| 摘要 |
Camptothecin (CT) oxepine analogue derivatives (I) are new: (a) CT analogues in which the hydroxy-lactone ring of CT is replaced by a beta -hydroxy-lactone (or the corresponding beta -hydroxy-acid obtained by opening the lactone ring), where the compound contains an optionally substituted oxazine ring grafted onto positions 10 and 11 of the 'A' ring; (b) CT analogues in which the hydroxy-lactone ring of CT is replaced by a beta -hydroxy-lactone protected by a readily cleavable protecting group (or the corresponding protected beta -hydroxy-acid obtained by opening the lactone ring); and (c) compounds of formula (I'), in racemic and/or enantiomeric form, and their salts. R1 = alkyl, alkenyl, alkynyl, haloalkyl, alkoxyalkyl or alkylthioalkyl; R2-R4 = H, halo, haloalkyl, alkyl, alkenyl, CN, cyanoalkyl, NO2, nitroalkyl, amido, amidoalkyl, hydrazino, hydrazinoalkyl, azido, azidoalkyl, (CH2)mQ, O(CH2)mNR6R7, OCONR6R7, OCO(CH2)mCOOR6, (CH2)nN=X, OCON=X, Ar or Ar-alkyl; or R3+R4 = chain consisting or 3 or 4 members selected from CH, CH2, O, S, N and NR9; Q = NR6R7, OR6, COOR6, NR6COR8, COR8, OCOR8 or OCON=X; R5 = H, halo, haloalkyl, alkyl, alkoxy, alkoxyalkyl, alkylthioalkyl, cycloalkyl, cycloalkylalkyl, CN, cyanoalkyl, alkylsulphonylalkyl, hydroxyalkyl, NO2, (CH2)mQ', (CH2)2P(S)R12R13, (CH2)nN=X, OCON=X, Ar or Ar-alkyl; Q' = COR8, NR6COR8, NR6R7, N(Me)(CH2)nNR6R7, OCOR8, OCONR6R7, S(O)qR11, P(O)R12R13 or OCON=X; X = chain of O, S, CH2, CH, N, NR9 and COR10 units, completing a 4-7 membered heterocycle; R6, R7 = H, alkyl, hydroxyalkyl, alkylaminoalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkoxyalkyl, haloalkyl, Ar or Ar-alkyl; R8 = H, alkyl, hydroxyalkyl, NH2, alkylamino, alkylaminoalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkoxy, alkoxyalkyl, haloalkyl, Ar or Ar-alkyl; R9 = H, alkyl, haloalkyl or Ar; R10 = H, alkyl, haloalkyl, alkoxy or Ar; R11 = alkyl, aryl, (CH2)mOR14, (CH2)mSR14, (CH2)2NR14R15 or (CH2)mN=X; R12, R13 = alkyl, aryl, alkoxy, aryloxy or NH2; R14, R15 = H, alkyl or aryl; R16 = H or OR21; R17 = OR6 or NR6R7; or R16+R17 = O (completing a fused oxepino ring); R18, R19 = H, halo, alkyl, alkoxy or OH; R20 = H or halo; R21 = H, alkyl, CHO or CO(CH2)mMe; Rp = H or readily cleavable group, preferably CO-A-NR22R23; A = alkylene (not restricted to 'lower'), optionally substituted by OH (optionally esterified or salified), halo, COOH (optionally esterified or salified), NH2 or mono- or dialkylamino (not restricted to 'lower'); R22, R23 = H, alkyl, hydroxyalkyl, alkylaminoalkyl, aminoalkyl, cycloalkyl, cycloalkylalkyl, alkenyl, alkoxyalkyl, haloalkyl, Ar or Ar-alkyl; or NR22R23 = 5-7 membered ring (optionally substituted and optionally containing a further O, N or S heteroatom); m = 0-6; n = 1 or 2; q = 0-2; Ar = aryl (optionally substituted by 1-4 of alkyl, halo, NO2, NH2, alkylamino, haloalkyl, hydroxyalkyl, alkoxy and alkoxyalkyl); all alkyl, alkenyl and alkynyl moieties are 'lower', i.e. up to 6C; provided that if Rp = H, then R3+R4 form a 3- or 4-membered chain. |
