Synthesis of polymer conjugates of indolocarbazole compounds

摘要

The present invention relates to a process for the preparation of polymer conjugates of indolocarbaxole compounds, in particular of polymer conjugates of K-252a and derivatives thereof, by a synthetic route which results in a highly pure product, with a high product yield. In a further aspect the present invention relates to novel polymer conjugates of K-252a and derivatives thereof, wherein the chemical group linking the polymer unity to the K-252a or to the K-252a derivative compound is characterized by a 5-member oxazolidindionic cyclic structure. These novel polymer conjugates are obtained through the novel synthetic route with high purity and high yields.

主权项

1. A process for the preparation of a polymer conjugate of an indolocarbazole compound of formula (I) wherein R1 and R2 are the same or a different residue and are each independently selected from the group consisting of: (a) hydrogen, halogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, hydroxy, lower alkoxy, carboxy, lower alcoxycarbonyl, acyl, nitro, carbamoyl, lower alkylaminocarbonyl, —NR5R6, wherein R5 and R6 are each independently selected from hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, substituted or unsubstituted lower alkylaminocarbonyl, substituted or unsubstituted lower arylaminocarbonyl, alkoxycarbonyl, carbamoyl, acyl or R5 and R6 are combined with a nitrogen atom to form a heterocyclic group, (b) —CO(CH2)jR4, wherein j is 1 to 6, and R4 is selected from the group consisting of
(i) hydrogen, halogen, —N3,(ii) —NR5R6, wherein R5 and R6 are as defined above,(iii) —SR7, wherein R7 is selected from the group consisting of hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted aralkyl, —(CH2)aCO2R10 (wherein a is 1 or 2, and wherein R10 is selected from the group consisting of hydrogen and substituted or unsubstituted lower alkyl) and —(CH2)aCO2NR5R6,(iv) —OR8, —OCOR8, wherein R8 is selected from hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl (c) —CH(OH)(CH2)jR4′ wherein j and R4 are as defined above; (d) —(CH2)dCHR11CO2R12 or —(CH2)dCHR11CONR5R6, wherein d is 0 to 5, R11 is hydrogen, —CONR5R6, or —CO2R13, wherein R13 is hydrogen or a wherein substituted or unsubstituted lower alkyl, and R12 is hydrogen or a substituted or unsubstituted lower alkyl; (e) —(CH2)kR14 wherein k is 2 to 6 and R14 is halogen, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —COOR15, —OR15, (wherein R15 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl or acyl), —SR7 (wherein R7 is as defined above), —CONR5R6, —NR5R6 (wherein R5 and R6 are as defined above) or —N3; (f) —CH═CH(CH2)mR16, wherein m is 0 to 4, and R16 is hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, —COOR15, —OR15 (wherein R15 is as defined above) —CONR5R6 or —NR5R6 (wherein R5 and R6 are as defined above); (g) —CH═C(CO2R12)2, wherein R12 is as defined above; (h) —C≡C(CH2)nR16, wherein n is 0 to 4 and R16 is as defined above; (i) —CH2OR22, wherein R22 is tri-lower alkyl silyl in which the three lower alkyl groups are the same or different or wherein R22 has the same meaning as R8 (j) —CH(SR23)2 and —CH2—SR7 wherein R23 is lower alkyl, lower alkenyl or lower alkynyl and wherein R7 is as defined above; and R3 is hydrogen, halogen, acyl, carbamoyl, substituted or unsubstituted lower alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted lower alkynyl or amino; and W1 and W2 are independently hydrogen, hydroxy or W1 and W2 together represent oxygen; and wherein X is a polymer moiety, whereby the process comprises reacting a ω-1H-imidazole-carboxamide polymer compound of general formula (II) wherein X is defined as above with an indolocarbazole compound of general formula (III) wherein R1, R2, R3, W1 and W2 are defined as above and which are optionally protected by protecting groups and wherein Y represents a leaving group and wherein the process further optionally comprises deprotecting the groups R1, R2, R3, W1 and W2 in order to obtain the compound of Formula (I).