Macromolecule-supported aminobenzazepine compounds
The application provides macromolecule-supported compounds of Formula I or III comprising a macromolecular support linked by conjugation to one or more aminobenzazepine derivatives. The application also provides aminobenzazepine derivative intermediate compositions of Formula II comprising a reactive functional group. Such intermediate compositions are suitable substrates for formation of the macromolecule-supported compounds through a linker or linking moiety. The application further provides compositions comprising the macromolecule-supported compounds, as well as methods of treating cancer with the macromolecule-supported compounds.
1 . A macromolecule-supported compound comprising a macromolecular support covalently attached to one or more aminobenzazepine moieties by a linker, and having Formula I:
Ms-[L-Bza] p I
or a pharmaceutically acceptable salt thereof,
wherein:
“M S ” is the macromolecular support, wherein the macromolecular support is a peptide, protein, or antibody construct;
p is an integer from 1 to 50;
Bza is the aminobenzazepine moiety having the formula:
R 1 is C 1 -C 20 heteroaryl, and X 1 is a bond;
R 2 is C 1 -C 12 alkyl, and X 2 is a bond;
R 3 is C 1 -C 12 alkyl, and X 3 is O;
R 4 is H, and X 4 is a bond;
wherein R 1 or R 3 is attached to a linker L;
L is the linker selected from the group consisting of:
—C(═O)—(PEG)-;
—C(═O)—(PEG)-C(═O)—;
—C(═O)—(PEG)-O—;
—C(═O)—(PEG)-C(═O)N(R 5 )—(C 1 -C 12 alkyldiyl)-;
—C(═O)—(PEG)-C(═O)N(R 5 )—(C 1 -C 12 alkyldiyl)-N(R 5 ) C(═O)-(C 2 -C 5 monoheterocyclyldiyl)-; and
—C(═O)—(PEG)-N(R 5 )—;
R 5 is selected from the group consisting of H, C 6 -C 20 aryl, C 6 -C 20 aryldiyl, C 1 -C 12 alkyl, and C 1 -C 12 alkyldiyl, or two R 5 groups together form a 5- or 6-membered heterocyclyl ring;
PEG has the formula: —(CH 2 CH 2 O) n —(CH 2 ) m —; m is an integer from 1 to 5, and n is an integer from 5 to 20; and
alkyl, alkyldiyl, aryl, aryldiyl, heterocyclyl, heterocyclyldiyl, and heteroaryl are substituted with one or more groups independently selected from H, F, —CN, —CH 2 NH 2 , —CO 2 C(CH 3 ) 3 , —OCH 3 , —OCH 2 CH 3 .
2 . The macromolecule-supported compound of claim 1 , wherein subscript p is an integer from 1 to 25.
3 . The macromolecule-supported compound of claim 2 , wherein subscript p is an integer from 1 to 6.
4 . The macromolecule-supported compound of claim 1 wherein R 1 is pyrimidinyl.
5 . The macromolecule-supported compound of claim 4 wherein R 1 is attached to L, wherein L is —C(═O)—(PEG)-C(═O)N(R 5 )—(C 1 -C 12 alkyldiyl)-.
6 . The macromolecule-supported compound of claim 5 wherein R 5 is H and C 1 -C 12 alkyldiyl is —CH 2 —.
7 . The macromolecule-supported compound of claim 1 wherein PEG has the formula: —(CH 2 CH 2 O) n —(CH 2 ) m —; where m is 2 and n is 10.
8 . The macromolecule-supported compound of claim 1 wherein X 2 —R 2 is —CH 2 CH 2 CH 3 , and X 3 —R 3 is —OCH 2 CH 3 .
9 . The macromolecule-supported compound of claim 1 wherein the macromolecular support is an antibody construct.
10 . A method for treating cancer comprising administering a therapeutically effective amount of a macromolecule-supported compound according to claim 1 or a composition comprising a plurality of the macromolecule-supported compounds to a subject in need thereof.