Patent EA-002030-B1 (EA)
Title: Polymeric derivatives of camptothecins
Inventor: ANGELUCCI FRANSESCO
IPC: A61K47/48
Filed: 1998-09-22
Abstract: 1. A polymeric conjugate which consists of: (i) from 85 to 97 mol % of N-(2-hydroxypropyl)methacryloylamide units represented by formula (3)   (ii) from 3 to 15 mol % of 20-O-(N-methacryloyl-glycyl-aminoacyl-glycyl)camptothecin units represented by formula (4)   wherein n is from 2 to 8, --[O-CPT] represents the residue of a camptothecin of formula (2)   which is linked at the C-20 position and in which each of R1, R2, R3, R4 and R5, which are the same or different, is hydrogen, C1 -C2 linear or branched alkyl, nitro, amino, (CH2)aNR6R7 in which a is from 0 to 4 and R6 and R7 are hydrogen or one of R6 or R7 is hydrogen and the other of R6 or R7 is C1 -C6 alkyl, or NR6R7 represents a piperazino or N-alkyl-piperazino ring optionally substituted with C1 -C6 linear or branched alkyl, or a piperidino ring, (CH2)a NHCOR8 in which a is as above defined and R8 is C1 -C8 linear or branched alkyl or a group NR6R7 as above, hydroxy or O--CO-R8 in which R8 is as above defined or represents a 1-piperidino ring or 1,4'-bipiperidine, or R2 and R3 taken together represent the residue O--(CH2)b --O, in which b is 1 or 2, or R4 and R5 represent the residue (CH2)m, in which m is from 2 to 4, or the residue CH2 --O-CH2, or CH2NHCH2 and (iii) from 0 to 12 mol % of N-methacryloyl-glycine or N-(2-hydroxypropyl)methacryloyl-glycinamide units represented by formula (5)   wherein [Z] represents a hydroxy group or a residue of formula --NH-CH2--CH(OH)-CH3. 2. A polymeric conjugate according to claim 1 which contains the N-(2-hydroxypropyl)methacryloylamide units represented by the formula (3) in a molar proportion of 90%. 3. A polymeric conjugate according to claim 1 which contains 10 mol % of the units represented by the formula (4). 4. A polymeric conjugate according to claim 1 wherein the unit of formula (5) is absent. 5. A polymeric conjugate according to claim 1 in which --[O-CPT] in formula (4) is a residue of a camptothecin of formula (2) selected from: camptothecin, 9-aminocamptothecin, 9-nitrocamptothecin, 7-ethyl-10-hydroxy-camptothecin, 7-ethyl-10-[1,4'-bipiperidinyl]carbonyloxycamptothecin, 7-methylendimethylamino-10-hydroxycamptothecin and 7-[methylene-(4'-methylpiperazino)]-9,10-ethylendioxycamptothecin. 6. A polymeric conjugate according to claim 1 in which the content of active camptothecin derivative of formula (2) is 10% (w/w). 7. A process for producing a polymeric conjugate as defined in claim 1, which process comprises reacting a 20-O-(aminoacyl-glycyl)camptothecin derivative of formula (6)   NH2 --(CH2)n--CO-Gly-[OCPT]             (6)   wherein n and [O-CPT] are as defined in claim 1, with a polymer (B) consisting essentially of: from 85 to 97 mol % of N-(2-hydroxypropyl)methacryloylamide units represented by formula (3) as defined in claim 1, and from 3 to 15 mol % of N-methacryloyl-glycyl derivative units represented by formula (7)   wherein [Y] is the residue of an active ester or a hydroxy group; and optionally displacing the remaining active ester groups with 1-amino-2-propanol. 8. A process for producing a polymeric conjugate as defined in claim 1, which process comprises the polymerization between N-(2-hydroxypropyl)methacrylamide of the formula (8)   and 20-O-[methacryloyl-glycyl-(aminoacyl)-glycyl]camptothecin derivatives of the formula (9)   wherein n and [OCPT] are as defined in claim 1, in conditions capable of preserving the nature of linkage between camptothecin and spacer glycyl-aminoacyl-glycyl as well as that of the conjugate. 9. A 20-O-acylamino-glycyl-camptothecin derivative of the formula (6) as defined in claim 7 or a salt thereof. 10. A process for producing a compound of the formula (6) as defined in claim 7, which process comprises condensing a derivative of formula (2) as defined above with a N-protected aminoacyl-glycyl derivative of formula (10):   R9 --HN--(CH2)n --CO-Gly-[P]                 (10)   wherein n is as defined above, R9 represents an amino-protecting group and [P] is a residue of an activated ester, to give a compound represented by formula (11):   R9 --NH--(CH2)n --CO-Gly-[OCPT]           (11)   wherein n and R9 are as defined above and [OCPT] is as defined above; and removing the N-protecting group from the resulting compound. 11. A 20-O-[methacryloyl-glycyl-(aminoacyl)-glycyl]camptothecin derivative of the formula (9) as defined in claim 8 or a salt thereof. 12. A process for producing a derivative of the formula (9) as defined in claim 11 which process comprises condensing a camptothecin derivative of the formula (6) as defined above with N-methacryloyl-glycyl of formula (7'),   wherein [Y'] is a leaving group. 13. A polymeric conjugate according to claim 1 which is MAG-camptothecin, in which the camptothecin content is 10% (w/w). 14. A polymeric conjugate according to claim 1 which is obtainable by reacting a 20-O-(6-aminohexanoyl-glycyl)camptothecin derivative of formula (6)   NH2 --(CH2)6 --CO--Gly--[OCPT]              (6)   wherein [O-CPT] is the residue of camptothecin, with a polymer (B) consisting essentially of: from 85 to 97 mol % of N-(2-hydroxypropyl)methacryloylamide units represented by formula (3) as defined in claim 1, and from 3 to 15 mol % of N-methacryloyl-glycyl derivative units represented by formula (7)   wherein [Y] is p-nitrophenoxy group; and optionally displacing the remaining active ester groups with 1-amino-2-propanol. 15. A polymeric conjugate according to claim 1 which is obtainable by the polymerization between N-(2-hydroxypropyl)methacrylamide of the formula (8)   and 20-O-[methacryloyl-glycyl-(6-aminohexanoyl)-glycyl]camptothecin derivatives of the formula (9)   wherein [OCPT] is the residue of camptothecin. 16. A pharmaceutical composition comprising a pharmaceutically acceptable diluent or carrier and, as active ingredient, a polymeric conjugate according to any of claims 1 to 6 or 13 to 15, or a compound of formula (6) or (() according to claim 9 or 11.