0 mg milk sugar 80.0 mg corn starch 34.0 mg polyvinylpyrrolidone 4.0 mg magnesium stearate 2.0 mg 220.0 mg
  • Active ingredient, milk sugar and starch are mixed and moistened evenly with an aqueous solution of the polyvinylpyrrolidone. After sieving the moist mass (2.0 mm mesh size) and drying in a rack drying cabinet at 50 ° C., sieving is carried out again (1.5 mm mesh size) and the lubricant is added. The ready-to-press mixture is processed into tablets. Tablet weight: 220 mg, diameter: 10 mm, biplane with a double-sided facet. and one-sided partial notch.
  • 1 tablet contains: active substance 150.0 mg milk sugar powder 89.0 mg corn starch 40.0 mg colloids silica 10.0 mg polyvinylpyrrolidone 10.0 mg magnesium stearate 1.0 mq 300.0 mg
  • the active substance mixed with milk sugar, corn starch and silica is moistened with a 20% aqueous polyvinylpyrrolidone solution and passed through a sieve with a 1.5 mm mesh size.
  • 1 capsule contains: Active ingredient 150.0 mg corn starch dr. approx. 180.0 mg powdered milk sugar approx. 87.0 mg magnesium stearate 3.0 mq approx. 420.0 mg
  • the active ingredient is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously in a suitable device.
  • the final mix is filled into size 1 hard gelatin capsules.
  • 1 suppository contains: Active ingredient 150.0 mg polyethylene glycol 1500 550.0 mg polyethylene glycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg 2000.0 mg
  • 100 ml suspension contain: Active ingredient 1.00 g carboxymethyl cellulose Na salt 0.10 g p-hydroxybenzoic acid methyl ester 0.05 g p-hydroxybenzoic acid propyl ester 0.01 g cane sugar 10.00 g glycerin 5.00 g sorbitol solution 70% 20.00 g aroma 0.30 g water dist. ad 100 ml
  • Dest. Water is heated to 70 ° C. P-Hydroxybenzoic acid methyl ester and propyl ester as well as glycerol and carboxymethyl cellulose sodium salt are dissolved therein with stirring. It is cooled to room temperature and the active ingredient is added with stirring and dispersed homogeneously. After adding and dissolving the
  • 5 ml of suspension contain 50 mg of active ingredient.
  • composition active ingredient 10.0 mg 0.01 n hydrochloric acid sq Aqua bidest ad 2.0 ml production:
  • the active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 2 ml ampoules.
  • composition active ingredient 50.0 mg 0.01 N hydrochloric acid s.q. Aqua bidest to 10.0 ml
  • the active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 10 ml ampoules.

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Abstract

L'invention concerne une imidazopyridazindione de formule générale (I) dans laquelle R1 à R4 sont tels que définis dans la revendication 1. L'invention concerne également les énantiomères, les diastéréoisomères de ce composé, ainsi que leurs mélanges et leurs sels, lesquels présentent des propriétés pharmacologiques précieuses, en particulier, un effet inhibiteur de l'activité de l'enzyme dipeptidylpeptidase-IV (DPP-IV).
PCT/EP2005/002524 2004-03-13 2005-03-09 Imidazopyridazindione, sa fabrication et son utilisation comme medicament WO2005087774A1 (fr)

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EP05728980A EP1763530A1 (fr) 2004-03-13 2005-03-09 Imidazopyridazindione, sa fabrication et son utilisation comme medicament
CA002559444A CA2559444A1 (fr) 2004-03-13 2005-03-09 Imidazopyridazindione, sa fabrication et son utilisation comme medicament
JP2007502292A JP2007527888A (ja) 2004-03-13 2005-03-09 イミダゾピリダジンジオン、それらの製造、及び薬剤としての使用

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2007072083A1 (fr) 2005-12-23 2007-06-28 Prosidion Limited Traitement du diabete de type 2 par combinaison d'un inhibiteur de dpiv a de la metformine ou de la thiazolidinedione
US7906539B2 (en) 2004-06-24 2011-03-15 Boehringer Ingelheim International Gmbh Imidazoles and triazoles, their preparation, and their use as pharmaceutical compositions

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WO2005097798A1 (fr) * 2004-04-10 2005-10-20 Boehringer Ingelheim International Gmbh Nouvelles 2-amino-imidazo[4,5-d]pyridazin-4-ones et 2-amino-imidazo[4,5-c]pyridin-4-ones, leur production et leur utilisation comme medicaments
CA2741672A1 (fr) * 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabetiques utiles avec des derives de benzimidazole cycliques

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WO2003104229A1 (fr) * 2002-06-06 2003-12-18 エーザイ株式会社 Nouveau derive d'imidazole fondu
WO2004050658A1 (fr) * 2002-12-03 2004-06-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles imidazo-pyridinones et imidazo-pyridazinones substituees, leur production et leur utilisation en tant que medicaments
WO2004108730A1 (fr) * 2003-06-05 2004-12-16 Fujisawa Pharmaceutical Co., Ltd. Inhibiteur de l'enzyme dpp-iv
WO2005058901A1 (fr) * 2003-12-17 2005-06-30 Boehringer Ingelheim International Gmbh Nouvelles 2-(piperazin-1-yl)- et 2-([1,4]diazepan-1-yl)-imidazo[4,5-d]pyridazin-4-ones, leur production et leur utilisation en tant que medicaments pour traiter le diabete sucre

Patent Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2003104229A1 (fr) * 2002-06-06 2003-12-18 エーザイ株式会社 Nouveau derive d'imidazole fondu
EP1514552A1 (fr) * 2002-06-06 2005-03-16 Eisai Co., Ltd. Nouveau derive d'imidazole fondu
WO2004050658A1 (fr) * 2002-12-03 2004-06-17 Boehringer Ingelheim Pharma Gmbh & Co. Kg Nouvelles imidazo-pyridinones et imidazo-pyridazinones substituees, leur production et leur utilisation en tant que medicaments
WO2004108730A1 (fr) * 2003-06-05 2004-12-16 Fujisawa Pharmaceutical Co., Ltd. Inhibiteur de l'enzyme dpp-iv
WO2005058901A1 (fr) * 2003-12-17 2005-06-30 Boehringer Ingelheim International Gmbh Nouvelles 2-(piperazin-1-yl)- et 2-([1,4]diazepan-1-yl)-imidazo[4,5-d]pyridazin-4-ones, leur production et leur utilisation en tant que medicaments pour traiter le diabete sucre

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7906539B2 (en) 2004-06-24 2011-03-15 Boehringer Ingelheim International Gmbh Imidazoles and triazoles, their preparation, and their use as pharmaceutical compositions
WO2007072083A1 (fr) 2005-12-23 2007-06-28 Prosidion Limited Traitement du diabete de type 2 par combinaison d'un inhibiteur de dpiv a de la metformine ou de la thiazolidinedione

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