Polymer-conjugated METAP2 inhibitors, and therapeutic methods of use thereof
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Publication Number
US-10722532-B2
Publication Date
2020-07-28
Expiration Date
Abstract
One aspect of the invention provides polymer conjugated MetAP2 inhibitors. While not being bound by any particular theory, it is believed that coupling the MetAP2 inhibitory core via the linkers described herein provides compounds with superior efficacy to the parent small molecules and superior pharmacokinetic profiles. In one aspect of the invention, the polymer conjugated MetAP2 inhibitors are useful in methods of treating disease, comprising administering to a subject in need thereof a therapeutically effective amount of a polymer conjugated MetAP2 inhibitor.
Core Innovation
The invention relates to poly[HPMA-co-MA-GFLG-N-(trans-4-aminocyclohexyl)carbamoylfumagillol] and to a method of preparing it. The method comprises contacting p-nitrophenyl fumagill-6-yl carbonate with poly[HPMA-co-MA-GFLG-N-(trans-4-aminocyclohexylamine.HCl)] to form a mixture. The preparation specifies composition parameters x, y, and n constrained to defined ranges, with x between 1 and about 450, y between 1 and about 30, and n between 1 and about 50.
The contacting step forms the carbamoyl-linked fumagillol-containing polymer conjugate, transforming the p-nitrophenyl fumagill-6-yl carbonate into poly[HPMA-co-MA-GFLG-N-(trans-4-aminocyclohexyl)carbamoylfumagillol]. The polymer backbone is defined by the poly[HPMA-co-MA-GFLG-N-(trans-4-aminocyclohexylamine.HCl)] starting material, and the resulting polymer product is characterized by the specified x, y, and n ranges.
The disclosed content also describes a self-immolating linker and a release mechanism that releases the MetAP2 inhibitor as a carbamate derivative. The document includes structural formula embodiments illustrating conjugate scaffolds and a Z–Q–X–Y–C(O)–W conjugate scaffold, where W corresponds to a MetAP2 inhibitor moiety.
Claims Coverage
The claims center on one independent claim directed to preparing poly[HPMA-co-MA-GFLG-N-(trans-4-aminocyclohexyl)carbamoylfumagillol] by contacting a specified p-nitrophenyl fumagill-6-yl carbonate with a specified polymer amine, with the polymer composition defined by three inventive features. Dependent claims refine the contacting conditions and workup by adding optional base and solvent, a temperature progression, pH adjustment, additional pH conditioning, and lyophilization.
Contacting fumagillyl carbonate with specified HPMA/GFLG polymer amine
A method of preparing poly[HPMA-co-MA-GFLG-N-(trans-4-aminocyclohexyl)carbamoylfumagillol] comprising contacting p-nitrophenyl fumagill-6-yl carbonate with poly[HPMA-co-MA-GFLG-N-(trans-4-aminocyclohexylamine.HCl)] to form a mixture.
Constrained polymer composition parameters for x, y, and n
The method wherein x is between 1 and about 450, y is between 1 and about 30, and n is between 1 and about 50.
Optional use of diisopropylethylamine as base
The contacting optionally includes diisopropylethylamine as the base.
Using N,N-dimethylformamide as solvent
The contacting optionally includes N,N-dimethylformamide as the solvent.
Temperature progression from about 0°C to about room temperature
The contacting is defined by contacting at about 0°C and warming to about room temperature.
pH adjustment using aqueous sodium hydroxide to about 8.0
The method includes adding aqueous sodium hydroxide to adjust the mixture to a pH of about 8.0.
Wash/acid-treatment with a second pH and optional water washing
The method includes wash and acid-treatment steps to set a second pH, with optional water washing.
Lyophilization of the second mixture
The method includes lyophilizing the second mixture.
The claims cover forming the target carbamoyl fumagillol-containing polymer by contacting p-nitrophenyl fumagill-6-yl carbonate with poly[HPMA-co-MA-GFLG-N-(trans-4-aminocyclohexylamine.HCl)], while requiring that x, y, and n fall within specified ranges. Dependent refinements add optional base and solvent, a specified temperature progression, pH adjustment and pH conditioning, and lyophilization.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Therapeutic use for treating disease in mammals, including cancer treatment.
Comparison of polymer conjugates versus TNP-470 in tumor models, including measurements such as body weight/percentage weight change and tumor size.
Stated biological evaluations include in vitro cell viability measurements using A549, HCT-116, and HUVEC with IC50 tables and selectivity ratios, and in vivo mouse model outcomes including B16-F10 lung metastasis counts and A549 xenograft-related tumor growth/body weight measures.
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