Oligomer-protein tyrosine kinase inhibitor conjugates
View Patent ↗The invention relates to (among other things) oligomer-PTK inhibitor conjugates and related compounds. A compound of the invention, when administered by any of a number of administration routes, exhibits advantages over PTK inhibitor compounds lacking a water-soluble, non-peptidic oligomer.
1. A compound selected from:
and pharmaceutically acceptable salts thereof, wherein
X is a spacer moiety selected from a covalent bond, —C(O), —C(O)O—, —CH 2 C(O)O—, —CH 2 —OC(O)—, —C(O)O—CH 2 —, —C(O)—NH, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 , —CH 2 —O—, —CH 2 —O—CH 2 —, —CH 2 —CH 2 —O—, —CH 2 —O—CH 2 —CH 2 —, —CH 2 —CH 2 —O—CH 2 —, —CH 2 —CH 2 —CH 2 —O—, —CH 2 —O—CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —O—CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —O—CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —O—, —C(O)—NH—CH 2 —, —C(O)—NH—CH 2 —CH 2 , —CH 2 —C(O)—NH—CH 2 —, —CH 2 —CH 2 —C(O)—NH—, —C(O)—NH—CH 2 —CH 2 —CH 2 —, —CH 2 —C(O)—NH—CH 2 —CH 2 —, —CH 2 —CH 2 —C(O)—NH—CH 2 —, —CH 2 —CH 2 —CH 2 —C(O)—NH—, —C(O)—NH—CH 2 —CH 2 —CH 2 —CH 2 —, —CH 2 —C(O)—NH—CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —, —CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 —C(O)—NH—, —CH 2 —NH—C(O)—CH 2 —, —CH 2 —CH 2 —NH—C(O)—CH 2 —, —CH 2 —NH—C(O)—CH 2 —CH 2 —, —CH 2 —CH 2 —, —C(O)—NH—CH 2 —, —C(O)—NH—CH 2 —CH 2 , —CH 2 —NH—CH 2 , —CH 2 —CH 2 —NH—CH 2 —, —C(O)—CH 2 —, —C(O)—CH 2 —CH 2 —, —CH 2 —C(O)—CH 2 —, —CH 2 —CH 2 —C(O)—CH 2 —, —CH 2 —CH 2 —C(O)—CH 2 —CH 2 —, —CH 2 —CH 2 —C(O)—, —CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —NH—, —CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —NH—C(O)—, —CH 2 —CH 2 —CH 2 —C(O)—NH—CH 2 —CH 2 —NH—C(O)—CH 2 —, a bivalent cycloalkyl group, —N(R 6 )—, R 6 is H or an organic radical selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl and substituted aryl; and
POLY is a poly(alkylene oxide) oligomer.
2. The compound of claim 1 , wherein the poly(alkylene oxide) oligomer is a poly(ethylene oxide) oligomer.
3. The compound of claim 2 , wherein the poly(ethylene oxide) oligomer has from about 1 to about 30 monomers.
4. The compound of claim 3 , wherein the poly(ethylene oxide) oligomer has from about 1 to about 10 monomers.
5. The compound of claim 2 , wherein the poly(alkylene oxide) includes an alkoxy or hydroxy end-capping moiety.
6. The compound of claim 1 , wherein X is selected from a covalent bond, —C(O), —C(O)O—, —CH 2 C(O)O—, —CH 2 —OC(O)—, —C(O)O—CH 2 —, —C(O)—NH, —CH 2 —, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —CH 2 , —CH 2 —O—, —CH 2 —O—CH 2 —, —CH 2 —CH 2 —O—, —CH 2 —O—CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —O—, —C(O)—NH—CH 2 —, —C(O)—NH—CH 2 —CH 2 , —CH 2 —CH 2 —C(O)—NH—, —C(O)—NH—CH 2 —CH 2 —CH 2 —, —C(O)—NH—CH 2 —CH 2 —CH 2 —CH 2 —, CH 2 —CH 2 —CH 2 —CH 2 —C(O)—NH—, —C(O)—NH—CH 2 —CH 2 , —C(O)—CH 2 —, —C(O)—CH 2 —CH 2 —, and —CH 2 —CH 2 —C(O)—.
7. The compound of claim 1 , wherein the X is selected from a covalent bond, —C(O), —C(O)O—, —C(O)—NH—, —CH 2 —CH 2 —, —CH 2 —CH 2 —CH 2 —, and —CH 2 —CH 2 —CH 2 —CH 2 .
8. The compound of claim 1 , wherein X is a covalent bond.
9. A composition comprising a compound of claim 1 , and optionally, a pharmaceutically acceptable excipient.
10. A composition of matter comprising a compound of claim 1 , wherein the compound is present in a dosage form.
11. The compound of claim 1 , wherein the compound is selected from
wherein n is an integer from 1 to 30.
12. The compound of claim 11 , wherein n is an integer from 2 to 10.
13. A composition comprising a compound of claim 11 , and optionally, a pharmaceutically acceptable excipient.
14. A composition of matter comprising a compound of claim 11 , wherein the compound is present in a dosage form.