Patent FR-2941697-A1 (FR)
Title: New tagitinine derivatives are proteosome inhibitors useful for the treatment of cancer
Inventor: DERGUINI FADILA
IPC: A61K31/365
Filed: 2009-02-02
Abstract: Tagitinine derivatives (I) and their salts, isomers and mixtures of isomers in all proportions, preferably mixture of enantiomers, including a racemic mixture, are new. Tagitinine derivatives of formula (I) and their salts, isomers and mixtures of isomers in all proportions, preferably mixture of enantiomers, including a racemic mixture, are new. Dotted line : absent or single bond; dotted line with bond : single bond or double bond; A 1>C-H, C-OR 4>, C-SR 5>or CNR 15>R 16>, preferably C-OR 4>or C-SR 5>(when the dotted line with bond is single bond) or C (when the dotted line with bond is double bond); A 2>C (when the dotted line is single bond) or C-H, C-OR 6>, or C-SR 17>, preferably COR 6>(when the dotted line is absent); A 3>C=CH 2or CH-CH 2R 7>; R : CH 3, CH 2F, CF 3, CHF 2, CHO, CH 2OH, CH 2OR 8>, CH 2OCOR 8>or CH 2OC(O)NR 8>, preferably CH 3; either R 1>H (when the dotted line with bond between 1C and 2C is double bond) or H, OR 9>, SR 10>, or NR 11>R 12>(when the dotted line with bond between 1C and 2C is single bond); or R 1>R 6>a bond between C and O which forms an epoxide between 1C and 10C; either R 2>H or OR 13>; or R 2>R 6>a bond between C and O which forms an epoxide between 14C and 10C; R 3>-X-R 14>; X : CO, CON or bond; R 4>H or 1-6C alkyl optionally substituted by one or more halo; R 5>1-6C alkyl optionally substituted by OH or 1-6C alkoxy; either R 6>H, 1-6C alkyl (optionally substituted by one or more halo), aryl-1-6C-alkyl, or benzyloxy-1-6C alkyl (both optionally substituted by 1-6C alkoxy), -CO-1-6C alkyl or SiRaaRbbRcc; or R 1>R 6>a bond between the carbon atoms and oxygen which forms an epoxide ring between 1C and 10C; or R 2>R 6>a bond between the carbon atoms and oxygen which forms an epoxide ring between 14C and 10C; or R 14>R 6>group of formula ((CH 2) n-O-(CH 2) m); m, n : 1-3, preferably 1; R 7>H, OR 18>, SR 19>, or NR 20>R 21>, preferably OR 18>, SR 19>, or NR 20>R 21>; R 8>1-6C alkyl optionally substituted by one or more halo; R 18>, R 9>H, 1-6C alkyl (optionally substituted by one or more halo or OH), 1-6C alkoxy, aryl or -O-CO-1-6C alkyl; R 10>, R 17>, R 19>1-6C alkyl (optionally substituted by OH), 1-6C alkoxy or -O-CO-1-6C alkyl; either R 11>, R 12>H, OH, 1-6C alkyl, or aryl-1-6C alkyl, where R 11>and R 12>cannot represent OH at the same time; or NR 11>R 12>5 or 6 membered heterocycle optionally comprising one or more heteroatoms comprising O, S or N and optionally substituted by 1-6C alkyl; R 13>H, O-protecting group, 1-6C alkyl, CO-1-6C alkyl, SiRaaRbbRcc or -SO 2CF 3; R 14>benzyloxy1-6C alkyl, aryl or heteroaryl (all optionally substituted by one or more halo, 1-6C alkoxy, aryl or NR 22>R 33>), 1-6C alkyl, 1-6C epoxyalkyl, 2-6C alkenyl, 3-7C cycloalkyl, 3-7C cycloalkyl-1-6C alkyl, 5-10C polycycloalkyl, or aryl-1-6C alkyl; either R 15>, R 16>H, OH, 1-6C alkyl or aryl-1-6C alkyl, where R 15>and R 16>are not OH at the same time; or NR 15>R 16>5 or 6 membered heterocycle optionally comprising one or more heteroatoms comprising O, S or N and optionally substituted by 1-6C alkyl; either R 20>, R 21>H, OH, 1-6C alkyl or aryl-(1-6C) alkyl, where the R 20>and R 21>can not represent OH at the same time; or NR 20>R 21>5 or 6-membered heterocyclic ring, optionally containing, in addition to the nitrogen atom, one or more heteroatoms comprising O, S or N, and optionally substituted by 1-6C alkyl; R 22>, R 23>H or 1-6C alkyl; and Raa, Rbb, Rcc : 1-6C alkyl. Provided that (I) excludes: tagitinine C and tagitinine F; compound (in which A 2>-O is (C-O) (where the dotted line is single bond), the dotted line with bond is single bond, A 1>is C-OH or C-OCH 3, A 3>is CH=CH 2, R is CH 3, R 1>is OCH 3or OH, R 2>is H and R 3>is -COCH(CH 3) 2or -COCCH 3=CHCH 3); and compound (in which the dotted line is absent, (A 1>=O is C=O) the dotted line with bond between 1C and 2C is double bond, A 3>is CH=CH 2, R 1>and R 2>is H is OCH 3or OH, R is CH 3(R 3>is -COCH(CH 3) 2or -COCCH 3=CHCH 3) or CH 2OH (R 3>is -C(=O)-CCH 3=CH-CH 3)). Independent claims are included for: (1) the preparations of (I); (2) a composition comprising (I) in combination with a vehicle; (3) substituted tagitinine derivatives (III) of formula (IIIa) or (IIIb); and (4) preparation of (IIIa) (where R 1>is H, dotted line is single bond) from tagitinine C comprising: (a) optionally protecting the enone function in position 3 and/or protection of the double bond in C=CH 2position 11-13; (b) hydrolyzing isopropyl ester in position 8 to give the corresponding alcohol; (c) optionally deprotecting the enone function in position 3 and/or deprotection of the double bond in positions 11-13; and (d) isolating (IIIa) or (IIIb). R 1>H (when dotted line with bond is double bond) or OR 9>, SR 10>or NR 11>R 12>(when dotted line with bond is single bond); A 5>(C=O), CH-OH or CH-OGP1; GP1 : O-protecting group such as SiRaaRbbRcc; A 6>(C=CH 2) or CH-CH 2GP2; GP2 : a protective group of activated bonds such as imidazolyl or morpholinyl moiety; A 7>H, OH or OGP3; GP3 : O-protective group such as 1-6C alkyl or SiRddReeRff; and Rdd, Ree, Rff : 1-6C alkyl. [Image] [Image] ACTIVITY : Cytostatic. MECHANISM OF ACTION : Proteosome inhibitor.