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WO2005097798A1 - 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 - Google Patents

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 Download PDF

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Publication number
WO2005097798A1
WO2005097798A1 PCT/EP2005/003474 EP2005003474W WO2005097798A1 WO 2005097798 A1 WO2005097798 A1 WO 2005097798A1 EP 2005003474 W EP2005003474 W EP 2005003474W WO 2005097798 A1 WO2005097798 A1 WO 2005097798A1
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Prior art keywords
group
amino
alkyl
methyl
substituted
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PCT/EP2005/003474
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German (de)
English (en)
Inventor
Matthias Eckhardt
Frank Himmelsbach
Elke Langkopf
Norbert Hauel
Mohammad Tadayyon
Leo Thomas
Original Assignee
Boehringer Ingelheim International Gmbh
Boehringer Ingelheim Pharma Gmbh & Co. Kg
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Priority claimed from DE102004017739A external-priority patent/DE102004017739A1/de
Priority claimed from DE200410025552 external-priority patent/DE102004025552A1/de
Application filed by Boehringer Ingelheim International Gmbh, Boehringer Ingelheim Pharma Gmbh & Co. Kg filed Critical Boehringer Ingelheim International Gmbh
Priority to JP2007506703A priority Critical patent/JP2007531780A/ja
Priority to CA002561210A priority patent/CA2561210A1/fr
Priority to EP05716507A priority patent/EP1740589A1/fr
Publication of WO2005097798A1 publication Critical patent/WO2005097798A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • 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
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to new substituted imidazo [4,5-d] pyridazin-4-ones and 2-amino-imidazo [4,5-c] pyridin-4-ones of the general formula
  • DPP-IV dipeptidyl peptidase-IV
  • the 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 II diabetes mellitus, the a compound of the general formula (I) or a physiologically tolerable salt thereof medicament and method for the production thereof.
  • DPP-IV dipeptidyl peptidase-IV
  • WO 03/104229 discloses imidazo [4,5-d] pyridazin-4-one and imidazo [4,5-c] - pyridin-4-one, which are substituted in position 2 by cyclic groups.
  • R 1 is an arylmethyl or arylethyl group
  • an arylprop-2-enyl or heteroarylprop-2-enyl group in which the propenyl chain by 1 to 4 fluorine atoms or a cyan, C ⁇ . 3 -alkyloxy-carbonyl or nitro group can be substituted,
  • X is a nitrogen atom or a CR 5 group, where R 5 is a hydrogen atom or a C ⁇ _ 3 alkyl group,
  • R 2 is a hydrogen atom
  • R a is a C 3 - 7 cycloalkyl group in which one or two methylene groups independently of one another each through an oxygen or sulfur atom, through a -NH- or -N (C ⁇ _ 3 -alkyl) group or through a carbonyl, sulfinyl or sulfonyl group can be replaced, or a trifluoromethyl, aryl, heteroaryl, cyano, carboxy, C ⁇ . 3 -alkoxy-carbonyl-, aminocarbonyl-, C ⁇ _ 3 -alkylamino-carbonyl-, di- (C ⁇ .
  • a C 3 - 7 cycloalkyl group in which one or two methylene groups independently of one another each through an oxygen or sulfur atom, through a -NH or -N (C ⁇ - 3 alkyl) group, or through a carbonyl, sulfinyl or sulfonyl group can be replaced, or
  • R 3 is a C 5 optionally substituted by a C 3 alkyl group. 7- cycloalkenylmethyl group,
  • R is an amino group substituted by the radicals R lü and R, in which R 15 is a hydrogen atom, a C ⁇ . 6 -alkyl-, C 3 . 6 -cycloalkyl-, C 3 . 6- cycloalkyl-C 1 . 3 - alkyl, aryl or aryl -C 3 alkyl group and
  • R 16 is R 17 -C 2 . 3 -alkyl group, the C 2 . 3 -Alkylt.eil is straight-chain and can be substituted by 1 to 4 C ⁇ _ 3 alkyl groups, which may be the same or different, and wherein the C 2 - 3 alkyl group can be linked from position 2 with R 17 , and
  • R 17 represents an amino or C 3 alkylamino group
  • R 15 is defined as mentioned above and R 18 is a C 3 .io-cycloalkyl-C 2 -alkyl group substituted in the 1 position of the cycloalkyl radical by R 19 or a 1- or 2-position by an R 19 -C ⁇ - 2 alkyl group substituted C 3 . ⁇ 0 cycloalkyl group, where R 19 is an amino or C ⁇ . 3 -alkylamino group,
  • R 15 is as defined above and R 20 is a C 4 - or C 8 - ⁇ o-cycloalkyl group, in which a methylene group from position 3 of the C 4 - or C 8 - ⁇ o-cycloalkyl group by an -NH- group is replaced represents
  • R 15 and R 21 are independently defined as mentioned above and R 21 is a C 3 - 4 - substituted in the 2- or 3-position by an amino or C 3 alkyl alkyl group or Represents C 8 -o-cycloalkyl group, where the abovementioned radicals R 18 , R 20 and R 21 can be mono- or disubstituted by R b , where the substituents can be the same or different and R is a fluorine atom, a C 3 alkyl, trifluoromethyl or cyano -, Amino-, C ⁇ . 3 alkyl ⁇ amino, hydroxy or C ⁇ .
  • aryl groups mentioned in the definition of the abovementioned radicals are to be understood as meaning phenyl or naphthyl groups which can be mono-, di- or tri-substituted independently of one another by R h , where the substituents can be identical or different and R h is one Fluorine, chlorine, bromine or iodine atom, a trifluoromethyl, cyan, nitro, amino, aminocarbonyl, C ⁇ -3-alkoxy-carbonyl, aminosulfonyl, methylsulfonyl, acetylamino, methylsulfonylamino , C 1 -3- alkyl, cyclopropyl, ethenyl, ethinyl, morpholinyl, hydroxy, C ⁇ - 3 alkyloxy, difluoromethoxy or trifluoromethoxy group, and in which each hydrogen atom is additionally represented by a fluorine atom can be replaced
  • heteroaryl groups mentioned in the definition of the abovementioned radicals are to be understood as a pyrrolyl, furanyl, thienyl, pyridyl, indolyl, benzofuranyl, benzothiophenyl, 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 preferably contains a Ci- ⁇ - alkanoI, a phenyl-C ⁇ - 3 -alkanol, a C 3 .g- Cycloalkanol, where a C 5 . 8- Cycloalkanol additionally by one or two C- ⁇ . 3 alkyl groups can be substituted, a Cs-s-cycloalkanol in which a methylene group in the 3- or 4-position by an oxygen atom or by an optionally by a C ⁇ . 3 -alkyl, phenyl -CC.
  • R p a C ⁇ . 8 alkyl, C 5 - 7 cycloalkyl, C 8 8 alkyloxy, C 5 7 cycloalkyloxy, phenyl or phenyl C 3 alkyl group,
  • R q is a hydrogen atom, a C ⁇ . -Alkyl-, Cs- 7 -cycloalkyl or phenyl group and
  • R r 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 substituted by fluorine, chlorine, bromine or iodine atoms, by C 3 alkyl or C 1-4 alkoxy groups mono- or disubstituted Phenylcarbonyl group, where the substituents can 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 3,3,3-trichloropropionyl or allyloxycarbonyl group, a C ⁇ .
  • an imino or amino group in vivo for example a hydroxyl group, an acyl group such as one optionally substituted by fluorine, chlorine, bromine or iodine atoms, by C 3 alkyl or C 1-4 alkoxy
  • R s CRt (R s CRt) -O-CO- or C ⁇ . 6 -alkyl-CO-O- (R s CRt) - (RsCRt) -O-CO group, in which R p to R r are defined as mentioned above,
  • R s and Rt 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, 3.5 -Dimethoxybenzyl-, 2,6-dicyanbenzyl-, 5-cyanfuranylmethyl-, oxazolylmethyl-, isoxazolylmethyl-, 5-methoxycarbonylthienylmethyl-, pyridinylmethyl-, 3-cyanopyridine- 2-ylmethyl-, 6-cyanopyridin-2-ylmethyl-, 6-fluoropyridin-2-ylmethyl-, 3- (2-cyanophenyl) prop-2-enyl-, 3- (pyridin-2-yl) prop- 2-enyl-, 3- (pentafluorophenyl) prop-2-enyl-, phenylcarbonylmethyl-, 3-methoxyphenylcarbony
  • R 2 is, for example, the meaning of a hydrogen atom, a methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, 2-propen-1-yl, 2-propyn-1-yl, cyclopropylmethyl, phenyl, benzyl, 2-phenylethyl, 3-phenylpropyl, 2-hydroxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2- (dimethylamino) ethyl, pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl, piperazin-1-yl, carboxy, methoxycarbonyl -, ethoxycarbonyl, carboxymethyl, (methoxycarbonyl) methyl, aminocarbonyl,
  • R 3 for example, the meaning of 2-propen-1-yl, 2-methyl-2-propen-1-yl, 1-buten-1-yl, 2-buten-1-yl, 3- Buten-1-yl, 2-methyl-2-buten-1-yl, 3-methyl-2-buten-1-yl, 2,3-dimethyl-2-buten-1-yl, 3- Methyl-3-buten-1-yl-, 1-cyclopenten-1-ylmethyl-, (2-methyl-1-cyclopenten-1-yl) methyl-, 1-cyclohexen-1 -ylmethyl-, 2-propyne -1-yl-, 2-butyn-1-yl, 3-butyn-1-yl, 2-chlorobenzyl, 2-bromobenzyl, 2-iodobenzyl, 2-cyanobenzyl, 3-fluorobenzyl, 2-methoxybenzyl -, 2-furanylmethyl, 3-furanylmethyl, 2-thienylmethyl or 3-thienylmethyl group into
  • R 4 is, for example, the meaning of a (2-aminocyclopropyl) amino, N- (2-aminocyclopropyl) -N-methylamino, (2-aminocyclobutyl) amino, N- (2-aminocyclobutyl) -N -methyl-amino-, N- (3-aminocyclobutyl) -N-methyl-amino-, N- (2-aminoethyl) -N- methyl-amino-, N- (1-aminoprop-2-yl) -N-methyl-amino-, N- (2-aminopropyl) -N-methyl-amino-, N- (1-amino-2-methyl-prop-2-yl) -N-methyl-amino-, N- (2-aminopropyl) -N-methyl-amino-, N- (1-amino-2-methyl- prop-2-yl) -N-methylamino
  • Preferred compounds of the general formula I are those in which
  • R 1 and R 4 are defined as mentioned above,
  • X is a nitrogen atom or a -CH group
  • R 2 is a hydrogen atom, a Cu alkyl, C 3 - 6 cycloalkyl or phenyl group and
  • R 3 is a 1-buten-1-yl, 2-buten-1-yl, 2-butyn-1-yl, cyclopent-1-enylmethyl, furanylmethyl, thienylmethyl, chlorobenzyl, Bromobenzyl, iodobenzyl, methoxybenzyl or cyanbenzyl group,
  • R 1 is phenylmethyl, phenylcarbonylmethyl, phenylprop-2-enyl, pyridinylmethyl, pyrimidinylmethyl, naphthylmethyl, quinolinylmethyl, isoquinolinylmethyl, chinazolinylmethyl, quinoxalinylmethyl, naphthyridinylmethyl, or benzotriazole or two fluorine, chlorine, bromine atoms or one or two cyano, nitro, amino, C- ⁇ - 3 alkyl, C ⁇ - 3 alkyloxy and morpholinyl groups, where the substituents are the same or different .
  • X is a nitrogen atom or a -CH group
  • R is a hydrogen atom
  • R 3 is 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 represents an N- (2-aminoethyl) -N-methyl-amino group in which the ethyl group can be substituted by 1 to 4 methyl groups
  • R 1 is an isoquinolinylmethyl, quinazolinylmethyl or benzyl group which can be substituted by a 'methyl or cyano group,
  • X is a nitrogen atom or a -CH group
  • R 2 is a hydrogen atom
  • R 3 is a 2-butyn-1-yl group
  • R 4 is an N- (2-aminoethyl) -N-methylamino, N- (2-aminopropyl) -N-methylamino or N- (2-amino-2-methylpropyI) -N-methylamino group mean,
  • 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 and X are defined as mentioned at the outset and Z represents a leaving group such as a halogen atom, a substituted hydroxyl, mercapto, sulfinyl, sulfonyl or sulfonyloxy group such as a chlorine or bromine atom, a methanesulfonyl or methanesulfonyloxy group R 4 -H or salts thereof, where R 4 is as defined in the introduction.
  • Z represents a leaving group such as a halogen atom, a substituted hydroxyl, mercapto, sulfinyl, sulfonyl or sulfonyloxy group such as a chlorine or bromine atom, a methanesulfonyl or methanesulfonyloxy group R 4 -H or salts thereof, where R 4 is as defined in the introduction.
  • the reaction is advantageously carried out in a solvent such as isopropanol, butanol, tetrahydrofuran, dioxane, dimethylformamide, dimethyl sulfoxide, ethylene glycol monomethyl ether, ethylene glycol diethyl ether or sulfolane, optionally in the presence of an inorganic or tertiary organic base, for example sodium carbonate, potassium carbonate or potassium hydroxide, a tertiary organic base , for example triethylamine, or in the presence of N-ethyldiisopropylamine (Hünig base), these organic bases can also serve as solvents at the same time, and if appropriate 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
  • Z 2 represents one of the groups mentioned at the outset for R 4 which contains an amino group which is not bonded directly to the imidazopyridazinone backbone and which is Boc-protected in Z 2 , where Boc stands for a tert-butyloxycarbonyl radical.
  • 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, if appropriate using a solvent such as methylene chloride, ethyl acetate, dioxane, methanol, isopropanol or diethyl ether at temperatures between 0 and 80 ° C.
  • an acid such as trifluoroacetic acid or hydrochloric acid
  • bromotrimethylsilane or iodotrimethylsilane if appropriate using a solvent such as methylene chloride, ethyl acetate, dioxane, methanol, isopropanol or diethyl ether at temperatures between 0 and 80 ° C.
  • any reactive groups present such as amino, alkylamino or imino groups, can be protected during the reaction by customary protective groups, which are split off again after the reaction.
  • the formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for the amino group also includes the phthalyl group.
  • 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 aqueous solvent e.g. in water, isopropanol / water, acetic acid / water, tetrahydrofuran / water or dioxane / water
  • an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid
  • an alkali base
  • a benzyl, methoxybenzyl or benzyloxycarbonyl radical is cleaved off, for example, hydrogenolytically, for example using hydrogen in the presence of a catalyst such as palladium / carbon in a suitable solvent such as methanol, 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.
  • 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 general formula I obtained which occur in racemates, according to methods known per se (see Allinger NL and Eliel EL in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) in their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms on the basis of their physico-chemical differences according to methods known per se, for example by chromatography and / or fractionated crystallization, separate into their diastereomers, which, if they occur in racemic form, can then be separated into the enantiomers as mentioned above.
  • 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-op-toluoyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinic acid.
  • suitable optically active alcohol are (+) - or (-) - menthol and 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 thus obtained if they contain a carboxy group, can then, if desired, 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 compounds of general formulas II and III 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 XI).
  • the compounds of the general formula I according to the invention and their physiologically tolerable salts have valuable pharmacological properties, in particular an inhibitory action on the enzyme DPP-IV.
  • the cell extract was obtained from cells solubilized in a buffer (10 mM Tris HCl, 0.15 M NaCl, 0.04 tiu aprotinin, 0.5% Nonidet-P40, pH 8.0) by centrifugation at 35000 g for 30 minutes at 4 ° C (to remove cell debris) won.
  • a buffer (10 mM Tris HCl, 0.15 M NaCl, 0.04 tiu aprotinin, 0.5% Nonidet-P40, pH 8.0
  • 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 pre-diluted in 20 ⁇ l, 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 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 mellitus, diabetic complications (such as, for example, retinopathy, nephropathy or neuropathies), metabolic acidosis or ketosis, reactive hypoglycemia, insulin resistance , Metabolic syndrome, dyslipidemia of various origins, arthritis, atherosclerosis and related diseases, obesity, allograft transplantation and osteoporosis caused by calcitonin are suitable.
  • diseases or conditions such as type 1 and type 2 diabetes mellitus, diabetic complications (such as, for example, retinopathy, nephropathy or neuropathies), metabolic acidosis or ketosis, reactive hypoglycemia, insulin resistance , Metabolic 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 further suitable for improving or restoring the functionality of pancreatic cells, in addition to 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 sperm motility 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.
  • the compounds according to the invention are also suitable for the treatment of various autoimmune diseases such as, for example, rheumatoid arthritis, multiple sclerosis, thyroid disease and Graves' disease, etc.
  • they can be used for viral diseases such as HIV infections, for stimulating 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 can also be used for the therapy of tumors, in particular for changing tumor invasion, as well as metastatisation. Examples here are the use in T-cell lymphomas, acute lymphoblastic leukemia, cell-based thyroid carcinomas, basal cell carcinomas or breast carcinomas.
  • 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 and 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-glucose inhibitors (eg acarbose, Voglibose), other DPPIV inhibitors, alpha2-antagonists, insulin and insulin analogues, GLP-1 and GLP-1 analogues (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, the glycogen phosphorylase, glucagon receptor antagonists and inhibitors of the phosphoenolpyruvate carboxykinase, the glycogen synthase kinase or the pyruvate dehydrokinase, lipid-lowering agents such as HMG-CoA reductase inhibitor (e.g.
  • simvastatin deribibrate, fennafate, forafate (eg -alpha agonists, PPAR-delta agonists, ACAT inhibitors (eg Avasimibe) or cholesterol absorption inhibitors such as ezetimibe, bile acid binding substances such as for example colestyramine, inhibitors of ileal bile acid transport, HDL-increasing compounds such as, for example, inhibitors of CETP or regulators of ABC1 or active substances for the treatment of obesitas, such as sibutramine or tetrahydrolipstatin, dexfenfluramine, axokines, antagonists of the cannbinoidl receptor, MCH Receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists or ß 3 agonists such as SB-418790 or AD-9677 as well as agonists of the 5HT2c receptor.
  • fennafate eg
  • a combination with drugs 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.
  • Example VIII Methyl 2-bromo-5- (frans-2-methoxy-vinyl) -3H-imidazole-4-carboxylate Under an argon atmosphere, 38 ml of 38 ml of an ice-cooled solution of 6.64 g of methoxy-methyltriphenylphosphonium chloride in 140 ml of tetrahydrofuran a 0.5 M solution of potassium bis (trimethylsilyl) amide in toluene was added dropwise over 10 min. The reaction mixture is stirred for a further 15 min in an ice bath and then cooled to -70 ° C.
  • dichloromethane is added give and make the solution alkaline with sodium hydroxide solution.
  • the organic phase is separated off and the aqueous phase is extracted twice with dichloromethane.
  • the combined organic phases are dried over sodium sulfate, the solvent is removed and the residue is purified on silica gel (dichloromethane / methanol 99: 1-
  • Product (2) was obtained by reacting a 1: 1 mixture of 2-bromo-3- (2-butyn-1-yl) -5 - [(3-methyl-isoquinolin-1-yl) methyl] -3.5 -dihydro-imidazo [4,5-c] pyridin-4-one and 2-
  • 1 coated tablet contains: active substance 75.0 mg calcium phosphate 93.0 mg corn starch 35.5 mg polyvinylpyrrolidone 10.0 mg hydroxypropylmethyl cellulose 15.0 mg magnesium stearate 1.5 m ⁇ 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.
  • Composition 1 tablet contains: Active substance 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
  • 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 mg 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 mg 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 sugar, the sorbitol solution and the aroma, the suspension is evacuated with stirring for deaeration. 5 ml of suspension contain 50 mg of active ingredient.
  • composition active ingredient 10.0 mg 0.01 n hydrochloric acid s.q. Aqua bidest ad 2.0 ml
  • the active substance is dissolved in the required amount of 0.01N HCl, made isotonic with sodium chloride, sterile filtered and filled into 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

La présente invention concerne des 2-amino-imidazo[4,5-d]pyridazin-4-ones et 2-amino-imidazo[4,5-c]pyridin-4-ones de formule générale (I), dans laquelle R1 à R4 et X sont tels que définis dans les revendications 1 à 6, leurs tautomères, leurs énantiomères, leurs diastéréomères, leurs mélanges et leurs sels, lesquels composés présentent de précieuses propriétés pharmacologiques, en particulier un effet inhibiteur sur l'activité de l'enzyme dipeptidylpeptidase-IV (DPP-IV).
PCT/EP2005/003474 2004-04-10 2005-04-02 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 WO2005097798A1 (fr)

Priority Applications (3)

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JP2007506703A JP2007531780A (ja) 2004-04-10 2005-04-02 新規な２−アミノ−イミダゾ［４，５−ｄ］ピリダジン−４−オン及び２−アミノ−イミダゾ［４，５−ｃ］ピリダジン−４−オン、その製法及び医薬としての使用
CA002561210A CA2561210A1 (fr) 2004-04-10 2005-04-02 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
EP05716507A EP1740589A1 (fr) 2004-04-10 2005-04-02 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

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DE102004017739A DE102004017739A1 (de) 2004-04-10 2004-04-10 Neue 2-Amino-imidazo(4,5-d)pyridazin-4-one, deren Herstellung und deren Verwendung als Arzneimittel
DE102004017739.2 2004-04-10
DE102004025552.0 2004-05-25
DE200410025552 DE102004025552A1 (de) 2004-05-25 2004-05-25 Neue 2-Amino-imidazo[4,5-d]pyridazin-4-one und 2-Amino-imidazo[4,5-c]pyridin-4-one, deren Herstellung und deren Verwendung als Arzneimittel

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