Tosylproline analogs as thymidylate synthase inhibitors

Details Tosylproline analogs as thymidylate synthase inhibitors Tosylproline analogs as thymidylate synthase inhibitors

C - Chemistry, Metallurgy

07

D

C07D 207/48 (2006.01) A61K 31/401 (2006.01) A61K 31/445 (2006.01) A61P 31/04 (2006.01) A61P 31/12 (2006.01) A61P 33/00 (2006.01) C07D 211/96 (2006.01)

Patent

CA 2398752

Tosylproline analogs of formula (I), where R1 is -COOH, -CONH2, -SO3H, - SO2NH2, -PO3H2; R2 is C1-16 alkyl optionally substituted with -COOH, -CONH2, - CONHR3, -CONHCOR4, -CONHSO2R4, -SO3H, -SO2NH2, -SO2NHR3, -SO2NHCOR4, - SO2NHSO2R4, -PO3H2, -4-(1,2,3-triazolyl), -5-tetrazolyl, -5-(3-oxo-1,2,4- triazolyl), -S(O)m-4-(1,2,3-triazolyl), -S(O)m-5-tetrazolyl, or -S(O)m-5-(3- oxo-1,2,4-triazolyl); R3 is a group such that R3-NH2 is an amino acid; R4 is C1-4 alkyl, trifluoromethyl, or phenyl optionally substituted with methyl, trifluoromethyl, or nitro; m is 0, 1, or 2; each X and Y, which may be the same or different, is independently selected from methyl, ethyl, isopropyl, ethenyl, ethynyl, fluoro, chloro, bromo, methylthio, hydroxy, methoxy, carboxy, and methoxycarbonyl; n is 0, 1, 2, or 3; p is 0, 1, or 2; q is 1 or 2; R5 is -COOH, -CONH2, -CONHR2, -SO3H,-SO2NH2, -SO2NHR2, or -PO3H2, as an individual stereoisomer or mixture of stereoisomers, or a pharmaceutically acceptable salt or ester thereof, methods of making them, pharmaceutical compositions containing them, and methods for their use. The compounds are thymidylate synthase inhibitors; and are useful as anti-tumor agents and as anti-parasitics, anti-bacterials, anti-fungals, and anti-virals.

L'invention concerne des analogues de tosylproline représentés par la formule (I), dans laquelle: R?1¿ désigne -COOH, -CONH¿2?, -SO¿3?H, -SO¿2?NH¿2?, -PO¿3?H¿2?; R?2¿ représente un C¿1-16?alkyle éventuellement substitué par -COOH, -CONH¿2?, -CONHR?3¿, -CONHCOR?4¿, -CONHSO¿2?R?4¿, -SO¿3?H, -SO¿2?NH¿2?, -SO¿2?NHR?3¿, -SO¿2?NHCOR?4¿, -SO¿2?NHSO¿2?R?4¿, -PO¿3?H¿2?, -4-(1,2,3-triazolyle), -5-tétrazolyle, -5-(3-oxo-1,2,4-triazolyle), -S(O)¿m?-4-(1,2,3-triazolyle), -S(O)¿m?-5-tétrazolyle, ou -S(O)¿m?-5-(3-oxo-1,2,4-triazolyle); R?3¿ représente un groupe tel que R?3¿-NH¿2? Soit un amino acide; R?4¿ désigne un C¿1-4? alkyle, trifluorométhyle, ou phényle éventuellement substitué par un méthyle, trifluorométhyle, ou nitro; m désigne 0, 1, ou 2; chacun de X et Y, qui peuvent être identiques ou différents, est indépendamment choisi parmi méthyle, éthyle, isopropyle, ethenyle, éthynyle, fluoro, chloro, bromo, méthylthio, hydroxy, méthoxy, carboxy et méthoxycarbonyle; n désigne 0, 1, 2, ou 3; p représente 0, 1 ou 2; q représente 1 ou 2; R?5¿ désigne COOH, -CONH¿2?, -CONHR?2¿, -SO¿3?H, -SO¿2?NH¿2?, -SO¿2?NHR?2¿ ou -PO¿3?H¿2?, comme stéréoisomère simple ou mélange de stéréoisomères, ou comme un sel ou un ester pharmaceutiquement acceptable dudit composé. L'invention concerne également des procédés de fabrication de ces composés, des compositions pharmaceutiques les renfermant et leurs méthodes d'utilisation. Les composés selon l'invention, qui sont des inhibiteurs de la thymidylate synthase, sont donc utiles comme agents antitumoraux et comme agents antiparasitiques, antibactériens, antifongiques et antiviraux.

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