Polypeptide and protein derivatives and process for their preparation
AssigneeGryphon Therapeutics, Inc.
InventorsRobin Ewart Offord, Keith Rose
Life of this patent
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Abstract
Protein and polypeptide derivatives and their salts are claimed characterized in that a protein or polypeptide is conjugated via an intermediate grouping containing at least one radical of the formula —C(R)═N— (or —N═C(R)—) or —CH(R)—NH— (or —NH—CH(R)—), wherein R is hydrogen or a hydrocarbon residue which may be substituted, with the same or a different protein or polypeptide, with a reporter group or a cytotoxic agent as well as a process for their preparation and the novel intermediates therefor.
Claims69
A composition containing conjugated derivatized protein or polypeptide molecules, or salts thereof, wherein said conjugated derivatized protein or polypeptide molecules of said composition consist essentially of a compound selected from the formula:
- A—X—Z—X′—B
- wherein:
- A is a protein or polypeptide, and wherein A has a carboxy and amino terminus and is conjugated to X—Z—X′—B only at either said carboxy terminus of A or at said amino terminus of A;
- B is a polymeric compound;
- X and X′ independently from each other are bivalent organic radicals or independently from each other are present or absent;
- Z is a bivalent radical selected from the group consisting of:
- —C(R)═N—, —N═C(R)—, —CH(R)—NH—, —NH—CH(R)—, —C(R)═N—Y—N═C(R)—, —N═C(R)—Y—C(R)═N—, —CH(R)—NH—Y—NH—CH(R)—, —NH—CH(R)—Y—CH(R)—NH—, —C(R)═N—O—, —O—N═C(R)—, —CR(R)—NH—O—, —O—NH—CH(R)—, —C(R)═N—O—Y—O—N═C(R)—, —O—N═C(R)—Y—C(R)═N—O—, —CH(R)—NH—O—Y—O—NH—CH(R)— and —O—NH—CH(R)—Y—CH(R)—NH—O—;
- where R is hydrogen or an aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group and
- Y is a bivalent organic group;
- wherein said conjugated derivatized protein or polypeptide molecules of said composition are produced via formation of a Schiff base, hydrazone, oxime or azomethine compound that results in the presence of at least one radical having the formula —C(R)═N—, or —N═C(R)—, or, when reduced, —CH(R)—NH— or —NH—CH(R)—.
A composition containing conjugated derivative protein or polypeptide molecules, or salts thereof, wherein said conjugated derivatized protein or polypeptide molecules of said composition consist essentially of a compound selected from the formula:
- A—X—Z—X′—B
- wherein:
- A is a protein or polypeptide, and wherein A has a carboxy and amino terminus and is conjugated to X—Z—X′ only at either said carboxy terminus of A or at said amino terminus of A;
- B is a polymeric compound;
- X and X′ independently from each other are bivalent organic radicals or independently from each other are present or absent;
- Z is a bivalent radical selected from the group consisting of:
- —C(R)═N—, —N═C(R)—, —CH(R)—NH—, —NH—CH(R)—, —C(R)═N—Y—N═C(R)—, —N═C(R)—Y—C(R)═N—, —CH(R)—NH—Y—NH—CH(R)—, —NH—CH(R)—Y—CH(R)—NH—, —C(R)═N—O—, —O—N═C(R)—, —CH(R)—NH—O—, —O—NH—CH(R)—, —C(R)═N—O—Y—O—N═C(R)—, —O—N═C(R)—Y—C(R)═N—O—, —CH(R)—NH—O—Y—O—NH—CH(R)— and —O—NH—CH(R)—Y—CH(R)—NH—O—;
- where R is hydrogen or an aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group and Y is a bivalent organic group;
- wherein said conjugated derivatized protein or polypeptide molecules of said composition are produced via formation of a Schiff base, hydrazone, oxime or azomethine compound that results in the presence of at least one radical having the formula —C(R)═N—, or —N═C(R)—, or, when reduced, —CH(R)—NH— or —NH—CH(R)—;
- and
- wherein said modified protein or polypeptide or salt thereof is prepared by a process that employs a reaction selected from the group consisting of:
- reverse proteolysis, transamination, periodate oxidation and a combination or sub-combination thereof.
A composition containing modified protein or polypeptide molecules, or salts thereof, wherein said modified protein or polypeptide molecules of said composition consist essentially of a compound selected from the formula:
- A—X—Z—X′—B
- wherein:
- A is a residue of a protein or polypeptide having a carboxy and amino terminus and is connected to X—Z—X′—B exclusively at said carboxy or amino terminus;
- B is a polymeric compound;
- X and X′ independently from each other are bivalent organic radicals or independently from each other are present or absent;
- Z is a bivalent radical selected from the group consisting of:
- —C(R)═N—, —N═C(R)—, —CH(R)—NH—, —NH—CH(R)—, —C(R)═N—Y—N═C(R)—, —N═C(R)—Y—C(R)═N—, —CH(R)—NH—Y—NH—CH(R)—, —NH—CH(R)—Y—CH(R)—NH—, —C(R)═N—O—, —O—N═C(R)—, —CH(R)—NH—O—, —O—NH—CH(R)—, —C(R)═N—O—Y—O—N═C(R)—, —O—N═C(R)—Y—C(R)═N—O—, —CH(R)—NH—O—Y—O—NH—CH(R)— and —O—NH—CH(R)—Y—CH(R)—NH—O—;
- where
- R is hydrogen or an aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group;
- and Y is a bivalent organic group;
- said modified protein or polypeptide being produced by a method comprising condensing a compound of the formula:
- A—X—R1
- wherein R1 is a —CO—R group, an acetalized formyl group, or an amino or protected amino group, and A,R, and X are as defined above, with a compound of formula:
- R2—X′—B
- or a compound of formula:
- R2—Y—R2
- where R2 is amino when R1 is —CO—R or acetalized formyl and R2 is —CO—R or acetalized formyl when R1 is amino, and X′, Y, R and B are as defined above, to form a Schiff base, hydrazone, oxime or azomethine compound, and optionally, reducing the —C(R)═N— or —N═C(R) formed by the condensation to CH(R)—NH— or —NH—CH(R)—, respectively, and optionally forming a salt.
A composition containing conjugated protein or polypeptide derivatives, wherein said conjugated protein or polypeptide derivatives of said composition have a C-terminus and an N-terminus and consist essentially of a compound selected from the group consisting of (1) a protein or polypeptide that is connected only at said C-terminus to a reporter group through a Schiff-base radical of the formula —C(R)═N— or —N═C(R)—, or, when reduced, a radical of the formula —CH(R)—NH— or —NH—C(R)—, and (2) a protein or polypeptide that is connected only at said N-terminus to a reporter group through a Schiff-base radical of the formula —C(R)═N— or —N═C(R)—, or, when reduced, a radical of the formula —CH(R)—NH— or —NH—C(R)—, where R is hydrogen or an aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group.
A composition containing conjugated protein or polypeptide derivatives, wherein said conjugated protein or polypeptide derivatives of said composition have a C-terminus and an N-terminus and consist essentially of a compound selected from the group consisting of (1) a protein or polypeptide that is connected only at said C-terminus to a polymeric compound through a Schiff-base radical of the formula —C(R)═N— or —N═C(R)—, or, when reduced, a radical of the formula —CH(R)—NH— or —NH—C(R)—, and (2) a protein or polypeptide that is connected only at said N-terminus to a polymeric compound through a Schiff-base radical of the formula —C(R)═N— or —N═C(R)—, or, when reduced, a radical of the formula —CH(R)—NH— or —NH—C(R)—, where R is hydrogen or an aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group.
A composition containing conjugated protein or polypeptide derivatives, wherein said conjugated protein or polypeptide derivatives of said composition have a C-terminus and an N-terminus and consist essentially of a compound selected from the group consisting of (1) a protein or polypeptide that is connected only at said C-terminus to a cytotoxic agent through a Schiff-base radical of the formula —C(R)═N— or —N═C(R)—, or, when reduced, radical of the formula —CH(R)—NH— or —NH—C(R)—, and (2) a protein or polypeptide that is connected only at said N-terminus to a cytotoxic agent through a Schiff-base radical of the formula —C(R)═N— or —N═C(R)—, or, when reduced, a radical of the formula —CH(R)—NH— or —NH—C(R)—, where R is hydrogen or an aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group.
A composition containing conjugated protein or polypeptide derivatives, wherein said conjugated protein or polypeptide derivatives of said composition have a C-terminus and an N-terminus and consist essentially of a compound selected from the group consisting of (1) a protein or polypeptide that is connected only at said C-terminus to a polymeric conjugation reagent via a Schiff-base radical of the formula —C(R)═N— or —N═C(R)—, or, when reduced, a radical of the formula —CH(R)—NH— or —NH—C(R)—, and (2) a protein or polypeptide that is connected only at said N-terminus to a polymeric conjugation reagent through a Schiff-base radical of the formula —C(R)═NH═ or —NH—C(R)—, or, when reduced, a radical of the formula —CH(R)—NH— or —NH—C(R)—, where R is hydrogen or an aliphatic, cycloaliphatic, aromatic or araliphatic hydrocarbon group, said protein or polypeptide derivative being produced by condensation of complementary reactive moieties comprising a first reactant having a moiety selected from the group consisting of a reactive aldehyde, acetalized aldehyde and ketone, and a second reactant having a reactive amino group, wherein at least one of said reactants is a protein or polypeptide having a C- or N-terminus comprising said aldehyde, acetalized aldehyde, ketone or amino group.
Dependencies are inferred from the claim text.