C - Chemistry – Metallurgy – 07 – D
Patent
C - Chemistry, Metallurgy
07
D
C07D 305/14 (2006.01) A61K 9/10 (2006.01) A61K 9/127 (2006.01) A61K 31/337 (2006.01)
Patent
CA 2231750
Provided herein is a taxane having the formula: (see formula I) wherein: A1 is H or a group having the formula Z-C(O)NHCH(C6H5)CH(OR)-C(O)-, A2 is H or CH3C(O)- and A3 is H or OH; Z is C6H5-, C6H5CH2-O-, C(CH3)3-O- or CH(CH3)=C(CH3)-; each of R and R1 is H or a group having the formula Y1Y2, provided that at least one of R and R1 is not H; Y1 is -C(O)CHX1(CH2)n1(CH=CH)n2(CH2)n3(CH=CH)n4(CH2)n5 (CH=CH)n6(CH2)n7(CH=CH)n8(CH2)n9-: the sum of n1 + 2n2 + n3 + 2n4 + n5 +2n6 + n7 + 2n8 + n9 is an integer of from 1 to 21, each of n2, n4, n6 and n8 is independently zero or 1, n1 is zero or an integer of from 1 to 21, n3 is zero or an integer of from 1 to 18, n5 is zero or an integer of from 1 to 15, n7 is zero or an integer of from 1 to 12, n9 is zero or an integer of from 1 to 9 and each of n1 to n9 can be the same or different at each occurrence; X1 is an hydrolysis-promoting group which exhibits an electronegativity greater than hydrogen; and Y2 is -CH3, -CO2H or -CH2OH which has a hydrocarbon attached at the 2' and/or 7 positions, the hydrocarbons alpha position being occupied by a "hydrolysis-promoting group" ("HPG"). Substitution of an HPG for the methylene unit ordinarily occupying the alpha position allows for enhanced in vivo hydrolysis of the hydrocarbon-taxane bond, and hence, for enhanced taxane therapeutic activity. Also provided herein are taxane-containing compositions, and uses of those compositions for treating animals, including those afflicted with cancers, and also the use of the compositions for the manufacture of a medicament for the treatment of cancer.
L'invention se rapporte à un taxane possédant un hydrocarbure fixé aux positions 2' et/ou 7, la position alpha de l'hydrocarbure étant occupée par un "groupe favorisant l'hydrolyse". La substitution d'un groupe favorisant l'hydrolyse au motif méthylène occupant généralement la position alpha permet d'améliorer l'hydrolyse in vivo de la liaison hydrocarbure-taxane, et par conséquent, l'activité thérapeutique du taxane. L'invention se rapporte également à des compositions contenant des taxanes et à des procédés d'administration de taxanes à des animaux, y compris ceux atteints de cancers.
Ali Shaukat
Janoff Andrew S.
Mayhew Eric
Cephalon Limited
Osler Hoskin & Harcourt Llp
The Liposome Company Inc.
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