Multi-arm polymeric prodrug conjugates of pemetrexed-based compounds
Among other aspects, provided herein are multi-arm polymeric prodrug conjugates of pemetrexed-based compounds. Methods of preparing such conjugates as well as methods of administering the conjugates are also provided. Upon administration to a patient, release of the pemetrexed-based compound is achieved.
1. A conjugate according to Formula I:
wherein:
R is a residue of pentaerythritol;
R 1 is H;
R 2 is H;
R 3 is amino;
Q is —O—;
POLY 1 is a poly(alkylene glycol);
X is —C(O)—NHCH 2 CH 2 (OCH 2 CH 2 ) 2 NH—C(O)—, —CH 2 —C(O)—NHCH 2 CH 2 OCH 2 CH 2 O—C(O)—, or —CH 2 —C(O)—NH—CH 2 —CH(R 4 )—O—C(O)—;
R 4 is H, —CH 3 , —CH(CH 3 ) 2 , —CH 2 CH(CH 3 ) 2 , or —CH(CH 3 )CH 2 CH 3 ; and
q is 4;
and pharmaceutically acceptable salts and solvates thereof.
2. The conjugate of claim 1 , wherein POLY 1 is a poly(ethylene oxide).
3. The conjugate of claim 1 according to Formula Ia:
and pharmaceutically acceptable salts and solvates thereof, wherein each n is a positive integer from 10 to about 400.
4. The conjugate of claim 1 , having the following structure:
and pharmaceutically acceptable salts and solvates thereof, wherein each n is a positive integer from 10 to about 400.
5. The conjugate of claim 1 , having the following structure:
wherein:
each n is a positive integer from 10 to about 400;
and pharmaceutically acceptable salts and solvates thereof.
6. A composition comprising a plurality of conjugates, wherein at least 80% of the conjugates in the composition have a structure encompassed by claim 1 .
7. The composition of claim 6 , further comprising a pharmaceutical excipient.