Resumen
[0001] The present invention describes novel Axitinib sp<3>-analogues wherein the 1,2-disubstituted aromatic ring of commercial Axitinib is replaced by a 1,5-disubstituted bicyclo[2.1.1]hexane scaffold. The invention also describes pharmaceutical compositions comprising said compounds, and the medical uses thereof. The invention also refers to a method for preparing the Axitinib analogues. The new sp<3>-analogues, which encompass various stereoisomers, pharmaceutically acceptable salts and solvates, have proven more active than marketed Axitinib against several cancer cell lines.
Reivindicaciones
1. - A compound of formula I: a stereoisomer, a pharmaceutically acceptable salt or a solvate thereof; wherein X<1> is selected from H, C1-C6 alkyl, C1-C6 fluorinated alkyl and C6-C10 aryl; and wherein groups R<1>-R<7> are independently selected from H, <2>H, halogen, C1-C6 alkyl, C1-C6 fluorinated alkyl and C6 aryl. 2. - The compound according to claim 1, wherein the C1-C6 fluorinated alkyl is a C1-C6 perfluorinated alkyl. 3. - The compound according to claim 1 or 2, wherein X<1> is selected from H, C1-C3 alkyl, C1-C3 perfluorinated alkyl, preferably is H, CH<3> or CF<3>, more preferably is CH<3>. 4. - The compound according to any one of claims 1 to 3, wherein the groups R<1>-R<7> are independently selected from H, <2>H, halogen, C1-C3 alkyl, C1-C3 perfluorinated alkyl and phenyl, preferably wherein the groups R<1>-R<7> are independently selected from H, <2>H, halogen, CH<3> and CF<3>. 5. - The compound according to any one of the preceding claims, wherein R<5>, R<6> and R<7> are H, preferably wherein all of R<1>-R<7> are H. 6. - The compound according to any one of the preceding claims, wherein the compound of formula I is a mixture of enantiomers Ia and Ib: 7. - The compound according to any of claims 1 to 5, wherein the compound of formula I is: <img class="EMIRef" id="eb78b80c-04d5-4781-ad44-24f746827911-ib0063" /> 8. - The compound according to claim 7 which is a mixture of enantiomers Ia' and Ib' 9. - The compound according to claim 8 wherein the molar ratio between Ia' and Ib' is comprised between 99.9:0.1 and 90:10, preferably from 99:1 to 95:5, or is comprised between 10:90 and 0.1:99.9, preferably between 5:95 and 1:99. 10. - A pharmaceutical composition comprising the compound I according to any one of claim 1 to 9. 11. - A method for preparing a compound of formula I comprising the steps of: i. reacting a compound of formula XI with a compound of formula XII under light irradiation and in the presence of a base: <img class="EMIRef" id="eb78b80c-04d5-4781-ad44-24f746827911-ib0065" /> to obtain compound XIII: <img class="EMIRef" id="eb78b80c-04d5-4781-ad44-24f746827911-ib0066" /> wherein PAE is a photoredox-active ester; PG is a N-protecting group; R<11> is a C1-C6 alkyl or a C6-C10 aryl; and R<1>-R<7> are independently selected from H, <2>H, halogen, C1-C6 alkyl, C1-C6 fluorinated alkyl and C6 aryl; ii. ester hydrolysis of compound XIII under basic conditions to obtain free acid XIV iii. reacting free acid XIV with an amine of formula X<1>NH<2> in presence of an acid-activating reagent, wherein X<1> is selected from H, C1-C6 alkyl, C1-C6 fluorinated alkyl and C6-C10 aryl, to obtain a compound of formula XV: iv. subjecting compound XV to acidic hydrolysis to remove the protecting group (PG) and thereby to obtain a compound of formula I. 12. - The method according to claim 11, comprising the steps of: i. Reacting an alkyne of formula II with the organomagnesium compound of formula III: to obtain a compound of formula IV: wherein Ar<1> is a C6-C10 (hetero)aryl and Rs is a C1-C6 alkyl group or a C6-C10 aryl group; ii. Hydrolysis under basic conditions of compound IV into compound V iii. Coupling compound V with compound VI to obtain compound VII wherein R<9> and R<10> are independently selected from H, C1-C6 alkyl and C6-C10 aryl; iv. Subjecting compound VII to a crossed [2+2] photocycloaddition, optionally in an enantioselective manner, in presence of a rhodium catalyst, optionally an enantiomerically pure rhodium catalyst, to obtain compound VIII: v. Subjecting compound VIII to esterification with an alcohol of formula R<11>OH in presence of an inorganic chloride salt and tertiary amine, wherein R<11> is a C1-C6 alkyl or a C6-C10 aryl, to obtain a compound of formula IX: vi. Oxidizing compound IX to compound X in the presence of a Ru(III) salt and an oxidant, <img class="EMIRef" id="eb78b80c-04d5-4781-ad44-24f746827911-ib0076" /> vii. Derivatization of compound X to obtain compound XI: Wherein PAE is a photoredox-active ester and R<11> is defined as above; viii. reacting the compound of formula XI with a compound of formula XII under light irradiation and in the presence of a base: <img class="EMIRef" id="eb78b80c-04d5-4781-ad44-24f746827911-ib0078" /> to obtain compound XIII: wherein PAE and R<11> are as defined as above; PG is a N-protecting group; and R<1>-R<7> are independently selected from H, <2>H, halogen, C1-C6 alkyl, C1-C6 fluorinated alkyl and C6 aryl; ix. ester hydrolysis of compound XIII under basic conditions to obtain free acid XIV x. reacting free acid XIV with an amine of formula X<1>NH<2> in presence of an acid-activating reagent, wherein X<1> is selected from H, C1-C6 alkyl, C1-C6 fluorinated alkyl and C6-C10 aryl, to obtain a compound of formula XV; xi. subjecting compound XV to acidic hydrolysis to remove the protecting group (PG) and thereby to obtain a compound of formula I. 13. - A compound of formula I according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 for use in medicine. 14. - A compound of formula I according to any one of claims 1 to 9 or a pharmaceutical composition according to claim 10 for use in the treatment of cancer. 15. - The compound or pharmaceutical composition for use according to claim 14, wherein the cancer is selected from uveal melanoma, breast cancer and colon cancer.
