Patent NZ-334950-A (NZ)
Title: N-(aryl/heteroarylacetyl) amino acid esters and pharmaceutical compositions comprising same; useful for inhibiting beta-amyloid peptide release and/or its synthesis
Inventor: LATIMER LEE H
IPC: A61K31/381
Filed: 1997-11-20
Abstract: 1) The amino acid ester of formula (I) is used in the preparation of a medicament for inhibiting? b-amyloid peptide release and/or its synthesis in a cell in need thereof, wherein: R1 is: a) alkyl, alkenyl, alkcycloalkyl, phenyl-(R)m-, naphthyl-(R)m-, cycloalkyl, cycloalkenyl or optionally substituted heteroaryl having 3 to 10 atoms and 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen with the proviso that for such heteroaryls when there is at least one nitrogen heteroatom, there is also at least one oxygen and/or sulfur heteroatom; b) a substituted phenyl group of formula II; c) 1- or 2-naphthyl-(R)m- substituted at the 5, 6, 7 and/or 8 positions with 1 to 4 substituents selected from the group consisting alkyl, alkoxy, halo, cyano, nitro, trihalomethyl, and thioalkoxy; Ra and Ra' are independently hydrogen, hydroxy, fluoro or methyl; Rb and Rb' are independently hydrogen, alkyl, alkoxy, aryl, cyano, cycloalkyl, halo, heteroaryl, heterocyclic, nitro, trihalomethyl, thioalkoxy, thioaryloxy, thioheteroaryloxy, or -C(O)R4; Rc is hydrogen, alkyl, aryl, cyano, halo, or nitro or Rb and Rc can be fused to form a methylenedioxy ring with the phenyl ring or when Rb and/or Rb' and/or Rc is fluoro, chloro, bromo and/or nitro, then Ra and/or Ra' can also be chloro; R is an alkylene group; m  is 0 or 1; n is 0, 1 or 2 R2 is hydrogen, alkyl, phenyl, alkylalkoxy or alkylthioalkoxy; R3 is -(CH2)nCR10 R5R6; R5 and R6 are independently hydrogen, alkyl, alkenyl, aryl, heteroaryl, heterocyclic, -NR7R8, -COOR9  or R5 and R6 can be joined to form a cycloalkyl group, a cycloalkenyl group, an aryl group, a heteroaryl group, or a heterocyclic group; R10 is hydrogen or alkyl provided R5 and R6 do not join to form an aryl or heteroaryl group provided that R10 is hydrogen when n is zero or when n is greater than zero and R5 and R6 are joined to form an aryl or heteroaryl group, then R10 becomes a bond within that group; R4, R7, R8 and R9 are as defined in the specification; X is oxygen or sulphur; X' is hydrogen, hydroxy or fluoro; X" is hydrogen, hydroxy or fluoro, or X' and X" together form an oxo group, and pharmaceutically acceptable salts thereof with the provisos that: when R1 is phenyl, R2 is -CH(CH3)CH2CH3, X is oxygen, and X' and X" are hydrogen, then R3 is not -CH2CH3 or -CH2CH(CH3)2 when R1 is phenyl, R3 is -CH2CH(CH3)2, X is oxygen, and X' and X" are hydrogen, then R2 is not -CH(CH3)2 when R1 is pyrid-3-yl, R2 is ethyl, X is oxygen, and X' and X" are hydrogen, then R3 is not -CH2CH(CH3)2, when R1 is indoxazin-3-yl, 2,4-dimethylthiazol-5-yl, 4-methyl-1,2,5-thiooxadizol-3-yl or 3,5-di(trifluoromethyl)phenyl, R2 is methyl, X is oxygen, and X' and X" are hydrogen, then R3 is not -CH2CH(CH3)2, and when R1 is -CH2-phenyl, R3 is -CH2CH3, X is oxygen, and X' and X" are hydrogen, then R2 is not -CH2CH(CH3)2, and 2) a compound, identical to the compound of formula I, but with the added provisos: R2 cannot be hydrogen; the known compound N-(phenylacetyl)methionine ethyl ester is excluded; and when R1 is phenyl, X' and X'' are hydrogen, X is oxygen, R3 is methyl then R2 is not -CH3, -CH2CH(CH3)2 or -CH2OCH3; 3) pharmaceutical composition comprising a pharmaceutically inert carrier and a pharmaceutically effective amount of the compound of formula I, with the proviso that R2 may not be hydrogen.