Patent DE-102004017739-A1 (DE)
Title: New 2-amino-imidazo(4,5-d)pyridazin-4-one derivatives are dipeptidyl-peptidase IV inhibitors useful in the treatment of e.g. diabetes mellitus, autoimmune disease, rheumatoid arthritis, and multiple sclerosis
Inventor: ECKHARDT MATTHIAS
IPC: A61P3/10
Filed: 2004-04-10
Abstract: 2-Amino-imidazo[4,5-d]pyridazin-4-one derivatives or their tautomers, enantiomers, and/or diastereomers, prodrugs or salts are new. 2-Amino-imidazo[4,5-d]pyridazin-4-one derivatives of formula (I) and their tautomers, enantiomers, and/or diastereomers, prodrugs and salts are new. R1(hetero)arylmethyl or (hetero)arylethyl, (hetero)arylcarbonylmethyl or (hetero)arylprop-2-enyl, where the propenyl chain is optionally substituted; X : N or C-R5; R5H or 1-3C alkyl; R2H, 1-6C alkyl (optionally substituted), or (hetero)aryl (all optionally substituted)); Ra3-7C cycloalkyl, where 1 or 2 methylene groups may be replaced O, S, -NH- or -N(1-3C alkyl) group, or by a carbonyl, sulfinyl or sulfonyl; or CF3, (hetero)aryl, CN, carboxy, 1-3C alkoxy-carbonyl, aminocarbonyl, 1-3C alkylamino-carbonyl, di-(1-3C alkyl)-aminocarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(1-3C alkyl)-piperazin-1-ylcarbonyl, (hetero)arylcarbonyl, 1-3C alkylsulfinyl, 1-3C alkylsulfonyl, OH, 1-3C alkoxy, 1-3C alkylsulfanyl, amino, 1-3C alkylamino, di-(1-3C alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl or 4-(1-3C alkyl)-piperazin-1-yl; a CF3, carboxy, 1-4C alkoxy-carbonyl, aminocarbonyl, 1-3C alkylamino-carbonyl, di-(1-3C alkyl)-amino-carbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl, morpholin-4-ylcarbonyl, piperazin-1-ylcarbonyl, 4-(1-3C alkyl)-piperazin-1-ylcarbonyl, (hetero)arylcarbonyl, 1-3C alkylsulfinyl, 1-3C alkylsulfonyl, 1-4C alkoxy, 1-4C alkylsulfanyl, amino, 1-3C alkylamino or di-(1-3C alkyl)-amino, pyrrolidin-1-yl, piperidin-1-yl, morpholin-4-yl, piperazin-1-yl or 4-(1-3C alkyl)-piperazin-1-yl; 3-7C cycloalkyl, where one or two methylene groups may be replaced by O or S, by -NH- or N(1-3C alkyl), or by a carbonyl, sulfinyl or sulfonyl group; or 3-6C alkenyl or 3-6C alkynyl (all optionally substituted)); R35-7C cycloalkenyl-methyl optionally substituted by a 1-3C alkyl group; (hetero)arylmethyl; a straight or branched 2-8C alkenyl optionally substituted by 1 - 15 F or CN, NO2 or 1-3C alkoxy-carbonyl group; or a straight or branched 3-8C alkynyl optionally substituted by 1 - 9 F or CN, NO2 or 1-3C alkoxy-carbonyl group (all optionally substituted)); R4amino (substituted by R15 and R16 or R15 and R18 or R15 and R20 or R15 and R21); R15H, 1-6C alkyl, 3-6C cycloalkyl, 3-6C cycloalkyl-1-3C alkyl, aryl or aryl-1-3C alkyl ; R16R17-2-3C alkyl, where the 2-3C alkyl moiety is straight-chain and is optionally mono- - tetra-substituted by 1-3C alkyl; R17 and R19amino or 1-3C alkylamino; R183-10C cycloalkyl-1-2C alkyl substituted in the 1 position of the cycloalkyl group by R19 or a 3-10C cycloalkyl substituted in 1 or 2 position by a R19-1-2C alkyl (all optionally substituted); R204C- or 8-10C cycloalkyl, where a methylene group from position 3 onwards of the 4C- or 8-10C cycloalkyl group is replaced by an -NH- (all optionally substituted); and R213-4C- or 8-10C cycloalkyl substituted in the 2 or 3 position by an amino or 1-3C alkylamino (all optionally substituted). Full definitions are given in the "Definitions" section. An independent claim is included for the preparation of (I). [Image] ACTIVITY : Antidiabetic; Ophthalmological; Neuroprotective; Nephrotropic; Antiarthritic; Antiarteriosclerotic; Anorectic; Osteopathic; Sedative; Tranquilizer; Antihypertensive; Antiinflammatory; Gastrointestinal-Gen.; Antiulcer; Antiinfertility; Contraceptive; Immunosuppressive; Antirheumatic; Antithyroid; Uropathic; Virucide; Anti-HIV; Nootropic; Cytostatic; Cerebroprotective; Vasotropic; Antiparkinsonian; Antimigraine; Keratolytic; Antipsoriatic; Antidepressant; Antilipemic; Neuroleptic. MECHANISM OF ACTION : Dipeptidylpeptidase IV (DPP-IV) enzyme inhibitor. 2-[N-(2-Aminoethyl)-N-methyl-amino]-3-(2-butyn-1-yl)-5-[(4-methyl-quinazolin-2-yl)methyl]-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one (a) was tested for DPP-IV inhibitory activity using extract of human colon carcinoma cell line Caco-2 as DPP-IV source. A substrate solution (amido-4-trifluoromethylcoumarin (AFC)) (50 mu l) was placed in microtiter plate. An assay buffer (50 mM Tris HCl, pH 7.8, 50 mM NaCl, 1% dimethyl sulfoxide) was pipetted in the plate. The reaction was started by addition of solubilized Caco-2 protein (30 mu l). (a) Was added to the assay buffer and the reaction was carried out at ambient temperature. The mixture was incubated for 60 minutes and then the fluorescence was determined. (a) Showed DPP-IV inhibition at an IC50 of 1 nM.