Patent ID: 6635632
Filing Date: 2003-10-21
Classification: A61K,A61P,C07C,C07D

Abstract:
A method for inhibiting &bgr;-amyloid peptide release and/or its synthesis in a cell which method comprises administering to such a cell an amount of a compound or a mixture of compounds effective in inhibiting the cellular release and/or synthesis of &bgr;-amyloid peptide wherein said compounds are represented by formula I: wherein R1 is selected from the group consisting of:A) alkyl of from 1 to 10 carbon atoms; B) alkenyl of from 2 to 10 carbon atoms and 1-2 sites of alkenyl unsaturation; C) alkynyl of from 2 to 10 carbon atoms and from 1-2 sites of alkynyl unsaturation; D) cycloalkyl of from 3 to 12 carbon atoms; E) cycloalkenyl of from 4 to 8 carbon atoms; F) substituted alkyl of from 1 to 10 carbon atoms, having from 1 to 3 substituents selected from: 1) alkoxy of from 1 to 10 carbon atoms; 2) substituted alkoxy of the formula substituted alkyl-Oâ€” where substituted alkyl is as defined in F herein; 3) cycloalkyl which is as defined in D herein; 4) substituted cycloalkyl is defined in 1 herein; 5) cycloalkenyl which is defined in E herein; 6) substituted cycloalkenyl which is defined in J herein; 7) acyl selected from alkyl-C(O)â€”, substituted alkyl-C(O)â€”, cycloalkyl-C(O)â€”, substituted cycloalkyl-C(O)â€”, aryl-C(O)â€”, heteroaryl-C(O)â€” and heterocyclic-C(O)â€” wherein alkyl is defined in A herein; wherein substituted alkyl is defined in F herein; wherein cycloalkyl is defined in D herein; wherein substituted cycloalkyl is defined in 1 herein; wherein aryl is defined in F22 herein; wherein heteroaryl is defined in F23 herein; and wherein heterocyclic is defined in F24 herein; 8) acylamino having the formula â€”C(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl is defined in A herein; wherein substituted alkyl is defined in F herein; wherein aryl is defined in F22 herein; wherein heteroaryl is defined in F23 herein; and wherein heterocyclic is defined in F24 herein; 9) acyloxy selected from alkyl-C(O)Oâ€”, substituted alkyl-C(O)Oâ€”, cycloalkyl-C(O)Oâ€”, aryl-C(O)Oâ€”, heteroaryl-C(O)Oâ€”, and heterocyclic-C(O)Oâ€” wherein alkyl is defined in A herein; wherein substituted alkyl is defined in F herein; wherein cycloalkyl is defined in D herein; wherein aryl is defined in F22 herein; wherein heteroaryl is defined in F23 herein; and wherein heterocyclic is defined in F24 herein; 10) amino; 11) aminoacyl having the formula â€”NRC(O)R wherein each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic; wherein alkyl is defined in A herein; wherein substituted alkyl is defined in F herein; wherein aryl is defined in F22 herein; wherein heteroaryl is defined in F23 herein; and wherein heterocyclic is defined in F24 herein; 12) aminoacyloxy having the formula â€”NRC(O)OR wherein each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclic; wherein alkyl is defined in A herein; wherein substituted alkyl is defined in F herein; wherein aryl is defined in F22 herein; wherein heteroaryl is defined in F23 herein; and wherein heterocyclic is defined in F24 herein; 13) cyano; 14) halogen; 15) hydroxyl; 16) carboxyl; 18) carboxylalkyl having the formula â€œâ€”C(O)Oalkylâ€  wherein alkyl is defined in A herein; 19) thiol; 20) thioalkoxy having the formula â€”S-alkyl, wherein alkyl is defined in A herein; 21) substituted thioalkoxy having the formula â€”S-substituted alkyl, wherein substituted alkyl is defined in F herein; 22) aryl having from 6 to 14 ring carbon atoms, optionally substituted with from 1 to 5 substituents selected from the group consisting of: a) hydroxy; b) acyl as defined in F7 herein; c) acyloxy as defined in F9 herein; d) alkyl as defined in A herein; e) substituted alkyl as defined in F herein; f) alkoxy as defined in F1 herein; g) substituted alkoxy as defined in F2 herein; h) alkenyl as defined in B herein; i) substituted alkenyl as defined in G herein; j) alkynyl as defined in C herein; k) substituted alkynyl as defined in H herein; l) amino; m) aminoacyl as defined in F11 herein; n) acylamino as defined in F8 herein; o) alkaryl of the formula -alkylene-aryl having 8 carbon atoms in the alkylene moiety and aryl is defined in F22 herein; p) aryl as defined in F22 herein; q) aryloxy having the formula â€”O-aryl wherein aryl is defined in F22 herein; r) azido; s) carboxyl; t) carboxylalkyl having the formula â€œâ€”C(O)Oalkylâ€  wherein alkyl is defined in A herein; u) cyano; v) halo selected from fluoro, chloro, bromo and iodo; w) nitro; x) heteroaryl as defined in F23 herein; y) heterocyclic as defined in F24 herein; z) aminoacyloxy as defined in F12 herein; aa) oxyacylamino having the formula â€”OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl is defined in A herein; wherein substituted alkyl is defined in F herein; wherein aryl is defined in F22 herein; wherein heteroaryl is defined in F23 herein; and wherein heterocyclic is defined in F24 herein; bb) thioalkoxy having the formula â€”S-alkyl, wherein alkyl is defined in A herein; cc) substituted thioalkoxy having the formula â€”S-substituted alkyl, wherein substituted alkyl is defined in F herein; dd) thioaryloxy having the formula â€”S-aryl wherein aryl is defined in F22 herein; ee) thioheteroaryloxy having the formula â€”S-heteroaryl wherein heteroaryl is defined F23 herein; ff) â€”SO-alkyl wherein alkyl is defined in A herein; gg) â€”SO-substituted alkyl wherein substituted alkyl is defined in F herein; hh) â€”SO-aryl wherein aryl is defined in F22 herein; ii) â€”SO-heteroaryl wherein heteroaryl is defined in F23 herein; jj) â€”SO2-alkyl wherein alkyl is defined in A herein; kk) â€”SO2-substituted alkyl wherein substituted alkyl is defined in F herein; ll) â€”SO2-aryl wherein aryl is defined in F22 herein; mm) â€”SO2-heteroaryl wherein heteroaryl is defined in F23 herein; nn) trihalomethyl wherein halo is defined in I20 herein; oo) mono- and dialkylamino wherein alkyl is defined in A herein; pp) mono- and di-substituted alkylamino wherein substituted alkyl is defined in F herein; qq) mono- and di-arylamino wherein aryl is defined in F22 herein; rr) mono- and di-heteroarylamino wherein heteroaryl is defined in F23 herein; ss) mono- and di-heterocyclicamino wherein heterocyclic is defined in F24 herein; tt) unsymmetric di-substituted amino having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic wherein alkyl is defined in A herein; wherein substituted alkyl is defined in F herein; wherein aryl is defined in F22 herein; wherein heteroaryl is defined in F23 herein; and wherein heterocyclic is defined in F24 herein; 23) heteroaryl of from 1 to 15 ring carbon atoms and 1 to 4 ring heteroatoms selected from oxygen, nitrogen and sulfur, optionally substituted with from 1 to 5 substituents selected from: a) alkyl as defined in A herein; b) substituted alkyl as defined in F herein; c) alkoxy as defined in F1 herein; d) substituted alkoxy as defined in F2 herein; e) aryl as defined in F22 herein; f) aryloxy having the formula â€”O-aryl wherein aryl is defined in F22 herein; g) halo selected from fluoro, chloro, bromo and iodo; h) nitro; i) heteroaryl as defined in F23 herein; j) thiol; k) thioalkoxy having the formula â€”S-alkyl, wherein alkyl is defined in A herein; l) substituted thioalkoxy having the formula â€”S-substituted alkyl, wherein substituted alkyl is defined in F herein; m) thioaryloxy having the formula â€”S-aryl wherein aryl is defined in F22 herein; and n) trihalomethyl wherein halo is defined in 120 herein; 24) heterocyclic of from 1 to 15 ring carbon atoms and from 1 to 4 ring atoms selected from nitrogen, sulfur and oxygen, optionally substituted with from 1 to 5 substituents selected from: a) alkyl as defined in A herein; b) substituted alkyl as defined in F herein; c) alkoxy as defined in F1 herein; d) substituted alkoxy as defined in F2 herein; e) aryl as defined in F22 herein; f) aryloxy having the formula â€”O-aryl wherein aryl is defined in F22 herein; g) halo selected from fluoro, chloro, bromo and iodo; h) nitro; i) heteroaryl as defined in F23 herein; j) thiol; k) thioalkoxy having the formula â€”S-alkyl, wherein alkyl is defined in A herein; l) substituted thioalkoxy having the formula â€”S-substituted alkyl, wherein substituted alkyl is defined in F herein; m) thioaryloxy having the formula â€”S-aryl wherein aryl is defined in F22 herein; and n) trihalomethyl wherein halo is selected from fluoro, chloro, bromo and iodo; 25) aryloxy of the formula â€”O-aryl wherein aryl is defined in F22 herein; 26) heteroaryloxy of the formula â€”O-heteroaryl wherein heteroaryl is defined in F23 herein; 27) hydroxyamino; 28) alkoxyamino wherein alkoxy is defined in F1 herein; 29) nitro; 30) â€”SO-alkyl wherein alkyl is defined in A herein; 31) â€”SO-substituted alkyl wherein substituted alkyl is defined in F herein; 32) â€”SO-aryl wherein aryl is defined in F22 herein; 33) â€”SO-heteroaryl wherein heteroaryl is defined in F23 herein; 34) â€”SO2-alkyl wherein alkyl is defined in A herein; 35) â€”SO2-substituted alkyl wherein substituted alkyl is defined in F herein; 36) â€”SO2-aryl wherein aryl is defined in F22 herein; 37) â€”SO2-heteroaryl wherein heteroaryl is defined in F23 herein; 38) mono- and dialkylamino wherein alkyl is defined in A herein; 39) mono- and di-substituted alkylamino wherein substituted alkyl is defined in F herein; 40) mono- and di-arylamino wherein aryl is defined in F22 herein; 41) mono- and di-heteroarylamino wherein heteroaryl is defined in F23 herein; 42) mono- and di-heterocyclicamino wherein heterocyclic is defined in F24 herein; 43) unsymmetric di-substituted amino having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic wherein alkyl is defined in A herein; wherein substituted alkyl is defined in F herein; wherein aryl is defined in F22 herein; wherein heteroaryl is defined in F23 herein; and wherein heterocyclic is defined in F24 herein; G) substituted alkenyl having from 1 to 3 substituents selected from the group consisting of: 1) alkoxy as defined in F1 herein; 2) substituted alkoxy as defined in F2 herein; 3) acyl as defined in F7 herein; 4) acylamino as defined in F8 herein; 5) acyloxy as defined in F9 herein; 6) amino; 7) aminoacyl as defined in F11 herein; 8) aminoacyloxy as defined in F12 herein; 9) cyano; 10) halogen selected from fluoro, chloro, bromo and iodo; 11) hydroxyl; 12) carboxyl; 13) carboxylalkyl as defined in F18 herein; 14) thiol; 15) thioalkoxy as defined in F20 herein; 16) substituted thioalkoxy as defined in F21 herein; 17) aryl as defined in F22 herein; 18) heteroaryl as defined in F23 herein; 19) heterocyclic as defined in F24 herein; 20) nitro; 21) â€”SO-alkyl wherein alkyl is defined in A herein; 22) â€”SO-substituted alkyl wherein substituted alkyl is defined in F herein; 23) â€”SO-aryl wherein aryl is defined in F22 herein; 24) â€”SO-heteroaryl wherein heteroaryl is defined in F23 herein; 25) â€”SO2-alkyl wherein alkyl is defined in A herein; 26) â€”SO2-substituted alkyl wherein substituted alkyl is defined in F herein; 27) â€”SO2-aryl wherein aryl is defined in F22 herein; 28) â€”SO2-heteroaryl wherein heteroaryl is defined in F23 herein; 29) mono- and dialkylamino wherein alkyl is defined in A herein; 30) mono- and di-substituted alkylamino wherein substituted alkyl is defined in F herein; 31) mono- and di-arylamino wherein aryl is defined in F22 herein; 32) mono- and di-heteroarylamino wherein heteroaryl is defined in F23 herein; 33) mono- and di-heterocyclicamino wherein heterocyclic is defined in F24 herein; and 34) unsymmetric di-substituted amino having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic wherein alkyl is defined in A herein; wherein substituted alkyl is defined in F herein; wherein aryl is defined in F22 herein; wherein heteroaryl is defined in F23 herein; and wherein heterocyclic is defined in F24 herein; H) substituted alkynyl of from 1 to 3 substituents selected from: 1) alkoxy as defined in F1 herein; 2) substituted alkoxy as defined in F2 herein; 3) acyl as defined in F7 herein; 4) acylamino as defined in F8 herein; 5) acyloxy as defined in F9 herein; 6) amino; 7) aminoacyl as defined in F11 herein; 8) aminoacyloxy as defined in F12 herein; 9) cyano; 10) halogen selected from fluoro, chloro, bromo and iodo; 11) hydroxyl; 12) carboxyl; 13) carboxylalkyl as defined in F18 herein; 14) thiol; 15) thioalkoxy as defined in F20 herein; 16) substituted thioalkoxy as defined in F21 herein; 17) aryl as defined in F22 herein; 18) heteroaryl as defined in F23 herein; 19) heterocyclic as defined in F24 herein; 20) nitro; 21) â€”SO-alkyl wherein alkyl is defined in A herein; 22) â€”SO-substituted alkyl wherein substituted alkyl is defined in F herein; 23) â€”SO-aryl wherein aryl is defined in F22 herein; 24) â€”SO-heteroaryl wherein heteroaryl is defined in F23 herein; 25) â€”SO2-alkyl wherein alkyl is defined in A herein; 26) â€”SO2-substituted alkyl wherein substituted alkyl is defined in F herein; 27) â€”SO2-aryl wherein aryl is defined in F22 herein; 28) â€”SO2-heteroaryl wherein heteroaryl is defined in F23 herein; 29) mono- and dialkylamino wherein alkyl is defined in A herein; 30) mono- and di-substituted alkylamino wherein substituted alkyl is defined in F herein; 31) mono- and di-arylamino wherein aryl is defined in F22 herein; 32) mono- and di-heteroarylamino wherein heteroaryl is defined in F23 herein; 33) mono- and di-heterocyclicamino wherein heterocyclic is defined in F24 herein; and 34) unsymmetric di-substituted amino having different substituents selected from alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic wherein alkyl is defined in A herein; wherein substituted alkyl is defined in F herein; wherein aryl is defined in F22 herein; wherein heteroaryl is defined in F23 herein; and wherein heterocyclic is defined in F24 herein; I) substituted cycloalkyl having 3 to 12 carbon atoms and from 1 to 5 substituents selected from the group consisting of: 1) hydroxy; 2) acyl as defined in F7 herein; 3) acyloxy as defined in F9 herein; 4) alkyl as defined in A herein; 5) substituted alkyl as defined in F herein; 6) alkoxy as defined in F1 herein; 7) substituted alkoxy as defined in F2 herein; 8) alkenyl as defined in B herein; 9) substituted alkenyl as defined in G herein; 10) alkynyl as defined in C herein; 11) substituted alkynyl as defined in H herein; 12) amino; 13) aminoacyl as defined in F11 herein; 14) alkaryl of the formula -alkylene-aryl having 8 carbon atoms in the alkylene moiety and aryl is defined in F22 herein; 15) aryl as defined in F22 herein; 16) aryloxy having the formula â€”O-aryl wherein aryl is defined in F22 herein; 17) carboxyl; 18) carboxylalkyl having the formula â€œâ€”C(O)Oalkylâ€  wherein alkyl is defined in A herein; 19) cyano; 20) halo selected from fluoro, chloro, bromo and iodo; 21) nitro; 22) heteroaryl as defined in F23 herein; 23) thioalkoxy as defined in F20 herein; 24) substituted thioalkoxy as defined in F21 herein; and 25) trihalomethyl wherein halo is selected from fluoro, chloro, bromo and iodo; J) substituted cycloalkenyl having from 4 to 8 carbon atoms and from 1 to 5 substituents selected from the group consisting of: 1) hydroxy; 2) acyl as defined in F7 herein; 3) acyloxy as defined in F9 herein; 4) alkyl as defined in A herein; 5) substituted alkyl as defined in F herein; 6) alkoxy as defined in F1 herein; 7) substituted alkoxy as defined in F2 herein; 8) alkenyl as defined in B herein; 9) substituted alkenyl as defined in G herein; 10) alkynyl as defined in C herein; 11) substituted alkynyl as defined in H herein; 12) amino; 13) aminoacyl as defined in F11 herein; 14) alkaryl of the formula -alkylene-aryl having 8 carbon atoms in the alkylene moiety and aryl is defined in F22 herein; 15) aryl as defined in F22 herein; 16) aryloxy having the formula â€”O-aryl wherein aryl is defined in F22 herein; 17) carboxyl; 18) carboxylalkyl having the formula â€œâ€”C(O)Oalkylâ€  wherein alkyl is defined in A herein; 19) cyano; 20) halo selected from fluoro, chloro, bromo and iodo; 21) nitro; 22) heteroaryl as defined in F23 herein; 23) thioalkoxy as defined in F20 herein; 24) substituted thioalkoxy as defined in F21 herein; and 25) trihalomethyl wherein halo is selected from fluoro, chloro, bromo and iodo; K) aryl as defined in F22 herein; L) heteroaryl as defined in F23 herein; M) heterocyclic as defined in F24 herein; â€ƒR2 is independently selected from the group consisting of: N) alkyl as defined in A herein; O) substituted alkyl as defined in F herein; P) alkenyl as defined in B herein; Q) substituted alkenyl as defined in G herein; R) alkynyl as defined in C herein; S) substituted alkynyl as defined in H herein; T) cycloalkyl as defined in D herein; U) aryl as defined in F22 herein; V) heteroaryl as defined in F23 herein; W) heterocyclic as defined in F24 herein; Zâ€² is represented by the formula â€”CXâ€²Xâ€³â€”, â€”Tâ€”CH2â€” or â€”Tâ€”C(O)â€” where T is selected from the group consisting of oxygen, sulfur, â€”NR5 where R5 is: X) hydrogen; Y) acyl as defined in F7 herein; Z) alkyl as defined in A herein; AA) aryl as defined in F22 herein; or BB) heteroaryl as defined in F23 herein; Xâ€² is hydrogen, hydroxy or fluoro, Xâ€³ is hydrogen, hydroxy or fluoro, or Xâ€² and Xâ€³ together form an oxo group; and Q is selected from the group consisting of: â€ƒwherein: â€ƒeach V is independently selected from the group consisting of: CC) hydroxy; DD) acyl as defined in F7 herein; EE) acyloxy as defined in F9 herein; FF) alkyl as defined in A herein; GG) substituted alkyl as defined in F herein; HH) alkoxy as defined in F1 herein; II) substituted alkoxy as defined in F2 herein; JJ) alkenyl as defined in B herein; KK) substituted alkenyl as defined in G herein; LL) alkynyl as defined in C herein; MM) substituted alkynyl as defined in H herein; NN) amino; OO) aminoacyl as defined in F11 herein; PP) alkaryl as defined in I14 hererin; QQ) aryl as defined in F22 herein; RR) aryloxy as defined in I16 herein; SS) carboxyl; TT) carboxylalkyl as defined in I18 herein; UU) cyano; VV) halo selected from fluoro, chloro, bromo and iodo; WW) nitro; XX) heteroaryl as defined in F23 herein; YY) thioalkoxy as defined in F20 herein; ZZ) substituted thioalkoxy as defined in F21 herein; and AAA) trihalomethyl wherein halo is selected from fluoro, chloro, bromo and iodo; â€ƒRa is selected from the group consisting of: BBB) alkyl as defined in A herein; CCC) substituted alkyl as defined in F herein; DDD) alkoxy as defined in F1 herein; EEE) substituted alkoxy as defined in F2 herein; FFF) amino; GGG) carboxyl; HHH) carboxylalkyl as defined in F18 herein; III) cyano; and JJJ) halo selected from fluoro, chloro, bromo and iodo; â€ƒRb is selected from the group consisting of: KKK) hydrogen; LLL) alkyl as defined in A herein; MMM) substituted alkyl as defined in F herein; NNN) alkenyl as defined in B herein; OOO) substituted alkenyl as defined in G herein; PPP) alkynyl as defined in C herein; QQQ) substituted alkynyl as defined in H herein; RRR) acyl as defined in F7 herein; SSS) aryl as defined in F22 herein; TTT) heteroaryl as defined in F23 herein; UUU) heterocyclic as defined in F24 herein; â€ƒt is an integer from 0 to 4; and â€ƒw is an integer from 0 to 3; â€ƒand pharmaceutically acceptable salts thereof; â€ƒwith the following proviso: â€ƒwhen R1 is cyclopropyl, R2 is â€”CH3, Zâ€² is â€”CH2â€”, then Q is not an N-methylcaprolactam group.