Patent EP-2163552-A1 (EP)
Title: Indole derivatives and their use as antitumor agents
Inventor: EMIG PETER
IPC: C07D401/12
Filed: 2001-07-26
Abstract: N-Substituted or N,N-disubstituted indol-3-yl-glyoxylamide derivatives (I) are new. Indole derivatives of formula (I), including their tautomers and stereoisomers (specifically diastereomers and enantiomers) and salts are new. [Image] R : H, alkyl (optionally substituted (os) by one or more aryl, itself os by 1-5 of halo, alkyl, cycloalkyl, COOH, alkoxycarbonyl (preferably tert. butoxycarbonyl), mono- or polyfluoroalkyl (preferably CF 3), OH, alkoxy (preferably OMe or OEt), benzyloxy or arylalkyl (os by 1-5 of alkyl, halo or mono- or polyfluoroalkyl)), alkoxyalkyl, os aralkoxycarbonyl (preferably benzyloxycarbonyl), alkylcarbonyl (preferably COMe), 2-6C alkenyl (preferably CH 2CH=CH 2), 2-6C alkynyl (preferably CCH or CH 2CCH) or cyanoalkyl (preferably CH 2CN); R 1saturated, unsaturated or aromatic 2-10C heteroaryl (containing one or more of O, N and S as heteroatom(s)), bonded directly or via a 1-6C alkyl bridge, where a 1-4C alkyl residue is os by one or more of alkyl, halo or =O, and a 2-, 4-, 5- or 6-pyrimidinyl residue is os by 1-3 of alkyl, halo, NO 2, NH 2, mono- or dialkylamino, OH, alkoxy, OCH 2Ph, COOH, alkoxycarbonyl, alkoxycarbonylamino, mono- or polyfluoroalkyl (preferably CF 3), 6-10C aryl or (6-10C) aryl-alkyl; R 2H, or alkyl (os by one or more halo or by one or more Ph'), 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl-alkyl (os in the ring by 1-6 of halo, T or OT), 2-, 3- or 4-pyridylalkyl (os in the ring by 1-4 of halo, T or OT) or arylcarbonyl (os in the ring by 1-5 of halo, alkyl, cycloalkyl, COOH, CN, alkoxyycarbonyl, mono- or polyfluoroalkyl (preferably CF 3), OH, OT (preferably OMe or OEt) or aryl-(1-4C) alkoxy (preferably OCH 2Ph)); Ph' : phenyl (os by 1-5 of halo (preferably Cl, Br or I), alkyl, cycloalkyl, COOH, alkoxycarbonyl, mono- or polyhaloalkyl (preferably CF 3), OH, alkoxy (preferably OMe or OEt), phenylalkoxy (preferably OCH 2Ph), NO 2, NH 2, mono- or dialkylamino, mono- or di-(3-6C cycloalkyl)-amino, 1-6C acylamino, phenylalkylamino, arylcarbonylamino, heteroarylcarbonylamino, alkylsulfonamide, arylsulfonamido, maleimido, succinimido, phthalimido, NHCOOCH 2Ph, NHCOOCMe 3, 9-fluorenylmethoxycarbonylamino, NHCPh 3, 2-(4-pyridyl)-ethoxycarbonylamino, NHSiPh 2Me, NHCH 2COOH, NHCHMeCOOH, Me 2CH(CH 2) 2CH(NH) COOH, MeCH 2CHMeCH(NH)COOH, HOCH 2CH(NH)COOH, PhCH 2CH(NH)COOH, (4-imidazolyl)-CH 2CH(NH)COOH, HN=C(NH 2)NH(CH 2) 3CH(NH)COOH, H 2N(CH 2) 4CH(NH)COOH, H 2NCOCH 2CH(NH)COOH or HOOC(CH 2) 2CH(NH)COOH); T : 1-4C alkyl; R 3, R 4 (bonded to either ring) : H, OH, alkyl, cycloalkyl, alkylcarbonyl, alkoxy, halo, aryl-(1-4C) alkoxy (preferably OCH 2Ph), NO 2, NH 2, NHT, NT 2, alkoxycarbonylamino, alkoxycarbonylaminoalkyl, CN, cyanoalkyl, COOH, COOT, 1-4C mono- or polyfluoroalkyl (preferably CF 3), carboxyalkyl or alkoxycarbonylalkyl; Z 1O, S or (H,OH); and Z 2O or S; provided that R 1 is not unsubstituted 2- or 4-pyrimidinyl, mono- or polymethyl-2-pyrimidinyl, 2-, 3-, 4- or 8-quinolyl (os by alkyl, halo, NO 2, NH 2 or alkylamino) or 2-, 3- or 4-quinolylmethyl (in which the pyridylmethyl moiety is os by alkyl, alkoxy, NO 2, NH 2 or alkoxyamino). Unless specified otherwise alkyl moieties have 1-6C and cycloalkyl moieties 3-7C. An independent claim is included for the preparation of (I). ACTIVITY : Cytostatic. In tumor cell growth inhibition tests in vitro, N-(2-methyl-6-quinolyl)-(1-(4-chlorobenzyl)-indol-3-yl)-glyoxylamide (Ia) had IC 50 values of 0.17 MicroM, 0.17 MicroM, 0.26 MicroM and 0.35 MicroM against KB/Heal (human cervical cancer), SKOVs (human ovarian cancer) cells, MCF7 (human breast cancer) cells and L1210 (murine leukemia) cells respectively. MECHANISM OF ACTION : None given.