Rapamycin hydroxyesters, process for their preparation and...

C - Chemistry – Metallurgy – 07 – H

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C07H 19/01 (2006.01) A61K 31/70 (2006.01) C07D 498/18 (2006.01) C07H 23/00 (2006.01)

Patent

CA 2187024

A compound of structure (I) wherein R1 and R2 are each, independently, hydrogen or -CO(CR3R4)b(CR5R6)dCR7R8R9; R3 and R4 are each, independently, hydrogen, alkyl, alkenyle, alkynyl, trifluoromethyl, or -F; R5 and R6 are each, independently, hydrogen, alkyl, alkenyl, alkynyl, -(CR3R4)fOR10, -CF3, - F, or -CO2R11, or R5 and R6 may be taken together to form X or a cycloalkyl ring that is optionally mono-, di-, or tri-substituted with -(CR3R4)fOR10; R7 is hydrogen, alkyl, alkenyl, alkynyl, -(CR3R4)fOR10, -CF3, -F, or -CO2R11; R8 and R9 are each, independently, hydrogen, alkyl, alkenyl, alkynyl, - (CR3R4)fOR10, -CF3, -F, or -CO2R11, or R8 and R9 may be taken together to form X or a cycloalkyl ring that is optionally mono-, di-, or tri-substituted with - (CR3R4)fOR10; R10 is hydrogen, alkyl, alkenyl, alkynyl, tri-(alkyl)silyl, tri- (alkyl)silylethyl, triphenylmethyl, benzyl, alkoxymethyl, tri- (alkyl)silylethoxymethyl, chloroethyl, or tetrahydropyranyl; R11 is hydrogen, alkyl, alkenyl, alkynyl, or phenylalkyl; X is 5-(2,2-dialkyl)[1,3]dioxanyl, 5- (2-spiro-cycloalkyl)[1,3]dioxanyl, 4-(2,2-dialkyl)[1,3]dioxanyl, 4-(2-spiro- cycloalkyl)[1,3]dioxanyl, 4-(2,2-dialkyl)[1,3]-dioxalanyl, or 4-(2-spiro- cycloalkyl)[1,3]dioxalanyl; b = 0-6; d = 0-6; and f = 0-6 with the proviso that R1 and R2 are both not hydrogen and further provided that either R1 or R2 contains at least one -(CR3R4)fOR10, X, or -(CR3R4)fOR10 substituted cycloalkyl group, or a pharmaceutically acceptable salt thereof which is useful as an immunosuppressive, antiinflammatory, antifungal, antiproliferative, and antitumor agent.

Composé de structure (I) dans lequel: R?1¿ et R?2¿ sont chacun indépendamment hydrogène ou -CO(CR?3¿R?4¿)¿b?(CR?5¿R?6¿)¿d?CR?7¿R?8¿R?9¿; R?3¿ et R?4¿ sont chacun indépendamment hydrogène, alkyle, alcényle, alcynyle, trifluorométhyle ou -F; R?5¿ et R?6¿ sont chacun indépendamment hydrogène, alkyle, alcényle, alcynyle, -(CR?3¿R?4¿)¿f?OR?10¿, -CF¿3?, -F ou -CO¿2?R?11¿, ou bien R?5¿ et R?6¿ peuvent être réunis pour former X ou un cycle cycloalkyle pouvant optionnellement être mono, di ou tri-substitué par -(CR?3¿R?4¿)¿f?OR?10¿; R?7¿ est hydrogène, alkyle, alcényle, alcynyle, -(CR?3¿R?4¿)¿f?OR?10¿, -CF¿3?, -F ou CO¿2?R?11¿; R?8¿ et R?9¿ sont chacun indépendamment hydrogène, alkyle, alcényle, alcynyle, -(R?3¿R?4¿)¿f?OR?10¿, -CF¿3?, -F ou CO¿2?R?11¿, ou bien R?8¿ et R?9¿ peuvent être réunis pour former X ou un cycle cycloalkyle pouvant optionnellement être mono, di ou tri-substitué par -(CR?3¿R?4¿)¿f?OR?10¿; R?10¿ est hydrogène alkyle, alcényle, alcynyle, tri-(alkyl)silyle, tri-(alkyl)silyléthyle, triphénylméthyle, benzyle, alcoxyméthyle, tri-(alkyl)silyléthoxyméthyle, chloroéthyle, ou tétrahydropyranyle; R?11¿ est hydrogène alkyle, alcényle, alcynyle ou phénylalkyle; X est 5-(2,2-dialkyl)[1,3]dioxanyle, 5-(2-spiro-cycloalkyl)[1,3]dioxanyle, 4(2,2-dialkyl)[1,3]dioxanyle, 4(2-spiro-cycloalkyl)[1,3]dioxanyle, 4(2,2-dialkyl)[1,3]dioxalamyle, 4(2-spiro-cycloalkyl)[1,3]dioxalamyle; b = 0-6; d = 0-6; et f = 0-6 sous réserve que R?1¿ et R?2¿ ne soient ni l'un ni l'autre hydrogène et que R?1¿ et R?2¿ contiennent au moins un -(CR?3¿R?4¿)¿f?OR?10¿, un X ou un groupe cycloalkyle à substitution -(CR?3¿R?4¿)¿f?OR?10¿ ou un de leurs sels pharmaceutiquement acceptables servant d'immunosuppresseur, d'anti-inflammatoire, d'antifongique, d'antiproliférant, et d'antitumoral.

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