Polymeric benzyl carbonate-derivatives
Inventors
Yang, Guohan • Hai, Ton That • Melnick, Bennett P. • Sanders, Paul • Jiang, Cong • Quinn, Catherine • Li, Jie • Ambroise, Arounaguiry • Brown, Larry R.
Assignees
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Publication Number
US-8653131-B2
Publication Date
2014-02-18
Expiration Date
Abstract
The present invention relates to polymeric derivatives, which can be conjugated to an amino-containing drug to improve its in vivo properties. The polymeric derivative can subsequently be released to yield the drug in its native form. Methods of preparing and using these polymeric derivatives and drug conjugates are described.
Core Innovation
The invention is directed to polymeric benzyl carbonate-derivatives and corresponding drug conjugates of Formula I and Formula II. The structures include an activating group Y, a linkage region X, variable substituents R1, R2, R3, and n, and the polymer is a water soluble, non-peptidic polymer that does not comprise a poly(alkylene glycol) in the Formula I embodiments. The disclosed constructions are presented together with corresponding intermediates and activation forms used to enable attachment chemistry.
The drug-conjugate construction of Formula II links the polymer framework to a DRUG defined as an amino-containing molecule, peptide, or protein, or a pharmaceutically acceptable salt, ester, or solvate thereof. The document further describes specific activating-group-containing ester compounds, including succinimidyl-type activation elements and carbonate-type activation elements, and identifies polymeric derivatives such as polymeric derivative IAi and polymeric derivative IAvii prepared from methoxy-PEG intermediates.
The release mechanism is presented as a multi-step cleavage behavior in which carbamate hydrolysis is not rate-determining. Instead, the release rate is governed by hydrolysis of a neighboring ester moiety, followed by rapid elimination and rapid decarboxylation steps, and the rate can be tuned by sterics/electronics. The discussion also includes pharmaceutical formulation options with pharmaceutically acceptable excipients, encapsulation in microparticles, disease-treating administration, and analytical characterization approaches for the intermediates and polymeric derivatives.
Claims Coverage
The independent claims cover three inventive features: polymer-linked compounds of Formula I, drug conjugates of Formula II, and compounds having a structure selected from a specified set where POLYMER is polysialic acid.
Polymeric benzyl carbonate derivative of Formula I with activating group Y and water-soluble non-peptidic polymer
A compound of Formula I wherein Y is an activating group; X is selected from O, S and NR3; n is 1 or 2; POLYMER is a water soluble, non-peptidic polymer wherein POLYMER does not comprise a poly(alkylene glycol); and R1 and R2 are independently selected from hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylenearyl, and aryl with the proviso that at least one of R1 and R2 is different from hydrogen; and R3 is selected from hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylenearyl, and aryl.
Selected benzyl carbonate ester compounds with (2-methoxypolyethoxy)-substituted alkanoate moiety
A compound selected from the group consisting of the specifically enumerated benzyl carbonate ester compounds.
Drug conjugate of Formula II with amino-containing DRUG and polymer-linked carbamate structure
A drug conjugate of Formula II wherein X is selected from O, S and NR3; n is 1 or 2; POLYMER is a water soluble, non-peptidic polymer wherein POLYMER does not comprise a poly(alkylene glycol); R1 and R2 are independently selected from hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylenearyl, and aryl with the proviso that at least one of R1 and R2 is different from hydrogen; R3 is selected from hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylenearyl, and aryl; and DRUG is an amino-containing molecule, peptide, or protein, or a pharmaceutically acceptable salt, ester, or solvate thereof.
Compound structure selection with POLYMER as polysialic acid
A compound having a structure selected from the group consisting of where POLYMER is polysialic acid.
Polymeric benzyl carbonate derivative of Formula I with poly(alkylene glycol) polymer comprising PEG and defined substituents
A compound of Formula I wherein Y is an activating group; X is selected from O, S and NR3; n is 1 or 2; POLYMER is a water soluble, non-peptidic polymer wherein POLYMER comprises a poly(alkylene glycol); R1 is hydrogen; R2 is selected from (C1-C6)-alkyl, (C1-C6)-alkylenearyl, and aryl; and R3 is selected from hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylenearyl, and aryl.
Drug conjugate of Formula II with poly(alkylene glycol) polymer comprising poly(alkylene glycol) and DRUG amino-containing definition
A drug conjugate of Formula II wherein X is selected from O, S and NR3; n is 1 or 2; POLYMER is a water soluble, non-peptidic polymer wherein POLYMER comprises a poly(alkylene glycol); R1 is hydrogen; R2 is selected from (C1-C6)-alkyl, (C1-C6)-alkylenearyl, and aryl; R3 is selected from hydrogen, (C1-C6)-alkyl, (C1-C6)-alkylenearyl, and aryl; and DRUG is an amino-containing molecule, peptide, or protein, or a pharmaceutically acceptable salt, ester, or solvate thereof.
The claim coverage centers on the Formula I and Formula II polymer-linked framework defined by activating group Y, X, n, POLYMER, and substituent selections R1, R2, and R3, with a further structure-selected claim where POLYMER is polysialic acid. The claim set further includes a specific enumerated set of benzyl carbonate ester compounds and variants where POLYMER comprises a poly(alkylene glycol).
Stated Advantages
The release rate is governed by hydrolysis of a neighboring ester moiety that can be tuned by sterics/electronics.
Carbamate hydrolysis is not rate-determining.
The activating group Y is readily displaced by a drug amino group to form a carbamate linkage.
Documented Applications
Disease-treating administration.
Pharmaceutical formulation with pharmaceutically acceptable excipients.
Encapsulation in microparticles.
PEGylated tryptophan formation and cleavage or release behavior tracked by HPLC at pH 7.5 and pH 8.5.
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