| 摘要 |
<p>1,2,3,14-Tetrahydro- or 3,14-dihydro-7H-benzo-(a)-pyrano-(3,2-h)-acridin-7-one derivatives (I) are new. Pentacyclic acridone derivatives of formula (I) and their enantiomers, diastereomers, N-oxides and acid or base addition salts are new. [Image] X, Y : H, halo, OH, alkoxy, NO 2, CN, alkyl, 2-6C alkenyl, polyhaloalkyl or NR aR b; R a, R bH, COCF 3, CONH 2 or alkyl (optionally substituted (os) by NR' aR' b); or NR aR b = Het; R' a, R' bH, alkyl or aralkyl; or NR' aR' bHet; R 1H or alkyl; R 2H, alkyl, OR'' a, NR' aR' b, -O-T a-OR'' a, -NR'' a-T a-NR' aR' b, -NR'' a-CO-Ta-H, -O-CO-T a-H, -O-T a-NR' aR' b, -NR'' a-T a-OR'' a, -NR'' a-T a-COOR'' a or -NR'' a-CO-T a-NR' aR' b; T a1-6C alkylene; R'' aH or alkyl; R 3, R 4H or alkyl; or CR 3R 43-6 membered monocyclic ring (e.g. cycloalkyl); A : -CHR 5-CHR 6-, -CH=C(R 7)-, -C(R 7)=CH-, -CO-CH(R 8)- or -CH(R 8)-CO-; R 5, R 6H, OR c, NR cR d, SR c, -W 1-C(W 2)-U-V, -W 1-C(W 2)-W 3-T 1, -W 1-S(O) n-W 3-T 1, -W 1-S(O) n-U'-V' or -C(W 2)-T 1; or R 5 + R 6-O-C(Z)-O-, -NH-C(Z)-O-, -O-C(Z)-NH-, -NH-C(Z)-NH-, -O-(CH 2) m-O-, -O-C(O)-B-CO-O-, -NH-C(O)-B-CO-O-, -O-C(O)-B-CO-NH-, O, NH or N(alkyl); R c, R dH, alkyl, aryl, aralkyl or -CO-R e; R eH, aryl or NR''' aR''' b; R''' a, R''' bH or alkyl; or NR''' aR''' bHet; W 1O, S or NR c; W 2, Z : O or S; U : 1-8C alkylene or 2-8C alkenylene; or may also be a direct bond if W 2 is S and V is other than H, aryl or NH 2; V : H, aryl, OR c, COOR c, CONR' aR' b, NR' aR' b, N(R c)COOR' c or N(R c)COR' c; R' cH, alkyl, aryl or aralkyl; W 3O, S or NR c; T 1H, aryl or aralkyl; or alkyl or 2-6C alkenyl (both os by OR c or NR' aR' b); n : 1 or 2; U' : 1-8C alkylene or 2-8C alkenylene; V : H, aryl, OR c, COOR c, COR c, CONR' aR' b, NR' aR' b, N(R c)COOR' c or N(R c)COR' c; m : 1-4; B : direct bond, 1-6C alkylene or 2-6C alkenylene; R 7H, OR'' a, -W 1-C(W 2)-U-V, -W 1-C(W 2)-W 3-T 1, -W 1-S(O) n-W 3-T 1, -W 1-S(O) n-U'-V' or -C(W 2)-T 1; R 8H, alkylcarbonyloxy or OR'' a; aryl moieties : phenyl or naphthyl (both os by one or more of OH, halo, COOH, NO 2, NH 2, mono- or dialkylamino, aloxy, 1-6C acyl and/or alkylcarbonyloxy); Het : 5-7 membered monocyclic heterocycle (optionally containing a second O or N heteroatom), e.g. pyrrolidinyl, isoxazolidinyl, oxazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, oxazinanyl, morphol;inyl, hexahydropyridazinyl, hexahydropyrimidinyl, piperazinyl, azepanyl, oxazepanyl or diazepanyl; alkyl moieties have 1-6C unless specified otherwise. Independent claims are included for the preparation of (I). ACTIVITY : Cytostatic. In tests in mice with transplanted C38 colon adenocarcinoma, ()-cis-1,2-diacetoxy-6-methoxy-3,3,14-trimethyl-1,2,3,14-tetrahydro-7H-benzo-(a)-pyrano-(3,2-h)-acridin-7-one (Ia) at the optimum dose of 4 mg/kg i.v. (administered twice on days 12 and 22) inhibited tumor growth by 95% (T/C = 5%). For comparison, acronycin at the optimum dose of 100 mg/kg gave a T/C value of 27%. MECHANISM OF ACTION : Specific cell cycle blocker.</p> |
