Patent DE-102005050953-A1 (DE)
Title: New piperidine compounds are calcitonin gene-related peptide antagonists used for prophylaxis or treatment of e.g. headache, non-insulin dependent diabetes mellitus and cardiovascular disease
Inventor: MUELLER STEPHAN GEORG
IPC: A61K31/33
Filed: 2005-10-25
Abstract: Piperidine compounds (I), are new. Piperidine compound of formula (I), their tautomers, diastereomers, enantiomer, hydrates and/or salts, preferably salt with inorganic or organic acids or base, are new. R 1> = a group of formula (i)-(iii); R 11> = H or H 3C-O-; R 2> = 4-amino-3-chloro-5-methylphenyl, 4-amino-3-chloro-5-trifluoromethylphenyl, 3-chloro-4-hydroxy-5-methylphenyl or 3-chloro-4-hydroxy-5-trifluoromethylphenyl; R 3> = a group of formula (iv); X = N or C; R 31> = H, 1-3C-alkyl or R 31a>-O-C(O)-; R 31a> = H, 1-6C-alkyl-, H 2N-2-4C-alkyl, (1-3C-alkyl) 2-NH-2-4C-alkyl-, (1-3C-alkyl) 2N-2-4C-alkyl-, H 2N-C(O)-1-3C-alkyl-, (1-3C-alkyl)-NH-C(O)-1-3C-alkyl-, (1-3C-alkyl) 2N-C(O)-1-3C-alkyl- or R 31b>-2-4C-alkyl-; R 31b>= pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl, 2-oxopyrrolidin-1-yl or 2-oxopiperidin-1-yl; R 32> = free electron pair, when X is N, or R 32> = H, 1-3C-alkyl or R 32a>-O-C(O)-, when X is C; R 32a> = H, 1-6C-alkyl-, H 2N-2-4C-alkylene-, (1-3C-alkyl)-NH-2-4C-alkylene-, (1-3C-alkyl) 2N-2-4C-alkylene-, H 2N-C(O)-1-3C-alkylene-, (1-3C-alkyl)-NH-C(O)-1-3C-alkylene-, (1-3C-alkyl) 2N-C(O)-1-3C-alkylene- or R 32b>-2-4C-alkylene-; R 32b> = pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl, 2-oxopyrrolidin-1-yl or 2-oxopiperidin-1-yl; R 4> = a group of formula (v)-(xiii); Y' = C, and R41 = H or 1-3C alkyl, or Y' = N, and R 41> = free electron pair; R 42> = H, 1-3C-alkyl or R 42a>-O-C(O)-; R 42a> = H, 1-6C-alkyl-, H 2N-2-4C-alkylene-, (1-3C-alkyl)-NH-2-4C-alkylene-, (1-3C-alkyl) 2N-2-4C-alkylene-, H 2N-C(O)-1-3C-alkylene-, (1-3C-alkyl)-NH-C(O)-1-3C-alkylene-, (1-3C-alkyl) 2N-C(O)-1-3C-alkylene- or R 42b>-2-4C-alkylene-; R 42b> = pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl, 2-oxopyrrolidin-1-yl or 2-oxopiperidin-1-yl; R 43> = H, 1-6C-alkyl-, H 2N-2-4C-alkylene-, (1-3C-alkyl)-NH-2-4C-alkylene-, (1-3C-alkyl) 2N-2-4C-alkylene-, H 2N-C(O)-1-3C-alkylene-, (1-3C-alkyl)-NH-C(O)-1-3C-alkylene-, (1-3C-alkyl) 2N-C(O)-1-3C-alkylene- or R 43a>-2-4C-alkylene-; R 43a> = pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl, 2-oxopyrrolidin-1-yl or 2-oxopiperidin-1-yl; R 51> = H, 1-3C-alkyl-, R 51a>-O-C(O)-, R 51a>-O-C(O)-1-3C-alkylen-NH, R 51a>-O-C(O)-1-3C-alkylen-N(1-3C-alkyl)-, R 51a>-O-C(O)-1-3C-alkylen-O-, R 51a>-O-C(O)-1-3C-alkylen-, R 51a>-O-C(O)-C(O)-, R 51a>-O-C(O)-C(O)-O-, R 51a>-O-C(O)-1-3C-alkylene-C(O)- or R 51a>-O-C(O)-1-3C-alkylene-C(O)-O-; R 51a> = H, 1-8C-alkyl-, phenyl-, indanyl-, pyridyl-1-3C-alkylene-, HO-2-4C-alkylene-, 1-6C-alkyl-O-2-4C-alkylene-, H 2N-2-4C-alkylene-, (1-6C-alkyl)-NH-2-4C-alkylene-, (1-6C-alkyl) 2N-2-4C-alkylene-, H 2N-C(O)-1-3C-alkylene-, (1-6C-alkyl)-NH-C(O)-1-3C-alkylene-, (1-6C-alkyl) 2N-C(O)-1-3C-alkylene-, 1-6C-alkyl-C(O)-O-1-3C-alkylene-, 1-6C-alkyl-O-C(O)-O-1-3C-alkylene-, R 51b>-C(O)-1-3C-alkylen- or R 51c>-2-4C-alkylene-, or R 51b> = pyrrolidin-1-yl or piperidin-1-yl; R 51c> = pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl, 2-oxopyrrolidin-1-yl or 2-oxopiperidin-1-yl; R 52> = H, 1-3C-alkyl-, R 52a>-O-C(O)-1-3C-alkylene-NH-, R 52a>-O-C(O)-1-3C-alkylene-O-, R 52a>-O-C(O)-1-3C-alkylene-, R 52a>-O-C(O)-C(O)- or R 52a>-O-C(O)-1-3C-alkylene-C(O)-; R 52a> = H, 1-8C-alkyl-, phenyl-, indanyl-, pyridyl-1-3C-alkylene-, HO-2-4C-alkylene-, 1-6C-alkyl-O-2-4C-alkylene-, H 2N-2-4C-alkylene-, (1-6C-alkyl)-NH-2-4C-alkylene-, (1-6C-alkyl) 2N-2-4C-alkylene-, H 2N-C(O)-1-3C-alkylene-, (1-6C-alkyl)-NH-C(O)-1-3C-alkylene-, (1-6C-alkyl) 2N-C(O)-1-3C-alkylene-, 1-6C-alkyl-C(O)-O-1-3C-alkylene-, 1-6C-alkyl-O-C(O)-O-1-3C-alkylene-, R 52b>-C(O)-1-3C-alkylene, R 52c>-2-4C-alkylene- or a group of formula (xiv); R 52b> = pyrrolidin-1-yl or piperidin-1-yl, and R 52c> = pyrrolidin-1-yl, piperidin-1-yl, morpholin-1-yl, 2-oxopyrrolidin-1-yl or 2-oxopiperidin-1-yl, provided that X and Y' are not both N. An independent claim is included for the preparation of (I). [Image] [Image] [Image] [Image] ACTIVITY : Analgesic; Antimigraine; Tranquilizer; Antidiabetic; Cardiovascular-Gen.; Antidiarrheic; Dermatological; Antiemetic; Cytostatic; Vulnerary; Antiinflammatory; Antipruritic; Antiarthritic; Osteopathic; Antirheumatic; Respiratory-Gen.; Antiallergic; Antiasthmatic; Vasotropic; Antibacterial; Immunosuppressive; Neuroprotective; Gastrointestinal-Gen.; Endocrine-Gen. MECHANISM OF ACTION : Calcitonin gene-related peptide (CGRP) antagonist. In a test used to determine the affinity of (I) to bind calcitonin-gene related peptide receptor using SK-N-MC cells, results showed that (I) exhibited IC 50 values of upto 10000 nM.