Patent EP-1707206-A1 (EP)
Inventor: HEROLD PETER
IPC: A61P33/06
Filed: 2006-03-30
Abstract: Use of a piperidine compound (A) or its salt, prodrug or compound with which one or more atoms are substituted by its stable and non-radioactive isotope, to inhibit beta-secretase, cathepsin D-, plasmepsin II- and/or HIV protease, is new. Use of a piperidine compound (A) of formula (I) or (II) or its salt, prodrug or compound with which one or more atoms are substituted by its stable and non-radioactive isotope, to inhibit beta-secretase, cathepsin D-, plasmepsin II- and/or HIV protease. R1>aryl or heterocyclyl; R2>phenyl, naphthyl, acenaphthyl, cyclohexyl, pyridyl, pyrimidinyl, pyrazinyl, oxo-pyridinyl, diazinyl, triazolyl, thienyl, oxazolyl, oxadiazolyl, thiazolyl, pyrrolyl, furyl, tetrazolyl or imidazolyl (where the residue is substituted by 1-3 halo, OH, CN, CF3, 1-6C-alkyl, halo-1-6C-alkyl, OH-1-6C-alkyl, 1-6C-alkoxy-1-6C-alkyl, CN-1-6C-alkyl, carboxy-1-6C alkyl, 1-6C-alkanoyloxy-1-6C-alkyl, 1-6C-alkoxycarbonyloxy-1-6C-alkyl, 1-6C-alkoxycarbonyl, 1-6C-alkoxy, 1-6C-alkylendioxy or L1>-T1>-L2>-T2>-L3>-T3>-L4>-T4>-L5>-U1>); L1-L5 : a bond, 1-8C-alkylene, 2-8C-alkenylene or 2-8C-alkynylene or absent; T1-T4 : a bond, absent, -CH(OH)-, -CH(OR6>)-, -CH(NR5>R6>)-, -CO-, -CR7>R8>, -O- or -NR6>, -S(O)0-2, -SO2NR6>, -NR6>SO2, -CONR6>, -NR6>CO, -O-CO-, -CO-O, -O-CO-N(R6>), -N(R6>)-CO-N(R6>)-, -N(R6>)-CO-O-, pyrrolidinyl, piperidinyl or piperazinyl or -C(R11>)(R12>)- (where all the residues, except -CH(OH)-, are bonded to a saturated or aromatic C atom of the adjacent group, if the bond comes from a heteroatom, and not more than two groups of all the residues, except -CH(OH)-, is present); R3>H, 1-6C-alkyl, 2-6C-alkenyl, 1-6C-alkoxy, OH-1-6C-alkyl, 1-6C-alkoxy-1-6C-alkyl, benzyl, oxo or a group R4>-Z1-X1-; R4>H, 1-6C-alkyl-, 2-6C-alkenyl-, OH-1-6C-alkyl-, polyhydroxy-1-6C alkyl-, 1-6C-alkyl-O-1-6C-alkyl-, heterocyclyl-, (aryl)alkyl-, heterocyclylalkyl-, aryloxyalkyl-, heterocyclyloxyalkyl-, (R5>,R6>)N-(CH2)1-3-, (R5>,R6>)N-, 1-6C-alkyl-S(O)0-2-, aryl-S(O)0-2-, heterocyclyl-S(O)0-2-, HO-SO3- or its salt or NC- (where (R5>,R6>)N-, 1-6C-alkyl-S(O)0-2-, aryl-S(O)0-2-, heterocyclyl-S(O)0-2-, HO-SO3- or its salt and NC- are bonded to a C-atom of the adjacent group and the C atom is saturated if the bond comes from heteroatom); Z1 : a bond, absent, 1-6C alkylene, 2-6C-alkenylene, -O, -N(R11>)-, -S(O)0-2, -CO-, -O-CO-,-O-CO-O-, -O-CO-N(R11>)-, -NR11>-CO-O-, -CO-N(R11>)-, -N(R11>)-CO-, -N(R11>)-CO-N(R11>)- or -CH(OR9>)- (where -O, -N(R11>)-, -S(O)0-2, -O-CO-,-O-CO-O-, -O-CO-N(R11>)-, -NR11>-CO-O-, -CO-N(R11>)-, -N(R11>)-CO-, -N(R11>)-CO-N(R11>)- and -CH(OR9>)- are bonded to a C-atom of the adjacent group and the C-atom is saturated, if the bond comes from a heteroatom); X1 : absent or -(CH2)1-3-; either R5>, R6>H, 1-6C-alkyl, 2-6C-alkenyl, aryl-1-6C-alkyl or acyl; or NR5>R6>5-6 membered heterocyclic ring containing N-, O- or S atom or -SO or -SO2- group (where the N atom is optionally substituted by 1-6C alkyl); CR7>R8>3-7 membered ring containing one or two -O- or -S- atoms or -SO or -SO2-; R9>H, 1-6C-alkyl, 3-8C-cycloalkyl, 1-6C-alkoxy-1-6C-alkyl, acyl or arylalkyl; R10>carboxyalkyl, alkoxycarbonylalkyl, alkyl or H; R11>, R12>H or 1-6C-alkyl; U1>H, 1-6C-alkyl, cycloalkyl, CN, optionally substituted cycloalkyl, aryl or heterocyclyl or absent; Q : ethylene (in (I)) or ethylene or methyl (in (II)); X : =CH-R11>, =CR9>R11>, =CHOR9>, =CO or =C=NOR10>; Z : absent or 1-6C-alkylene, 2-6C-alkenyl, OH-1-6C-alkylidene, -CH-R11>-CO-NR9>-, -O-, -S-, -NR9>, -O-alk-, -S-alk-, -NR9>-alk-, -alk-O-, -alk-S or -alk-NR9>-; and alk : 1-6C-alkylene. Provided that if Z is -O- or - S, X is -CR9>-R11> and then either R2> is a substituent L1>-T1>-L2>-T2>-L3>-T3>-L4>-T4>-L5>-U1> or R3> is H; if Z is -O-alkene, -S-alk- or -NR9>-alk-, X is -CH-R9>R11>; if X is a bond, Z is 1-6C-alkenyl, -alk-O-, -alk-S or -alk-NR9>-. [Image] ACTIVITY : Neuroprotective; Nootropic; Antimalarial; Anti-HIV; Cerebroprotective; Hemostatic. MECHANISM OF ACTION : Beta-secretase inhibitor; Cathepsin D inhibitor; Plasmepsin II inhibitor; HIV protease inhibitor. The ability of (A) to inhibit beta-secretase was tested using biological assays. The results showed that (A) exhibited an IC50 value of 0.01 pM to 100 nM.