Prodrug forms of kinase inhibitors and their use in therapy

Details Prodrug forms of kinase inhibitors and their use in therapy Prodrug forms of kinase inhibitors and their use in therapy

C - Chemistry, Metallurgy

07

D

C07D 471/04 (2006.01) A61K 31/4178 (2006.01) A61K 31/4709 (2006.01) A61K 31/517 (2006.01) A61K 31/519 (2006.01) A61P 35/00 (2006.01) C07D 239/94 (2006.01) C07D 403/12 (2006.01) C07D 403/14 (2006.01) C07D 405/14 (2006.01)

Patent

CA 2754808

The invention provides novel prodrug compounds comprising a kinase inhibitor and a reductively-activated fragmenting aromatic nitroheterocycle or aromatic nitrocarbocycle trigger, where the compound carries a positive charge. In preferred embodiments, the compounds are of Formula I: where: X is any negatively charged counterion; R1 is a group of the formula (CH2)n Tr, where Tr is an aromatic nitroheterocycle or aromatic nitrocarbocycle and -(CH2)n Tr acts as a reductively-activated fragmenting trigger; and n is an integer from 0 to 6; R2, R3 and R4 may each independently be selected from aliphatic or aromatic groups of a tertiary amine kinase inhibitor (R2)(R3)(R4)N, or two of R2, R3, and R4 may form an aliphatic or aromatic heterocyclic amine ring of a kinase inhibitor, or one of R2, R3 and R4 may be absent and two of R2, R3 and R4 form an aromatic heterocyclic amine ring of a kinase inhibitor. The compounds of the invention are useful in treating proliferative diseases such as cancer.

La présente invention concerne de nouveaux composés promédicaments comprenant un inhibiteur de kinase et un élément déclencheur de type nitrohétérocycle aromatique ou nitrocarbocycle aromatique pouvant se fragmenter, activé par réduction, le composé transportant une charge positive. Dans des modes de réalisation préférés, les composés sont de formule I, dans laquelle X représente tout contre-ion chargé négativement; R1 représente un groupe de formule (CH2)nTr, dans laquelle Tr représente un nitrohétérocycle aromatique ou un nitrocarbocycle aromatique et (CH2)nTr agit comme élément déclencheur pouvant se fragmenter, activé par réduction; et n représente un entier de 0 à 6; R2, R3 et R4 peuvent être chacun indépendamment choisis dans des groupes aliphatiques ou aromatiques d'un inhibiteur de kinase de type amine tertiaire (R2)(R3)(R4)N, ou deux parmi R2, R3 et R4 peuvent former un cycle de type amine hétérocyclique aliphatique ou aromatique d'un inhibiteur de kinase, ou un parmi R2, R3 et R4 peut être absent et deux parmi R2, R3 et R4 forment un cycle de type amine hétérocyclique aromatique d'un inhibiteur de kinase. Les composés selon l'invention sont utiles dans le traitement de maladies prolifératives telles que le cancer.

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