Analogues of n-acetylardeemin, method of preparation and...

C - Chemistry – Metallurgy – 07 – D

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C07D 487/22 (2006.01) A61K 31/505 (2006.01) A61K 31/519 (2006.01) A61K 31/70 (2006.01)

Patent

CA 2209775

The present invention provides a compound having structure (I) wherein R1, R6 and R7 are independently hydrogen, OH, NH2. SH, halogen, C1-C9 linear or branched chain alkyl, alkylmercapto, alkylamino, dialkylamino, alkoxy, phenyl, etc; wherein R0 and R2 are independently hydrogen, OH, linear or branched chain alkyl, -CR3R3-CH(O)CH2, -CR3R3-CH2CH3, -CR3R3- CH2CH2OH, -CR3R3-CH(OH)R4 or -CR3R3-CH-CHR4, wherein R3 and R4 are independently hydrogen, halogen, C1-C9 linear or branched chain alkyl, phenyl, etc; wherein R5 is hydrogen, C1-C9 linear or branched chain alkyl, phenyl, etc; an wherein R8 is hydrogen C1-C9 linear or branched chain acyl, benzoyl, etc; with the proviso that (a) when R2 is -CR3R3-CH(O)CH2, -CR3R3-CH2CH3, -CR3R3-CH2CH2OH, -CR3R3-CH(OH)R4 or -CR3R3-CH=CHR4, then R0 is hydrogen; (b) when R0 is -CR3R3-CH(O)CH2, -CR3R3-CH2CH3, -CR3R3-CH2CH2OH, -CR3R3- CH(OH)R4 or -CR3R3-CH=CHR4, then R2 is OH; and (c) when (i) R0 or R2 is -CR3R3-CH=CHR4, (ii) R3 and R5 are CH3 and (iii) R4 is hydrogen, then R1, R6 and R7 are not all hydrogen. Also provided are related compounds and compositions, and methods of inhibiting the growth of multidrug resistant cells by means of MDR reversal, collateral sensitivity and quantitative synergism.

L'invention concerne un composé ayant la structure (1). Dans cette formule, R1, R6 et R7 représentent indépendamment l'un de l'autre, un hydrogène, OH, NH2, SH, halogène, C1-C9 alkyle linéaire ou ramifié, alkylmercapto, alkylamino, dialkylamino, alcoxy, phényle, etc; R0 et R2 représentent indépendamment l'un de l'autre, un hydrogène, OH, alkyle linéaire ou ramifié, -CR3R3-CH(O)CH2, -CR3R3-CH2CH3, -CR3R3-CH2CH2OH, -CR3R3-CH(OH)R4 ou -CR3R3-CH=CHR4; R3 et R4 représentent indépendamment l'un de l'autre, un hydrogène, halogène, C1-C9 alkyle linéaire ou ramifié, phényle, etc; R5 est un hydrogène, C1-C9 alkyle linéaire ou ramifié, phényle, etc; R8 est un hydrogène, un C1-C9 acyle linéaire ou ramifié, benzoyle, etc; à condition que (a) quand R2 est -CR3R3-CH(O)CH2, -CR3R3-CH2CH3, -CR3R3-CH2CH2OH, -CR3R3-CH(OH)R4 ou -CR3R3-CH=CHR4, R0 soit un hydrogène; (b) quand R0 est -CR3R3-CH(O)CH2, -CR3R3-CH2CH3, -CR3R3-CH2CH2OH, -CR3R3-CH(OH)R4 ou -CR3R3-CH=CHR4, R2 soit OH; et (c) quand (i) R0 ou R2 est -CR3R3-CH=CHR4, (ii) R3 et R5 sont CH3 et (iii) R4 est un hydrogène, R1, R6 et R7 ne soient pas tous des hydrogènes. L'invention concerne également des composés dérivés et des compositions les contenant, ainsi que des méthodes pour inhiber la croisance de cellules présentant une résistance multiple aux médicaments, par une diminution de cette résistance, une augmentation de la sensibilité collatérale et par un effet de synergie.

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