New 4-aminopyrazol-(1,5-a)-1,3,5-triazine derivatives, are potent and selective phosphodiesterase 4 inhibitors useful e.g. for treating CNS disorders, neuroinflammation, Crohn's disease, asthma, cancer or epilepsy

摘要

4-Aminopyrazolo-(1,5-a)-1,3,5-triazine derivatives (I) are new. 4-Aminopyrazolo-(1,5-a)-1,3,5-triazine derivatives of formula (I) and their enantiomer, diastereomers and salts are new. [Image] R : (CH 2) n-R 4or (CH 2) m-X-(CH 2) p-R 4; n : 1-7 (preferably 1-6); R 4phosphate group, aryl, arylalkyl, A 1-Het, NR bR c, COR a, CH(OH)-R 5, NHCOR 5or OR 6; A 1direct bond, alkylene, O or alkyleneoxy; Het : mono- or bi-cyclic, saturated or unsaturated heterocyclyl containing 1-5 of O, S and/or N as heteroatoms; R b, R cH, OH, alkyl, cycloalkyl, cycloalkylalkyl, 2-6C alkenyl, 2-6C alkynyl, aryl, arylalkyl or A 1-Het, or NR bR c5-7 membered heterocyclyl optionally containing another O, S or NR 5heteroatom; R 5H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, alkoxy, cycloalkoxy, cycloalkylalkoxy, aryloxy, arylalkoxy or A 1-Het; R aH, OH, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, alkoxy, cycloalkoxy, cycloalkylalkoxy, aryloxy, arylalkoxy, NR bR cor A 1-Het; R 6H, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl or heterocyclyl; m, p : 0-2, but not both 0; X : O, S or NR 5; R 1-R 3as for R band R c; alkyl, alkenyl, alkynyl, cycloalkyl, aryl and Het groups are optionally substituted e.g. by 1-5 of halo, NO 2, CN, phosphate, COOH, alkoxycarbonyl, CONH 2(optionally substituted by 1 or 2 alkyl, 1 or 2 aryl, 1 or 2 6-12C heteroaryl, 1 or 2 arylalkyl or 1 or 2 (6-12C) heteroarylalkyl), OH, alkoxy, alkyl, NH 2(optionally substituted by one or more of alkyl, cycloalkyl, aryl, 6-12C heteroaryl, aryalkyl, (6-12C) heteroarylalkyl, (1-7C) alkanoyl, (3-8C) cycloalkanoyl, (6-12C) aroyl or aryl-(1-7C) alkanoyl) or -A 1-Het; unless specified otherwise alkyl or alkylene moieties have 1-6C, cycloalkyl moieties 3-8C and aryl moieties 6-12C. ACTIVITY : Neuroprotective; Antiinflammatory; Antiasthmatic; Antiallergic; Dermatological; Antipsoriatic; Antirheumatic; Antiarthritic; Immunosuppressive; Nephrotropic; Osteopathic; Cytostatic; Antibacterial; Anti-HIV; Anorectic; Antidepressant; Neuroleptic; Tranquilizer; Nootropic; Analgesic; Anticonvulsant; Antiparkinsonian. MECHANISM OF ACTION : Phosphodiesterase (PDE) 4 inhibitor; Cyclic adenosine monophosphate (cAMP) degradation inhibitor. In test, N-hydroxy-3-(2-methyl-4-(methylamino)-pyrazolo-(1,5-a)-1,3,5-triazin-8-yl)-propamide (Ia) exhibited an IC 50value of 31 nM for inhibition of PDE 4 and inhibited PDE 3 by 4.8% at a concentration of 10 mu M.