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 method of treating a condition selected from the group consisting of chronic myelogenous leukemia, gastrointestinal stromal tumors, renal cell carcinoma, breast cancer, lung cancer and colorectal cancer, the method comprising administering to a patient in need thereof 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 method of claim 1 , wherein the poly(alkylene oxide) oligomer is a poly(ethylene oxide) oligomer.
3. The method of claim 2 , wherein the poly(ethylene oxide) oligomer has from about 1 to about 30 monomers.
4. The method of claim 3 , wherein the poly(ethylene oxide) oligomer has from about 1 to about 10 monomers.
5. The method of claim 2 , wherein the poly(alkylene oxide) includes an alkoxy or hydroxy end-capping moiety.
6. The method 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 method 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 method of claim 1 , wherein X is a covalent bond.
9. The method of claim 1 , wherein the compound is selected from
wherein n is an integer from 1 to 30.
10. The method of claim 9 , wherein n is an integer from 2 to 10.