Patent EP-2172457-A2 (EP)
Inventor: ABEL ULRICH
IPC: C07D405/12
Filed: 2003-03-20
Abstract: Ring A-derivatized fredericamycin derivatives (I) are new. Fredericamycin derivatives (I) of formula (IA) or (IB) and their stereoisomers, tautomers, salts and inclusion compounds are new. [Image] R 1H, alkyl, cycloalkyl or 1-4C alkyl-cycloalkyl; R 2H, 1-14C alkyl, 2-14C alkenyl, aryl, 1-4C alkyl-aryl, heteroaryl, 1-4C alkyl-heteroaryl, 2-4C alkenyl-heteroaryl, cycloalkyl, 1-4C alkyl-cycloalkyl, heterocycloalkyl, 1-4C alkyl-heterocycloalkyl, -C mH 2 m + o - pY' p, -(CH 2) r-CH 2-Q 1, -(CH 2) r-CHO, -(CH 2) r-CH(OH)-R 2 1, -(CH 2) r-CH=N-Q 2, -(CH 2) r-CH=CR 2 4R 2 5 (cis or trans), -(CH 2) r-COOH, -(CH 2) r-COOR 2 1, -(CH 2) r-CONR 2 1R 2 2 or heterocyclic group of formula (a); m : 1-6 when o = 1; 2-6 when o = -1; 4-6 when o = -2; p : 1 to 2m + o; Y' : halo, OH, OR 2 1, NH 2, NHR 2 1, NR 2 1R 2 2, SH or SR 2 1; Q 1NHCOR 2 1, OCOR 2 1, NHCSR 2 1 or S(O) nR 2 1; n : 0-2; Q 2OH, OR 2 1, OCOR 2 1, OCH2CONR 2 1R 2 2, OCHMeCONR 2 1R 2 2, OCMe 2CONR 2 1R 2 2, NHCOR 2 3, NHCONHR 2 3, NHCSNHR 2 3, NHC(=NH)NHR 2 3, NHC(=NH)R 2 3, NHCOCH 2NHCOR 2 1, OCH 2NHCOR 2 1, NHCSR 2 3, R 2 1, NR 2 1R 2 2, NHSO 2-aryl or NHSO 2-heteroaryl; X' : NR 2 1 5, O or S; R 2 1 1 - R 2 1 5H or alkyl; r : 0-5 (preferably 0); R 2 1, R 2 2H, 1-14C alkyl, 1-14C alkanoyl, hydroxyalkyl, alkoxy, alkylamino, mono- or dialkylaminoalkyl, cycloalkyl, 1-4C alkyl-cycloalkyl, heterocycloalkyl, 1-4C alkyl-heterocycloalkyl, aryl, aroyl, 1-4C alkyl-aryl, heteroaryl, heteroaroyl, 1-4C alkyl-heteroaryl, cycloalkanoyl, 1-4C alkanoyl-cycloalkyl, heterocycloalkanoyl, 1-4C alkanoyl-heterocycloalkyl, 1-4C alkanoyl-aryl, 1-4C alkanoyl-heteroaryl or mono- or disaccharide residue (bonded via a hydroxylated C-atom of the sugar; and where each saccharide unit is selected from glucuronic acid (or its stereoisomers), aldopentoses, aldohexoses and corresponding deoxy compounds, e.g. glucose, desoxyglucose, ribose or desoxyribose); or NR 2 1R 2 24-8 membered ring, optionally containing a further N, O or S heteroatom; R 2 3as R 2 1; or -CH 2-pyridinium salt, -CH 2-trialkylammonium salt, CONH 2, CSNH 2, CN or CH 2CN; R 2 4, R 2 5as R 2 1; or H, CN, COMe, COOH, COOR 2 1, CONR 2 1R 2 2, NH 2 or NHCOR 2 1; or NR 2 4R 2 5ring as defined for NR 2 1R 2 2; R 3H, halo, OH, OR 3 1, NO 2, NH 2, NHR 3 1, NR 3 1R 3 2, NHCHO, NHCOR 3-1, NHCOCF 3, CH 3 - mHal m or OCOR 3 1; Hal : F or Cl, preferably F; R 3 1, R 3 2alkyl; or NR 3 1R 3 2ring as defined for NR 2 1R 2 2; R 5H, 1-20C alkyl, cycloalkyl, 2-20C alkenyl, 2-10C alkynyl, 1-4C alkyl-cycloalkyl, aryl, 1-4C alkyl-aryl, heteroaryl, 1-4C alkyl-heteroaryl, -C mH 2 m + o - pY' p, -(CH 2) r-CH 2-NHCOR 2 1, -(CH 2) r-CH 2-NHCSR 2 1, -(CH 2) r-CH 2-S(O) nR 2 1, -(CH 2) r-CH 2-SCOR 2 1, -(CH 2) r-CH 2-OCOR 2 1, -(CH 2) r-CH 2-OSO 2R 2 1, -(CH 2) r-CH(OH)-R 2 1, -(CH 2) r-COOH, -(CH 2) r-COOR 2 1, -(CH 2) r-CONR 2 1R 2 2 or a mono- or disaccharide residue as defined for R 2 1; R 4, R 6, R 7H, alkyl or COR 2 1; X : O, S, NH or NR 8; R 8as R 8; or NR 5R 8ring as defined for NR 2 1R 2 2; or X-R 5H; Y : O, S or NR 9; and R 9H or alkyl. The following compounds (I') are excluded as new compounds, unless they are in cyclodextrin inclusion compound form: (1) (IA; R 1 = H or alkyl; R 2 = alkyl or 2-6C alkenyl; R 3 = H; R 4, R 6 (identical) = H, alkyl, CO-alkyl or CO-aryl; R 7 = H or alkyl; Y= O) and (2) (IB; R 1, R 3, R 4, R 6 = H; R 2 = pentyl, 1-pentenyl, 3-pentenyl or 1,3-pentadienyl; XR 5 = OMe; Y = O). Alkyl moieties have 1-6C unless specified otherwise. [Image] ACTIVITY : Cytostatic; Antiparasitic; Immunosuppressive; Dermatological; Antiinflammatory; Antimicrobial. Potassium (8S)-4',9,9'-trihydroxy-6'-methoxy-1,1',3',5',8'-pentaoxo-1,1',2,3',5',6,7,8-octahydro-spiro-(cyclopenta (g) isoquinoline-8.2'-cyclopenta (b) napthalene)-3-carboxylate (Ia) had an average IC 7 0 against 12 cancer cell lines of 0.005 Microg/ml, compared with 0.279 Microg/ml for fredericamycin and 0.0210 Microg/ml for adriamycin. MECHANISM OF ACTION : Topoisomerase I and/or II inhibitor.